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Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis:

Analysis of published guidance and meta-analysis of cohort studies

Journal: BMJ Open

Manuscript ID: bmjopen-2013-004143

Article Type: Research

Date Submitted by the Author: 30-Sep-2013

Complete List of Authors: Hwang, Thomas; Harvard University, Faculty of Arts and Sciences Dotsenko, Svetlana; Harvard University, Faculty of Arts and Sciences Jafarov, Azizkhon; World Health Organization, Weyer, Karin; World Health Organization, Falzon, Dennis; World Health Organization, Lunte, Kaspars; World Health Organization and Stop TB Partnership, Global Drug Facility Nunn, Paul; Global Infectious Disease Consulting, Jaramillo, Ernesto; World Health Organization, Keshavjee, Salmaan; Harvard Medical School, Department of Global Health

and Social Medicine Wares, Douglas; World Health Organization,

<b>Primary Subject Heading</b>:

Global health

Secondary Subject Heading: Infectious diseases, Public health, Evidence based practice

Keywords: Tuberculosis < INFECTIOUS DISEASES, INFECTIOUS DISEASES, Public health < INFECTIOUS DISEASES, Tropical medicine < INFECTIOUS DISEASES

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Safety and availability of clofazimine in

the treatment of multidrug and

extensively drug-resistant tuberculosis:

Analysis of published guidance and meta-

analysis of cohort studies

Thomas J. Hwang,† Svetlana Dotsenko,

† Azizkhon Jafarov,

§ Karin Weyer,

§ Dennis Falzon,

§

Kaspars Lunte,* Paul Nunn,

** Ernesto Jaramillo,

§ Salmaan Keshavjee,

†† Douglas F. Wares

§

† Faculty of Arts and Sciences, Harvard University, Cambridge, Massachusetts USA § Global TB Programme, World Health Organization, Geneva, Switzerland *Global Drug Facility, Stop TB Partnership and World Health Organization, Geneva, Switzerland ** Global Infectious Disease Consulting, London, UK †† Program in Infectious Disease and Social Change, Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA Correspondence to Thomas Hwang and Douglas Wares. Email: [email protected], [email protected] Word Count: 3,048 words (excluding abstract, references, exhibits, and acknowledgements) Abstract: 251 words Keywords: Clofazimine, safety, clinical practice, meta-analysis, drug resistant tuberculosis.

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Clofazimine Paper – WHO & Harvard | 27 September 2013 | Page 2

ABSTRACT

Objectives: Given the spread of multidrug-resistant tuberculosis (MDR-TB), new therapies are urgently needed, including the repurposing of existing drugs. We aimed to assess key considerations for the clinical and programmatic use of clofazimine (Cfz), a riminophenazine with anti-mycobacterial activity currently used to treat leprosy. Design: Fixed and random effects meta-analysis of cohort studies and systematic review Setting: Electronic and manual searches were combined. Inclusion criteria: Observational studies on treatment of multidrug- and extremely drug-resistant tuberculosis with clofazimine or a clofazimine-containing regimen, and published guidance and documents relating to cost and availability were eligible. Results: Five observational studies enrolled 861 patients, of which 602 received Cfz. The pooled proportion of adverse drug reactions requiring discontinuation of Cfz treatment was 0.1% (95% CI: [0.0, 0.6%]), and the median frequency of all adverse events was 5.1%. Cfz showed in vitro efficacy against Mycobacterium tuberculosis, and Cfz-containing regimens may have had a useful role in the treatment of patients with drug-resistant strains and who had limited alternative treatment options. However, Cfz uptake remains insufficient to meet global needs; there is only one internationally quality-assured manufacturer, which produces a limited quantity of the drug prioritised for treatment of leprosy, the only indication for which the drug is registered. Conclusions: While the data were limited, Cfz was associated with a risk for adverse drug reactions comparable to that of first-line TB treatment, which could be reasonably managed under programmatic conditions. However, low market availability and high cost are important barriers to access to Cfz for MDR-TB patients.

STRENGTHS AND LIMITATIONS OF THIS STUDY

• We have reviewed a comprehensive body of peer-reviewed literature and policy guidance relating to the safety, use, cost, and availability of clofazimine in clinical practice.

• Few studies were included in the meta-analysis since only a smaller number of trials have been conducted with clofazimine. Further research is needed.

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1. INTRODUCTION Drug-resistant strains of tuberculosis (TB) pose a serious obstacle to progress in global TB control.1 In 2011, there were an estimated half a million new cases of multidrug-resistant tuberculosis (MDR-TB; resistance to, at least, rifampicin and isoniazid) worldwide.2 Extensively drug-resistant (XDR-TB) cases, a form of MDR-TB with additional resistance to any fluoroquinolone and an injectable second-line drug, have been identified in 84 countries.2,3 Recent survey evidence from Belarus reported nearly one in two of all enrolled TB patients had MDR-TB, the highest proportion of MDR ever recorded.4 The recent approval of bedaquiline by the United States Food and Drug Administration (FDA), the first drug developed for TB treatment in nearly a half-century, and the filing of delamanid with the European Medicines Agency (EMA), are promising developments for treatment of TB.5,6 However, the management of drug-resistant strains of Mycobacterium tuberculosis (M.tb) necessitates new effective treatment regimens, composed of at least four effective drugs. In light of the limited treatment options available for patients affected by severe patterns of drug-resistant TB, some have recommended repurposing older drugs, though there are significant concerns with the adverse drug reaction (ADR) profiles and long term safety of several agents, and conflicting evidence of their efficacy.7,8 One potential candidate to be repurposed is clofazimine (Cfz), a riminophenazine derived from a R-substitution at the imino group.9 Cfz has apparent anti-mycobacterial and anti-inflammatory activity, though its precise mechanism of action is still unclear.10 The drug is known to be highly lipophilic, accumulating in fatty tissues with uptake by human mononuclear phagocytes, the same cells infected by M. tb.11 Cfz also appears to exhibit a property uniquely relevant for tuberculosis treatment: despite its long half-life and accumulation in tissue, the risk of developing resistance is relatively low.12 Although Cfz was originally developed for the treatment of tuberculosis, its current medical indication is for the treatment of multi- and paucibacillary leprosy, including severe erythema nodosum leprosum reactions in leprosy patients.13 While in vitro studies suggested high anti-TB activity, poor in vivo results in the mid-1950s led to the abandonment of clinical development as an anti-tuberculosis agent.14,15 In the past decade, there has been renewed and growing interest in the use of Cfz as an anti-TB agent. An MDR-TB treatment observational study conducted in Bangladesh showed favourable outcomes, even with a significantly shorter treatment duration than the current WHO recommended regimen.16 A multi-country randomised control trial to evaluate a standardised nine-month regimen containing Cfz for the treatment of MDR-TB is currently under way, and observational cohort studies are being conducted in some West African countries.17 Given the growing evidence supporting the use of Cfz in the treatment of patients with MDR- and XDR-TB treatment, we sought to assess the key considerations, including safety, effectiveness, management, and cost, in relation to the programmatic and clinical use of Cfz by national TB programmes (NTP).

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2. METHODS

Study Design and Data Sources

Our meta-analysis and systematic review were conducted using a prospective protocol according to MOOSE (Meta-analysis of Observational Studies in Epidemiology) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines for reporting systematic

reviews of observational study results (Supplementary Material online).18,19 Studies published between 1950 and May 2013 were identified from an electronic search of the PubMed, MEDLINE, Embase, and Cochrane Library databases. The key words and Medical Subject Heading terms included: ‘clofazimine’, ‘B663’, Lamprene’, ‘tuberculosis’, ‘side effects’, ‘adverse events’, ‘adverse drug reactions’, ‘sequella’, ‘toxicity’, ‘tolerability’, ‘outcomes’, ‘treatment’, ‘effectiveness’, ‘efficacy’, ‘cure’, ‘success’, ‘guideline’, ‘treatment’, or ‘safety’. We contacted researchers and manually collected references of all retrieved articles, selected review articles, clinical trial registration notices, and conference abstracts, as needed. These additional studies were merged with our search results, following exclusion of non-relevant or duplicate citations. Policy guidelines and drug label information were retrieved from manual searches of World Health Organization publications, as well as those of two stringent regulatory agencies, the US FDA and EMA. Data Extraction

Data on study characteristics, methodological quality, and results were independently extracted from each selected article using a pre-defined extraction form by two authors (TJH and SD). This form captured: author, study location, study design, observation period, number of patients treated, patient age, sex and reported race or ethnicity, drug resistance profile, prior treatment with second-line drugs, HIV status, treatment regimen with Cfz, dosage, duration of treatment, treatment outcomes, reported ADRs by agent and rate of discontinuation. An additional author (DFW) independently assessed the validity of included citations and extracted data. Since serious adverse events and the criteria for judging an adverse event as serious were not consistently reported, we used ADR as a measure of Cfz’s safety profile, using methods described elsewhere.20,21 Briefly, challenge-dechallenge was used to evaluate ADR data: a reaction was attributed solely to Cfz if discontinuation of the drug or reducing the dose led to reported disappearance of the toxicity.22,23 Prevalence (%) was measured as a proportion relative to the total number of drug-receiving patients. Statistical Analysis

We calculated point estimates and 95% confidence intervals (CI) for the frequency of adverse events and ADRs. We then calculated the I2 and heterogeneity χ2 statistics to assess the relative proportionate effects of heterogeneity and chance on total variation across data points. From this analysis, we determined that the DerSimonian and Laird random effects model was more appropriate for pooling estimates of adverse event frequencies (I2=98.7%; P<0.001),24 whereas the inverse-variance weighted fixed effects model was used for ADRs (I2=11.5%; P=0.34). We defined statistical significance at the P < 0.05 level. Forest plots illustrate the distributions of

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pooling adverse event data by various stratification criteria. Statistical analyses were performed using Stata (version 10.0, Stata Corp, College Station, TX, USA).

3. RESULTS

Safety

From 1,248 citations identified by our search strategy, 147 were selected for full-text review (Figure 1). A total of five studies were subsequently included in the review for safety. The characteristics of the five selected studies with safety data are summarised in Table 1.16,25,26,27,28 Of the total 861 participants, 602 patients received Cfz as part of their TB treatment regimens. The study periods ranged from 1993 to 2012. The average study population was 144 patients (range: 10-427). The daily dose range of Cfz administered in clinical settings was 50-100 mg, though one study reported a daily dose of 300 mg.25 Drug resistance patterns, duration and extent of prior TB treatment, HIV status, and types of ADRs were variably reported. The two most reported adverse event categories were dermal (skin discoloration) and gastrointestinal. As shown in Figure 2, the overall pooled proportion of all adverse events attributed to Cfz was 21.9% (95% CI: [0.0, 46.1%]), though the median frequency of adverse events was 5·1%. The pooled proportion was disproportionately affected by an outlier reporting adverse events in 88·6% (95% CI: [75.4, 96.2%]) of cases.27 Not all reported adverse events required discontinuation of Cfz treatment. From our fixed effects model, the pooled proportion of ADRs requiring discontinuation or withdrawal of Cfz was 0.1% (95% CI: [0.0, 0.6%]), with the frequency of ADRs ranging from 0% (95% CI: [0.0, 1.1%]) to 11·8% (95% CI: [2.0, 35.6%]).

Efficacy

Early in vitro studies of Cfz reported positive bactericidal efficacy of Cfz.29,30,31,32,33 More recent in vitro and in vivo evidence suggests that Cfz also has sustained sterilizing activity against latent or persistent bacterial populations of M. tuberculosis.34 Currently novel analogues of Cfz are under investigation with comparable efficacy but shorter half-lives, potentially reducing tissue accumulation and resulting skin pigmentation.35 In vivo studies in mice and hamsters reported significant activity of Cfz, though accumulation in animal tissues may lead to overestimation of drug activity when subsequently plated on solid media.12,30,36,37,38 Earlier studies had showed that Cfz had little or no activity in guinea pig and monkey models.39,40 It was later thought that these poor in vivo results and monotherapy-induced resistance in guinea pigs and monkeys may have been a result of low absorption of the drug by the oral route.29 Recently, Cfz combined with bedaquiline and pyrazinamide has been shown to be superior to the current first-line regimen in reducing colony-forming unit counts at one month in mice.41Cfz combined with the standard second-line regimen also significantly improved culture conversion and relapse prevention, compared with a regimen without Cfz, in mice.42 In

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addition, the sterilizing activity of bedaquiline and pyrazinamide was significantly improved with the addition of Cfz.43

Effectiveness

In a recent systematic review and meta-analysis of 3,489 patients treated for drug resistant TB across 10 countries, Dey et al. reported a pooled treatment success rate of 62.0% (95% CI: [52.8–71.1%]) from treatment regimens containing Cfz, with success defined as cure and/or treatment completion.44 The success rate in HIV/MDR-TB co-infected patients was not significantly different from the overall success rate. In another systematic review of patients treated with Cfz-containing regimens, Gupta et al. found no significant differences in the proportions with favourable outcomes between MDR- (65%; 95% CI: [52-79%]) and XDR-TB patients (66%; 95% CI: [42-89%]).45 There was substantial variation in estimates of mortality during treatment with Cfz-containing regimens, ranging from 1.0% (95% CI: 0.1%–2.6%) to 63.4% (95% CI: 38.3%–85.0%), though the risk of death attributed solely to Cfz, after adjusting for covariates, was not reported. Further cohort studies showing a favourable effect of Cfz-containing regimens have been reported in Benin,46 South Africa,47 and Ukraine,48 though limited benefit from Cfz was found in studies in Brazil49 and Sri Lanka50. Two clinical trials are currently ongoing involving the investigation of the efficacy and safety of treatment regimens containing Cfz (Table 2). The Global Alliance for TB Drug Development is conducting a Phase 2 study to evaluate the early bactericidal activity of Cfz (dosed at 300 mg for the first two days and 100 mg thereafter) combined with bedaquiline and pyrazinamide, compared with first-line treatment.51 The Phase 3 STREAM trial, sponsored by the International Union Against Tuberculosis and Lung Disease, is comparing a modified MDR-TB treatment regimen, based on the shorter treatment regimens assessed in Bangladesh,16 with regimens based on the current WHO guidelines for MDR-TB treatment. The STREAM trial involves sites in Ethiopia, India, South Africa and Viet Nam.17 Follow up is expected for all patients in the study for 27-33 months, with final results anticipated after October 2016.

Availability, Cost and Demand Forecast

Cfz was registered under the trade name Lamprene™ by Novartis in the U.S. in 1986.52 Quality-assured Cfz is available on very limited quantities for the treatment of MDR-TB patients on a patient-named basis through the Global Drug Facility (GDF) mechanism of the Stop TB Partnership, which uses a distributor authorised by Novartis.53,54,55 Securing a steady supply of quality-assured Cfz that can meet the increasing demand for MDR-TB treatment, without jeopardizing the needs of the global programme for leprosy elimination, is currently a major challenge in the response to MDR-TB.56 The price of the 100mg product through the GDF mechanism is US$120.86 per hundred capsules, or roughly US$1.21 per one capsule. The cost of a daily dosage of Cfz varies between US$1.21 (when a 100mg dosage is used) and US$3.63 (when 300 mg are used). Depending on the regimen and dosage, the cost of Cfz can be higher than the cost of a daily dosage of most injectables used in the treatment of intensive phase of MDR-TB treatment. By our calculations, the estimated annual cost of procuring a 24 month-regimen of Cfz will range between $2-$20

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million, depending on the number of patients (low estimate: XDR-TB patients only; high estimate: all MDR-TB patients) treated.

Global policy, guidelines, and national practices

From a search of national, regional, and international guidelines and regulations relating to the use of Cfz, two policy sources were retrieved from the World Health Organization57,58,59,60 and the U.S. Food and Drug Administration (FDA)61 (Table 3). Cfz is currently indicated solely for leprosy by the WHO and the US FDA, and is included in the WHO Model Lists of Essential Medicines for adults and children.62,63 For this use, the drug is provided free to endemic countries through an agreement with the sole manufacturer of quality-assured Cfz, Novartis, first signed in 1999 and renewed in 2010.64 The most recent donation, valued at US$26 million, will treat an estimated 1.1 million patients with leprosy over five years (2010-2015). In the U.S., Cfz can only be obtained through the National Hansen’s Disease Program under a single-patient treatment investigational new drug protocol administered by the US FDA.65 WHO guidelines currently do not recommend the routine use of Cfz for the treatment of DR-TB, due to insufficient data supporting the drug’s efficacy and long term safety.57,58 A WHO

consultation in early 2012 on diagnostic definition and treatment options for so-called “totally

drug-resistant TB” concluded, based on expert opinion, that Cfz (at a daily dose of 100mg) and linezolid were likely to be the most effective in the Group 5 category of second-line anti-TB drugs for the treatment of XDR-TB.66 Seven articles were identified from the literature on the national policies, guidelines and practices on the use of Cfz to treat MDR-TB.67,68, 70,71,72,73,74 There has been virtually no published evidence of the use of Cfz in the Russian Federation. The two articles retrieved from the Russian-language literature mention solely that Cfz is included in international guidelines as a third-line therapy but note that the drug is not currently registered in the country.67,68 Cfz was previously registered with the Russian Ministry of Health for the indication of leprosy in 1977 and re-registered in 1989. In 1995, Cfz’s registration was annulled for unknown reasons and was not identifiable through the State Registry of Medical Substances as of May 2013.69 In India, use of Cfz has been associated with varying degrees of success in a number of settings,

including in TB cases with strains described as so-called “totally drug-resistant.”70 A survey of

the clinical practices in the management of DR-TB cases by chest physicians in the Indian state of Maharashtra found that Cfz was a preferred drug, being included in the treatment regimens by 15 respondents out of the 29 surveyed.71 A number of studies have reported the use of aggressive supervised therapies, including Cfz and other Group 5 drugs such as linezolid and clarithromycin.72,73 In one such study with 14 patients with XDR-TB, only two cases achieved complete cure (defined to be at least five negative culture results for the final 12 months of treatment), compared with four deaths.74

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4. DISCUSSION

This study has shown a low proportion of adverse events requiring discontinuation of treatment attributed to Cfz at doses ranging from 50-300mg daily. Our pooled frequency of Cfz ADRs at 0.1% is comparable to the incidence of serious ADRs reported with first-line TB treatment.75 These findings are in line with those made in an unpublished report on spontaneous individual case safety reports (ICSR) submitted between 1976 and 2012 to the WHO’s International Drug Monitoring Programme, which found that Cfz was associated with 288 ICSRs accounting for 674 ADRs (Wang S et al., unpublished data). The three most frequent systemic categories involved in the TB-specific ADRs were central and peripheral nervous system (23.2%), gastrointestinal (17.9%), and skin (16.1%). Our review of preclinical studies of Cfz suggests that this drug has sterilizing activity against M.tb. Observational cohort studies in Bangladesh, Benin, China, Niger, Peru, and Sri Lanka, among other settings, show an association between treatment regimens containing Cfz and favourable outcomes, including shortened treatment duration, and add support to its inclusion by WHO in the Group 5 of drugs to be considered in the management of MDR-TB.58 A high variance in mortality rates of patients receiving Cfz-containing drug combinations is observed in some studies. While these data might be confounded by indication— as patients who receive Cfz-containing regimens tend to be those with broader-spectrum drug resistance patterns and more advanced disease — the increasing use of Cfz should be coupled with strengthening of active pharmacovigilance systems.22 Results from the Phase 3 STREAM and Phase 2 Global TB Alliance trials will help to elucidate further the long-term safety and effectiveness of Cfz in the treatment of MDR-TB. Our analysis is limited by the small number of available studies and published materials on Cfz. While we attempted to categorise ADRs based on resolution after withdrawal or recurrence with re-challenge, reporting varied across studies, and different thresholds may have been applied to report adverse events and ADRs. In the Xu et al. study for instance, 39 out of 44 (87%) patients were reported to have experienced adverse events after starting Cfz, but only two discontinued Cfz altogether.34 There were also insufficient data on extent of prior treatment, drug susceptibility, and HIV status—factors that could result in varying severity of disease. In addition, to review the global landscape of policies and regulatory actions relating to Cfz, we relied on databases, search engines, and manual searches which are biased in favour of English-language publications. Many more national and local policies may exist that were not captured by this paper. The use of Cfz in the clinical settings where MDR-TB patients are treated has been increasing over the last two decades. The progress countries are making towards universal access to diagnosis and treatment of MDR-TB76 is resulting in sustained and increasing demand for this product, at least until more new and effective drugs are available. The GDF’s projected forecast based on the ongoing global scale up of MDR-TB management suggests that the current supply line is insufficient to meet this demand. GDF and the Global Fund regularly publish joint invitations to manufacturers of first, second and third-line anti-tuberculosis medicines to submit an Expression of Interest for TB drug products evaluation by the Expert Review Panel. However,

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to date, no successful review of clofazimine has been reported through this mechanism. To improve access to the drug, generic manufacturers that can complement Novartis’ production capacity should be identified. The inclusion of more manufacturers in the market may also contribute to a reduction in the cost of the drug, further improving access. Despite these limitations, this paper underscores the potential value of Cfz’s inclusion in the treatment regimens for MDR- and XDR-TB cases. However, even if the ongoing clinical trials and observational studies confirm the earlier findings reviewed here, much more will need to be done to make Cfz both available and affordable.

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5. ACKNOWLEDGEMENTS

The authors thank Shu-Hua Wang for help with data from the WHO’s International Drug Monitoring Programme. The authors also thank the editor and anonymous reviewers at the journal for their review of the manuscript.

Contributors

AJ, DFW, PN, SK, and TJH had the idea for and designed the study. TJH and SD undertook data collection, and DFW supervised extraction and analysis. TJH analysed the data and developed drafts of the manuscript. AJ, DF, DFW, EJ, KL, KW, PN, and SK contributed to interpretation of the results, drafting of the paper, and revisions of the manuscript. All authors contributed to and approved the final draft for publication.

Funding and Interests

TJH and SD were supported by fellowships from the Harvard Kennedy School Institute of Politics. SK has received partial salary support through a grant from the Eli Lilly Foundation’s MDR-TB Partnership to Brigham and Women’s Hospital. DF, DFW, EJ, KL, and KW are staff members of WHO. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of WHO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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Figure 1 Study selection process for meta-analysis of safety of Cfz in treatment of TB

Potentially relevant citations identified, without duplicates

(n = 1248)

Citations excluded after screening titles and

abstracts (n = 1101)

147 full-text articles screened for eligibility criteria

Studies included in meta-analysis

(n = 5)

Journal articles excluded (n = 143) = No or incomplete adverse event data (n = 141)

+ Case reports, < 10 patients (n = 2)

1 additional reference identified through manual

review of conference abstracts

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Table 1 Characteristics of studies included in a systematic review of safety of clofazimine in the treatment of TB

Author, year, reference Country Study period Study design Study population N. included subjects

Treatment duration (mo.) Regimen

N. given Cfz

Daily Cfz dose (mg)

Goble et al., 199325

USA 1973-1983 Retrospective 171 patients included Age: 46 (17-79) DS: 0; DR: 98

7 Individualised 17 300

Geerligs et al., 200026

Netherlands 1985-1998 Retrospective 44 patients included Age: 33 (10-82) DS: 0; DR: 44

20-53 Individualised 39 Not stated.

Van Deun et al., 201016

Bangladesh 1997-2007 Prospective 427 patients included Age: 33.8 (mean) DS: 0; DR: 427

3-15 Cfz, Km, Ofx, E, H, Z, Pto

427 50-100

Xu et al., 201227

China, PR 2006-2011 Retrospective 144 patients included Age: 38.8 ± 10.8 (Cfz); 47.4 ± 11.8 (non-Cfz) DS: 0; DR: 144

2.2 ± 1.7 (Cfz); 2.1 ± 1.3 (non-

Cfz)

Individualised 44 100

Piubello et al., 201228

Niger 2008-2010 Retrospective 65 patients included Age: 32.7 (16-66) DS: 0; DR: 65

12 Cfz, Km, Ga, E, H, Z, Pth

65 50-100

DS = drug-sensitive; DR = drug-resistant (to at least two agents in standard-line therapy). Cfz = clofazimine; H = isoniazid; E = ethambutol; Z = pyrazinamide; S = streptomycin; Et = ethionamide; Km = kanamycin; Ofx = ofloxacin; Ga = gatifloxacin; Pto = prothionamide.

Table 2 Current preclinical and clinical development of Cfz for TB indications

Phase Date Trial name (identifier) Sponsor Design Treatment arms (Cfz daily dose) Primary endpoint

Phase III 2011-2016 STREAM (ISRCTN78372190)

17

International Union Against Tuberculosis and Lung Disease

Non-inferiority Bangladesh regimen16

vs. locally used WHO MDR-TB regimen (Cfz = 50-100 mg)

Proportion of patients with a favourable outcome (cure or completion) 27 months after randomisation

Phase II 2012-2013 NC-003 (NCT01691534)

51

Global Alliance for TB Drug Development

Superiority Bedaquiline (J), PA-824 (PA), Z, Cfz vs. J-PA-Z vs. J-PA-Cfz vs. J-Z-Cfz vs. Z alone vs. Cfz alone vs. Rifafour (Cfz = 100-300 mg)

Early bactericidal activity (rate of change of log CFU per ml sputum)

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Table 3 Guidelines and labelling regulations for clofazimine

Authority Region Indication Adverse effects Off-label use Recommendation for Cfz in TB use

World Health Organization

57,58

Global MDR- and XDR-TB Gastrointestinal intolerance Named patient basis on “exceptional” grounds

2011: “May be used but not included among drugs making up the standard regimen” 2008: “Only if additional drugs are needed to bring the total to four”


59,60

Global Leprosy and severe erythema nodosum leprosum (ENL) reactions in leprosy

Discoloration, ichthyosis Named patient basis on “exceptional” grounds

“…In the treatment of multi-drug resistant tuberculosis (MDR TB)…WHO has found no evidence of its effectiveness for these forms of treatment”

59

Food and Drug Administration

61

USA Lepromatous leprosy, including dapsone-resistant lepromatous leprosy and lepromatous leprosy complicated by ENL

Skin pigmentation, gastrointestinal, conjunctival and corneal pigmentation, discoloration of urine, feces, sputum, and sweat

Single-patient treatment investigational new drug protocol

Not stated.

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Figure 2 Forest plot of all reported adverse events associated with or ADRs attributed to clofazimine and clofazimine-containing regimens

Pooled estimates using inverse-variance weighted fixed effects (F-E) and random effects (R-E) models are shown. The random effects model was used for adverse events estimates (I2=98.7%; P<0.001) and fixed effects for ADRs (I2=11.5%; P=0.34).

All adverse events

Goble et al.25

Geerligs et al.26

Van Deun et al.16

Xu et al.27

Piubello et al.28

F-E Subtotal R-E Subtotal

ADRs only

Goble et al.25

Geerligs et al.26

Van Deun et al.16 Xu et al.

27

Piubello et al.28

F-E Subtotal

R-E Subtotal

Study

1993

2000

2010

2012

2013

1993

2000

2010

2012

2013

Year

11.76 (2.03, 35.59) 5.13 (0.52, 17.79)

0.00 (0.00, 1.07) 88.64 (75.57, 95.50) 4.62 (1.06, 13.23)

0.32 (0.00, 0.85) 21.89 (0.00, 46.13)

11.76 (2.03, 35.59) 5.13 (0.52, 17.79)

0.00 (0.00, 1.07) 4.55 (0.42, 15.97)

0.00 (0.00, 6.68) 0.05 (0.00, 0.58) 0.35 (0.00, 1.74)

Proportion (95% CI)

2

2

0

39

3

2

2

0

2

0

Events

17

39

427

44

65

17

39

427

44

65

Number

00 20 40 60 80 100

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V. REFERENCES

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Effectiveness of a therapeutic regimen using clofazimine for MDR-TB treatment in Brazil. In: The 42nd World Congress on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union), Lille, France, 2011. p. S320. 50 Senaratne WV. Outcome of treatment of multidrug resistant tuberculosis. Ceylon Med J 2004;49(3):86-7. 51 Evaluation of early bactericidal activity in pulmonary tuberculosis with clofazimine (C)-TMC207 (J)-PA-824 (Pa)-pyrazinamide (Z) (NC-003). Identifier: NCT01691534. Available from: <http://clinicaltrials.gov/ct2/show/NCT01691534> 52 US FDA. Orange Book: Clofazimine (Lamprene). FDA, 2013. 53 Green Light Committee Initiative. Annual Report 2008. Geneva, Switzerland: WHO/STP, 2009. 54 WHO. Multidrug therapy (MDT): Use of clofazimine for treating ENL reactions in leprosy [Online]. Geneva, Switzerland: WHO. Accessed from: <http://www.who.int/lep/mdt/clofazimine/en/index.html> 55 Medecins Sans Frontières. 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57 WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB 2008.402. Geneva, Switzerland: WHO, 2008. 58 WHO. Guidelines for the programmatic management of drug-resistant tuberculosis – 2011 update. WHO/HTM/TB 2011.6. Geneva, Switzerland: WHO, 2011. 59 WHO. Guidelines for the management of severe erythema nodosum leprosum (ENL) reactions. Geneva, Switzerland: WHO. Accessed from: <http://www.who.int/lep/research/WHOenlguide.pdf> 60 WHO. Guide to eliminate leprosy as a public health problem. WHO/CDS/CPE/CEE/2000.14. Geneva, Switzerland: WHO, 2000. 61 US FDA. Label and Prescribing Information: Lamprene® (Novartis). FDA, 1998. 62 WHO. WHO Model List of Essential Medicines, 17th edition. Geneva, Switzerland: WHO, 2011. 63 WHO. WHO Model List of Essential Medicines for Children, 3rd edition. Geneva, Switzerland: WHO, 2011. 64 WHO. New Memorandum of Understanding for MDT. Geneva, Switzerland: WHO, 2010. 65 Worobec SM. Current approaches and future directions in the treatment of leprosy. Res Rep Trop Med 2012;3:79-91. 66 WHO. “Totally Drug-Resistant TB”: A WHO consultation on the diagnostic definition and treatment options. Geneva, Switzerland: WHO, 2012. 67 Borisov GB, Sokolova. Etiotropnoe lechenie tuberkuleza pri lekarstvennoj ustojchivosti M. tuberculosis: vzglyady I rekomendatsii mezhdunarodnyh organizatsij. Consilium Medicum 2001;3:12. 68 Chukanov VI. Problema izlecheniya bolnyh tuberkulezom organov dynahiya. Central Scientific Research Institute of Tuberculosis of Russian Academy of Sciences. 954. 69 Russian State Registry of Medical Substances. Lamprene (Лампрен). Accessed from: <http://grls.rosminzdrav.ru/> 70 Udwadia Z, Vendoti D. Totally drug-resistant tuberculosis (TDR-TB) in India: Every dark cloud has a silver lining. J Epidemiol Community Health 2013;67(6):471-2. 71 Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. Clin Infect Dis 2012;54(4):579-81. 72 Dutta NK, Karakousis PC. Tuberculosis chemotherapy: Present situation, possible solutions, and progress towards a TB-free world. Indian J Med Microbiol 2012;30(3):261-3. 73 Prasad M, Shashirekha K, Bhattacharyya D, Grover N. Extensively drug-resistant (XDR) pulmonary tuberculosis in HIV negative cases. In: The ERS Annual Congress (Session 252-The Challenge of Multidrug-Resistant Tuberculosis), Berlin, Germany, 2008. p.441s 74 Prasad M, Rai S, Falleiro J, Ravishankar V. Prevalence and treatment outcome of drug resistant pulmonary tuberculosis in HIV negative cases – experience from a tuberculosis treatment center in India. In: The ERS Annual Congress (Session 400-Multi/Extensively-drug resistant tuberculosis), Vienna, Austria, 2009. p.4447. 75 Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003;167(11):1472-7. 76 Falzon D, Jaramillo E, Wares F, Zignol M, Floyd K, Raviglione MC. Universal access to care for multidrug-resistant tuberculosis: an analysis of surveillance data. Lancet Infectious Dis 2013: In Press. doi:10.1016/S1473-3099(13)70130-0.

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Clofazimine Meta-Analysis Study Protocol v2 16 August 2012 Page 1

Safety and Availability of Clofazimine in the Treatment of Multidrug and Extensively Drug-Resistant Tuberculosis

Preliminary Study Protocol

Background The global incidence of multi-drug resistant tuberculosis (MDR-TB) is estimated to number half a million annually. In the short- to medium-term future, the number of MDR-TB cases is expected to grow significantly. The rise of MDR-strains has highlighted the urgency and need not only for the development of new drugs but also, in the interim, of incorporating older agents into treatment programmes for MDR-TB cases. However, the evidence base for these second-line drugs is limited, preventing more widespread use. One potential candidate for repurposing is clofazimine, a riminophenazine with anti-mycobacterial activity currently used to treat leprosy. There has been growing interest from several high-burden countries of the use of clofazimine for TB, especially cases of multidrug- and extensively drug-resistant TB (XDR-TB). Objectives

1. Determine the prevalence of adverse events and adverse drug events due to clofazimine using meta-analysis;

2. Assess the evidence relating to efficacy and effectiveness of clofazimine in treatment of MDR- and XDR-TB; and

3. Review published guidance, policy documents, and other sources for information relating to the management and cost of clofazimine

Methods Study eligibility

Human studies including 10 or more participants in treatment of tuberculosis;

Study publication between 1950 and May 2013;

Treatment using clofazimine or clofazimine-containing regimen;

No language restrictions Search strategy We will search PubMed, MEDLINE, Embase, and Cochrane Library databases using the following key words and Medical Subject Heading terms, and combinations thereof: ‘clofazimine’, ‘B663’, Lamprene’, ‘tuberculosis’, ‘side effects’, ‘adverse events’, ‘adverse drug reactions’, ‘sequella’, ‘toxicity’, ‘tolerability’, ‘outcomes’, ‘treatment’, ‘effectiveness’, ‘efficacy’, ‘cure’, ‘success’, ‘guideline’, ‘treatment’, or ‘safety’.

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We will also manually review conference abstracts from the annual Union World Conference on Lung Health and contact researchers of selected abstracts. For policy guidelines and drug labels, we will manually search the electronic publications and websites of the World Health Organization, U.S. Food and Drug Administration, and the European Medicines Agency (EMA), in addition to searches using the database above and conventional online search engines. Data extraction The key domains for data extraction are:

1. Study characteristics 2. Outcomes 3. Methodological quality, i.e. assessment of risk of bias

The following fields will be collected for each of the included studies:

1. Author 2. Study location 3. Study design 4. Observation period/study period 5. Number of patients treated (total, with clofazimine) 6. Patient age (mean, range) 7. Sex 8. Drug resistance profile 9. Prior treatment with second-line TB drugs 10. HIV status 11. Treatment regimen with clofazimine 12. Dosage of clofazimine 13. Duration of treatment (with and without clofazimine) 14. Treatment outcomes 15. Number and type of adverse events, by agent 16. Number and type of adverse drug reactions, by agent 17. Rate of discontinuation (if different from #16)

We define adverse drug reactions using challenge-dechallenge, attributing an ADR to clofazimine if discontinuation of the drug or reduction in the dosage leads to reported disappearance of the toxicity. We will then calculate the prevalence as a proportion relative to the total number of drug-receiving patients. For each of the included studies, we will identify and assess risks of bias according to the Cochrane Collaboration’s risk of bias framework comprising five primary domains: (1) selection bias (random sequence generation and allocation concealment); (2)

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performance bias (masking of outcomes of interest for participants and study investigators); (3) detection bias (blinding of outcome assessors); (4) attrition bias (incomplete outcome data); and (5) reporting bias (selective outcome reporting). Risk of bias for each domain will be categorised as low, high, or unclear, and used to make judgments about the overall risk of bias for each study. Statistical analysis We will calculate point estimates and 95% confidence intervals (CI) for the frequency of adverse events and ADRs. Then, we will calculate the I2 and heterogeneity χ2 statistics to assess the relative proportionate effects of heterogeneity and chance on total variation across data points. From this analysis, we will use either the DerSimonian and Laird random effects model or the inverse-variance weighted fixed effects model, depending on the I2 statistic.

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Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis:

Analysis of published guidance and meta-analysis of cohort studies

Journal: BMJ Open

Manuscript ID: bmjopen-2013-004143.R1

Article Type: Research

Date Submitted by the Author: 20-Nov-2013

Complete List of Authors: Hwang, Thomas; Harvard University, Faculty of Arts and Sciences Dotsenko, Svetlana; Harvard University, Faculty of Arts and Sciences Jafarov, Azizkhon; World Health Organization, Weyer, Karin; World Health Organization, Falzon, Dennis; World Health Organization, Lunte, Kaspars; World Health Organization and Stop TB Partnership, Global Drug Facility Nunn, Paul; Global Infectious Disease Consulting, Jaramillo, Ernesto; World Health Organization, Keshavjee, Salmaan; Harvard Medical School, Department of Global Health

and Social Medicine Wares, Douglas; World Health Organization,

<b>Primary Subject Heading</b>:

Global health

Secondary Subject Heading: Infectious diseases, Public health, Global health

Keywords: Tuberculosis < INFECTIOUS DISEASES, INFECTIOUS DISEASES, Public health < INFECTIOUS DISEASES, Tropical medicine < INFECTIOUS DISEASES


BMJ Open on A

pril 25, 2020 by guest. Protected by copyright.

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Safety and availability of clofazimine in the treatment of multidrug and extensively drug-

resistant tuberculosis: Analysis of published guidance and meta-analysis of cohort studies

Thomas J. Hwang,1,2 Svetlana Dotsenko,1 Azizkhon Jafarov,3 Karin Weyer,3 Dennis Falzon,3 Kaspars Lunte,4 Paul Nunn,5 Ernesto Jaramillo,3 Salmaan Keshavjee,6* Douglas F. Wares3*

Author Affiliations: 1 Faculty of Arts and Sciences, Harvard University, Cambridge, USA 2 Program on Regulation, Therapeutics, and Law, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, USA 3 Global TB Programme, World Health Organization, Geneva, Switzerland 4 Global Drug Facility, Stop TB Partnership and World Health Organization, Geneva, Switzerland 5 Global Infectious Disease Consulting, London, UK 6 Program in Infectious Disease and Social Change, Department of Global Health and Social Medicine, Harvard Medical School, Boston, USA * These individuals contributed equally as senior authors. Corresponding Authors: Thomas Hwang and Salmaan Keshavjee. Emails: [email protected], [email protected] Date: November 11, 2013 Word Count: 3,048 (excluding abstract, references, exhibits, and acknowledgements) Keywords: Clofazimine, safety, clinical practice, meta-analysis, drug resistant tuberculosis.

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ABSTRACT




• This study shows that the burden of safety issues associated with Cfz use appears to be manageable by national TB programmes. The widespread use of Cfz is limited by low availability and relatively high cost.

• Few studies were included in the meta-analysis since only a smaller number of studies have been conducted with clofazimine. Further research is needed.

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Clofazimine Paper – BMJ Open | 11 November 2013 | Page 3

1. INTRODUCTION

Drug-resistant strains of tuberculosis (TB) pose a serious obstacle to progress in global TB control.1 In 2011, there were an estimated half a million new cases of multidrug-resistant tuberculosis (MDR-TB; resistance to, at least, rifampicin and isoniazid) worldwide.2 Extensively drug-resistant (XDR-TB) cases, a form of MDR-TB with additional resistance to any fluoroquinolone and an injectable second-line drug, have been identified in 84 countries.2,3 Recent survey evidence from Belarus reported nearly one in two of all enrolled TB patients had MDR-TB, the highest proportion of MDR ever recorded.4 The recent approval of bedaquiline by the United States Food and Drug Administration (FDA), the first drug developed for TB treatment in nearly a half-century, and the filing of delamanid with the European Medicines Agency (EMA), are promising developments for treatment of TB.5,6 However, the management of drug-resistant strains of Mycobacterium tuberculosis (M.tb) necessitates new effective treatment regimens, composed of at least four effective drugs. In light of the limited treatment options available for patients affected by severe patterns of drug-resistant TB, some have recommended repurposing older drugs, though there are significant concerns with the adverse drug reaction (ADR) profiles and long term safety of several agents, and conflicting evidence of their efficacy.7,8 One potential candidate to be repurposed is clofazimine (Cfz), a riminophenazine derived from a R-substitution at the imino group.9 Cfz has apparent anti-mycobacterial and anti-inflammatory activity, though its precise mechanism of action is still unclear.10 The drug is known to be highly lipophilic, accumulating in fatty tissues with uptake by human mononuclear phagocytes, the same cells infected by M. tb.11 Cfz also appears to exhibit a property uniquely relevant for tuberculosis treatment: despite its long half-life and accumulation in tissue, the risk of developing resistance is relatively low.12 Although Cfz was originally developed for the treatment of tuberculosis, its current medical indication is for the treatment of multi- and paucibacillary leprosy, including severe erythema nodosum leprosum reactions in leprosy patients.13 While in vitro studies suggested high anti-TB activity, poor in vivo results in the mid-1950s led to the abandonment of clinical development as an anti-tuberculosis agent.14,15 In the past decade, there has been renewed and growing interest in the use of Cfz as an anti-TB agent. An MDR-TB treatment observational study conducted in Bangladesh showed favourable outcomes, even with a significantly shorter treatment duration than the current WHO recommended regimen.16 A multi-country randomised control trial to evaluate a standardised nine-month regimen containing Cfz for the treatment of MDR-TB is currently under way, and observational cohort studies are being conducted in some West African countries.17 Given the growing evidence supporting the use of Cfz in the treatment of patients with MDR- and XDR-TB treatment, we sought to assess the key considerations, including safety, effectiveness, management, and cost, in relation to the programmatic and clinical use of Cfz by national TB programmes (NTP).

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2. METHODS


Our meta-analysis and systematic review were conducted using a prospective protocol according to MOOSE (Meta-analysis of Observational Studies in Epidemiology) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines for reporting systematic

reviews of observational study results (Supplementary Material online).18,19 Studies published between 1950 and May 2013 were identified from an electronic search of the PubMed, MEDLINE, Embase, and Cochrane Library databases. The key words and Medical Subject Heading terms included: ‘clofazimine’, ‘B663’, Lamprene’, ‘tuberculosis’, ‘side effects’, ‘adverse events’, ‘adverse drug reactions’, ‘sequella’, ‘toxicity’, ‘tolerability’, ‘outcomes’, ‘treatment’, ‘effectiveness’, ‘efficacy’, ‘cure’, ‘success’, ‘guideline’, ‘treatment’, or ‘safety’. We contacted researchers and manually collected references of all retrieved articles, selected review articles, clinical trial registration notices, and conference abstracts, as needed. These additional studies were merged with our search results, following exclusion of non-relevant or duplicate citations. Policy guidelines and drug label information were retrieved from manual searches of World Health Organization publications, as well as those of two stringent regulatory agencies, the US FDA and EMA. Outcome Variables and Data Extraction

The primary aims of our study was to perform a meta-analysis of the safety of Cfz from published studies and a systematic analysis of the effectiveness, management, and cost of Cfz from the peer-reviewed literature as well as published guidance. For our safety analysis, our primary outcomes of interest were adverse events and adverse drug reactions (ADR). We defined an adverse drug reaction (ADR) as an appreciably harmful or unpleasant reaction caused by a drug that is serious enough to warrant the discontinuation or revision of treatment.20 In contrast, an adverse event included any undesirable reactions reported by patients or clinicians, including mild reactions that had no bearing on treatment. Since the use of the term “adverse event” and “serious adverse events” was inconsistent in the reviewed studies and the criteria for judging an adverse event as serious were not consistently reported, we used ADR as a measure of Cfz’s safety profile. Using methods described previously,21 we used challenge-dechallenge to evaluate ADR data: a reaction was attributed solely to Cfz if discontinuation of the drug or reducing the dose led to reported disappearance of the toxicity.22

Prevalence (%) was measured as a proportion relative to the total number of drug-receiving patients. Data on study characteristics, methodological quality, and results were independently extracted from each selected article using a pre-defined extraction form by two authors (TJH and SD). This form captured: author, study location, study design, observation period, number of patients treated, patient age, sex and reported race or ethnicity, drug resistance profile, prior treatment with second-line drugs, HIV status, treatment regimen with Cfz, dosage, duration of treatment, treatment outcomes, reported ADRs by agent and rate of discontinuation. An additional author (DFW) independently assessed the validity of included citations and extracted data.

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Statistical Analysis

We calculated point estimates and 95% confidence intervals (CI) for the frequency of adverse events and ADRs. We assessed the heterogeneity between studies using the I2 statistic, which reports the proportion of total variance across studies that is due to between-study heterogeneity rather than by randomness (Appendix). Based on this assessment, we used the DerSimonian and Laird random effects model for pooling estimates and calculating 95% CI of adverse event frequencies, and the inverse-variance weighted fixed effects model for ADRs. 23 24 Since some studies reported no ADRs, we also performed a post hoc sensitivity analysis to calculate 95% CI of adverse events and ADRs using the Wilson score method and found that the intervals did not differ significantly. We defined statistical significance at the P < 0.05 level. Forest plots illustrate the distributions of pooling adverse event data by various stratification criteria. Statistical analyses were performed using Stata (version 12.0, Stata Corp.).

3. RESULTS

Safety

From 1,248 citations identified by our search strategy, 147 were selected for full-text review (Figure 1). A total of five studies were subsequently included in the review for safety. The characteristics of the five selected studies with safety data are summarised in Table 1.16,25,26,27,28 Of the total 861 participants, 602 patients received Cfz as part of their TB treatment regimens. The study periods ranged from 1993 to 2012. The average study population was 144 patients (range: 10-427). The daily dose range of Cfz administered in clinical settings was 50-100 mg, though one study reported a daily dose of 300 mg.25 Drug resistance patterns, duration and extent of prior TB treatment, HIV status, and types of ADRs were variably reported. The two most reported adverse event categories were dermal (skin discoloration) and gastrointestinal. As shown in Figure 2, the overall pooled proportion of all adverse events attributed to Cfz was 21.9% (95% CI: [0.0, 46.1%]), though the median frequency of adverse events was 5·1%. The pooled proportion was disproportionately affected by an outlier reporting adverse events in 88·6% (95% CI: [75.4, 96.2%]) of cases.27 Not all reported adverse events required discontinuation of Cfz treatment. From our fixed effects model, the pooled proportion of ADRs requiring discontinuation or withdrawal of Cfz was 0.1% (95% CI: [0.0, 0.6%]), with the frequency of ADRs ranging from 0% (95% CI: [0.0, 1.1%]) to 11·8% (95% CI: [2.0, 35.6%]).

Efficacy

Early in vitro studies of Cfz reported positive bactericidal efficacy of Cfz.29,30,31,32,33 More recent in vitro and in vivo evidence suggests that Cfz also has sustained sterilizing activity against latent or persistent bacterial populations of M. tuberculosis.34 Currently novel analogues of Cfz are

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under investigation with comparable efficacy but shorter half-lives, potentially reducing tissue accumulation and resulting skin pigmentation.35 In vivo studies in mice and hamsters reported significant activity of Cfz, though accumulation in animal tissues may lead to overestimation of drug activity when subsequently plated on solid media.12,30,36,37,38 Earlier studies had showed that Cfz had little or no activity in guinea pig and monkey models.39,40 It was later thought that these poor in vivo results and monotherapy-induced resistance in guinea pigs and monkeys may have been a result of low absorption of the drug by the oral route.29 Recently, Cfz combined with bedaquiline and pyrazinamide has been shown to be superior to the current first-line regimen in reducing colony-forming unit counts at one month in mice.41Cfz combined with the standard second-line regimen also significantly improved culture conversion and relapse prevention, compared with a regimen without Cfz, in mice.42 In addition, the sterilizing activity of bedaquiline and pyrazinamide was significantly improved with the addition of Cfz.43

Effectiveness

In a recent systematic review and meta-analysis of 3,489 patients treated for drug resistant TB across 10 countries, Dey et al. reported a pooled treatment success rate of 62.0% (95% CI: [52.8–71.1%]) from treatment regimens containing Cfz, with success defined as cure and/or treatment completion.44 The success rate in HIV/MDR-TB co-infected patients was not significantly different from the overall success rate. In another systematic review of patients treated with Cfz-containing regimens, Gupta et al. found no significant differences in the proportions with favourable outcomes between MDR- (65%; 95% CI: [52-79%]) and XDR-TB patients (66%; 95% CI: [42-89%]).45 There was substantial variation in estimates of mortality during treatment with Cfz-containing regimens, ranging from 1.0% (95% CI: 0.1%–2.6%) to 63.4% (95% CI: 38.3%–85.0%), though the risk of death attributed solely to Cfz, after adjusting for covariates, was not reported. Further cohort studies showing a favourable effect of Cfz-containing regimens have been reported in Benin,46 South Africa,47 and Ukraine,48 though limited benefit from Cfz was found in studies in Brazil49 and Sri Lanka50. Two clinical trials are currently ongoing involving the investigation of the efficacy and safety of treatment regimens containing Cfz (Table 2). The Global Alliance for TB Drug Development is conducting a Phase 2 study to evaluate the early bactericidal activity of Cfz (dosed at 300 mg for the first two days and 100 mg thereafter) combined with bedaquiline and pyrazinamide, compared with first-line treatment.51 The Phase 3 STREAM trial, sponsored by the International Union Against Tuberculosis and Lung Disease, is comparing a modified MDR-TB treatment regimen, based on the shorter treatment regimens assessed in Bangladesh,16 with regimens based on the current WHO guidelines for MDR-TB treatment. The STREAM trial involves sites in Ethiopia, India, South Africa and Viet Nam.17 Follow up is expected for all patients in the study for 27-33 months, with final results anticipated after October 2016.

Availability, Cost and Demand Forecast

Cfz was registered under the trade name Lamprene™ by Novartis in the U.S. in 1986.52 Quality-assured Cfz is available on very limited quantities for the treatment of MDR-TB patients on a

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patient-named basis through the Global Drug Facility (GDF) mechanism of the Stop TB Partnership, which uses a distributor authorised by Novartis.53,54,55 Securing a steady supply of quality-assured Cfz that can meet the increasing demand for MDR-TB treatment, without jeopardizing the needs of the global programme for leprosy elimination, is currently a major challenge in the response to MDR-TB.56 The price of the 100mg product through the GDF mechanism is US$120.86 per hundred capsules, or roughly US$1.21 per one capsule. The cost of a daily dosage of Cfz varies between US$1.21 (when a 100mg dosage is used) and US$3.63 (when 300 mg are used). Depending on the regimen and dosage, the cost of Cfz can be higher than the cost of a daily dosage of most injectables used in the treatment of intensive phase of MDR-TB treatment. By our calculations, the estimated annual cost of procuring a 24 month-regimen of Cfz will range between $2-$20 million, depending on the number of patients (low estimate: XDR-TB patients only; high estimate: all MDR-TB patients) treated.



consultation in early 2012 on diagnostic definition and treatment options for so-called “totally

drug-resistant TB” concluded, based on expert opinion, that Cfz (at a daily dose of 100mg) and linezolid were likely to be the most effective in the Group 5 category of second-line anti-TB drugs for the treatment of XDR-TB.66 Seven articles were identified from the literature on the national policies, guidelines and practices on the use of Cfz to treat MDR-TB.67,68, 70,71,72,73,74 There has been virtually no published evidence of the use of Cfz in the Russian Federation. The two articles retrieved from the Russian-language literature mention solely that Cfz is included in international guidelines as a third-line therapy but note that the drug is not currently registered in the country.67,68 Cfz was previously registered with the Russian Ministry of Health for the indication of leprosy in 1977 and re-registered in 1989. In 1995, Cfz’s registration was annulled for unknown reasons and was not identifiable through the State Registry of Medical Substances as of May 2013.69

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In India, use of Cfz has been associated with varying degrees of success in a number of settings,

including in TB cases with strains described as so-called “totally drug-resistant.”70 A survey of

the clinical practices in the management of DR-TB cases by chest physicians in the Indian state of Maharashtra found that Cfz was a preferred drug, being included in the treatment regimens by 15 respondents out of the 29 surveyed.71 A number of studies have reported the use of aggressive supervised therapies, including Cfz and other Group 5 drugs such as linezolid and clarithromycin.72,73 In one such study with 14 patients with XDR-TB, only two cases achieved complete cure (defined to be at least five negative culture results for the final 12 months of treatment), compared with four deaths.74

4. DISCUSSION

While data were limited, this study has shown a low proportion of adverse events requiring discontinuation of treatment attributed to Cfz at doses ranging from 50-300mg daily. Our pooled frequency of Cfz ADRs at 0.1% is comparable to the incidence of serious ADRs reported with first-line TB treatment.75 These findings are in line with those made in an unpublished report on spontaneous individual case safety reports (ICSR) submitted between 1976 and 2012 to the WHO’s International Drug Monitoring Programme, which found that Cfz was associated with 288 ICSRs accounting for 674 ADRs (Wang S et al., unpublished data). The three most frequent systemic categories involved in the TB-specific ADRs were central and peripheral nervous system (23.2%), gastrointestinal (17.9%), and skin (16.1%). Our review of preclinical studies of Cfz suggests that this drug has sterilizing activity against M.tb. Observational cohort studies in Bangladesh, Benin, China, Niger, Peru, and Sri Lanka, among other settings, show an association between treatment regimens containing Cfz and favourable outcomes, including shortened treatment duration, and add support to its inclusion by WHO in the Group 5 of drugs to be considered in the management of MDR-TB.58 A high variance in mortality rates of patients receiving Cfz-containing drug combinations is observed in some studies. While these data might be confounded by indication— as patients who receive Cfz-containing regimens tend to be those with broader-spectrum drug resistance patterns and more advanced disease — the increasing use of Cfz should be coupled with strengthening of active pharmacovigilance systems.22 Results from the Phase 3 STREAM and Phase 2 Global TB Alliance trials will help to elucidate further the long-term safety and effectiveness of Cfz in the treatment of MDR-TB. Our analysis is limited by the small number of available studies and published materials on Cfz. As ADRs are often rare, the paucity of clinical investigations with Cfz in the treatment of TB means that our results should be interpreted with some caution. While we attempted to categorise ADRs based on resolution after withdrawal or recurrence with re-challenge, reporting varied across studies, and different thresholds may have been applied to report adverse events and ADRs. In the Xu et al. study, for instance, 39 out of 44 (87%) patients were reported to have experienced adverse events after starting Cfz.27 This high level of adverse events could be attributed to the high frequency of reported skin discolouration (36 patients), a known reaction to Cfz treatment, but only two patients discontinued Cfz altogether. There were also insufficient

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data on extent of prior treatment, drug susceptibility, and HIV status—factors that could result in varying severity of disease. Another limitation was that we considered participants in our meta-analysis as those with at least one ADR while being treated with Cfz, rather than cumulatively counting multiple ADRs that may have been experienced. In addition, to review the global landscape of policies and regulatory actions relating to Cfz, we relied on databases, search engines, and manual searches which are biased in favour of English-language publications. Many more national and local policies may exist that were not captured by this paper. The use of Cfz in the clinical settings where MDR-TB patients are treated has been increasing over the last two decades. The progress countries are making towards universal access to diagnosis and treatment of MDR-TB76 is resulting in sustained and increasing demand for this product, at least until more new and effective drugs are available. The GDF’s projected forecast based on the ongoing global scale up of MDR-TB management suggests that the current quality-assured supply line is insufficient to meet this demand. GDF and the Global Fund regularly publish joint invitations to manufacturers of first, second and third-line anti-tuberculosis medicines to submit an Expression of Interest for TB drug products evaluation by the Expert Review Panel. However, to date, no successful review of clofazimine has been reported through this mechanism. To improve access to the drug, generic manufacturers that can complement Novartis’ production capacity should be identified. The inclusion of more manufacturers in the market may also contribute to a reduction in the cost of the drug, further improving access. Despite these limitations, this paper underscores the potential value of Cfz’s inclusion in the treatment regimens for MDR- and XDR-TB cases. However, even if the ongoing clinical trials and observational studies confirm the earlier findings reviewed here, much more will need to be done to make Cfz both available and affordable.

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Acknowledgements

The authors thank Shu-Hua Wang for help with data from the WHO’s International Drug Monitoring Programme. The authors also thank the editor and two reviewers at the journal for their review of the manuscript.

Contributors


Funding

TJH and SD were supported by fellowships from the Harvard Kennedy School Institute of Politics. TJH also received a research grant for this study from the Dunwalke Fund at Harvard University.

Competing Interests

SK has received partial salary support through a grant from the Eli Lilly Foundation’s MDR-TB Partnership to Brigham and Women’s Hospital. DF, DFW, EJ, KL, and KW are staff members of WHO. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of WHO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Data Sharing

The dataset is available from the corresponding author.

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N. given Cfz

Daily Cfz dose (mg)










427 50-100

Xu et al., 201227


2.2 ± 1.7 (Cfz); 2.1 ± 1.3 (non-

Cfz)





65 50-100





17





Phase II 2012-2013 NC-003 (NCT01691534)

51




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57,58




59,60




59


61




Not stated.

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Figure 2 Forest plot of all reported adverse events associated with or ADRs attributed to clofazimine and clofazimine-containing regimens Pooled estimates using inverse-variance weighted fixed effects (F-E) and random effects (R-E) models are shown. The random effects model was used for adverse events estimates (I2=98.7%; P<0.001) and fixed effects for ADRs (I2=11.5%; P=0.34).

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Chemother 2002;49(2):275-82. 34 Xu J, Lu Y, Fu L, et al. In vitro and in vivo activity of clofazimine against Mycobacterium tuberculosis persisters. Int J Tuberc Lung

Dis 2012;16(8):1119-25. 35 Lu Y, Zheng M, Wang B, et al. Clofazimine analogs with efficacy against experimental tuberculosis and reduced potential for accumulation. Antimicrob Agents Chemother 2011 Nov;55(11):5185-93. 36 Adams LB, Sinha I, Franzblau SG, et al. Effective treatment of acute and chronic murine tuberculosis with liposome-encapsulated clofazimine. Antimicrob Agents Chemother 1999;43(7):1638-43. 37 Barry VC, Conalty ML. Antituberculosis activity in the phenazine series. Am Rev Tuberc 1958;78:62-73. 38 Vischer WA. The experimental properties of G30320 (B663)—a new antileprotic agent. Leprosy Rev 1969;40:107-10. 39 Steenken W Jr, Montalbine V, Smith MM. Antituberculous activity of rimino compound of the phenazine series. Am Rev Respir Dis 1960;81:764–767. 40 Schmidt LH, Hoffman R, Jolly PN. Induced pulmonary tuberculosis in the rhesus monkey: its usefulness in evaluating chemotherapeutic agents. Proceedings of 14


31. 41 Tasneen R, Li SY, Peloquin CA, et al. Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. Antimicrob Agents Chemother 2011;55(12):5485-92. 42 Grosset JH, Tyagi S, Almeida DV, et al. Assessment of clofazimine activity in a second-line regimen for tuberculosis in mice. Am J Respir Crit Care Med 2013 Jul 3. [Epub ahead of print] 43 Williams K, Minkowski A, Amoabeng O, et al. Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis. Antimicrob Agents Chemother 2012;56(6):3114-20. 44 Dey T, Brigden G, Cox H, et al. Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother 2013;68(2):284-93. 45 Gopal M, Padayatchi N, Metcalfe JZ, et al. Systematic review of clofazimine for the treatment of drug-resistant tuberculosis. Int J

Tuberc Lung Dis 2013;17(8):1001-7. 46 Kassa F, Affolabi D, Ade G, et al. Successful 12-month treatment for multidrug-resistant tuberculosis patients in Benin. In: The 43rd World Congress on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union), Kuala Lumpur, Malaysia, 2012. p. S310. 47 Gopal M, Naidoo R, O’Donnell M, et al. A retrospective cohort study of clofazimine in the treatment of extensively drug-resistant tuberculosis in South Africa. In: The 43rd World Congress on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union), Kuala Lumpur, Malaysia, 2012. p. S214. 48 Lyepshina S, Serduk O, Tyshchenko H. Treatment results of clofazimine used in the management of multidrug-resistant tuberculosis patients during the intensive phase of treatment. In: The 43rd World Congress on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union), Kuala Lumpur, Malaysia, 2012. p. S216. 49 Braga JU, Bastos LGV, Rocha JL, et al. Effectiveness of a therapeutic regimen using clofazimine for MDR-TB treatment in Brazil. In: The 42nd World Congress on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union), Lille, France, 2011. p. S320. 50 Senaratne WV. Outcome of treatment of multidrug resistant tuberculosis. Ceylon Med J 2004;49(3):86-7. 51 Evaluation of early bactericidal activity in pulmonary tuberculosis with clofazimine (C)-TMC207 (J)-PA-824 (Pa)-pyrazinamide (Z) (NC-003). Identifier: NCT01691534. Available from: <http://clinicaltrials.gov/ct2/show/NCT01691534> 52 US FDA. Orange Book: Clofazimine (Lamprene). FDA, 2013. 53 Green Light Committee Initiative. Annual Report 2008. Geneva, Switzerland: WHO/STP, 2009. 54 WHO. Multidrug therapy (MDT): Use of clofazimine for treating ENL reactions in leprosy [Online]. Geneva, Switzerland: WHO. Accessed from: <http://www.who.int/lep/mdt/clofazimine/en/index.html> 55 Medecins Sans Frontières. DR-TB drugs under the microscope: Sources and prices for drug-resistant tuberculosis medicines, 2nd edition. MSF, 2012. 56 WHO. Global Green Light Committee meeting report. Geneva, Switzerland: WHO, 2012. Accessed from: <http://www.who.int/tb/challenges/mdr/greenlightcommittee/Meetingreport2ndgGLCmeeting.pdf> 57 WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB 2008.402. Geneva, Switzerland: WHO, 2008.

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58 WHO. Guidelines for the programmatic management of drug-resistant tuberculosis – 2011 update. WHO/HTM/TB 2011.6. Geneva, Switzerland: WHO, 2011. 59 WHO. Guidelines for the management of severe erythema nodosum leprosum (ENL) reactions. Geneva, Switzerland: WHO. Accessed from: <http://www.who.int/lep/research/WHOenlguide.pdf> 60 WHO. Guide to eliminate leprosy as a public health problem. WHO/CDS/CPE/CEE/2000.14. Geneva, Switzerland: WHO, 2000. 61 US FDA. Label and Prescribing Information: Lamprene® (Novartis). FDA, 1998. 62 WHO. WHO Model List of Essential Medicines, 17th edition. Geneva, Switzerland: WHO, 2011. 63 WHO. WHO Model List of Essential Medicines for Children, 3rd edition. Geneva, Switzerland: WHO, 2011. 64 WHO. New Memorandum of Understanding for MDT. Geneva, Switzerland: WHO, 2010. 65 Worobec SM. Current approaches and future directions in the treatment of leprosy. Res Rep Trop Med 2012;3:79-91. 66 WHO. “Totally Drug-Resistant TB”: A WHO consultation on the diagnostic definition and treatment options. Geneva, Switzerland: WHO, 2012. 67 Borisov GB, Sokolova. Etiotropnoe lechenie tuberkuleza pri lekarstvennoj ustojchivosti M. tuberculosis: vzglyady I rekomendatsii mezhdunarodnyh organizatsij. Consilium Medicum 2001;3:12. 68 Chukanov VI. Problema izlecheniya bolnyh tuberkulezom organov dynahiya. Central Scientific Research Institute of Tuberculosis of Russian Academy of Sciences. 954. 69 Russian State Registry of Medical Substances. Lamprene (Лампрен). Accessed from: <http://grls.rosminzdrav.ru/> 70 Udwadia Z, Vendoti D. Totally drug-resistant tuberculosis (TDR-TB) in India: Every dark cloud has a silver lining. J Epidemiol

Community Health 2013;67(6):471-2. 71 Udwadia ZF, Amale RA, Ajbani KK, et al. Totally drug-resistant tuberculosis in India. Clin Infect Dis 2012;54(4):579-81. 72 Dutta NK, Karakousis PC. Tuberculosis chemotherapy: Present situation, possible solutions, and progress towards a TB-free world. Indian J Med Microbiol 2012;30(3):261-3. 73 Prasad M, Shashirekha K, Bhattacharyya D, et al. Extensively drug-resistant (XDR) pulmonary tuberculosis in HIV negative cases. In: The ERS Annual Congress (Session 252-The Challenge of Multidrug-Resistant Tuberculosis), Berlin, Germany, 2008. p.441s 74 Prasad M, Rai S, Falleiro J, et al. Prevalence and treatment outcome of drug resistant pulmonary tuberculosis in HIV negative cases – experience from a tuberculosis treatment center in India. In: The ERS Annual Congress (Session 400-Multi/Extensively-drug resistant tuberculosis), Vienna, Austria, 2009. p.4447. 75 Yee D, Valiquette C, Pelletier M, et al. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003;167(11):1472-7. 76 Falzon D, Jaramillo E, Wares F, et al. Universal access to care for multidrug-resistant tuberculosis: an analysis of surveillance data. Lancet Infectious Dis 2013: In Press. doi:10.1016/S1473-3099(13)70130-0.

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Supplemental Appendix for: “Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis:

Analysis of published guidance and meta-analysis of cohort studies” The following appendix provides more detail on the data and methods used to conduct our systematic review and meta-analysis. The appendix is comprised of the following: A. Statistical Methodology B. Meta-analysis of Observational Studies in Epidemiology (MOOSE) Checklist C. Study Protocol A. Statistical Methodology We calculated the I2 and heterogeneity χ2 statistics to assess the relative proportionate effects of heterogeneity and chance on total variation across data points. From this analysis, we determined that the DerSimonian and Laird random effects model was more appropriate for pooling estimates of adverse event frequencies (I2=98.7%; P<0.001), whereas the inverse-variance weighted fixed effects model was used for ADRs (I2=11.5%; P=0.34).1 2 The calculation and interpretation of rare events through standard meta-analytic methods is complicated by the fact that most methods are based on approximations of large samples.3 4 As adverse drug reactions were rare in our included studies, we conducted a post hoc analysis to calculate the confidence intervals of prevalence proportions using the Wilson score method.5 We report the comparison of the 95% CI using the two methods: 95% CI using DL/IV 95% CI using Wilson All adverse events Study 25 (2.03, 35.59) (3.29, 34.34) Study 26 (0.52, 17.79) (1.42, 16.89) Study 16 (0.00, 1.07) (0.00, 0.89) Study 27 (75.57, 95.50) (76.02, 95.05) Study 28 (1.06, 13.23) (1.58, 12.71) ADRs Study 25 (2.03, 35.59) (3.29, 34.34) Study 26 (0.52, 17.79) (1.42, 16.89) Study 16 (0.00, 1.07) (0.00, 0.89) Study 27 (0.42, 15.97) (1.26, 15.13) Study 28 (0.00, 6.68) (0.00, 5.58)

1 DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7:177-188. 2 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-58. 3 Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med 2007;26:53-77. 4 Cai T, Parast L, Ryan L. Meta-analysis for rare events. Stat Med 2010;29:2078-89. 5 Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998;17:857-72.

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2

B. MOOSE Checklist Manuscript Title: “Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis: Analysis of published guidance and meta-analysis of cohort studies”

Criteria Brief description of how the criteria were handled in the meta-analysis

Reporting of background should include

√ Problem definition Given the spread of multidrug-resistant tuberculosis (MDR-TB), new therapies are urgently needed, including the repurposing of existing drugs. We aimed to assess the safety of clofazimine (Cfz), a riminophenazine with anti-mycobacterial activity currently used to treat leprosy.

√ Hypothesis statement The use of Cfz is associated with a risk of adverse drug reactions (ADR) comparable to that of first-line TB treatment.

√ Description of study outcomes Prevalence of adverse events Prevalence of ADRs (Definitions of AEs and ADRs provided in text)

√ Type of exposure or intervention used

Clofazimine and/or clofazimine-containing regimens for treatment of TB

√ Type of study designs used All study designs were included but only cohort studies were identified

√ Study population No restriction applied Reporting of search strategy should include

√ Qualifications of searchers The credentials of the three investigators (who contributed to the search strategy) TH, SD, FW are indicated in the authors list and the Acknowledgments section.

√ Search strategy, including time period included in the synthesis and keywords

Medline, EMBASE, Cochrane Library until May 2013 See Methodology

√ Databases and registries searched

Medline, EMBASE, Cochrane Library World Health Organization, US FDA, EMA

√ Search software used, name and version, including special features

We detailed the MeSH Headings and text words in the the Methods section

√ Use of hand searching Bibliographies of the retrieved papers were hand searched for additional references.

√ List of citations located and those excluded, including justifications

Details of the literature search process are outlined in the flow chart (Figure 1).

√ Method of addressing articles published in languages other than English

We placed no restrictions on language; We were able to obtained all articles potentially eligible for inclusion in English language

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√ Method of handling abstracts and unpublished studies

We contacted a number of authors for full report of relevant unpublished studies

√ Description of any contact with authors

We contacted authors of relevant articles for full report of their unpublished studies, or for extra data about adverse events prevalence. Details of the authors who provided extra unpublished information available upon request.

Reporting of methods should include

√ Description of relevance or appropriateness of studies assembled for assessing the hypothesis to be tested

Detailed inclusion and exclusion criteria are described in the paper

√ Rationale for the selection and coding of data

A data extraction sheet was developed (available on request). Data on study characteristics, methodological quality, and results were independently extracted from each selected article

√ Assessment of confounding We conducted a subgroup analysis for adverse drug reactions only versus all adverse events

√ Assessment of study quality, including blinding of quality assessors; stratification or regression on possible predictors of study results

We assessed risks of bias according to the Cochrane Collaboration’s risk of bias framework comprising five primary domains: (1) selection bias (random sequence generation and allocation concealment); (2) performance bias (masking of outcomes of interest for participants and study investigators); (3) detection bias (blinding of outcome assessors); (4) attrition bias (incomplete outcome data); and (5) reporting bias (selective outcome reporting).

√ Assessment of heterogeneity We used the I2 value to assess heterogeneity √ Description of statistical

methods in sufficient detail to be replicated

We mentioned type of analysis we used (meta-analysis and subgroup meta-analysis) and type of software we used (Stata). Additional detail in the Appendix

√ Provision of appropriate tables and graphics

We included a flow chart to show the method of studies identification (Figure 1), Table 1 showing characteristics of included studies, Table 3 showing characteristics of reviewed guidance documents, and Figure 2 the forest plot with subgroup analyses

Reporting of results should include

√ Graph summarizing individual study estimates and overall estimate

Figure 2

√ Table giving descriptive information for each study included

Table 1

√ Results of sensitivity testing

Figure 2

√ Indication of statistical uncertainty of findings

95% CI intervals were presented for all analyses together with I2 values for the meta-analysis

Reporting of discussion should include

√ Quantitative assessment of Results of subgroup analyses are discussed in the

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bias Results and Discussion sections. Risk of publication bias is provided in the Appendix

√ Justification for exclusion Reasons for exclusion were reported in Figure 1 √ Assessment of quality of

included studies Included in the Discussion, mentioned with respect to the fact that there was a “paucity of clinical investigations with Cfz in the treatment of TB”

Reporting of conclusions should include

√ Consideration of alternative explanations for observed results

We mentioned in the Discussion that there were few included studies, which may introduce some bias into our results.

√ Generalization of the conclusions

Our results are specific to the use of Cfz

√ Guidelines for future research Further research in the form of randomized controlled trials assessing the use of Cfz-regimens for shortening MDR-TB treatment duration is currently ongoing and discussed in the paper.

√ Disclosure of funding source Funding statement was provided. C. Study Protocol (on following pages)

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Clofazimine Meta-Analysis Study Protocol v2 16 August 2012

Safety and Availability of Clofazimine in the Treatment of Multidrug and Extensively Drug-Resistant Tuberculosis

Preliminary Study Protocol

Background The global incidence of multi-drug resistant tuberculosis (MDR-TB) is estimated to number half a million annually. In the short- to medium-term future, the number of MDR-TB cases is expected to grow significantly. The rise of MDR-strains has highlighted the urgency and need not only for the development of new drugs but also, in the interim, of incorporating older agents into treatment programmes for MDR-TB cases. However, the evidence base for these second-line drugs is limited, preventing more widespread use. One potential candidate for repurposing is clofazimine, a riminophenazine with anti-mycobacterial activity currently used to treat leprosy. There has been growing interest from several high-burden countries of the use of clofazimine for TB, especially cases of multidrug- and extensively drug-resistant TB (XDR-TB). Objectives

1. Determine the prevalence of adverse events and adverse drug events due to clofazimine using meta-analysis;

2. Assess the evidence relating to efficacy and effectiveness of clofazimine in treatment of MDR- and XDR-TB; and

3. Review published guidance, policy documents, and other sources for information relating to the management and cost of clofazimine

Methods Study eligibility • Human studies in treatment of tuberculosis and/or drug-resistant tuberculosis; • Study publication between 1950 and May 2013; • Treatment using clofazimine or clofazimine-containing regimen; • No language restrictions Search strategy We will search PubMed, MEDLINE, Embase, and Cochrane Library databases using the following key words and Medical Subject Heading terms, and combinations thereof: ‘clofazimine’, ‘B663’, Lamprene’, ‘tuberculosis’, ‘side effects’, ‘adverse events’, ‘adverse drug reactions’, ‘sequella’, ‘toxicity’, ‘tolerability’, ‘outcomes’, ‘treatment’, ‘effectiveness’, ‘efficacy’, ‘cure’, ‘success’, ‘guideline’, ‘treatment’, or ‘safety’.

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We will also manually review conference abstracts from the annual Union World Conference on Lung Health and contact researchers of selected abstracts. For policy guidelines and drug labels, we will manually search the electronic publications and websites of the World Health Organization, U.S. Food and Drug Administration, and the European Medicines Agency (EMA), in addition to searches using the database above and conventional online search engines. Data extraction The key domains for data extraction are:

1. Study characteristics 2. Outcomes 3. Methodological quality, i.e. assessment of risk of bias

The following fields will be collected for each of the included studies:

1. Author 2. Study location 3. Study design 4. Observation period/study period 5. Number of patients treated (total, with clofazimine) 6. Patient age (mean, range) 7. Sex 8. Drug resistance profile 9. Prior treatment with second-line TB drugs 10. HIV status 11. Treatment regimen with clofazimine 12. Dosage of clofazimine 13. Duration of treatment (with and without clofazimine) 14. Treatment outcomes 15. Number and type of adverse events, by agent 16. Number and type of adverse drug reactions, by agent 17. Rate of discontinuation (if different from #16)

We define adverse drug reactions using challenge-dechallenge, attributing an ADR to clofazimine if discontinuation of the drug or reduction in the dosage leads to reported disappearance of the toxicity. We will then calculate the prevalence as a proportion relative to the total number of drug-receiving patients. For each of the included studies, we will identify and assess risks of bias according to the Cochrane Collaboration’s risk of bias framework comprising five primary domains: (1) selection bias (random sequence generation and allocation concealment); (2)

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performance bias (masking of outcomes of interest for participants and study investigators); (3) detection bias (blinding of outcome assessors); (4) attrition bias (incomplete outcome data); and (5) reporting bias (selective outcome reporting). Risk of bias for each domain will be categorised as low, high, or unclear, and used to make judgments about the overall risk of bias for each study. Statistical analysis We will calculate point estimates and 95% confidence intervals (CI) for the frequency of adverse events and ADRs. Then, we will calculate the I2 and heterogeneity χ2 statistics to assess the relative proportionate effects of heterogeneity and chance on total variation across data points. From this analysis, we will use either the DerSimonian and Laird random effects model or the inverse-variance weighted fixed effects model, depending on the I2 statistic.

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Figure 1

134x120mm (300 x 300 DPI)

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Figure 2

162x122mm (300 x 300 DPI)

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Safety and availability of clofazimine in the treatment of multidrug and extensively drug-

resistant tuberculosis: Analysis of published guidance and meta-analysis of cohort studies

Thomas J. Hwang,†,1,2 Svetlana Dotsenko,†,1 Azizkhon Jafarov,§,3 Karin Weyer,§,3 Dennis

Falzon,§,3 Kaspars Lunte,*,4 Paul Nunn,**,5 Ernesto Jaramillo,§,3 Salmaan Keshavjee,††,6* Douglas F. Wares§Wares3*

† Author Affiliations: 1 Faculty of Arts and Sciences, Harvard University, Cambridge, Massachusetts USA §2 Program on Regulation, Therapeutics, and Law, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, USA 3 Global TB Programme, World Health Organization, Geneva, Switzerland *4 Global Drug Facility, Stop TB Partnership and World Health Organization, Geneva, Switzerland **5 Global Infectious Disease Consulting, London, UK ††6 Program in Infectious Disease and Social Change, Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA Correspondence to* These individuals contributed equally as senior authors. Corresponding Authors: Thomas Hwang and Douglas Wares. Email: [email protected] Keshavjee. Emails: [email protected], [email protected] Date: November 11, 2013 Word Count: 3,048 (excluding abstract, references, exhibits, and acknowledgements) Keywords: Clofazimine, safety, clinical practice, meta-analysis, drug resistant tuberculosis.

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ABSTRACT




• This study shows that the burden of safety issues associated with Cfz use appears to be manageable by national TB programmes. The widespread use of Cfz is limited by low availability and relatively high cost.

• Few studies were included in the meta-analysis since only a smaller number of trialsstudies have been conducted with clofazimine. Further research is needed.

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Clofazimine Paper – WHO & Harvard | 27 SeptemberBMJ Open | 11 November 2013 | Page 3

1. INTRODUCTION Drug-resistant strains of tuberculosis (TB) pose a serious obstacle to progress in global TB control.1 In 2011, there were an estimated half a million new cases of multidrug-resistant tuberculosis (MDR-TB; resistance to, at least, rifampicin and isoniazid) worldwide.2 Extensively drug-resistant (XDR-TB) cases, a form of MDR-TB with additional resistance to any fluoroquinolone and an injectable second-line drug, have been identified in 84 countries.2,3 Recent survey evidence from Belarus reported nearly one in two of all enrolled TB patients had MDR-TB, the highest proportion of MDR ever recorded.4 The recent approval of bedaquiline by the United States Food and Drug Administration (FDA), the first drug developed for TB treatment in nearly a half-century, and the filing of delamanid with the European Medicines Agency (EMA), are promising developments for treatment of TB.5,6 However, the management of drug-resistant strains of Mycobacterium tuberculosis (M.tb) necessitates new effective treatment regimens, composed of at least four effective drugs. In light of the limited treatment options available for patients affected by severe patterns of drug-resistant TB, some have recommended repurposing older drugs, though there are significant concerns with the adverse drug reaction (ADR) profiles and long term safety of several agents, and conflicting evidence of their efficacy.7,8 One potential candidate to be repurposed is clofazimine (Cfz), a riminophenazine derived from a R-substitution at the imino group.9 Cfz has apparent anti-mycobacterial and anti-inflammatory activity, though its precise mechanism of action is still unclear.10 The drug is known to be highly lipophilic, accumulating in fatty tissues with uptake by human mononuclear phagocytes, the same cells infected by M. tb.11 Cfz also appears to exhibit a property uniquely relevant for tuberculosis treatment: despite its long half-life and accumulation in tissue, the risk of developing resistance is relatively low.12 Although Cfz was originally developed for the treatment of tuberculosis, its current medical indication is for the treatment of multi- and paucibacillary leprosy, including severe erythema nodosum leprosum reactions in leprosy patients.13 While in vitro studies suggested high anti-TB activity, poor in vivo results in the mid-1950s led to the abandonment of clinical development as an anti-tuberculosis agent.14,15 In the past decade, there has been renewed and growing interest in the use of Cfz as an anti-TB agent. An MDR-TB treatment observational study conducted in Bangladesh showed favourable outcomes, even with a significantly shorter treatment duration than the current WHO recommended regimen.16 A multi-country randomised control trial to evaluate a standardised nine-month regimen containing Cfz for the treatment of MDR-TB is currently under way, and observational cohort studies are being conducted in some West African countries.17 Given the growing evidence supporting the use of Cfz in the treatment of patients with MDR- and XDR-TB treatment, we sought to assess the key considerations, including safety, effectiveness, management, and cost, in relation to the programmatic and clinical use of Cfz by national TB programmes (NTP).

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2. METHODS


Our meta-analysis and systematic review were conducted using a prospective protocol according to MOOSE (Meta-analysis of Observational Studies in Epidemiology) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines for reporting systematic reviews of observational study results (Supplementary Material online).18,19 Studies published between 1950 and May 2013 were identified from an electronic search of the PubMed, MEDLINE, Embase, and Cochrane Library databases. The key words and Medical Subject Heading terms included: ‘clofazimine’, ‘B663’, Lamprene’, ‘tuberculosis’, ‘side effects’, ‘adverse events’, ‘adverse drug reactions’, ‘sequella’, ‘toxicity’, ‘tolerability’, ‘outcomes’, ‘treatment’, ‘effectiveness’, ‘efficacy’, ‘cure’, ‘success’, ‘guideline’, ‘treatment’, or ‘safety’. We contacted researchers and manually collected references of all retrieved articles, selected review articles, clinical trial registration notices, and conference abstracts, as needed. These additional studies were merged with our search results, following exclusion of non-relevant or duplicate citations. Policy guidelines and drug label information were retrieved from manual searches of World Health Organization publications, as well as those of two stringent regulatory agencies, the US FDA and EMA. Outcome Variables and Data Extraction

The primary aims of our study was to perform a meta-analysis of the safety of Cfz from published studies and a systematic analysis of the effectiveness, management, and cost of Cfz from the peer-reviewed literature as well as published guidance. For our safety analysis, our primary outcomes of interest were adverse events and adverse drug reactions (ADR). We defined an adverse drug reaction (ADR) as an appreciably harmful or unpleasant reaction caused by a drug that is serious enough to warrant the discontinuation or revision of treatment.20 In contrast, an adverse event included any undesirable reactions reported by patients or clinicians, including mild reactions that had no bearing on treatment. Since the use of the term “adverse event” and “serious adverse events” was inconsistent in the reviewed studies and the criteria for judging an adverse event as serious were not consistently reported, we used ADR as a measure of Cfz’s safety profile. Using methods described previously,21 we used challenge-dechallenge to evaluate ADR data: a reaction was attributed solely to Cfz if discontinuation of the drug or reducing the dose led to reported disappearance of the toxicity.22

Prevalence (%) was measured as a proportion relative to the total number of drug-receiving patients. Data on study characteristics, methodological quality, and results were independently extracted from each selected article using a pre-defined extraction form by two authors (TJH and SD). This form captured: author, study location, study design, observation period, number of patients treated, patient age, sex and reported race or ethnicity, drug resistance profile, prior treatment with second-line drugs, HIV status, treatment regimen with Cfz, dosage, duration of treatment, treatment outcomes, reported ADRs by agent and rate of discontinuation. An additional author (DFW) independently assessed the validity of included citations and extracted data.

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Since serious adverse events and the criteria for judging an adverse event as serious were not consistently reported, we used ADR as a measure of Cfz’s safety profile, using methods described elsewhere.23,24 Briefly, challenge-dechallenge was used to evaluate ADR data: a reaction was attributed solely to Cfz if discontinuation of the drug or reducing the dose led to reported disappearance of the toxicity.25,26 Prevalence (%) was measured as a proportion relative to the total number of drug-receiving patients. Statistical Analysis

We calculated point estimates and 95% confidence intervals (CI) for the frequency of adverse events and ADRs. We then calculatedassessed the I2 and heterogeneity χ2 statistics to assess the relative proportionate effectsbetween studies using the I2 statistic, which reports the proportion of total variance across studies that is due to between-study heterogeneity and chancerather than by randomness (Appendix). Based on total variation across data points. From this analysisassessment, we determined that used the DerSimonian and Laird random effects model was more appropriate for pooling estimates and calculating 95% CI of adverse event frequencies (I2=98.7%; P<0.001),27 whereas, and the inverse-variance weighted fixed effects model was used for ADRs (I2=11.5%; P=0.34).. 28 29 Since some studies reported no ADRs, we also performed a post hoc sensitivity analysis to calculate 95% CI of adverse events and ADRs using the Wilson score method and found that the intervals did not differ significantly. We defined statistical significance at the P < 0.05 level. Forest plots illustrate the distributions of pooling adverse event data by various stratification criteria. Statistical analyses were performed using Stata (version 1012.0, Stata Corp, College Station, TX, USA)..).

3. RESULTS

Safety

From 1,248 citations identified by our search strategy, 147 were selected for full-text review (Figure 1). A total of five studies were subsequently included in the review for safety. The characteristics of the five selected studies with safety data are summarised in Table 1.16,30,31,32,33 Of the total 861 participants, 602 patients received Cfz as part of their TB treatment regimens. The study periods ranged from 1993 to 2012. The average study population was 144 patients (range: 10-427). The daily dose range of Cfz administered in clinical settings was 50-100 mg, though one study reported a daily dose of 300 mg.30 Drug resistance patterns, duration and extent of prior TB treatment, HIV status, and types of ADRs were variably reported. The two most reported adverse event categories were dermal (skin discoloration) and gastrointestinal. As shown in Figure 2, the overall pooled proportion of all adverse events attributed to Cfz was 21.9% (95% CI: [0.0, 46.1%]), though the median frequency of adverse events was 5·1%. The pooled proportion was disproportionately affected by an outlier reporting adverse events in 88·6% (95% CI: [75.4, 96.2%]) of cases.32

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Not all reported adverse events required discontinuation of Cfz treatment. From our fixed effects model, the pooled proportion of ADRs requiring discontinuation or withdrawal of Cfz was 0.1% (95% CI: [0.0, 0.6%]), with the frequency of ADRs ranging from 0% (95% CI: [0.0, 1.1%]) to 11·8% (95% CI: [2.0, 35.6%]).

Efficacy

Early in vitro studies of Cfz reported positive bactericidal efficacy of Cfz.34,35,36,37,38 More recent in vitro and in vivo evidence suggests that Cfz also has sustained sterilizing activity against latent or persistent bacterial populations of M. tuberculosis.39 Currently novel analogues of Cfz are under investigation with comparable efficacy but shorter half-lives, potentially reducing tissue accumulation and resulting skin pigmentation.40 In vivo studies in mice and hamsters reported significant activity of Cfz, though accumulation in animal tissues may lead to overestimation of drug activity when subsequently plated on solid media.12,35,41,42,43 Earlier studies had showed that Cfz had little or no activity in guinea pig and monkey models.44,45 It was later thought that these poor in vivo results and monotherapy-induced resistance in guinea pigs and monkeys may have been a result of low absorption of the drug by the oral route.34 Recently, Cfz combined with bedaquiline and pyrazinamide has been shown to be superior to the current first-line regimen in reducing colony-forming unit counts at one month in mice.46Cfz combined with the standard second-line regimen also significantly improved culture conversion and relapse prevention, compared with a regimen without Cfz, in mice.47 In addition, the sterilizing activity of bedaquiline and pyrazinamide was significantly improved with the addition of Cfz.48

Effectiveness

In a recent systematic review and meta-analysis of 3,489 patients treated for drug resistant TB across 10 countries, Dey et al. reported a pooled treatment success rate of 62.0% (95% CI: [52.8–71.1%]) from treatment regimens containing Cfz, with success defined as cure and/or treatment completion.49 The success rate in HIV/MDR-TB co-infected patients was not significantly different from the overall success rate. In another systematic review of patients treated with Cfz-containing regimens, Gupta et al. found no significant differences in the proportions with favourable outcomes between MDR- (65%; 95% CI: [52-79%]) and XDR-TB patients (66%; 95% CI: [42-89%]).50 There was substantial variation in estimates of mortality during treatment with Cfz-containing regimens, ranging from 1.0% (95% CI: 0.1%–2.6%) to 63.4% (95% CI: 38.3%–85.0%), though the risk of death attributed solely to Cfz, after adjusting for covariates, was not reported. Further cohort studies showing a favourable effect of Cfz-containing regimens have been reported in Benin,51 South Africa,52 and Ukraine,53 though limited benefit from Cfz was found in studies in Brazil54 and Sri Lanka55. Two clinical trials are currently ongoing involving the investigation of the efficacy and safety of treatment regimens containing Cfz (Table 2). The Global Alliance for TB Drug Development is conducting a Phase 2 study to evaluate the early bactericidal activity of Cfz (dosed at 300 mg for the first two days and 100 mg thereafter) combined with bedaquiline and pyrazinamide, compared with first-line treatment.56 The Phase 3 STREAM trial, sponsored by the International

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Union Against Tuberculosis and Lung Disease, is comparing a modified MDR-TB treatment regimen, based on the shorter treatment regimens assessed in Bangladesh,16 with regimens based on the current WHO guidelines for MDR-TB treatment. The STREAM trial involves sites in Ethiopia, India, South Africa and Viet Nam.17 Follow up is expected for all patients in the study for 27-33 months, with final results anticipated after October 2016. Availability, Cost and Demand Forecast

Cfz was registered under the trade name Lamprene™ by Novartis in the U.S. in 1986.57 Quality-assured Cfz is available on very limited quantities for the treatment of MDR-TB patients on a patient-named basis through the Global Drug Facility (GDF) mechanism of the Stop TB Partnership, which uses a distributor authorised by Novartis.58,59,60 Securing a steady supply of quality-assured Cfz that can meet the increasing demand for MDR-TB treatment, without jeopardizing the needs of the global programme for leprosy elimination, is currently a major challenge in the response to MDR-TB.61 The price of the 100mg product through the GDF mechanism is US$120.86 per hundred capsules, or roughly US$1.21 per one capsule. The cost of a daily dosage of Cfz varies between US$1.21 (when a 100mg dosage is used) and US$3.63 (when 300 mg are used). Depending on the regimen and dosage, the cost of Cfz can be higher than the cost of a daily dosage of most injectables used in the treatment of intensive phase of MDR-TB treatment. By our calculations, the estimated annual cost of procuring a 24 month-regimen of Cfz will range between $2-$20 million, depending on the number of patients (low estimate: XDR-TB patients only; high estimate: all MDR-TB patients) treated.



consultation in early 2012 on diagnostic definition and treatment options for so-called “totally drug-resistant TB” concluded, based on expert opinion, that Cfz (at a daily dose of 100mg) and linezolid were likely to be the most effective in the Group 5 category of second-line anti-TB drugs for the treatment of XDR-TB.71

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Seven articles were identified from the literature on the national policies, guidelines and practices on the use of Cfz to treat MDR-TB.72,73, 75,76,77,78,79 There has been virtually no published evidence of the use of Cfz in the Russian Federation. The two articles retrieved from the Russian-language literature mention solely that Cfz is included in international guidelines as a third-line therapy but note that the drug is not currently registered in the country.72,73 Cfz was previously registered with the Russian Ministry of Health for the indication of leprosy in 1977 and re-registered in 1989. In 1995, Cfz’s registration was annulled for unknown reasons and was not identifiable through the State Registry of Medical Substances as of May 2013.74 In India, use of Cfz has been associated with varying degrees of success in a number of settings,

including in TB cases with strains described as so-called “totally drug-resistant.”75 A survey of the clinical practices in the management of DR-TB cases by chest physicians in the Indian state of Maharashtra found that Cfz was a preferred drug, being included in the treatment regimens by 15 respondents out of the 29 surveyed.76 A number of studies have reported the use of aggressive supervised therapies, including Cfz and other Group 5 drugs such as linezolid and clarithromycin.77,78 In one such study with 14 patients with XDR-TB, only two cases achieved complete cure (defined to be at least five negative culture results for the final 12 months of treatment), compared with four deaths.79

4. DISCUSSION

ThisWhile data were limited, this study has shown a low proportion of adverse events requiring discontinuation of treatment attributed to Cfz at doses ranging from 50-300mg daily. Our pooled frequency of Cfz ADRs at 0.1% is comparable to the incidence of serious ADRs reported with first-line TB treatment.80 These findings are in line with those made in an unpublished report on spontaneous individual case safety reports (ICSR) submitted between 1976 and 2012 to the WHO’s International Drug Monitoring Programme, which found that Cfz was associated with 288 ICSRs accounting for 674 ADRs (Wang S et al., unpublished data). The three most frequent systemic categories involved in the TB-specific ADRs were central and peripheral nervous system (23.2%), gastrointestinal (17.9%), and skin (16.1%). Our review of preclinical studies of Cfz suggests that this drug has sterilizing activity against M.tb. Observational cohort studies in Bangladesh, Benin, China, Niger, Peru, and Sri Lanka, among other settings, show an association between treatment regimens containing Cfz and favourable outcomes, including shortened treatment duration, and add support to its inclusion by WHO in the Group 5 of drugs to be considered in the management of MDR-TB.63 A high variance in mortality rates of patients receiving Cfz-containing drug combinations is observed in some studies. While these data might be confounded by indication— as patients who receive Cfz-containing regimens tend to be those with broader-spectrum drug resistance patterns and more advanced disease — the increasing use of Cfz should be coupled with strengthening of active pharmacovigilance systems.22 Results from the Phase 3 STREAM and Phase 2 Global TB

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Alliance trials will help to elucidate further the long-term safety and effectiveness of Cfz in the treatment of MDR-TB. Our analysis is limited by the small number of available studies and published materials on Cfz. As ADRs are often rare, the paucity of clinical investigations with Cfz in the treatment of TB means that our results should be interpreted with some caution. While we attempted to categorise ADRs based on resolution after withdrawal or recurrence with re-challenge, reporting varied across studies, and different thresholds may have been applied to report adverse events and ADRs. In the Xu et al. study, for instance, 39 out of 44 (87%) patients were reported to have experienced adverse events after starting Cfz.32 This high level of adverse events could be attributed to the high frequency of reported skin discolouration (36 patients), a known reaction to Cfz treatment, but only two patients discontinued Cfz altogether.34. There were also insufficient data on extent of prior treatment, drug susceptibility, and HIV status—factors that could result in varying severity of disease. Another limitation was that we considered participants in our meta-analysis as those with at least one ADR while being treated with Cfz, rather than cumulatively counting multiple ADRs that may have been experienced. In addition, to review the global landscape of policies and regulatory actions relating to Cfz, we relied on databases, search engines, and manual searches which are biased in favour of English-language publications. Many more national and local policies may exist that were not captured by this paper. The use of Cfz in the clinical settings where MDR-TB patients are treated has been increasing over the last two decades. The progress countries are making towards universal access to diagnosis and treatment of MDR-TB81 is resulting in sustained and increasing demand for this product, at least until more new and effective drugs are available. The GDF’s projected forecast based on the ongoing global scale up of MDR-TB management suggests that the current quality-assured supply line is insufficient to meet this demand. GDF and the Global Fund regularly publish joint invitations to manufacturers of first, second and third-line anti-tuberculosis medicines to submit an Expression of Interest for TB drug products evaluation by the Expert Review Panel. However, to date, no successful review of clofazimine has been reported through this mechanism. To improve access to the drug, generic manufacturers that can complement Novartis’ production capacity should be identified. The inclusion of more manufacturers in the market may also contribute to a reduction in the cost of the drug, further improving access. Despite these limitations, this paper underscores the potential value of Cfz’s inclusion in the treatment regimens for MDR- and XDR-TB cases. However, even if the ongoing clinical trials and observational studies confirm the earlier findings reviewed here, much more will need to be done to make Cfz both available and affordable.

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5. ACKNOWLEDGEMENTS

Acknowledgements

The authors thank Shu-Hua Wang for help with data from the WHO’s International Drug Monitoring Programme. The authors also thank the editor and anonymoustwo reviewers at the journal for their review of the manuscript.

Contributors


Funding and Interests TJH and SD were supported by fellowships from the Harvard Kennedy School Institute of Politics. TJH also received a research grant for this study from the Dunwalke Fund at Harvard University. Competing Interests

SK has received partial salary support through a grant from the Eli Lilly Foundation’s MDR-TB Partnership to Brigham and Women’s Hospital. DF, DFW, EJ, KL, and KW are staff members of WHO. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of WHO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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Potentially relevant citations identified, without duplicates

(n = 1248)

Citations excluded after screening titles and

abstracts (n = 1101)

147 full-text articles screened for eligibility criteria

Studies included in meta-analysis

(n = 5)

Journal articles excluded (n = 143) = No or incomplete adverse event data (n = 141)

+ Case reports, < 10 patients (n = 2)

1 additional reference identified through manual

review of conference abstracts

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N. given Cfz

Daily Cfz dose (mg)










427 50-100

Xu et al., 201232


2.2 ± 1.7 (Cfz); 2.1 ± 1.3 (non-

Cfz)





65 50-100





17





Phase II 2012-2013 NC-003 (NCT01691534)

56




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62,63




64,65




64


66




Not stated.

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Figure 2 Forest plot of all reported adverse events associated with or ADRs attributed to clofazimine and clofazimine-containing regimens

Pooled estimates using inverse-variance weighted fixed effects (F-E) and random effects (R-E) models are shown. The random effects model was used for adverse events estimates (I2=98.7%; P<0.001) and fixed effects for ADRs (I2=11.5%; P=0.34).

All adverse events

Goble et al.25

Geerligs et al.26

Van Deun et al.16

Xu et al.27

Piubello et al.28

F-E Subtotal R-E Subtotal

ADRs only

Goble et al.25

Geerligs et al.26

Van Deun et al.16 Xu et al.

27

Piubello et al.28

F-E Subtotal

R-E Subtotal

Study

1993

2000

2010

2012

2013

1993

2000

2010

2012

2013

Year

11.76 (2.03, 35.59) 5.13 (0.52, 17.79)

0.00 (0.00, 1.07) 88.64 (75.57, 95.50) 4.62 (1.06, 13.23)

0.32 (0.00, 0.85) 21.89 (0.00, 46.13)

11.76 (2.03, 35.59) 5.13 (0.52, 17.79)

0.00 (0.00, 1.07) 4.55 (0.42, 15.97)

0.00 (0.00, 6.68) 0.05 (0.00, 0.58) 0.35 (0.00, 1.74)

Proportion (95% CI)

2

2

0

39

3

2

2

0

2

0

Events

17

39

427

44

65

17

39

427

44

65

Number

00 20 40 60 80 100

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in a high HIV prevalence setting. Int J Tuberc Lung Dis 2013;17(1):100-6. 2 World Health Organization (WHO). Global tuberculosis report 2012. WHO/HTM/TB/2012.6. Geneva, Switzerland: WHO, 2012. 3 WHO. Towards universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant tuberculosis by 2015: WHO progress report 2011. WHO/HTM/TB/2011.3. Geneva, Switzerland: WHO, 2011. 4 Skrahina A, Hurevich H, Zalutskaya A, Sahalchyk E, Astrauko A, van Gemert W, Hoffner S, Rusovich V, Zignol M. Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk. Eur Respir J 2012;39(6):1425-31. 5 U.S. Food and Drug Administration (US FDA). Press release: Approval of Sirturo (bedaquiline). FDA, 2012. 6 Otsuka Pharmaceutical Co., Ltd. News release: Otsuka’s Novel treatment for multidrug-resistant tuberculosis, delamanid, submitted for regulatory approval. Otsuka, 2013. 7 Caminero JA, Sotgiu G, Zumla A, Migliori GB. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis 2010;10(9):621-9. 8 Dooley KE, Mitnick CD, Ann DeGroote M, Obuku E, Belitsky V, Hamilton CD, Makhene M, Shah S, Brust JC, Durakovic N, Nuermberger E; Efficacy Subgroup, RESIST-TB. Old drugs, new purpose: retooling existing drugs for optimized treatment of

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