multicenter clinical trial of nifurtimox-eflornithine ......m it s 0 5 10 15 20 25 d ays since st r...
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Multicenter clinical trial of nifurtimox-eflornithine combination therapy
for second-stage sleeping sickness
G. Priotto, S. Kasparian, D. Ngouama, S. Ghorashian, U. Arnold, S. Ghabri, E. Baudin, V. Buard, S. Kazadi-Kyanza, V. Kande, W. Mutombo,
M. Ilunga, W. Mutangala, C. Schmid, E. Torreele, U. Karunakara
XVIIth International Congress for Tropical Medicine and MalariaJeju, Korea, September 2008
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Treatment of HAT in second-stage⢠Melarsoprol:
â High toxicity, treatment failure rates rising
⢠Eflornithine (DFMO):
â Less toxic, efficacious, but resource-intensive
⢠Nifurtimox:
â Cheap, easy to use, but limited efficacy in monotherapy & not registered for HAT
No new drugs under clinical development
Drug combinations can be avenues of improvement
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Initial studies on drug combinationsNorthern Uganda, MSF-France, 2001-2004
⢠Trial comparing 3 combinations (n=54): â Melarsoprol - Nifurtimox (M+N)
â Melarsoprol - Eflornithine (M+E)
â Nifurtimox - Eflornithine (N+E)
High toxicityand fatality
Observations in both studies:â Safety: acceptable
â Efficacy: 100% at 24 months
⢠Nifurtimox â Eflornithine case-series (n=31)
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N+E Combination Therapy (NECT)
⢠Started in Rep. of Congo, MSF-Holland, 2003
⢠Two-arms comparative trial â E: Eflornithine 400 mg /kg/d, QID, 14 d
â N+E: Nifurtimox 15 mg/kg/d, 10 d . Eflornithine 400 mg /kg/d, BID, 7 d
⢠Primary objective: To compare the efficacy
⢠Secondary objective: To evaluate the safety
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NECT methodology⢠Randomized, parallel, open, non-inferiority trial
⢠Sample size planned = 280 patients
⢠Common Toxicity Criteria
⢠Hematology & Biochemistry
⢠Pharmacology
⢠18-months active follow-up
⢠Primary outcomes:â Efficacy: Cure rate at 18 months
â Safety: Proportion of patients suffering major (grade 3 & 4) related adverse events
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Enrollment criteria
⢠Confirmed case: parasites seen
⢠Stage 2, >20 leukocytes/uL in CSF
⢠Naive of second-stage treatment
⢠>14 yrs of age
⢠Non-pregnant
⢠Reasonable chances of follow-up
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NECT multicentric
Nkayi2003-2006
N=103
Isangi2005-2007
N=64
Dipumba2006-2008
N=60
Katanda2006-2008
N=60
Sites 2003 2004 2005 2006 2007 2008
Nkayi
Isangi
Dipumba
Katanda
EnrollmentFollow-up
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Results: Efficacy follow-up
⢠Excellent follow-upâ 99% at least one assessment
â 93% completed the follow-up
1 (0.7%) 2 (1.4%)8 (5.6%) 9 (6.3%)
134 (93.7%) 132 (92.3%)Death due to AE 3 1Relapsed 8 2Cured 123 129
N+E (n=143)
Complete follow-up until endpointPartial follow-upNo follow-up
E (n=143)
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Primary efficacy analysis
Difference in cure rate:
E minus N+E = Î
91.6% - 96.5% = -4.9%
92.3% - 97.9% = -5.6%
91.7% - 97.7% = -6.0%
One-sided non-inferiority test
-15 -10 -5 0 5 10 15
PP
MITT
ITT
-15 -10 -5 0 5 10 15
PP
MITT
ITT
NEW TREATMENT BETTER
NEW TREATMENT WORSE
â
Noninferioritymargin ,â = 10%
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Secondary efficacy analysis: Method: Survival analysis
Failure events: relapses and deaths (treatment-or HAT-related)
Probability of event-free survival:
E N+E Log-rank
ITT: 84.8% 94.3% p= 0.0497
MITT: 84.8% 94.3% p= 0.0497
PP : 83.5% 94.1% p= 0.0460
0.00
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Pro
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sur
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0 6 12 18 24Months since start of treatment
E N+E
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Overview of safety data
⢠1754 adverse events reportedâ 1262 Clinical events (351 multiple events)
⢠153 laboratory events⢠Overall frequency = 4.9 events/patient
⢠Difficult to establish causality: â Disease/s vs. Treatment
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Principal safety results
n % n % p- value
At least one AE 138 96.5 136 95.1 0.555
At least one Serious AE 6 4.2 1 0.7 0.120
Deaths 3 2.1 1 0.7 0.622
PRIMARY SAFETY OUTCOME:
At least one Major AE 41 28.7 20 14.0 0.002
N° of patients presenting:E (n=143) N+E (n=143)
Treatment pauses 9 6.3 1 0.7 0.019
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Major adverse eventsMajor AE E (n=143) N+E (n=143)
n % n %Seizures 6 4.2 6 4.2Coma 3 2.1 1 0.7Confusion 1 0.7 2 1.4Hallucinations 1 0.7 1 0.7Other neurological 2 1.4 3 2.1Gastrointestinal 2 1.4 2 1.4Fever 18 12.6 7 4.9Infection 7 4.9 1 0.7Hypertension 3 2.1 0 0.0Headache 2 1.4 1 0.7Acute Respiratory Distress 1 0.7 1 0.7Other clinical AE 2 1.4 2 1.4Anemia 1 0.7 2 1.4Leucopenia 0 0.0 0 0.0Neutropenia 10 7.2 2 1.4
Total 65 31
Major AE E (n=143) N+E (n=143)n % n %
Seizures 6 4.2 6 4.2Coma 3 2.1 1 0.7Confusion 1 0.7 2 1.4Hallucinations 1 0.7 1 0.7Other neurological 2 1.4 3 2.1Gastrointestinal 2 1.4 2 1.4Fever 18 12.6 7 4.9Infection 7 4.9 1 0.7Hypertension 3 2.1 0
Major AE E (n=143) N+E (n=143)n % n %
Seizures 6 4.2 6 4.2Coma 3 2.1 1 0.7Confusion 1 0.7 2 1.4Hallucinations 1 0.7 1 0.7Other neurological 2 1.4 3 2.1Gastrointestinal 2 1.4 2 1.4Fever 18 12.6 7 4.9Infection 7 4.9 1 0.7Hypertension 3 2.1 0 0.0Headache 2 1.4 1 0.7Acute Respiratory Distress 1 0.7 1 0.7Other clinical AE 2 1.4 2 1.4Anemia 1 0.7 2 1.4Leucopenia 0 0.0 0 0.0Neutropenia 10 2 1.4
Total 65 31
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Discussion: efficacy
⢠Non-inferiority of N+E cure rate
⢠Significant advantage of N+E in:⢠Probability of event-free survival
⢠Other secondary indicators
⢠Excellent follow-up
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Discussion: safety
⢠In the context of second-stage HAT, both treatments were well tolerated
⢠Low fatality rate in both arms
⢠Significant advantages of N+E:
â Lower risk of major adverse events
â Lower risk treatment interruptions
â Lower risk of infections, diarrhea, fever peaks, neutropenia
⢠Higher risk of nausea and vomiting with N+E
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Discussion: practical aspects
⢠Simpler regimen
â More feasible than eflornithine
â Fits the routine of health centers
â Cheaper: staff, infrastructure, logistics
â Short hospitalization
⢠Prevent the emergence of resistance
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Conclusion
⢠N+E combination can be used as first-line treatment for stage 2 HAT
â Efficacy and safety comparable with eflornithine
â Improved feasibility
â Less toxic than melarsoprol
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AcknowledgmentsSponsors:
â MSF-Holland and DNDi
Field implementation: â MSF-Holland, MSF-Belgium, DNDi, STI, PNLTHA (RoC and DRC)
Collaborating institutions:â Institut de MĂŠdecine Tropicale â Antwerpâ Swiss Tropical Institute â Baselâ Haskins Laboratories â New Yorkâ World Health Organizationâ TDR / WHO - Genevaâ UniversitĂŠ RenĂŠ Descartes â Parisâ FacultĂŠ de Pharmacie â Paris XIâ INRB - Kinshasa
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Secondary efficacy indicators
n/N % n/N %
Treatment failure rate 11/142 7.7 3/141 2.1 p=0.027
Relapse rate at 12 Months 5/139 3.6 0/140 0 p=0.030
Relapse rate at 18 Months 8/139 5.8 2/140 1.4 p=0.060
Parasitologically confirmed relapse rate 5/139 3.6 0/140 0 p=0.030
Fatality rate (within 30 days) 3/142 2.1 1/141 0.7 p=0.622
Overall cure rate at 12 months 133/142 93.7 137/141 97.2 p=0.256
Treatment response rate 141/142 99.3 140/141 99.3 p=1.000
Treatment outcome - MITT analysisE (n=142) N+E (n=141)
p-value
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Most frequent clinical events (selected)
n % n %
Seizures 13 9.1 18 12.6Anxiety/agitation 11 7.7 4 2.8Dizziness 24 16.8 27 18.9Inner ear disturbance 7 4.9 10 7.0Insomnia 14 9.8 14 9.8
Abdominal pain 42 29.4 35 24.5Anorexia 20 14.0 36 25.2Diarrhea 41 28.7 9 6.3Nausea/Vomits 29 20.3 69 48.3
Arrythmia 31 21.7 27 18.9Hypertension 19 13.3 6 4.2
Fever 61 42.7 37 25.9Infection 32 22.4 18 12.6
CARDIOVASCULAR
OTHER
GASTROINTESTINAL
E (n=143) N+E (n=143)
NEUROLOGICAL
Not-related events are excluded
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Onset time of adverse events
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E N+E
Fever -- Kaplan-Meier curves
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Nausea/Vomits -- Kaplan-Meier curves
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Prop
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0 5 10 15 20 25Days since start of treatment
E N+E
Diarrhea -- Kaplan-Meier curves
1st week 2nd week 1st week 2nd week
1st week 2nd week
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E N+E
Infections -- Kaplan-Meier curves
1st week 2nd week