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C.Q. Deng, MD, MPH, PhD

8 September 2017

Randomized Withdrawal and Delayed Start Design in Rare Disease Clinical Trials

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United Therapeutics is a biotech company in Rare Disease Arena

Presenter

Presentation Notes

PAH pulmonary artery pressure systolic : >=25 mmHG Neuroblastoma is a cancer that develops from immature nerve cells found in several areas of the body.

http://www.mayoclinic.org/diseases-conditions/pulmonary-hypertension/pulmonary-hypertension-care-at-mayo-clinic/ovc-20197508

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Challenges in Clinical Trial Design In Rare Diseases• Small number of patients affected• Small number of patients for clinical trials• Limited understanding of the disease’s natural history• Lack of well-defined study endpoints• Limited early phase clinical trial data

Design a study to extract the most amount of knowledge from the limited number of participants.

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• Enrichment design / Randomized withdrawal design

• Delayed start design / Delayed start analysis

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Enrichment Design – Selecting a study population more likely to show the treatment effect

FDA (2012) Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products

• Pretty much all clinical trials have some sort of enrichment (inclusion/exclusion criteria)• Select a study population that is

• more homogeneous • more likely to show the treatment effect• more likely to tolerate the treatment

This is even more important in rare disease clinical trialsEnriched population -> with larger treatment effect -> smaller sample size needed

The downside: more difficult for patient enrollment

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm332181.pdf

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R

R – randomize

Active

Placebo

SuperiorityActive

Run-in x weeksResponders

Randomized Withdrawal Design

orSubjects who can tolerate the active treatment

Active Drug

Active Drug

Active Drug

PlaceboR

Run in RCT

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Delayed-Start Design

• One group receives active treatment and another group receives placebo during the first stage of the trial

• Both groups receive active treatment during the second stage of the trial. • The results in the second stage may show whether an effect is long term /

disease modifying or short term / symptomatic. • The positive results at the end of both stages provide strong evidence of

efficacy

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Delayed-Start Analysis

• Two trials: First trial as typical RCTFollowed by an OLE (open label extension) study

• Data from two studies are pooled for analysis – delayed start analysis

Active Drug Active Drug

Active DrugPlacebo

Early-StartGroup

Delayed-StartGroup

Primary Efficacy Endpoint

Delayed StartAnalysis

RCT OLE

RandomizationStart of Trial

• Good results from delayed-start analysis can strengthen the efficacy evidence in rare disease clinical trials

RCT

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Randomized Withdrawal versus Delayed Start Design

Randomized Withdrawal Design: All patients receive active drug, then randomized to continue the active drug or placebo (withdrawal of the active drug)

Delayed Start Design: Patients are randomized to receive active drug or placebo, then all patients receive active drug

Maximize the amount of information from the fewest patients

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Randomized Withdraw Design- Droxidopa in Symptomatic Neurogenic Orthostatic Hypotention

Biaggioni (2015) Randomized Withdrawal Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension Responsive to Droxidopa

Presenter

Presentation Notes

OST: orthostatic standing test OHQ: Orthostatic Hypotension Questionnaire

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354798/pdf/hyp-65-101.pdf

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Randomized Withdraw Design- Droxidopa in Symptomatic Neurogenic Orthostatic Hypotention• 181 subjects participated in OL phase, • Responders from OL phase are eligible for randomization

Determined by improvement of at least one point on a symptom question (Orthostatic Hypotension Symptom Assessment (OHSA) Item 1) and an improvement in SBP of at least 10 mmHg at 3 minutes post-standing

• 101 responders are randomized in the double-blind phase (51 to placebo group)

• Despite its enrichment design, Study failed on its primary efficacy endpoint - the change from baseline in OHSA Item 1.

• Second study used a different endpoint show positive results – eventually resulted in FDA approval.

Cardiovascular and Renal Drug Advisory Committee Meeting January 14, 2014

https://wayback.archive-it.org/7993/20170403223807/https:/www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm378911.htm

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CIDP is debilitating chronic disorder caused by the damaged myelin sheaths in peripheral nervous system affecting both motor and sensory nerves in both legs and arms

Patients have weakness, numbness, tingling, pain and difficulty in walking

40,000 patients in the US

Randomized Withdrawal Design – ICE Study Example- Immunoglobulin (IGIV) in CIDP (Chronic Inflammatory DemyelinatingPolyneuropathy)

Presenter

Presentation Notes

the rubber coating over electrical wires myelin sheath, which is the protective fatty coating around nerve fibers in the central nervous system conduction in a biological tissue and conduction in an electrical wire

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Randomized Withdrawal Design - Immunoglobulin in CIDP (Chronic Inflammatory Demyelinating Polyneuropathy)

IGIV

Placebo

IGIV

PlaceboResponders

Non-responders

Out of the study

Time to relapse

Hughes RAC et al Lancet Neurology 2008

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Randomized Withdrawal Design - Immunoglobulin in CIDP (Chronic Inflammatory Demyelinating Polyneuropathy)

IGIV

Placebo

IGIV

PlaceboResponders

Non-responders

Out of the study

Time to relapse


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IGIV Placebo

n 59 58

Responder 32 (54%) 12 (21%)

Difference (95% CI) 33.5% (14.4% - 51.75)

p-value 0.0002

ICE Study: first randomized portion

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ICE Study: re-randomized portion

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Advantages:

• Two studies in one including randomized withdrawal• Multiple endpoints (responder rate and time to relapse)

Disadvantages:• Lengthy trial• Loss some efficiency

ICE Study Design: Advantages and Disadvantages

Drug (Gamunex-C) was approved in 2008 for CIDP (Chronic Inflammatory Demyelinating Polyneuropathy)

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116946.htm

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Delayed-Start Analysis

• Two trials: First trial as typical RCTFollowed by an OLE (open label extension) study

• Data from two studies are pooled for analysis – delayed start analysis

Active Drug Active Drug

Active DrugPlacebo

Early-StartGroup

Delayed-StartGroup

Primary Efficacy Endpoint

Delayed StartAnalysis

RCT OLE

RandomizationStart of Trial

• Good results from delayed-start analysis can strengthen the efficacy evidence in orphan drug trials

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Delayed-Start Analysis – RAPID study of A1PI augmentation therapy in Alpha-1 Antitrypsin Deficiency

Chapman et al (2015) Intravenous augmentation treatment and lung density in severe α1 Antitrypsin Deficiency (RAPID): a randomized, double-blind, placebo-controlled trial. The Lancet

Presenter

Presentation Notes

“Our analysis of the open-label treatment extension makes an artefactual effect of augmentation treatment unlikely. If deposition of exogenous protein in the epithelial lining fluid of the lung could lead to lung density overestimation by CT techniques, we would expect delayed introduction of augmentation treatment to patients previously given placebo to return their estimated lung density to that of continuously treated patients. Instead, their rate of lung density loss slowed to match that of continuously augmented patients, but the density lost was not recovered.

http://alfa1.org.br/wp-content/uploads/2016/04/14tl4296.pdf

http://alfa1.org.br/wp-content/uploads/2016/04/14tl4296.pdf

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Delayed-Start Design

• One group receives active treatment and another group receives placebo during the first stage of the trial

• Both groups receive active treatment during the second stage of the trial. • The results in the second stage may show whether an effect is long term /

disease modifying or short term / symptomatic. • The positive results at the end of both stages provide strong evidence of

efficacy

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Delayed-Start Design – ADAGIO study of Rasagiline in Idiopathic Parkinson’s Disease

Olanow et al (2009) NEJM

N=288

N=300

N=295

N=293

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Delayed-Start Design – ADAGIO study for Rasagiline in Idiopathic Parkinson’s Disease

Olanow et al (2009) NEJM

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Olanow et al (2009) NEJMOctober 17, 2011 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee

1 mg versus placebo: all three hypothesis tests are met2 mg versus placebo: only the first hypothesis testing criterion met

FDA declined to grant the Rasagiline as a disease modifier therapy

https://wayback.archive-it.org/7993/20170403224053/https:/www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/ucm235850.htm

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Conclusion

Randomized Withdrawal Design and Delayed Start Design are useful in extracting the most amount of knowledge from the limited number of participants

Randomized withdrawal design and delayed start design are especially useful in rare disease clinical trials

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