Design of Phase II Clinical Trials - UC Davis Health

1 1 Clinical and Translational Science Center1 Clinical and Translational Science CenterCLINICAL AND TRANSLATIONAL SCIENCE CENTERCLINICAL AND TRANSLATIONAL SCIENCE CENTERD esign of Phase II Clinical TrialsSusan Stewart, of BiostatisticsThe UC Davis CTSC receives support from the NIH National Center for Advancing Translational Sciences (award TR001860).2 Clinical and Translational Science Center2 Clinical and Translational Science CenterTopics Objectives TypesoMulti-stageoRandomizedoPlatformoCr ossover3 Clinical and Translational Science Center3 Clinical and Translational Science CenterPhase II Clinical Trials Phase II (NIH definition): Study the biomedical or behavioral intervention in a larger group of people (several hundred) to determine efficacy and further evaluate there any biological activity?

2 OMay or may not have concurrent controlsoMay be shorter term with different outcome and more exclusion criteria than Phase III trialsoPhase IIA-evaluate dosing; Phase IIB determine effectiveness4 Clinical and Translational Science Center4 Clinical and Translational Science CenterPhase II: Multi-stage designs PurposeoIdentify drugs that are promising for further testing in a Phase III trialoPreliminary efficacy assessmentoAvoid exposing patients to sub-therapeutic dose levelsoTerminate the study if the treatment is ineffective5 Clinical and Translational Science Center5 Clinical and Translational Science CenterSingle arm Trials Optimal two-stage designsoPermit early stopping if there is a moderately long sequence of initial failuresoEnroll n1patients in stage 1oIf r1responses, stop the trialoOtherwise.

3 Enroll n2more patientsoDecide whether or nottreatment is promising based on the n1+n2patients6 Clinical and Translational Science Center6 Clinical and Translational Science CenterTwo-stage designs Null hypothesis: probability of response is unacceptably low Alternative hypothesis: probability of response is sufficiently high to warrant further study Simon s optimaltwo-stage Design minimizes the expectedsample size under the null hypothesis for the given error constraints Simon s minimaxdesign minimizes the maximumsample size for the given error constraints7 Clinical and Translational Science Center7 Clinical and Translational Science CenterExample.

4 Intravenous aflibercept in patients with ovarian cancer Drug is a vascular endothelial growth factor (VEGF) inhibitor 2 dose levels tested (2 mg/kg and 4 mg/kg), based on previous Phase 1 & 2 studies Patients with advanced platinum-resistant ovarian cancer Simon minimax2-stage Design Primary outcome: objective response rate (ORR) Null hypothesis: ORR 5% Alternative hypothesis: ORR 15% Tested at the level, 1-sidedTe wet al. Cancer 2014; 120:335-438 Clinical and Translational Science Center8 Clinical and Translational Science Center2-stage Design Plan.

5 Enroll 42 patients in each group in stage 1 If at least 3 responders in stage 1in a group, go on to enroll 25 patients in stage 2 Declare drug suitable for future study if at least 8 responders total (stages 1 & 2) in a group Allowed to enroll additional patients beyond the 2-stage Design to reach a planned total sample size of 2009 Clinical and Translational Science Center9 Clinical and Translational Science CenterSample size calculation and Translational Science Center10 Clinical and Translational Science CenterMultiple stage designs Can extend to 3 (or even 4 stages)

6 May require at least one response at first stage to go on to the second stage Considerations for any multi-stage designoHow long will it take to determine whether there are enough responses to proceed to the next stage?oWill we stop the study or keep on enrolling while waiting for the results from the previous stage?11 Clinical and Translational Science Center11 Clinical and Translational Science CenterRandomized Phase II designs May randomize patients to different drugs or dose levels of the same drug Can estimate differences between treatments Can pick the treatment with best response Randomization produces balanced groups12 Clinical and Translational Science Center12 Clinical and Translational Science CenterExample: Phase II trial Oncken(2006) Background:Evaluated 4 vareniclinedose regimens for promoting smoking cessation.

7 Methods:Multicenter, double-blind, placebo-controlled. randomized healthy smokers aged 18-65 to vareniclinetartrate or placebo twice daily for 12 mg non-titrated (n=129); mg titrated (n=130) mg non-titrated (n=129); mg titrated (n=130)oplacebo (n=129)with 40-week follow-up to assess long-term efficacy outcomes: carbon-monoxide confirmed 4-week continuous quit rates; continuous abstinenceArch Intern Med. 2006 166(15):1571-713 Clinical and Translational Science Center13 Clinical and Translational Science CenterData Analysis Quit rates: binaryoCompared each treatment group separately vs.

8 PlacebooCompared pooled dosage groups vs. placebooStep-down procedure to account for multiple comparisonsoLogistic regression Independent variables: treatment and center Computed odds ratios with 95% confidence intervals MNWS (withdrawal), mCEQ(cigarette evaluation): numericoAnalysis of covariance (ANCOVA) Covariate: baseline level of outcome variable Independent variables: treatment and center14 Clinical and Translational Science Center14 Clinical and Translational Science CenterResults Weeks 9-12 continuous quit rates greater in mg group and mg group than placebo Weeks 9-52 abstinence rates greater in mg group and mg group than placebo Generally well toleratedoNausea in 16%-42% of vareniclinetreated subjectsoLess nausea with titrated dosing15 Clinical and Translational Science Center15 Clinical and Translational Science CenterDate of download.

9 3/30/2014 Copyright 2014 American Medical Association. All rights : Efficacy and Safety of the Novel Selective Nicotinic Acetylcholine Receptor Partial Agonist, Varenicline, for Smoking CessationArch Intern Med. 2006;166(15):1571-1577. quit rates. P<.001 for each treatment group vs placebo. BID indicates twice daily. The odds ratios (ORs) and 95% confidence intervals (CIs) for the weeks 4 through 7 evaluation were (95% CI, ) for the group and (95%CI, ) for the group; for the weeks 9 through 12 evaluation, (95% CI, ) and (95% CI, ), Legend:16 Clinical and Translational Science Center16 Clinical and Translational Science CenterDate of download: 3/30/2014 Copyright 2014 American Medical Association.

10 All rights : Efficacy and Safety of the Novel Selective Nicotinic Acetylcholine Receptor Partial Agonist, Varenicline, for Smoking CessationArch Intern Med. 2006;166(15):1571-1577. monoxide confirmed weekly point prevalence abstinence rates. BID indicates twice daily. *P<.001 vs Legend:17 Clinical and Translational Science Center17 Clinical and Translational Science CenterDate of download: 3/30/2014 Copyright 2014 American Medical Association. All rights : Efficacy and Safety of the Novel Selective Nicotinic Acetylcholine Receptor Partial Agonist, Vrenicline, for Smoking CessationArch Intern Med.