Outline Review of a phase I trial What is a phase II trial Phase II trial process Standard trial designs Innovative trial designs Phase II trial examples Guess that trial Phase II thalidomide study ID: 1022320
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1. Phase II Clinical TrialAustin Goodrich and Laura Peterman
2. OutlineReview of a phase I trialWhat is a phase II trial?Phase II trial processStandard trial designsInnovative trial designsPhase II trial examplesGuess that trialPhase II thalidomide studyPhase II rituximab studySummary of phase II trial
3. Review of a Phase 1 Clinical TrialFirst to have peopleSmall sample sizeFocus on safety and maximum dose sizeNo placebos used
4. What is a Phase II trial?Test for efficacyLittle larger sample size Watch for less common side effects Many drug trials fail hereOr succeed here and fail in Phase III
5. Phase II Trial ProcessTherapeutic considerationsTrial AimOutcome of interestOutcome measure distributionDesign
6. Therapeutic ConsiderationsHow we approach the illness/diseaseSingle vs. Combination therapyBiomarker dependent (enrichment or endpoint)
7. Trial GoalsOutcome of InterestRemissionNon-inferioritySide-effectsCureTrial AimTreatment selection for phase IIIProof of concept
8. Outcome MeasureBinaryContinuous (biomarker)Ordered categoriesTime to eventRatios of time to progression
9. RandomisationRandomisation is the process of assigning clinical trial participants to treatment groups such that each participation has a known chance of being assigned to any of the groups.
10. Common Phase II Trial DesignsSingle-armSingle-arm two-stageRandomised with control armMulti-armMulti-arm two-stage
11. Single ArmSimplest designAll resources are concentrated on one groupEasy analysis
12. Single-arm two-stageBinary responseStopping ruleSaves CostSaferCould end a useful treatmentTemporal benefitsEnroll small nEnroll More patientsStop TrialPhase IIIFutilityFailed TrialFutility
13. Randomised Trial with Control ArmTwo Trial GroupsNew interventionControl (standard or placebo)Two birds with one trialAllows for comparisonsProvides information on recruitment rates
14. Randomised Trial with Several Intervention ArmsTwo or more treatmentsSubjects randomised to different groupsSometimes called "pick the winner" or winnersAll arms are tested like a single arm trial
15. Randomised Trial with Several Arms and Two-Stage DesignSimply a combination of two stages and several intervention armsA two-stage version of "pick the winner"
16. Innovative Trial DesignsMultiple-arm multi-stageEnrichment TrialsAdaptive trialsFlexible Design trials(Un)planned change
17. Multiple Arm StudiesIncrease size, complexity, and costMitigates historical controls, and false positive ratesRequires much more patientsRare diseases
18. Outcomes for early patients vs. later patients
19. Enrichment TrialsLook for benefits in specific subpopulationsEnroll patients with certain criteria Trial Strategies: Randomize patients and analyze subgroup with targetOnly include patients with drug targetAnalyze with and without target groups separately
20. Adaptive TrialsAllows for prespecified modifications to designTypes:Prospective- alter size, primary endpointsPlatform study- end arms due to futilityConcurrent- re-steer study, hone hypothesesRetrospective- change primary endpoint, analysis after study closed
21. Goals of Adaptive TrialKeep type I error lowShorter phase II trials –early terminationElimination of phase III trials with RP-II studiesLess expensive due to smaller overall sample sizeMore accurate prediction of phase III success
22. For Full Adaptive Trial BenefitsShort follow-up time relative to total trial lengthReal time data accumulationIncorporate decisions on data cleaning vs. using all data in database
23. Adaptive Trials Criticisms:Dropping a treatment arm increases Type I errorNot known if more effectiveIncrease type I and II errorStatistically complexOperational biasRecommended by FDAOrphan drugs small population size Use of adaptive trials limited
24. Guess That Trial
25. Guess That Trial!Evaluate the Safety and Efficacy of PH100 Tablet in T2DM Patients With recent cardiovascular diseaseAfter a screening, 114 patients will be randomized in a 1:1:1 ratio to the 3 arms (PH100 800mg/day, PH100 1600mg/day, Placebo) to evaluate the safety and efficacy of PH100.Subjects will visit the centers on Week 4, 8 and 12 during the entire 12-week treatment period.AimProcedure
26. Guess That Trial!To assess the efficacy and safety of Temozolomide for second-line treatment of Neuroendocrine Carcinomas progressing after first-line Platinum-based therapy.25 individuals with Histologically confirmed Metastatic Neuroendocrine Carcinoma are recruited for treatment.Patients receive alternating weekly doses of Temozolomide at 75mg/m2 Outcomes are observed at 3 monthsAimProcedure
27. Guess That Trial!Assess Traditional Chinese Medicine Formula Liu-Wei-Die-Huang-Wan in the Treatment of Osteoarthritis81 patients were randomized into an experiment arm or a placebo arm.Experimental arm received 3g of TCM OA2 twice dailyPlacebo receive 3g of placebo twice dailyOutcomes were measured at 4 weeks and 8 weeksAimProcedure
28. Choosing Outcome MeasuresTrials conducted in a relatively short time frameSurrogate endpointsMultiple endpoints can be selected
29. Standard Sample Size ConsiderationsNumber of stages (one or two)Assumes there is only one area of uncertainty (treatment arm)Significance level (alpha, beta)One-sided vs. two-sided
30. Sample Size CalculationN=size per group p= the response rate of standard treatment group p0= the response rate of new drug treatment group zx= the standard normal deviate for a one or two-sided x d= the real difference between two treatment effectδ0= a clinically acceptable margin S2= Pooled standard deviation of both comparison groups
31. Simon's Two-Stage Optimumlibrary(clinfun
32. Problems with Phase II StudiesSmall sample size, short durationsSingle Arm Studies insufficient long termSelection biasHistorical control- use old data to compare toNot a good predictor of phase III success>58% of drugs go on to fail in phase III
33. Reasons for Phase II FailurePreviously unknown toxic side effectsInferiority/EfficacyCommercial viability looks poor
34. Thalidomide Case Study
35. Thalidomide and Advanced Small Cell Lung CancerTwo small single-arm phase II trial and a small randomised placebo-controlled trialPatient survival was higher than expected- 46%, 52%, and 49% (expected: 20-30%)Median survival was 11.7 months vs. Placebo 8.7 months
36. Phase III resultsLarge double-blind placebo-controlled phase III trial was conducted on 724 patientsResults found no evidence of increased survivalMedian survival was 10.1 months for treatment vs 10.5 months for the placebo
37. Phase II Rituximab Study
38. Rituximab OverviewB Cells -> Pulse Cells -> antibodiesMonoclonal AntibodyOrphan DrugUsed to Treat:Blood CancersRheumatoid ArthritisForms of Vasculitis
39. VasculitisGroup of autoimmune diseasesSmall-vessel to large-vesselInflammation of blood vessels
40. Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis (RAVE)
41. CYC was the golden standard9998
42.
43. SummaryUseful for obtaining preliminary informationDesigns should be pre-specifiedSubjects should be monitored closelyPatients characteristics need sufficient detailInterpretations of results require cautionProceed after considering efficacy, safety, and feasibility
44. ReferencesBerti, A, Cornec, D, Crowson, CS, Specks, U, and Matteson, EL (2017). The epidemiology of ANCA associated vasculitis in Olmsted County, Minnesota (USA): a 20 year population-based study. Arthritis Rheumatol 69, 2338–2350.Brown, SR, Gregory, WM, Twelves, CJ, Buyse, M, Collinson, F, Parmar, M, Seymour, MT, and Brown, JM (2011). Designing phase II trials in cancer: a systematic review and guidance. British Journal of Cancer 105, 194–199.Hackshaw, AK (2009). A concise guide to clinical trials, Chichester, UK: Chichester, UK.Stone, JH et al. (2010). Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis. N Engl J Med 363, 221–232.Van Norman, GA (2019). Phase II Trials in Drug Development and Adaptive Trial Design. BTS 4, 428.Rituximab for the Treatment of Wegener’s Granulomatosis and Microscopic Polyangiitis - Study Results - ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/results/NCT00104299. Accessed November 30, 2019.