1. Clinical Trials Penny Hogarth, MD OHSU Department of Neurology April 6th, 2007

2. What is a clinical trial? A clinical trial is a tool for testing a drug, device or technique

3. Why do a clinical trial? To answer a clinical problem To gain new knowledge about a new or established treatment To support an application for government regulatory approval To support the marketing of a drug, device, or technique

4. Guiding Principles Ethics Scientific validity & integrity Medical relevance Regulatory & medico-legal considerations Cost

5. Guiding Principles Start with a hypothesis –Put in the form of a statement Turn it into a question –The question must be “answerable” –This forms the basis of the study’s “objectives”

6. Observational studies Case reports Case-control studies Cohort studies

7. Case-control studies Retrospective Subjects classified on basis of outcome, with prior exposure status determined after outcome Case = those with outcome of interest Control = those without outcome of interest

8. Cohort studies Prospective / longitudinal / concurrent Subjects classified on basis of exposure to some risk factor of interest and followed to determine outcome Most rigorous of observational studies

9. Interventional studies Cross-over trials –Subject acts as own control –Decreases variability Parallel group trials

10. Study population Active treatment Control treatment Active treatment Random assignment washout

11. Study population Active treatment Control treatment YES Random assignment NO Outcome of interest Follow-up period

12. Phase I studies Early human use of drug Often in normal subjects, rather than those with disease of interest Mainly aimed at establishing tolerated dose range, PK / PD, acute toxicity of compound Usually open-label, no control groups Small number of subjects: usually 10-100 Days to weeks long

13. Phase II studies In human subjects with disease of interest Establishing safety, tolerability of compound Preliminary measures of efficacy Usually controlled, randomized, blinded Larger numbers of subjects: ~100-300 Weeks to months long

14. Phase III studies In subjects with disease of interest Establishing efficacy, long-term safety and tolerability Raandomized, controlled, blinded Comparator may be placebo, or standard treatment Large numbers of subjects: 100s - 1000s Months to years long

15. Phase IV studies “Post-marketing” studies Long-term risks, benefits, optimal use

16. Anatomy of a study protocol Introduction and study rationale Study objectives Overall study design / study flowsheet Eligibility criteria Specific study procedures Sample size calculations / data analysis plan Ethical considerations

17. Common errors in trial design Question to be answered unclear Population too broadly or narrowly defined Outcome measures not quantifiable, or not relevant Controls inadequate Measures to protect against bias inadequate Study inadequately powered

19. From genetics to treatments Recognize and describe the phenotype Identify the gene Make an animal model Use the model to understand the pathophysiology of the disease Develop rational therapeutics based on the pathophysiology Test in animal models Test in humans

20. From genetics to treatments Recognize and describe the phenotype Identify the gene Make an animal model Use the model to understand the pathophysiology of the disease Develop rational therapeutics based on the pathophysiology Test in animal models Test in humans

21. “There are three marked peculiarities of this disease: its hereditary nature, a tendency to insanity and suicide, and its manifesting itself as a grave disease only in adult life…..” George Huntington, 1872

22. Huntington Disease Progressive neurodegenerative disorder –Movement disorder –Cognitive decline –Psychiatric, behavioral disturbances Average age of onset ~ 38 yo < 10% juvenile onset < 20 yo Late onset cases probably under-recognized

23. From genetics to treatments Recognize and describe the phenotype Identify the gene Make an animal model Use the model to understand the pathophysiology of the disease Develop rational therapeutics based on the pathophysiology Test in animal models Test in humans

24. Gene discovery: Venezuela 1993

25. Genetics of HD Autosomal dominant inheritance Expanded and unstable trinucleotide repeat (CAG) on short arm of chromosome 4  expanded polyglutamine tract in mutant protein Age dependent penetrance

26. From genetics to treatments Recognize and describe the phenotype Identify the gene Make an animal model Use the model to understand the pathophysiology of the disease Develop rational therapeutics based on the pathophysiology Test in animal models Test in humans

27. Animal models: 1996 Transgenic mice Drosophila C. elegans

28. From genetics to treatments Recognize and describe the phenotype Identify the gene Make an animal model Use the model to understand the pathophysiology of the disease Develop rational therapeutics based on the pathophysiology Test in animal models Test in humans

29. gln-gln-gln-gln Transcriptional dysregulation Transcriptional dysregulation Mitochondrial dysfunction Mitochondrial dysfunction Proteasome dysfunction Proteasome dysfunction Aggregate formation Aggregate formation caspases gln-gln-gln

30. From genetics to treatments Recognize and describe the phenotype Identify the gene Make an animal model Use the model to understand the pathophysiology of the disease Develop rational therapeutics based on the pathophysiology Test in animal models Test in humans

31. From genetics to treatments Recognize and describe the phenotype Identify the gene Make an animal model Use the model to understand the pathophysiology of the disease Develop rational therapeutics based on the pathophysiology Test in animal models Test in humans

32. HDAC inhibitors in Drosophila Drosophila HD model treated with HDAC inhibitors SAHA and butyrate show rescue of neurodegenerative process Steffan et al., Nature (2001) 413:739 HDNormalTx HD

33. HDAC Inhibitor SPB ameliorates R6/2 HD mouse phenotype Extended survival in dose-dependent fashion Improved motor performance Delayed neuropath sequelae Ferrante et al. J. Neuroscience 23(28):94

34. From genetics to treatments Recognize and describe the phenotype Identify the gene Make an animal model Use the model to understand the pathophysiology of the disease Develop rational therapeutics based on the pathophysiology Test in animal models Test in humans

35. SPB in HD Dose-finding study of SPB completed here at OHSU Pilot study of promising gene expression biomarker Multi-center phase II study just comleted

36. Clinical trial design in HD Individuals carrying HD gene spend ~2/3 life pre-symptomatic, ~1/3 symptomatic If neuroprotective treatment identified, when should it be started? How can we measure efficacy of putative neuroprotective treatment in pre- symptomatic individuals?

37. Clinical trial design in HD HD gene is perfect “trait” marker Current clinical measures are imperfect “state” markers “Delay of symptom onset” as trial outcome measure inaccurate and expensive Search for biomarkers, surrogate markers a high priority

38. What is a clinical endpoint? A measure that reflects how a subject feels, functions or survives Distinct measures used in a clinical trial that reflect the effect of a therapeutic intervention –death, BP reduction, self-report of pain –In pre-sx HD, onset of signs / sx

39. What is a biomarker? “A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” (Downing, 2000) “Marker of disease severity that reflects underlying pathogenesis and predicts clinical events in the absence of treatment, thus establishing the biological plausibility of the marker.” (Mildvan, 2000)

40. What is a surrogate endpoint? Characterization of a biomarker as a surrogate endpoint requires it to be “reasonably likely, based on epidemiologic therapeutic, pathophysiologic, or other evidence to predict clinical benefit.” (FDA, 1997) Examples: ↑ CD4 Cell Count in HIV

41. MRI Scans in HD Normal Subject: Age 38 HD Subject: Age 31

42. Globus Pallidus Putamen Caudate

43. Can we use striatal volume as biomarker / surrogate endpoint in HD? Can be objectively measured –High inter- intra-rater reliability Reflects pathogenic process –Striatal volume decreased in pre-sx subjects –Striatal volume decreases as approach onset sx –Longitudinal change can be detected over relatively short time Predicts clinical events –Rate of change significant 10-12 years prior to sx onset –Striatal volume can predict incident cases

44. Striatal volume decreases as onset approaches +1 s.d. for 19 controls -1 s.d. for 19controls Mean Volume for 19 controls

45. Caudate volume Putamen volume 25 (N = 67) (N = 67) (N = 42) (N = 22) (N = 16) Years to Onset (current estimate) Mean caudate volume for controls Mean putamen volume for controls

46. Striatal volume predicts clinical events Putamen and caudate volumes are about ½ of normal volume at the time of diagnosis Functioning can remain normal even as basal ganglia volumes are declining All subjects with caudate volume 5.3cc were presymptomatic All subjects with putamen volume 5.1cc were asymptomatic

47. Application of striatal volume as biomarker “may be applied as a stratification variable in controlled trials, distinguishing populations with varying degrees of risk of disease.” (Mildvan, 2000) Biomarkers have several valuable applications, including:  use as a diagnostic tool  use as a tool for staging disease  use as an indicator of disease  use to predict and monitor clinical response to in intervention (Downing, 2000)

48. Striatal volumes as surrogate endpoint No existing good clinical measures for pre- sx subjects Can be used in far-from-onset subjects, for whom onset is not feasible measure Can use data from all subjects, not just incident cases No practice effects, no placebo effects Relatively small study sample sizes needed

49. Striatal volumes as surrogate endpoint Assume for sample size calculation: –Treatment effective in reducing atrophy by one-half –Trial included only those subjects whose estimated onset was <12 years from the initiation of the trial – Trial would be approximately 30 months duration Would need approximately 84 presymptomatic subjects per group

50. –MRI striatal volumes can be considered a biomarker –MRI striatal volumes can be used to select cases for future clinical trial to determine when the first neurobiological changes of HD begin –More evidence needed to consider MRI striatal volume as a surrogate endpoint??? –Need to be ready with a cost-effective method that is reliable and valid for future clinical trials –Would likely be used in combination with other proposed biomarkers / surrogate markers

51. Acknowledgement Elizabeth Aylward, PhD University of Washington Seattle, WA