lecture 13 - topics in Neuroscience

Question 1

What is a clinical trial?

Answer 1

Clinical trials, in their purest form, are designed to observe outcomes of
human subjects under “experimental” conditions controlled by the scientist

Question 2

The different stages of clinical trials

Answer 2

Classically clinical trials are divided into phases I-IV.

Question 3

Phase 0:

Answer 3

Preclinical research
* Some studies (e.g. behaviour or lifestyle change studies) often do not fit neatly into those phases
* Some drug trials not fit into a single phase (e.g. some blend Phase I and II or II and III)
→ Easier to think of studies based on their developmental stages

Question 4

The different stages of clinical trials

Answer 4

Question 5

Phase I

Answer 5

• Generally done on healthy volunteers
• Estimate drug tolerance and characterize pharmacokinetics and pharmacodynamics.
• Identify the maximally tolerated dose
• Provide early assessment of drug activity

Question 6

Phase II

Answer 6

• Larger than Phase I trials (up to 100s)
• Involves a control (e.g. control group or pre vs post-treatment)
• Narrow inclusion criteria for participants
• Usually explore different doses
• Evaluate whether the drug has any biological activity or effect

Question 7

Phase III

Answer 7

• Usually larger than Phase II trials (100s to 1000s)
• Fewer exclusion criteria
• Assess and confirm the effectiveness of the new intervention
• Monitor safety

Question 8

=Phase III trials are limited in terms of:

Answer 8

• Size (100s or 1000s)
• Duration (weeks or months)
• Incomplete information about clinical outcomes (e.g. Drug approved based on intermediate outcomes or
  biomarkers)

Question 9

Phase IV:

Answer 9

Long term surveillance of an intervention believed to be effective in phase III trials

Question 10

Design

Answer 10

• Parallel, crossover, and factorial design trials
• Based on the treatment structure, clinical trial designs are classified into parallel, crossover, and factorial
  designs

Question 11

Outcomes

Answer 11

variables that are monitored during a study to document the impact that a given intervention or
exposure has on the health of a given population.

Question 12

primary vs secondary outcome measure

Answer 12

Primary outcome measure: variable that is the most relevant to answer the research question
* Secondary outcome measures: additional outcomes monitored to help interpret the results of
the primary outcome

Question 13

consideration of outcomes

Answer 13

Outcomes should be stated a priori
➢ Sample size must be sufficient to detect effect of the intervention on the primary outcome
➢ Outcome suitability must be based on the research question and hypothesis

Question 14

What is FXS?

Answer 14

• Neurodevelopmental disorder.
• X-linked, single-gene disorder caused by the absence or deficiency of the fragile X messenger
  ribonucleoprotein (FMRP).
• Leading single-gene cause of and ASD intellectual disabilities.

Question 15

FMRP

Answer 15

• FMR1 encodes for the Fragile X protein (FMRP).
• FMRP is an mRNA-binding protein
• Binds to approximately 4% of all mRNA in the mammalian brain
• including several that encode proteins which have been implicated in ASD (TSC2, PTEN, Neuroligin3, Neurexin1,
  SHANK3 and NF1)
• It is expressed ubiquitously and is particularly abundant in the brain and in testicles.
• FMRP is mainly involved in regulating mRNA metabolism, controlling many steps leading to protein
  production

Question 16

mGluR theory of FXS

Answer 16

Question 17

Testing the mGluR theory of FXS

Answer 17

Question 18

Clinical trials - Lovastatin

Answer 18

• An open-label study was undertaken to assess the safety and efficacy of lovastatin in FXS:
• Significant improvement in aberrant behaviour (primary outcome measure)
• Significant improvement in 12 secondary outcome measures.
• Follow-up randomized controlled trial:
• Failed to replicate these findings
• No clear benefit of lovastatin over placebo.
• Two additional clinical trials:
• Awaiting results

Question 19

Key issues with the methodology and design of the trials:

Answer 19

• Timing and length of trial:
• Trials were done in adults and adolescents → Might have missed the critical time window
• Earlier in life treatment is initiated, the better the chance may be of success
• Outcome measure:
• Primary outcome measures were mostly questionnaires-based → large placebo response.
• Need for objective measures of core phenotypes, such as direct assessments of cognition and
  language, and biomarkers
• Measuring disease modification in neurodevelopmental disorders:
• FXS-specific drug treatment could enact improvements in neurobiological parameters that may
  actually enhance learning over time as a primary readout versus quickly providing behavioural
  symptomatic relief.
• If true, trials need to pair new treatments with learning interventions measuring cognitive and
  developmental outcome

Question 20

Clinical trials – lessons learned

Answer 20

Clinical trial study design :
* Reliance on post-hoc analyses of preliminary studies in making critical subsequent clinical trial study
design decisions for larger, more pivotal studies examining efficacy → risk of it being based on type II
error
* Study participant:
* Stratification of participants
* Performed on “high functioning” individuals → not representative of FXS

Question 21

From the preclinical side:

Answer 21

• Animal model:
• Are genetically homogenous inbred mice raised in controlled settings a good model for humans?
• Translatable outcome:
• There are no clear correlates between outcomes employed in FXS animal studies and outcomes
  employed in initial human FXS clinical trials.
• For example: a drug may correct protein synthesis, dendritic spine morphology, learning, and
  audiogenic seizure deficits in the Fmr1 KO mouse. Then, in human studies, outcomes include parent-
  report checklists focused on interfering behaviour, mood, anxiety, inattention, and adaptive
  behaviour.