Projeto Praa Onze Universidade Federal do Rio de Janeiro

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Projeto Praça OnzeUniversidade Federal do Rio de
Janeiro
Clinical Trials at AIDS Vaccine 09
Mauro Schechter Principal Investigator, Projeto
Praça Onze Professor of Infectious
Diseases Universidade Federal do Rio de Janeiro
Scientific Journalists Training Program Global
HIV Vaccine Enterprise Paris, October 19, 2009
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Development of HIV vaccines
Pre-clinical phase

• Laboratory and animal protection
• experiments

2050 HIV-negative volunteers (lower risk)
safety and immunogenicity
I
100s of HIV-negative volunteers (lower and higher
risk) safety, immunogenicity doses, routes of
administration, different populations

II
Clinical Phases

1000s of HIV-negative volunteers (higher risk)
efficacy
III
IV
Effectiveness operational research
Randomized clinical trials
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Randomised Controlled Trials (RCTs)

• Experimental, (usually) longitudinal, prospective
• Randomised ensures that treatment groups are
  similar at start of trial any differences are
  due to chance only
• Controlled control group allows to conclude
  that outcome is due to the test vaccine rather
  than some other factor
• Comparison is usually between a new regimen or
  intervention and an existing standard of care or
  placebo

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Limitations of randomized clinical trials

• Generalisability
• Participants can be different from those that
  will use the vaccine
• Eligibility criteria often leads to groups of
  patients being excluded (e.g. STI co-infection)
• Length of trial and primary endpoints
• Typically 1-3 years long, thus efficacy of over
  the longer-term is not assessed
• Surrogate markers versus clinical events

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Limitations of randomized clinical trials

• Follow-up of patients
• Participants are generally seen more regularly
  and followed more intensely than in routine
  practice - this may influence behaviour, etc.
• Feasibility
• Potential participants may not want to leave an
  important decision up to chance
• Rare events are difficult to assess in RCTs as
  long follow-up periods and large numbers of
  patients are required
• Ethics
• It may be unethical to withhold an intervention
  to form a control group

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Practical aspects of clinical trials

• Question being studied
• Trial population/Control group
• Trial design
• Analysis (pre-specified vs. post-hoc)

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Practical aspects of clinical trials

• Question being studied
• Trial population/Control group
• Trial design
• Analysis (pre-specified vs. post-hoc)

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Practical aspects of clinical trials

• Question being studied
• Trial population/Control group
• Trial design
• Analysis (pre-specified vs. post-hoc)

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Trial populations

• Explicit and objective inclusion and exclusion
  criteria are required for any RCT
• Narrow and restrictive inclusion criteria can
  allow to focus on a specific group of people and
  reduce variability in the outcome
• However, included participants may not be
  representative of those who may receive the
  vaccine in the future

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The need for a control group

• Hawthorn effect observation that patients in
  clinical trials generally do better than similar
  patients on same treatment (closer monitoring,
  clear treatment plan, enthusiastic team, etc.)
• Therefore, a control group provides the
  opportunity to see what would have happened
  without the new intervention

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The need for randomisation

• Patient allocation to new intervention or control
  groups is determined purely by chance
• Thus, any differences between the different arms
  of the trial are due to chance alone
• This includes both known and unknown factors
• Thus, provided individuals are treated similarly
  during the study period, any differences in
  outcome between the two groups can be attributed
  to the intervention

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Practical aspects of clinical trials

• Question being studied
• Trial population/Control group
• Trial design
• Analysis (pre-specified vs. post-hoc)

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Blinding

• Bias can occur if a patient or treatment team are
  aware of treatment allocation
• Patient psychological effect on behaviour
• Clinical team intensity of counselling

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Types of RCTs

• Parallel group each patient is randomised to
  receive only one of the two different strategies
• Crossover trial each patient receives first one
  treatment strategy then the other, but the
  treatment order is randomised
• Cluster randomised each cluster of patients
  (hospitals, outpatient clinics) randomised to
  receive one of the two different treatment
  strategies

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Parallel design trials
New intervention
Randomisation
Compare treatment groups
Control group
Starting point
Present time
Follow individuals
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Cross-over trials
New Intervention
Control group
Randomisation

• New Intervention

Wash out
Control group
Starting point
Present time
Future time
Follow individuals
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Crossover trial

• Crossover trials are particularly useful for
  short term outcomes in chronic conditions
• The treatment must be one that does not
  permanently alter the disease or condition under
  study
• The main limitation of a crossover trial is that
  the effect of the first treatment administered
  may carry over and alter subsequent responses

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Cluster randomised trials
Randomisation of Hospital/Clinic
New Intervention
Control group
All patients at hospital/clinic receive new
intervention

• All patients at
• hospital/clinic
• receive new
• intervention

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Clinical Trials at AIDS Vaccine 09
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SS01-02Clinical outcomes from the STEP study

• Background
• 3,000 men and women
• 3 doses of MRKAd5 gag/pol/nef vaccine or placebo
• Vaccinations stopped after a pre-specified
  interim analysis in Ad5 seronegative participants
  demonstrated no protective effect on HIV
  acquisition or early plasma viral load
• Further analysis demonstrated an increased hazard
  ratio (HR) for HIV acquisition among Ad5
  seropositive and uncircumcised vaccinees vs.
  placebo recipients

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SS01-02Clinical outcomes from the STEP study

• Objective
• To compare rates of HIV acquisition among vaccine
  vs. placebo recipients
• Methods
• Pre-unblinding data were frozen as of Oct 17,
  2007
• Post-unblinding data are from Oct 18, 2007
  through January 23, 2009

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SS01-04Interim efficacy analysis of Phambili
study

• Background
• Step sister study conducted in South Africa
• In September 2007, because of results of the Step
  study, vaccinations were suspended but follow up
• Objective
• To compare rates of HIV acquisition among vaccine
  vs. placebo recipients
• Methods
• Pre-unblinding and post-unblinding data
• 801 participants enrolled, 7 received all 3
  study injections 66 received two and 27
  received one

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OA04-01Safety and immunogenicity of LIPO-5, a
HIV-1 lipopeptide vaccine

• Background
• The vaccine includes 5 long peptides, containing
  multiple CD8 and CD4 T-cell epitopes
• Phase 1 studies have shown that vaccine dosage at
  500µg/lipopeptide elicits cellular immune
  responses
• Objective
• Investigate if HIV-LIPO5 immunogenicity varies
  with the dosage
• Methods
• ELISpot and PBMC lymphoproliferation were
  assessed at baseline, two weeks after each
  injection, and at week 48

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• OA04-02
• Strong HIV-specific CD4 and CD8 T-lymphocyte
  proliferation in HIV-1 DNA prime/ modified
  vaccinia virus Ankara (MVA) heterologous boost
  vaccinees
• OA04-03
• Characterization of cell-mediated immune
  responses generated by recombinant modified
  vaccinia Ankara (rMVA)-HIV-1 in a phase I vaccine
  trial

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OA04-05Safety and viral load changes in HIV-1
infected subjects treated with autologous
dendritic immunetherapy following ART
discontinuation

• Background
• In a phase 1 trial, immunotherapy consisting of a
  monocyte-derived dendritic cells and RNA encoding
  autologous HIV antigens derived from the
  patients own pre-ART plasma induced
  immunogenicity in most patients
• Objective
• Assess the safety and proportion of patients
  demonstrating viral load lt 1000, lt5000 and
  lt10,000 copies/mL during the 12 week ART
  structured treatment interruption (STI)

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TAKE HOME MESSAGES
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Take home message 1
How to interpret what scientists predict a trial
will show
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• All predictions are difficult, particularly when
  they involve the future
• Dan Quayle
• Former US Vice-President

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Take home message 2
How to interpret what reputable scientists mean
when they criticize trials that will be conducted
by other reputable scientists
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If we knew what we are doing, we wouldn't call
it research.

• Albert Einstein

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Take home message 3
How to interpret what scientists say they have
learned from a trial
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Half of what we have taught you is wrong.
Unfortunately, we do not know which half.

• C. Sidney Burwell, M.D.
• Address to the graduation class
• Harvard Medical School

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Merci ! Thank You ! Obrigado !