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Projeto Praça Onze Universidade Federal do Rio de Janeiro Clini cal Trials at AIDS V accin e µ09 Scientific Journalists Training Program Global HIV Vaccine Enterprise Paris, October 19, 2009 Mauro Schechter Principal Investigator , Projeto Praça Onze Professor of Infectious Diseases Universidade Federal do Rio de Janeiro

Clinical Trials (Mauro Schechter)

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Projeto Praça OnzeUniversidade Federal do Rio de Janeiro

Clinical Trials at AIDS Vaccine µ09

Scientific Journalists Training Program

Global HIV Vaccine Enterprise

Paris, October 19, 2009

Mauro Schechter Principal Investigator, Projeto Praça Onze

Professor of Infectious DiseasesUniversidade Federal do Rio de Janeiro

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Development of HIV vaccines

Laboratory and animal protection

experiments

20±50 HIV-negative volunteers (lower risk);safety and immunogenicity 

I I 

II II 

III III IV IV 

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

1000s of HIV-negative volunteers (higher risk);

efficacy 

Effectiveness; operational research

Pre-clinical phase

Clinical

Phases

*

*

* Randomized clinical trials

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Randomised Controlled Trials (RCTs)

� Experimental, (usually) longitudinal, prospective

� R andomised ± ensures that treatment groups aresimilar at start of trial; any differences are due to

chance only

� Controlled ± control group allows to conclude thatoutcome is due to the test vaccine rather than someother factor

� Comparison is usually between a new regimen orintervention and an existing standard of care orplacebo

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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

Limitations of randomized

clinical trials

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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 controlgroup

Limitations of randomized

clinical trials

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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 criteriaare required for any R CT

� Narrow and restrictive inclusion criteria can allow to

focus on a specific group of people and reducevariability in the outcome

� However, included participants may not berepresentative of those who may receive the vaccine inthe future

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The need for a control group

� µHawthorn effect¶: observation that patients in clinicaltrials generally do better than similar patients on sametreatment (closer monitoring, clear treatment plan,enthusiastic team, etc.)

� Therefore, a control group provides the opportunity tosee µwhat would have happened without the newintervention¶

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The need for randomisation

� Patient allocation to new intervention or controlgroups 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 duringthe 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 awareof 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 receiveonly one of the two different strategies

� Crossover trial: each patient receives first one

treatment strategy then the other, but the treatmentorder is randomised

� Cluster randomised: each µcluster¶ of patients(hospitals, outpatient clinics) randomised to receiveone of the two different treatment strategies

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Parallel design trials

Randomisation

New intervention

Control group

Present time

Comparetreatment

groups

Follow individuals

Starting point

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Cross-over trials

Randomisation

New Intervention

Control group

Present time Future timeFollow individuals

Starting point

New Intervention

Control group

Wash out

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Crossover trial

� Crossover trials are particularly useful for short termoutcomes 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 theeffect of the first treatment administered may carryover and alter subsequent responses

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Cluster randomised trials

Randomisation of 

Hospital/Clinic

New Intervention

All patients at

hospital/clinic

receive new

intervention

All patients at

hospital/clinic

receive new

intervention

Control group

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Clinical Trials at AIDS Vaccine µ09

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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

500 g/lipopeptide elicits cellular immune responses

Objective

� Investigate if HIV-LIPO5 immunogenicity varies with thedosage

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 responsesgenerated 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 patient¶s own

pre-ART plasma induced immunogenicity in most patients

Objective

�Assess the safety and proportion of patients demonstrating

viral load < 1000, <5000 and <10,000 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 interpretwhat scientists predict a trial will show

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³All predictions are difficult,

particularly when theyinvolve the future´

Dan Quayle

Former US Vice-President 

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Take home message # 2

How to interpretwhat reputable scientists mean when

they criticize trials that will be

conducted by other reputable scientists

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³If we knew what we aredoing, we wouldn't call it

research.´

± Albert Einstein

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Take home message # 3

How to interpretwhat scientists say

they have learned from a trial

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³Half of what we havetaught you is wrong.

Unfortunately, we do notknow which half.´

± C. Sidney Burwell, M.D.

Address to the graduation class

Harvard Medical School

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Merci !

Thank You !Obrigado !