Download Powerpoint - Florida/Caribbean AIDS Education & Training Center

Clinical Trials Panel
Savita Pahwa, MD
Director, Miami Center for AIDS Research
University of Miami Miller School of
Medicine, Miami FL
Disclosures of Financial Relationships
This speaker has no significant financial
relationships with commercial entities to
disclose.
This speaker will not discuss any off-label
use or investigational product during the
program.
This slide set has been peer-reviewed to ensure that there are no
conflicts of interest represented in the presentation.
Learning Objectives
• Describe opportunities to advance basic
knowledge about HIV/AIDS through
clinical trials
• Discuss examples of successful clinical
trials which have potential for benefit
HIV/AIDS prevention and treatment
Building Ancillary Studies into Clinical Trials
Rationale
• Clinical trials require considerable investment
in time and research resources-- building in
ancillary research studies is a good investment
• Clinical trials serve as sources of wellcharacterized patient populations
• Ancillary studies that are built into existing or
planned clinical trials serve to minimize
expenses related to cohort recruitment and
primary intervention
Ancillary Studies
Focus of ancillary studies is typically in areas
that are not being studied in the parent trial
Examples:
• Basic genetic mechanisms of disease or
response to intervention
• Pathogenesis of disease, including
biomarkers and mechanisms of response to
intervention
• Behavioral and Quality of life issues
Types of Interventions in Clinical Trials for HIV/AIDS
A proposed classification scheme
• Type 1: Treatment drugs aimed at primary disease
– Type 1a: Directed at infectious etiology, such as novel
antiretroviral therapy (ART)
– Type 1b: Directed at associated co-infections, such as
tuberculosis (TB), hepatitis B or C
– Type 1c: Directed at non-infectious disease co-morbidities,
such as cardiovascular disease, neurocognitive
dysfunction, AIDS malignancies
• Type 2: Pathogenesis driven trials with drugs aimed at
mitigating conditions believed to be contributing to disease
progression, such as immune activation
• Type 3: Non-drug interventions
Type 1a study example: Prospective Study, ACTG
• Clinical Trial: A5202-a comparison of 4 potent cART regimens
(double blind TDF/FTC or ABC/3TC with open label EFV or ATV/r) in
treatment naïve adults; end-point, virologic failure
• Substudy: Incidence of immune reconstruction inflammatory
syndrome (IRIS)
• Immunology ancillary study: Pathogenesis of IRIS-(NIH ARRA funds)
– In the context of the causative agent
– Characteristics of Immune dysfunction
– Correlation with Immunological and clinical outcome
• Requirement: Cells and plasma collection on site at time of event
and prospectively at intervals, with adequate storage (
• Outcome: Study completed–extensive data analysis by SDAC is
ongoing
A5202: IRIS sub-study
IRIS Events noted by number of events by pathogen/process.
Type 1a study example: Prospective Study, ACTG
• Clinical Trial: A5202-a comparison of 4 potent cART regimens
(double blind TDF/FTC or ABC/3TC with open label EFV or ATV/r) in
treatment naïve adults; end-point, virologic failure
• Substudy: Incidence of immune reconstruction inflammatory
syndrome (IRIS)
• Immunology ancillary study: Pathogenesis of IRIS-(NIH ARRA funds)
– In the context of the causative agent
– Characteristics of Immune dysfunction
– Correlation with Immunological and clinical outcome
• Requirement: Cells and plasma collection on site at time of event
and prospectively at intervals, with adequate storage (
• Outcome: Study completed–extensive data analysis by SDAC is
ongoing
Example: Industry Sponsored Type 1a Pilot Study
• Clinical Trial: Viral decay dynamics in Integrase inhibitor
containing regimen in treatment naïve patients
• Ancillary pilot study: To investigate rapidity and magnitude of
immune reconstitution in relation to virus decay and immune
activation, (study sponsored by same company)
• Requirement: Cells and plasma collection at intervals with
adequate storage
• Study results: Rapid virus decay and immune reconstitution, but
residual low level immune activation persisted, with evidence of
low level ongoing microbial translocation
• Significance: Immune activation remains a barrier to immunologic
recovery with implications for non-infectious co-morbidities
• Future direction: Investigate mechanism of residual immune
activation with repository samples
Example: Repository Study, International MaternalPediatric-Adolescent AIDS Clinical Trials (IMPAACT)
• Clinical trial: Completed trial PACTG 338 with an established
repository of clinical samples (PBMC, plasma)
• Research question: How well does viral suppression control
immune activation and microbial translocation in children
• Requirement: Cells and plasma and linkage to clinical outcome
• Study results: Showed evidence of persistent immune activation
and microbial translocation despite virus suppression (PilakkaKanthikeel S et al, Ped Inf Dis J 31: 583, 2012)
• Significance: A prospective study with rigorous attention to sample
collection, additional investigations of the gut microbiome and of
mechanisms of immune activation was funded by the NIH (R01, PI
Mitchell,C at UM)
Type 2 proof of concept trials
• Pathogenesis driven trials with drugs aimed at
– mitigating conditions believed to be
contributing to disease progression, such as
immune activation
– eradication of HIV reservoirs
– overcoming HIV dysfunction
Examples, Type 2 Trials, AIDS Clinical Trials Group
(ACTG)
•
A5286: Pilot Study of Rifaximin as a Modulator of Gut
Translocation and Systemic Immune Activation in HIV-Infected
Individuals with Incomplete CD4+ T-cell Recovery on
Antiretroviral Therapy
•
A5296: Sevelamer Carbonate for Reducing Endotoxemia and
Immune Activation: A Proof of Concept Study
•
A5325: Active, Double-Blind, Randomized Placebo-Controlled
Study to Evaluate the Effect of Isotretinoin on Immune
Activation among HIV-1 Infected Subjects with Incomplete
CD4+ T cell Recovery on Suppressive ART
•
A5301: Administration of an Anti-PD-1 Antibody (MK3475) for
Reducing the Latent Reservoir: A Phase I Pilot Study
(courtesy, M Fischl, UM)
PrEP Demonstration Project
(U Miami and UCSF)
• NIAID-funded
Demonstration Project
• Multi-site, prospective,
open-label
• 500 at-risk HIV-negative
MSM and transgender
women
• Offered up to 48 weeks
of PrEP (FTC/TDF)
Courtesy: M Kolber, MD, Miami CFAR
OBJECTIVES
• Uptake
• Adherence
• Persistence
• Side effects and toxicities
• Changes in sexual risk
behaviors
Florida Consortium for HIV/AIDS Research (FCHAR)
•
•
Collaboration between Florida/Caribbean AETC, AIDS
Institute, Miami CFAR and FL HIV Research Groups
Created to bring together HIV research resources to
Florida for advancing HIV prevention, care and
treatment efforts, and to promote inter-institutional and
interdisciplinary collaboration on HIV research
– FOCUS project, Strategies to Enhance Detection
and Increase Linkage to Care and Treatment
– Goals: Increase identification of acute infection,
statewide clinical trial.
(Source: M Fischl, MD, Miami CFAR)
How can we advance scientific knowledge in the
context of clinical trials?
• Develop a good networking system to alert
care-givers and patients of ongoing research
studies and clinical trials- FCHAR initiative
• Discuss ways of establishing repositories in
select patient groups-logistics and cost
• Think of novel ways to address important
issues, specially in the prevention field
• Develop novel trials within our research
community, independently or in partnership
with existing clinical trial networks
Planning for ancillary studies and novel clinical trials
• Develop database for entry criteria and endpoints in
current trials to identify populations classifiable by
disease/infection status (age, nadir CD4 count, virus
load, ethnicity, risk groups)
• Target special populations for critical research
questions: HESN, elite controllers, acute Infection,
discordant couples, high risk groups, aging
populations, menopausal women, others
• Utilize routine interventions in defined populations to
ask research questions, e.g. influenza vaccination and
immune response
University of Miami Resources
• Extensive clinical resources with participation in several NIH
funded networks and groups: (ACTG, IMPAACT, ATN, AMC,
CTN, WIHS, PrEP Demo project)
• CTSI
• Center for AIDS Research (CFAR) with Cores and SARs
CFAR Scientific Areas of Research (SARs)
1. Drug Abuse and HIV Prevention
2. HIV &women; Co-morbidities in HIV
3. Therapeutics and Prevention (Cure)
4. Vaccines and Immunology
5. AIDS Malignancies
6. HIV/SIV molecular biology and viral
immune/neuropathogenesiss
Contact us at [email protected]
Visit us at our website www.cfar.med.miami.edu
CFAR Cores
A: Administrative
B: Developmental
C: Clinical Sciences
D: Laboratory Sciences
E: Behavioral
Thank you