Clinical Trials Panel

Savita Pahwa, MDDirector, 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 well-characterized 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

IRIS Events noted by number of events by pathogen/process.

A5202: IRIS sub-study

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 Maternal-Pediatric-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 (Pilakka-Kanthikeel 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)

OBJECTIVES• Uptake• Adherence• Persistence• Side effects and toxicities• Changes in sexual risk

behaviors

Courtesy: M Kolber, MD, Miami CFAR

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

CFAR Cores

A: Administrative

B: Developmental

C: Clinical Sciences

D: Laboratory Sciences

E: Behavioral

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 cfar@med.miami.edu

Visit us at our website www.cfar.med.miami.edu

• 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

Thank you