NIAID TB Clinical Research Agenda Current and Future OCTOBER, 2011 - PowerPoint PPT Presentation

NIAID TB Clinical Research Agenda Current and Future OCTOBER, 2011

Clinical Research Funding NIH/ NIAID funds are not significantly expanding 2

What do we need and how to get it done?  Enhance/ adapt existing clinical research resources for TB  Coordination and Collaborations  Develop research strategies/ agendas and trials designs for more efficient therapeutics development 3

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NIAID TB  DM ID NIAID Clinical Team (TB and TB/ HIV ) NIAID Clinical Team (TB and TB/ HIV ) NIAID HIV  DAIDS Clinical Non-Clinical Fundamental Ph I Ph IIA Ph IIB Ph III-IV DM ID Resources DAIDSResources Systems Biology, Biomarker Animal M odels Programs (Candidate Selection) Research Reagents “ omics” Support Preclinical Services, Ph I Clinical Trials Networks Programs IND-enabling Units * Solicited and Unsolicited Grants - R34/ U01/ BAA HIV-TB Basic/ Pre-clinical Grants Vaccine & Treatment Evaluation Units * Tuberculosis Research Unit * TB specific * Clinical Diagnostics Research Consortium

NIAID Clinical Trials/Research Infrastructure NIAID Clinical Trials/Research Infrastructure DAIDS Cooperative Agreements  AIDS Clinical Trials Group (ACTG)  International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT)  International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)  HIV Vaccine Trials Networks (HVTN) DMID Contracts  Vaccine and Treatment Evaluation Units (VTEU)  Phase I Clinical Trials Units  Tuberculosis Research Unit (TBRU)*  Tuberculosis Clinical Diagnostics Research Consortium (CDRC) * Both Divisions  Support for U nsolicited Clinical Research Projects * TB specific 6

AIDSClinical Trials Group  International cooperative network established in 1987  34 domestic and 18 international ACTUs  71 Clinical Research Sites  Alliance of academic, industry, and government investigators plus community representatives  Statistics and Data M anagement Center  Harvard School of Public Health Funding  NIAID and other collaborating institutes  Current year CORE funding, $25 million  ~$13 million site support grants

Tuberculosis Transformative Science Group Formed in June, 2011  Chair, Dr. Richard Chaisson  Johns Hopkins  Vice Chair, Dr. Diane Havlir  San Francisco General Hospital/ UCSF  International Vice Chair, Dr. Gavin Churchyard  University of Witwatersrand

ACTG Clinical Research Sites UNAIDS 2001

K-RITH HHMI: $70 M plus • 2008-2018 • Building • Recruitment 5-7 PIs • No Clinical Space • 1/3 of space uncommitted • No running costs for PIs BSL-3 Lab BSL-2 Labs (3 PIs per Offices & Meeting Rooms floor)

Leadership and Sites for HIV/AIDS Therapeutic Clinical Trials - Renewals FY 13 DAIDS FOA Objective: To establish the Leadership of 1 to 2 HIV International Clinical Trial Networks to carry out the NIAID therapeutic research agenda in the following areas :  Treatment and chemoprevention of tuberculosis  Treatment and chemoprevention of infectious hepatitis  Cure and/or functional cure for AIDS  Non-infectious co-morbidities and novel interventions for HIV-infected individuals FY14 DAIDS FOA Objective: To establish clinical trials units/sites for performance of studies to carry out the NIAID therapeutic research agenda Ver. 11 11/ 2/ 2011 1.1

Consortium for TB Biomarkers (CTBB – aka “Frozen Trial Initiative”) GATB, ACTG, TBTC collaborative project for standardized sample biobanking  Funded by FDA grant, ACTG supplement (ACTG 5302), and ? NIAID R24 grant  Form joint governance body to coordinate, develop policies/ procedures, oversee operations, etc.  Develop umbrella protocol to specify type, timing, processing, shipping of samples, etc. from selected treatment trials  Contract with repository vendors to establish biobank(s), QA  Constitute advisory group to review sample use proposals Other trial sponsors are welcome to join 12

Coordination of Phase II Combo Trials WHO, NGOs, NIAID – ACTG, TBRU etc. GATB CDC – TBTC Coordinate Phase II FDA/ EM A, etc. PHARM As Combination Work EDCTP – PANACEA UKM RC

Forum to Coordinate Phase II/ III Clinical Trials- Initial M eeting 10/ 23/ 11  Phase II combination development plan coordination  Which combinations would be done by whom/ when  Efficiently/ promptly sharing new study results  Necessary pre-clinical and clinical data to allow study of specific combos  Coordination of discussions with Pharmaceutical sponsors  Establishment of an ongoing Phase II/ III Planning Forum  Drafting a proposal for how groups will work to coordinate  Proposal for support of future activities (conference calls and meetings)  Quarterly discussions with 1-2 meetings/ year

Forum to Coordinate Phase II/ III Clinical Trials Other Possible Objectives  Discuss key characteristics to establish new combinations as high priority candidates  Consider standardization of study designs, site procedures, labs, endpoint definitions, etc. to improve study comparisons or combining data  Discuss potential trial collaborations, necessary standardizations, mutually acceptable study monitoring and QA strategies, etc.

CPTR Initiative BM GF—in association with the TB Alliance and C-Path—will work to accelerate the development of new TB drug regimens 1 2 3 CPTR Tools Consortium CPTR Infrastructure CPTR Drug Coalition “Regulatory Science” “Key Success Factors” “Drug Development” Focus  Data standards/ integration  New clinical trial designs  Clinical trial capacity  Qualified biomarkers  Drug combination testing  Regulatory harmonization  Disease progression models  Funding and development Participants  Pharma companies  Pharma companies  Pharma companies  TB Alliance  TB Alliance  TB Alliance  TB experts  TB experts  Regulators  Regulators  Others  Patient representatives  Patient representatives  Reagan-Udall Foundation  NIH  Others?  CDC  BM GF  Other funders

Planning for M DR Trials with New Drugs  Site surveys  Initial – Completed in ACTG and TBTC  Initial Observational studies to better define local drug susceptibility patterns and feasibility issues  EARLY coordination of planning/ drug choices  Trials  Change emphasis to new combos, not single drug additions to OBT Include M DR/ XDR into new combo trials as soon as possible  Rapid PZA DST will be essential for next generation of M DR trials  Careful monitoring for new resistance 17

Recently Completed Studies  ACTG 5221 STRIDE: Timing of ART for HIV-1 infection and tuberculosis  Camelia ( ANRS1295/ NIAID-DAIDSCIPRA KH001) Early versus late start of antiretroviral therapy in adults with AIDSand tuberculosis  Both appear in yesterdays NEJ M  ACTG 5267 PK interaction of TM C 207 + EFV 18

Summary of NIAID Studies for TB - 1 STUDY BRIEF DESCRIPTION NUM BER Biomarkers A5302 Evaluation of TB biomarkers of treatment response in upcoming ACTG (A5289/ A5290) and TBTC (Study 31) clinical trials Diagnostics A5253 Sensitivity and specificity of TB diagnostics A5255 FASTER: Rapid TB DST study A5295 Evaluation of Xpert M TG/ RIF Assay DM ID 07- Interferon-Gamma Release Assays in TB-HIV co-infected children 0061 19

Summary of NIAID Studies for TB – 2 STUDY BRIEF DESCRIPTION NUM BER HIV/ TB A5274 REM EM BER: Empiric TB treatment + ART to reduce early mortality following ART initiation A5284 RIF + GS-9350 (Cobicistat) PK interaction Comparison of LPV/ r-based ARV ± RAL with RBT and double dose LPV/ r A5290 with RIF-based TB RX LTBI A5259 Rifapentine-INH x 3 mos vs SOC for LTBI (TBTC Study 26) A5279 Ultra-short (1 month) daily course of RPT/ INH for LTBI Phase I Study of Whether Preclearance of LTBI with INH Enhances Specific DM ID 07- Immune Responses to M TB following Subsequent BCG Revaccination in 0083 Healthy, HIV-uninfected, PPD+ Adults 20

Summary of NIAID Studies for TB – 3 STUDY BRIEF DESCRIPTION NUM BER M DR A5300 TM C-207 for preventive therapy for M DR/ XDR contacts A5312 The Early Bactericidal Activity of High-Dose Isoniazid among Adult Patients with inhA-related INH-Resistant Tuberculosis Harvard Inhaled Colistin to Decrease XDR TB Infectivity - Nardell CFAR Optimizing Standard Treatment Regimen A5307 Essentiality of INH After Two Doses: Randomized 14-day EBA Comparison of Standard RHZE with Only 2d INH + RZE or Substituting M oxifloxacin for INH (RM ZE) During Days 3 and 14 A5311 Phase I Clinical Trial of the Pharmacokinetics of High-dose Daily Rifapentine, Given as a Single Dose or in Divided Doses to Healthy Volunteers 21

Summary of NIAID Studies for TB – 4 STUDY BRIEF DESCRIPTION NUM BER Optimizing Standard Treatment Regimen – continued DM ID 11- Double Blind randomized dose ranging trial of high dose rifampin (10-15- 0050 20 mg/ day) for safety and improving treatment outcomes Pediatrics Study of IRISin children  5 years of age P1073 P1078 Safety and Efficacy of Antepartum vs. Postpartum INH Preventive Therapy in HIV-infected Women and Infants IM PAACT CS TM C-207 with OBT for treatment of M DR TB in children Other TBRU EBA Feasibility Study with Standard EHRZ Chemotherapy in Kampala/ M ulago 22