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Microbicides in Clinical Trials: A Detailed Look Polly F. Harrison, PhD Director, Alliance for Microbicide Development University of North Carolina at.

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Presentation on theme: "Microbicides in Clinical Trials: A Detailed Look Polly F. Harrison, PhD Director, Alliance for Microbicide Development University of North Carolina at."— Presentation transcript:

1 Microbicides in Clinical Trials: A Detailed Look Polly F. Harrison, PhD Director, Alliance for Microbicide Development University of North Carolina at Chapel Hill School of Public Health, Office of Global Health 21 October 2004

2 clinical trial phases ParticipantsLengthPurpose Phase 110-100several mos.safety Phase 1/2several 100several mos.safety/ dose ranging Phase 2~200 (couples)6 mos.- 1 yr.expanded safety Phase 2/2Bseveral 1,000~3 yrs.safety/ direct estimate effectiveness Phase 3300-30,0001-4 yrs.effectiveness

3 current microbicide clinical trial sites Phase 1 Phase 1/2 Phase 2 Phase 2/2B Phase 3 Multi-Phase

4 current microbicide clinical trials Australia (1 trial) -VivaGel™ (Phase 1) India (3 trials) - Tenofovir Gel (Phase 2) -BufferGel™, PRO 2000 (Phase 2/2B) -Cellulose sulfate (Phase 3) United Kingdom (1 trial) -Cellulose acetate phthalate (Phase 1) Kenya (1 trial) -Cellulose sulfate (Phase 3) Uganda (2 trials) -Cellulose sulfate (Phase 3) -PRO 2000 (Phase 3) Cameroon (1 trial) -Invisible Condom (Phase 1/2) Burkina Faso (1 trial) -Cellulose Sulfate (Phase 3) Ghana (1 trial) -Savvy® (Phase 3) Benin (1 trial) -Cellulose sulfate (Phase 3) Zambia (2 trials) -BufferGel™, PRO 2000 (Phase 2/2B) -PRO 2000 (Phase 3) Tanzania (2 trials) -BufferGel™, PRO 2000 (Phase 2/2B) -PRO 2000 (Phase 3) Malawi (1 trial) -BufferGel™, PRO 2000 (Phase 2/2B) Zimbabwe (2 trials) -Cellulose sulfate + Diaphragm (Phase 1) -BufferGel™, PRO 2000 (Phase 2/2B) South Africa (7 trials) -Acidform™/Amphora™ + Diaphragm (Phase 1) -Carraguard® (Phase 1) -PRO 2000, Tenofovir (Phase 2) -BufferGel™, PRO 2000 (Phase 2/2B) -Carraguard® (Phase 3) -Cellulose sulfate (Phase 3) -PRO 2000 (Phase 3) United States (9 trials) GA -UC 781 (Phase 1) NY: - Tenofovir (Phase 2) PA: -Lactin- V capsule (Phase 1) -Polystyrene sulphonate (Phase 1) -BufferGel™, PRO 2000 (Phase 2/2B) RI: -Polystyrene sulphonate (Phase 1) TX: -Polystyrene sulphonate (Phase 1) VA: -UC 781 (Phase 1) WA: -Lactin-V capsule (Phase 1) Nigeria (2 trials) -Cellulose sulfate (Phase 3) -Savvy® (Phase 3) Thailand (1 trial) - Carraguard® (Phase 1)

5 candidates in clinical trials (by phase) PHASETOTALMICROBICIDE CANDIDATES 16Acidform TM /Amphora TM Cellulose acetate phthalate/CAP Lactin-V capsule Polystyrene sulphonate/PSS UC-781 VivaGel/SPL7013 TM 1/22Invisible Condom TM, Praneem polyherbal 23Human monoclonal antibodies (C2F5, C2G12, C4E10) Protected lactobacillus in combination with BZK Tenofovir/PMPA 2/2B2BufferGel TM PRO2000 33Carraguard ® Cellulose sulfate/CS Savvy TM /C-31G TOTAL16

6 all current clinical trials (by product and phase) 11/222/2B3 Acidform™/ Amphora™ + Diaphragm Invisible Condom™ Human monoclonal antibodies (C2F5, C2G12, C4E10) BufferGel™Carraguard® Praneem Polyherbal PRO 2000 Tenofovir/ PMPA PRO 2000Cellulose sulfate Cellulose acetate phthalate* Protected lactobacillus in combination w/ BZK PRO 2000 Cellulose acetate phthalate 13% Tenofovir/ PMPA**Savvy™/C-31G Cellulose sulfate + Diaphragm Lactin-V capsule Lemon/Lime Juice** Polystyrene sulphonate* UC-781 (2 trials) VivaGel™ *Candidates “On Hold”, ** Trial Protocol Under Development

7 phase 1 clinical trials CANDIDATE MICROBICIDE MECHANISM OF ACTION SPONSORPOP. SIZETRIAL SITESSTATUS Acidform™/ Amphora™ + Diaphragm 6 month safety (Diaphragm w/Acidform, Diaphragm w/ KY Jelly) Acid BufferCONRAD GMP 120 60 each arm South AfricaOn-going began enrollment Carraguard®Adsorption Inhibitor Population Council South Africa/Durban Thailand/Chiang Rai On-going Cellulose acetate phthalate/CAP Multiple Mechanisms Imperial College London, UK Part A- 10 Part B- 50 UK/LondonPart A recruitment has been suspended at 5. Resume once the product has been reformulated and appropriate permission received.

8 phase 1 clinical trials (cont.) CANDIDATE MICROBICIDE MECHANISM OF ACTION SPONSORPOP. SIZETRIAL SITESSTATUS Cellulose acetate phthalate 13%/CAP 13% Multiple Mechanisms Emory U.N.D. Enrollment Mar 05 Cellulose sulfate + Diaphragm 6 months safety sexually active women Adsorption Inhibitor CONRAD GMP 180ZimbabweEnrollment began Aug 04 Lactin-V capsuleVaginal Defense NIAID Osel, Inc. 90US/Pittsburgh, PA US/Seattle, WA Approved by FDA Lemon/ Lime Juice N.D. Polystyrene sulphonate/PSS Adsorption Inhibitor GMP72US/Houston, TX US/Pittsburgh, PA US/Providence, RI Stopped Phase 1 studies- report to be submitted to FDA

9 phase 1 clinical trials (concl.) CANDIDATE MICROBICIDE MECHANISM OF ACTION SPONSORPOP. SIZETRIAL SITESSTATUS UC-781Replication Inhibitor CONRAD Biosyn, Inc. 48US/Norfolk, VAPlanned Male tolerance UC-781Replication Inhibitor Biosyn, Inc.54 women, 36 men US/Atlanta, GAEnrollment Dec 04 VivaGel™ (SPL7013gel) Entry & Fusion Inhibitor Starpharma Pty Limited 36Australia/ AdelaideCohorts who received 0.5% and 1% w/w SPL7013 gel completed. Cohorts receiving 3% w/w SPL7013 gel strength on- going.

10 phase 1/2 clinical trials CANDIDATE MICROBICIDE MECHANISM OF ACTION SPONSORPOP. SIZETRIAL SITESSTATUS Invisible Condom™ Entry & Fusion Inhibitor CRI452CameroonFunded Phase of production/ preparation of applicators and formulations for trial. Praneem polyherbal UncharacterizedIndian Council of Medical Research (ICMR) N.D. Being reformulated (Working on a Phase 3 of formulation to treat BV; probably Indian funding?)

11 phase 2 clinical trials CANDIDATE MICROBICIDE MECHANISM OF ACTION SPONSORPOP. SIZETRIAL SITESSTATUS Human monoclonal antibodies (C2F5, C2G12, C4E10) Entry & Fusion Inhibitor Polymun Scientific N.D.United StatesUnder IND soon PRO 2000 Tenofovir/PMPA Entry & Fusion Inhibitor Nucleotide Reverse Transcriptase Inhibitor EcoBio1,000South Africa/ Vulindlela, Northern KwaZulu- Natal Protocol in “re- development.” Enrollment to begin late 1 st quarter or early 2 nd quarter 2005. Protected lactobacillus in combination with BZK Vaginal Defense Biofem, IncPart 1- 28 participants Part 2- 50 participants PendingIn development Tenofovir/PMPA (HPTN 059) Nucleotide Reverse Transcriptase Inhibitor NIH/DAIDS (HPTN) Gilead Sciences 200India/ Pune US/ Bronx, NY Protocol under development

12 late-stage clinical trials PHASECANDIDATESSTATUS 2/2B BufferGel™ PRO 2000 Enrollment to begin Nov. 2004 3Carraguard® Enrollment began Mar. 2004 Cellulose sulfate/CS (2 trials: FHI/CONRAD) Enrollment to begin (Nov. 2004/Apr. 2005) PRO 2000 (0.5%, 2%) Enrollment to begin Jan. 2005 Savvy™/C-31G Enrollment began Sep. 2004

13 overview of late-stage clinical trials 5 microbicide candidates, entering into 6 large- scale clinical trials mechanisms of action: – 1 acid buffer (BufferGel™) – 1 entry & fusion inhibitor (PRO 2000) – 2 adsorption inhibitors (Carraguard®, Cellulose sulfate) – 1 surfactant (Savvy™) total of 30,458 women to be enrolled

14 late-stage clinical trials (concl.) primary endpoint is HIV secondary endpoints: – BV (BufferGel™, PRO 2000) – chlamydia (BufferGel™, Cellulose sulfate, PRO 2000, Savvy™) – genital ulcer disease (BufferGel™, PRO 2000) – gonorrhea (BufferGel™, Cellulose sulfate, PRO 2000, Savvy™) – HSV-2 (BufferGel™, PRO 2000) – syphilis (BufferGel™, PRO 2000) – trichomoniasis (BufferGel™, PRO 2000) 3 are contraceptive: – BufferGel™, PRO 2000, Savvy™ clinical trial sites: – 11 Africa countries, India (Pune and ?), 1 US site (Philadelphia)

15 phase 2/2B clinical trials CANDIDATE MICROBICIDE MECHANISM OF ACTION SPONSORPOP. SIZE TRIAL SITESSTATUS BufferGel™ PRO 2000 Acid Buffer Entry & Fusion Inhibitor NIAID3220India/ Pune Malawi/ Blantyre, Lilongwe South Africa/ Durban, Hlabisa Tanzania/ Moshi USA/ Philadelphia Zambia/ Lusaka Zimbabwe/ Harare, Chitungwiza Protocol Finalized Aug 04 Enroll- ment Nov 04

16 phase 3 clinical trials CANDIDATE MICROBICIDE MECHANIS OF ACTION SPONSORPOP. SIZETRIAL SITESSTATUS Carraguard®Adsorption Inhibitor Population Council 6300South Africa/ Durban, Edendale, GaRankuwa, Soshanguve Enrollment Mar 04 (MEDUNSA) Enrollment Apr 04 (UCT) Enrollment Sep 04 (MRC) Cellulose sulfate/CS Adsorption Inhibitor CONRAD2574Benin Burkina Faso India Kenya South Africa Uganda Enrollment Apr 05 FHI2160Nigeria (2 sites)Screening Oct 04 Enrollment Nov 04

17 phase 3 clinical trials (concl.) CANDIDATE MICROBICIDE MECHANISM OF ACTION SPONSORPOP. SIZETRIAL SITESSTATUS PRO 2000 (0.5 % and 2%) Entry & Fusion Inhibitor Indevus Medical Research Council 11920South Africa/ Durban, Johannesburg, Mtubatuba Tanzania/ Mwanza City Uganda/ Masaka Zambia/ Lusaka Enrollment Jan 05 Savvy™/C-31G* (2 studies combined) SurfactantFHI4284Ghana (2 sites) Nigeria (2 sites) Enrollment Sep 04 *Also in a phase 2/3 contraceptive effectiveness trial

18 clinical trial challenges complex clinical trial design new, unfamiliar type of product healthy individuals -- yet at “high risk” results affected by user behavior sensitive issues – sex, power, gender stigma associated with HIV and sexual activity transnational collaborations unclear regulatory guidance/ requirements ethical issues Sources: Harrison et al. (2003) Topical microbicides for disease prevention: status and challenges, CID/ Heise L. Ethical challenges in clinical testing of microbicides Presentation at Microbicides 2004

19 ethical issues equitable distribution of burdens and benefits -- avoiding exploitation avoiding “wishful thinking” – also known as the “therapeutic misconception” standard of care for trial participants – What package of prevention and care should be provided to trial participants? – What obligation do we have to those who seroconvert during a trial? Source: Heise L. Ethical challenges in clinical testing of microbicides Presentation at Microbicides 2004

20 brief background and update tenofovir gel in two phase 2 trials in the microbicide pipeline: – PRO 2000 and tenofovir gel trial in South Africa – tenofovir gel (HPTN 059) trial in Pune, India and Bronx, NY an example: tenofovir

21 conclusions With leadership, sufficient financial resources, collaborative efforts and product development expertise, women in developing countries should have access to effective microbicides within the next 5 to 10 years.

22 acknowledgments Franka N. des Vignes, PhD Program Officer Trisha L. Lamphear, MPH Research Associate Jana C. Bowcut, MPH Research Associate Cecilia D. Fox Administrative Associate Pamela Norick Senior Legislative and Policy Adviser The work of the Alliance has been made possible by the dedication of its participants and contributions from the: William and Flora Hewlett Foundation, International Partnership for Microbicides, Moriah Fund, Rockefeller Foundation, Bill and Melinda Gates Foundation through the Global Microbicide Project, and the generosity of private contributors.

23 visit our continually updated website at: www.microbicide.org or contact the Alliance directly: 8484 Georgia Avenue, Suite 940 Silver Spring, MD 20910 tel: 301-587-9690; fax: 301-588-8390 email: info@microbicide.org for more information

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