microbicides in clinical trials: a detailed look polly f. harrison, phd director, alliance for...

Microbicides in Clinical Trials: A Detailed Look

Polly F. Harrison, PhDDirector, Alliance for Microbicide Development

University of North Carolina at Chapel HillSchool of Public Health, Office of Global Health

21 October 2004

clinical trial phases

Participants Length PurposePhase 1 10-100 several mos. safety

Phase 1/2 several 100 several mos. safety/ dose ranging

Phase 2 ~200 (couples) 6 mos.- 1 yr. expanded safety

Phase 2/2B several 1,000 ~3 yrs. safety/ direct estimate

effectiveness

Phase 3 300-30,000 1-4 yrs. effectiveness

current microbicide clinical trial sites

Phase 1

Phase 1/2

Phase 2

Phase 2/2B

Phase 3

Multi-Phase

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)


Uganda (2 trials)


-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)


Zambia (2 trials)


-PRO 2000 (Phase 3)

Tanzania (2 trials)


-PRO 2000 (Phase 3)

Malawi (1 trial)


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)


-Carraguard® (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)


-Savvy® (Phase 3)Thailand (1 trial)

- Carraguard® (Phase 1)

candidates in clinical trials (by phase)

PHASE TOTAL MICROBICIDE CANDIDATES

1 6 AcidformTM/AmphoraTM

Cellulose acetate phthalate/CAPLactin-V capsule Polystyrene sulphonate/PSS UC-781 VivaGel/SPL7013TM

1/2 2 Invisible CondomTM,

Praneem polyherbal

2 3 Human monoclonal antibodies (C2F5, C2G12, C4E10)Protected lactobacillus in combination with BZKTenofovir/PMPA

2/2B 2 BufferGelTM

PRO2000

3 3 Carraguard®

Cellulose sulfate/CSSavvyTM/C-31G

TOTAL 16

all current clinical trials (by product and phase)

1 1/2 2 2/2B 3

Acidform™/ Amphora™ + Diaphragm

Invisible Condom™

Human monoclonal antibodies (C2F5, C2G12, C4E10)

BufferGel™ Carraguard®

Carraguard® Praneem Polyherbal

PRO 2000

Tenofovir/ PMPA

PRO 2000 Cellulose 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

phase 1 clinical trialsCANDIDATE

MICROBICIDEMECHANISM OF ACTION

SPONSOR POP. SIZE TRIAL SITES STATUS

Acidform™/ Amphora™ + Diaphragm6 month safety(Diaphragm w/Acidform, Diaphragm w/ KY Jelly)

Acid Buffer CONRADGMP

12060 each arm

South Africa On-going began enrollment

Carraguard® Adsorption Inhibitor

Population Council

South Africa/DurbanThailand/Chiang Rai

On-going

Cellulose acetate phthalate/CAP

Multiple Mechanisms

Imperial College London, UK

Part A- 10Part B- 50

UK/London Part A recruitment has been suspended at 5. Resume once the product has been reformulated and appropriate permission received.

phase 1 clinical trials (cont.)CANDIDATE



Cellulose acetate phthalate 13%/CAP 13%

Multiple Mechanisms

Emory U. N.D. N.D. Enrollment Mar 05

Cellulose sulfate + Diaphragm6 months safetysexually active women

Adsorption Inhibitor

CONRADGMP

180 Zimbabwe Enrollment began Aug 04

Lactin-V capsule Vaginal Defense

NIAIDOsel, Inc.

90 US/Pittsburgh, PAUS/Seattle, WA

Approved by FDA

Lemon/ Lime Juice

N.D. N.D. N.D. N.D. N.D.

Polystyrene sulphonate/PSS

Adsorption Inhibitor

GMP 72 US/Houston, TXUS/Pittsburgh, PAUS/Providence, RI

Stopped Phase 1 studies- report to be submitted to FDA

phase 1 clinical trials (concl.)CANDIDATE



UC-781 Replication Inhibitor

CONRADBiosyn, Inc.

48 US/Norfolk, VA Planned Male tolerance

UC-781 Replication Inhibitor

Biosyn, Inc. 54 women, 36 men

US/Atlanta, GA Enrollment Dec 04

VivaGel™ (SPL7013gel)

Entry & Fusion Inhibitor

Starpharma Pty Limited

36 Australia/ Adelaide Cohorts who received 0.5% and 1% w/w SPL7013 gel completed. Cohorts receiving 3% w/w SPL7013 gel strength on-going.

phase 1/2 clinical trialsCANDIDATE



Invisible Condom™


CRI 452 Cameroon Funded Phase of production/ preparation of applicators and formulations for trial.

Praneem polyherbal

Uncharacterized Indian Council of Medical Research (ICMR)

N.D. N.D. Being reformulated(Working on a Phase 3 of formulation to treat BV; probably Indian funding?)




Human monoclonal antibodies (C2F5, C2G12, C4E10)


Polymun Scientific

N.D. United States Under IND soon

PRO 2000Tenofovir/PMPA


Nucleotide Reverse

Transcriptase Inhibitor

EcoBio 1,000 South Africa/Vulindlela, Northern KwaZulu- Natal

Protocol in “re-development.”Enrollment to begin late 1st quarter or early 2nd quarter 2005.

Protected lactobacillus in combination with BZK

Vaginal Defense

Biofem, Inc Part 1- 28 participantsPart 2- 50 participants

Pending In development

Tenofovir/PMPA (HPTN 059)

Nucleotide Reverse

Transcriptase Inhibitor

NIH/DAIDS(HPTN)Gilead Sciences

200 India/ PuneUS/ Bronx, NY

Protocol under development

late-stage clinical trialsPHASE CANDIDATES STATUS

2/2BBufferGel™

PRO 2000

Enrollment to begin

Nov. 2004

3 Carraguard®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-31GEnrollment began

Sep. 2004

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

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)

phase 2/2B clinical trialsCANDIDATE


SPONSOR POP. SIZE

TRIAL SITES STATUS

BufferGel™

PRO 2000

Acid Buffer


NIAID 3220 India/ PuneMalawi/ Blantyre, LilongweSouth Africa/ Durban, HlabisaTanzania/ MoshiUSA/ PhiladelphiaZambia/ LusakaZimbabwe/ Harare, Chitungwiza

Protocol Finalized Aug 04Enroll-ment Nov 04


MICROBICIDEMECHANISOF ACTION


Carraguard® AdsorptionInhibitor

PopulationCouncil

6300 South Africa/ Durban,Edendale, GaRankuwa,Soshanguve

Enrollment Mar 04(MEDUNSA)Enrollment Apr 04(UCT)Enrollment Sep 04(MRC)

Cellulosesulfate/CS

AdsorptionInhibitor

CONRAD 2574 BeninBurkina FasoIndiaKenyaSouth AfricaUganda

Enrollment Apr 05

FHI 2160 Nigeria (2 sites) Screening Oct 04Enrollment Nov 04

phase 3 clinical trials (concl.)

CANDIDATE MICROBICIDE

MECHANISM OF ACTION


PRO 2000(0.5 % and 2%)


IndevusMedical Research Council

11920 South Africa/ Durban, Johannesburg, MtubatubaTanzania/ Mwanza CityUganda/ MasakaZambia/ Lusaka

Enrollment Jan 05

Savvy™/C-31G* (2 studies combined)

Surfactant FHI 4284 Ghana (2 sites) Nigeria (2 sites)

Enrollment Sep 04

*Also in a phase 2/3 contraceptive effectiveness trial

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 issuesSources: 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

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

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

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.

acknowledgments

Franka N. des Vignes, PhD Program OfficerTrisha L. Lamphear, MPH Research AssociateJana C. Bowcut, MPH Research AssociateCecilia D. Fox Administrative AssociatePamela 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.

visit our continually updated website at:

www.microbicide.org

or contact the Alliance directly:8484 Georgia Avenue, Suite 940

Silver Spring, MD 20910tel: 301-587-9690; fax: 301-588-8390

email: [email protected]

for more information

microbicides in clinical trials: a detailed look polly f. harrison, phd director, alliance for...

Documents

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