Microbicides The Population Council Experience and Future Directions Don E. Waldron Medical Director Don E. Waldron Medical Director

HistoryHistory  Early research in the late 80’s identified large molecular structured entity derived from sea weed as a potential HIV blocking agent  In vitro tissue studies showed Carraguard ® protective against HIV  In vivo mouse and monkey experiments demonstrated blocking  Methyl cellulose placebo was not protective against HIV  Early research in the late 80’s identified large molecular structured entity derived from sea weed as a potential HIV blocking agent  In vitro tissue studies showed Carraguard ® protective against HIV  In vivo mouse and monkey experiments demonstrated blocking  Methyl cellulose placebo was not protective against HIV

Phase I  Trials conducted in many countries including South Africa (SA)  Results showed that Carraguard ® is safe and acceptable  Couples study for male tolerance and acceptability is under analysis  Two studies in HIV positive cohorts are underway  Trials conducted in many countries including South Africa (SA)  Results showed that Carraguard ® is safe and acceptable  Couples study for male tolerance and acceptability is under analysis  Two studies in HIV positive cohorts are underway

Phase II Experience (Preliminary Observations)  Two trials conducted in Thailand (165) and SA (400), two arms, Intent to Treat (ITT)  Safety and acceptability confirmed  Condom use similar in both arms with condom usage in Thailand higher than in SA  Recruitment and retention similar for both arms  Seroconversions only in SA, 8 in each arm  Two trials conducted in Thailand (165) and SA (400), two arms, Intent to Treat (ITT)  Safety and acceptability confirmed  Condom use similar in both arms with condom usage in Thailand higher than in SA  Recruitment and retention similar for both arms  Seroconversions only in SA, 8 in each arm

Gel & Condom Usage During Sex Acts, Phase II SA (ITT)

Phase III Overall Design Considerations  A classic placebo controlled, two arm, double blind ITT trial in 4500 non infected women in SA  The active arm Carraguard® and a methyl cellulose placebo  Maximum trial duration is 48 months with a 24 month maximum subject participation  We are examining a design of closing the trial 12 months after the last patient is enrolled  A classic placebo controlled, two arm, double blind ITT trial in 4500 non infected women in SA  The active arm Carraguard® and a methyl cellulose placebo  Maximum trial duration is 48 months with a 24 month maximum subject participation  We are examining a design of closing the trial 12 months after the last patient is enrolled

Trial Criteria  Two major exclusion criteria –Women who test positive for HIV –Pregnant women  Women with STIs will be accepted  Primary endpoint: HIV seroconversion  Safety endpoints: STIs & vaginal lesions  Two major exclusion criteria –Women who test positive for HIV –Pregnant women  Women with STIs will be accepted  Primary endpoint: HIV seroconversion  Safety endpoints: STIs & vaginal lesions

Compliance Methods  Compliance will be tested using several methods –Visit questionnaires administered by clinic staff –Applicator tracking using bar code –Compliance with visit schedule –Applicator usage test under evaluation  Non compliant subjects will be excluded from the ITT analyses  Compliance will be tested using several methods –Visit questionnaires administered by clinic staff –Applicator tracking using bar code –Compliance with visit schedule –Applicator usage test under evaluation  Non compliant subjects will be excluded from the ITT analyses