1. CONRAD’s Cellulose Sulfate HIV Prevention Trial Dr. Lut Van Damme
On behalf of
The CS Phase III Study Team

2. Preclinical Testing
CS was tested in different models with different endpoints and using several strains of HIV and showed in vitro effectiveness
Preclinical testing in the rabbit vaginal irritation model, in monkeys, or explants gave no indication for potential of harm; no increase in pro-inflammatory markers

3. Conclusions from safety studies and contraceptive trial in women
Ten safety studies in women and two contraceptive trials
No difference in symptoms, colposcopy findings, vaginal infections, systemic labs, or cytokines when compared with KY Jelly
Increase in E. coli in the CS group and decrease in Lactobacillus H202+ in both groups:
Both changes have been previously reported with the use of other products
Effective contraceptive with few adverse events related to gel use
Also two male tolerance studies were done.

4. HIV Prevention Trial

5. Objectives and Endpoints
Primary:
Effectiveness in preventing male-to-female transmission of HIV-infection through vaginal intercourse by comparing HIV incidence in both arms (ITT)
Secondary:
Effectiveness in preventing male-to-female transmission of gonorrhea and chlamydia infection through vaginal intercourse by comparing the incidence in both arms (ITT – time to first event)

6. Design and Population Design:
Randomized (1:1 allocation), placebo-controlled, blinded, two-arm, multicenter
Study Population:
HIV negative women, 18 years or older, with multiple partners
Randomization used permuted blocks, stratified on site.

7. Organizational Chart and Sites
BENIN
PI- Michel Alary
Co-PI- Fernand Guedou
INDIA-CH
PI- Suniti Solomon
CONRAD
FHI
ITM
INDIA-BA
PI- Marissa Becker
Co-PI- Reynold Washington
UGANDA
PI- Florence Mirembe
Mention roles of FHI (monitoring; DM/DA; BSS; audits) and ITM; IDMC
SOUTH AFRICA
PI- Roshini Govinden
Co-PI- Gita Ramjee

8. Placebo & Gel Delivery Placebo:
“Universal” placebo specially developed to have “no” effect on pathogens or microflora
Gel delivery:
Single use opaque applicators, delivering 3.5ml
Gels were to be used within one hour before each vaginal intercourse
The placebo has been specifically developed for microbicide trials and is used in other trials as well. It has been tested for safety by CONRAD.

10. Procedures Informed consent with questionnaire Monthly clinic visits
HIV tests: screening, enrollment, FU1, 3, 6, 9 and 12 (final)
Pelvic exams: quarterly
Tracing of participants
Behavioral and Social Science work
Repeat ICQ every quarter; monthly visits: questions on compliance, AE collection and condom/gel counseling and distribution

11. Lab Endpoints Testing HIV Gonorrhea and Chlamydia: SDA testing
Screening and enrollment: national/local algorithm
Follow-up: Rapid tests: Determine, Bioline, Unigold on finger prick blood; second venous sample if first algorithm positive
Final sample: PCR (except for Bangalore)
Gonorrhea and Chlamydia: SDA testing
QC program: all positive and 10% of negative samples; most HIV seroconversions confirmed by ITM
Diagnose pas na twee stalen pos; SDA because of inhibition. Voor 4 seroconvertors in Durban geen bevestiging in Antwerpen.

13. Sample Size and Power Planned sample size = 2,574 HIV negative women
Assumptions:
50% effectiveness of CS
2-sided significance level of 0.05
80% power
80% of participants completing 12-month follow up
HIV-incidence in control arm: 4%
66 events required

14. (Interim) Analysis and IDMC
One planned interim analysis with Independent Data Monitoring Committee meeting after ~ 33 HIV seroconversions - 26 January 2007
Guidance from the IDMC requested if p<0.10 in the direction of harm (i.e. stop for harm or futility)

15. Population Tree Screened 2985 Enrolled 1428 CS Placebo Total
3 PCR Positive CS
Placebo
Total
ITT population
717
708
1425
HIV analysis
706
692
1398
Lost to follow-up
10.7%
9.0%
9.9%
Discontinued early
2.4%
1.0%
1.7%
Completed final visit
86.9%
90.0%
88.4%
Screening/enrollment started in July 2005; last visit on 31 March Staggered start of sites. Women excluded from primary HIV analysis when no HIV FU test (10 LFU and 1 early disc. on CS, 15 LFU and 1 early disc. on placebo).  98.1% contributed data to the effectiveness analysis.
Data base is still not 100% final. Some queries have not been answered yet, no effect on HIV # but may slightly change incidence. LTFU: benin: 24%; SA:11%; Ug: 5%; almost zero in India.

16. Baseline characteristics
Placebo
Age (years)
30.3
30.9
Education (years)
7.8
Ever pregnant
90.0%
92.5%
Married
22.7%
23.2%
Vaginal acts in past 7 days
11.6
11.0
Condom use (screening)
60.7%
61.3%
Condom use (enrollment)
81.3%
80.8%

17. Results Events RR (95% CI) Two-sided p value CS Placebo HIV (Interim)24 11
2.23
(1.05, 5.03)
0.022
HIV (ITT - Final) 25 16
1.61
(0.86, 3.01)
0.135
HIV (per protocol) 23
2.17
(1.06, 4.45)
0.030
Gonorrhea 53 49
1.10
(0.74, 1.62)
0.634
Chlamydia 37 52
0.71
(0.47, 1.08)
0.111
Conditional power < 1%
Data on adherence were presented this morning
No PCR for BA.
Incidence: CS 5.3 – P:3.34 – overall: 4.31

18. KM Estimates of Incident HIV Infection Probabilities, by Treatment Group
Placebo CS

19. Conclusion CS is not effective against HIV transmission
All polyanions are different, two other trials are ongoing and passed several IDMC meetings
The field may learn from this experience if further exploration leads to potential markers of no effect/increased risk
A range of HIV prevention tools/products needed

20. Possible biological causes of CS clinical failure
Hypothesis I. CS stimulates HIV capture through DC sign interaction
Hypothesis II. Repeated and frequent exposure of cervicovaginal mucosa to CS causes a subclinical inflammatory reaction or local immune dysfunction
Hypothesis III. Repeated daily administration of CS causes microflora disturbances and/or pathogenic outgrowth
Do not mention Balzarini

21. Plans Explore phase III data base
Send panel of blinded products to different laboratories for further testing
Analyze self-collected vaginal swabs
Evaluate data from ongoing monkey study
Initiate safety study in 60 women in the USA (Norfolk and Pittsburgh)

23. Sponsors and Collaborators
Sponsors: USAID and Bill & Melinda Gates Foundation
CS PHASE III TEAM
South Africa Team Medical Research Council
Gita Ramjee Roshini Govinden Vinodh Edward Raju Evasen Rashika Maharaj
Uganda Team Makerere University Medical School
Florence Mirembe Clemensia Nakabiito Bina Pande Tom Tenywa
Benin Team Centre hospitalier Affilié Universitaire de Québec
Michel Alary Fernand Guédou Isaac Minani Marguérite Massinga Loembé
CONRAD Team
Lut Van Damme Suzanne Murphy Louisa Wahala Laria Jones
FHI Doug Taylor Jennifer Deese Lisa Saylor Wes Rountree
Betsy Tolley And Monitors
ITM
Tania Crucitti Said Abdellati Katrien Fransen Greet Beelaert Vicky Cuylaerts
Chennai Team Y R Gaitonde Medical Education & Research Foundation
Suniti Solomon Aylur K. Ganesh A K Srikrishnan Sethulakshmi C. Johnson Murugavel G. Kailapuri
Bangalore Team University of Manitoba/St. John’s Medical College
Marissa Becker B S Pradeep Reynold Washington Stephen Moses Satya Narayana Kevin Mendonca