1. Jared Baeten, MD PhD Thesla Palanee, PhD Site trainings 2012
OVERVIEW
Jared Baeten, MD PhD
Thesla Palanee, PhD
Site trainings 2012

2. Overview Background and rationale Dapivirine for HIV prevention
MTN-020/ASPIRE overview
MTN-020/ASPIRE sites, timelines, goals
MTN-020 and IPM 027
Lessons learned and thinking ahead

3. Background and Rationale

4. MTN-020 / ASPIRE
A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase III Safety and Effectiveness Trial of a Vaginal Matrix Ring Containing Dapivirine for the Prevention of HIV-1 Infection in Women

5. A Study to Prevent Infection with a
MTN-020 / ASPIRE
A Study to Prevent Infection with a
Ring for Extended Use

6. Antiretrovirals for HIV prevention
Right drug
(safe, effective, ideally not overlapping treatment)
Right place
(sufficient concentrations at site of exposure)
Right time
(present when exposed, user-independent adherence) 6

7. Tenofovir for HIV prevention: successes and challenges
During the past two years, large studies of oral and topical tenofovir-based PrEP have demonstrated efficacy for HIV protection:
Trial
PrEP regimen
Population
Reduction in HIV risk
CAPRISA 004
Peri-coital tenofovir gel
Women
39%
iPrEx
Daily oral FTC/TDF
Men who have sex with men
44%
TDF2
Young heterosexuals
62%
Partners PrEP
Daily oral TDF and FTC/TDF
HIV serodiscordant couples
67% (TDF)
75% (FTC/TDF) 7

8. Tenofovir for HIV prevention: successes and challenges
However, not all trials of tenofovir-based PrEP have found HIV protection:
No efficacy for daily oral FTC/TDF in FEM-PrEP trial and for daily tenofovir gel and daily TDF in VOICE study, both studies of women with high HIV incidence
Across PrEP studies, adherence is likely an important driver of HIV protection
Vaginal rings provide slow, continuous delivery of a drug or multiple drugs to cells inside the vagina over a period of weeks or months. Marketed vaginal ring products include those used for contraceptive delivery and hormone replacement. However, vaginal rings can also be used as a vehicle for delivering potent ARV drugs into the vagina to prevent HIV infection. Because they could be used for one month at a time, vaginal rings may offer a long-acting and convenient prevention option for women. 8

9. Developing a range of options for antiretroviral-based HIV prevention
Pill
Gel
Vaginal film
Vaginal ring
Injectable
Landmark health research is a process of continued development. Tenofovir is critical first proof on a future pathway.
Goals: long acting, safe, effective, low cost and user- friendly
Maximize choice & optimize effectiveness 9

10. Vaginal ring for HIV prevention: advantages and considerations
Long acting: Monthly or longer
Could potentially improve adherence
Better adherence  better effectiveness
Easy to use, comfortable
Flexible ring, can be self-inserted
Rarely felt by women or male partners
Little or no impact on sexual activity
Suitable for a wide range of settings
Relatively low manufacturing cost
Good safety and acceptability data
Potential for drug combinations
For example, contraception, in the future

11. Dapivirine Vaginal Ring for HIV Prevention

12. Dapivirine (TMC 120)
Dapivirine is a di-amino-pyrimidine (DAPY) substituted highly potent non-nucleoside reverse transciptase inhibitor (NNRTI) of HIV-1 replication
Initially developed and tested as oral antiretroviral treatment agent by Tibotec
Potent activity both in vitro and in vivo

13. Dapivirine ring Flexible ring made of an elastic silicone material
Off white, platinum-catalyzed
Measures 56 mm (about 2 ½”) in diameter and 7.7 mm (3/4”) thick
Designed for monthly use
Developed by the International Partnership for Microbicides (IPM)

14. Dapivirine vaginal ring composition
Tested for description, weight, tensile strength, ID, assay, content uniformity, impurities, dissolution and microbial limits

15. Dapivirine safety studies
11 oral dosing studies, for HIV treatment (N=211)
9 studies in healthy volunteers
2 studies in HIV-infected patients
8 vaginal gel studies, for HIV prevention (N=774)
6 vaginal ring studies, for HIV prevention (N=393)
Ring-001: 1 trial
Ring-002: 2 trials
Ring-003: 1 trial
Ring-004: 3 trials

16. IPM dapivirine Ring-004 trials
Description
Phase
Countries N
IPM 024
Safety and PK
(28 days) I
Belgium 16
(8:8)
IPM 013
(56/57 days) 48
(36:12)
IPM 015
(84 days)
I/II
Kenya
Malawi
Tanzania
South Africa
280
(140:140)

17. Ring-004 safety and pharmacokinetic studies
IPM 024 : Phase 1 Study, 16 Women, 4 weeks, Belgium (2009)
Desired sustainable release, PK properties, no safety concerns
Vaginal fluid levels on Day 28 at least 4000 times higher than the in vitro inhibitory concentration in cervical tissues; plasma levels <1 ng/mL
IPM 013 : Phase 1 study, 48 women, 8 weeks, Belgium (2010)
Multiple dosing of monthly rings well tolerated, no safety concerns
PK data support sustained release over a 35-day period
Vaginal fluid levels on Day 35 at least 3000 times higher than the in vitro 99% inhibitory concentration in cervical tissue, Plasma levels < 1ng/ml
IPM 015: Phase I/II study, 280 women, 12 weeks, Africa ( )
Active and placebo rings safe and well tolerated. Adverse events probably or possible related to ring use were similar for dapivirine and placebo
Plasma levels <1ng/mL; ring residual levels found that ~4mg dapivirine is released from Ring-004 over 28 days

18. IPM 015: ring acceptability
Ring was comfortable : 97%
Ring not felt during daily activities : 89%
Willing to use if effective : 97%
Prefer to wear ring every day : 97%
Prefer ring use during menses : 69%
Concerned ring might fall out : 16%
Concerned ring might get lost in body : 22%
Male partner did not feel ring during sex : 63%
Male partner felt ring, but no problem: 22%
Male partner felt ring might be or definitely a problem : 1%

19. IPM 015: safety data Dapivirine N=140 n (%) Placebo SAEs 1 (0.7)
4 (2.9)
HIV seroconversions
3 (2.1)
Positive pregnancy tests
2 (1.4)
Non-serious AEs resulting in product discontinuation
AEs definitely related to product
AEs possibly/probably related to product
30 (21.4)
31 (22.1)

20. IPM 015: ring adherence Frequency of ring use
Perfect adherence (ring never came out for >1 day) : 92%
Ring removals
Median number of times ring came out : 1 time per visit interval
Frequency decreased over time
Most frequent activity for involuntary expulsion: urination/ defecation
Most common reason for removal: cleaning
Had sex during the time that the ring was out : 17% - 36%

21. Dapivirine ring for HIV prevention: Ring-004
SAFETY:
Safe and well-tolerated
No related SAEs, AEs similar in treatment and placebo groups
PK:
High vaginal, low systemic concentrations
Sustained release for at least 35 days
Acceptability
High willingness, good adherence, most common reason for removal = menses

22. ASPIRE: Design, Objectives, and Overview

23. ASPIRE Study Design

24. Primary Objectives EFFECTIVENESS
To determine the effectiveness of dapivirine (25 mg) administered in a silicone elastomer vaginal matrix ring, when inserted once every 4 weeks, in preventing HIV infection among healthy sexually active HIV-uninfected women
Primary Effectiveness Outcome: HIV seroconversion

25. Primary Objectives SAFETY
To assess the safety of dapivirine (25 mg) administered in a silicone elastomer vaginal matrix ring, when inserted once every 4 weeks over the investigational product use period
Primary Safety Outcomes:
Grade 2 adverse events (AEs) judged to be related to study product
Grade 3 and 4 AEs
All serious adverse events

26. Secondary Objectives Acceptability Adherence Drug resistance
Self-report
Adherence
Including ring expulsions & removals
Drug resistance
In HIV-1 seroconverters
Relationship between drug concentrations and HIV-1 seroconversion
Concentrations of dapivirine in blood and self-collected vaginal swabs

27. Exploratory Objectives
Describe changes in the genital microenvironment
Changes in candidate biomarkers of safety and efficacy
Assess correlation of steady-state drug concentrations and adherence measures
Assess delayed seroconversion
4 week post-product completion visit

28. Behavioral components
Quantitative assessments
CRFs
ACASI
Qualitative component
Subset of 6 sites (35-40♀/site) / ~5% sub-sample (~n=200)
Serial IDIs (M3; Y1 and/or PUEV)
Single IDIs with serconverters/ product discontinuers
Post PUEV FGDs (2 per site)
Adherence Counseling & Education (ACE)
Modeled after NSC and VASP (use experience, needs focused)
Integrates product adherence and visit retention
Main trial conducted at 17 sites in 5 countries
Qualitative data collected at 6 sites in 4 countries:
MU-JHU (Kampala, Uganda)
Spilhaus (Harare, Zimbabwe)
UNC Lilongwe (Lilongwe, Malawi)
WRHI (Johannesburg, South Africa)
DTHF (Cape Town, South Africa)
MRC Chatsworth (Durban, South Africa)

29. Participants
3476 sexually active HIV-uninfected women who are non-pregnant, contracepting, and years of age
Accrual will require approximately months, with total study duration approximately 24 months
Designed so that all participants will achieve 12 months on study product

30. Follow-up Monthly follow-up, including: HIV serologic testing
Contraceptive counseling and provision
Clinical safety assessment
Study produce provision and adherence counseling
Physical and pelvic examination, laboratory safety assessment (every 3-6 months)

31. Pregnancy
Women who become pregnant while in the study will need to stop using the ring but can remain in the study to continue with follow-up visits
Women will be referred for appropriate care and invited to join MTN-016, an observational registry study that aims to understand if product use has an effect on pregnancy outcomes
She may be able to rejoin ASPIRE after her pregnancy

32. HIV acquisition
Sites are required to have procedures for care and support for participants who acquire HIV and referral agreements with HIV primary care and ART providers
The study product will be discontinued immediately
Antiretroviral resistance testing will be done
Seroconverters will be invited to join MTN-015
MTN-015 is a long-term observational study / registry of seroconverters from MTN studies

33. Sites, Timelines, and Goals

34. Proposed sites Blantyre Lilongwe Malawi Cape Town Durban (8 sites)
Johannesburg
South Africa
Kampala
Uganda
Lusaka
Zambia
Harare (3 sites)
Zimbabwe

35. Timeline
2011
Initiate site IRB and regulatory approval process
2012
IRB/regulatory approvals, trainings,
enrollments begin Q3
2013
Enrollments and follow-up continue
2014
End of participant follow-up
2015
Results 35

36. The Big Five Accrual Retention Adherence Clinical and Laboratory
There is a reason why the african big five have appropriately earned this title.  The elephant, lion, cape buffalo, leopard, and rhino are among the most dangerous and difficult animals for an experienced hunter to attain- however with careful considered strategy- even these animals can be captured. The Big Five of MTN 020 are as above. There isn’t one that is more powerful than the other and with considered strategy and support from today the highest quality is achievable.
Clinical and
Laboratory
Participant
Safety
Data Quality
and Timeliness

37. Design efficiencies Accrual
Large number of sites, modest sample size = achievable number of recruitments
Focus will be on protocol adherence during screening and enrollment – i.e., really trying to enroll only those who will return as scheduled for follow-up
Follow-up
Streamlined data collection and study procedures = reduced time spent in clinic
Allowances for efficiencies for individual women – protocol provisions for extra ring dispensing and off-site visits 37

38. Design efficiencies (2)
Retention
Focus from day one from participant one : resource and attention allocation will be critical
No retention = no adherence
Provision of services on-site
Contraception : expanding method mix and convenience
Partner HIV testing, STI evaluation/referral 38

39. MTN-020 and IPM 027

40. Until end of study (12-24 months)
MTN-020 and IPM 027
MTN-020
IPM 027
Design
endpoint driven
fixed time
No. of participants
3,476
1,650
Randomization
1:1
2:1
Age
18-45 yrs
Product use period
Until end of study (12-24 months)
24 months fixed
Person-years follow-up (all / Dapivirine Vaginal Ring)
4,396 / 2,198
3,150 / 2,100
HIV-1 seroconversions
120 80
Power for 50% effect
97%
83%

43. Similarities
Very similar primary, secondary, and exploratory objectives and endpoints

44. Similarities
Very similar primary, secondary, and exploratory objectives and endpoints
Key goals are identical: efficient enrollment, high retention, promotion of product use/adherence, definitively testing whether this product is safe and effective

45. Differences Sample size (3476 vs. 1650)
Follow-up (open-ended vs. fixed 24 months)
Randomization (1:1 vs. 1:2)
Sample collection (somewhat different repositories), laboratory testing (027 has more tests), pregnancy (027 will terminate at pregnancy)

46. Coordination
MTN-020 and IPM 027 teams have worked tirelessly to ensure that data collection, counseling/clinical management, oversight are moving in parallel
MTN-020 and IPM 027 are coordinated within single regulatory/investigational new drug applications (FDA, EMA)

48. Dapivirine ring for HIV prevention
Dapivirine ring has shown safety and acceptability in phase I and phase II trials but its large-scale safety and its effectiveness for HIV protection are unknown
These studies will provide the definitive data to determine whether dapivirine vaginal ring will have the strength of evidence to support potential licensure

49. Key Considerations for Optimization of Implementation

50. Everything else flows from these
Numbers that matter
3476 = total number of women enrolled
>95% = retention, product distribution
100% = attention to data quality, safety
Everything else flows from these

51. Getting to 3476 To date, have defined site targets for start-up
These are clearly not set in stone and will flux depending on timing of site initiation
A portion of 3476 not currently assigned at all – pending early performance
Period of accrual is about 12 months, driven by quality and appropriate pacing

52. Lessons learned… #1. Efficiency matters Efficient and focused start-up
Targeted participant visits
Attention to what is important for a quality study

53. Lessons learned… #2. Adherence is key
Products don’t work if they aren’t used
How will we set up a culture in ASPIRE so that women can accurately report non-use?

54. Lessons learned… #3. Retention is adherence
Missed visit = month of zero adherence

55. Lessons learned…
#4. We all work together – all parts of the study are all our business
Recruitment QC/QA
Retention Regulatory
Adherence Safety Monitoring
Sample collection Space/facilities
Staff morale Study drug/pharmacy
Community/outreach Contraception
Communications Lab-clinic interface
Lab quality Monitoring follow-up

56. Lessons learned… #5. Metrics and competition are healthy Retention #s
Data quality #s

57. Lessons learned… #6. Bigger is not always better
Smaller sites / new sites can be models of success

58. Lessons learned… #7. No one knows how to do this perfectly
Cross-site, cross-team sharing is important
Some of our ideas: job-specific list servs, biweekly calls with FHI360, regular protocol team meetings that focus on site-led presentations
Talk with each other…

59. Lessons learned… #8. Talk with participants
We have much to learn from them

60. Lessons learned… #9. Stakeholder and community involvement is ongoing
Continuous contact

61. Lessons learned…
#10. It takes a team
We are all in this together

62. Malawi College of Medicine – JHU Research Project
ASPIRE TEAM
Malawi College of Medicine – JHU Research Project
UNC Project - Malawi

63. Acknowledgements
MTN is funded by NIAID (5U01AI068633), NICHD and NIMH, all of the U.S. National Institutes of Health