1. Microbicides Trial Network
Safety and acceptability trial of the dapivirine vaginal ring in U.S. adolescents
K. Bunge, L. Levy, D. Szydlo, J. Zhang, A. Gaur, D. Reirden, K. Mayer, D. Futterman, C. Hoesley, S. Hillier, M. Marzinke, C. Dezzutti, C. Wilson, L. Soto-Torres, B. Kapogiannis, A. Nel, K. Squires, MTN-023/IPM 030 Protocol Team
Microbicides Trial Network
July 25, 2017
K. Bunge1, L. Levy2, D. Szydlo3, J. Zhang3, A. Gaur4, D. Reirden5, K. Mayer6, D. Futterman7, C. Hoesley8, S. Hillier9, M. Marzinke10, C. Dezzutti9, C. Wilson8, L. Soto-Torres11, B. Kapogiannis12, A. Nel13, K. Squires14, MTN-023/IPM 030 Protocol Team

2. HIV and adolescent girls
Young women ages years are disproportionately affected by the HIV epidemic
Among girls AIDS is the leading cause of death (UNAIDS 2016-AIDS by the numbers)
In Sub-Saharan Africa, 25% of new infections occur among young women in the year age group (UNAIDS 2016 estimates)

3. HIV Prevention in ASPIRE and The Ring Study
27% reduction
31%
reduction AN
Overall 31% reduction in HIV (statistically significant)
77 infections out of 1300 women in active group (4.1% incidence rate)
56 infections out of 650 women in placebo group (6.1% incidence rate)
Explain the randomisation again. Why 77 vs 56 (confusing to civil society sometimes)
Baeten et al, N Engl J Med Nel et al, N Engl J Med 2016

4. In ASPIRE, HIV protection differed by age
Among women who were 25 and older when they enrolled, 61% fewer acquired HIV in the dapivirine ring group compared to the placebo ring group
Further analysis of data found the age cutoff for HIV protection was age 21
Age – no protection (and lowest adherence)
Age – 56% fewer HIV infections among women in the dapivirine ring group vs. placebo group
Our question: is the ring safe and acceptable in year olds? Is there a reason to be concerned about safety?
In a pre-planned analysis, we looked at different characteristics of women, one of which was age -- older and younger than 25. This was the only characteristic in which there was a statistically significant difference between women in the placebo group and women in the dapivirine group.
Among women who were 25 and older when they enrolled, 61% fewer acquired HIV during the study in the dapivirine ring group compared to the placebo ring group. And this was highly statistically significant.
Additional analyses were performed to further explore these results. Participants were stratified by age and divided into three groups with approximately equal numbers of HIV infections to balance statistical power. These results were also statistically significant - and you can see that the difference is really for those older than 21, that in fact women ages 22, 23, 24, 25 had significant reduction in HIV.
If asked:
Age 18-21: -27% effective (95% CI %) p=0.45
451 women, 44 HIV infections, placebo annual incidence 5.4% (95% CI )
Age 22-26: 56% reduced risk of HIV (95% CI 19-76%) p = 0.009
752 women, 51 HIV infections, placebo annual incidence 6.1% (95% CI )
Age 27-45: 51% reduced risk of HIV (95% CI 8-74%) p =0.028
1,192 women, 44 infections, placebo annual incidence 3.0% (95% CI )
Baeten et al, N Engl J Med 2016

5. MTN023/IPM 030 Project iMatter
Phase 2a randomized, double-blind placebo controlled trial of a dapivirine vaginal ring in year olds in the US
Collaboration between Adolescent Trials Network and Microbicide Trials Network
Dapivirine vaginal ring was developed and supplied by IPM
6 sites
ATN
Denver
Bronx
Boston
Memphis
MTN
Birmingham
Pittsburgh

6. Randomization and participant criteria
Randomized 3:1 to dapivirine or placebo ring
Inserted monthly for 6 months
Key inclusion criteria
Participant assent and guardian consent
Ages 15-17
Healthy, HIV-negative
History of sexual activity
Using an effective method of contraception at enrollment

7. Primary objective and endpoint
To assess the safety of dapivirine (25 mg) administered via a silicone vaginal ring in HIV-uninfected adolescent females, when inserted once every 4 weeks during 24 weeks of study product use
Primary endpoints
Grade 2 adverse events (AE) deemed related to study product
Grade 3 or higher adverse events

8. Secondary objectives and endpoints
Acceptability
Participant self report of acceptability via ACASI
Adherence
Frequency of VR expulsions and removals by self report
Pharmacokinetics (local and systemic)
Dapivirine concentrations in plasma and vaginal fluid

9. Exploratory objectives
Adherence: To investigate the association between systemic and local drug concentration, ring residual drug levels and self-reported adherence measures
Vaginal microenvironment: To describe the genital microenvironment over 24 weeks of study product use

10. Visit schedule / sample collection
Screen
Enrollment
Phone contact
Clinical evaluation
Clinical evaluation
Phone contact
≤56 Days
Day 0
1 week
2 weeks
q4 week x 6
25 weeks
Each visit: AE assessment, adherence, acceptability
2, 4, 12 and 24 weeks: blood and vaginal fluid for drug level
Each month: returned ring for residual drug level
Ask SLH- PK instead of drug

11. Demographics Dapivirine (n=73) Placebo (n=23) Age, mean (SD) Range
16.3 (0.8)
(15-17)
16.2 (0.7)
Age at first menses
11.7
(8-15)
(10-14)
Latina or Hispanic
22%
17%
Race
Black or African American
White
Other
47%
27%
26%
57%
Lifetime sexual partners, median 3
(1-23)
(1-12)
No condom last sex
49%
Anal sex no condom, ever
21% 0%

12. Primary endpoint: Safety assessment
Dapivirine
(n=73)
Placebo
(n=23)
Odds Ratio
P-Value
Participants with one or more
Grade 2 related AE
8 (11%)
2 (9%)
1.29
(0.25, 6.57)
1.00
Grade 3 or higher AE
3 (4%)
0 (0%) --
Total
11 (15%)
1.86
(0.36, 18.55)
0.73

13. Product hold: none due to product toxicity
Dapivirine
(n=73)
Placebo
(n=23)
Total
(n=96)
Number with at least one product hold
7 (10%)
2 (9%)
9 (9%)
Total no. of product holds 8 2 10
Total no. of permanent discontinuation
2 (25%)
1 (50%)
3 (30%)
Reasons for product hold AE
Pregnancy
Other
4 (50%)
0 (0%)
2 (50%)
4 (40%)
AEs prompting hold: PID (2), trichomonas, IUD expulsion
Fill in “other”?

14. Adherence: biologic measures and self-report
Dapivirine plasma drug concentration > 95 pg/mL
87% of plasma samples with levels suggestive of adherence to study product in the day prior to visit
Dapivirine residual drug levels in used rings <23.5 mg
95% of returned vaginal rings with levels suggestive of adherence over the past month
Self report
42% (95% CI, 32, 52) of participants reported that they never removed the ring except to replace it monthly.
Most removals were brief

15. Spaghetti plot of residual dapivirine concentration over time
Better figure from SCHARP

16. Acceptability: assessed at 3 and 6 months
Since your last visit…
% visits
It was easy or very easy to use the ring
95%
Never experienced any physical discomfort because of the ring
87%
Never aware of the ring during normal activities
74%
Never felt the ring inside you when you had vaginal or anal sex
63%
….if you felt the ring, how much did it bother you? Not at all
A little
76%
13%
Did your sex partner feel the ring when you had sex? Never
Not at all
…if your partner was aware, did it bother him/her A little
Unknown
41%
18%
49%
17%
Did you like the ring? Yes, liked it
93%
Choose a couple to emphasize?

17. Conclusions
The dapivirine vaginal ring is safe and acceptable in year old US girls
Both plasma and residual vaginal ring drug levels indicated high adherence
Consistency between dapivirine plasma levels and residual dapivirine levels in used rings supports appropriate study product use

18. Next steps
Dapivirine licensure package has been submitted to the European Medicines Agency; SA MCC and FDA to follow
Safety data among adolescents are required to support product labelling of new prevention products in this at risk group
MTN-034 to begin in Q4, 2017
A Phase 2a crossover trial evaluating the safety of and adherence to a vaginal matrix ring containing dapivirine and oral emtricitabine/tenofovir disoproxil fumarate in year olds
4 sites: S Africa, Uganda, Kenya, Zimbabwe
A Phase 2a Crossover Trial Evaluating the Safety of and Adherence to a Vaginal Matrix Ring Containing Dapivirine and Oral Emtricitabine/Tenofovir Disoproxil Fumarate in an Adolescent Female Population

19. Funding
The Microbicide Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. The Adolescent Medicine Trials Network (ATN) for HIV/AIDS intervention is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD ).

20. Acknowledgements Most especially, THANK YOU to the participants
MTN 023/IPM030 study staff: Aditya Gaur, Daniel Reirden, Kenneth Mayer, Donna Futterman, Craig Hoesley International Partnership for Microbicides: Annalene Nel Dapivirine vaginal rings were developed and supplied by IPM SCHARP: Elizabeth Brown, Daniel Szydlo, Jingyang Zhang FHI360: Lisa Levy, Sherri Johnson MTN: Sharon Hillier, Jared Baeten, Devika Singh, Charlene Dezzutti, Mark Marzinke, Craig Hendrix ATN: Craig Wilson, Pamina Gorbach NIH: Lydia Soto-Torres, Roberta Black, Bill Kapogiannis
Most especially, THANK YOU to the participants
and their guardians