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 SotoTorres B Kapogiannis A Nel K Squires MTN023IPM 030 Protocol Team ID: 919902
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Slide1
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 NetworkJuly 25, 2017
Slide2HIV and adolescent girlsYoung women ages 15-25 years are disproportionately affected by the HIV epidemic
Among girls 10-19 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 15-24 year age group (UNAIDS 2016 estimates)
Slide331%
reductionHIV Prevention in
ASPIRE and The Ring Study
27%
reduction
Baeten et al, N
Engl
J Med 2016 Nel et al, N
Engl
J Med 2016
Slide4In 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 18-21 – no protection
(and lowest adherence)
Age 22-45 – 56% fewer HIV infections
among women in the dapivirine ring group vs. placebo group
Our question: is the ring safe and acceptable in 15-17 year
olds
? Is there a reason to be concerned about safety?
Baeten et al, N
Engl
J Med 2016
Slide5MTN023/IPM 030Project iMatter
Phase 2a randomized, double-blind placebo controlled trial of a dapivirine vaginal ring in 15-17 year olds in the US Collaboration between Adolescent Trials Network and Microbicide Trials NetworkDapivirine vaginal ring was developed and supplied by IPM6 sites
ATN
Denver
Bronx
Boston
Memphis
MTN
Birmingham
Pittsburgh
Slide6Randomization and participant criteria
Randomized 3:1 to dapivirine or placebo ringInserted monthly for 6 monthsKey inclusion criteriaParticipant assent and guardian consentAges 15-17Healthy, HIV-negativeHistory of sexual activityUsing an effective method of contraception at enrollment
Slide7Primary objective and endpoint
Primary objectiveTo 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 endpointsGrade 2 adverse events (AE) deemed related to study productGrade 3 or higher adverse events
Slide8Secondary objectives and endpoints
AcceptabilityParticipant self report of acceptability via ACASIAdherenceFrequency of VR expulsions and removals by self reportPharmacokinetics (local and systemic)Dapivirine concentrations in plasma and vaginal fluid
Slide9Exploratory objectives
Adherence: To investigate the association between systemic and local drug concentration, ring residual drug levels and self-reported adherence measuresVaginal microenvironment: To describe the genital microenvironment over 24 weeks of study product use
Slide10Visit schedule / sample collection
Each visit: AE assessment, adherence, acceptability2, 4, 12 and 24 weeks: blood and vaginal fluid for drug levelEach month: returned ring for residual drug level Screen
Enrollment
Phone contact
Clinical evaluation
≤56 Days
25 weeks
2 weeks
Day 0
Clinical evaluation
q4 week x 6
Phone contact
1 week
Slide11Demographics
Dapivirine(n=73)
Placebo
(n=23)
Age, mean (SD)
Range
16.3 (0.8)
(15-17)
16.2 (0.7)
(15-17)
Age
at first menses
Range11.7
(8-15)11.7 (10-14)
Latina or Hispanic22%17%
Race Black or African American White Other
47%
27%
26%
57%
17%
26%Lifetime
sexual partners, median
Range
3
(1-23)
3
(1-12)
No condom last sex
49%
49%
Anal sex
no condom, ever
21%
0%
Slide12Primary 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%)
--
1.00
Total
11 (15%)
2 (9%)
1.86
(0.36,
18.55)
0.73
Slide13Product 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%)
2 (25%)
2 (25%)
0 (0%)
1 (50%)
2 (50%)
4 (40%)
3 (30%)
4 (40%)
AEs prompting hold: PID (2), trichomonas, IUD expulsion
Slide14Adherence: 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 visitDapivirine residual drug levels in used rings <23.5 mg95% of returned vaginal rings with levels suggestive of adherence over the past monthSelf report42% (95% CI, 32, 52) of participants reported that they never removed the ring except to replace it monthly.Most removals were brief
Slide15Spaghetti plot of residual dapivirine concentration over time
Slide16Acceptability: assessed at 3 and 6 months
Since your last visit…
% visits
It was eas
y 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
Un
known
41%
18%
49%
17%
Did you like the ring? Yes, liked it
93%
Slide17Conclusions
The dapivirine vaginal ring is safe and acceptable in 15-17 year old US girlsBoth plasma and residual vaginal ring drug levels indicated high adherenceConsistency between dapivirine plasma levels and residual dapivirine levels in used rings supports appropriate study product use
Slide18Next steps
Dapivirine licensure package has been submitted to the European Medicines Agency; SA MCC and FDA to followSafety data among adolescents are required to support product labelling of new prevention products in this at risk groupMTN-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 16-21 year olds4 sites: S Africa, Uganda, Kenya, Zimbabwe
Slide19Funding
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 040533).
Slide20Acknowledgements
MTN 023/IPM030 study staff: Aditya Gaur, Daniel Reirden, Kenneth Mayer, Donna Futterman, Craig Hoesley International Partnership for Microbicides: Annalene NelDapivirine vaginal rings were developed and supplied by IPMSCHARP: Elizabeth Brown, Daniel Szydlo, Jingyang ZhangFHI360: 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