Safety and acceptability trial of the dapivirine vaginal ring in U.S. adolescents - PowerPoint Presentation

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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

HIV 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)

31%

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

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 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

MTN023/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

Randomization 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

Primary 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

Secondary 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

Exploratory 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

Visit 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

Demographics

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%

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%)

--

1.00

Total

11 (15%)

2 (9%)

1.86

(0.36,

18.55)

0.73

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%)

2 (25%)

2 (25%)

0 (0%)

1 (50%)

2 (50%)

4 (40%)

3 (30%)

4 (40%)

AEs prompting hold: PID (2), trichomonas, IUD expulsion

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 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

Spaghetti plot of residual dapivirine concentration over time

Acceptability: 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%

Conclusions

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

Next 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

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 040533).

Acknowledgements

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