Transcript Microbicides 2008

OVERVIEW
Jared Baeten, MD PhD
Thesla Palanee, PhD
Site trainings 2012
Overview
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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
Background and
Rationale
MTN-020 / ASPIRE
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A Multi-Center, Randomized, DoubleBlind, Placebo-Controlled Phase III
Safety and Effectiveness Trial of a
Vaginal Matrix Ring Containing
Dapivirine for the Prevention of HIV-1
Infection in Women
MTN-020 / ASPIRE
A Study to Prevent Infection with a
Ring for Extended Use
Antiretrovirals for HIV prevention
Right drug
(safe, effective, ideally not overlapping treatment)
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Right place
(sufficient concentrations at site of exposure)
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Right time
(present when exposed, user-independent adherence)
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Tenofovir for HIV prevention:
successes and challenges
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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
Daily oral FTC/TDF
Young
heterosexuals
62%
Partners PrEP
Daily oral TDF and
FTC/TDF
HIV serodiscordant
couples
67% (TDF)
75% (FTC/TDF)
Tenofovir for HIV prevention:
successes and challenges
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However, not all trials of tenofovir-based PrEP
have found HIV protection:
 No efficacy for daily oral FTC/TDF in FEMPrEP trial and for daily tenofovir gel and daily
TDF in VOICE study, both studies of women
with high HIV incidence
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Across PrEP studies, adherence is likely an
important driver of HIV protection
Developing a range of options for
antiretroviral-based HIV prevention
Pill
Gel
Vaginal film
Vaginal ring
Injectable
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Landmark health research is a process of continued
development. Tenofovir is critical first proof on a future
pathway.
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Goals: long acting, safe, effective, low cost and userfriendly
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Maximize choice & optimize effectiveness
Vaginal ring for HIV prevention:
advantages and considerations
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Long acting: Monthly or longer
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Could potentially improve adherence
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Better adherence  better effectiveness
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Easy to use, comfortable
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Flexible ring, can be self-inserted
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Rarely felt by women or male partners
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Little or no impact on sexual activity
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Suitable for a wide range of settings
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Relatively low manufacturing cost
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Good safety and acceptability data
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Potential for drug combinations
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For example, contraception, in the future
Dapivirine Vaginal Ring
for HIV Prevention
Dapivirine (TMC 120)
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Dapivirine is a di-aminopyrimidine (DAPY) substituted
highly potent non-nucleoside
reverse transciptase inhibitor
(NNRTI) of HIV-1 replication
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Initially developed and tested
as oral antiretroviral treatment
agent by Tibotec
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Potent activity both in vitro
and in vivo
Dapivirine ring
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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)
Dapivirine vaginal ring composition
Tested for description, weight, tensile
strength, ID, assay, content uniformity,
impurities, dissolution and microbial limits
Dapivirine safety studies
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11 oral dosing studies, for HIV treatment (N=211)
 9 studies in healthy volunteers
 2 studies in HIV-infected patients
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8 vaginal gel studies, for HIV prevention (N=774)
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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
IPM dapivirine Ring-004 trials
Trial
Description
Phase
Countries
N
IPM 024
Safety and PK
(28 days)
I
Belgium
16
(8:8)
IPM 013
Safety and PK
(56/57 days)
I
Belgium
48
(36:12)
I/II
Kenya
Malawi
Tanzania
South Africa
280
(140:140)
IPM 015
Safety and PK
(84 days)
Ring-004 safety and
pharmacokinetic studies
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IPM 024 : Phase 1 Study, 16 Women, 4 weeks, Belgium (2009)
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IPM 013 : Phase 1 study, 48 women, 8 weeks, Belgium (2010)
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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
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 (2010- 2011)
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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
IPM 015: ring acceptability
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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%
IPM 015: safety data
Dapivirine
N=140
n (%)
Placebo
N=140
n (%)
1 (0.7)
4 (2.9)
0
3 (2.1)
2 (1.4)
4 (2.9)
Non-serious AEs resulting in product
discontinuation
0
0
AEs definitely related to product
0
0
30 (21.4)
31 (22.1)
SAEs
HIV seroconversions
Positive pregnancy tests
AEs possibly/probably related to product
IPM 015: ring adherence
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Frequency of ring use
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Perfect adherence (ring never came out for >1 day) : 92%
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Ring removals
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Median number of times ring came out : 1 time per visit interval
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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%
Dapivirine ring for HIV prevention:
Ring-004
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SAFETY:
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PK:
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Safe and well-tolerated
No related SAEs, AEs similar in
treatment and placebo groups
High vaginal, low systemic
concentrations
Sustained release for at least 35 days
Acceptability
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High willingness, good adherence,
most common reason for removal =
menses
ASPIRE:
Design, Objectives,
and Overview
ASPIRE Study Design
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
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Primary Effectiveness Outcome: HIV seroconversion
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
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Primary Safety Outcomes:
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Grade 2 adverse events (AEs) judged to be related to
study product
Grade 3 and 4 AEs
All serious adverse events
Secondary Objectives
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Acceptability
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Adherence
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Including ring expulsions & removals
Drug resistance
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Self-report
In HIV-1 seroconverters
Relationship between drug concentrations and
HIV-1 seroconversion
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Concentrations of dapivirine in blood and selfcollected vaginal swabs
Exploratory Objectives
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Describe changes in the genital
microenvironment
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Changes in candidate biomarkers of safety and efficacy
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Assess correlation of steady-state drug
concentrations and adherence measures
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Assess delayed seroconversion
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4 week post-product completion visit
Behavioral components
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Quantitative assessments
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Qualitative component
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CRFs
ACASI
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)
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Modeled after NSC and VASP (use experience, needs focused)
Integrates product adherence and visit retention
Participants
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3476 sexually active HIV-uninfected
women who are non-pregnant,
contracepting, and 18-45 years of age
Accrual will require approximately
12 months, with total study duration
approximately 24 months
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Designed so that all participants will achieve
12 months on study product
Follow-up
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Monthly follow-up, including:
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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)
Pregnancy
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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
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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
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HIV acquisition
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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
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The study product will be discontinued immediately
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Antiretroviral resistance testing will be done
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Seroconverters will be invited to join MTN-015
 MTN-015 is a long-term observational study /
registry of seroconverters from MTN studies
Sites, Timelines, and
Goals
Proposed sites
Blantyre
Lilongwe
Malawi
Cape Town
Durban (8 sites)
Johannesburg
South Africa
Kampala
Uganda
Lusaka
Zambia
Harare (3 sites)
Zimbabwe
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
The Big Five
Accrual
Adherence
Data Quality
and Timeliness
Retention
Clinical and
Laboratory
Participant
Safety
Design efficiencies
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Accrual
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Large number of sites, modest sample size = achievable
number of recruitments
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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
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Follow-up
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Streamlined data collection and study procedures =
reduced time spent in clinic
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Allowances for efficiencies for individual women –
protocol provisions for extra ring dispensing and off-site
visits
Design efficiencies (2)
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Retention
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Focus from day one from participant one : resource and
attention allocation will be critical
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No retention = no adherence
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Provision of services on-site
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Contraception : expanding method mix and convenience
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Partner HIV testing, STI evaluation/referral
MTN-020 and IPM 027
MTN-020 and IPM 027
Design
No. of participants
Randomization
Age
Product use period
MTN-020
IPM 027
endpoint driven
fixed time
3,476
1,650
1:1
2:1
18-45 yrs
18-45 yrs
Until end of study
24 months fixed
(12-24 months)
Person-years follow-up (all
4,396 / 2,198
3,150 / 2,100
HIV-1 seroconversions
120
80
Power for 50% effect
97%
83%
/ Dapivirine Vaginal Ring)
Similarities
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Very similar primary, secondary, and
exploratory objectives and endpoints
Similarities
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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
Differences
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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)
Coordination
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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)
Dapivirine ring for HIV prevention
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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
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These studies will provide the
definitive data to determine
whether dapivirine vaginal ring
will have the strength of evidence
to support potential licensure
Key Considerations
for Optimization of
Implementation
Numbers that matter
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3476 = total number of women enrolled
>95% = retention, product distribution
100% = attention to data quality, safety
Everything else flows from these
Getting to 3476
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To date, have defined site targets for
start-up
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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
Lessons learned…
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#1. Efficiency matters
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Efficient and focused start-up
Targeted participant visits
Attention to what is important for a quality
study
Lessons learned…
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#2. Adherence is key
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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?
Lessons learned…
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#3. Retention is adherence
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Missed visit = month of zero adherence
Lessons learned…
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#4. We all work together – all parts of the
study are all our business
Recruitment
Retention
Adherence
Sample collection
Staff morale
Community/outreach
Communications
Lab quality
QC/QA
Regulatory
Safety Monitoring
Space/facilities
Study drug/pharmacy
Contraception
Lab-clinic interface
Monitoring follow-up
Lessons learned…
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#5. Metrics and competition are healthy
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Retention #s
Data quality #s
Lessons learned…
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#6. Bigger is not always better
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Smaller sites / new sites can be models of
success
Lessons learned…
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#7. No one knows how to do this
perfectly
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Cross-site, cross-team sharing is important
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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…
Lessons learned…
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#8. Talk with participants
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We have much to learn from them
Lessons learned…
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#9. Stakeholder and community
involvement is ongoing
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Continuous contact
Lessons learned…
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#10. It takes a team
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We are all in this together
ASPIRE TEAM
Malawi College of
Medicine – JHU
Research Project
UNC Project Malawi
Acknowledgements
MTN is funded by NIAID (5U01AI068633),
NICHD and NIMH, all of the U.S. National
Institutes of Health