Transcript Microbicides 2008

A Study to Prevention Infection
with a Ring for Extended Use
[INSERT NAME]
[INSERT CRS/INSTITUTION]
A Study to Prevent Infection with a
Ring for Extended Use
at a Glance
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A Phase III trial of a vaginal ring that contains an
antiretroviral (ARV) drug called dapivirine
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A vaginal ring is a new and different approach
for HIV prevention in women
Being conducted by the Microbicide Trials
Network (MTN) and will involve about 3,476
women at several sites in Africa
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MTN is also leading VOICE
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Many of the same trial sites for VOICE will be
conducting ASPIRE
Results are expected late 2014 or early 2015
at a Glance
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Funded by the U.S. National Institutes of Health
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The International Partnership for Microbicides
(IPM) developed the dapivirine ring
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IPM is also leading The Ring Study
Both ASPIRE and The Ring Study are designed
to provide the kind of information needed to
support potential licensure of the ring
Why a vaginal ring?
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Vaginal rings are flexible products that
fit comfortably high up inside the vagina
where they release a drug slowly over
time
 They stay in place during sex and
are not usually felt by the partner
Vaginal ring products are licensed for
both contraception delivery and
hormone replacement in some countries
The vaginal ring being tested in ASPIRE is not for
contraception. It contains an ARV developed to treat HIV
that also has promise for preventing HIV
Why are we conducting
To answer these questions:
 Can the ring protect against HIV?
 Is it safe to use?
 Will women like using it?
 Will women actually use it?
Women need safe
and effective HIV
prevention products!
?
Overview
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Background and rationale
Design and objectives
Who may participate and what’s involved
Safety monitoring
The current microbicide landscape
Summary and Conclusions
Background and
Rationale
Developing a range of HIV prevention
options for women
Tablet
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Vaginal gel
Vaginal ring
Injectable
Vaginal film
Goals: long acting, safe, effective, low cost and
user-friendly
Maximize choice & optimize effectiveness
Are all women the same?
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Some women may favor a daily tablet
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Some women may prefer using a gel, such as before
and after sex
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Some women may prefer wearing a vaginal ring that
she replaces once a month
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It’s about giving women choice – a product that best
suits a woman’s needs and lifestyles is more likely to
be used
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Only if it is used does it have a chance of being
effective
ARVs and HIV Prevention
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ARVs are drugs that when used in combination are safe
and effective for treating HIV
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Generally three different ARVs are needed to
suppress virus
For prevention, the idea is that one – maybe two ARVs –
can protect an HIV-uninfected person if exposed to HIV
(e.g., through unprotected sex)
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The ARV will already be in the blood and/or vaginal
tissue and will hamper HIV’s ability to establish
infection
Different Approaches
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Oral pre-exposure
prophylaxis (PrEP)
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Involves taking an ARV tablet
by mouth
Vaginal microbicides
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Involves use of a vaginal
product - gel or ring - that
contains an ARV
Other formulations are being
developed, like a film
What do we know so far about ARVs
for prevention?
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Some trials have found ARV-based prevention is effective
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And some trials have found these not to be effective
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Partners PrEP in serodiscordant couples – with Truvada, tenofovir
iPrEx in men who have sex with men – with Truvada
CDC TDF2 study in heterosexual men and women – with Truvada
CAPRISA 004 in women – with tenofovir gel (used before/after sex)
FEM-PrEP in women – with Truvada
VOICE in women – with tenofovir and with tenofovir gel (used daily)
Other trials don’t have results yet
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FACTS 001 in women – with tenfovir gel (used before/after sex);
Results expected in 2014
VOICE in women – with Truvada; Results expected early 2013
What do we know so far about ARVs
for prevention?
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Safety has not been an issue in any trial so far
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ARV drug resistance rare among those who acquired HIV
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Results of Partners PrEP, iPrEx and CAPRISA 004 show
there is greater protection with regular use
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In FEM-PrEP, less than half the women took the daily
tablet – too few to measure whether Truvada
prevented HIV
Remember!
 Even if a product is active against HIV, if for whatever
reason it’s not used, it can’t help prevent HIV
About the dapivirine ring
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Flexible ring made of an
elastic silicone material
Measures 56 mm (2 ¼”) in
diameter and 7.7 mm
(3/8”) thick
Designed for 28-day use
When inside the vagina,
the ring releases dapivirine
slowly over time
Dapivirine
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Developed by Tibotec Pharmaceuticals for treating HIV
 Studies showed a favorable safety profile and that it
was effective in reducing the “viral load”
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At the same time, Tibotec was looking at a very similar
drug (etravirine) that was equally promising
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It had to decide the one to develop further for treatment
and the one it would donate for prevention
 Dapivirine can be manufactured at lower cost
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Tibotec assigned a royalty-free license to IPM in 2004
to develop it as a microbicide for HIV prevention
Clinical safety of the ring
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To date, 25 phase I/II trials of dapivirine
(in oral, gel, and ring form) have been
conducted
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Studies of the ring have shown that high
levels of drug can be delivered throughout
the cervix and vagina for up to one month
and that the ring is safe and women find
using the ring acceptable
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These studies support moving the ring
into Phase III testing to determine its
large-scale safety and effectiveness in
protecting against HIV
Phase III Sister Studies
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The Ring Study
 1,650 women
 Trial sites in South Africa and Rwanda
 Started enrolling in April 2012
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ASPIRE
 3,476 women
 Trial sites in South Africa, Uganda,
Zambia, Zimbabwe, Malawi
 Started screening in July 2012
ASPIRE Study Design
and Objectives
Study Design
Women will replace the ring every 4 weeks while
in the study - over the course of at least 1 year
Two Primary Objectives
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Is the ring effective in preventing HIV?
 When used for a month at a time?
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Is the ring safe to use?
 When used for a month at a time?
How will we know it’s effective?
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At the end of the study we will
compare the number of HIV
infections that occurred among
women in the group using the
dapivirine ring with the number
of HIV infections in the group
using a placebo ring
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We hope to see a minimum of
60% fewer infections compared
to the placebo
How will we know it’s safe?
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Participants’ health assessed at
each monthly study visit
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We will compare the number,
frequency and type of side
effects/problems between the
two groups
 Were they related to use of
the product or not?
Secondary Objectives
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Will women find it acceptable to use?
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Will women actually use the ring, and use it
properly?
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If a women becomes infected, will drug
resistance be a problem?
How will we know if she likes the ring –
and is using it?
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Participants will be asked questions by staff
and will use ACASI (Audio Computer-Assisted
Self-Interview) and by questionnaire
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Looking to know:
 Does she have discomfort?
 Is the ring noticeable during daily activity or sex?
 Is her partner aware of the ring during sex?
 How easy is it to insert and remove?
 Did she take the ring out or did it come out on its own?
 If so, why? And how long was it out?
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More objective measures of adherence include tests that
to assess drug levels in blood or vaginal fluid
Is drug resistance a concern?
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Our first goal is to prevent HIV
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All women receive HIV and risk reduction counseling and
condoms every month
All women are tested for HIV every month
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If she tests positive, we will stop product immediately to
reduce the risk for resistance
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Although resistance has been rare in prevention trials
involving tenofovir-based products, we need to closely
monitor women and better understand possible risks
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Studies of the dapivirine ring indicate that very little of
the drug gets absorbed into the blood, so resistance is
less likely to be a concern than with oral ARVs
Who may participate
and what’s involved?
Proposed
Sites
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Malawi
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South Africa
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Kampala
Zambia
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Cape Town
Durban (7 sites)
Johannesburg
Uganda
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Blantyre
Lilongwe
Lusaka
Zimbabwe
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Harare (3 sites)
Who may participate?
HIV-uninfected, sexually active women who :
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Are between ages of 18 to 45
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Are not pregnant, breastfeeding, or intending to become
pregnant; and agree to use an effective contraceptive
method during their participation
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Have no medical conditions that would make their
participation unsafe
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Are not currently participating or have recently participated
in research study involving drugs, devices, vaginal
products or vaccines
Informed Consent
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Women must also be able and
willing to provide written
informed consent
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To be screened for the study
To enroll in the study
To have leftover specimens
stored for future research
Materials are translated into local languages to help
ensure understanding and inclusiveness
Informed consent is a continuous process throughout
the study
Study Visits and Procedures
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Women will be seen monthly
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HIV and pregnancy testing
HIV/STI risk reduction, contraceptive
counseling and provision of condoms
Clinical follow up on symptoms as needed
Adherence interviews and counseling
Informed consent as needed
Receive and insert a new ring
At quarterly visits, behavioral and social harms
assessments, physical exam and additional safety
labs also conducted
At semiannual visits pelvic exams and STI tests
also conducted
Learning how to use the ring
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Women will learn how to insert and remove
the ring on the day they are enrolled
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Staff will explain that the ring should remain
in place until the next monthly visit, when
she will remove the ring and insert a new
one
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Staff will remind women at each visit how the
ring is inserted and removed
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A woman can ask for help at anytime, and
she will have educational materials she can
take home
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 when she is no
longer breastfeeding
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HIV
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All women receive HIV and risk reduction counseling,
condoms, and treatment for STIs at each clinic visit
Women who acquire HIV will need to stop using the ring
but can remain in the study to continue follow-up visits
Counseling and testing for her partner will be offered and
she will be referred to local care and support services
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All sites required to have procedures for care and support and
referral agreements with HIV primary care and ART providers
Resistance testing is done for those who acquire HIV; if
identified, this information may help to better manage her
care
If she is confirmed HIV+, she will be invited to join MTN015, a long-term observational study
Safety Monitoring
Many Layers of Safety Monitoring
External Review
NIAID DSMB
Study Monitoring Committee
Protocol Team Level Review
Protocol Safety
Physicians
Protocol Safety
Review Team
SCHARP Clinical
Affairs
US NIH Division
of AIDS
Local and Site Level Review
Site IRBs and Ethics Committees
Site Clinicians
At the local and site level
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IRBs/ECs must review and approve protocol and any
subsequent amendments; and provide oversight
throughout the study
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Site clinicians monitor safety and wellbeing of
participants at each monthly visit
 Clinical and laboratory evaluations and questions
about key symptoms
 HIV and pregnancy testing
 Counseling on safe use of the product and practices
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If there is ever any question about safety, staff will stop a
participant’s use of the ring
External Safety Monitoring: DSMBs
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A Data Safety Monitoring Board (DSMB) is a group of
independent experts that conducts routine reviews of
data while a trial is ongoing
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A DSMB looks at “blinded” data at several time points
during a trial – about two times a year
 Are there safety concerns?
 Will the trial be able to answer the study questions?
 Do any of study questions already have clear
answers?
 Should the trial keep going, stop early or be
modified?
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Also may evaluate emergent data from other trials
The DSMB for
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Routine reviews of ASPIRE will be conducted by a
National Institute of Allergy and Infectious Diseases
DSMB with expertise in international HIV prevention trials
 The majority of its members are from developing
countries
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Decisions whether to continue, stop or modify the study
are based on:
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Pre-determined statistical parameters and stopping
rules set by the study team and the DSMB
International ethical principles and standards
The Current
Microbicide
Landscape
As
moves forward…
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ASPIRE expects to be completed by 2014, and have
results late 2014, early 2015
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We are committed to open communication and
discussion throughout ASPIRE about:
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The clinical trial process
Progress and milestones
Possible outcomes and their implications
Especially important to talk about:
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DSMB reviews of ASPIRE
DSMB reviews of The Ring Study
Other HIV prevention trials, e.g., VOICE
New HIV prevention guidelines or products
2012-13 Microbicide Studies and Sites
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ASPIRE – dapivirine ring
Malawi, Uganda, South Africa,
Zambia, Zimbabwe
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The Ring Study – dapivirine ring
Rwanda, South Africa
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FACTS 001 – tenofovir gel
South Africa
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CAPRISA 008 – tenofovir gel
South Africa
We need to be mindful
of the entire landscape!
What if the landscape changes?
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What happens when VOICE results
are available?
 Will former participants at ASPIRE sites have
access to Truvada through an “open-label” trial?
 Plans are to conduct CHOICE, but this will
depend on the results of VOICE (early 2013)
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What if Truvada becomes more widely available?
 WHO and UNAIDS are discussing PrEP
guidelines
 Depending on timing, changes to ASPIRE
may be required.
 We will follow all relevant national policies
What if the ring is effective?
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If both ASPIRE and The Ring Study find the
ring safe and effective, IPM intends to seek
product approval from regulatory agencies
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If the ring is approved, IPM is committed to
making it available at the lowest possible cost
in countries where women urgently need
tools to protect themselves against sexual
transmission of HIV
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Participants in both studies will likely have
access prior to the ring’s availability through
an open-access trial
Summary
Summary and Final Thoughts
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Women need more than one option for HIV prevention
ASPIRE is testing a new approach called a vaginal ring
that women replace once a month. The active drug in the
ring is dapivirine
Results are expected late 2014/early 2015:
 Can the ring protect against HIV?
 Is it safe to use?
 Will women like using it?
 Will women actually use it?
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ASPIRE, and its sister study, The Ring Study, are designed
to support possible licensure of the ring for HIV prevention
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Open communication is key to success
Vaginal ring for HIV prevention:
advantages and considerations
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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
ASPIRE TEAM
Malawi College of
Medicine – JHU
Research Project
UNC Project Malawi
Acknowledgements
MTN is funded by NIAID (5UM1 AI068633-07),
NICHD and NIMH, all of the U.S. National
Institutes of Health