IPM 014B protocol synopsis - International Partnership For ...

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IPM 014B protocol synopsis - International Partnership For ...

IPM014BA DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED PHASE I/II STUDY TOEVALUATE THE SAFETY AND ACCEPTABILITY OF DAPIVIRINE GEL 4789, 0.05% 2.5G, AVAGINAL MICROBICIDE, CONDUCTED USING DAILY MONITORED ADHERENCE INHEALTHY HIV-NEGATIVE WOMENInternational Partnership for Microbicides8401 Colesville Road, Suite 200Silver Spring, MD 20910 U.S.A.Final Version 5.024 February 2009Restricted * Confidential – Limited Access


IPM014B 24 February 2009Final Version 5.0 Page 9 of 75PROTOCOL SYNOPSISIPM014BA DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED PHASE I/II STUDY TOEVALUATE THE SAFETY AND ACCEPTABILITY OF DAPIVIRINE GEL 4789, 0.05% 2.5G, AVAGINAL MICROBICIDE, CONDUCTED USING DAILY MONITORED ADHERENCE INHEALTHY HIV-NEGATIVE WOMENBACKGROUND:OBJECTIVES:To date, candidate vaginal microbicides have been formulatedpredominantly as gels. Multiple safety and efficacy studies with variousmicrobicides are currently underway, most of which are designed todeliver the microbicide in gel form via a single-use vaginal applicator justprior to coitus. However, at the present time, there is no standardized andvalidated method to accurately ensure adherence of gel use. Furthermore,anecdotal evidence suggests that adherence of using gel before coitusmay be lower than expected and may be a critical factor in assessingmicrobicide efficacy in a Phase III study. Under certain situations wheretreatment non-adherence may be a public health concern, such as fortuberculosis and HIV infection, medication has been administered by amethod called Directly Observed Therapy (DOT) whereby a health careprovider, family member or member of the community directly observesthe administration of medication on a daily basis to ensure adherence andproper treatment. To reduce the influence of adherence as a factor in theinterpretation of efficacy results, IPM is considering using a DOT basedmethod for vaginal microbicide gel delivery in a future Phase III study. IPMhas denoted this DOT based method as Daily Monitored Adherence(DMA). IPM014B is a Phase I/II study designed: (1) to assess andcompare the safety of a once daily application of Dapivirine Gel 4789,0.05% 2.5g and a matching vehicle placebo gel; (2) to assess theacceptability of a once daily application of Dapivirine gel 4789, 0.05% 2.5gand a matching vehicle placebo gel; and (3) to assess the feasibility ofutilizing the DMA method for a large-scale phase III efficacy study.The primary objectives are:• To assess and compare the safety of a once daily application ofDapivirine Gel 4789, 0.05% 2.5g, a vaginal microbicide, to amatching vehicle placebo gel over a 6-week period in healthy,sexually active, HIV-negative women.The secondary objectives are:• To assess the acceptability of a once daily application of a vaginalmicrobicide over a 6-week period in healthy, sexually active, HIVnegativewomen.• To assess the feasibility of utilizing DMA in a Phase III vaginalmicrobicide gel study.• To evaluate adherence to daily use of vaginal gel and factorspredicting adherence.Restricted * Confidential – Limited Access*


IPM014B 24 February 2009Final Version 5.0 Page 10 of 75• To assess the effect of Dapivirine Gel 4789, 0.05% 2.5g on thevaginal flora and vaginal pH as compared with a matching vehicleplacebo gel.• To assess condom use and sexual behaviour of women using anintravaginal microbicide with DMA.ENDPOINTS:To address the primary objectives, the following will be assessed:• Gynaecological examinations, including pelvic/speculumexamination and colposcopy, and laboratory STI testing.• Safety laboratory tests.• Adverse event/serious adverse event reports.To address the secondary objectives, the following will be assessed:• Questionnaires concerning acceptability and adherence to dailyuse of vaginal gel.• Documentation of adherence to the DMA method including theApplicator Collection Checklist, focus groups and maleinterviews.• Quantitative measures of adherence to daily use of vaginal gelas assessed by reconciliation of returned applicators and coitallogs.• Vaginal flora and vaginal pH analysis.• Self-reported condom use and sexual behaviour.DESIGN:IPM014B is a double-blind, randomized, placebo-controlled Phase I/IIstudy conducted at up to 10 research centres in Kenya, Malawi, Rwanda,South Africa and Tanzania among approximately 320 healthy, sexuallyactive, HIV-negative women to assess the safety and acceptability ofDapivirine Gel 4789, 0.05% 2.5g, a vaginal microbicide. Upon enrolmentat each research centre, participants will be randomly assigned in a 1:1ratio to one of two study groups: those using dapivirine Gel 4789, 0.05%2.5g once daily for a period of 6 weeks, or those using the matchingvehicle placebo gel containing no dapivirine once daily for a period of 6weeks. Using the DMA method, designated study staff will monitoradherence by collecting used/unused applicators from both groups ofwomen on a daily basis Monday to Friday. On Saturday, Sunday andPublic Holidays participants may not have contact with study staff, and willthen return used/unused applicators on the following Monday, or in thecase of a Public Holiday, on the following day. After the screening period(up to 28 days), both groups will participate in the study for a period of 10weeks, including a follow-up visit 4 weeks post gel discontinuation. Ateach research centre, 12-20 women participating in the study may beasked to participate in focus groups to assess gel acceptability and thefeasibility of conducting a Phase III study utilizing the DMA method. Ateach research centre, 6-10 male partners of women participating in thestudy may be asked to participate in individual interviews to assess gelacceptability and the feasibility of conducting a Phase III study utilizing theDMA method. Assays performed on returned applicators may be used toconfirm that intravaginal applicators have been used correctly.Restricted * Confidential – Limited Access*


IPM014B 24 February 2009Final Version 5.0 Page 11 of 75STUDYPOPULATION:SAMPLESIZE:REGIMEN:STUDYDURATION:STATISTICALANALYSIS:Healthy, sexually active, HIV-negative women 18-40 years of age whounderstand the study and can provide informed consent.Approximately 320 women (20-50 per research centre) will be enrolled.Potential participants who consent will be invited to screen for the study.All participants who consent to participate in the study, meet specifiedinclusion/exclusion criteria, have normal findings based upon a physicaland pelvic/speculum examination with colposcopy, and have negativepregnancy, HIV and STI tests, will be invited to enrol in the study. Eligiblewomen will be randomly assigned in a 1:1 ratio to one of two study arms:• Study arm 1: Dapivirine Gel 4789, 0.05% 2.5g• Study arm 2: Matching vehicle placebo gel 2.5g containing nodapivirine.Dapivirine Gel 4789 or placebo gel will be applied by participants oncedaily and adherence will be monitored by the collection of used applicatorsby study staff Monday to Friday (DMA) for a period of 6 weeks. OnSaturday, Sunday and Public Holidays participants may not have contactwith study staff, and may then return used applicators on the followingMonday, or in the case of a public holiday, on the following day. Clinicvisits will be conducted at weeks 0 (enrolment), 1, 2, 4, and 6 where safetyevaluations will be performed. Participants will have a follow-up visit atweek 10, 4 weeks post gel discontinuation. At enrolment and at eachstudy visit, all participants will undergo a pelvic/speculum examination withcollection of cervico-vaginal specimens for vaginal flora assessment; preandpost-test HIV counselling; appropriate HIV/STI risk reductioncounselling including condom dispensing; HIV and pregnancy testing; andcollection of locator, menses, and concomitant medications information.Appropriate contraceptive counselling will be done at screening and allstudy visits except week 10. Colposcopy will be performed at week 0(baseline), and weeks 1, 2, and 6. Cervico-vaginal samples for STI testingand safety laboratory testing will be performed at screening and week 6 oras clinically indicated. Adverse events (AEs) will be assessed at all visitsfollowing enrolment. Acceptability and adherence questionnaire will beadministered at baseline (week 0), and at weeks 2, 6 and 10.The maximum allowable time between screening and enrolment perparticipant is 28 days. Following enrolment into the study, each participantwill be followed for a total of 6 weeks during daily gel use, and 4 weekspost gel discontinuation. It is anticipated that full enrolment per researchcentre will be completed in 24 weeks for a total of up to 38 weeks studyduration. If a research centre cannot complete enrolment within 7 monthsof the Site Initiation Visit (SIV), enrolment at the centre may be terminated.The primary analysis will focus on safety assessments, using the intentto-treatpopulation, and comparing the women who are using DapivirineGel 4789 to women who are using a matching vehicle placebo gel.Restricted * Confidential – Limited Access*


IPM014B 24 February 2009Final Version 5.0 Page 12 of 75Exploratory analyses using a per-protocol population or subgroups ofparticular interest may also be performed.The secondary analysis will focus on assessment of gel acceptability; thefeasibility of using a DMA method; the changes in vaginal flora andvaginal pH as compared between the 2 study arms; and sexual behaviourand condom use of women using an intravaginal microbicide. Appropriatestatistical analyses will be performed.An interim analysis of the safety assessment data will be conducted afterapproximately 100 participants have completed 6 weeks of gel use.Restricted * Confidential – Limited Access*

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