Feasibility of Vaginal Progesterone to Reduce HIV-Associated Preterm Birth

Study Overview
=================
Brief Summary
-----------------
More than 1.5 million HIV-infected women become pregnant each year. Approximately half have access to antiretroviral therapy (ART), but all are at increased risk of preterm birth (PTB). Vaginal progesterone (VP) is a promising and cost-effective intervention to prevent PTB that should be studied in this high-risk population. This pilot study will provide critical insight into the feasibility of a phase III trial by determining whether women are willing to participate, to adhere to study drug, and to complete follow-up.

Detailed Description
-----------------
This will be a mixed method study to evaluate the feasibility and acceptability of a trial of VP to prevent PTB among HIV-infected Zambian women. To assess the feasibility of a full-scale clinical trial, the investigators will implement a pilot two-arm, double-masked, placebo-controlled trial of VP among HIV-infected women in antenatal care in Lusaka, Zambia. Participants will be randomly assigned to either daily self-administered VP or indistinguishable placebo prior to 24 weeks gestational age. In this pilot study, the investigators will be able to estimate study uptake, adherence to study product and protocol, and study retention. To assess the acceptability of a trial to test VP among HIV-infected women in Zambia, the investigators will employ a qualitative approach of longitudinal semi-structured interviews among women agreeing to trial participation and one-time semi-structured interviews (SSIs) among those who decline to participate.

Official Title
-----------------
A Pilot Study of Vaginal Progesterone to Reduce Preterm Birth Among Women Receiving Antiretroviral Therapy in Pregnancy

Conditions
-----------------
PreTerm Birth

Intervention / Treatment
-----------------
* Drug: Vaginal Progesterone
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18 years of age or older viable intrauterine pregnancy confirmed by ultrasound presentation to antenatal care prior to 24 weeks gestation antibody-confirmed HIV-1 infection initiating or continuing ART treatment in pregnancy ability and willingness to provide written informed consent willing to adhere to study visit schedule Exclusion Criteria: multiple gestation non-research indication for antenatal progesterone (i.e. prior spontaneous PTB and/or cervical length <20mm on screening ultrasound) planned or in situ cervical cerclage evidence of threatened abortion, preterm labor, or ruptured membranes major fetal anomaly detected on screening ultrasound known uterine anomaly known or suspected allergy or contraindication to VP or placebo components

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vaginal Progesterone<br>Daily self-administered vaginal progesterone | Drug: Vaginal Progesterone<br>* 200 mg micronized vaginal progesterone suppository<br>|
| Placebo Comparator: Placebo<br>Daily self-administered indistinguishable placebo | Drug: Placebo<br>* Indistinguishable placebo vaginal suppository<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adequate Adherence to Study Product | Number of participants who achieved adequate adherence to study product, defined as proper self-administration of at least 80% of prescribed study product doses, as measured by a dye stain assay of returned applicators | Enrollment through 36th gestational week, an overall total of up to 17 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acceptability of Use of Vaginal Progesterone (VP) | Semi-structured interviews will be held with a random sample of participants who enroll and those who decline enrollment. | At enrollment (20-24 weeks gestation), at 28 weeks gestation, and at 36 weeks gestation | 
| Reported Barriers and Facilitators to Adherence to Study Product, Returning Used Applicators, and Retention in the Study | Number of participants reporting barriers and facilitators to study product adherence, returning used applicators, and retention in the study during a semi-structured interview. Participants were selected for an interview based on their overall adherence rates, including those with excellent adherence throughout the study and those with lower adherence rates early or late in their participation. A trained female staff member conducted each 30-minute interview using an interview guide. Interviews were audiotaped, transcribed, and translated into English as necessary. | Late in pregnancy or postpartum | 
| Summary of Reported Knowledge, Attitudes, and Practices Related to HIV, Antiretroviral Therapy (ART), Risk of Preterm Birth, and Participation in Placebo Controlled Randomized Clinical Trials (RCTs) | Number of participants reporting attitudes and practices related to participation in placebo controlled RCTs during a semi-structured interview. Participants were selected for an interview based on their overall adherence rates, including those with excellent adherence throughout the study and those with lower adherence rates early or late in their participation. A trained female staff member conducted each 30-minute interview using an interview guide. Participants were asked about their attitudes toward participation in the study and research in general as HIV-infected women taking ART and at risk of preterm birth, but they were not specifically asked about their underlying knowledge of these conditions. Interviews were audio-taped, transcribed, and translated into English as necessary. | Late in pregnancy or postpartum | 
| Acceptability of a Vaginal Medication to Prevent Preterm Birth | Number of participants reporting specific attitudes about medications for the prevention of preterm birth (PTB), including acceptability of daily vaginal administration as measured on the Exit Satisfaction Survey using a Likert scale of five possible options ranging from strongly agree to strongly disagree. The form included a range of facial illustrations to facilitate comprehension of the answer choices, particularly for illiterate participants. | Visit 9.0 (36 weeks of gestation) | 
| Reported Barriers to Adherence to Study Product | Number of participants reporting challenges with taking the study medication as measured on the Exit Satisfaction Survey. The survey was administered by a study nurse who asked each participant what was the hardest part about taking the medication and presented all possible answer choices. Participant were asked to select only one answer. | Visit 9.0 (36 weeks of gestation) | 
| Sensitivity, Specificity, and Predictive Value of Dose Diaries | Comparison of self-reported adherence rates (Dose Diary/DD) and use of returned applicators measured by dye stain assay (DSA) | Enrollment through 36th gestational week, an overall total of up to 17 weeks | 
| Enrollment of Eligible Participants | Number of eligible participants who enrolled in the study | Screening through Enrollment | 
| Ascertainment of Date of Delivery and Infant Vital Status | Number of women for whom date of delivery and infant vital status at birth was ascertained | Visit 10.0 (Delivery) | 
| Preliminary Efficacy | Number of participants delivering before 34 and 37 completed weeks of gestation, grouped based on whether the participant went into labor spontaneously or was induced by a provider | Visit 10.0 (Delivery) | 
| Birth Weight | Number of participants with neonates weighing less than 2500 grams at birth | Visit 10.0 (Delivery) | 
| Stillbirth | Number of participants who experienced a stillbirth | Visit 10.0 (Delivery) | 
| Adverse Events | Number of women experiencing a serious adverse event or event that resulted in study product discontinuation | Enrollment through Visit 10.0 (Delivery) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PreTerm Birth, HIV, Vaginal Progesterone, ART, Adherence, Feasibility