To Assess the Drug-drug Interaction Potential Between Dapivirine Vaginal Ring-004, Containing 25 mg of Dapivirine, and Clotrimazole 10 mg/g (1%)

Study Overview
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Brief Summary
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A Study to assess the drug-drug interaction potential, between Dapivirine Vaginal Ring-004, containing 25 MG of Dapivirine.

Detailed Description
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AN OPEN-LABEL, RANDOMISED TRIAL, WITH A THREE-PERIOD CROSSOVER PART IN HEALTHY HIV-NEGATIVE WOMEN TO ASSESS THE DRUG-DRUG INTERACTION POTENTIAL BETWEEN DAPIVIRINE VAGINAL RING-004, CONTAINING 25 MG OF DAPIVIRINE, AND CLOTRIMAZOLE 10 mg/g (1%) ADMINISTERED AS A VAGINAL CREAM, WITH A FOLLOW-ON PERIOD TO ASSESS THE EFFECT OF MULTIPLE RING REMOVALS AND RE-INSERTIONS DURING THE 28-DAY PERIOD OF THE DAPIVIRINE VAGINAL RING-004 USE ON THE SYSTEMIC AND LOCAL EXPOSURE AND RESIDUAL AMOUNT OF DAPIVIRINE IN USED RINGS

Official Title
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AN OPEN-LABEL, RANDOMISED TRIAL, WITH A THREE-PERIOD CROSSOVER PART IN HEALTHY HIV-NEGATIVE WOMEN TO ASSESS THE DRUG-DRUG INTERACTION POTENTIAL BETWEEN DAPIVIRINE VAGINAL RING-004, CONTAINING 25 MG OF DAPIVIRINE, AND CLOTRIMAZOLE 10 mg/g (1%) ADMINISTERED AS A VAGINAL CREAM, WITH A FOLLOW-ON PERIOD TO ASSESS THE EFFECT OF MULTIPLE RING REMOVALS AND RE-INSERTIONS DURING THE 28-DAY PERIOD OF THE DAPIVIRINE VAGINAL RING-004 USE ON THE SYSTEMIC AND LOCAL EXPOSURE AND RESIDUAL AMOUNT OF DAPIVIRINE IN USED RINGS

Conditions
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HIV- Prevention

Intervention / Treatment
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* Drug: Dapivirine Ring-004
* Drug: Dapivirine Ring-004 for 28 days along with clotrimazole
* Drug: Clotrimazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must meet all the following criteria to be eligible to enrol in the trial: Women 18 and ≤ 45 years of age who can give written informed consent Available for all visits and consent to follow all procedures scheduled for the trial Healthy, based on medical history, vital signs, physical examination, urinalysis (dipstick and microscopy), laboratory evaluations for genital infections (bacterial vaginosis, gonorrhoea, chlamydia and trichomonas), and laboratory evaluations for haematology and chemistry HIV-negative as determined by an HIV test at the time of screening On a stable form of contraception, defined as: A stable oral contraceptive regimen for at least 2 months prior to enrolment, OR Transdermal contraceptive patch for at least 3 months prior to enrolment, OR Long-acting progestins for at least 6 months prior to enrolment, OR An intra-uterine device (IUD) inserted (with no vaginal or gynaecological complaints associated with its use) at least 3 months prior to enrolment, OR Have undergone surgical sterilisation at least 3 months prior to enrolment, AND willing to use oral contraceptives if necessary to delay menstruation during the vaginal sampling period 6. Upon pelvic examination at the time of enrolment, the cervix and vagina appear normal as determined by the Investigator/Physician Asymptomatic for genital infections at the time of enrolment (if a woman is diagnosed with any treatable STI, either clinically or by laboratory test at the time of screening, she must complete treatment prior to enrolment) 8. Willing to refrain from the use of topical vaginal medications, vaginal products or objects, including female condoms, tampons, cotton wool, rags, diaphragms, cervical caps (or any other vaginal barrier method), douches, lubricants, vibrators/dildos, and drying agents for 14 days prior to enrolment and for the duration of the trial 9. Documentation of no abnormality on cervical cytology, including grossly bloody smear, within 90 days prior to screening 10. Willing to refrain from participation in any other research trial for the duration of this trial 11. Willing to provide adequate locator information for trial retention purposes and be reachable per local standard procedures, e.g. by home visit or telephone, or via family or close neighbour contacts (confidentiality to be maintained) 12. Willing to agree to abstain for a total of 2 days (48 hours) prior to each trial visit from: Penile-vaginal intercourse Oral contact with her genitalia 13. Hepatitis B and C negative at the time of screening Exclusion Criteria: Participants who have any of the following criteria are NOT eligible to enrol in the trial: Currently pregnant or had their last pregnancy outcome within 3 months prior to screening Currently breast-feeding Currently or within 2 months of participation in any other clinical research trial involving investigational or marketed products prior to screening Untreated symptomatic urogenital infections, e.g. urinary tract or other STIs, or other gynaecological conditions such as vaginal itching, pain, or discharge within 14 days prior to enrolment History of significant urogenital or uterine prolapse, undiagnosed vaginal bleeding, urethral obstruction, incontinence, urge incontinence or an anatomical variation that will not allow placement or retention of the ring Current vulvar or vaginal symptoms/abnormalities that could influence the trial results Cervical cytology at screening that requires cryotherapy, biopsy, treatment (other than for infection), or further evaluation Symptomatic genital herpes simplex virus (HSV) infection or a history of genital herpetic infection Any Grade 2, 3 or 4 haematology, biochemistry or urinalysis laboratory abnormality at baseline (screening) according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events; Addendum 1 Female Genital Grading Table for Use in Microbicide Studies Unexplained, abnormal bleeding per vagina during or following vaginal intercourse, or gynaecologic surgery within 90 days prior to enrolment Any history of anaphylaxis or severe allergy resulting in angioedema; or a history of sensitivity/allergy to latex or silicone Any serious acute, chronic or progressive disease (e.g. any known history of neoplasm, cancer, diabetes, epilepsy, cardiac disease, autoimmune disease, HIV, Acquired Immunodeficiency Syndrome [AIDS], or blood dyscrasias), or signs of cardiac disease, renal failure, or severe malnutrition Have undergone a hysterectomy Any condition(s) that, in the opinion of the Investigator, might interfere with adherence to trial requirements or evaluation of the trial objectives. Participants who have the following criterion are NOT eligible for Treatment F: Using a hormonal intrauterine device.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment A<br>Dapivirine Ring-004 for 28 days | Drug: Dapivirine Ring-004<br>* Treatment A: Dapivirine Ring-004 for 28 days<br>* Other names: Treatment A;|
| Active Comparator: Treatment B<br>Dapivirine Ring-004 for 28 days along with clotrimazole, 5 g per day for 7 days | Drug: Dapivirine Ring-004 for 28 days along with clotrimazole<br>* Treatment B: Dapivirine Ring-004 for 28 days along with clotrimazole, 5 g per day for 7 days<br>* Other names: Treatment B;|
| Active Comparator: Treatment C<br>Clotrimazole, 5 g per day for 7 days | Drug: Clotrimazole<br>* Treatment C: Clotrimazole, 5 g per day for 7 days<br>* Other names: Treatment C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dapivirine concentrations in plasma | Dapivirine concentrations in plasma, measured at specified time points during each 28-day period that the ring is inserted, and for 14 days following ring removal | 28-day | 
| Clotrimazole concentrations in plasma | Clotrimazole concentrations in plasma, measured at specified time points during 7 days of once daily dosing, and for 14 days after the last administration. | 7 days of once daily dosing, and for 14 days after the last administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dapivirine concentrations in vaginal fluid | Dapivirine concentrations in vaginal fluid, collected at the cervix, measured at specified time points during each 28-day period that the ring is inserted, and for three days following ring removal. | 28 days | 
| Clotrimazole concentrations in vaginal fluid | Clotrimazole concentrations in vaginal fluid, measured at specified time points during 7 days of once daily dosing, and following 14 days after the last administration. | 7 days of once daily dosing, and following 14 days after the last administration. |