Evaluate the Safety & Assess Local and Systemic PK of DS003 Vaginal Tablets Administered to Healthy HIV-negative Women

Study Overview
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Brief Summary
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A double-blind, randomised, placebo-controlled, dose escalation trial to evaluate the safety and to assess local and systemic pharmacokinetics of ds003 vaginal tablets administered to healthy HIV-negative women.

Official Title
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A Double-blind, Randomised, Placebo-controlled, Dose Escalation Trial to Evaluate the Safety and to Assess Local and Systemic Pharmacokinetics of DS003 Vaginal Tablets Administered to Healthy HIV-negative Women

Conditions
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HIV

Intervention / Treatment
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* Drug: DS003 vaginal tablet
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women must meet all of the following criteria to be eligible for enrolment: Women ≥ 18 and ≤ 45 years of age who can give written informed consent BMI of ≥ 18 and < 30 kg/m2 Vital signs within normal limits and no clinically significant ECG findings 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 biochemistry 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 Subcutaneous implant inserted at least 3 months prior to enrolment, OR Long-acting progestins for at least 2 consecutive injections, OR An 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 be willing to use oral contraceptives if necessary to delay menstruation while taking part in the trial Upon pelvic examination and colposcopy at screening and visual inspection of the cervix at the time of enrolment, the cervix and vagina appear normal as determined by the Investigator Asymptomatic for urogenital infections at the time of screening (if a woman is diagnosed with any curable STI, either clinically or by laboratory test at the time of screening, she must complete the full course of treatment and have a healthy genital tract before being considered for potential re-screening) Willing to refrain from the use of topical vaginal medications, vaginal products or objects, including tampons, female condoms, cotton wool, rags, diaphragms, cervical caps (or any other vaginal barrier method), douches, lubricants, vibrators/dildos, and drying agents for 7 days prior to enrolment and for the duration of the trial Documentation of no abnormality on cervical cytology, including grossly bloody smear, within 90 days prior to screening Willing to refrain from participation in any other research trial for the duration of this trial 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) Willing to agree to abstain from all the following for a total of 2 days (48 hours) prior to each trial visit, and for a total of 3 days (72 hours) after the biopsy procedure: Penile-vaginal intercourse • Oral contact with her genitalia Hepatitis B and C negative at the time of screening Exclusion Criteria: Women who meet any of the exclusion criteria below are not eligible: 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 sexually transmitted infections, or other gynaecological conditions such as vaginal itching, pain, or discharge, prior to enrolment Have a Grade 2 or higher pelvic examination finding, according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events; Addendum 1 Female Genital Grading Table for Use in Microbicide Studies History of significant urogenital or uterine prolapse, undiagnosed vaginal bleeding, urethral obstruction, incontinence or urge incontinence Current vulvar or vaginal symptoms/abnormalities that could influence the trial results Cervical cytology at screening that requires cryotherapy, biopsy, treatment, 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 current version of the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 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 Any serious acute, chronic or progressive disease (e.g. any known history of neoplasm, cancer, diabetes, epilepsy, cardiac disease, autoimmune disease, HIV, AIDS, or blood dyscrasias), or signs of cardiac disease, renal failure, or severe malnutrition Have undergone a hysterectomy History of drug or substance abuse within 1 year of enrolment Use of tobacco within 6 months of enrolment Not willing to abstain from alcohol from 14 days prior to enrolment until completion of trial participation Have had significant blood loss, or have donated or received one or more units of blood within 6 weeks prior to enrolment Have a positive urine drug or positive breath alcohol screen at screening or enrolment Any disease or condition (medical or surgical) that might compromise haematological, cardiovascular, pulmonary, renal, gastrointestinal, or central nervous system function; or any other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the investigational product, or that would place the participant at increased risk, as determined by the Investigator Regular use of, or have received, any concomitant prescription, over-the-counter, or herbal medications or nutritional supplements within 14 days prior to enrolment Any condition(s) that, in the opinion of the Investigator, might interfere with adherence to trial requirements or evaluation of the trial objectives

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DS003 vaginal tablet<br>participants will be randomised in a 3:1 ratio to receive either DS003 or placebo on Day 0 and Day 17. | Drug: DS003 vaginal tablet<br>* The trial will be conducted in three cohorts of 12 women each. In each cohort, participants will be randomised in a 3:1 ratio to receive either DS003 or placebo on Day 0 and Day 17. In each cohort, therefore, 9 participants will receive DS003 vaginal tablets and 3 participants will receive placebo vaginal tablets.<br>|
| Placebo Comparator: placebo<br>participants will be randomised in a 3:1 ratio to receive either DS003 or placebo on Day 0 and Day 17. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety of three escalating doses of DS003 (1 mg, 3 mg and 10 mg), administered in a vaginal tablet formulation, to healthy, HIV-negative female volunteers. | Gynaecological assessments, including pelvic examination and colposcopy | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the local (vaginal fluids) and systemic (plasma) DS003 PK profile and the 24 hour cervical tissue concentration when administered in three escalating doses of a vaginal tablet formulation. | Measurement of DS003 concentrations in plasma, vaginal fluids and cervical tissue collected at various time points after administration of the vaginal tablet(s). | 12 weeks |