Griffithsin-based Rectal Microbicide for PREvention of Viral ENTry (PREVENT)

Study Overview
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Brief Summary
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This is the first-in-human clinical study to see if a single dose of an investigational enema made from a modified plant protein called Q-Griffithsin is safe, tolerated, and acceptable for use by healthy adults 18-45 years of age who practice receptive anal intercourse.

Detailed Description
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A microbicide is a drug or agent designed to prevent transmission of HIV. Griffithsin, or GRFT, is an investigational product that is being developed as a microbicide. GRFT is a naturally occurring protein originally isolated from the red alga Griffithsia found in the South Pacific Ocean. GRFT is one of the most powerful, broad-spectrum antivirals ever tested and its activity is under study for potential therapeutic applications against several viral pathogens including HIV, herpes simplex virus type-2, human papillomavirus (HPV), and hepatitis C. GRFT can be formulated into a number of delivery vehicles including gels, films, suppositories and even simple enemas or rinses. The product is intended for use prior to sexual activity by people who practice receptive anal intercourse (RAI), and thus represent the population most vulnerable to HIV-1 transmission due to the high concentration of HIV target cells in the rectal mucosa and the presence of mucosal trauma commonly associated with RAI. For the purposes of this study GRFT has been genetically modified to produce a more stable compound less prone to oxidation, Q-GRFT. Up to 21 HIV-uninfected individuals between the ages of 18 - 45 years will be enrolled in this study at the University of Pittsburgh, the only study site. Participants will be screened to exclude those with HIV infection, and anorectal sexually transmitted infections (STIs) (Visit 1). Up to 28 days after screening, eligible participants will return for a baseline visit (Visit 2), be assigned to a study arm, and undergo sample collection including flexible sigmoidoscopy with collection of colorectal biopsies. The first 3 participants will be assigned to Arm 1 and receive a clinician administered single dose exposure of open-label Q-GRFT. Once the participants in Arm 1 complete Visit 4, study activity will be paused while the study Protocol Safety Review Team (PSRT) conducts an interim review of the clinical and laboratory data. In the absence of any significant safety concerns, the PSRT will be asked to approve enrollment of Study Arms 2 and 3. The remaining 18 participants will be assigned 2:1 in a randomized and blinded fashion to either Study Arm 2 (Q-GRFT) or 3 (placebo), respectively. At Visit 3, participants will receive a clinician-administered single-dose exposure followed by flexible sigmoidoscopy with collection of colorectal biopsies at 1-hr and PK sampling of blood and rectal fluid at 1-hr and 4-hr. Participants will return to clinic the next day (Visit 4) for colorectal biopsies and 24-hr PK sampling. Participants in Arm 1 will additionally return for PK sampling including colorectal biopsies at 48 hrs (Visit 4a) following Visit 3. Participants will be contacted by study staff approximately 3 days after Visit 4 to collect safety information. Participants will return for a final study visit, Visit 5, 4 weeks +/- 1 week after Visit 4/4a to collect blood samples for PK and immunogenicity assessments. A final study exit call for safety will occur within one week after the final study visit.

Official Title
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A Randomized, Double-Blind Phase 1 Safety and Pharmacokinetic Study of Q-Griffithsin Enema Administered Rectally to HIV-1 Seronegative Adults

Conditions
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HIV Prevention

Intervention / Treatment
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* Drug: Q-Griffithsin (Q-GRFT) enema
* Other: Placebo enema


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 18 through 45 years at screening, verified per site SOP Male participants, born male; female participants, born female. Availability to return for all study visits, barring unforeseen circumstances Willing and able to communicate in English provide written informed consent to take part in the study provide adequate locator information, as defined in site SOP Must agree not to participate in other concurrent interventional and/or drug trials to use study-provided condoms for vaginal or anal intercourse for the duration of the study to avoid insertion of anything in the vagina or rectum (e.g., penis, sex toy, medication, enemas) 72 hours before and after study product exposure and rectal sampling visits Understands and agrees to local STI reporting requirements HIV-1 seronegative at screening and enrollment A history of RAI at least 5 times in lifetime and once in the prior year. (Required to assure that participants are comfortable with study procedures and study product administration.) Must be in general good health in the opinion of the investigator Using an effective method of contraception and intending to continue use of an effective method for the duration of study participation. Acceptable methods include: Males male condoms sterilization of participant or partner partner use of hormonal contraception or intrauterine device [IUD] identifies as a man who has sex with men exclusively and/or sexually abstinent for the past 90 days Females hormonal methods IUD inserted at least 28 days prior to enrollment sterilization of participant or partner and/or sexually abstinent for the past 90 days In addition to the criteria listed above, female participants must meet the following criteria: Not pregnant or breastfeeding Regular menstrual cycles of approximately 21 to 35 days apart with no untreated intermenstrual bleeding Note: This criterion is not applicable to participants using continuous combination oral contraceptive pills or progestin-only methods (such as Depo-Provera or levonorgestrel-releasing IUD), as the absence of regular menstrual cycles is an expected, normal consequence in this context. Exclusion Criteria: Undergoing or completed gender reassignment Participant reports any of the following at Screening: Post-exposure prophylaxis for HIV exposure within 4 weeks prior to screening Condomless insertive or receptive anal intercourse with more than one partner in the past six months Known HIV-positive sexual partner within the last 6 months History of STI in the last 3 months Transactional sex within the last 12 months Non-therapeutic injection drug use in the 12 months prior to screening Any use of methamphetamine, gamma hydroxybutyrate, cocaine or heroin in the 12 months prior to screening History of recurrent urticaria Use of antiretroviral medications with activity against HIV within the 4 weeks prior to the Enrollment, including PrEP with Truvada® Use of systemic immunomodulatory medications within the 4 weeks prior to the Enrollment Use of rectally administered medications or products (including condoms) containing Nonoxynol-9 (N-9) within the 4 weeks prior to the Enrollment Participating in another research study involving drugs or medical devices within the 4 weeks prior to the Enrollment Has plans to relocate away from the study site area during the period of study participation Per participant report at screening, anticipated use and/or unwillingness to abstain from the following medications during the period of study participation: Heparin, including Lovenox® (enoxaparin sodium) Warfarin Plavix® (clopidogrel bisulfate) Any other drugs that are associated with increased likelihood of bleeding following mucosal biopsy (e.g., daily high dose aspirin > than 81 mg, NSAIDs, or Pradaxa®) Rectally or vaginally administered medications (including over-the-counter products) Antiretroviral medications with activity against HIV History of significant gastrointestinal bleeding in the opinion of the investigator Abnormalities of the colorectal mucosa, or significant symptom(s), which in the opinion of the clinician represents a contraindication to protocol-required biopsies (including but not limited to presence of any unresolved injury, infectious or inflammatory condition of the local mucosa, and presence of symptomatic external hemorrhoids). At screening: participant-reported symptoms, and/or clinical or laboratory diagnosis of active rectal or reproductive tract infection requiring treatment per current CDC guidelines or symptomatic urinary tract infection (UTI). Infections requiring treatment include CT, GC, syphilis, active HSV lesions, chancroid, genital sores or ulcers, or symptomatic genital warts requiring treatment. Note: • HSV-1 or HSV-2 seropositive diagnosis with no active lesions is allowed, since treatment is not required Has any of the following laboratory abnormalities at Screening: White blood cell count Grade 2 or higher Hemoglobin Grade 1 or higher Platelet count Grade 1 or higher International Normalized Ratio (INR) Grade 2 or higher Calculated creatinine clearance ≤ 70 mL/minute using the Cockcroft-Gault equation: ♀: (140 - age in yrs) x (weight in kg) x (0.85)/72 x (serum Cr in mg/dL) ♂: (140 - age in yrs) x (weight in kg) /72 x (serum Cr in mg/dL) Grade 2 or higher ALT and/or AST Grade 2 or higher Total bilirubin Positive for Hepatitis B surface antigen (HBsAg) Positive for Hepatitis C antibody (HCV Ab) Positive for HIV Any other condition or prior therapy that, in the opinion of the investigator, would preclude informed consent, make study participation unsafe, make the individual unsuitable for the study or unable to comply with the study requirements. Such conditions may include, but are not limited to, current or recent history of severe, progressive, or uncontrolled substance abuse, or renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, or cerebral disease In addition to the criteria listed above, female participants will be excluded if they meet any of the following criteria: Participant reports any of the following at Screening: Last pregnancy outcome or gynecological surgery 90 days or less prior to screening Intends to become pregnant during the period of study participation Chronic and/or recurrent symptomatic vaginal candidiasis

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

Sexes Eligible for Study
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All

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: Parallel Assignment
Interventional Model Description: randomized, double-blind
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label Q-GRFT enema<br>Open-label Q-GRFT enema administered rectally once as a single dose (Arm 1) | Drug: Q-Griffithsin (Q-GRFT) enema<br>* Investigational enema composed of 4.2mL Q-Griffithsin (Q-GRFT) 9.6mg/mL combined with approximately 120.8mL of 0.9% sodium chloride solution to yield an active enema study product that will contain and deliver a dose of approximately 40mg of Q-GRFT<br>* Other names: Study product enema;|
| Experimental: Randomized, blinded Q-GRFT enema<br>Blinded Q-GRFT enema administered rectally once as a single dose (Arm 2) | Drug: Q-Griffithsin (Q-GRFT) enema<br>* Investigational enema composed of 4.2mL Q-Griffithsin (Q-GRFT) 9.6mg/mL combined with approximately 120.8mL of 0.9% sodium chloride solution to yield an active enema study product that will contain and deliver a dose of approximately 40mg of Q-GRFT<br>* Other names: Study product enema;|
| Placebo Comparator: Randomized, blinded placebo enema<br>Blinded placebo enema administered once as a single dose (Arm 3) | Other: Placebo enema<br>* Approximately 125mL of 0.9% sodium chloride solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number and frequency of adverse events Grade 2 or higher and genitourinary adverse events Grade 1 or higher | Safety analysis will be conducted on all participants who have receive study product. The number and the frequency of ≥ Grade 2 adverse events (AEs) and ≥ Grade 1 Genitourinary AEs as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs, Version 2.1 (March 2017), Addendum 1 Female Genital Grading Table for Use in Microbicide Studies (November 2007), and/or Addendum 3 Rectal Grading Table for Use in Microbicide Studies (Clarification dated May 2012) to this table will be tabulated for each of the three methods of administration from Baseline through the final study contact. To determine whether AEs are occurring excessively, the proportion of subjects that experience an AE will be calculated for each method of administration. Additional safety analyses will also tabulate the number and type of AEs observed overall, and by severity, site, and study product. AEs that lead to discontinuation of study participation will be tabulated separately. | Baseline through the final study contact, or about 8 weeks | 
| The proportion of participants who report product characteristics to be considered a barrier in study product use, operationalized as having a rating of lower than 3 on a 5-point Likert scale, in disliking or likelihood of future use | One day after study product administration, participants will complete an acceptability questionnaire to provide descriptive statistics on participants' opinions on the enema's characteristics, application process, the applicator design and the use-regimen, as well as the degree to which participants believe these characteristics and side-effects could pose barriers in future sustained use. On a 5-point Likert scale, with 1 being completely unacceptable and 5 being highly acceptable, the distributions of scores on all product characteristics will be examined to determine product characteristics that pose or could pose significant barriers in current or future product use. | Once 24 hours post-dose | 
| Area under the concentration-time curve (AUC) of Q-GRFT | AUC of Q-GRFT as measured in plasma, rectal fluid, rectal mucosal tissue homogenates, and enema fluid effluent. | Pre-dose and 1, 4, and 24 hours post-dose | 
| Maximum concentration (Cmax) of Q-GRFT | Cmax of Q-GRFT as measured in plasma, rectal fluid, rectal mucosal tissue homogenates, and enema fluid effluent. | Pre-dose and 1, 4, and 24 hours post-dose | 
| Time to maximum concentration (Tmax) of Q-GRFT | Tmax of Q-GRFT as measured in plasma, rectal fluid, rectal mucosal tissue homogenates, and enema fluid effluent . | Pre-dose and 1, 4, and 24 hours post-dose | 
| Minimum concentration (Cmin) of Q-GRFT | Cmin of Q-GRFT as measured in plasma, rectal fluid, rectal mucosal tissue homogenates, and enema fluid effluent. | Pre-dose and 1, 4, and 24 hours post-dose | 
| Half-life (t½) of Q-GRFT | t½ of Q-GRFT as measured in plasma, rectal fluid, rectal mucosal tissue homogenates, and enema fluid effluent. | Pre-dose and 1, 4, and 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in humoral antibody responses to Q-GRFT in blood by ELISA and PBMC Q-GRFT antigen stimulation | The titer of immunoglobulins in blood and rectal secretions will be assessed. Lymphocytes collected from peripheral blood will be stimulated with Q-GRFT and an ELISPot assay used to quantify number of B-cells that produce specific antibodies. | Baseline and 4 weeks post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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microbicide, enema, receptive anal intercourse, HIV prevention, HIV transmission