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K2 BIOMEDICAL A Randomized, Double Blind, Placebo-Controlled Phase 1 Safety, Acceptability, and Pharmacokinetic Study of K2B-01 Gel Administered Vaginally & Rectally to HIV-1 Seronegative Adults Sponsored by: K2 BIOMEDICAL Protocol Concept August 11th, 2015 Version 0.2 1 PROTOCOL CONCEPT Short Title: K2B-01 Gel Vaginal & Rectal Safety and PK Study Clinical Phase: Phase 1 IND Sponsor: K2 BIOMEDICAL Protocol Chair: TBD Sample Size: Approximately 24 evaluable participants Study Population: HIV-uninfected men and women between the ages of 18 and 45 years (inclusive) Participating Clinical Research Site (CRS): TBD Study Design: Phase 1 randomized, double-blinded, single site, and placebocontrolled trial. Study Duration: Participant accrual will take approximately 4 months and each participant will be on study for approximately 8 to 10 weeks. The total duration of the study will be approximately 8-12 months. Study Regimen: The site will screen and enroll 6 participants who will receive a single vaginal dose of K2B-01 gel. Once all six participants have received K2B-01 gel an interim analysis will be undertaken to assess the safety and acceptability of single vaginal dose K2B-01 gel exposure. In the absence of any safety signals the study will proceed to the randomized placebo controlled phase of the study in which a total of 18 participants will be randomized to receive K2B01 gel or a HEC placebo gel (K2B-01: placebo; 2:1). Each participant will receive 1 week of daily vaginal K2B-01 gel. The first and last dose of vaginal study product will be administered under direct observation in the clinic. There will be a one week recovery period between the Baseline visit and the initiation of dosing with study product. Colposcopy and mucosal sampling will be conducted at the Baseline Visit and at the completion of the one week dosing period. Following the vaginal phase of the study the site will screen and enroll 6 participants who will receive a single rectal dose of K2B-01 gel. The participants can be individuals who complete the vaginal 2 dosing phase of the study or can be new participants. Once all six participants have received K2B-01 gel an interim analysis will be undertaken to assess the safety and acceptability of single rectal dose K2B-01 gel exposure. In the absence of any safety signals the study will proceed to the randomized placebo controlled phase of the study in which a total of 18 participants will be randomized to receive K2B-01 gel or a HEC placebo gel (K2B-01: placebo; 2:1). Each participant will receive 1 week of daily rectal K2B-01 gel. The first and last dose of rectal study product will be administered under direct observation in the clinic. There will be a one week recovery period between the Baseline visit and the initiation of dosing with study product. Sigmoidoscopy and mucosal sampling will be conducted at the Baseline Visit and at the completion of the one week dosing period. Study specific visits and procedures are illustrated in Figure 1 and summarized in Tables 1 and 2. 3 : Figure 1 Study Design Primary Objectives: Safety To evaluate the safety of K2B-01 rectally gel formulation when applied vaginally and Acceptability To evaluate the acceptability of K2B-01 gel when applied vaginally and rectally 4 Pharmacokinetics To characterize the systemic and compartmental pharmacokinetics of K2B-01 gel following vaginal & rectal application Primary Endpoints: Safety Grade 2 or higher clinical and laboratory adverse events as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, Dec 2004 and Addendum 3- Rectal Grading Table for Use in Microbicide Studies (Clarification dated May 2012) Acceptability Product attributes considered likely to challenge future sustained use by participants. Pharmacokinetics K2B-01 concentrations o Plasma o Vaginal and rectal fluid o Vaginal and rectal mucosal tissue homogenates Secondary Objective: Mucosal Safety To evaluate the mucosal safety of K2B-01 gel when applied vaginally and rectally Secondary Endpoints: Vaginal and rectal proteomics Vaginal and rectal transcriptome and selective RT-PCR Vaginal and rectal microflora Vaginal and rectal histology Vaginal and rectal CD4+ T cell phenotype/activation 5 Exploratory Objective: Ex Vivo Efficacy To assess the preliminary (ex vivo) efficacy of K2B-01 gel formulation using colorectal explants after product is applied rectally Exploratory Endpoint: Changes in laboratory-applied HIV-1 p-24 levels in colorectal explant supernatant obtained from biopsies collected after K2B-01 gel application Inclusion Criteria: Individuals who meet the following criteria are eligible for inclusion in the study: Age of 18 – 45 years (inclusive) Previous history of receptive anal intercourse (RAI) in the past year HIV-1 status antibody negative as documented at Screening and Enrollment Understands and agrees to local STI reporting requirements Able and willing to provide written informed consent in English to take part in the study Able and willing to provide adequate information for locator purposes Availability to return for all study visits, barring unforeseen circumstances Willing to be sexually abstinent (anal and vaginal sex) for 72 hours before and after visits involving mucosal sampling. Exclusion Criteria: Individuals who meet any of the following criteria at screening will be excluded from the study: HIV positive at Enrollment At screening: o Hemoglobin < 10.0 g/dL o Platelet count less than 100,000/mm3 o White blood cell count < 2,000 cells/mm3 or > 15,000 cells/mm3 6 o Serum creatinine > 1.3× the site laboratory upper limit of normal (ULN) o Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) > o 2.5× the site laboratory ULN o ≥1+ glucose or ≥1+ protein on urinalysis (UA) History of bleeding\ problems History of inflammatory bowel disease by participant history Active inflammatory condition of the GI tract at baseline Allergy to methylparaben, propylparaben, sorbic acid Per participant report at screening, anticipated use and/or unwillingness to abstain from the following medications during the period of study participation: o o o o o o o Heparin, including Lovenox® Warfarin Plavix® (clopidogrel bisulfate) Rectally administered medications (including over-the-counter products) Aspirin Non-steroidal anti-inflammatory drugs (NSAIDS) Any other drugs that are associated with increased likelihood of bleeding By participant report at screening, use of post-exposure prophylaxis for HIV exposure, systemic immunomodulatory medications, rectally administered medications, rectally administered products (including condoms) containing N-9, or any investigational products within the 4 weeks prior to the Enrollment/Baseline Evaluation Visit and throughout study participation Use of rectally administered medications, with the exception of over the counter enemas, within 4 weeks of Visit 2 Use of antiretroviral PEP 4 weeks of screening. 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 symptomatic bacterial vaginosis, symptomatic vaginal candidiasis, other vaginitis, trichomoniasis, Chlamydia (CT), gonorrhea (GC), syphilis, active HSV lesions, chancroid, pelvic inflammatory disease, genital sores or ulcers, cervicitis, or symptomatic genital warts requiring treatment. Note that an HSV-1 or HSV-2 seropositive diagnosis with no active lesions is allowed, since treatment is not required 7 Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the patient 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 renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, or cerebral disease. In addition to the criteria listed above, female participants must meet the following criteria: Postmenopausal or using (or willing to use) an acceptable form of contraception (e.g., barrier method, IUD, hormonal contraception, surgical sterilization, vasectomization of male partner). If the female participant has female partners only, the method of contraception will be noted as a barrier method in the study documentation. Not pregnant at the Enrollment/Baseline Visit Not breastfeeding at screening or intend to breastfeed during study participation per participant report. 8 Table 1 Study Visit Schedule (Vaginal Dosing) Study procedures Informed consent Demographics Locator information Test results Behavioral questionnaire Confirm eligibility Reimbursement Schedule next study visit Randomization Med history Concomitant meds Physical exam Vaginal exam Record/update AEs Dipstick UA Urine NAAT for GC/CT HCG (females only) CBC w/ diff and platelets AST ALT Creatinine Plasma PK levels Syphilis RPR HIV-1 serology HSV-1 and -2 serology Visit 1 Screening Visit 2 Baseline Week 1 X X X Week 2 X X X X X X X X X X X X X X X X X X Visit 3 Single Dose Exposure Week 4 Visit 4 Screening (▲) X X X X X X X ▲ ▲ X X X X X X X X X ▲ X X ▲ ▲ X ▲ ▲ ▲ ▲ X ▲ ▲ X X ▲ X X ▲ ▲ X ▲ X X ▲ ▲ X ▲ ▲ X ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ Visit 5 Baseline (▲) Visit 6 Multiple Doses (1-6) Week 6 X ▲ X X X X X X X ▲ ▲ X ▲ ▲ X ▲ ▲ ▲ ▲ ▲ ▲ ▲ X X X X X ▲ X X ▲ ▲ X ▲ ▲ ▲ ▲ ▲ ▲ Visits 7 Final Dose Visit 8 Telephone Contact Week 7 X X X X X X X ▲ X X ▲ ▲ X ▲ ▲ ▲ ▲ X ▲ ▲ X 9 Vaginal microflora Colposcopy Histology Cervicovaginal cell phenotype Drug levels Plasma Cervicovaginal tissue Vaginal fluid Gene array in cervical mucosal tissue Proteomics in cervical mucosal tissue Gene array in vaginal mucosal tissue Proteomics in vaginal mucosal tissue Study product Male condoms Product admin phone call each day Safety phone call ▲= if indicated ▲ ▲ X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 10 Table 2 Study Visit Schedule (Rectal Dosing) Study procedures Informed consent Demographics Locator information Test results Behavioral questionnaire Confirm eligibility Reimbursement Schedule next study visit Randomization Med history Concomitant meds Physical exam Rectal exam Record/update AEs HIV test Dipstick UA Urine NAAT for GC/CT HCG (females only) CBC w/ diff and platelets AST ALT Creatinine Visit 1 Screening Visit 2 Baseline Week 1 X X X Week 2 X X X Visit 3 Single Dose Exposure Week 4 X X X X X X X X X X X X X X X X X X X X X X ▲ X X ▲ ▲ ▲ X ▲ X X X ▲ ▲ ▲ Visit 4 Screening (▲) ▲ ▲ X Visit 5 Baseline (▲) X ▲ Visit 6 Multiple Doses (1-6) Week 6 X Visits 7 Final Dose Visit 8 Telephone Contact Week 7 X X X X X X X X X X X X X X X X ▲ X X ▲ ▲ X ▲ ▲ ▲ X ▲ X X X ▲ ▲ X ▲ ▲ ▲ X ▲ X X ▲ X X ▲ ▲ ▲ X ▲ X X ▲ X X ▲ ▲ ▲ X ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ X X ▲ X X ▲ ▲ ▲ 11 Plasma PK levels Syphilis RPR HIV-1 serology HSV-1 and -2 serology Rectal microflora Flexible sigmoidoscopy Histology Intestinal cell phenotype Drug levels Plasma Rectal tissue Rectal fluid Gene array in rectal mucosal tissue Proteomics in rectal mucosal tissue Intestinal explant infection Study product Male condoms Product admin phone call each day Safety phone call ▲= if indicated X X X X X ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ X ▲ ▲ ▲ ▲ ▲ X X X X ▲ ▲ ▲ ▲ X X X X X X X X ▲ ▲ ▲ ▲ X X X X X ▲ X X ▲ X X X X X X X X X X X X X 12