Fourteen-day safety and acceptability study of the universal placebo gel

Schwartz, Jill L.; Ballagh, Susan A.; Kwok, Cynthia; Mauck, Christine; Weiner, Donald A.; Rencher, William F.; Callahan, Marianne M.

doi:10.1016/j.contraception.2006.09.003

Cited by 61 publications

(41 citation statements)

References 7 publications

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“…The HEC placebo gel contained hydroxyethyl cellulose as the gel thickener, purified water, sodium chloride, sorbic acid, and sodium hydroxide. 23 The gel was isotonic with a pH of 4.4, osmolarity of 304 mOsmol/kg, 24 and viscosity similar to the other microbicide gel candidates. Both TFV and HEC gels were prefilled into single-use, opaque applicators (HTI Plastics, Lincoln, NE) containing approximately 4 ml of gel.…”

Section: Study Productsmentioning

confidence: 99%

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

Anton

Cranston

Kashuba

et al. 2012

AIDS Research and Human Retroviruses

131

176

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This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs ( p = 0.002). Only 25% of participants liked the TFV gel. Likelihood of use ''if somewhat protective'' was *75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) C max 30 min after single rectal exposure was 6-10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p = 0.12, analysis of covariance (ANCOVA) p = 0.006; 7-day rectal: p = 0.02, ANCOVA p = 0.005]. Tissue PK-PD was significantly correlated ( p = 0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK-PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations.

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Section: Study Productsmentioning

confidence: 99%

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

Anton

Cranston

Kashuba

et al. 2012

AIDS Research and Human Retroviruses

131

176

View full text Add to dashboard Cite

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“…Women were evaluated before, during, and after 13½ consecutive days of twice-daily vaginal applications of either the Universal HEC (hydroxyethylcellulose) Placebo, 24 4% N-9 gel (Conceptrol), or 6% CS for the following parameters:…”

Section: Study Design and Endpointsmentioning

confidence: 99%

“…It was developed for use as an inert comparator in clinical trials of vaginal microbicides and was designed to be nonreactive and to approximate the physical properties of candidate active products. 24 CS (Patheon, Mississauga, Ontario) 6% (60 mg/g) is formulated in a water base with benzyl alcohol, glycerin, sorbitol, and carbomer.…”

mentioning

confidence: 99%

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Mauck

Lai

Weiner

et al. 2013

AIDS Research and Human Retroviruses

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TitleToward early safety alert endpoints: exploring biomarkers suggestive of microbicide failure. Several microbicides, including nonoxynol-9 (N-9) and cellulose sulfate (CS), looked promising during early trials but failed in efficacy trials. We aimed to identify Phase I mucosal safety endpoints that might explain that failure. In a blinded, randomized, parallel trial, 60 healthy premenopausal sexually abstinent women applied Universal HEC placebo, 6% CS or 4% N-9 gel twice daily for 13½ days. Endpoints included immune biomarkers in cervicovaginal lavage (CVL) and endocervical cytobrushes, inflammatory infiltrates in vaginal biopsies, epithelial integrity by naked eye, colposcopy, and histology, CVL anti-HIV activity, vaginal microflora, pH, and adverse events. Twenty women enrolled per group. Soluble/cellular markers were similar with CS and placebo, except secretory leukocyte protease inhibitor (SLPI) levels decreased in CVL, and CD3 + and CD45 + cells increased in biopsies after CS use. Increases in interleukin (IL)-8, IL-1, IL-1RA, and myeloperoxidase (MPO) and decreases in SLPI were significant with N-9. CVL anti-HIV activity was significantly higher during CS use compared to N-9 or placebo. CS users tended to have a higher prevalence of intermediate Nugent score, Escherichia coli, and Enterococcus and fewer gram-negative rods. Most Nugent scores diagnostic for bacterial vaginosis were in N-9 users. All cases of histological inflammation or deep epithelial disruption occurred in N-9 users. While the surfactant N-9 showed obvious biochemical and histological signs of inflammation, more subtle changes, including depression of SLPI, tissue influx of CD45 + and CD3 + cells, and subclinical microflora shifts were associated with CS use and may help to explain the clinical failure of nonsurfactant microbicides.

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“…Early microbicide trials generally involve the use of a placebo as a negative control in either a parallel or crossover design. The Universal HEC placebo was designed as a placebo for use in microbicide trials because it has few, if any, effects of its own on symptoms and signs of irritation or on effectiveness (Schwartz et al 2007). Studies with a parallel design require a shorter duration of participation by each subject and thus tend to retain a larger proportion of participants than crossover studies.…”

Section: Guidelines For the Clinical Evaluation Of Microbicidesmentioning

confidence: 99%

Clinical Safety and Pharmacology Trial

Mauck

Thurman

Schwartz

2013

Current Topics in Microbiology and Immunology

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Guidelines for establishing clinical safety of microbicides in early clinical studies have evolved significantly since the first trials. In addition, because of the difficulty of establishing efficacy of a microbicide prior to Phase III testing, there has been an increasing emphasis on establishing pharmacokinetic (PK)/pharmacodynamic (PD) relationships using genital samples collected in vivo in Phase I studies. A healthy pipeline is critical to success; however, it is unlikely that the majority of microbicide candidates will progress to clinical testing. Those that do enter clinical testing may have different mechanisms of action than early candidates. Given this, drug-specific modifications for early clinical assessment will need to be considered. These emerging issues associated with early clinical trials of microbicides will be reviewed, along with recommendations for future clinical safety and PK/PD evaluation.

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Fourteen-day safety and acceptability study of the universal placebo gel

Cited by 61 publications

References 7 publications

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Clinical Safety and Pharmacology Trial

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