Physical Activity Assessment in the Charcot Population.

Charcot neuroarthropathy is a degenerative disorder that significantly impairs a patient's functional capacity. It has been reported that a Charcot patient's quality of life is significantly impacted by the disease state. The aim of this study is to compare measured energy expenditure to a patient's perceived quality of life and physical ability. The study enrolled 43 patients by set inclusion and exclusion criteria. Patients' total energy expenditure was measured with doubly labeled water. The patients also completed 2 quality of life assessments: 36-Item Short Form Survey (SF-36) and International Physical Activity Questionnaire-Long Form (IPAQ-LF). The measured energy expenditure was then compared to the patient's perceived functional capacity. Scores reaching statistical significance included general health (60 ± 21; p = .011), pain (62 ± 27; p = .025), emotional (61 ± 40; p < .017), physical limitation (45 ± 39; p < .0001), and physical function (50 ± 29; p < .001). SF-36 survey variables that did not reach statistical significance included mental (73 ± 26; p = .690), energy (55 ± 21; p = .205), and social (74 ± 26; p = .105). The IPAQ-LF and physical activity level (PAL) were compared. No identified variation was noted between the 2 test methods (p = .57). The patients' PAL was measured at 1.4 ± 0.42, which is comparable to the general population. Data from this study identify the Charcot population as comparable to the general population. The inferences taken from this study indicate that this population suffers from poor health outlooks compared with the general population but may be overestimating the level of perceived disability.

Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment.

BACKGROUND: Long-acting injectable antiretroviral agents are being developed for HIV-1 prevention. The MWRI-01 study was done to characterise the safety, acceptability, and pharmacokinetic and pharmacodynamic profile of long-acting rilpivirine. METHODS: We did a phase 1 open-label study at the University of Pittsburgh. We enrolled healthy individuals (aged 18-45 years) who were seronegative for HIV-1. Participants were assigned alternately one intramuscular dose of either 1200 mg or 600 mg long-acting rilpivirine, beginning with the 1200 mg dose. We obtained plasma specimens, genital and rectal fluids, and tissue samples (rectal, cervical, and vaginal) before and after exposure to long-acting rilpivirine for assessment of pharmacokinetics and ex-vivo biopsy challenge with HIV-1. Our primary objective was to characterise product safety, and the analysis included all enrolled participants. This trial is registered with ClinicalTrials.gov, number NCT01656018. FINDINGS: 36 participants were enrolled into the study, of whom 24 were women and 12 men. 12 women and six men received each dose. 204 adverse events were reported among the 36 participants, of which 200 (98%) were grade 1-2. The most common adverse event was injection site reaction. All grade 3 and 4 adverse events were deemed not related to rilpivirine. Geometric mean (90% CI) concentrations in plasma of rilpivirine at day 28 post dose were 53 ng/mL (38-67) in women and 43 ng/mL (23-63) in men for the 1200 mg dose and 28 ng/mL (19-37) in women and 17 ng/mL (9-24) in men for the 600 mg dose. The tissue-to-plasma ratio for rilpivirine in rectal tissue was about two-fold higher than in vaginal and cervical tissue (1·10-1·53 vs 0·61-0·72 and 0·50-0·71, respectively). Exposure to long-acting rilpivirine suppressed viral replication significantly in rectal tissue (p<0·0001), and this suppression persisted for up to 4 months. By contrast, no viral suppression was seen in cervical or vaginal tissue. INTERPRETATION: Ongoing research will characterise longer term safety and acceptability of multiple injections and help ascertain whether long-acting rilpivirine should advance to assessment of efficacy in preventing HIV-1 infection. FUNDING: Bill & Melinda Gates Foundation.

Project Gel a Randomized Rectal Microbicide Safety and Acceptability Study in Young Men and Transgender Women.

OBJECTIVES: The purpose of Project Gel was to determine the safety and acceptability of rectal microbicides in young men who have sex with men (MSM) and transgender women (TGW) at risk of HIV infection. METHODS: MSM and TGW aged 18-30 years were enrolled at three sites; Pittsburgh, PA; Boston, MA; and San Juan, PR. Stage 1A was a cross-sectional assessment of sexual health and behavior in MSM and TGW. A subset of participants from Stage 1A were then enrolled in Stage 1B, a 12-week evaluation of the safety and acceptability of a placebo rectal gel. This was followed by the final phase of the study (Stage 2) in which a subset of participants from Stage 1B were enrolled into a Phase 1 rectal safety and acceptability evaluation of tenofovir (TFV) 1% gel. RESULTS: 248 participants were enrolled into Stage 1A. Participants' average age was 23.3 years. The most common sexually transmitted infection (STIs) at baseline were Herpes simplex (HSV)-2 (16.1% by serology) and rectal Chlamydia trachomatis (CT) (10.1% by NAAT). 134 participants were enrolled into Stage 1B. During the 12 week period of follow-up 2 HIV, 5 rectal CT, and 5 rectal Neisseria gonorrhea infections were detected. The majority of adverse events (AEs) were infections (N = 56) or gastrointestinal (N = 46) and were mild (69.6%) or moderate (28.0%). Of the participants who completed Stage 1B, 24 were enrolled into Stage 2 and randomized (1:1) to receive TFV or placebo gel. All participants completed Stage 2. The majority of AEs were gastrointestinal (N = 10) and of mild (87.2%) or moderate (10.3%) severity. CONCLUSIONS: In this study we were able to enroll a sexually active population of young MSM and TGW who were willing to use rectal microbicides. TFV gel was safe and acceptable and should be further developed as an alternative HIV prevention intervention for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT01283360.

A Phase 1 Randomized, Open Label, Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Three Formulations of Tenofovir 1% Gel (the CHARM-01 Study).

OBJECTIVES: The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK), and pharmacodynamics (PD) of three tenofovir (TFV) gels for rectal application. The vaginal formulation (VF) gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF) gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF) gel was also evaluated in the CHARM-01 study. METHODS: Participants received 4 mL of the three TFV gels in a blinded, crossover design: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. Safety, acceptability, compartmental PK, and explant PD were monitored throughout the trial. RESULTS: All three gels were found to be safe and acceptable. RF and RGVF PK were not significantly different. Median mucosal mononuclear cell (MMC) TFV-DP trended toward higher values for RF compared to RGVF (1136 and 320 fmol/106 cells respectively). Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal tissue HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV-DP, MMC TFV-DP, rectal fluid TFV, and explant HIV-1 infection. CONCLUSIONS: All three formulations were found to be safe and acceptable. However, the safety profile of the VF gel was only based on exposure to one dose whereas participants received seven doses of the RGVF and RF gels. There was a trend towards higher tissue MMC levels of TFV-DP associated with use of the RF gel. Use of all gels was associated with significant inhibition of ex vivo tissue HIV infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT01575405.

Exploring the feasibility of multi-site flow cytometric processing of gut associated lymphoid tissue with centralized data analysis for multi-site clinical trials.

The purpose of this study was to determine whether the development of a standardized approach to the collection of intestinal tissue from healthy volunteers, isolation of gut associated lymphoid tissue mucosal mononuclear cells (MMC), and characterization of mucosal T cell phenotypes by flow cytometry was sufficient to minimize differences in the normative ranges of flow parameters generated at two trial sites. Forty healthy male study participants were enrolled in Pittsburgh and Los Angeles. MMC were isolated from rectal biopsies using the same biopsy acquisition and enzymatic digestion protocols. As an additional comparator, peripheral blood mononuclear cells (PBMC) were collected from the study participants. For quality control, cryopreserved PBMC from a single donor were supplied to both sites from a central repository (qPBMC). Using a jointly optimized standard operating procedure, cells were isolated from tissue and blood and stained with monoclonal antibodies targeted to T cell phenotypic markers. Site-specific flow data were analyzed by an independent center which analyzed all data from both sites. Ranges for frequencies for overall CD4+ and CD8+ T cells, derived from the qPBMC samples, were equivalent at both UCLA and MWRI. However, there were significant differences across sites for the majority of T cell activation and memory subsets in qPBMC as well as PBMC and MMC. Standardized protocols to collect, stain, and analyze MMC and PBMC, including centralized analysis, can reduce but not exclude variability in reporting flow data within multi-site studies. Based on these data, centralized processing, flow cytometry, and analysis of samples may provide more robust data across multi-site studies. Centralized processing requires either shipping of fresh samples or cryopreservation and the decision to perform centralized versus site processing needs to take into account the drawbacks and restrictions associated with each method.