TY - JOUR
T1 - A phase 1 randomized, open label, rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of three formulations of tenofovir 1% Gel (the CHARM-01 study)
AU - Mcgowan, Ian
AU - Cranston, Ross D.
AU - Duffill, Kathryn
AU - Siegel, Aaron
AU - Engstrom, Jarret C.
AU - Nikiforov, Alexyi
AU - Jacobson, Cindy
AU - Rehman, Khaja K.
AU - Elliott, Julie
AU - Khanukhova, Elena
AU - Abebe, Kaleab
AU - Mauck, Christine
AU - Spiegel, Hans M.L.
AU - Dezzutti, Charlene S.
AU - Rohan, Lisa C.
AU - Marzinke, Mark A.
AU - Hiruy, Hiwot
AU - Hendrix, Craig W.
AU - Richardson-Harman, Nicola
AU - Anton, Peter A.
N1 - Funding Information:
This analysis was supported by a subcontract with Advanced BioScience Laboratories, Inc., Rockville, MD, and its subcontractor, Alpha StatConsult, LLC, through an NIH/NIAID/DAIDS contract: ''Comprehensive Resources for HIV Microbicides and Biomedical Prevention'' (#HHSN272201000001C). Co-author Nicola Richardson-Harman is employed by Alpha StatConsult, LLC. Co-author C. Hendrix has had research support from Gilead Sciences from 05/01/09-04/30/10. The contract was managed by the Johns Hopkins School of Medicine. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
Publisher Copyright:
© 2015, Public Library of Science. All rights reserved.
PY - 2015/5/5
Y1 - 2015/5/5
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0125363
DO - 10.1371/journal.pone.0125363
M3 - Article
C2 - 25942472
AN - SCOPUS:84929208690
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 5
M1 - e0125363
ER -