a phase 1 randomized, double-blind, placebo-controlled rectal safety and acceptability study of...
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A Phase 1 Randomized, Double-Blind, Placebo-Controlled Rectal Safety and
Acceptability Study of Tenofovir 1% Gel
Ian McGowan, Craig Hoesley, Ross Cranston, Philip Andrew, Laura Janocko, James Dai, Alex Carballo-Dieguez, Ratiya Kunjara Na Ayudhya,
Jeanna Piper, Florian Hladik, Ken Mayer, and the MTN-007 Protocol Team.
19th Conference on Retroviruses and Opportunistic Infections Seattle
6th March, 2012
MTN-007
Background
Receptive anal intercourse is a high risk but common sexual behavior among men and women in the developed and developing world.
Non human primate studies have demonstrated that an antiretroviral rectal microbicide (RM) can reduce the acquisition of SIV#.
RMP-02/MTN-006 demonstrated a favorable PK/PD profile for rectal tenofovir (TFV) 1% gel but suboptimal safety profile* Gastrointestinal symptoms
#Cranage M et al. PLoS Med, 2008; *Anton PA et al. CROI 2011
Rationale for MTN-007
To characterize the safety and acceptability of a reduced glycerin (RG) formulation of TFV 1% gel Original TFV 1% gel: 3111 mOsmol/kg RG TFV 1% gel: 836 mOsmol/kg Iso-osmolar: 290 mOsmol/kg
To evaluate the utility of a broad range of biomarkers of mucosal safety
Study Population
Healthy, receptive anal intercourse abstinent, HIV-1 uninfected men and women
Key exclusion criteria Rectal or reproductive tract STI Hepatitis B surface antigen positive Bleeding tendency Pregnancy or breastfeeding
Study Design
N=65
HEC(N=16)
1% TFV(N=16)
2% N-9(N=17)
Single dose
7 day daily doses
7-14 dayinterval
EndoscopySafety/behavioral
assessment
ScreeningNo
Treatment(N=16)
BaselineEvaluation
7-14 dayinterval
Study Endpoints
Primary Grade 2 or higher adverse events
Secondary The proportion of participants who at their
final clinic visit report via the acceptability questionnaire that they would be very likely to use the candidate microbicide during receptive anal intercourse
Changes in mucosal parameters
Mucosal Safety Endpoints Histopathology Epithelial sloughing Fecal calprotectin Rectal microflora Mucosal mononuclear cell phenotype by
flow cytometry Cytokines and chemokines
qRT-PCR Luminex
Gene expression by microarray
Baseline Demographics by ArmAll Arms TFV Gel N9 Gel HEC No Rx
N 65 16 17 16 16
Mean Age 35.7 35.3 37.0 36.8 33.5
Gender
• Male (%) 45 (69%) 10 (63%) 13 (76%) 12 (75%) 10 (63%)
• Female (%) 20 (31%) 6 (38%) 4 (24%) 4 (25%) 6 (38%)
Hispanic 6 (9%) 1 (6%) 2 (12%) 2 (13%) 1 (6%)
Race
• Black (%) 11 (17%) 3 (19%) 2 (12%) 5 (31%) 1 (6%)
• White (%) 44 (68%) 10 (63%) 13 (76%) 9 (56%) 12 (75%)
• Other (%) 10 (15%) 3 (19%) 2 (12%) 2 (13%) 3 (19%)
Incident Adverse Events by ArmAll Arms TFV Gel N9 Gel HEC No Rx
N 65 16 17 16 16
Grade 1 30 (46.2%) 7 (43.8%) 10 (58.8%) 7 (43.8%) 6 (37.5%)
Grade 2 18 (27.7%) 3 (18.8%) 7 (41.2%) 4 (25.0%) 4 (25.0%)
Grade 3 2 (3.1%) 0 0 0 2 (12.5%)
Grade 4 1 (1.5%) 0 0 1 (6.3%) 0
Grade 5 0 0 0 0 0
Total 51 (78.5%) 10 (62.5%) 17 (100.0%) 12 (75.0%) 12 (75.0%)
Incident GI Adverse EventsGI Adverse Eventsin the Tenofovir Arm
MTN-007(N = 16)
RG Formulation
N %
Abdominal pain 3 19%
Rectal urgency 0 0%
Bloating 0 0%
Nausea 0 0%
Diarrhea 1 6%
Flatulence 6 38%
Proctalgia 1 6%
Other 3 19%
Total 9 56%
Gastrointestinal Adverse EventsGI Adverse Eventsin the Tenofovir Arm
MTN-007(N = 16)
RG Formulation
RMP-02/MTN-006(N = 12)
Original Formulation
N % N %
Abdominal pain 3 16% 6 50%
Rectal urgency 0 0% 5 42%
Bloating 0 0% 5 42%
Nausea 0 0% 4 33%
Diarrhea 1 6% 7 58%
Flatulence 6 38% 3 25%
Proctalgia 1 6% 0 0%
Other 4 25% 5 42%
Total 9 56% 12 100%
Acceptability
Product (N) Intention to Use (%)
RG Tenofovir (15) 87%
HEC Placebo (15) 93%
N-9 (16) 63%
Mucosal Safety Assays No significant changes were seen in
histology, fecal calprotectin, and epithelial sloughing after single dose (SD) or 7 daily doses (7D)
Suggestive evidence of change (▲ and ▼) were seen with flow cytometry, qRT-PCR, and Luminex assays at SD and 7D
The majority of changes were seen when comparing N-9 to the other arms of the study
Mucosal qRT-PCR
9 cm 15 cm
BL SD 7D BL SD 7D
Mucosal Safety Parameters (1)qRT-PCR SD 7D SD + 7D Comparison P Value (s)
IL-1 b (9 cm) ▲ N9 vs. No Rx 1.3e-3
▲ N9 vs. HEC 6.8e-4
▼ TNF vs. N-9 6.1e-4
IL-6 (9 cm) ▲ ▲ N9 vs. HEC 3.0e-4; 8.4e-5
▼ ▼ TNF vs. N-9 1.3e-5; 1.8e-4
IL-6 (15 cm) ▼ N9 vs. HEC 1.8e-3
IL-8 (9 cm) ▲ N9 vs. HEC 2.8e-4
▼ ▼ TNF vs. N-9 4.2e-5; 1.4e-3
MIP-1 a (9 cm) ▼ TNF vs. N-9 2.7e-4
Mucosal Safety Parameters (2)
Flow Cytometry SD 7D SD + 7D Comparison P Value (s)
CD3+/CD8+ ▼ ▼ N9 vs. No Rx 1.6e-3; 4.0e-4
Luminex
RANTES ▲ ▲ N9 vs. HEC 1.3e-3; 2.7e-4
Microarray Data Gene array studies were performed on a subset
of 8 participants per study arm (9 cm and 15 cm samples)
Labeled cRNA were hybridized to Illumina Human-HT12 v4 gene expression BeadChips.
The Benjamini Hochberg method was used to control for multiple testing (false discovery rate).
Fold change was calculated as the fold difference between treatment over baseline.
N-9 gel
HEC gel
No Treatment
Tenofovir gel
9 cm Gene Expression at Day 7
Summary of Microarray Data
N9 TNF HEC No Rx
Gene expression 9 cm rectum following 7 days of product application
Summary
The reduced glycerin formulation of TFV 1% gel was safe and acceptable and should move forward to Phase 2 development
The majority of mucosal safety signals were associated with the use of N-9
TFV 1% gel associated changes in gene expression require further evaluation
Key Issues Moving Forward
Determine whether gene array signals are important
Validation initial observations MTN-007 & Project Gel
Linked to hyperosmolar formulations: CHARM-01
Linked to tenofovir: MTN-017
Implications for vaginal microbicides
Acknowledgements
The MTN-007 study participants CONRAD MTN is funded by NIAID (5UM1AI068633),
NICHD and NIMH, all of the United States National Institutes of Health