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Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03239483
Recruitment Status : Completed
First Posted : August 4, 2017
Results First Posted : November 7, 2019
Last Update Posted : November 7, 2019
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition HIV Infections
Interventions Drug: Dapivirine gel
Drug: Placebo gel
Enrollment 28
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Dapivirine Gel Placebo Gel
Hide Arm/Group Description

Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally

Participants will receive a single dose of placebo gel rectally, followed by 7 daily doses of placebo gel to be administered under direct observation in the clinic.

Placebo gel: Universal HEC placebo gel; administered rectally

Period Title: Overall Study
Started [1] 19 9
Completed 17 9
Not Completed 2 0
Reason Not Completed
Lost to Follow-up             1             0
Withdrawal by Subject             1             0
[1]
one participant withdrew consent and did not receive any study product
Arm/Group Title Dapivirine Gel Placebo Gel Total
Hide Arm/Group Description

Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally

Participants will receive a single dose of placebo gel rectally, followed by 7 daily doses of placebo gel to be administered under direct observation in the clinic.

Placebo gel: Universal HEC placebo gel; administered rectally

Total of all reporting groups
Overall Number of Baseline Participants 19 9 28
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 9 participants 28 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
19
 100.0%
9
 100.0%
28
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 19 participants 9 participants 28 participants
26
(18 to 42)
35
(21 to 40)
33
(18 to 42)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 9 participants 28 participants
Female
4
  21.1%
5
  55.6%
9
  32.1%
Male
15
  78.9%
4
  44.4%
19
  67.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 9 participants 28 participants
Hispanic or Latino
1
   5.3%
0
   0.0%
1
   3.6%
Not Hispanic or Latino
18
  94.7%
9
 100.0%
27
  96.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 9 participants 28 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
7
  36.8%
4
  44.4%
11
  39.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   5.3%
3
  33.3%
4
  14.3%
White
11
  57.9%
2
  22.2%
13
  46.4%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 19 participants 9 participants 28 participants
United States 13 6 19
Thailand 6 3 9
1.Primary Outcome
Title Frequency of Grade 2 or Higher Adverse Events (AEs)
Hide Description As defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and/or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital [Dated November 2007] and Rectal [Clarification Dated May 2012] Grading Tables for Use in Microbicide Studies)
Time Frame Measured after the participant has started study product until the participant's study termination at approximately Day 40
Hide Outcome Measure Data
Hide Analysis Population Description
enrolled participants receiving at least one dose of study product
Arm/Group Title Dapivirine Gel Placebo Gel
Hide Arm/Group Description:

Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally

Participants will receive a single dose of placebo gel rectally, followed by 7 daily doses of placebo gel to be administered under direct observation in the clinic.

Placebo gel: Universal HEC placebo gel; administered rectally

Overall Number of Participants Analyzed 18 9
Measure Type: Count of Participants
Unit of Measure: Participants
3
  16.7%
5
  55.6%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dapivirine Gel, Placebo Gel
Comments two-sided Fisher's Exact Test
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.072
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
2.Primary Outcome
Title Measurement of Dapivirine Concentrations in Plasma
Hide Description As assessed by pharmacokinetic sampling and analysis
Time Frame Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose, 24 hours after first dose during daily dosing, before last dose and 1,2, 24,48, and 72 hours after last dose.
Hide Outcome Measure Data
Hide Analysis Population Description
enrolled participants on the Dapivirine arm who received at least one dose of study product and had a sample collected at the specific time-point. 0 is an estimate for values below the limit of quantification (LLOQ = 20 pg/mL) since only numeric values are allowed. The value would be somewhere between the LLOQ and 0.
Arm/Group Title Dapivirine Gel
Hide Arm/Group Description:

Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally

Overall Number of Participants Analyzed 18
Median (Inter-Quartile Range)
Unit of Measure: pg/mL
30 to 60 minutes after single dose Number Analyzed 18 participants
31.5
(0 to 54.6)
120 minutes after single dose Number Analyzed 10 participants
326
(153 to 481)
24 hours after single dose Number Analyzed 18 participants
20.1
(0 to 56.6)
48 hours after single dose Number Analyzed 18 participants
0
(0 to 27.3)
72 hours after single dose Number Analyzed 18 participants
0
(0 to 0)
24 hours after first daily dose Number Analyzed 18 participants
67.9
(43.1 to 111.0)
Before last daily dose Number Analyzed 17 participants
167
(136 to 219)
30 to 60 minutes after last daily dose Number Analyzed 8 participants
290.5
(147.0 to 506.5)
120 minutes after last daily dose Number Analyzed 9 participants
403
(330 to 493)
24 hours after last daily dose Number Analyzed 17 participants
119.0
(86.4 to 172.0)
48 hours after last daily dose Number Analyzed 17 participants
113
(69 to 132)
72 hours after last daily dose Number Analyzed 17 participants
80.3
(47.3 to 129.0)
3.Primary Outcome
Title Measurement of Dapivirine Concentrations in Rectal Fluid
Hide Description As assessed by pharmacokinetic rectal fluid sampling and analysis
Time Frame Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose, 24 hours after first dose during daily dosing, and 1,2, 24,48, and 72 hours after last dose.
Hide Outcome Measure Data
Hide Analysis Population Description
enrolled participants on the Dapivirine arm who received at least one dose of product and had a sample collected at the specific time-point. 0 is an estimate for values below the limit of quantification (LLOQ = 0.001 ng/mg) since only numeric values are allowed. The value would be somewhere between the lower limit of quantification and 0.
Arm/Group Title Dapivirine Gel
Hide Arm/Group Description:

Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally

Overall Number of Participants Analyzed 18
Median (Inter-Quartile Range)
Unit of Measure: ng/mg
30 to 60 minutes after first application Number Analyzed 8 participants
30.1
(16.1 to 43.9)
120 minutes after single dose Number Analyzed 8 participants
12.765
(6.055 to 141.500)
24 hours after single dose Number Analyzed 8 participants
0
(0 to 0.016)
48 hours after single dose Number Analyzed 4 participants
0.009
(0 to 0.038)
72 hours after single dose Number Analyzed 6 participants
0
(0 to 0)
24 hours after first daily dose Number Analyzed 18 participants
0.180
(0 to 1.910)
30 to 60 minutes after last daily dose Number Analyzed 7 participants
89.7
(44.9 to 258.0)
120 minutes after last daily dose Number Analyzed 8 participants
26.65
(4.95 to 278.50)
24 hours after last daily dose Number Analyzed 7 participants
0.007
(0 to 0.096)
48 hours after last daily dose Number Analyzed 4 participants
0
(0 to 0.042)
72 hours after last daily dose Number Analyzed 6 participants
0
(0 to 0.013)
4.Primary Outcome
Title Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates
Hide Description As assessed by pharmacokinetic rectal mucosal tissue homogenates sampling and analysis
Time Frame Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose and 1,2, 24,48, and 72 hours after last dose.
Hide Outcome Measure Data
Hide Analysis Population Description
enrolled participants on the Dapivirine gel arm who received at least one dose of study product and had a sample collected at the specific time-point. 0 is an estimate for values below the limit of quantification (LLOQ = 0.001 ng/mg) since only numeric values are allowed. The value would be somewhere between the LLOQ and 0.
Arm/Group Title Dapivirine Gel
Hide Arm/Group Description:

Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally

Overall Number of Participants Analyzed 18
Median (Inter-Quartile Range)
Unit of Measure: ng/mg
30 to 60 minutes after single dose Number Analyzed 8 participants
0.256
(0 to 0.666)
120 minutes after single dose Number Analyzed 10 participants
0
(0 to 0.600)
24 hours after single dose Number Analyzed 8 participants
0
(0 to 0)
48 hours after single dose Number Analyzed 4 participants
0
(0 to 0)
72 hours after single dose Number Analyzed 6 participants
0
(0 to 0)
30 to 60 minutes after last daily dose Number Analyzed 7 participants
0
(0 to 0)
120 minutes after last daily dose Number Analyzed 8 participants
0
(0 to 0.151)
24 hours after last daily dose Number Analyzed 7 participants
0
(0 to 0)
48 hours after last daily dose Number Analyzed 3 participants
0
(0 to 0)
72 hours after last daily dose Number Analyzed 6 participants
0
(0 to 0)
5.Primary Outcome
Title Terminal Half-life of Dapivirine Concentrations in Plasma
Hide Description The terminal half-life of dapivirine in plasma samples was estimated by fitting a linear regression on the log-transformed concentrations from the 24, 48 and 72 hour time-points after the single and multiple doses.Each regression model includes an adjustment for the difference in concentration after multiple dosing. For each participant, Beta was calculated as the negative of the slope of their repression and half-life was log(2)/Beta. Due to the large number of concentrations below the limit of quantification after the single dose, the estimateion of Beta and half-life relied only on concentration after the multiple dosing for most of the participants.
Time Frame From samples collected 24 hours after first dose to 72 hours after last daily dose
Hide Outcome Measure Data
Hide Analysis Population Description
enrolled participants on the Dapivirine gel arm who received at least one dose of study product. One participant with a negative estimate for the elimination rate due to an increasing trend in their concentration after multiple dosing and one participant with no values above the limit of quantification were excluded.
Arm/Group Title Dapivirine Gel
Hide Arm/Group Description:

Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally

Overall Number of Participants Analyzed 16
Median (Inter-Quartile Range)
Unit of Measure: hours
52.6
(35.3 to 86.2)
6.Secondary Outcome
Title Acceptability: Ease of Use
Hide Description The number of participants who responded by questionnaire that the study product was easy or very easy to use.
Time Frame after completing the study (study day 40)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants who completed the exit behavioral questionnaire.
Arm/Group Title Dapivirine Gel Placebo Gel
Hide Arm/Group Description:

Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally

Participants will receive a single dose of placebo gel rectally, followed by 7 daily doses of placebo gel to be administered under direct observation in the clinic.

Placebo gel: Universal HEC placebo gel; administered rectally

Overall Number of Participants Analyzed 17 9
Measure Type: Count of Participants
Unit of Measure: Participants
16
  94.1%
9
 100.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dapivirine Gel, Placebo Gel
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments This is a calculated p-value. P-values of 1.0 are possible when using the Fisher Exact test method.
Method Fisher Exact
Comments [Not Specified]
7.Secondary Outcome
Title Acceptability: Comfort
Hide Description The number of participants who responded on a questionnaire that the study product was comfortable or very comfortable.
Time Frame after completing the study (study day 40)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Dapivirine Gel Placebo Gel
Hide Arm/Group Description:

Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally

Participants will receive a single dose of placebo gel rectally, followed by 7 daily doses of placebo gel to be administered under direct observation in the clinic.

Placebo gel: Universal HEC placebo gel; administered rectally

Overall Number of Participants Analyzed 17 9
Measure Type: Count of Participants
Unit of Measure: Participants
15
  88.2%
7
  77.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dapivirine Gel, Placebo Gel
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.591
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Time Frame Adverse event data was collected through study completion (between 40 to 86 days).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Dapivirine Gel Placebo Gel
Hide Arm/Group Description

Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic.

Dapivirine gel: Dapivirine gel (0.05%); administered rectally

Participants will receive a single dose of placebo gel rectally, followed by 7 daily doses of placebo gel to be administered under direct observation in the clinic.

Placebo gel: Universal HEC placebo gel; administered rectally

All-Cause Mortality
Dapivirine Gel Placebo Gel
Affected / at Risk (%) Affected / at Risk (%)
Total   0/18 (0.00%)      0/9 (0.00%)    
Hide Serious Adverse Events
Dapivirine Gel Placebo Gel
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/18 (0.00%)      0/9 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Dapivirine Gel Placebo Gel
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/18 (33.33%)      7/9 (77.78%)    
Gastrointestinal disorders     
Anal pruritus  1  1/18 (5.56%)  1 0/9 (0.00%)  0
Diarrhoea  1  2/18 (11.11%)  2 2/9 (22.22%)  2
Dyschezia  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Gastritis  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Haematochezia  1  1/18 (5.56%)  1 0/9 (0.00%)  0
Nausea  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Proctalgia  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Vomiting  1  0/18 (0.00%)  0 1/9 (11.11%)  1
General disorders     
Malaise  1  0/18 (0.00%)  0 1/9 (11.11%)  2
Infections and infestations     
Respiratory tract infection viral  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Injury, poisoning and procedural complications     
Joint dislocation  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Post procedural haemorrhage  1  0/18 (0.00%)  0 1/9 (11.11%)  1
procedural pain  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Investigations     
blood pressure increased  1  1/18 (5.56%)  2 0/9 (0.00%)  0
Musculoskeletal and connective tissue disorders     
coccydynia  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Nervous system disorders     
Headache  1  0/18 (0.00%)  0 2/9 (22.22%)  2
Psychiatric disorders     
Insomnia  1  2/18 (11.11%)  2 0/9 (0.00%)  0
Renal and urinary disorders     
Dysuria  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Pollakiuria  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Reproductive system and breast disorders     
Oropharyngeal pain  1  1/18 (5.56%)  1 0/9 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Nasal congestion  1  0/18 (0.00%)  0 1/9 (11.11%)  1
Upper-airway cough syndrome  1  1/18 (5.56%)  1 0/9 (0.00%)  0
Skin and subcutaneous tissue disorders     
Erythema  1  1/18 (5.56%)  1 0/9 (0.00%)  0
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Ross D. Cranston
Organization: Fundacio Lluita Contra la Sida, Hospital Universitari Germans Trias | Pujol
Phone: 34-934-657-897
EMail: rdcranston@outlook.com
Layout table for additonal information
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03239483    
Other Study ID Numbers: MTN-026
12021 ( Registry Identifier: DAIDS-ES Registry Number )
First Submitted: August 2, 2017
First Posted: August 4, 2017
Results First Submitted: September 19, 2019
Results First Posted: November 7, 2019
Last Update Posted: November 7, 2019