Emtricitabine/Tenofovir Disoproxil Fumarate for HIV Prevention in Men (iPrEx)

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
Condition	HIV Infections
Interventions	Drug: daily TDF/FTC; Drug: Placebo
Enrollment	2499

Participant Flow

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Top of Page Participant Flow Baseline Characteristics Outcome Measures Adverse Events Limitations and Caveats Information More Information

Recruitment Details	The study recruited HIV uninfected participants whose sexual practices put them at risk for HIV infection. They were recruited from community clinics.
Pre-assignment Details

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description	Daily oral emtricitabine/tenofovir disoproxil fumarate Emtricitabine/tenofovir disoproxil fumarate: Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate	Daily oral placebo Placebo: Placebo for emtricitabine/tenofovir disoproxil fumarate
Period Title: Overall Study
Started	1251	1248
Completed	942	953
Not Completed	309	295
Reason Not Completed
Withdrawal by Subject	67	80
Physician Decision	31	22
Relocated	77	81
Lost to Follow-up	115	92
Sites marked other on the form.	19	20

Baseline Characteristics

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Arm/Group Title		TDF/FTC	Placebo	Total
Arm/Group Description		Daily oral emtricitabine/tenofovir disoproxil fumarate Emtricitabine/tenofovir disoproxil fumarate: Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate	Daily oral placebo Placebo: Placebo for emtricitabine/tenofovir disoproxil fumarate	Total of all reporting groups
Overall Number of Baseline Participants		1251	1248	2499
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1251 participants	1248 participants	2499 participants
	<=18 years	92 7.4%	101 8.1%	193 7.7%
	Between 18 and 65 years	1158 92.6%	1147 91.9%	2305 92.2%
	>=65 years	1 0.1%	0 0.0%	1 0.0%
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	1251 participants	1248 participants	2499 participants
		25; (18 to 67)	24; (18 to 63)	24; (18 to 67)
Sex/Gender, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	1251 participants	1248 participants	2499 participants
Male Sex at Birth. Identify Trans		155 12.4%	155 12.4%	310 12.4%
Male Sex at Birth. Identify Female		15 1.2%	14 1.1%	29 1.2%
Male Sex at Birth. Identify Male		1081 86.4%	1079 86.5%	2160 86.4%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	1251 participants	1248 participants	2499 participants
Ecuador		150	150	300
United States		113	114	227
Brazil		186	184	370
South Africa		45	43	88
Thailand		57	57	114
Peru		700	700	1400

Outcome Measures

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1. Primary Outcome

Title	HIV Seroconversion
Description	Confirmed HIV infection
Time Frame	Monthly follow-up through a median of 1.2 years

Outcome Measure Data

Analysis Population Description

Excludes participants who were HIV+ at enrollment (2 TDF/FTC, 8 Placebo) and those with no follow-up HIV test (25 TDF/FTC and 22 Placebo).

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate Emtricitabine/tenofovir disoproxil fumarate: Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate	Daily oral placebo Placebo: Placebo for emtricitabine/tenofovir disoproxil fumarate
Overall Number of Participants Analyzed	1224	1218
Measure Type: Count of Participants; Unit of Measure: Participants
	48 3.9%	83 6.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	Primary null hypothesis: Relative hazard of 0.7 or less. Secondary null hypothesis: Relative hazard of 1.0 or less.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.002
	Comments	secondary p-value given.
	Method	Log Rank
	Comments	stratified by site
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.577
	Confidence Interval	(2-Sided) 95%; .404 to .824
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.105
	Estimation Comments	Efron correction for ties. Placebo is reference. Results typically quoted as efficacy = 100*(1-HR)

2. Primary Outcome

Title	Grade 1 or Higher Creatinine Toxicity
Description	Creatinine which reach grade 1 (mild, 1.1 to 1.3 local upper limit of normal) or higher by the US Division of AIDS grading table (version 1) or a 50% increase in creatinine from the baseline value. The DAIDS table can be found at https://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf
Time Frame	Duration of follow-up, median 1.2 years

Outcome Measure Data

Analysis Population Description

All randomized participants which at least 1 follow-up creatinine value

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	1216	1217
Measure Type: Count of Participants; Unit of Measure: Participants
	32 2.6%	24 2.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.28
	Comments	p-value is not adjusted for multiple comparisons, a priori threshold for statistical significance was p < 0.05
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 95%; 0.79 to 2.25
	Estimation Comments	[Not Specified]

3. Primary Outcome

Title	Grade 3 or Higher Phosphorous Toxicity
Description	Grade 3 or higher phosphorous toxicity (hypophosphatemia) by the Division of AIDS Grading Table (severe, level at or below 1.9 mg/dL)
Time Frame	The entire follow-up period, median 1.2 years

Outcome Measure Data

Analysis Population Description

All participants with at least 1 follow-up phosphorus value

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	1225	1226
Measure Type: Count of Participants; Unit of Measure: Participants
	13 1.1%	10 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.54
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.3
	Confidence Interval	(2-Sided) 95%; .57 to 2.96
	Estimation Comments	[Not Specified]

4. Primary Outcome

Title	Grade 2, 3, or 4 Laboratory Adverse Events
Description	Number of participants with at least one Grade 2, 3, or 4 laboratory adverse events (moderate, severe of life threatening based one the US Division of AIDS Grading of adverse events, version 1.0). The table can be found at https://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf
Time Frame	Entire follow-up, median 1.2 years

Outcome Measure Data

Analysis Population Description

At participants with at least one visit with laboratory values post-baseline

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	1229	1226
Measure Type: Count of Participants; Unit of Measure: Participants
	70 5.7%	79 6.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.50
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.23
	Estimation Comments	[Not Specified]

5. Primary Outcome

Title	Grade 2, 3, or 4 Clinical Adverse Events
Description	Number of participants with at least 1 Grade 2, 3, or 4 clinical adverse events (moderate, severe of life threatening based one the US Division of AIDS Grading of adverse events, version 1.0). The table can be found at https://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf
Time Frame	Entire follow-up, median 1.2 years

Outcome Measure Data

Analysis Population Description

At participants with at least one follow-up visit

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	1226	1230
Measure Type: Count of Participants; Unit of Measure: Participants
	157 12.8%	162 13.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.92
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.23
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Hepatitis Flares Among Hepatitis B Virus (HBV) Infected Persons During and After Chemoprophylaxis
Description	A hepatic flare is defined as an increase in alanine transaminase or aspartate transaminase to >5 fold upper limit of normal at any visit, or an increase to >2.5 fold upper limit of normal for 3 months, within 24 weeks of permanently stopping study drug. More details in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752387/
Time Frame	Quarterly lab tests through a median follow-up of 1.2 years

Outcome Measure Data

Analysis Population Description

Those with chronic active hepatitis B at enrollment.

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate Emtricitabine/tenofovir disoproxil fumarate: Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate	Daily oral placebo Placebo: Placebo for emtricitabine/tenofovir disoproxil fumarate
Overall Number of Participants Analyzed	6	6
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	Null hypothesis of no difference
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Desc
Statistical Test of Hypothesis	P-Value	1.00
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.00
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Percentage Change in Bone Mineral Density
Description	% Change from baseline in bone mineral density (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in in hip and L1-L4 spine by dual-energy x-ray absorptiometry
Time Frame	baseline and week 24.

Outcome Measure Data

Analysis Population Description

Participants confirmed to be HIV negative at enrollment who consented to participate in the metabolic substudy. Full details in https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25908682/

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate Emtricitabine/tenofovir disoproxil fumarate: Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate	Daily oral placebo Placebo: Placebo for emtricitabine/tenofovir disoproxil fumarate
Overall Number of Participants Analyzed	210	211
Mean (Standard Error); Unit of Measure: percent change from baseline
L1-L4 Spine bone mineral density	-0.59 (0.21)	0.32 (0.21)
Hip bone mineral density	-0.34 (0.16)	0.29 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.001
	Comments	< 0.05 for statistical significance. no adjustment for multiple comparisons
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-.91
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Percentage Change in Body Fat
Description	Percentage Change (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in Body Fat from Baseline by dual-energy x-ray absorptiometry
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All participants in the body composition substudy who made a week 24 body scan

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	210	211
Median (Standard Error); Unit of Measure: percent change from baseline
	0.0 (1.0)	3.8 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.009
	Comments	[Not Specified]
	Method	median regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-3.8
	Confidence Interval	(2-Sided) 95%; -6.6 to -0.95
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Percentage Change in Fasting Triglycerides
Description	Percentage Change (Percentage Change (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in Triglycerides from Baseline from a fasting sample.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All participants in the metabolic substudy with a week 24 fast triglyceride value

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	199	194
Median (Standard Error); Unit of Measure: percent change from baseline
	0.0 (3.3)	0.0 (3.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	[Not Specified]
	Method	median regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -9.3 to 9.3
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Percent Change in Total Cholesterol
Description	Percent change (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in fasting total cholesterol from baseline
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All participants in the metabolic substudy with a week 24 fasting cholesterol

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	199	194
Median (Standard Error); Unit of Measure: percent change from baseline
	-3.2 (1.2)	-1.1 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.19
	Comments	[Not Specified]
	Method	median regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -5.5 to 1.1
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Viral Load Among HIV Infected Participants
Description	HIV-RNA in log10 units among HIV infected participants at the time closest to HIV detection
Time Frame	At the time closest to HIV detection

Outcome Measure Data

Analysis Population Description

All HIV infections detected during the study including prior to, during and after study treatment

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	54	93
Mean (Standard Error); Unit of Measure: log RNA copies per ml
	5.2 (0.11)	5.1 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.56
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -.18 to 0.33
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Among HIV Infected Participants Drug Resistance
Description	Genotypic resistance by clinical assays among the seroconverters from baseline to the end of the study treatment period
Time Frame	at the time of HIV acquisition

Outcome Measure Data

Analysis Population Description

There were 2 TDF/FTC seroconversions at enrollment and 48 during follow-up. There were 8 Placebo seroconversions at enrollment and 83 during follow-up.

Arm/Group Title		TDF/FTC	Placebo
Arm/Group Description:		Daily oral emtricitabine/tenofovir disoproxil fumarate Emtricitabine/tenofovir disoproxil fumarate: Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate	Daily oral placebo Placebo: Placebo for emtricitabine/tenofovir disoproxil fumarate
Overall Number of Participants Analyzed		50	91
Measure Type: Count of Participants; Unit of Measure: Participants
Infected at Enrollment (prior to randomization)	Number Analyzed	2 participants	8 participants
		2 100.0%	1 12.5%
Infected after Randomization	Number Analyzed	48 participants	83 participants
		0 0.0%	0 0.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	Null hypothesis is the proportion of mutations is identical.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.00
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.00
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	CD4 Count Among HIV Infected Participants
Description	CD4 cell count for HIV infected participants during the trial
Time Frame	at the time infection was detected

Outcome Measure Data

Analysis Population Description

HIV infected participants during the trial including those HIV+ at baseline

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	51	87
Mean (95% Confidence Interval); Unit of Measure: cells per cubic mm
	495; (470 to 520)	502; (483 to 521)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.32
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7
	Confidence Interval	(2-Sided) 95%; -69 to 54
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Proportion of Missed Doses by Pill Count
Description	Estimated proportion of missed doses by pill count (assuming pills taken in unreturned bottles)
Time Frame	At 24 weeks

Outcome Measure Data

Analysis Population Description

Those who bottles returned at the week 24 visit.

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate Emtricitabine/tenofovir disoproxil fumarate: Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate	Daily oral placebo Placebo: Placebo for emtricitabine/tenofovir disoproxil fumarate
Overall Number of Participants Analyzed	983	999
Mean (95% Confidence Interval); Unit of Measure: proportion of pills not returned
	0.92; (0.91 to 0.93)	0.93; (0.92 to 0.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	Null hypothesis is equal proportion of pills returned
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.53
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.005
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.01
	Estimation Comments	[Not Specified]

15. Secondary Outcome

Title	Percentage of Missed Doses by Estimate During CASI Interview
Description	Percentage of missed doses by estimate during computer assisted structured interview
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

All participants who answered the adherence question with an estimated adherence on the week 24 computer assisted structured interview

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	884	902
Mean (Standard Error); Unit of Measure: percentage of doses taken
	91.0 (0.5)	91.2 (0.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.70
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; -1.1 to 1.6
	Estimation Comments	[Not Specified]

16. Secondary Outcome

Title	Number of Condomless Sexual Partners With HIV Positive or Unknown Status
Description	Participants self-report of the number of sexual partners with HIV positive or unknown status in the previous 12 weeks with whom they had condomless anal sex
Time Frame	At 24 weeks

Outcome Measure Data

Analysis Population Description

Participants interviewed about sexual practices at week 24

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	1091	1114
Median (Inter-Quartile Range); Unit of Measure: count
	0; (0 to 0)	0; (0 to 0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.99
	Comments	Not adjusted for multiple comparisons and the a priori threshold for statistical significance was p < 0.05
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0
	Estimation Comments	[Not Specified]

17. Secondary Outcome

Title	Total Number of Sexual Partners
Description	Self-reported total number of sexual partners in the previous 12 weeks.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Participants interviewed about sexual practices at week 24

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	1091	1114
Median (Inter-Quartile Range); Unit of Measure: Count
	3; (1 to 6)	3; (1 to 7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.76
	Comments	Not adjusted for multiple comparisons, a priori threshold for statistical significance, p < 0.05
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -.42 to .42
	Estimation Comments	[Not Specified]

18. Secondary Outcome

Title	Condomless Receptive Anal Intercourse in the Previous 12 Weeks With Any Partners Regardless of Status.
Description	Self-reported condomless receptive anal intercourse in the previous 12 weeks with any partners regardless of status.
Time Frame	At 24 weeks

Outcome Measure Data

Analysis Population Description

Participants interviewed about sexual practices at week 24

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate Emtricitabine/tenofovir disoproxil fumarate: Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate	Daily oral placebo Placebo: Placebo for emtricitabine/tenofovir disoproxil fumarate
Overall Number of Participants Analyzed	1091	1114
Measure Type: Count of Participants; Unit of Measure: Participants
	332 30.4%	348 31.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	Null is no difference between arms
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.68
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.008
	Confidence Interval	(2-Sided) 95%; -0.047 to 0.030
	Estimation Comments	[Not Specified]

19. Secondary Outcome

Title	Incidence of Confirmed Syphilis During Follow-Up
Description	Number of participants who have at least 1 confirmed syphilis infection during the study
Time Frame	All Follow-Up median of 1.2 years of follow-up

Outcome Measure Data

Analysis Population Description

Participants without active syphilis at baseline with a follow-up syphilis test.

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate Emtricitabine/tenofovir disoproxil fumarate: Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate	Daily oral placebo Placebo: Placebo for emtricitabine/tenofovir disoproxil fumarate
Overall Number of Participants Analyzed	1155	1171
Measure Type: Count of Participants; Unit of Measure: Participants
	147 12.7%	132 11.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	Null hypothesis of no difference between the arms
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.30
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.43
	Estimation Comments	[Not Specified]

20. Secondary Outcome

Title	Incidence of HSV-2 During the Follow-up Period
Description	Incidence of HSV-2 during the follow-up period among those HIV-2 negative at baseline
Time Frame	Total study follow-up, a median of 1.2 years

Outcome Measure Data

Analysis Population Description

All HSV-2 negative participants with a follow-up HSV-2 test.

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	671	676
Measure Type: Count of Participants; Unit of Measure: Participants
	65 9.7%	60 8.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.41
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; 0.8 to 1.7
	Estimation Comments	[Not Specified]

21. Secondary Outcome

Title	Diagnosis of Gonorrhea During the Follow-up Period
Description	Diagnosis of gonorrhea during the follow-up period by PCR
Time Frame	All of follow-up period, median of 1.2 years

Outcome Measure Data

Analysis Population Description

All participants with at least one follow-up test for gonorrhea

Arm/Group Title	TDF/FTC	Placebo
Arm/Group Description:	Daily oral emtricitabine/tenofovir disoproxil fumarate	Daily oral placebo
Overall Number of Participants Analyzed	1226	1229
Measure Type: Count of Participants; Unit of Measure: Participants
	18 1.5%	30 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TDF/FTC, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.09
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.34 to 1.09
	Estimation Comments	[Not Specified]

Adverse Events

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Top of Page Participant Flow Baseline Characteristics Outcome Measures Adverse Events Limitations and Caveats Information More Information

Time Frame	Monthly follow-up with quarterly lab assessments though a median of 1.2 years of follow-up
Adverse Event Reporting Description	Adverse events graded by the NIH Division of AIDS grading tables, version 1.0
Arm/Group Title	TDF/FTC		Placebo
Arm/Group Description	Daily oral emtricitabine/tenofovir disoproxil fumarate Emtricitabine/tenofovir disoproxil fumarate: Fixed-dose coformulation of 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate		Daily oral placebo Placebo: Placebo for emtricitabine/tenofovir disoproxil fumarate
All-Cause Mortality
	TDF/FTC		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	TDF/FTC		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	92/1226 (7.50%)		94/1230 (7.64%)
Blood and lymphatic system disorders
CREATININE INCREASE † 1	9/1226 (0.73%)	9	7/1230 (0.57%)	7
ALT INCREASE † 1	1/1226 (0.08%)	1	4/1230 (0.33%)	4
AST † 1	4/1226 (0.33%)	4	5/1230 (0.41%)	5
General disorders
OTHER EVENTS † 1 [1]	28/1226 (2.28%)	28	29/1230 (2.36%)	29
Hepatobiliary disorders
APPENDICITIS † 1	3/1226 (0.24%)	3	3/1230 (0.24%)	3
Musculoskeletal and connective tissue disorders
Bone Fracture † 1	8/1226 (0.65%)	8	9/1230 (0.73%)	9
Psychiatric disorders
SUICIDE ATTEMPT † 1	17/1226 (1.39%)	17	14/1230 (1.14%)	14
SUICIDAL IDEATION † 1	5/1226 (0.41%)	5	6/1230 (0.49%)	6
DEPRESSION † 1	7/1226 (0.57%)	7	11/1230 (0.89%)	11
SUICIDAL DEPRESSION † 1	5/1226 (0.41%)	5	6/1230 (0.49%)	6
MAJOR DEPRESSION † 1	5/1226 (0.41%)	5	0/1230 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (10.0); [1] EVENTS AFFECTING LESS THAN A TOTAL OF 5 PARTICIPANTS
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	TDF/FTC		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	906/1226 (73.90%)		937/1230 (76.18%)
Gastrointestinal disorders
PARASITIC INFECTION INTESTINAL † 1	231/1226 (18.84%)	231	216/1230 (17.56%)	216
DIARRHOEA † 1	109/1226 (8.89%)	109	123/1230 (10.00%)	123
Infections and infestations
SYPHILIS † 1	82/1226 (6.69%)	82	71/1230 (5.77%)	71
UPPER RESPIRATORY TRACT INFECTION † 1	73/1226 (5.95%)	73	76/1230 (6.18%)	76
SECONDARY SYPHILIS † 1	81/1226 (6.61%)	81	64/1230 (5.20%)	64
BLOOD AMYLASE INCREASED † 1	62/1226 (5.06%)	62	57/1230 (4.63%)	57
Investigations
ALANINE AMINOTRANSFERASE INCREASED † 1	151/1226 (12.32%)	151	155/1230 (12.60%)	155
BILIRUBIN INCREASE † 1	127/1226 (10.36%)	127	132/1230 (10.73%)	132
BLOOD GLUCOSE INCREASED † 1	109/1226 (8.89%)	109	123/1230 (10.00%)	123
BLOOD PHOSPHORUS DECREASED † 1	122/1226 (9.95%)	122	100/1230 (8.13%)	100
ASPARTATE AMINOTRANSFERASE INCREASED † 1	76/1226 (6.20%)	76	93/1230 (7.56%)	93
Musculoskeletal and connective tissue disorders
BACK PAIN † 1	84/1226 (6.85%)	84	87/1230 (7.07%)	87
Nervous system disorders
HEADACHE † 1	102/1226 (8.32%)	102	107/1230 (8.70%)	107
DEPRESSION † 1	81/1226 (6.61%)	81	84/1230 (6.83%)	84
Renal and urinary disorders
URETHRITIS † 1	84/1226 (6.85%)	84	102/1230 (8.29%)	102
Respiratory, thoracic and mediastinal disorders
PHARYNGITIS † 1	248/1226 (20.23%)	248	282/1230 (22.93%)	282
NASOPHARYNGITIS † 1	98/1226 (7.99%)	98	92/1230 (7.48%)	92
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (10.0)

Limitations and Caveats

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[Not Specified]

More Information

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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

Name/Title: David Glidden

Organization: University of California, San Francisco

Phone: 415-514-8009

EMail: david.glidden@ucsf.edu

Publications of Results:

Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapía M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernández T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallás EG, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng JH, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99. doi: 10.1056/NEJMoa1011205. Epub 2010 Nov 23.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Glidden DV, Mulligan K, McMahan V, Anderson PL, Guanira J, Chariyalertsak S, Buchbinder SP, Bekker LG, Schechter M, Grinsztejn B, Grant RM. Metabolic Effects of Preexposure Prophylaxis With Coformulated Tenofovir Disoproxil Fumarate and Emtricitabine. Clin Infect Dis. 2018 Jul 18;67(3):411-419. doi: 10.1093/cid/ciy083.

Glidden DV, Mulligan K, McMahan V, Anderson PL, Guanira J, Chariyalertsak S, Buchbinder SP, Bekker LG, Schechter M, Grinsztejn B, Grant RM. Brief Report: Recovery of Bone Mineral Density After Discontinuation of Tenofovir-Based HIV Pre-exposure Prophylaxis. J Acquir Immune Defic Syndr. 2017 Oct 1;76(2):177-182. doi: 10.1097/QAI.0000000000001475.

Gandhi M, Glidden DV, Mayer K, Schechter M, Buchbinder S, Grinsztejn B, Hosek S, Casapia M, Guanira J, Bekker LG, Louie A, Horng H, Benet LZ, Liu A, Grant RM. Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study. Lancet HIV. 2016 Nov;3(11):e521-e528. doi: 10.1016/S2352-3018(16)30153-9. Epub 2016 Aug 31.

Castillo-Mancilla J, Seifert S, Campbell K, Coleman S, McAllister K, Zheng JH, Gardner EM, Liu A, Glidden DV, Grant R, Hosek S, Wilson CM, Bushman LR, MaWhinney S, Anderson PL. Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6692-6697. doi: 10.1128/AAC.01017-16. Print 2016 Nov.

Glidden DV, Amico KR, Liu AY, Hosek SG, Anderson PL, Buchbinder SP, McMahan V, Mayer KH, David B, Schechter M, Grinsztejn B, Guanira J, Grant RM. Symptoms, Side Effects and Adherence in the iPrEx Open-Label Extension. Clin Infect Dis. 2016 May 1;62(9):1172-7. doi: 10.1093/cid/ciw022. Epub 2016 Jan 20.

Mulligan K, Glidden DV, Anderson PL, Liu A, McMahan V, Gonzales P, Ramirez-Cardich ME, Namwongprom S, Chodacki P, de Mendonca LM, Wang F, Lama JR, Chariyalertsak S, Guanira JV, Buchbinder S, Bekker LG, Schechter M, Veloso VG, Grant RM; Preexposure Prophylaxis Initiative Study Team. Effects of Emtricitabine/Tenofovir on Bone Mineral Density in HIV-Negative Persons in a Randomized, Double-Blind, Placebo-Controlled Trial. Clin Infect Dis. 2015 Aug 15;61(4):572-80. doi: 10.1093/cid/civ324. Epub 2015 Apr 23.

Liu A, Glidden DV, Anderson PL, Amico KR, McMahan V, Mehrotra M, Lama JR, MacRae J, Hinojosa JC, Montoya O, Veloso VG, Schechter M, Kallas EG, Chariyalerstak S, Bekker LG, Mayer K, Buchbinder S, Grant R; iPrEx Study team. Patterns and correlates of PrEP drug detection among MSM and transgender women in the Global iPrEx Study. J Acquir Immune Defic Syndr. 2014 Dec 15;67(5):528-37. doi: 10.1097/QAI.0000000000000351.

Liegler T, Abdel-Mohsen M, Bentley LG, Atchison R, Schmidt T, Javier J, Mehrotra M, Eden C, Glidden DV, McMahan V, Anderson PL, Li P, Wong JK, Buchbinder S, Guanira JV, Grant RM; iPrEx Study Team. HIV-1 drug resistance in the iPrEx preexposure prophylaxis trial. J Infect Dis. 2014 Oct 15;210(8):1217-27. doi: 10.1093/infdis/jiu233. Epub 2014 Apr 16.

Buchbinder SP, Glidden DV, Liu AY, McMahan V, Guanira JV, Mayer KH, Goicochea P, Grant RM. HIV pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial. Lancet Infect Dis. 2014 Jun;14(6):468-75. doi: 10.1016/S1473-3099(14)70025-8. Epub 2014 Mar 7.

Amico KR, Mansoor LE, Corneli A, Torjesen K, van der Straten A. Adherence support approaches in biomedical HIV prevention trials: experiences, insights and future directions from four multisite prevention trials. AIDS Behav. 2013 Jul;17(6):2143-55. doi: 10.1007/s10461-013-0429-9. Review.

Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00458393 History of Changes
Obsolete Identifiers:	NCT00350324
Other Study ID Numbers:	CO-US-104-0288; 10445 ( Registry Identifier: DAIDS ES ); 1U01AI064002 ( U.S. NIH Grant/Contract ); iPrEx ( Other Identifier: Study team )
First Submitted:	April 6, 2007
First Posted:	April 10, 2007
Results First Submitted:	December 27, 2016
Results First Posted:	January 24, 2018
Last Update Posted:	January 24, 2018