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Clinical Trial Results:
A Phase 3, Two-Part Study to Evaluate the Efficacy of Tenofovir Alafenamide versus Placebo Added to a Failing Regimen Followed by Treatment with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide plus Atazanavir in HIV-1 Positive, Antiretroviral Treatment-Experienced Adults

Summary
EudraCT number	2013-002830-19
Trial protocol	DE GB
Global end of trial date	31 Jul 2017

Results information
Results version number	v2(current)
This version publication date	18 May 2019
First version publication date	03 Aug 2018
Other versions	v1
Version creation reason	Correction of full data set Adding text to “Limitations and Caveats” section

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GS-US-292-0117

ISRCTN number

US NCT number

NCT01967940

WHO universal trial number (UTN)

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

333 Lakeside Drive, Foster City, CA, United States, 94404

Public contact

Gilead Clinical Study Information Center, Gilead Sciences , GileadClinicalTrials@gilead.com

Scientific contact

Gilead Clinical Study Information Center, Gilead Sciences , GileadClinicalTrials@gilead.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Jul 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

21 May 2015

Global end of trial reached?

Yes

Global end of trial date

31 Jul 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study is to evaluate the efficacy of tenofovir alafenamide (TAF) versus placebo, each administered with the existing, failing antiretroviral (ARV) regimen.

Protection of trial subjects

The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

25 Oct 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Uganda: 28

Country: Number of subjects enrolled

Thailand: 10

Country: Number of subjects enrolled

United States: 8

Country: Number of subjects enrolled

Dominican Republic: 6

Country: Number of subjects enrolled

Russian Federation: 3

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled at study sites in the United States, Uganda, Thailand, Russian Federation, and Dominican Republic. The first participant was screened on 25 October 2013. The last study visit occurred on 31 July 2017. Sites were initiated in Germany and the UK, but were unable to recruit any participants.

Screening details

259 participants were screened.

Period 1 title

Part 1

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Part 1 consisted of 2 cohorts, starting with a sentinel cohort, in which participants were enrolled to receive open-label TAF in addition to their current failing ARV regimen. This cohort was then be followed by a randomized, double-blind, cohort to compare the addition of TAF or placebo in HIV-1 positive adults who are failing their current ARV regimen.

Are arms mutually exclusive

Yes

Part 1 Sentinel Cohort TAF

Arm description

TAF + their current failing regimen for 10 days

Arm type

Experimental

Investigational medicinal product name

Tenofovir alafenamide

Investigational medicinal product code

Other name

TAF, GS-7340, Vemlidy®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablet administered once daily with food

Part 1 Randomized Cohort TAF

Arm description

TAF + their current failing regimen for 10 days

Arm type

Experimental

Investigational medicinal product name

Tenofovir alafenamide

Investigational medicinal product code

Other name

TAF, GS-7340, Vemlidy®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg tablet administered once daily with food

Part 1 Randomized Cohort Placebo

Arm description

Placebo + their current failing regimen for 10 days

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily with food

Number of subjects in period 1	Part 1 Sentinel Cohort TAF	Part 1 Randomized Cohort TAF	Part 1 Randomized Cohort Placebo
Started	12	28	15
Completed	12	28	15

Period 2 title

Part 2

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

All participants who completed Part 1 of the study discontinued their failing ARV regimen and TAF or placebo for a 14-day washout period. Participants in the Part 1 Randomized Cohort TAF group with a > 0.5 log10 decline in HIV-1 RNA and all participants completing the Part 1 Randomized Cohort Placebo group were eligible to enroll into Part 2 of the study.

Part 2 E/C/F/TAF + ATV

Arm description

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen (STR) plus atazanavir (ATV) once daily for 48 weeks

Arm type

Experimental

Investigational medicinal product name

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

Investigational medicinal product code

Other name

E/C/F/TAF, Genvoya®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

150/150/200/10 mg STR administered once daily with food

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg tablet administered once daily with food

Number of subjects in period 2 ^[1]	Part 2 E/C/F/TAF + ATV
Started	38
Completed	35
Not completed	3
Enrolled in Part 2 and Never Treated	1
Unknown Reason	1
Adverse event, non-fatal	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 17 participants completed Part 1 and did not enter Part 2; 38 participants from Part 1 entered Part 2 of the study.

Baseline characteristics

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Reporting group title

Part 1 Sentinel Cohort TAF

Reporting group description

TAF + their current failing regimen for 10 days

Reporting group title

Part 1 Randomized Cohort TAF

Reporting group description

TAF + their current failing regimen for 10 days

Reporting group title

Part 1 Randomized Cohort Placebo

Reporting group description

Placebo + their current failing regimen for 10 days

Reporting group values	Part 1 Sentinel Cohort TAF	Part 1 Randomized Cohort TAF	Part 1 Randomized Cohort Placebo	Total
Number of subjects	12	28	15	55
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	38 ± 7.3	40 ± 9.1	43 ± 8.2	-
Gender categorical
Units: Subjects
Female	3	16	4	23
Male	9	12	11	32
Ethnicity
Units: Subjects
Hispanic or Latino	5	0	1	6
Not Hispanic or Latino	7	28	14	49
Race
Units: Subjects
Asian	0	5	5	10
Black	3	22	9	34
White	4	1	0	5
Other	5	0	1	6
HIV-1 RNA Category
Units: Subjects
≤ 100,000 copies/mL	12	27	12	51
> 100,000 to ≤ 400,000 copies/mL	0	1	3	4
HIV-1 RNA
Units: log10 copies/mL
arithmetic mean (standard deviation)	4.18 ± 0.648	4.16 ± 0.544	4.03 ± 0.953	-
CD4 Cell Count
Units: cells/μL
arithmetic mean (standard deviation)	269 ± 207.1	245 ± 244.6	232 ± 162.4	-
CD4 Percentage
Units: percentage
arithmetic mean (standard deviation)	17.4 ± 10.14	16.5 ± 11.09	14.3 ± 8.61	-

End points

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Reporting group title

Part 1 Sentinel Cohort TAF

Reporting group description

TAF + their current failing regimen for 10 days

Reporting group title

Part 1 Randomized Cohort TAF

Reporting group description

TAF + their current failing regimen for 10 days

Reporting group title

Part 1 Randomized Cohort Placebo

Reporting group description

Placebo + their current failing regimen for 10 days

Reporting group title

Part 2 E/C/F/TAF + ATV

Reporting group description

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen (STR) plus atazanavir (ATV) once daily for 48 weeks

Primary: Part 1: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 10

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End point title

Part 1: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 10

End point description

Part 1 Full Analysis Set: participants who enrolled into Part 1 of the study and received at least one dose of study drug in Part 1.

End point type

Primary

End point timeframe

Day 10

End point values	Part 1 Sentinel Cohort TAF	Part 1 Randomized Cohort TAF	Part 1 Randomized Cohort Placebo
Number of subjects analysed	12	28	15
Units: percentage of participants
number (not applicable)	58.3	60.7	0

Statistical Analysis - TAF vs Placebo

Statistical analysis description

A sample size of 90 participants, randomized in a 2:1 ratio, achieves 89% power to detect a 35% difference in the proportion of participants with HIV-1 RNA decreases from baseline exceeding 0.5 log10 between the TAF and placebo arms at Day 10. Sample size and power computation was based on the assumption that 50% of participants in the TAF arm and 15% of participants in the placebo arm achieved a reduction exceeding 0.5 log10 HIV-1 RNA.

Comparison groups

Part 1 Randomized Cohort TAF v Part 1 Randomized Cohort Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[1]

Method

Fisher exact

Parameter type

Difference in proportions

Point estimate

60.7

Confidence interval

level

95%

sides

2-sided

lower limit

42.6

upper limit

78.8

Notes
[1] - The 95% confidence interval was estimated based on unconditional exact method using 2 inverted 1-sided tests with the standardized statistic.

Secondary: Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10

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End point title

Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10

End point description

Participants in the Part 1 Full Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Baseline; Day 10

End point values	Part 1 Sentinel Cohort TAF	Part 1 Randomized Cohort TAF	Part 1 Randomized Cohort Placebo
Number of subjects analysed	12	28	15
Units: log10 copies/mL
arithmetic mean (standard deviation)	-0.72 ± 0.574	-0.70 ± 0.628	-0.04 ± 0.233

No statistical analyses for this end point

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities Through Week 24

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End point title

Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities Through Week 24

End point description

Part 2 Safety Analysis Set: participants who enrolled into Part 2 of the study and received at least one dose of study drug in Part 2.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	37
Units: percentage of participants
number (not applicable)	37.8

No statistical analyses for this end point

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities Through Week 48

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End point title

End point description

Participants in the Part 2 Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	37
Units: percentage of participants
number (not applicable)	48.6

No statistical analyses for this end point

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Any Treatment-Emergent Adverse Event Through Week 24

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End point title

Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Any Treatment-Emergent Adverse Event Through Week 24

End point description

Participants in the Part 2 Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	37
Units: percentage of participants
number (not applicable)	75.7

No statistical analyses for this end point

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Any Treatment-Emergent Adverse Event Through Week 48

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End point title

End point description

Participants in the Part 2 Safety Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	37
Units: percentage of participants
number (not applicable)	81.1

No statistical analyses for this end point

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24

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End point title

Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24

End point description

The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Part 2 Full Analysis Set included participants who enrolled into Part 2 of the study and received at least one dose of study drug in Part 2.

End point type

Secondary

End point timeframe

Week 24

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	37
Units: percentage of participants
number (not applicable)	86.5

No statistical analyses for this end point

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48

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End point title

Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48

End point description

The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Participants in the Part 2 Full Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Week 48

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	37
Units: percentage of participants
number (not applicable)	97.3

No statistical analyses for this end point

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24

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End point title

Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24

End point description

The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Participants in the Part 2 Full Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Week 24

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	37
Units: percentage of participants
number (not applicable)	94.6

No statistical analyses for this end point

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48

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End point title

Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48

End point description

The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Participants in the Part 2 Full Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Week 48

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	37
Units: percentage of participants
number (not applicable)	97.3

No statistical analyses for this end point

Secondary: Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 24

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End point title

Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 24

End point description

Participants in the Part 2 Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 24

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	35
Units: log10 copies/mL
arithmetic mean (standard deviation)	-2.96 ± 0.754

No statistical analyses for this end point

Secondary: Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 48

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End point title

Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 48

End point description

Participants in the Part 2 Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	35
Units: log10 copies/mL
arithmetic mean (standard deviation)	-3.04 ± 0.594

No statistical analyses for this end point

Secondary: Part 2: Change From Baseline in CD4+ Cell Count at Week 24

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End point title

Part 2: Change From Baseline in CD4+ Cell Count at Week 24

End point description

Participants in the Part 2 Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 24

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	35
Units: cells/μL
arithmetic mean (standard deviation)	76 ± 92.8

No statistical analyses for this end point

Secondary: Part 2: Change From Baseline in CD4+ Cell Count at Week 48

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End point title

Part 2: Change From Baseline in CD4+ Cell Count at Week 48

End point description

Participants in the Part 2 Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	35
Units: cells/μL
arithmetic mean (standard deviation)	125 ± 109.0

No statistical analyses for this end point

Secondary: Part 2: Change From Baseline in CD4+ Percentage at Week 24

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End point title

Part 2: Change From Baseline in CD4+ Percentage at Week 24

End point description

Participants in the Part 2 Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 24

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	35
Units: percentage change
arithmetic mean (standard deviation)	4.4 ± 2.35

No statistical analyses for this end point

Secondary: Part 2: Change From Baseline in CD4+ Percentage at Week 48

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End point title

Part 2: Change From Baseline in CD4+ Percentage at Week 48

End point description

Participants in the Part 2 Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	Part 2 E/C/F/TAF + ATV
Number of subjects analysed	35
Units: percentage change
arithmetic mean (standard deviation)	5.7 ± 2.99

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to the last dose date plus 30 days (average exposure: Part 1 = 10 days; Part 2 = 86.5 weeks)

Adverse event reporting additional description

Safety Analysis Set: participants who enrolled into the study and received at least one dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Part 1 Sentinel Cohort TAF

Reporting group description

TAF + their current failing regimen for 10 days

Reporting group title

Part 1 Randomized Cohort TAF

Reporting group description

TAF + their current failing regimen for 10 days

Reporting group title

Part 1 Randomized Cohort Placebo

Reporting group description

Placebo + their current failing regimen for 10 days

Reporting group title

Part 2 E/C/ F/TAF + ATV

Reporting group description

E/C/F/TAF plus ATV for 48 weeks plus the extension phase

Serious adverse events	Part 1 Sentinel Cohort TAF	Part 1 Randomized Cohort TAF	Part 1 Randomized Cohort Placebo	Part 2 E/C/ F/TAF + ATV
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 12 (0.00%)	3 / 28 (10.71%)	0 / 15 (0.00%)	4 / 37 (10.81%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 12 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Enlarged uvula
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Myopathy
subjects affected / exposed	0 / 12 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	0 / 12 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part 1 Sentinel Cohort TAF	Part 1 Randomized Cohort TAF	Part 1 Randomized Cohort Placebo	Part 2 E/C/ F/TAF + ATV
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 12 (58.33%)	6 / 28 (21.43%)	5 / 15 (33.33%)	26 / 37 (70.27%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	1 / 37 (2.70%)
occurrences all number	0	0	1	1
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	1	0	0	2
Chest pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	2
Malaise
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	1 / 37 (2.70%)
occurrences all number	0	0	1	1
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	2
Oropharyngeal pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	2
Dyspnoea
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	0	1
Injury, poisoning and procedural complications
Limb injury
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	2
Epicondylitis
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0	0
Nervous system disorders
Neuropathy peripheral
subjects affected / exposed	0 / 12 (0.00%)	1 / 28 (3.57%)	1 / 15 (6.67%)	3 / 37 (8.11%)
occurrences all number	0	1	1	3
Headache
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	4 / 37 (10.81%)
occurrences all number	0	0	0	6
Dizziness
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	2
Gastrointestinal disorders
Toothache
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	3 / 37 (8.11%)
occurrences all number	0	0	1	5
Diarrhoea
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	1	0	0	2
Nausea
subjects affected / exposed	2 / 12 (16.67%)	1 / 28 (3.57%)	0 / 15 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	1	0	0
Haemorrhoids
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0	0
Proctalgia
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 12 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	3 / 37 (8.11%)
occurrences all number	0	1	0	4
Jaundice
subjects affected / exposed	0 / 12 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	3 / 37 (8.11%)
occurrences all number	0	1	0	3
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	1	0	0	2
Eosinophilic cellulitis
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0	0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	0	1
Back pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	2
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	11 / 37 (29.73%)
occurrences all number	0	1	0	17
Malaria
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	5 / 37 (13.51%)
occurrences all number	0	0	0	5
Influenza
subjects affected / exposed	0 / 12 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	3 / 37 (8.11%)
occurrences all number	0	1	0	11
Urinary tract infection
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	2	0	0	2
Viral upper respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	1 / 28 (3.57%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	1	0	5
Gastroenteritis
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	2
Oral candidiasis
subjects affected / exposed	1 / 12 (8.33%)	0 / 28 (0.00%)	0 / 15 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	0	1
Pyuria
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	2
Tonsillitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	2
Bacterial infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 37 (0.00%)
occurrences all number	0	0	1	0
Disseminated tuberculosis
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	1 / 15 (6.67%)	0 / 37 (0.00%)
occurrences all number	0	0	1	0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 28 (0.00%)	0 / 15 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	0	4

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Were there any global substantial amendments to the protocol? Yes

16 Aug 2013

● Updated eligibility for Part 2 of study to only include participants from the Part 1 Randomized Cohort TAF group who had ≥ 0.5 log 10 decline in HIV-1 RNA ● Updated some inclusion and exclusion criteria slightly

16 Dec 2013

● In Part 2 adding atazanavir 300mg to the E/C/F/TAF regimen for patients to be more in line with standard of care for patients on a failing regimen. ● Including an open label, un-randomized, Sentinel Cohort to Part 1. ● Requiring a subject dosing diary for Part 1.

12 Dec 2014

● Updated inclusion and exclusion criteria slightly ● Added storage conditions for Atazanavir

22 Apr 2015

● The amendment is designed to focus the investigation on the efficacy of TAF against HIV-1 mutants with K65R, a signature mutation associated with TDF.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

An unplanned review of unblinded clinical trial data was performed in this study that was not prospectively specified in the protocol. There was no impact on the overall integrity or conclusions of the study.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 10

Primary: Part 1: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 10

Secondary: Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10

Secondary: Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities Through Week 24

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities Through Week 24

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities Through Week 48

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Grade 3 or 4 Laboratory Abnormalities Through Week 48

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Any Treatment-Emergent Adverse Event Through Week 24

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Any Treatment-Emergent Adverse Event Through Week 24

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Any Treatment-Emergent Adverse Event Through Week 48

Secondary: Part 2: Safety of E/C/F/TAF STR Plus ATV in Participants Who Switched From a Failing Regimen as Assessed by the Percentage of Participants Experiencing Any Treatment-Emergent Adverse Event Through Week 48

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48

Secondary: Part 2: Percentage of Participants With Plasma HIV-1 RNA < 400 Copies/mL as Defined by the FDA Snapshot Analysis at Week 48

Secondary: Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 24

Secondary: Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 24

Secondary: Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 48

Secondary: Part 2: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Week 48

Secondary: Part 2: Change From Baseline in CD4+ Cell Count at Week 24

Secondary: Part 2: Change From Baseline in CD4+ Cell Count at Week 24

Secondary: Part 2: Change From Baseline in CD4+ Cell Count at Week 48

Secondary: Part 2: Change From Baseline in CD4+ Cell Count at Week 48

Secondary: Part 2: Change From Baseline in CD4+ Percentage at Week 24

Secondary: Part 2: Change From Baseline in CD4+ Percentage at Week 24

Secondary: Part 2: Change From Baseline in CD4+ Percentage at Week 48

Secondary: Part 2: Change From Baseline in CD4+ Percentage at Week 48

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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