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Study to Evaluate Efficacy and Safety of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Regimen Versus Boosted Protease Inhibitor (bPI) Along With Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) Regimen in Virologically-Suppressed, HIV-1 Infected Participants

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ClinicalTrials.gov Identifier: NCT02269917
Recruitment Status : Active, not recruiting
First Posted : October 21, 2014
Results First Posted : November 9, 2018
Last Update Posted : November 9, 2018
Sponsor:
Information provided by (Responsible Party):
Janssen R&D Ireland

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Human Immunodeficiency Virus Type 1
Interventions Drug: D/C/F/TAF
Drug: Boosted Protease Inhibitor (bPI)
Drug: FTC/TDF
Enrollment 1149

Recruitment Details  
Pre-assignment Details Results are reported through Week 48 (primary analysis). Complete data through final analysis (including extension through Week 96 and follow-up) will be reported within 1 year of end of trial date when final data based on study completion date will be available. Total 1149 participants were randomized out of which 1141 were treated.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48. Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Period Title: Overall Study
Started 766 383
Treated 763 378
Completed 0 0
Not Completed 766 383
Reason Not Completed
Lost to Follow-up             4             3
Ongoing             731             360
Other             6             3
Withdrawal by Subject             9             8
Adverse Event             11             4
Non-compliance with study drug             2             0
Randomized but not treated             3             5
Arm/Group Title D/C/F/TAF Control Total
Hide Arm/Group Description Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48. Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48. Total of all reporting groups
Overall Number of Baseline Participants 763 378 1141
Hide Baseline Analysis Population Description
Intent-to-treat (ITT) analysis set included all the participants who were randomized and received at least 1 dose of study treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 763 participants 378 participants 1141 participants
45.3  (10.86) 44.8  (10.77) 45.1  (10.83)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 763 participants 378 participants 1141 participants
Female
140
  18.3%
65
  17.2%
205
  18.0%
Male
623
  81.7%
313
  82.8%
936
  82.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 763 participants 378 participants 1141 participants
Hispanic or Latino
111
  14.5%
59
  15.6%
170
  14.9%
Not Hispanic or Latino
649
  85.1%
317
  83.9%
966
  84.7%
Unknown or Not Reported
3
   0.4%
2
   0.5%
5
   0.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 763 participants 378 participants 1141 participants
American Indian or Alaska Native
5
   0.7%
2
   0.5%
7
   0.6%
Asian
17
   2.2%
9
   2.4%
26
   2.3%
Native Hawaiian or Other Pacific Islander
2
   0.3%
0
   0.0%
2
   0.2%
Black or African American
155
  20.3%
82
  21.7%
237
  20.8%
White
573
  75.1%
282
  74.6%
855
  74.9%
More than one race
5
   0.7%
1
   0.3%
6
   0.5%
Unknown or Not Reported
6
   0.8%
2
   0.5%
8
   0.7%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 763 participants 378 participants 1141 participants
Asian
17
   2.2%
9
   2.4%
26
   2.3%
Black or African American
155
  20.3%
82
  21.7%
237
  20.8%
Hispanic or Latino
95
  12.5%
56
  14.8%
151
  13.2%
Other
20
   2.6%
6
   1.6%
26
   2.3%
White Non-Hispanic
476
  62.4%
225
  59.5%
701
  61.4%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 763 participants 378 participants 1141 participants
Belgium
32
   4.2%
20
   5.3%
52
   4.6%
Canada
45
   5.9%
21
   5.6%
66
   5.8%
France
69
   9.0%
28
   7.4%
97
   8.5%
Poland
91
  11.9%
35
   9.3%
126
  11.0%
Spain
117
  15.3%
52
  13.8%
169
  14.8%
Sweden
23
   3.0%
5
   1.3%
28
   2.5%
Switzerland
26
   3.4%
13
   3.4%
39
   3.4%
United Kingdom
47
   6.2%
23
   6.1%
70
   6.1%
United States
313
  41.0%
181
  47.9%
494
  43.3%
1.Primary Outcome
Title Percentage of Participants With Virologic Rebound (HIV-1 RNA >=50 Copies/mL) Cumulative Through Week 48
Hide Description Virologic rebound was defined as: confirmed plasma human immunodeficiency virus - 1 (HIV-1) Ribonucleic Acid (RNA) level greater than or equal to (>=)50 copies per milliliter (copies/mL) up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=50 copies/mL at premature discontinuation (irrespective of reason). Percentage of participants with virologic rebound were reported.
Time Frame Through Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) analysis set included all the participants who were randomized and received at least 1 dose of study treatment.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 763 378
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
2.5
(1.5 to 3.9)
2.1
(0.9 to 4.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments 4
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Stratum-adjusted Mantel-Haenszel (MH)
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 0.4
Confidence Interval (2-Sided) 95%
-1.5 to 2.2
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants With Virologic Rebound (Plasma HIV-1 RNA >=20 Copies/mL) Cumulative Through 48 Weeks
Hide Description Virologic rebound was defined as: confirmed plasma HIV-1 RNA >=20 copies/mL up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=20 copies/mL at premature discontinuation (irrespective of reason). Percentage of participants with virologic rebound were reported.
Time Frame Through 48 Weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all participants who were randomized and received at least 1 dose of study treatment.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 763 378
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
10.5
(8.4 to 12.9)
11.4
(8.4 to 15.0)
3.Secondary Outcome
Title Percentage of Participants With Virologic Rebound (Plasma HIV-1 RNA >=200 Copies/mL) Cumulative Through 48 Weeks
Hide Description Virologic rebound was defined as: confirmed plasma HIV-1 RNA >=200 copies/mL up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=200 copies/mL at premature discontinuation (irrespective of reason). Percentage of participants with virologic rebound were reported.
Time Frame Through 48 Weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all participants who were randomized and received at least 1 dose of study treatment.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 763 378
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
0.4
(0.1 to 1.1)
0.0 [1] 
(NA to NA)
[1]
Here NA signifies that the Confidence Interval (CI) was not estimable as no participants had virologic rebound in this group.
4.Secondary Outcome
Title Time to Virologic Rebound
Hide Description Time to virologic rebound was calculated from baseline until the first rebound time point (that is, time point before confirmation of rebound). Virologic rebound was defined as: confirmed plasma HIV-1 RNA >=50 copies/mL up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=50 copies/mL at premature discontinuation (irrespective of reason).
Time Frame Baseline up to Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all participants who were randomized and received at least 1 dose of study treatment.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 763 378
Median (95% Confidence Interval)
Unit of Measure: Weeks
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
The median and confidence interval (CI - lower or upper limit) could not be estimated due to low number of rebounders.
5.Secondary Outcome
Title Percentage of Participants Experiencing Grade 3 and 4 Adverse Events (AEs)
Hide Description An AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events were symptoms causing inability to perform usual social & functional activities. Grade 4 (Life-threatening) events were symptoms causing inability to perform basic self-care functions or medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death.
Time Frame Up to Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 763 378
Measure Type: Number
Unit of Measure: Percentage of Participants
Grade 3 5.6 6.3
Grade 4 1.2 1.9
6.Secondary Outcome
Title Change From Baseline in Serum Creatinine Levels at Weeks 24 and 48
Hide Description Change from baseline in serum creatinine levels at Weeks 24 and 48 was assessed.
Time Frame Baseline and Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all participants randomized and received at least 1 dose of study treatment. Here, N (number of participants analyzed) indicates number of participants evaluable for this endpoint; and ‘n’ specifies participants analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 761 378
Least Squares Mean (Standard Error)
Unit of Measure: micro mole per liter
Change at Week 24 Number Analyzed 735 participants 362 participants
1.22  (0.358) 0.88  (0.509)
Change at Week 48 Number Analyzed 725 participants 350 participants
1.27  (0.368) 0.65  (0.530)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.580
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square (LS) Mean Difference
Estimated Value 0.34
Confidence Interval (2-Sided) 95%
-0.88 to 1.57
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.623
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Change at Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.340
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square (LS) Mean Difference
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
-0.65 to 1.88
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.646
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Weeks 24 and 48
Hide Description Change from baseline in eGFRcr (by Cockcroft-Gault formula) was assessed at Weeks 24 and 48. eGFRcr according to the Cockcroft Gault formula- Male: (140 - age in years)*(weight in kilogram [kg])/72*(serum creatinine in milligram per deciliter [mg/dL])=eGFRcr (milliliter per minute [mL/min]); Female: (140 - age in years)*(weight in kg)/72*(serum creatinine in mg/dL)*0.85=eGFRcr (mL/min).
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment. Here, N (number of participants analyzed) indicates number of participants evaluable for this endpoint; and ‘n’ specifies those participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 761 378
Least Squares Mean (Standard Error)
Unit of Measure: milliliter per minute (mL/min)
Change at Week 24 Number Analyzed 735 participants 362 participants
-0.38  (0.502) 0.20  (0.715)
Change at Week 48 Number Analyzed 725 participants 350 participants
-0.94  (0.492) -0.20  (0.708)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.506
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.58
Confidence Interval (2-Sided) 95%
-2.30 to 1.13
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.874
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Change Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.392
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.74
Confidence Interval (2-Sided) 95%
-2.43 to 0.95
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.862
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Weeks 24 and 48
Hide Description Change from baseline in eGFRcr (by CKD-EPI) was assessed at Weeks 24 and 48. eGFRcr per CKD-EPI formula - Female: 1) Serum creatinine (Scr) less than or equal to (<=)0.7 mg/dL: 144*(Scr/0.7)^-0.329*0.993age; 2) Scr greater than (>)0.7 mg/dL: 144*(Scr/0.7)^-1.209*0.993age. Male: 1) Scr <=0.9 mg/dL: 141*(Scr/0.9)^-0.411*0.993age; 2) Scr >0.9 mg/dL: 141*(Scr/0.9)^-1.209*0.993age.
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment. Here, N (number of participants analyzed) indicates number of participants evaluable for this endpoint; and ‘n’ specifies those participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 761 378
Least Squares Mean (Standard Error)
Unit of Measure: mL/min/1.73 m^2
Change at Week 24 Number Analyzed 735 participants 362 participants
-1.67  (0.359) -0.75  (0.510)
Change at Week 48 Number Analyzed 725 participants 350 participants
-1.97  (0.369) -0.88  (0.531)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.143
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.92
Confidence Interval (2-Sided) 95%
-2.14 to 0.31
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.624
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Change at Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.092
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -1.09
Confidence Interval (2-Sided) 95%
-2.36 to 0.18
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.646
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst, by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Weeks 24 and 48
Hide Description Change from baseline in eGFRcyst (by CKD-EPI) was assessed at Weeks 24 and 48. eGFRcyst according to the CKD-EPI formula - 1) Serum Cystatin C (Scyst) <=0.8 mg/L: 133*(Scyst/0.8)^-0.499*0.996age (*0.932 if female); 2) Scyst >0.8 mg/L: 133*(Scyst/0.8)^-1.328*0.996age (*0.932 if female).
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment. Here, ‘n’ specifies those participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 763 378
Least Squares Mean (Standard Error)
Unit of Measure: mL/min/1.73 m^2
eGFRcyst: Change at Week 24 Number Analyzed 734 participants 360 participants
0.21  (0.338) -0.93  (0.483)
eGFRcyst: Change at Week 48 Number Analyzed 724 participants 351 participants
-0.42  (0.360) -1.76  (0.517)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.054
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 1.14
Confidence Interval (2-Sided) 95%
-0.02 to 2.29
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.590
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Change at Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.034
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 1.34
Confidence Interval (2-Sided) 95%
0.10 to 2.57
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.630
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Change From Baseline in Urine Albumin to Creatinine Ratio (UACR) and Urine Protein to Creatinine Ratio (UPCR) at Weeks 24 and 48
Hide Description Change from baseline in UACR and UPCR was assessed at Weeks 24 and 48. Lower levels of albumin or protein in the urine indicates better proximal tubular function.
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment. Here, N (number of participants analyzed) indicates number of participants evaluable for this endpoint; and ‘n’ specifies those participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 761 378
Median (Full Range)
Unit of Measure: milligram per gram (mg/g)
UACR: Baseline Number Analyzed 761 participants 378 participants
6.20
(1.4 to 632.1)
7.14
(1.1 to 268.0)
UACR: Change at Week 24 Number Analyzed 735 participants 362 participants
-0.78
(-185.4 to 422.2)
0.44
(-238.5 to 145.0)
UACR: Change at Week 48 Number Analyzed 723 participants 351 participants
-0.76
(-195.8 to 344.3)
0.40
(-121.7 to 110.9)
UPCR: Baseline Number Analyzed 758 participants 375 participants
61.56
(16.9 to 1158.1)
62.90
(14.7 to 870.9)
UPCR: Change at Week 24 Number Analyzed 727 participants 357 participants
-14.63
(-509.6 to 734.6)
0.07
(-359.9 to 400.8)
UPCR: Change at Week 48 Number Analyzed 710 participants 347 participants
-22.25
(-520.1 to 386.6)
-7.37
(-368.7 to 432.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments UACR - Change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Van Elteren Test
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments UACR - Change at Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Van Elteren Test
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments UPCR - Change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Van Elteren Test
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments UPCR - Change at Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Van Elteren Test
Comments [Not Specified]
11.Secondary Outcome
Title Change From Baseline in Urine Retinol Binding Protein to Creatinine Ratio (URBPCR) and Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Weeks 24 and 48
Hide Description Change from baseline in URBPCR and UB2MGCR was assessed at Weeks 24 and 48. Retinol binding protein is a marker of proximal tubular function.
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment. Here, N (number of participants analyzed) indicates number of participants evaluable for this endpoint; and ‘n’ specifies those participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 748 371
Median (Full Range)
Unit of Measure: microgram per gram (mcg/g)
URBPCR: Baseline Number Analyzed 748 participants 371 participants
126.19
(20.3 to 116216.2)
137.16
(12.9 to 73958.4)
URBPCR: Change at Week 24 Number Analyzed 721 participants 356 participants
-30.27
(-69873.2 to 2004.4)
7.76
(-6040.1 to 60740.4)
URBPCR: Change at Week 48 Number Analyzed 710 participants 344 participants
-27.09
(-67540.0 to 1764.3)
19.66
(-5778.3 to 65203.3)
UB2MGCR: Baseline Number Analyzed 736 participants 366 participants
156.85
(3.8 to 91216.2)
172.25
(9.8 to 92740.1)
UB2MGCR: Change at Week 24 Number Analyzed 702 participants 348 participants
-72.64
(-72264.6 to 13536.2)
12.08
(-20084.8 to 58357.6)
UB2MGCR: Change at Week 48 Number Analyzed 693 participants 338 participants
-67.02
(-72323.4 to 21190.2)
20.24
(-22173.5 to 135576.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments URBPCR: Change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Van Elteren Test
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments URBPCR: Change at Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Van Elteren Test
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments UB2MGCR: Change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Van Elteren Test
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments UB2MGCR: Change at Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Van Elteren Test
Comments [Not Specified]
12.Secondary Outcome
Title Percent Change From Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Weeks 24 and 48
Hide Description Percent change from baseline in urine FEPO4 was assessed at Weeks 24 and 48.
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment. Here ‘n’ specifies those participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 763 378
Median (Full Range)
Unit of Measure: Percent change
Percent change at Week 24 Number Analyzed 729 participants 358 participants
3.58
(-89.4 to 1940.4)
8.55
(-78.5 to 281.8)
Percent change at Week 48 Number Analyzed 719 participants 346 participants
8.42
(-97.9 to 1430.3)
8.57
(-76.3 to 452.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments FEPO4 - Change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.288
Comments [Not Specified]
Method Van Elteren Test
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments FEPO4 - Change at Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.148
Comments [Not Specified]
Method Van Elteren Test
Comments [Not Specified]
13.Secondary Outcome
Title Percentage of Participants With Virologic Response Based on HIV-1 RNA Less Than (<)20, <50, and <200 Copies/mL Threshold at Week 48 as Defined by the Food and Drug Administration (FDA) Snapshot Approach
Hide Description Percentage of participants with virologic response based on HIV-1 RNA <20, <50, and <200 copies/mL threshold were analyzed at Week 48 using FDA snapshot approach. FDA Snapshot approach analysis was based on the last observed viral load data: virologic response was defined as HIV-1 RNA <20/50/200 copies/mL (observed case).
Time Frame Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 763 378
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
<20 copies/mL
89.8
(87.4 to 91.8)
88.4
(84.7 to 91.4)
<50 copies/mL
94.9
(93.1 to 96.3)
93.7
(90.7 to 95.9)
<200 copies/mL
95.0
(93.2 to 96.5)
94.2
(91.3 to 96.3)
14.Secondary Outcome
Title Percentage of Participants With Virologic Response Based on HIV-1 RNA <20, <50, and <200 Copies/mL Threshold at Week 48 as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm
Hide Description Percentage of participants with virologic response based on HIV-1 RNA <20, <50, and <200 copies/mL threshold were analyzed at Week 48 using TLOVR algorithm approach. TLOVR was defined as sustained HIV-1 RNA <20/50/200 copies/mL.
Time Frame Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 763 378
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
<20 copies/mL
86.0
(83.3 to 88.4)
83.6
(79.5 to 87.2)
<50 copies/mL
93.7
(91.7 to 95.3)
92.9
(89.8 to 95.2)
<200 copies/mL
95.4
(93.7 to 96.8)
94.7
(91.9 to 96.7)
15.Secondary Outcome
Title Change From Baseline in Cluster of Differentiation 4 Plus (CD4+) Cell Count at Weeks 24 and 48
Hide Description Change from baseline in CD4+ cell count was assessed at Weeks 24 and 48.
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment. Here ‘n’ specifies those participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 763 378
Mean (Standard Error)
Unit of Measure: Cells per cubic millimeter (cells/mm^3)
Baseline Number Analyzed 763 participants 378 participants
653.3  (9.12) 641.7  (13.15)
Change at Week 24 Number Analyzed 731 participants 362 participants
14.3  (5.99) 8.5  (7.76)
Change at Week 48 Number Analyzed 722 participants 351 participants
21.0  (5.97) 9.1  (8.41)
16.Secondary Outcome
Title Percentage of Participants With Treatment Adherence of Greater Than (>)95 Percent (%) (Approach 1) Through Week 48
Hide Description Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability cumulative through Week 48 (Approach 1).
Time Frame Through Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment. Here, N (number of participants analyzed) indicates the number of participants evaluable for this endpoint.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 215 102
Measure Type: Number
Unit of Measure: Percentage of Participants
91.6 85.3
17.Secondary Outcome
Title Percentage of Participants With Treatment Adherence of >95% (Approach 2) Through Week 48
Hide Description Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability cumulative treatment adherence up to time point where not more than one bottle was missing, or if available, through Week 48, whichever came sooner (Approach 2).
Time Frame Through Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all the participants who were randomized and received at least 1 dose of study treatment. Here, 'N' (number of participants analyzed) indicates the number of participants evaluable for this endpoint.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 631 268
Measure Type: Number
Unit of Measure: Percentage of Participants
82.7 77.2
18.Secondary Outcome
Title Number of Participants With Resistance to Study Drug
Hide Description HIV-1 genotypes were analyzed from samples of participants with confirmed virologic rebound (virologic rebound was defined as: confirmed HIV-1 RNA >=50 copies/mL up to, and including the upper bound of the Week 48 window) and with HIV-1 RNA value greater than or equal to (>=)400 copies/mL or who discontinued with last HIV-1 RNA >=400 copies/mL. Number of participants who developed resistance to any of the study drug was determined.
Time Frame Up to Week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT population with confirmed virologic rebound and with HIV-1 RNA value >=400 copies/mL was analyzed.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 19 8
Measure Type: Number
Unit of Measure: Participants
1 3
19.Secondary Outcome
Title Predose (Trough) Plasma Concentration (C0h) of Darunavir
Hide Description Predose (trough) plasma concentration (C0h) of darunavir was determined. Pharmacokinetic (PK) data was only analyzed for participants in the D/C/F/TAF group as per planned analysis.
Time Frame Predose at Weeks 2, 4, 8, 12, 24, 36, and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The PK analysis set included all participants randomized to D/C/F/TAF group and received at least 1 dose of study drug in study, and for whom plasma concentration data of any analytes of interest were available. Here ‘n’ specifies participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Overall Number of Participants Analyzed 750
Mean (Standard Deviation)
Unit of Measure: Nanogram per milliliter (ng/mL)
Week 2 Number Analyzed 130 participants
1775.29  (1698.84)
Week 4 Number Analyzed 110 participants
1732.00  (1389.44)
Week 8 Number Analyzed 104 participants
1910.30  (1501.94)
Week 12 Number Analyzed 114 participants
1643.38  (1328.41)
Week 24 Number Analyzed 112 participants
2022.99  (1965.64)
Week 36 Number Analyzed 100 participants
1806.37  (1669.43)
Week 48 Number Analyzed 126 participants
1899.79  (1833.09)
20.Secondary Outcome
Title Percent Change From Baseline in Serum Procollagen 1 N-Terminal Propeptide (P1NP) and Serum Collagen Type 1 Beta Carboxy Telopeptide (CTX) Levels at Weeks 24 and 48
Hide Description Percent change from baseline in bone biomarkers: P1NP and CTX was assessed at Weeks 24 and 48.
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The bone investigation substudy (BIS) analysis set included all participants who were randomized and received at least 1 dose of study drug in the study, and had at least one postbaseline value for biomarker data. Here ‘n’ specifies participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 209 108
Mean (Standard Error)
Unit of Measure: Percent Change
P1NP: Percent change at Week 24 Number Analyzed 195 participants 99 participants
-22.971  (1.8818) -0.027  (2.7325)
P1NP: Percent change at Week 48 Number Analyzed 191 participants 98 participants
-26.752  (1.8960) -3.751  (2.6988)
CTX: Percent change at Week 24 Number Analyzed 190 participants 97 participants
-16.772  (2.2575) 16.312  (3.8855)
CTX: Percent change at Week 48 Number Analyzed 185 participants 98 participants
-10.517  (3.2325) 5.433  (4.1118)
21.Secondary Outcome
Title Percent Change From Baseline in Parathyroid Hormone (PTH) at Weeks 24 and 48
Hide Description Percent change from baseline in bone biomarker: PTH was assessed at Weeks 24 and 48.
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The bone investigation substudy (BIS) analysis set included all participants who were randomized and received at least 1 dose of study drug in the study, and had at least one postbaseline value for biomarker data. Here ‘n’ specifies participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 209 108
Mean (Standard Error)
Unit of Measure: Percent change
Percent change at Week 24 Number Analyzed 199 participants 102 participants
-3.092  (2.5941) 12.034  (4.1777)
Percent change at Week 48 Number Analyzed 193 participants 103 participants
-4.510  (2.5375) 9.436  (4.4784)
22.Secondary Outcome
Title Percent Change From Baseline in 25-hydroxy Vitamin D at Weeks 24 and 48
Hide Description Percent change from baseline in bone biomarker: 25-hydroxy vitamin D was assessed at Weeks 24 and 48.
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The bone investigation substudy (BIS) analysis set included all participants who were randomized and received at least 1 dose of study drug in the study, and had at least one postbaseline value for biomarker data. Here ‘n’ specifies participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 209 108
Mean (Standard Error)
Unit of Measure: Percent change
Percent change at Week 24 Number Analyzed 146 participants 72 participants
-3.0  (5.06) 4.2  (6.13)
Percent change at Week 48 Number Analyzed 142 participants 72 participants
25.2  (5.51) 24.9  (7.46)
23.Secondary Outcome
Title Percent Change From Baseline in Spine and Hip Bone Mineral Density (BMD) at Weeks 24 and 48
Hide Description Percent change from baseline in spine and hip BMD was assessed at Weeks 24 and 48.
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The bone investigation substudy (BIS) analysis set included all participants who were randomized and received at least 1 dose of study drug in the study, and had at least one postbaseline value for bone mineral density (BMD) data. Here ‘n’ specifies participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 209 108
Least Squares Mean (Standard Error)
Unit of Measure: Percent change
Spine BMD: Percent change at Week 24 Number Analyzed 192 participants 97 participants
1.55  (0.276) 0.18  (0.342)
Spine BMD: Percent change at Week 48 Number Analyzed 192 participants 101 participants
2.06  (0.324) 0.01  (0.391)
Hip BMD: Percent change at Week 24 Number Analyzed 184 participants 93 participants
0.91  (0.230) 0.00  (0.279)
Hip BMD: Percent change at Week 48 Number Analyzed 188 participants 97 participants
1.62  (0.244) -0.08  (0.288)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Spine BMD: Percent change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 1.37
Confidence Interval (2-Sided) 95%
0.697 to 2.037
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.340
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Spine BMD: Percent change at Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 2.05
Confidence Interval (2-Sided) 95%
1.277 to 2.814
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.390
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Hip BMD: Percent change at Week 24
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.90
Confidence Interval (2-Sided) 95%
0.366 to 1.436
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.272
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection D/C/F/TAF, Control
Comments Hip BMD: Percent change at Week 48
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 1.70
Confidence Interval (2-Sided) 95%
1.144 to 2.248
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.280
Estimation Comments [Not Specified]
24.Secondary Outcome
Title Change From Baseline in Bone Mineral Density (BMD) T-Score at Weeks 24 and 48
Hide Description Change from baseline in spine, hip, and femoral neck BMD T-Score was assessed at Week 24 and 48. T-score values >= -1.0 were considered normal, T-score values < -1.0 to -2.5 indicate osteopenia and T-score values < -2.5 indicate osteoporosis.
Time Frame Baseline, Weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The bone investigation substudy (BIS) analysis set included all participants who were randomized and received at least 1 dose of study drug in the study, and had at least one postbaseline value for BMD data. Here ‘n’ specifies those participants who were analyzed for this endpoint at given time point.
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description:
Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48.
Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
Overall Number of Participants Analyzed 209 108
Mean (Standard Error)
Unit of Measure: Units on a scale
Spine BMD T-score: Baseline Number Analyzed 206 participants 107 participants
-0.713  (0.0850) -0.467  (0.1260)
Spine BMD T-score: Change at Week 24 Number Analyzed 192 participants 97 participants
0.102  (0.0172) -0.033  (0.0253)
Spine BMD T-score: Change at Week 48 Number Analyzed 192 participants 101 participants
0.132  (0.0217) -0.063  (0.0264)
Hip BMD T-score: Baseline Number Analyzed 204 participants 104 participants
-0.575  (0.0643) -0.484  (0.0839)
Hip BMD T-score: Change at Week 24 Number Analyzed 184 participants 93 participants
0.037  (0.0108) -0.024  (0.0144)
Hip BMD T-score: Change at Week 48 Number Analyzed 188 participants 97 participants
0.095  (0.0122) -0.016  (0.0139)
Femoral Neck BMD T-score: Baseline Number Analyzed 204 participants 104 participants
-0.782  (0.0625) -0.699  (0.0899)
Femoral Neck BMD T-score: Change at Week 24 Number Analyzed 184 participants 93 participants
0.019  (0.0128) -0.044  (0.0183)
Femoral Neck BMD T-score: Change at Week 48 Number Analyzed 188 participants 97 participants
0.039  (0.0146) -0.039  (0.0214)
Time Frame Up to Week 48
Adverse Event Reporting Description Safety was performed using intent-to-treat (ITT) analysis set which included all the participants who were randomized and received at least 1 dose of study treatment.
 
Arm/Group Title D/C/F/TAF Control
Hide Arm/Group Description Participants received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48. Participants received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
All-Cause Mortality
D/C/F/TAF Control
Affected / at Risk (%) Affected / at Risk (%)
Total   0/763 (0.00%)   0/378 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
D/C/F/TAF Control
Affected / at Risk (%) Affected / at Risk (%)
Total   35/763 (4.59%)   18/378 (4.76%) 
Cardiac disorders     
Coronary artery disease * 1  1/763 (0.13%)  0/378 (0.00%) 
Myocardial infarction * 1  1/763 (0.13%)  1/378 (0.26%) 
Ventricular tachycardia * 1  1/763 (0.13%)  0/378 (0.00%) 
Gastrointestinal disorders     
Abdominal pain upper * 1  1/763 (0.13%)  0/378 (0.00%) 
Anal fistula * 1  1/763 (0.13%)  0/378 (0.00%) 
Diarrhoea * 1  1/763 (0.13%)  0/378 (0.00%) 
Gastrointestinal inflammation * 1  1/763 (0.13%)  0/378 (0.00%) 
Inguinal hernia * 1  1/763 (0.13%)  0/378 (0.00%) 
Intestinal obstruction * 1  0/763 (0.00%)  1/378 (0.26%) 
Nausea * 1  0/763 (0.00%)  1/378 (0.26%) 
Pancreatitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Vomiting * 1  0/763 (0.00%)  1/378 (0.26%) 
General disorders     
Hernia * 1  1/763 (0.13%)  0/378 (0.00%) 
Pyrexia * 1  1/763 (0.13%)  0/378 (0.00%) 
Hepatobiliary disorders     
Hepatitis acute * 1  0/763 (0.00%)  1/378 (0.26%) 
Infections and infestations     
Abscess limb * 1  0/763 (0.00%)  1/378 (0.26%) 
Cellulitis * 1  1/763 (0.13%)  1/378 (0.26%) 
Diverticulitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Epididymitis * 1  0/763 (0.00%)  1/378 (0.26%) 
Gastroenteritis * 1  2/763 (0.26%)  0/378 (0.00%) 
Herpes simplex meningitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Infection * 1  0/763 (0.00%)  1/378 (0.26%) 
Influenza * 1  1/763 (0.13%)  0/378 (0.00%) 
Lymphogranuloma venereum * 1  1/763 (0.13%)  0/378 (0.00%) 
Perineal abscess * 1  0/763 (0.00%)  1/378 (0.26%) 
Pneumonia * 1  3/763 (0.39%)  0/378 (0.00%) 
Syphilis * 1  0/763 (0.00%)  1/378 (0.26%) 
Upper respiratory tract infection * 1  1/763 (0.13%)  0/378 (0.00%) 
Injury, poisoning and procedural complications     
Ankle fracture * 1  2/763 (0.26%)  0/378 (0.00%) 
Fibula fracture * 1  1/763 (0.13%)  0/378 (0.00%) 
Meniscus injury * 1  0/763 (0.00%)  1/378 (0.26%) 
Investigations     
Amylase increased * 1  0/763 (0.00%)  1/378 (0.26%) 
Biopsy lymph gland * 1  1/763 (0.13%)  0/378 (0.00%) 
Metabolism and nutrition disorders     
Dehydration * 1  0/763 (0.00%)  1/378 (0.26%) 
Diabetic ketoacidosis * 1  1/763 (0.13%)  0/378 (0.00%) 
Musculoskeletal and connective tissue disorders     
Osteonecrosis * 1  1/763 (0.13%)  0/378 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Hodgkin's disease * 1  1/763 (0.13%)  0/378 (0.00%) 
Lymphoma * 1  1/763 (0.13%)  0/378 (0.00%) 
Prostate cancer * 1  1/763 (0.13%)  0/378 (0.00%) 
Retinal melanoma * 1  0/763 (0.00%)  1/378 (0.26%) 
Nervous system disorders     
Epilepsy * 1  1/763 (0.13%)  0/378 (0.00%) 
Loss of consciousness * 1  1/763 (0.13%)  0/378 (0.00%) 
Paraparesis * 1  1/763 (0.13%)  0/378 (0.00%) 
Pregnancy, puerperium and perinatal conditions     
Ectopic pregnancy * 1  0/763 (0.00%)  1/378 (0.26%) 
Product Issues     
Device breakage * 1  0/763 (0.00%)  1/378 (0.26%) 
Psychiatric disorders     
Anxiety * 1  1/763 (0.13%)  0/378 (0.00%) 
Drug abuse * 1  2/763 (0.26%)  0/378 (0.00%) 
Major depression * 1  0/763 (0.00%)  1/378 (0.26%) 
Suicidal ideation * 1  0/763 (0.00%)  1/378 (0.26%) 
Suicide attempt * 1  1/763 (0.13%)  1/378 (0.26%) 
Renal and urinary disorders     
Acute kidney injury * 1  0/763 (0.00%)  1/378 (0.26%) 
Bladder mass * 1  0/763 (0.00%)  1/378 (0.26%) 
Reproductive system and breast disorders     
Endometrial thickening * 1  1/763 (0.13%)  0/378 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Asthma * 1  1/763 (0.13%)  0/378 (0.00%) 
Chronic obstructive pulmonary disease * 1  2/763 (0.26%)  0/378 (0.00%) 
Vascular disorders     
Aortic stenosis * 1  0/763 (0.00%)  1/378 (0.26%) 
1
Term from vocabulary, MedDRA Version 19.1
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
D/C/F/TAF Control
Affected / at Risk (%) Affected / at Risk (%)
Total   622/763 (81.52%)   310/378 (82.01%) 
Blood and lymphatic system disorders     
Anaemia * 1  3/763 (0.39%)  4/378 (1.06%) 
Eosinophilia * 1  1/763 (0.13%)  0/378 (0.00%) 
Iron deficiency anaemia * 1  0/763 (0.00%)  1/378 (0.26%) 
Lymphadenopathy * 1  12/763 (1.57%)  1/378 (0.26%) 
Lymphopenia * 1  1/763 (0.13%)  0/378 (0.00%) 
Neutrophilia * 1  1/763 (0.13%)  0/378 (0.00%) 
Thrombocytopenia * 1  1/763 (0.13%)  1/378 (0.26%) 
Cardiac disorders     
Angina pectoris * 1  1/763 (0.13%)  0/378 (0.00%) 
Atrial fibrillation * 1  0/763 (0.00%)  1/378 (0.26%) 
Atrial flutter * 1  1/763 (0.13%)  0/378 (0.00%) 
Bradycardia * 1  1/763 (0.13%)  0/378 (0.00%) 
Cardiac flutter * 1  1/763 (0.13%)  0/378 (0.00%) 
Extrasystoles * 1  1/763 (0.13%)  0/378 (0.00%) 
Palpitations * 1  3/763 (0.39%)  4/378 (1.06%) 
Tachycardia * 1  2/763 (0.26%)  1/378 (0.26%) 
Congenital, familial and genetic disorders     
Dermoid cyst * 1  1/763 (0.13%)  0/378 (0.00%) 
Pulmonary arteriovenous fistula * 1  0/763 (0.00%)  1/378 (0.26%) 
Type V hyperlipidaemia * 1  2/763 (0.26%)  0/378 (0.00%) 
Ear and labyrinth disorders     
Cerumen impaction * 1  1/763 (0.13%)  2/378 (0.53%) 
Deafness * 1  1/763 (0.13%)  1/378 (0.26%) 
Deafness bilateral * 1  1/763 (0.13%)  0/378 (0.00%) 
Deafness unilateral * 1  1/763 (0.13%)  0/378 (0.00%) 
Ear discomfort * 1  3/763 (0.39%)  0/378 (0.00%) 
Ear disorder * 1  0/763 (0.00%)  1/378 (0.26%) 
Ear pain * 1  3/763 (0.39%)  3/378 (0.79%) 
Ear pruritus * 1  1/763 (0.13%)  0/378 (0.00%) 
Eustachian tube dysfunction * 1  1/763 (0.13%)  0/378 (0.00%) 
Excessive cerumen production * 1  1/763 (0.13%)  1/378 (0.26%) 
Hypoacusis * 1  1/763 (0.13%)  0/378 (0.00%) 
Middle ear effusion * 1  0/763 (0.00%)  1/378 (0.26%) 
Tinnitus * 1  3/763 (0.39%)  0/378 (0.00%) 
Tympanic membrane disorder * 1  0/763 (0.00%)  1/378 (0.26%) 
Tympanic membrane hyperaemia * 1  0/763 (0.00%)  1/378 (0.26%) 
Vertigo * 1  16/763 (2.10%)  4/378 (1.06%) 
Vertigo positional * 1  2/763 (0.26%)  0/378 (0.00%) 
Endocrine disorders     
Adrenal suppression * 1  1/763 (0.13%)  0/378 (0.00%) 
Hyperthyroidism * 1  1/763 (0.13%)  0/378 (0.00%) 
Hypogonadism * 1  3/763 (0.39%)  1/378 (0.26%) 
Eye disorders     
Blepharitis * 1  1/763 (0.13%)  2/378 (0.53%) 
Cataract * 1  2/763 (0.26%)  0/378 (0.00%) 
Conjunctivitis allergic * 1  0/763 (0.00%)  1/378 (0.26%) 
Dry eye * 1  2/763 (0.26%)  1/378 (0.26%) 
Eczema eyelids * 1  1/763 (0.13%)  0/378 (0.00%) 
Eye pain * 1  0/763 (0.00%)  2/378 (0.53%) 
Eye pruritus * 1  1/763 (0.13%)  1/378 (0.26%) 
Eye swelling * 1  0/763 (0.00%)  3/378 (0.79%) 
Eyelid disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Eyelid haematoma * 1  1/763 (0.13%)  0/378 (0.00%) 
Eyelid pain * 1  0/763 (0.00%)  1/378 (0.26%) 
Glaucoma * 1  1/763 (0.13%)  0/378 (0.00%) 
Lacrimal disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Lacrimation increased * 1  1/763 (0.13%)  0/378 (0.00%) 
Ocular hyperaemia * 1  2/763 (0.26%)  0/378 (0.00%) 
Ocular hypertension * 1  2/763 (0.26%)  0/378 (0.00%) 
Presbyopia * 1  1/763 (0.13%)  0/378 (0.00%) 
Vision blurred * 1  4/763 (0.52%)  2/378 (0.53%) 
Visual impairment * 1  2/763 (0.26%)  0/378 (0.00%) 
Gastrointestinal disorders     
Abdominal discomfort * 1  2/763 (0.26%)  1/378 (0.26%) 
Abdominal distension * 1  9/763 (1.18%)  0/378 (0.00%) 
Abdominal hernia * 1  1/763 (0.13%)  1/378 (0.26%) 
Abdominal pain * 1  29/763 (3.80%)  7/378 (1.85%) 
Abdominal pain lower * 1  1/763 (0.13%)  1/378 (0.26%) 
Abdominal pain upper * 1  11/763 (1.44%)  5/378 (1.32%) 
Abdominal tenderness * 1  1/763 (0.13%)  0/378 (0.00%) 
Acquired oesophageal web * 1  2/763 (0.26%)  0/378 (0.00%) 
Aerophagia * 1  1/763 (0.13%)  0/378 (0.00%) 
Anal fissure * 1  3/763 (0.39%)  1/378 (0.26%) 
Anal fistula * 1  0/763 (0.00%)  1/378 (0.26%) 
Anal haemorrhage * 1  1/763 (0.13%)  0/378 (0.00%) 
Anal incontinence * 1  2/763 (0.26%)  0/378 (0.00%) 
Anal polyp * 1  1/763 (0.13%)  0/378 (0.00%) 
Anal pruritus * 1  4/763 (0.52%)  0/378 (0.00%) 
Anal ulcer * 1  0/763 (0.00%)  1/378 (0.26%) 
Anogenital dysplasia * 1  3/763 (0.39%)  4/378 (1.06%) 
Anorectal discomfort * 1  1/763 (0.13%)  2/378 (0.53%) 
Anorectal disorder * 1  0/763 (0.00%)  1/378 (0.26%) 
Aphthous ulcer * 1  5/763 (0.66%)  1/378 (0.26%) 
Bowel movement irregularity * 1  1/763 (0.13%)  0/378 (0.00%) 
Breath odour * 1  2/763 (0.26%)  0/378 (0.00%) 
Colitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Constipation * 1  13/763 (1.70%)  4/378 (1.06%) 
Crohn's disease * 1  0/763 (0.00%)  1/378 (0.26%) 
Dental caries * 1  1/763 (0.13%)  3/378 (0.79%) 
Dental discomfort * 1  1/763 (0.13%)  0/378 (0.00%) 
Diarrhoea * 1  59/763 (7.73%)  16/378 (4.23%) 
Diverticulum * 1  2/763 (0.26%)  0/378 (0.00%) 
Dry mouth * 1  2/763 (0.26%)  2/378 (0.53%) 
Dyspepsia * 1  13/763 (1.70%)  4/378 (1.06%) 
Dysphagia * 1  0/763 (0.00%)  1/378 (0.26%) 
Enterocolitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Faeces discoloured * 1  1/763 (0.13%)  0/378 (0.00%) 
Faeces soft * 1  1/763 (0.13%)  2/378 (0.53%) 
Flatulence * 1  8/763 (1.05%)  3/378 (0.79%) 
Food poisoning * 1  5/763 (0.66%)  1/378 (0.26%) 
Gastric disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Gastritis * 1  3/763 (0.39%)  4/378 (1.06%) 
Gastritis erosive * 1  1/763 (0.13%)  0/378 (0.00%) 
Gastrointestinal disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Gastrointestinal polyp haemorrhage * 1  1/763 (0.13%)  0/378 (0.00%) 
Gastrooesophageal reflux disease * 1  8/763 (1.05%)  3/378 (0.79%) 
Gingival bleeding * 1  1/763 (0.13%)  0/378 (0.00%) 
Gingival pain * 1  1/763 (0.13%)  0/378 (0.00%) 
Gingival recession * 1  1/763 (0.13%)  0/378 (0.00%) 
Gingival swelling * 1  1/763 (0.13%)  0/378 (0.00%) 
Glossodynia * 1  1/763 (0.13%)  0/378 (0.00%) 
Haematochezia * 1  1/763 (0.13%)  1/378 (0.26%) 
Haemorrhoidal haemorrhage * 1  1/763 (0.13%)  0/378 (0.00%) 
Haemorrhoids * 1  7/763 (0.92%)  6/378 (1.59%) 
Hiatus hernia * 1  1/763 (0.13%)  1/378 (0.26%) 
Inguinal hernia * 1  1/763 (0.13%)  1/378 (0.26%) 
Intra-abdominal haematoma * 1  1/763 (0.13%)  0/378 (0.00%) 
Large intestine polyp * 1  2/763 (0.26%)  1/378 (0.26%) 
Leukoplakia oral * 1  1/763 (0.13%)  0/378 (0.00%) 
Mouth ulceration * 1  1/763 (0.13%)  0/378 (0.00%) 
Nausea * 1  21/763 (2.75%)  7/378 (1.85%) 
Odynophagia * 1  1/763 (0.13%)  1/378 (0.26%) 
Oesophagitis * 1  3/763 (0.39%)  1/378 (0.26%) 
Oral disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Oral pigmentation * 1  1/763 (0.13%)  0/378 (0.00%) 
Palatal disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Pancreatic insufficiency * 1  0/763 (0.00%)  1/378 (0.26%) 
Pigmentation lip * 1  1/763 (0.13%)  0/378 (0.00%) 
Proctalgia * 1  0/763 (0.00%)  2/378 (0.53%) 
Proctitis * 1  0/763 (0.00%)  1/378 (0.26%) 
Rectal discharge * 1  0/763 (0.00%)  1/378 (0.26%) 
Rectal fissure * 1  1/763 (0.13%)  0/378 (0.00%) 
Rectal haemorrhage * 1  1/763 (0.13%)  2/378 (0.53%) 
Stomatitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Tongue disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Tongue oedema * 1  0/763 (0.00%)  1/378 (0.26%) 
Tooth disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Tooth impacted * 1  1/763 (0.13%)  0/378 (0.00%) 
Toothache * 1  11/763 (1.44%)  4/378 (1.06%) 
Umbilical hernia * 1  2/763 (0.26%)  0/378 (0.00%) 
Vomiting * 1  22/763 (2.88%)  3/378 (0.79%) 
General disorders     
Adverse drug reaction * 1  1/763 (0.13%)  0/378 (0.00%) 
Asthenia * 1  9/763 (1.18%)  1/378 (0.26%) 
Chest discomfort * 1  2/763 (0.26%)  1/378 (0.26%) 
Chest pain * 1  2/763 (0.26%)  1/378 (0.26%) 
Chills * 1  4/763 (0.52%)  0/378 (0.00%) 
Cyst * 1  0/763 (0.00%)  1/378 (0.26%) 
Discomfort * 1  0/763 (0.00%)  1/378 (0.26%) 
Energy increased * 1  1/763 (0.13%)  0/378 (0.00%) 
Face oedema * 1  1/763 (0.13%)  0/378 (0.00%) 
Fatigue * 1  34/763 (4.46%)  10/378 (2.65%) 
Gait disturbance * 1  2/763 (0.26%)  0/378 (0.00%) 
Haemorrhagic cyst * 1  1/763 (0.13%)  0/378 (0.00%) 
Hypertrophy * 1  0/763 (0.00%)  1/378 (0.26%) 
Influenza like illness * 1  14/763 (1.83%)  7/378 (1.85%) 
Local swelling * 1  1/763 (0.13%)  0/378 (0.00%) 
Malaise * 1  3/763 (0.39%)  0/378 (0.00%) 
Mass * 1  1/763 (0.13%)  0/378 (0.00%) 
Nodule * 1  1/763 (0.13%)  0/378 (0.00%) 
Non-cardiac chest pain * 1  3/763 (0.39%)  2/378 (0.53%) 
Oedema peripheral * 1  9/763 (1.18%)  1/378 (0.26%) 
Pain * 1  3/763 (0.39%)  0/378 (0.00%) 
Peripheral swelling * 1  4/763 (0.52%)  0/378 (0.00%) 
Pyrexia * 1  21/763 (2.75%)  5/378 (1.32%) 
Suprapubic pain * 1  0/763 (0.00%)  1/378 (0.26%) 
Systemic inflammatory response syndrome * 1  1/763 (0.13%)  0/378 (0.00%) 
Temperature regulation disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Thirst * 1  1/763 (0.13%)  0/378 (0.00%) 
Xerosis * 1  1/763 (0.13%)  0/378 (0.00%) 
Hepatobiliary disorders     
Biliary colic * 1  1/763 (0.13%)  0/378 (0.00%) 
Cholelithiasis * 1  0/763 (0.00%)  1/378 (0.26%) 
Hepatic steatosis * 1  1/763 (0.13%)  1/378 (0.26%) 
Jaundice * 1  3/763 (0.39%)  0/378 (0.00%) 
Liver injury * 1  1/763 (0.13%)  0/378 (0.00%) 
Immune system disorders     
Allergy to arthropod bite * 1  2/763 (0.26%)  0/378 (0.00%) 
Drug hypersensitivity * 1  1/763 (0.13%)  0/378 (0.00%) 
Food allergy * 1  0/763 (0.00%)  1/378 (0.26%) 
Hypersensitivity * 1  3/763 (0.39%)  2/378 (0.53%) 
Seasonal allergy * 1  8/763 (1.05%)  7/378 (1.85%) 
Infections and infestations     
Abscess jaw * 1  1/763 (0.13%)  0/378 (0.00%) 
Abscess limb * 1  1/763 (0.13%)  0/378 (0.00%) 
Abscess oral * 1  0/763 (0.00%)  1/378 (0.26%) 
Acute hepatitis C * 1  5/763 (0.66%)  3/378 (0.79%) 
Acute sinusitis * 1  8/763 (1.05%)  2/378 (0.53%) 
Amoebiasis * 1  1/763 (0.13%)  0/378 (0.00%) 
Anal chlamydia infection * 1  4/763 (0.52%)  3/378 (0.79%) 
Angular cheilitis * 1  0/763 (0.00%)  2/378 (0.53%) 
Anorectal human papilloma virus infection * 1  0/763 (0.00%)  2/378 (0.53%) 
Bacterial vaginosis * 1  2/763 (0.26%)  0/378 (0.00%) 
Balanitis candida * 1  1/763 (0.13%)  0/378 (0.00%) 
Blastocystis infection * 1  1/763 (0.13%)  1/378 (0.26%) 
Body tinea * 1  2/763 (0.26%)  0/378 (0.00%) 
Bronchiolitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Bronchitis * 1  33/763 (4.33%)  10/378 (2.65%) 
Bronchitis viral * 1  1/763 (0.13%)  0/378 (0.00%) 
Candida infection * 1  0/763 (0.00%)  2/378 (0.53%) 
Carbuncle * 1  1/763 (0.13%)  1/378 (0.26%) 
Cellulitis * 1  8/763 (1.05%)  0/378 (0.00%) 
Chikungunya virus infection * 1  1/763 (0.13%)  0/378 (0.00%) 
Chlamydial infection * 1  10/763 (1.31%)  4/378 (1.06%) 
Chronic sinusitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Clostridium difficile infection * 1  0/763 (0.00%)  1/378 (0.26%) 
Conjunctivitis * 1  4/763 (0.52%)  3/378 (0.79%) 
Conjunctivitis viral * 1  1/763 (0.13%)  0/378 (0.00%) 
Cystitis * 1  1/763 (0.13%)  1/378 (0.26%) 
Dermatophytosis * 1  1/763 (0.13%)  0/378 (0.00%) 
Dermo-hypodermitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Diarrhoea infectious * 1  1/763 (0.13%)  0/378 (0.00%) 
Diverticulitis * 1  0/763 (0.00%)  2/378 (0.53%) 
Ear infection * 1  3/763 (0.39%)  3/378 (0.79%) 
Epididymitis * 1  3/763 (0.39%)  0/378 (0.00%) 
Escherichia infection * 1  1/763 (0.13%)  0/378 (0.00%) 
Escherichia urinary tract infection * 1  0/763 (0.00%)  1/378 (0.26%) 
Eye infection * 1  1/763 (0.13%)  0/378 (0.00%) 
Folliculitis * 1  6/763 (0.79%)  1/378 (0.26%) 
Fungal infection * 1  4/763 (0.52%)  1/378 (0.26%) 
Fungal skin infection * 1  1/763 (0.13%)  0/378 (0.00%) 
Furuncle * 1  2/763 (0.26%)  1/378 (0.26%) 
Gastroenteritis * 1  20/763 (2.62%)  11/378 (2.91%) 
Gastroenteritis viral * 1  3/763 (0.39%)  0/378 (0.00%) 
Genital herpes * 1  2/763 (0.26%)  1/378 (0.26%) 
Genital herpes simplex * 1  1/763 (0.13%)  0/378 (0.00%) 
Genital infection fungal * 1  0/763 (0.00%)  1/378 (0.26%) 
Giardiasis * 1  1/763 (0.13%)  1/378 (0.26%) 
Gingival abscess * 1  0/763 (0.00%)  1/378 (0.26%) 
Gingivitis * 1  6/763 (0.79%)  1/378 (0.26%) 
Gonorrhoea * 1  12/763 (1.57%)  7/378 (1.85%) 
Groin abscess * 1  1/763 (0.13%)  0/378 (0.00%) 
Helicobacter infection * 1  0/763 (0.00%)  1/378 (0.26%) 
Hepatitis C * 1  0/763 (0.00%)  2/378 (0.53%) 
Herpes simplex * 1  3/763 (0.39%)  1/378 (0.26%) 
Herpes simplex hepatitis * 1  0/763 (0.00%)  1/378 (0.26%) 
Herpes virus infection * 1  3/763 (0.39%)  0/378 (0.00%) 
Herpes zoster * 1  5/763 (0.66%)  3/378 (0.79%) 
Herpes zoster infection neurological * 1  1/763 (0.13%)  0/378 (0.00%) 
Hordeolum * 1  2/763 (0.26%)  1/378 (0.26%) 
Infected bite * 1  2/763 (0.26%)  0/378 (0.00%) 
Infected dermal cyst * 1  0/763 (0.00%)  1/378 (0.26%) 
Influenza * 1  21/763 (2.75%)  7/378 (1.85%) 
Kidney infection * 1  1/763 (0.13%)  0/378 (0.00%) 
Labyrinthitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Laryngitis * 1  3/763 (0.39%)  0/378 (0.00%) 
Latent syphilis * 1  0/763 (0.00%)  1/378 (0.26%) 
Localised infection * 1  2/763 (0.26%)  0/378 (0.00%) 
Lower respiratory tract infection * 1  4/763 (0.52%)  2/378 (0.53%) 
Lymphogranuloma venereum * 1  2/763 (0.26%)  1/378 (0.26%) 
Nasal abscess * 1  0/763 (0.00%)  1/378 (0.26%) 
Nasopharyngitis * 1  81/763 (10.62%)  39/378 (10.32%) 
Oesophageal candidiasis * 1  1/763 (0.13%)  0/378 (0.00%) 
Onychomycosis * 1  8/763 (1.05%)  1/378 (0.26%) 
Oral candidiasis * 1  1/763 (0.13%)  0/378 (0.00%) 
Oral fungal infection * 1  1/763 (0.13%)  0/378 (0.00%) 
Oral herpes * 1  6/763 (0.79%)  5/378 (1.32%) 
Oropharyngeal gonococcal infection * 1  1/763 (0.13%)  2/378 (0.53%) 
Otitis externa * 1  2/763 (0.26%)  1/378 (0.26%) 
Otitis media * 1  6/763 (0.79%)  3/378 (0.79%) 
Otitis media acute * 1  0/763 (0.00%)  1/378 (0.26%) 
Papilloma viral infection * 1  1/763 (0.13%)  1/378 (0.26%) 
Paronychia * 1  2/763 (0.26%)  0/378 (0.00%) 
Pelvic inflammatory disease * 1  1/763 (0.13%)  0/378 (0.00%) 
Pharyngeal chlamydia infection * 1  0/763 (0.00%)  1/378 (0.26%) 
Pharyngitis * 1  25/763 (3.28%)  10/378 (2.65%) 
Pharyngitis bacterial * 1  2/763 (0.26%)  0/378 (0.00%) 
Pharyngitis streptococcal * 1  5/763 (0.66%)  1/378 (0.26%) 
Pharyngotonsillitis * 1  0/763 (0.00%)  1/378 (0.26%) 
Pilonidal cyst * 1  1/763 (0.13%)  0/378 (0.00%) 
Pneumonia * 1  5/763 (0.66%)  1/378 (0.26%) 
Pneumonia bacterial * 1  1/763 (0.13%)  0/378 (0.00%) 
Primary syphilis * 1  2/763 (0.26%)  0/378 (0.00%) 
Proctitis chlamydial * 1  0/763 (0.00%)  1/378 (0.26%) 
Proctitis gonococcal * 1  3/763 (0.39%)  2/378 (0.53%) 
Pseudomonas infection * 1  0/763 (0.00%)  1/378 (0.26%) 
Pulpitis dental * 1  1/763 (0.13%)  0/378 (0.00%) 
Purulent discharge * 1  1/763 (0.13%)  0/378 (0.00%) 
Pyuria * 1  1/763 (0.13%)  0/378 (0.00%) 
Rash pustular * 1  1/763 (0.13%)  0/378 (0.00%) 
Rectal abscess * 1  1/763 (0.13%)  0/378 (0.00%) 
Respiratory tract infection * 1  11/763 (1.44%)  5/378 (1.32%) 
Respiratory tract infection viral * 1  1/763 (0.13%)  2/378 (0.53%) 
Rhinitis * 1  13/763 (1.70%)  4/378 (1.06%) 
Rhinovirus infection * 1  1/763 (0.13%)  0/378 (0.00%) 
Secondary syphilis * 1  0/763 (0.00%)  2/378 (0.53%) 
Sexually transmitted disease * 1  1/763 (0.13%)  0/378 (0.00%) 
Shigella infection * 1  1/763 (0.13%)  1/378 (0.26%) 
Sinusitis * 1  28/763 (3.67%)  12/378 (3.17%) 
Skin infection * 1  1/763 (0.13%)  0/378 (0.00%) 
Spirochaetal infection * 1  1/763 (0.13%)  0/378 (0.00%) 
Staphylococcal infection * 1  2/763 (0.26%)  2/378 (0.53%) 
Staphylococcal skin infection * 1  0/763 (0.00%)  1/378 (0.26%) 
Subcutaneous abscess * 1  3/763 (0.39%)  0/378 (0.00%) 
Syphilis * 1  21/763 (2.75%)  12/378 (3.17%) 
Syphilis genital * 1  1/763 (0.13%)  0/378 (0.00%) 
Tinea pedis * 1  1/763 (0.13%)  1/378 (0.26%) 
Tinea versicolour * 1  3/763 (0.39%)  0/378 (0.00%) 
Tonsillitis * 1  2/763 (0.26%)  5/378 (1.32%) 
Tooth abscess * 1  6/763 (0.79%)  8/378 (2.12%) 
Tooth infection * 1  8/763 (1.05%)  6/378 (1.59%) 
Tracheitis * 1  1/763 (0.13%)  1/378 (0.26%) 
Trichomoniasis * 1  2/763 (0.26%)  0/378 (0.00%) 
Upper respiratory tract infection * 1  81/763 (10.62%)  39/378 (10.32%) 
Ureteritis * 1  2/763 (0.26%)  1/378 (0.26%) 
Urethritis * 1  6/763 (0.79%)  4/378 (1.06%) 
Urethritis chlamydial * 1  1/763 (0.13%)  1/378 (0.26%) 
Urethritis gonococcal * 1  1/763 (0.13%)  1/378 (0.26%) 
Urinary tract infection * 1  11/763 (1.44%)  8/378 (2.12%) 
Urinary tract infection bacterial * 1  1/763 (0.13%)  0/378 (0.00%) 
Urinary tract infection enterococcal * 1  0/763 (0.00%)  1/378 (0.26%) 
Vaginal infection * 1  0/763 (0.00%)  1/378 (0.26%) 
Vaginitis bacterial * 1  1/763 (0.13%)  1/378 (0.26%) 
Vaginitis gardnerella * 1  1/763 (0.13%)  0/378 (0.00%) 
Viral infection * 1  5/763 (0.66%)  3/378 (0.79%) 
Viral pharyngitis * 1  2/763 (0.26%)  0/378 (0.00%) 
Viral rhinitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Viral upper respiratory tract infection * 1  2/763 (0.26%)  4/378 (1.06%) 
Vulvovaginal candidiasis * 1  2/763 (0.26%)  0/378 (0.00%) 
Injury, poisoning and procedural complications     
Accidental overdose * 1  1/763 (0.13%)  0/378 (0.00%) 
Animal bite * 1  3/763 (0.39%)  2/378 (0.53%) 
Ankle fracture * 1  1/763 (0.13%)  0/378 (0.00%) 
Arthropod bite * 1  4/763 (0.52%)  1/378 (0.26%) 
Arthropod sting * 1  1/763 (0.13%)  0/378 (0.00%) 
Burns second degree * 1  1/763 (0.13%)  0/378 (0.00%) 
Chemical eye injury * 1  1/763 (0.13%)  0/378 (0.00%) 
Chest injury * 1  2/763 (0.26%)  0/378 (0.00%) 
Clavicle fracture * 1  1/763 (0.13%)  0/378 (0.00%) 
Contusion * 1  7/763 (0.92%)  0/378 (0.00%) 
Ear canal abrasion * 1  1/763 (0.13%)  0/378 (0.00%) 
Epicondylitis * 1  4/763 (0.52%)  2/378 (0.53%) 
Exposure to communicable disease * 1  1/763 (0.13%)  0/378 (0.00%) 
Exposure to toxic agent * 1  1/763 (0.13%)  0/378 (0.00%) 
Face injury * 1  0/763 (0.00%)  1/378 (0.26%) 
Fall * 1  0/763 (0.00%)  1/378 (0.26%) 
Hand fracture * 1  1/763 (0.13%)  1/378 (0.26%) 
Head injury * 1  1/763 (0.13%)  0/378 (0.00%) 
Incision site pain * 1  1/763 (0.13%)  0/378 (0.00%) 
Injury * 1  1/763 (0.13%)  0/378 (0.00%) 
Joint dislocation * 1  1/763 (0.13%)  0/378 (0.00%) 
Joint injury * 1  0/763 (0.00%)  1/378 (0.26%) 
Laceration * 1  3/763 (0.39%)  5/378 (1.32%) 
Ligament sprain * 1  9/763 (1.18%)  3/378 (0.79%) 
Limb injury * 1  5/763 (0.66%)  4/378 (1.06%) 
Medication error * 1  1/763 (0.13%)  0/378 (0.00%) 
Meniscus injury * 1  1/763 (0.13%)  0/378 (0.00%) 
Muscle injury * 1  2/763 (0.26%)  0/378 (0.00%) 
Muscle rupture * 1  1/763 (0.13%)  2/378 (0.53%) 
Muscle strain * 1  7/763 (0.92%)  1/378 (0.26%) 
Overdose * 1  1/763 (0.13%)  0/378 (0.00%) 
Post procedural discomfort * 1  0/763 (0.00%)  1/378 (0.26%) 
Post-traumatic neck syndrome * 1  1/763 (0.13%)  0/378 (0.00%) 
Post-traumatic pain * 1  0/763 (0.00%)  2/378 (0.53%) 
Procedural dizziness * 1  1/763 (0.13%)  0/378 (0.00%) 
Procedural pain * 1  4/763 (0.52%)  3/378 (0.79%) 
Radius fracture * 1  0/763 (0.00%)  1/378 (0.26%) 
Rib fracture * 1  2/763 (0.26%)  0/378 (0.00%) 
Road traffic accident * 1  0/763 (0.00%)  1/378 (0.26%) 
Skin abrasion * 1  4/763 (0.52%)  2/378 (0.53%) 
Splinter * 1  2/763 (0.26%)  0/378 (0.00%) 
Sunburn * 1  0/763 (0.00%)  1/378 (0.26%) 
Thermal burn * 1  1/763 (0.13%)  2/378 (0.53%) 
Tooth fracture * 1  3/763 (0.39%)  1/378 (0.26%) 
Toxicity to various agents * 1  1/763 (0.13%)  0/378 (0.00%) 
Wound * 1  1/763 (0.13%)  0/378 (0.00%) 
Wrist fracture * 1  2/763 (0.26%)  0/378 (0.00%) 
Investigations     
Alanine aminotransferase increased * 1  5/763 (0.66%)  3/378 (0.79%) 
Alpha-1 acid glycoprotein decreased * 1  0/763 (0.00%)  1/378 (0.26%) 
Amylase increased * 1  3/763 (0.39%)  1/378 (0.26%) 
Aspartate aminotransferase increased * 1  4/763 (0.52%)  3/378 (0.79%) 
Beta 2 microglobulin increased * 1  3/763 (0.39%)  2/378 (0.53%) 
Beta 2 microglobulin urine * 1  1/763 (0.13%)  0/378 (0.00%) 
Beta 2 microglobulin urine increased * 1  3/763 (0.39%)  7/378 (1.85%) 
Blood bilirubin increased * 1  1/763 (0.13%)  2/378 (0.53%) 
Blood cholesterol increased * 1  8/763 (1.05%)  2/378 (0.53%) 
Blood creatine phosphokinase increased * 1  7/763 (0.92%)  5/378 (1.32%) 
Blood creatinine increased * 1  4/763 (0.52%)  2/378 (0.53%) 
Blood glucose increased * 1  3/763 (0.39%)  0/378 (0.00%) 
Blood parathyroid hormone increased * 1  1/763 (0.13%)  1/378 (0.26%) 
Blood pressure diastolic increased * 1  1/763 (0.13%)  1/378 (0.26%) 
Blood pressure increased * 1  4/763 (0.52%)  2/378 (0.53%) 
Blood thyroid stimulating hormone increased * 1  1/763 (0.13%)  0/378 (0.00%) 
Blood triglycerides increased * 1  2/763 (0.26%)  2/378 (0.53%) 
Blood urea increased * 1  1/763 (0.13%)  0/378 (0.00%) 
Blood uric acid increased * 1  1/763 (0.13%)  0/378 (0.00%) 
Body temperature increased * 1  0/763 (0.00%)  1/378 (0.26%) 
Bone density decreased * 1  0/763 (0.00%)  1/378 (0.26%) 
Breath sounds abnormal * 1  1/763 (0.13%)  0/378 (0.00%) 
C-telopeptide increased * 1  1/763 (0.13%)  0/378 (0.00%) 
Cardiac murmur * 1  2/763 (0.26%)  0/378 (0.00%) 
Carotid bruit * 1  1/763 (0.13%)  0/378 (0.00%) 
Creatinine renal clearance decreased * 1  6/763 (0.79%)  2/378 (0.53%) 
Cryptococcus test positive * 1  0/763 (0.00%)  1/378 (0.26%) 
Cystatin C increased * 1  0/763 (0.00%)  1/378 (0.26%) 
Eosinophil count increased * 1  1/763 (0.13%)  0/378 (0.00%) 
Faecal calprotectin increased * 1  1/763 (0.13%)  0/378 (0.00%) 
Gamma-glutamyltransferase increased * 1  0/763 (0.00%)  1/378 (0.26%) 
Glomerular filtration rate decreased * 1  1/763 (0.13%)  0/378 (0.00%) 
Hepatic enzyme increased * 1  1/763 (0.13%)  1/378 (0.26%) 
Intestinal transit time decreased * 1  0/763 (0.00%)  1/378 (0.26%) 
Liver function test abnormal * 1  1/763 (0.13%)  0/378 (0.00%) 
Low density lipoprotein increased * 1  6/763 (0.79%)  3/378 (0.79%) 
Mycobacterium tuberculosis complex test positive * 1  0/763 (0.00%)  1/378 (0.26%) 
Neutrophil count increased * 1  0/763 (0.00%)  1/378 (0.26%) 
Occult blood positive * 1  1/763 (0.13%)  0/378 (0.00%) 
Platelet count decreased * 1  1/763 (0.13%)  0/378 (0.00%) 
Prostatic specific antigen increased * 1  1/763 (0.13%)  0/378 (0.00%) 
Serum ferritin decreased * 1  0/763 (0.00%)  1/378 (0.26%) 
Serum procollagen type I N-terminal propeptide increased * 1  1/763 (0.13%)  0/378 (0.00%) 
Transaminases increased * 1  0/763 (0.00%)  3/378 (0.79%) 
Urine leukocyte esterase positive * 1  1/763 (0.13%)  0/378 (0.00%) 
Vitamin D decreased * 1  3/763 (0.39%)  3/378 (0.79%) 
Weight decreased * 1  7/763 (0.92%)  2/378 (0.53%) 
Weight increased * 1  9/763 (1.18%)  1/378 (0.26%) 
White blood cell count increased * 1  0/763 (0.00%)  1/378 (0.26%) 
Metabolism and nutrition disorders     
Cachexia * 1  0/763 (0.00%)  1/378 (0.26%) 
Decreased appetite * 1  4/763 (0.52%)  2/378 (0.53%) 
Dehydration * 1  0/763 (0.00%)  3/378 (0.79%) 
Diabetes mellitus * 1  6/763 (0.79%)  0/378 (0.00%) 
Diabetes mellitus inadequate control * 1  1/763 (0.13%)  0/378 (0.00%) 
Dyslipidaemia * 1  2/763 (0.26%)  0/378 (0.00%) 
Folate deficiency * 1  0/763 (0.00%)  1/378 (0.26%) 
Glucose tolerance impaired * 1  0/763 (0.00%)  1/378 (0.26%) 
Gout * 1  3/763 (0.39%)  0/378 (0.00%) 
Hypercholesterolaemia * 1  12/763 (1.57%)  4/378 (1.06%) 
Hyperchylomicronaemia * 1  1/763 (0.13%)  0/378 (0.00%) 
Hyperglycaemia * 1  3/763 (0.39%)  2/378 (0.53%) 
Hyperlipidaemia * 1  13/763 (1.70%)  1/378 (0.26%) 
Hypertriglyceridaemia * 1  4/763 (0.52%)  2/378 (0.53%) 
Hypoglycaemia * 1  2/763 (0.26%)  0/378 (0.00%) 
Hypokalaemia * 1  1/763 (0.13%)  1/378 (0.26%) 
Hyponatraemia * 1  1/763 (0.13%)  0/378 (0.00%) 
Hypophagia * 1  1/763 (0.13%)  0/378 (0.00%) 
Hypophosphataemia * 1  4/763 (0.52%)  0/378 (0.00%) 
Increased appetite * 1  2/763 (0.26%)  0/378 (0.00%) 
Iron deficiency * 1  0/763 (0.00%)  1/378 (0.26%) 
Lactose intolerance * 1  1/763 (0.13%)  0/378 (0.00%) 
Obesity * 1  1/763 (0.13%)  0/378 (0.00%) 
Type 2 diabetes mellitus * 1  2/763 (0.26%)  0/378 (0.00%) 
Vitamin D deficiency * 1  50/763 (6.55%)  27/378 (7.14%) 
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  26/763 (3.41%)  9/378 (2.38%) 
Arthritis * 1  3/763 (0.39%)  0/378 (0.00%) 
Arthritis reactive * 1  1/763 (0.13%)  0/378 (0.00%) 
Back pain * 1  54/763 (7.08%)  21/378 (5.56%) 
Bone pain * 1  2/763 (0.26%)  2/378 (0.53%) 
Bursitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Flank pain * 1  6/763 (0.79%)  1/378 (0.26%) 
Foot deformity * 1  1/763 (0.13%)  1/378 (0.26%) 
Groin pain * 1  1/763 (0.13%)  0/378 (0.00%) 
Intervertebral disc degeneration * 1  2/763 (0.26%)  0/378 (0.00%) 
Intervertebral disc protrusion * 1  3/763 (0.39%)  2/378 (0.53%) 
Joint stiffness * 1  1/763 (0.13%)  0/378 (0.00%) 
Joint swelling * 1  0/763 (0.00%)  1/378 (0.26%) 
Limb discomfort * 1  0/763 (0.00%)  1/378 (0.26%) 
Metatarsalgia * 1  1/763 (0.13%)  0/378 (0.00%) 
Muscle contracture * 1  3/763 (0.39%)  0/378 (0.00%) 
Muscle fatigue * 1  1/763 (0.13%)  0/378 (0.00%) 
Muscle spasms * 1  10/763 (1.31%)  2/378 (0.53%) 
Muscle tightness * 1  2/763 (0.26%)  0/378 (0.00%) 
Muscular weakness * 1  4/763 (0.52%)  0/378 (0.00%) 
Musculoskeletal chest pain * 1  5/763 (0.66%)  6/378 (1.59%) 
Musculoskeletal pain * 1  15/763 (1.97%)  8/378 (2.12%) 
Musculoskeletal stiffness * 1  1/763 (0.13%)  1/378 (0.26%) 
Myalgia * 1  12/763 (1.57%)  4/378 (1.06%) 
Neck pain * 1  10/763 (1.31%)  4/378 (1.06%) 
Osteoarthritis * 1  2/763 (0.26%)  2/378 (0.53%) 
Osteopenia * 1  38/763 (4.98%)  21/378 (5.56%) 
Osteoporosis * 1  10/763 (1.31%)  4/378 (1.06%) 
Pain in extremity * 1  27/763 (3.54%)  12/378 (3.17%) 
Pain in jaw * 1  0/763 (0.00%)  1/378 (0.26%) 
Periarthritis * 1  1/763 (0.13%)  0/378 (0.00%) 
Periostitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Peripheral arthritis * 1  0/763 (0.00%)  1/378 (0.26%) 
Plantar fasciitis * 1  1/763 (0.13%)  1/378 (0.26%) 
Rhabdomyolysis * 1  1/763 (0.13%)  1/378 (0.26%) 
Rotator cuff syndrome * 1  5/763 (0.66%)  1/378 (0.26%) 
Scoliosis * 1  1/763 (0.13%)  0/378 (0.00%) 
Spinal osteoarthritis * 1  1/763 (0.13%)  0/378 (0.00%) 
Spinal pain * 1  1/763 (0.13%)  0/378 (0.00%) 
Synovitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Tendon calcification * 1  1/763 (0.13%)  0/378 (0.00%) 
Tendon pain * 1  1/763 (0.13%)  0/378 (0.00%) 
Tendonitis * 1  1/763 (0.13%)  0/378 (0.00%) 
Torticollis * 1  1/763 (0.13%)  0/378 (0.00%) 
Trigger finger * 1  2/763 (0.26%)  0/378 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Acrochordon * 1  1/763 (0.13%)  0/378 (0.00%) 
Anogenital warts * 1  12/763 (1.57%)  2/378 (0.53%) 
Basal cell carcinoma * 1  4/763 (0.52%)  1/378 (0.26%) 
Bladder cancer * 1  0/763 (0.00%)  1/378 (0.26%) 
Cervix carcinoma stage 0 * 1  1/763 (0.13%)  0/378 (0.00%) 
Haemangioma of skin * 1  0/763 (0.00%)  1/378 (0.26%) 
Lipofibroma * 1  1/763 (0.13%)  0/378 (0.00%) 
Lipoma * 1  2/763 (0.26%)  0/378 (0.00%) 
Melanocytic naevus * 1  2/763 (0.26%)  0/378 (0.00%) 
Neoplasm skin * 1  1/763 (0.13%)  0/378 (0.00%) 
Oral papilloma * 1  1/763 (0.13%)  0/378 (0.00%) 
Ovarian neoplasm * 1  0/763 (0.00%)  1/378 (0.26%) 
Prostate cancer * 1  2/763 (0.26%)  0/378 (0.00%) 
Seborrhoeic keratosis * 1  2/763 (0.26%)  0/378 (0.00%) 
Skin papilloma * 1  8/763 (1.05%)  1/378 (0.26%) 
Uterine leiomyoma * 1  1/763 (0.13%)  0/378 (0.00%) 
Nervous system disorders     
Amnesia * 1  1/763 (0.13%)  0/378 (0.00%) 
Aphasia * 1  1/763 (0.13%)  0/378 (0.00%) 
Carpal tunnel syndrome * 1  3/763 (0.39%)  0/378 (0.00%) 
Cervical radiculopathy * 1  0/763 (0.00%)  2/378 (0.53%) 
Cognitive disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Dizziness * 1  2/763 (0.26%)  0/378 (0.00%) 
Dizziness exertional * 1  2/763 (0.26%)  0/378 (0.00%) 
Dizziness postural * 1  10/763 (1.31%)  1/378 (0.26%) 
Drug withdrawal headache * 1  0/763 (0.00%)  1/378 (0.26%) 
Dysgeusia * 1  1/763 (0.13%)  0/378 (0.00%) 
Epilepsy * 1  1/763 (0.13%)  0/378 (0.00%) 
Facial paralysis * 1  0/763 (0.00%)  1/378 (0.26%) 
Headache * 1  58/763 (7.60%)  16/378 (4.23%) 
Hyperaesthesia * 1  1/763 (0.13%)  0/378 (0.00%) 
Hypersomnia * 1  1/763 (0.13%)  0/378 (0.00%) 
Hypoaesthesia * 1  4/763 (0.52%)  1/378 (0.26%) 
Hypogeusia * 1  1/763 (0.13%)  1/378 (0.26%) 
Irregular sleep phase * 1  1/763 (0.13%)  0/378 (0.00%) 
Lumbar radiculopathy * 1  1/763 (0.13%)  0/378 (0.00%) 
Memory impairment * 1  1/763 (0.13%)  0/378 (0.00%) 
Migraine * 1  6/763 (0.79%)  1/378 (0.26%) 
Neuralgia * 1  2/763 (0.26%)  0/378 (0.00%) 
Neuropathy peripheral * 1  6/763 (0.79%)  1/378 (0.26%) 
Occipital neuralgia * 1  0/763 (0.00%)  1/378 (0.26%) 
Paraesthesia * 1  8/763 (1.05%)  4/378 (1.06%) 
Radiculopathy * 1  1/763 (0.13%)  1/378 (0.26%) 
Sacral radiculopathy * 1  1/763 (0.13%)  0/378 (0.00%) 
Sciatica * 1  9/763 (1.18%)  1/378 (0.26%) 
Seizure * 1  1/763 (0.13%)  0/378 (0.00%) 
Sensory loss * 1  1/763 (0.13%)  0/378 (0.00%) 
Sinus headache * 1  1/763 (0.13%)  1/378 (0.26%) 
Somnolence * 1  3/763 (0.39%)  0/378 (0.00%) 
Syncope * 1  2/763 (0.26%)  3/378 (0.79%) 
Tension headache * 1  1/763 (0.13%)  0/378 (0.00%) 
Thoracic outlet syndrome * 1  1/763 (0.13%)  0/378 (0.00%) 
Tremor * 1  2/763 (0.26%)  0/378 (0.00%) 
Tunnel vision * 1  0/763 (0.00%)  1/378 (0.26%) 
Psychiatric disorders     
Abnormal dreams * 1  9/763 (1.18%)  1/378 (0.26%) 
Adjustment disorder with depressed mood * 1  2/763 (0.26%)  0/378 (0.00%) 
Affective disorder * 1  1/763 (0.13%)  0/378 (0.00%) 
Alcohol abuse * 1  2/763 (0.26%)  0/378 (0.00%) 
Anxiety * 1  15/763 (1.97%)  8/378 (2.12%) 
Attention deficit/hyperactivity disorder * 1  2/763 (0.26%)  1/378 (0.26%) 
Binge drinking * 1  0/763 (0.00%)  1/378 (0.26%) 
Bipolar disorder * 1  0/763 (0.00%)  1/378 (0.26%) 
Claustrophobia * 1  1/763 (0.13%)  0/378 (0.00%) 
Depressed mood * 1  1/763 (0.13%)  2/378 (0.53%) 
Depression * 1  14/763 (1.83%)  11/378 (2.91%) 
Depression suicidal * 1  1/763 (0.13%)  0/378 (0.00%) 
Depressive symptom * 1  2/763 (0.26%)  1/378 (0.26%) 
Drug abuse * 1  3/763 (0.39%)  0/378 (0.00%) 
Dysphoria * 1  1/763 (0.13%)  0/378 (0.00%) 
Euphoric mood * 1  1/763 (0.13%)  0/378 (0.00%) 
Gender dysphoria * 1  1/763 (0.13%)  0/378 (0.00%) 
Grief reaction * 1  0/763 (0.00%)  1/378 (0.26%) 
Hallucination, visual * 1  1/763 (0.13%)  0/378 (0.00%) 
Initial insomnia * 1  1/763 (0.13%)  0/378 (0.00%) 
Insomnia * 1  15/763 (1.97%)  8/378 (2.12%) 
Irritability * 1  1/763 (0.13%)  0/378 (0.00%) 
Libido decreased * 1  3/763 (0.39%)  1/378 (0.26%) 
Loss of libido * 1  1/763 (0.13%)  0/378 (0.00%) 
Major depression * 1  2/763 (0.26%)  0/378 (0.00%) 
Mood altered * 1  0/763 (0.00%)  1/378 (0.26%) 
Mood swings * 1  0/763 (0.00%)  1/378 (0.26%) 
Nervousness * 1  1/763 (0.13%)  0/378 (0.00%) 
Panic attack * 1  0/763 (0.00%)  1/378 (0.26%) 
Persistent depressive disorder * 1  0/763 (0.00%)  1/378 (0.26%) 
Sleep disorder * 1  8/763 (1.05%)  2/378 (0.53%) 
Stress * 1  1/763 (0.13%)  2/378 (0.53%) 
Substance abuse * 1  0/763 (0.00%)  1/378 (0.26%) 
Tearfulness * 1  1/763 (0.13%)  0/378 (0.00%) 
Tobacco withdrawal symptoms * 1  1/763 (0.13%)  0/378 (0.00%) 
Renal and urinary disorders     
Bladder spasm * 1  1/763