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

• ClinicalTrials.gov Identifier: NCT02269917
• Recruitment Status: Completed
• First Posted: October 21, 2014
• Results First Posted: November 9, 2018
• Last Update Posted: December 17, 2020
• Sponsor: Janssen R&D Ireland
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		D/C/F/TAF	Control	Total
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
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%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Virologic Rebound (HIV-1 RNA >=50 Copies/mL) Cumulative Through Week 48
Time Frame	Through Week 48

Outcome Measure Data

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
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)

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
Time Frame	Through 48 Weeks

Outcome Measure Data

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
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
Time Frame	Through 48 Weeks

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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)
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

Outcome Measure Data

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
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
Description	Change from baseline in serum creatinine levels at Weeks 24 and 48 was assessed.
Time Frame	Baseline and Weeks 24 and 48

Outcome Measure Data

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
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)

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]

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
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

Outcome Measure Data

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
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)

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]

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
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

Outcome Measure Data

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
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)

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]

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
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

Outcome Measure Data

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
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)

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]

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
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

Outcome Measure Data

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
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)

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]

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]

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]

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
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

Outcome Measure Data

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
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)

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]

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]

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]

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
Description	Percent change from baseline in urine FEPO4 was assessed at Weeks 24 and 48.
Time Frame	Baseline, Weeks 24 and 48

Outcome Measure Data

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
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)

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]

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
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

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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
Description	Change from baseline in CD4+ cell count was assessed at Weeks 24 and 48.
Time Frame	Baseline, Weeks 24 and 48

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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
Description	Percent change from baseline in bone biomarker: PTH was assessed at Weeks 24 and 48.
Time Frame	Baseline, Weeks 24 and 48

Outcome Measure Data

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
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
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

Outcome Measure Data

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
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
Description	Percent change from baseline in spine and hip BMD was assessed at Weeks 24 and 48.
Time Frame	Baseline, Weeks 24 and 48

Outcome Measure Data

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
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)

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]

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]

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]

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
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

Outcome Measure Data

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
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)

Adverse Events

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
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%)
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
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 (0.13%)	0/378 (0.00%)
Chromaturia * 1	1/763 (0.13%)	0/378 (0.00%)
Chronic kidney disease * 1	1/763 (0.13%)	0/378 (0.00%)
Costovertebral angle tenderness * 1	1/763 (0.13%)	0/378 (0.00%)
Crystalluria * 1	0/763 (0.00%)	1/378 (0.26%)
Cystitis haemorrhagic * 1	0/763 (0.00%)	1/378 (0.26%)
Dysuria * 1	6/763 (0.79%)	4/378 (1.06%)
Glycosuria * 1	1/763 (0.13%)	0/378 (0.00%)
Haematuria * 1	4/763 (0.52%)	1/378 (0.26%)
Leukocyturia * 1	1/763 (0.13%)	0/378 (0.00%)
Micturition disorder * 1	0/763 (0.00%)	1/378 (0.26%)
Nephrolithiasis * 1	2/763 (0.26%)	1/378 (0.26%)
Nephropathy toxic * 1	0/763 (0.00%)	1/378 (0.26%)
Pollakiuria * 1	3/763 (0.39%)	1/378 (0.26%)
Polyuria * 1	1/763 (0.13%)	0/378 (0.00%)
Proteinuria * 1	5/763 (0.66%)	2/378 (0.53%)
Renal colic * 1	0/763 (0.00%)	1/378 (0.26%)
Renal tubular disorder * 1	0/763 (0.00%)	1/378 (0.26%)
Terminal dribbling * 1	1/763 (0.13%)	0/378 (0.00%)
Urethral discharge * 1	3/763 (0.39%)	2/378 (0.53%)
Urethral pain * 1	1/763 (0.13%)	0/378 (0.00%)
Urinary retention * 1	1/763 (0.13%)	0/378 (0.00%)
Urinary tract obstruction * 1	0/763 (0.00%)	1/378 (0.26%)
Urine odour abnormal * 1	2/763 (0.26%)	0/378 (0.00%)
Reproductive system and breast disorders
Balanoposthitis * 1	2/763 (0.26%)	0/378 (0.00%)
Benign prostatic hyperplasia * 1	3/763 (0.39%)	1/378 (0.26%)
Breast mass * 1	1/763 (0.13%)	0/378 (0.00%)
Breast pain * 1	1/763 (0.13%)	0/378 (0.00%)
Cervical dysplasia * 1	1/763 (0.13%)	0/378 (0.00%)
Dysmenorrhoea * 1	0/763 (0.00%)	1/378 (0.26%)
Erectile dysfunction * 1	8/763 (1.05%)	1/378 (0.26%)
Genital haemorrhage * 1	1/763 (0.13%)	0/378 (0.00%)
Genital lesion * 1	2/763 (0.26%)	1/378 (0.26%)
Genital rash * 1	1/763 (0.13%)	0/378 (0.00%)
Haematospermia * 1	0/763 (0.00%)	1/378 (0.26%)
Menometrorrhagia * 1	1/763 (0.13%)	0/378 (0.00%)
Menopausal symptoms * 1	1/763 (0.13%)	0/378 (0.00%)
Menorrhagia * 1	2/763 (0.26%)	1/378 (0.26%)
Metrorrhagia * 1	1/763 (0.13%)	0/378 (0.00%)
Pelvic pain * 1	0/763 (0.00%)	1/378 (0.26%)
Penile discharge * 1	0/763 (0.00%)	1/378 (0.26%)
Penis disorder * 1	0/763 (0.00%)	1/378 (0.26%)
Prostatitis * 1	3/763 (0.39%)	4/378 (1.06%)
Pruritus genital * 1	0/763 (0.00%)	1/378 (0.26%)
Retrograde ejaculation * 1	1/763 (0.13%)	0/378 (0.00%)
Scrotal angiokeratoma * 1	1/763 (0.13%)	0/378 (0.00%)
Scrotal pain * 1	2/763 (0.26%)	0/378 (0.00%)
Scrotal ulcer * 1	1/763 (0.13%)	0/378 (0.00%)
Testicular disorder * 1	1/763 (0.13%)	0/378 (0.00%)
Testicular mass * 1	1/763 (0.13%)	0/378 (0.00%)
Testicular pain * 1	1/763 (0.13%)	0/378 (0.00%)
Vaginal discharge * 1	1/763 (0.13%)	0/378 (0.00%)
Respiratory, thoracic and mediastinal disorders
Allergic sinusitis * 1	1/763 (0.13%)	0/378 (0.00%)
Asthma * 1	7/763 (0.92%)	1/378 (0.26%)
Bronchial hyperreactivity * 1	0/763 (0.00%)	1/378 (0.26%)
Bronchitis chronic * 1	0/763 (0.00%)	1/378 (0.26%)
Bronchospasm * 1	0/763 (0.00%)	1/378 (0.26%)
Catarrh * 1	2/763 (0.26%)	0/378 (0.00%)
Chronic obstructive pulmonary disease * 1	1/763 (0.13%)	0/378 (0.00%)
Cough * 1	32/763 (4.19%)	17/378 (4.50%)
Dysphonia * 1	1/763 (0.13%)	2/378 (0.53%)
Dyspnoea * 1	8/763 (1.05%)	1/378 (0.26%)
Dyspnoea exertional * 1	1/763 (0.13%)	0/378 (0.00%)
Emphysema * 1	0/763 (0.00%)	2/378 (0.53%)
Epistaxis * 1	2/763 (0.26%)	3/378 (0.79%)
Nasal congestion * 1	8/763 (1.05%)	4/378 (1.06%)
Nasal septum deviation * 1	1/763 (0.13%)	1/378 (0.26%)
Oropharyngeal pain * 1	25/763 (3.28%)	11/378 (2.91%)
Paranasal sinus hypersecretion * 1	0/763 (0.00%)	1/378 (0.26%)
Pharyngeal erythema * 1	0/763 (0.00%)	2/378 (0.53%)
Pharyngeal ulceration * 1	0/763 (0.00%)	1/378 (0.26%)
Pleuritic pain * 1	0/763 (0.00%)	1/378 (0.26%)
Productive cough * 1	8/763 (1.05%)	4/378 (1.06%)
Pulmonary mass * 1	1/763 (0.13%)	0/378 (0.00%)
Rales * 1	1/763 (0.13%)	1/378 (0.26%)
Respiratory symptom * 1	1/763 (0.13%)	0/378 (0.00%)
Respiratory tract congestion * 1