Trial Outcomes & Findings for Safety and Efficacy of Cobicistat-boosted Atazanavir Compared to Ritonavir-boosted Atazanavir in Combination With Emtricitabine/Tenofovir Disoproxil Fumarate in HIV-1 Infected, Antiretroviral Treatment-Naive Adults (NCT NCT00892437)

Last Updated: 2016-02-15

Results Overview

The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 24 was analyzed using the missing = failure method, where participants with missing data were considered to have failed to achieve the endpoint.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

85 participants

Primary outcome timeframe

Week 24

Results posted on

2016-02-15

Participant Flow

Participants were enrolled and treated in 32 study centers in the United States. The first participant was screened on 04 May 2009, and the last study visit occurred on 15 January 2015.

137 participants were screened.

Participant milestones

Participant milestones
Measure	ATV+COBI+FTC/TDF Randomized Phase: Cobicistat (COBI) 150 mg + ritonavir (RTV) placebo + atazanavir (ATV) 300 mg + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily	ATV+RTV+FTC/TDF Randomized Phase: RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily
Randomized Phase STARTED	56	29
Randomized Phase Randomized and Treated	50	29
Randomized Phase COMPLETED	45	24
Randomized Phase NOT COMPLETED	11	5
Open-Label Extension Phase STARTED	44	19
Open-Label Extension Phase COMPLETED	32	15
Open-Label Extension Phase NOT COMPLETED	12	4

Reasons for withdrawal

Reasons for withdrawal
Measure	ATV+COBI+FTC/TDF Randomized Phase: Cobicistat (COBI) 150 mg + ritonavir (RTV) placebo + atazanavir (ATV) 300 mg + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily	ATV+RTV+FTC/TDF Randomized Phase: RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily
Randomized Phase Randomized but not treated	6	0
Randomized Phase Adverse Event	2	2
Randomized Phase Lost to Follow-up	1	3
Randomized Phase Investigator's Discretion	1	0
Randomized Phase Withdrew Consent	1	0
Open-Label Extension Phase Adverse Event	4	2
Open-Label Extension Phase Lack of Efficacy	1	0
Open-Label Extension Phase Lost to Follow-up	3	1
Open-Label Extension Phase Investigator's Discretion	1	0
Open-Label Extension Phase Withdrew Consent	3	1

Baseline Characteristics

Safety and Efficacy of Cobicistat-boosted Atazanavir Compared to Ritonavir-boosted Atazanavir in Combination With Emtricitabine/Tenofovir Disoproxil Fumarate in HIV-1 Infected, Antiretroviral Treatment-Naive Adults

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ATV+COBI+FTC/TDF n=50 Participants Randomized Phase: COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily	ATV+RTV+FTC/TDF n=29 Participants Randomized Phase: RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily	Total n=79 Participants Total of all reporting groups
Age, Continuous	37 years STANDARD_DEVIATION 9.6 • n=93 Participants	34 years STANDARD_DEVIATION 10.1 • n=4 Participants	36 years STANDARD_DEVIATION 9.8 • n=27 Participants
Sex: Female, Male Female	3 Participants n=93 Participants	4 Participants n=4 Participants	7 Participants n=27 Participants
Sex: Female, Male Male	47 Participants n=93 Participants	25 Participants n=4 Participants	72 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	7 Participants n=93 Participants	5 Participants n=4 Participants	12 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	43 Participants n=93 Participants	24 Participants n=4 Participants	67 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race/Ethnicity, Customized Asian	0 participants n=93 Participants	2 participants n=4 Participants	2 participants n=27 Participants
Race/Ethnicity, Customized Black	18 participants n=93 Participants	9 participants n=4 Participants	27 participants n=27 Participants
Race/Ethnicity, Customized White	31 participants n=93 Participants	16 participants n=4 Participants	47 participants n=27 Participants
Race/Ethnicity, Customized Other	1 participants n=93 Participants	2 participants n=4 Participants	3 participants n=27 Participants
HIV-1 RNA	4.56 log_10 copies/mL STANDARD_DEVIATION 0.657 • n=93 Participants	4.69 log_10 copies/mL STANDARD_DEVIATION 0.530 • n=4 Participants	4.61 log_10 copies/mL STANDARD_DEVIATION 0.614 • n=27 Participants
HIV-1 RNA Category ≤ 100,000 copies/mL	38 participants n=93 Participants	18 participants n=4 Participants	56 participants n=27 Participants
HIV-1 RNA Category > 100,000 copies/mL	12 participants n=93 Participants	11 participants n=4 Participants	23 participants n=27 Participants
Cluster of differentiation (CD4) Cell Count	365 cells/uL STANDARD_DEVIATION 201.3 • n=93 Participants	343 cells/uL STANDARD_DEVIATION 178.1 • n=4 Participants	357 cells/uL STANDARD_DEVIATION 192.2 • n=27 Participants
CD4 Cell Count Category ≤ 50 cells/μL	1 participants n=93 Participants	1 participants n=4 Participants	2 participants n=27 Participants
CD4 Cell Count Category 51 to ≤ 200 cells/μL	9 participants n=93 Participants	6 participants n=4 Participants	15 participants n=27 Participants
CD4 Cell Count Category 201 to ≤ 350 cells/μL	16 participants n=93 Participants	7 participants n=4 Participants	23 participants n=27 Participants
CD4 Cell Count Category 351 to ≤ 500 cells/μL	17 participants n=93 Participants	11 participants n=4 Participants	28 participants n=27 Participants
CD4 Cell Count Category > 500 cells/μL	7 participants n=93 Participants	4 participants n=4 Participants	11 participants n=27 Participants
HIV Disease Status Asymptomatic	41 participants n=93 Participants	25 participants n=4 Participants	66 participants n=27 Participants
HIV Disease Status Symptomatic HIV Infections	1 participants n=93 Participants	1 participants n=4 Participants	2 participants n=27 Participants
HIV Disease Status AIDS	8 participants n=93 Participants	3 participants n=4 Participants	11 participants n=27 Participants
Chronic Hepatitis B Infection Status Negative	50 participants n=93 Participants	29 participants n=4 Participants	79 participants n=27 Participants
Chronic Hepatitis B Infection Status Positive	0 participants n=93 Participants	0 participants n=4 Participants	0 participants n=27 Participants
Chronic Hepatitis C Infection Status Negative	50 participants n=93 Participants	29 participants n=4 Participants	79 participants n=27 Participants
Chronic Hepatitis C Infection Status Positive	0 participants n=93 Participants	0 participants n=4 Participants	0 participants n=27 Participants

PRIMARY outcome

Timeframe: Week 24

Population: ITT Analysis Set: participants who were randomized and received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	ATV+COBI+FTC/TDF n=50 Participants Randomized Phase: COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily	ATV+RTV+FTC/TDF n=29 Participants Randomized Phase: RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24	84.0 percentage of participants	89.7 percentage of participants

SECONDARY outcome

Timeframe: Week 48

Population: ITT Analysis Set

The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 48 was analyzed using the missing = failure method.

Outcome measures

Outcome measures
Measure	ATV+COBI+FTC/TDF n=50 Participants Randomized Phase: COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily	ATV+RTV+FTC/TDF n=29 Participants Randomized Phase: RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48	82.0 percentage of participants	89.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the ITT Analysis Set with available change data at Week 24 were analyzed.

The change from baseline in log\_10 HIV-1 RNA at Week 24 was analyzed.

Outcome measures

Outcome measures
Measure	ATV+COBI+FTC/TDF n=46 Participants Randomized Phase: COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily	ATV+RTV+FTC/TDF n=27 Participants Randomized Phase: RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily
Change From Baseline in HIV-1 RNA at Week 24	-2.80 log_10 copies/mL Standard Deviation 0.619	-2.97 log_10 copies/mL Standard Deviation 0.707

SECONDARY outcome

Timeframe: Baseline to Week 48

Population: Participants in the ITT Analysis Set with available change data at Week 48 were analyzed.

The change from baseline in log\_10 HIV-1 RNA at Week 48 was analyzed.

Outcome measures

Outcome measures
Measure	ATV+COBI+FTC/TDF n=46 Participants Randomized Phase: COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily	ATV+RTV+FTC/TDF n=27 Participants Randomized Phase: RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily
Change From Baseline in HIV-1 RNA at Week 48	-2.79 log_10 copies/mL Standard Deviation 0.678	-2.96 log_10 copies/mL Standard Deviation 0.765

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the ITT Analysis Set with available change data at Week 24 were analyzed.

The change from baseline in CD4 cell count at Week 24 was analyzed.

Outcome measures

Outcome measures
Measure	ATV+COBI+FTC/TDF n=46 Participants Randomized Phase: COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily	ATV+RTV+FTC/TDF n=26 Participants Randomized Phase: RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily
Change From Baseline in CD4 Cell Count at Week 24	200 cells/μL Standard Deviation 164.6	202 cells/μL Standard Deviation 115.1

SECONDARY outcome

Timeframe: Baseline to Week 48

Population: Participants in the ITT Analysis Set with available change data at Week 48 were analyzed.

The change from baseline in CD4 cell count at Week 48 was analyzed.

Outcome measures

Outcome measures
Measure	ATV+COBI+FTC/TDF n=46 Participants Randomized Phase: COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily	ATV+RTV+FTC/TDF n=27 Participants Randomized Phase: RTV 100 mg + COBI placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily Open-Label Extension Phase: COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) once daily
Change From Baseline in CD4 Cell Count at Week 48	243 cells/μL Standard Deviation 186.5	213 cells/μL Standard Deviation 168.2

Adverse Events

ATV+COBI+FTC/TDF

Serious events: 2 serious events

Other events: 34 other events

Deaths: 0 deaths

ATV+RTV+FTC/TDF

Serious events: 2 serious events

Other events: 23 other events

Deaths: 0 deaths

All ATV+COBI+FTC/TDF

Serious events: 13 serious events

Other events: 54 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trial Disclosures

Gilead Sciences, Inc.

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: * The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or * The study has been completed at all study sites for at least 2 years
Publication restrictions are in place

Restriction type: OTHER

Measure	ATV+COBI+FTC/TDF n=50 participants at risk For the reporting of Adverse Events, this group includes participants who were randomized to receive COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily in the randomized phase, and were analyzed from Baseline to Week 60.	ATV+RTV+FTC/TDF n=29 participants at risk For the reporting of Adverse Events, this group includes participants who were randomized to receive RTV 100 mg+COBI placebo+ATV 300 mg+FTC 200 mg/TDF 300 mg once daily in the randomized period, and were analyzed from Baseline to Week 60.	All ATV+COBI+FTC/TDF n=69 participants at risk The All ATV+COBI+FTC/TDF Safety Analysis Set included all participants who received at least 1 dose of COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) in the randomized phase or in the open-label extension phase. Adverse event data presented in this group include the following: Adverse events collected from participants who were initially randomized to the double-blind ATV+COBI+FTC/TDF group while they received double-blind ATV+COBI+FTC/TDF during the randomized phase and open-label ATV+COBI+FTC/TDF during the extension phase; adverse events collected from the open-label ATV+COBI+FTC/TDF extension phase only from the participants who were initially randomized to the ATV+RTV+FTC/TDF group during the randomized phase. Adverse event data collected up to Week 286 are presented in this entry.
Cardiac disorders Pericarditis	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
General disorders Accidental death	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Hepatobiliary disorders Hepatitis alcoholic	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Hepatobiliary disorders Jaundice	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Appendicitis	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	3.4% 1/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Cellulitis	2.0% 1/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	2.9% 2/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Meningitis	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Pneumonia	2.0% 1/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	3.4% 1/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Injury, poisoning and procedural complications Laceration	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Injury, poisoning and procedural complications Overdose	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer stage 0	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Nervous system disorders Altered state of consciousness	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Psychiatric disorders Suicide attempt	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Renal and urinary disorders Nephrolithiasis	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Renal and urinary disorders Renal colic	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)

Measure	ATV+COBI+FTC/TDF n=50 participants at risk For the reporting of Adverse Events, this group includes participants who were randomized to receive COBI 150 mg + RTV placebo + ATV 300 mg + FTC/TDF (200/300 mg) once daily in the randomized phase, and were analyzed from Baseline to Week 60.	ATV+RTV+FTC/TDF n=29 participants at risk For the reporting of Adverse Events, this group includes participants who were randomized to receive RTV 100 mg+COBI placebo+ATV 300 mg+FTC 200 mg/TDF 300 mg once daily in the randomized period, and were analyzed from Baseline to Week 60.	All ATV+COBI+FTC/TDF n=69 participants at risk The All ATV+COBI+FTC/TDF Safety Analysis Set included all participants who received at least 1 dose of COBI 150 mg + ATV 300 mg + FTC/TDF (200/300 mg) in the randomized phase or in the open-label extension phase. Adverse event data presented in this group include the following: Adverse events collected from participants who were initially randomized to the double-blind ATV+COBI+FTC/TDF group while they received double-blind ATV+COBI+FTC/TDF during the randomized phase and open-label ATV+COBI+FTC/TDF during the extension phase; adverse events collected from the open-label ATV+COBI+FTC/TDF extension phase only from the participants who were initially randomized to the ATV+RTV+FTC/TDF group during the randomized phase. Adverse event data collected up to Week 286 are presented in this entry.
Eye disorders Ocular icterus	14.0% 7/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	13.8% 4/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	13.0% 9/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Gastrointestinal disorders Abdominal pain	4.0% 2/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	3.4% 1/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	8.7% 6/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Gastrointestinal disorders Diarrhoea	10.0% 5/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	31.0% 9/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	15.9% 11/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Gastrointestinal disorders Flatulence	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Gastrointestinal disorders Haemorrhoids	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Gastrointestinal disorders Nausea	10.0% 5/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	14.5% 10/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
General disorders Chest pain	6.0% 3/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	7.2% 5/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
General disorders Fatigue	8.0% 4/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	17.2% 5/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	11.6% 8/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Hepatobiliary disorders Hyperbilirubinaemia	8.0% 4/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	7.2% 5/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Hepatobiliary disorders Jaundice	4.0% 2/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	2.9% 2/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Acute sinusitis	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Bronchitis	8.0% 4/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	13.8% 4/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	18.8% 13/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Cellulitis	2.0% 1/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	5.8% 4/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Folliculitis	2.0% 1/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	13.8% 4/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	2.9% 2/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Gonorrhoea	2.0% 1/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	3.4% 1/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	7.2% 5/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Influenza	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	7.2% 5/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Nasopharyngitis	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	10.3% 3/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	7.2% 5/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Pharyngitis	4.0% 2/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	3.4% 1/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	5.8% 4/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Sinusitis	10.0% 5/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	10.3% 3/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	15.9% 11/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Syphilis	4.0% 2/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	3.4% 1/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	8.7% 6/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Infections and infestations Upper respiratory tract infection	12.0% 6/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	15.9% 11/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Investigations Weight increased	0.00% 0/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Musculoskeletal and connective tissue disorders Arthralgia	8.0% 4/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	10.1% 7/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Musculoskeletal and connective tissue disorders Back pain	2.0% 1/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	4.3% 3/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Anogenital warts	4.0% 2/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	3.4% 1/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	8.7% 6/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Nervous system disorders Dizziness	4.0% 2/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	10.3% 3/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	7.2% 5/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Nervous system disorders Headache	6.0% 3/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	11.6% 8/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Nervous system disorders Sinus headache	6.0% 3/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	4.3% 3/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Psychiatric disorders Anxiety	6.0% 3/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	10.3% 3/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	11.6% 8/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Psychiatric disorders Depression	10.0% 5/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	13.8% 4/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	13.0% 9/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Psychiatric disorders Insomnia	10.0% 5/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	15.9% 11/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Renal and urinary disorders Nephrolithiasis	6.0% 3/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	7.2% 5/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Reproductive system and breast disorders Erectile dysfunction	8.0% 4/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	7.2% 5/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Respiratory, thoracic and mediastinal disorders Cough	12.0% 6/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	14.5% 10/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	2.0% 1/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	1.4% 1/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Respiratory, thoracic and mediastinal disorders Sinus congestion	6.0% 3/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	7.2% 5/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Skin and subcutaneous tissue disorders Pruritus	6.0% 3/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	0.00% 0/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	5.8% 4/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)
Skin and subcutaneous tissue disorders Rash	2.0% 1/50 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	6.9% 2/29 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)	7.2% 5/69 • Baseline through end of study (average of 169.9 weeks; maximum of 286 weeks)