SPRING-2: A Trial Comparing GSK1349572 50mg Once Daily to Raltegravir 400mg Twice Daily

• Sponsor: ViiV Healthcare (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01227824
• Collaborator: Shionogi (Industry), GlaxoSmithKline (Industry)
• Enrollment: 828
• Locations: 101
• Arms: 2
• Duration (Months): 74.3
• Patients Per Site: 8.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this trial is to assess the non-inferior antiviral activity of GSK1349572 50 mg once daily versus RAL 400mg twice daily over 48 weeks; non-inferiority will also be tested at Week 96. Both GSK1349572 and RAL will be given in combination with fixed-dose dual NRTI therapy (ABC/3TC or TDF/FTC). This study will be conducted in HIV-1 infected ART-naïve adult subjects.

Condition or Disease	Intervention/Treatment	Phase
Infection, Human Immunodeficiency Virus I	Drug: GSK1349572 (dolutegravir); Drug: raltegravir; Other: GSK1349572 Placebo; Other: ABC/3TC; Other: TDF/FTC; Other: raltegravir Placebo	Phase 3

Detailed Description

ING113086 is a Phase 3 randomized, double-blind, double dummy, active-controlled, multicenter, study conducted in approximately 788 HIV-1 infected ART-naïve subjects. Subjects will be randomized 1:1 one of the following treatment arms:

1. GSK1349572 50 mg once daily (approximately 394 subjects) + fixed-dose dual NRTI therapy (either ABC/3TC or TDF/FTC)

OR

1. 400 mg RAL twice daily (approximately 394 subjects) + fixed-dose dual NRTI therapy (either ABC/3TC or TDF/FTC)

Analyses will be conducted at 48 weeks and 96 weeks. Subjects randomized to receive GSK1349572 and who successfully complete 96 weeks of treatment will continue to have access to GSK1349572 through the study until either it is locally available, as long as they continue to derive clinical benefit.

ViiV Healthcare is the new sponsor of this study, and GlaxoSmithKline is in the process of updating systems to reflect the change in sponsorship

Study Design

• Study Type: Interventional
• Actual Enrollment: 828 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double Blind Study of the Safety and Efficacy of GSK1349572 50mg Once Daily to Raltegravir 400mg Twice Daily Both Administered With Fixed-dose Dual Nucleoside Reverse Transcriptase Inhibitor Therapy Over 96 Weeks in HIV-1 Infected Antiretroviral Therapy Naive Adult Subjects
• Study Start Date: Oct 19, 2010
• Actual Primary Completion Date: Feb 6, 2012
• Actual Study Completion Date: Dec 27, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GSK1349572 (N=~394) GSK1349572 50mg once daily + raltegravir placebo twice daily + NRTI background therapy once daily	Drug: GSK1349572 (dolutegravir); GSK1349572 50 mg taken once daily with or without food; Other: GSK1349572 Placebo; GSK1349572 placebo taken once daily; Other: ABC/3TC; Abacavir/Lamivudine background therapy once daily; Other: TDF/FTC; Tenofovir/emtricitabine background therapy once daily
Active Comparator: raltegravir (N=~394) raltegravir 400mg twice daily + GSK1349572 placebo once daily + NRTI background therapy once daily	Drug: raltegravir; raltegravir 400mg taken twice daily; Other: ABC/3TC; Abacavir/Lamivudine background therapy once daily; Other: TDF/FTC; Tenofovir/emtricitabine background therapy once daily; Other: raltegravir Placebo; raltegravir placebo taken twice daily

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) [HIV-1RNA] <50 Copies (c)/Milliliter (mL) Through Week 48 [Baseline up to Week 48]

   Percentage of participants with plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) with <50 c/mL was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) snapshot algorithm. The algorithm treats all participants without HIV-1 RNA data as non-responders, as well as participants who switch their concomitant Antiretroviral Therapy (ART) prior to Week 48 as follows: background ART substitutions not permitted per study; background ART substitutions permitted per study unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure will be determined by the last available HIV-1 RNA assessment while the subject was on-treatment. Intent-to-Treat Exposed (ITT-E) Population comprised all randomized participants who received at least one dose of study medication.

Secondary Outcome Measures

1. Number of Participants With Detectable HIV-1 Virus That Has Genotypic or Phenotypic Evidence of INI Resistance. [Week 48 and Week 96]

   Number of participants with detectable virus that has genotypic or phenotypic evidence of Integrase Inhibitor (INI) resistance were assessed at Week 48 and Week 96. Integrase inhibitors are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the deoxyribonucleic acid (DNA) of the host cell.

2. Number of Participants With Plasma HIV-1 RNA <50 c/mL [Week 96]

   The number of participants with plasma HIV-1 RNA level <50 c/mL was assessed at Week 96.

3. Number of Participants With Plasma HIV-1 RNA <400 c/mL [Week 48 and Week 96]

   The number of participants with plasma HIV-1 RNA level <400 c/mL was assessed at Week 48 and Week 96.

4. Change From Baseline in Plasma HIV-1 RNA Over Time [Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96]

   Change from Baseline in plasma HIV-1 RNA over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Baseline was defined as the measurements performed on Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles).

5. Absolute Values in Plasma HIV-1 RNA Over Time [Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96]

   Absolute values in plasma HIV-1 RNA over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles).

6. Change From Baseline in Cluster of Differentiation (CD)4+ Cell Counts Over Time [Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96]

   CD4 lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immuno compromise. The CD4 count is used to stage the participants disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start ART. Changes from Baseline in CD4+ cell counts over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Baseline was defined as measurements performed on Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles).

7. Absolute Values in CD4+ Cell Counts Over Time [Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96]

   CD4 lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immuno compromise. The CD4 count is used to stage the patient's disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start antiretroviral therapy absolute values in CD4+ cell counts over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles).

8. Number of Participants With the Indicated Post-Baseline HIV-associated Conditions and Progression, Excluding Recurrences [From Baseline until Week 96]

   Clinical disease progression (CDP) was assessed according to the Centers for Disease Control and Prevention (CDC) HIV-1 classification system. Category (CAT) A: one or more of the following conditions (CON), without any CON listed in Categories B and C: asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying illness or history of acute HIV infection. CAT B: symptomatic CON that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or that are considered by physicians to have a clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C: the clinical CON listed in the AIDS surveillance case definition. Indicators of CDP were defined as: CDC CAT A at Baseline to a CDC CAT C event (EV); CDC CAT B at Baseline to a CDC CAT C EV; CDC CAT C at Baseline to a new CDC CAT C EV; or CDC CAT A, B, or C at Baseline to death.

9. Number of Participants With the Indicated Grade 1 to 4 Clinical Chemistry and Hematology Toxicities/Laboratory Adverse Events (AEs) [From Baseline until Week 96]

   All Grade 1 to 4 post-Baseline-emergent chemistry toxicities included alanine aminotransferase (ALT), alkaline phosphatase (ALP), asparate aminotransferase (AST), carbon dioxide (CO2) content/bicarbonate, cholesterol, creatine kinase (CK), creatinine, hyperglycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hyponatremia, low density lipoprotein (LDL) cholesterol calculation, lipase, phosphorus inorganic, total bilirubin, and triglycerides. All Grade 1 to 4 post-Baseline-emergent hematology toxities included hemoglobin, platelet count, total neutrophils, and white blood cell count. The Division of AIDS (DAIDS) defined toxicity grades as follows: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, potentially life threatening; Grade 5, death. Safety Population: all participants who received at least one dose of investigational product

10. Area Under the Plasma Concentration-time Curve From Time Zero to Time Tau [AUC(0-tau)] of DTG [Week 4, Week 24, and Week 48]

    AUC is defined as the area under the DTG concentration-time curve as a measure of drug exposure over time. AUC(0-tau) is defined as the area under the plasma concentration-time curve from time zero to time tau over a dosing interval at steady state, where tau is the length of the dosing interval of DTG. The predicted individual AUC(0-tau) were obtained from the final population PK model by an empirical Bayes estimation. Blood samples for PK assessments were collected at pre-dose (within 15 minutes prior to dose) at Week 4, Week 24, and Week 48 and 1 to 3 hours post-dose or 4 to 12 hours post-dose at Week 4 and Week 24. If 1 to 3 hours post-dose was completed at Week 4, then the 4 to12 hour post-dose must be obtained at Week 48, and vice versa. The Pharmacokinetic (PK) Concentration Population comprised of all participants who received DTG, had undergone PK sampling during the study, and provided evaluable DTG plasma concentration data.

11. Maximum Plasma Concentration (Cmax) and Concentration at the End of a Dosing Interval (Ctau) of DTG [Week 4, Week 24, and Week 48]

    The maximum plasma concentration (Cmax) and concentration at the end of a dosing interval (Ctau) of DTG were assessed at Week 48. The predicted individual Cmax and Ctau were obtained from the final population PK model by simulation of the concentration-time profiles. Blood samples for PK assessments were collected at pre-dose (within 15 minutes prior to dose) at Week 4, Week 24, and Week 48 and 1 to 3 hours post-dose or 4 to 12 hours post-dose at Week 4 and Week 24. If 1 to 3 hour post-dose was completed at Week 4, then the 4 to12 hour post-dose must be obtained at Week 48, and vice versa.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Screening plasma HIV-1 RNA ≥1000 c/mL

• Antiretroviral-naïve (≤ 10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection)

• Ability to understand and sign a written informed consent form

• Willingness to use approved methods of contraception to avoid pregnancy (women of child bearing potential only)

• Age equal to or greater than 18 years

Exclusion Criteria:

• Women who are pregnant or breastfeeding;

• Active Center for Disease and Prevention Control (CDC) Category C disease

• Moderate to severe hepatic impairment

• Anticipated need for HCV therapy during the study

• Allergy or intolerance to the study drugs or their components or drugs of their class

• Malignancy within the past 5 years

• Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening

• Treatment with radiation therapy, cytotoxic chemotherapeutic agents or any immunomodulator within 28 days of Screening

• Exposure to an agent with documented activity against HIV-1 in vitro or an experimental vaccine or drug within 28 days of first dose of study medication

• Primary viral resistance in the Screening result

• Verified Grade 4 laboratory abnormality

• ALT >5 xULN

• ALT ≥ 3xULN and bilirubin ≥ 1.5xULN (with >35% direct bilirubin);

• Estimated creatinine clearance <50 mL/min

• Recent history (≤3 months) of upper or lower gastrointestinal bleed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Phoenix	Arizona	United States	85012
2	GSK Investigational Site	Little Rock	Arkansas	United States	72207
3	GSK Investigational Site	Long Beach	California	United States	90813
4	GSK Investigational Site	Los Angeles	California	United States	90048
5	GSK Investigational Site	Los Angeles	California	United States	90069
6	GSK Investigational Site	Torrance	California	United States	90502
7	GSK Investigational Site	Denver	Colorado	United States	80209
8	GSK Investigational Site	Washington	District of Columbia	United States	20009
9	GSK Investigational Site	Fort Lauderdale	Florida	United States	33316
10	GSK Investigational Site	Fort Pierce	Florida	United States	34982
11	GSK Investigational Site	Atlanta	Georgia	United States	30339
12	GSK Investigational Site	Saint Louis	Missouri	United States	63108
13	GSK Investigational Site	Hillsborough	New Jersey	United States	08844
14	GSK Investigational Site	Charlotte	North Carolina	United States	28209
15	GSK Investigational Site	Columbia	South Carolina	United States	29203
16	GSK Investigational Site	Austin	Texas	United States	78705
17	GSK Investigational Site	Dallas	Texas	United States	75246
18	GSK Investigational Site	Houston	Texas	United States	77004
19	GSK Investigational Site	Houston	Texas	United States	77098
20	GSK Investigational Site	Seattle	Washington	United States	98104
21	GSK Investigational Site	Darlinghurst	New South Wales	Australia	2010
22	GSK Investigational Site	Surry Hills	New South Wales	Australia	2010
23	GSK Investigational Site	Melbourne	Victoria	Australia	3004
24	GSK Investigational Site	Vancouver	British Columbia	Canada	V6Z 1Y6
25	GSK Investigational Site	Hamilton	Ontario	Canada	L8N 3Z5
26	GSK Investigational Site	Ottawa	Ontario	Canada	K1H 8L6
27	GSK Investigational Site	Toronto	Ontario	Canada	M4N 3M5
28	GSK Investigational Site	Toronto	Ontario	Canada	M4T 3A7
29	GSK Investigational Site	Montreal	Quebec	Canada	H2L 5B1
30	GSK Investigational Site	Montreal	Quebec	Canada	H2X 2P4
31	GSK Investigational Site	Garches		France	92380
32	GSK Investigational Site	Le Kremlin Bicêtre cedex		France	94275
33	GSK Investigational Site	Levallois Perret		France	92300
34	GSK Investigational Site	Lyon Cedex 03		France	69437
35	GSK Investigational Site	Marseille		France	13003
36	GSK Investigational Site	Nantes		France	44093
37	GSK Investigational Site	Paris Cedex 10		France	75475
38	GSK Investigational Site	Paris Cedex 12		France	75571
39	GSK Investigational Site	Paris Cedex 13		France	75651
40	GSK Investigational Site	Paris Cedex 4		France	75181
41	GSK Investigational Site	Paris		France	75018
42	GSK Investigational Site	Fuerth	Bayern	Germany	90762
43	GSK Investigational Site	Muenchen	Bayern	Germany	80335
44	GSK Investigational Site	Frankfurt	Hessen	Germany	60596
45	GSK Investigational Site	Hannover	Niedersachsen	Germany	30625
46	GSK Investigational Site	Bonn	Nordrhein-Westfalen	Germany	53127
47	GSK Investigational Site	Dortmund	Nordrhein-Westfalen	Germany	44137
48	GSK Investigational Site	Koeln	Nordrhein-Westfalen	Germany	50937
49	GSK Investigational Site	Berlin		Germany	13353
50	GSK Investigational Site	Hamburg		Germany	20146
51	GSK Investigational Site	Hamburg		Germany	20246
52	GSK Investigational Site	Cona (Ferrara)	Emilia-Romagna	Italy	44124
53	GSK Investigational Site	Roma	Lazio	Italy	00168
54	GSK Investigational Site	Genova	Liguria	Italy	16128
55	GSK Investigational Site	Brescia	Lombardia	Italy	25123
56	GSK Investigational Site	Torino	Piemonte	Italy	10149
57	GSK Investigational Site	Rovigo	Veneto	Italy	45100
58	GSK Investigational Site	Krasnodar		Russian Federation	350015
59	GSK Investigational Site	Lipetsk		Russian Federation	398043
60	GSK Investigational Site	Moscow		Russian Federation	105275
61	GSK Investigational Site	N.Novgorod		Russian Federation	603005
62	GSK Investigational Site	Orel		Russian Federation	302040
63	GSK Investigational Site	Perm		Russian Federation	614088
64	GSK Investigational Site	Saratov		Russian Federation	410009
65	GSK Investigational Site	Smolensk		Russian Federation	214006
66	GSK Investigational Site	St. Petersburg		Russian Federation	190103
67	GSK Investigational Site	St. Petersburg		Russian Federation	196645
68	GSK Investigational Site	Volgograd		Russian Federation	400040
69	GSK Investigational Site	(Móstoles) Madrid		Spain	28935
70	GSK Investigational Site	Alcala de Henares		Spain	28805
71	GSK Investigational Site	Alicante		Spain	03010
72	GSK Investigational Site	Almería		Spain	04009
73	GSK Investigational Site	Badalona		Spain	08916
74	GSK Investigational Site	Barcelona		Spain	08003
75	GSK Investigational Site	Barcelona		Spain	08025
76	GSK Investigational Site	Barcelona		Spain	08036
77	GSK Investigational Site	Barcelona		Spain	08907
78	GSK Investigational Site	Cartagena (Murcia)		Spain	30202
79	GSK Investigational Site	Córdoba		Spain	14004
80	GSK Investigational Site	Granada		Spain	18014
81	GSK Investigational Site	Granada		Spain
82	GSK Investigational Site	La Coruña		Spain	15006
83	GSK Investigational Site	La Laguna (Santa Cruz De Tenerife)		Spain	38320
84	GSK Investigational Site	Madrid		Spain	28006
85	GSK Investigational Site	Madrid		Spain	28029
86	GSK Investigational Site	Madrid		Spain	28034
87	GSK Investigational Site	Madrid		Spain	28040
88	GSK Investigational Site	Madrid		Spain	28041
89	GSK Investigational Site	Madrid		Spain	28046
90	GSK Investigational Site	Malaga		Spain	29010
91	GSK Investigational Site	Mataró		Spain	08304
92	GSK Investigational Site	Murcia		Spain
93	GSK Investigational Site	San Sebastián		Spain	20014
94	GSK Investigational Site	Sevilla		Spain	41071
95	GSK Investigational Site	Valencia		Spain	46010
96	GSK Investigational Site	Vigo ( Pontevedra)		Spain	36204
97	GSK Investigational Site	Birmingham	Warwickshire	United Kingdom	B29 6JD
98	GSK Investigational Site	Brighton		United Kingdom	BN2 1ES
99	GSK Investigational Site	Crumpsall, Manchester		United Kingdom	M8 5RB
100	GSK Investigational Site	London		United Kingdom	E1 1BB
101	GSK Investigational Site	London		United Kingdom	SW10 9TH

Sponsors and Collaborators

• ViiV Healthcare
• Shionogi
• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, ViiV Healthcare

Study Documents (Full-Text)

None provided.

More Information

Publications

• Brinson C, Walmsley S, Arasteh K, et al. Dolutegravir treatment response and safety by key subgroups in treatment naive HIV-infected individuals. Published at: Conference on Retroviruses and Opportunistic Infections - 20th Annual; March 3-6, 2013; Atlanta, GA.
• Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, Bloch M, Podzamczer D, Pokrovsky V, Pulido F, Almond S, Margolis D, Brennan C, Min S; SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013 Mar 2;381(9868):735-43. doi: 10.1016/S0140-6736(12)61853-4. Epub 2013 Jan 8.

• Responsible Party: ViiV Healthcare
• ClinicalTrials.gov Identifier: NCT01227824
• Other Study ID Numbers: 113086
• First Posted: Oct 25, 2010
• Last Update Posted: Oct 9, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by ViiV Healthcare: integrase inhibitor; HIV Infection; raltegravir; GSK1349572
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Raltegravir Potassium; Dolutegravir

Study Results

Participant Flow

Recruitment Details	This was a randomized, parallel group, non-inferiority study to demonstrate the antiviral activity of Dolutegravir. Participants were enrolled from 9 countries. Participants in Dolutegravir arm who completed 96 Weeks double-blind phase continued to receive Dolutegravir in open-label phase, until dolutegravir was locally available commercially.
Pre-assignment Detail	Total 1035 participants were screened; 827 participants were randomized, and 822 participants entered the treatment period. Of the 5 participants who were randomized but not treated with investigational product, 4 withdrew consent and 1 was randomized in error. 338 participants were enrolled in open label phase to receive Dolutegravir.

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID	DTG 50 mg Once a Day (Open-label)
Arm/Group Description	Participants received Dolutegravir (DTG) 50 milligrams (mg) once a day in combination with Nonnucleoside Reverse Transcriptase Inhibitor (NRTI) therapy, either with Abacavir (ABC)/Lamivudine (3TC) or Tenofovir (TDF)/Emtricitabine (FTC). Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received Raltegravir (RTG) 400 mg twice a day (BID) in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.	Participants who successfully completed 96 weeks of double blind phase continued to receive DTG 50 mg once a day during open label phase, until dolutegravir was locally available commercially. Participants received DTG 50 mg once a day in combination with NRTI therapy, with either ABC/3TC or TDF/FTC.
Period Title: Double-blind Phase: 96 Weeks Duration
STARTED	411	411	0
COMPLETED	304	332	0
NOT COMPLETED	107	79	0
Period Title: Double-blind Phase: 96 Weeks Duration
STARTED	0	0	338
COMPLETED	0	0	294
NOT COMPLETED	0	0	44

Baseline Characteristics

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID	Total
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF)/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.	Total of all reporting groups
Overall Participants	411	411	822
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	37.3 (9.19)	36.6 (10.02)	37.0 (9.61)
Sex: Female, Male (Count of Participants)
Female	63 15.3%	56 13.6%	119 14.5%
Male	348 84.7%	355 86.4%	703 85.5%
Race/Ethnicity, Customized (Count of Participants)
African American/African Heritage (Her)	49 11.9%	39 9.5%	88 10.7%
American Indian or Alaska Native	7 1.7%	9 2.2%	16 1.9%
Central/South Asian Her	2 0.5%	0 0%	2 0.2%
Japanese/East Asian Her/South East Asian Her	4 1%	10 2.4%	14 1.7%
Native Hawaiian or other Pacific Islander	2 0.5%	0 0%	2 0.2%
White	346 84.2%	352 85.6%	698 84.9%
African American/African Her and Asian and White	1 0.2%	0 0%	1 0.1%
Asian and White	0 0%	1 0.2%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) [HIV-1RNA] <50 Copies (c)/Milliliter (mL) Through Week 48
Description	Percentage of participants with plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) with <50 c/mL was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) snapshot algorithm. The algorithm treats all participants without HIV-1 RNA data as non-responders, as well as participants who switch their concomitant Antiretroviral Therapy (ART) prior to Week 48 as follows: background ART substitutions not permitted per study; background ART substitutions permitted per study unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure will be determined by the last available HIV-1 RNA assessment while the subject was on-treatment. Intent-to-Treat Exposed (ITT-E) Population comprised all randomized participants who received at least one dose of study medication.
Time Frame	Baseline up to Week 48

Outcome Measure Data

Analysis Population Description

ITT-E Population.

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	411	411
Number [Percentage of participants]	88 21.4%	85 20.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DTG 50 mg Once a Day, RTG 400 mg BID
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority could be concluded if the lower bound of a two-sided 95% confidence interval for the difference (DTG - RAL) in percentages between the two treatment arms was > -10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; -2.2 to 7.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was based on Cochran-Mantel Haenszel stratified analysis adjusted for the following Baseline stratification factors: baseline HIV-1 RNA and background dual NRTI.

2. Secondary Outcome

Title	Number of Participants With Detectable HIV-1 Virus That Has Genotypic or Phenotypic Evidence of INI Resistance.
Description	Number of participants with detectable virus that has genotypic or phenotypic evidence of Integrase Inhibitor (INI) resistance were assessed at Week 48 and Week 96. Integrase inhibitors are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the deoxyribonucleic acid (DNA) of the host cell.
Time Frame	Week 48 and Week 96

Outcome Measure Data

Analysis Population Description

ITT-E Population

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	411	411
Week 48, genotypic	0 0%	1 0.2%
Week 48, phenotypic	1 0.2%	2 0.5%
Week 96, genotypic	0 0%	1 0.2%
Week 96, phenotypic	1 0.2%	2 0.5%

3. Secondary Outcome

Title	Number of Participants With Plasma HIV-1 RNA <50 c/mL
Description	The number of participants with plasma HIV-1 RNA level <50 c/mL was assessed at Week 96.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

ITT-E Population

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	411	411
Number [Participants]	332 80.8%	314 76.4%

4. Secondary Outcome

Title	Number of Participants With Plasma HIV-1 RNA <400 c/mL
Description	The number of participants with plasma HIV-1 RNA level <400 c/mL was assessed at Week 48 and Week 96.
Time Frame	Week 48 and Week 96

Outcome Measure Data

Analysis Population Description

ITT-E Population

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	411	411
Week 48	369 89.8%	356 86.6%
Week 96	338 82.2%	321 78.1%

5. Secondary Outcome

Title	Change From Baseline in Plasma HIV-1 RNA Over Time
Description	Change from Baseline in plasma HIV-1 RNA over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Baseline was defined as the measurements performed on Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles).
Time Frame	Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96

Outcome Measure Data

Analysis Population Description

ITT-E Population.

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	411	411
Baseline n=411, 411	4.538 (0.7258)	4.599 (0.7048)
Week 4, n=402, 406	-2.817 (0.6198)	-2.801 (0.6041)
Week 8, n=397, 402	-2.897 (0.6837)	-2.886 (0.6754)
Week 12, n=396, 395	-2.908 (0.6863)	-2.918 (0.6834)
Week 16, n=395, 388	-2.917 (0.6949)	-2.943 (0.6841)
Week 24, n=393, 390	-2.896 (0.7889)	-2.933 (0.7398)
Week 32, n=386, 377	-2.907 (0.7609)	-2.947 (0.7613)
Week 40, n=375, 358	-2.920 (0.7219)	-2.946 (0.6700)
Week 48, n=374, 358	-2.915 (0.7237)	-2.942 (0.6737)
Week 60, n=366, 355	-2.912 (0.7344)	-2.937 (0.6685)
Week 72, n=361, 350	-2.917 (0.7261)	-2.932 (0.6728)
Week 84, n=352, 338	-2.932 (0.7073)	-2.916 (0.6646)
Week 96, n=342, 329	-2.938 (0.7004)	-2.901 (0.7072)

6. Secondary Outcome

Title	Absolute Values in Plasma HIV-1 RNA Over Time
Description	Absolute values in plasma HIV-1 RNA over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles).
Time Frame	Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96

Outcome Measure Data

Analysis Population Description

ITT-E Population.

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	411	411
Baseline n=411, 411	4.538 (0.7258)	4.599 (0.7048)
Week 4, n=402, 406	1.718 (0.2593)	1.800 (0.4095)
Week 8, n=397, 402	1.646 (0.2006)	1.709 (0.3791)
Week 12, n=396, 395	1.626 (0.1323)	1.672 (0.3125)
Week 16, n=395, 388	1.620 (0.1252)	1.648 (0.2647)
Week 24, n=393, 390	1.643 (0.2950)	1.655 (0.3476)
Week 32, n=386, 377	1.620 (0.1917)	1.636 (0.2721)
Week 40, n=375, 358	1.603 (0.0821)	1.601 (0.0784)
Week 48, n=374, 358	1.606 (0.0866)	1.599 (0.0582)
Week 60, n=366, 355	1.605 (0.1134)	1.599 (0.0560)
Week 72, n=361, 350	1.601 (0.0803)	1.605 (0.0836)
Week 84, n=352, 338	1.607 (0.1337)	1.614 (0.1279)
Week 96, n=342, 329	1.599 (0.830)	1.630 (0.2515)

7. Secondary Outcome

Title	Change From Baseline in Cluster of Differentiation (CD)4+ Cell Counts Over Time
Description	CD4 lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immuno compromise. The CD4 count is used to stage the participants disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start ART. Changes from Baseline in CD4+ cell counts over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Baseline was defined as measurements performed on Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles).
Time Frame	Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96

Outcome Measure Data

Analysis Population Description

ITT-E Population.

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	411	411
Baseline n=411, 411	379.2 (178.32)	374.3 (163.37)
Week 4, n=398, 403	93.3 (116.27)	97.2 (129.35)
Week 8, n=398, 402	121.6 (127.97)	126.6 (134.59)
Week 12, n=392, 397	130.7 (131.49)	145.1 (144.08)
Week 16, n=394, 392	155.1 (137.23)	173.0 (159.10)
Week 24, n=392, 389	199.3 (161.23)	204.2 (162.28)
Week 32, n=384, 375	223.4 (165.30)	241.3 (167.64)
Week 40, n=371, 357	224.1 (173.59)	239.8 (173.33)
Week 48, n=374, 357	238.9 (171.81)	257.5 (178.69)
Week 60, n=367, 355	247.8 (184.11)	264.2 (188.63)
Week 72, n=360, 350	247.8 (168.37)	278.6 (182.76)
Week 84, n=351, 338	281.3 (175.07)	292.9 (199.42)
Week 96, n=343, 328	292.2 (195.70)	286.2 (192.45)

8. Secondary Outcome

Title	Absolute Values in CD4+ Cell Counts Over Time
Description	CD4 lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immuno compromise. The CD4 count is used to stage the patient's disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start antiretroviral therapy absolute values in CD4+ cell counts over time was assessed at Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96. Only those participants with data available at the specified time points were analyzed (represented by n=x,x in the category titles).
Time Frame	Baseline and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96

Outcome Measure Data

Analysis Population Description

ITT-E Population.

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	411	411
Baseline n=411, 411	379.2 (172.32)	374.3 (163.37)
Week 4, n=398, 403	474.2 (199.06)	471.8 (191.02)
Week 8, n=398, 402	502.3 (205.15)	502.4 (187.99)
Week 12, n=392, 397	513.3 (218.75)	518.3 (195.59)
Week 16, n=394, 392	536.4 (219.47)	550.1 (221.77)
Week 24, n=392, 389	582.0 (232.93)	580.8 (218.76)
Week 32, n=384, 375	606.5 (242.95)	618.7 (237.56)
Week 40, n=371, 357	609.1 (239.11)	623.1 (234.82)
Week 48, n=374, 357	623.8 (247.82)	641.2 (241.75)
Week 60, n=367, 355	635.6 (241.27)	648.5 (238.99)
Week 72, n=360, 350	635.2 (237.78)	664.0 (239.86)
Week 84, n=351, 338	668.0 (246.50)	677.5 (249.64)
Week 96, n=343, 328	679.8 (257.89)	672.4 (237.54)

9. Secondary Outcome

Title	Number of Participants With the Indicated Post-Baseline HIV-associated Conditions and Progression, Excluding Recurrences
Description	Clinical disease progression (CDP) was assessed according to the Centers for Disease Control and Prevention (CDC) HIV-1 classification system. Category (CAT) A: one or more of the following conditions (CON), without any CON listed in Categories B and C: asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying illness or history of acute HIV infection. CAT B: symptomatic CON that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or that are considered by physicians to have a clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C: the clinical CON listed in the AIDS surveillance case definition. Indicators of CDP were defined as: CDC CAT A at Baseline to a CDC CAT C event (EV); CDC CAT B at Baseline to a CDC CAT C EV; CDC CAT C at Baseline to a new CDC CAT C EV; or CDC CAT A, B, or C at Baseline to death.
Time Frame	From Baseline until Week 96

Outcome Measure Data

Analysis Population Description

ITT-E Population

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	411	411
Any category condition	10 2.4%	8 1.9%
Any Category B condition	3 0.7%	3 0.7%
Any Category C condition	6 1.5%	4 1%
Any death	1 0.2%	1 0.2%
Progression from CAT A to CAT C	4 1%	2 0.5%
Progression from CAT B to CAT C	3 0.7%	1 0.2%
Progression from CAT C to new CAT C	0 0%	1 0.2%
Progression from CAT A, B, or C to death	1 0.2%	1 0.2%

10. Secondary Outcome

Title	Number of Participants With the Indicated Grade 1 to 4 Clinical Chemistry and Hematology Toxicities/Laboratory Adverse Events (AEs)
Description	All Grade 1 to 4 post-Baseline-emergent chemistry toxicities included alanine aminotransferase (ALT), alkaline phosphatase (ALP), asparate aminotransferase (AST), carbon dioxide (CO2) content/bicarbonate, cholesterol, creatine kinase (CK), creatinine, hyperglycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hyponatremia, low density lipoprotein (LDL) cholesterol calculation, lipase, phosphorus inorganic, total bilirubin, and triglycerides. All Grade 1 to 4 post-Baseline-emergent hematology toxities included hemoglobin, platelet count, total neutrophils, and white blood cell count. The Division of AIDS (DAIDS) defined toxicity grades as follows: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, potentially life threatening; Grade 5, death. Safety Population: all participants who received at least one dose of investigational product
Time Frame	From Baseline until Week 96

Outcome Measure Data

Analysis Population Description

Safety Population.

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	411	411
ALT	57 13.9%	70 17%
ALP	7 1.7%	15 3.6%
AST	67 16.3%	75 18.2%
CO2 content/bicarbonate	58 14.1%	67 16.3%
Cholesterol	90 21.9%	73 17.8%
CK	61 14.8%	47 11.4%
Creatinine	11 2.7%	7 1.7%
Hyperglycaemia	70 17%	87 21.2%
Hyperkalemia	7 1.7%	4 1%
Hypernatremia	4 1%	6 1.5%
Hypoglycaemia	17 4.1%	27 6.6%
Hypokalemia	10 2.4%	15 3.6%
Hyponatremia	34 8.3%	48 11.7%
LDL cholesterol calculation	74 18%	49 11.9%
Lipase	55 13.4%	62 15.1%
Phosphorus, inorganic	65 15.8%	71 17.3%
Total bilirubin	27 6.6%	24 5.8%
Triglycerides	7 1.7%	8 1.9%
Hemoglobin	10 2.4%	5 1.2%
Platelet count	19 4.6%	19 4.6%
Total neutrophils	54 13.1%	48 11.7%
White Blood Cell count	19 4.6%	7 1.7%

11. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to Time Tau [AUC(0-tau)] of DTG
Description	AUC is defined as the area under the DTG concentration-time curve as a measure of drug exposure over time. AUC(0-tau) is defined as the area under the plasma concentration-time curve from time zero to time tau over a dosing interval at steady state, where tau is the length of the dosing interval of DTG. The predicted individual AUC(0-tau) were obtained from the final population PK model by an empirical Bayes estimation. Blood samples for PK assessments were collected at pre-dose (within 15 minutes prior to dose) at Week 4, Week 24, and Week 48 and 1 to 3 hours post-dose or 4 to 12 hours post-dose at Week 4 and Week 24. If 1 to 3 hours post-dose was completed at Week 4, then the 4 to12 hour post-dose must be obtained at Week 48, and vice versa. The Pharmacokinetic (PK) Concentration Population comprised of all participants who received DTG, had undergone PK sampling during the study, and provided evaluable DTG plasma concentration data.
Time Frame	Week 4, Week 24, and Week 48

Outcome Measure Data

Analysis Population Description

PK Concentration Population

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	403	0
Geometric Mean (Geometric Coefficient of Variation) [Micrograms*hour per milliliter(µg*hr/mL)]	53.6 (26.8)

12. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) and Concentration at the End of a Dosing Interval (Ctau) of DTG
Description	The maximum plasma concentration (Cmax) and concentration at the end of a dosing interval (Ctau) of DTG were assessed at Week 48. The predicted individual Cmax and Ctau were obtained from the final population PK model by simulation of the concentration-time profiles. Blood samples for PK assessments were collected at pre-dose (within 15 minutes prior to dose) at Week 4, Week 24, and Week 48 and 1 to 3 hours post-dose or 4 to 12 hours post-dose at Week 4 and Week 24. If 1 to 3 hour post-dose was completed at Week 4, then the 4 to12 hour post-dose must be obtained at Week 48, and vice versa.
Time Frame	Week 4, Week 24, and Week 48

Outcome Measure Data

Analysis Population Description

PK Concentration Population.

Arm/Group Title	DTG 50 mg Once a Day	RTG 400 mg BID
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.	Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.
Measure Participants	403	0
Cmax	3.69 (19.6)
Ctau	1.10 (46.5)

Adverse Events

Time Frame	Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the study (up to a median of 1267 days).
Adverse Event Reporting Description	AEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Arm/Group Title	DTG 50 mg Once a Day		RTG 400mg BID		DTG 50 mg Once a Day (Open-label)
Arm/Group Description	Participants received DTG 50 mg once a day in combination with NRTI therapy, either with ABC/3TC or TDF/FTC. Participants were given the opportunity to receive DTG 50 mg once a day during an Open-label Phase of the study.		Participants received RTG 400 mg BID in combination with NRTI therapy, either with ABC/3TC or TDF/FTC.		Participants who successfully completed 96 weeks of double blind phase continued to receive DTG 50 mg once a day during open label phase, until DTG was locally available commercially. Participants received DTG 50 mg once a day in combination with NRTI therapy, with either ABC/3TC or TDF/FTC.
All Cause Mortality
	DTG 50 mg Once a Day		RTG 400mg BID		DTG 50 mg Once a Day (Open-label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/411 (0.2%)		1/411 (0.2%)		0/338 (0%)
Serious Adverse Events
	DTG 50 mg Once a Day		RTG 400mg BID		DTG 50 mg Once a Day (Open-label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/411 (10%)		45/411 (10.9%)		21/338 (6.2%)
Blood and lymphatic system disorders
Anaemia	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Lymphadenopathy	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Cardiac disorders
Arrhythmia	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Ear and labyrinth disorders
Vertigo	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Gastrointestinal disorders
Anal fissure	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Anal fistula	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Abdominal pain lower	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Anal inflammation	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Diarrhoea	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Inguinal hernia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Irritable bowel syndrome	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Pancreatic pseudocyst	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Peptic ulcer	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Proctitis ulcerative	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
General disorders
Chest pain	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Polyserositis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Pyrexia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Hepatobiliary disorders
Hepatitis	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Cholecystitis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Hepatotoxicity	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Portal vein thrombosis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Immune system disorders
Drug hypersensitivity	3/411 (0.7%)	3	0/411 (0%)	0	1/338 (0.3%)	1
Hypersensitivity	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Immune reconstitution inflammatory syndrome	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Infections and infestations
Appendicitis	2/411 (0.5%)	2	5/411 (1.2%)	5	1/338 (0.3%)	1
Pneumonia	0/411 (0%)	0	2/411 (0.5%)	2	1/338 (0.3%)	1
Anal abscess	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Arthritis bacterial	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Cellulitis	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Gastroenteritis	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Peritonsillar abscess	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Pneumonia bacterial	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Subcutaneous abscess	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Syphilis	0/411 (0%)	0	0/411 (0%)	0	2/338 (0.6%)	2
Abscess	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Acute hepatitis C	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Atypical mycobacterial infection	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Bacteraemia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Corneal abscess	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Encephalitis viral	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Gastroenteritis bacterial	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Gastrointestinal infection	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Influenza	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Lung infection	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Lymphadenitis viral	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Meningitis tuberculous	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Neurosyphilis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Osteomyelitis chronic	1/411 (0.2%)	2	0/411 (0%)	0	0/338 (0%)	0
Pneumocystis jirovecii pneumonia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Pneumonia cytomegaloviral	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Rhinitis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Secondary syphilis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Sepsis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Staphylococcal infection	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Urinary tract infection	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Viral infection	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Injury, poisoning and procedural complications
Laceration	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Rib fracture	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Alcohol poisoning	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Intentional overdose	0/411 (0%)	0	1/411 (0.2%)	2	0/338 (0%)	0
Lower limb fracture	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Multiple fractures	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Penis injury	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Post procedural haemorrhage	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Tibia fracture	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Toxicity to various agents	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Upper limb fracture	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Investigations
Blood creatine phosphokinase increased	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Musculoskeletal and connective tissue disorders
Arthritis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Back pain	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Costochondritis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Osteoarthritis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Anogenital warts	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Breast cancer	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Malignant melanoma	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Metastatic malignant melanoma	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Papilloma	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Transitional cell carcinoma	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Nervous system disorders
Seizure	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Aphasia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Cerebrovascular accident	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Cognitive disorder	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Sciatica	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Status epilepticus	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Psychiatric disorders
Suicide attempt	2/411 (0.5%)	2	3/411 (0.7%)	4	1/338 (0.3%)	1
Suicidal ideation	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Completed suicide	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Depression	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Renal and urinary disorders
Nephrolithiasis	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	2
Renal colic	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Renal impairment	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Reproductive system and breast disorders
Cervical dysplasia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Erectile dysfunction	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Menorrhagia	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Pneumonia aspiration	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Pneumothorax	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Social circumstances
Homicide	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Surgical and medical procedures
Keratoplasty	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Vascular disorders
Thrombosis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Other (Not Including Serious) Adverse Events
	DTG 50 mg Once a Day		RTG 400mg BID		DTG 50 mg Once a Day (Open-label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	353/411 (85.9%)		344/411 (83.7%)		256/338 (75.7%)
Blood and lymphatic system disorders
Lymphadenopathy	9/411 (2.2%)	13	4/411 (1%)	4	3/338 (0.9%)	4
Anaemia	0/411 (0%)	0	4/411 (1%)	4	0/338 (0%)	0
Iron deficiency anaemia	1/411 (0.2%)	1	2/411 (0.5%)	2	1/338 (0.3%)	1
Neutropenia	1/411 (0.2%)	2	2/411 (0.5%)	2	0/338 (0%)	0
Lymphadenitis	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Eosinophilia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Granulocytopenia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Leukopenia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Polycythaemia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Red blood cell abnormality	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Thrombocytopenia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Thymus disorder	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Cardiac disorders
Angina pectoris	1/411 (0.2%)	1	4/411 (1%)	4	1/338 (0.3%)	1
Palpitations	1/411 (0.2%)	1	2/411 (0.5%)	2	1/338 (0.3%)	1
Tachycardia	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Cardiomyopathy	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Myocarditis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Ventricular hypokinesia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Congenital, familial and genetic disorders
Hereditary non-polyposis colorectal cancer syndrome	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Ichthyosis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Kidney duplex	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Odontogenic cyst	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Ear and labyrinth disorders
Vertigo	6/411 (1.5%)	6	5/411 (1.2%)	5	1/338 (0.3%)	1
Tinnitus	5/411 (1.2%)	5	4/411 (1%)	5	0/338 (0%)	0
Ear pain	1/411 (0.2%)	1	0/411 (0%)	0	2/338 (0.6%)	2
Hypoacusis	2/411 (0.5%)	2	0/411 (0%)	0	1/338 (0.3%)	1
Deafness	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Ear disorder	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Eustachian tube obstruction	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Excessive cerumen production	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
External ear inflammation	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
External ear pain	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Middle ear effusion	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Tympanic membrane disorder	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Endocrine disorders
Hypothyroidism	1/411 (0.2%)	1	1/411 (0.2%)	1	1/338 (0.3%)	1
Goitre	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Androgen deficiency	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Basedow's disease	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Hyperthyroidism	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Hypogonadism	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Thyroid mass	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Eye disorders
Vision blurred	2/411 (0.5%)	2	5/411 (1.2%)	5	0/338 (0%)	0
Conjunctivitis allergic	1/411 (0.2%)	1	2/411 (0.5%)	2	1/338 (0.3%)	1
Ocular hyperaemia	3/411 (0.7%)	3	0/411 (0%)	0	0/338 (0%)	0
Visual acuity reduced	1/411 (0.2%)	1	1/411 (0.2%)	1	1/338 (0.3%)	1
Chalazion	0/411 (0%)	0	0/411 (0%)	0	2/338 (0.6%)	2
Conjunctival haemorrhage	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Conjunctival hyperaemia	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Dry eye	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Eye pruritus	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Blepharitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Cataract	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Corneal erosion	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Diplopia	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Eye inflammation	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Eye pain	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Eyelids pruritus	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Hypermetropia	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Keratitis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Ocular discomfort	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Photophobia	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Retinal haemorrhage	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Retinal tear	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Scleritis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Gastrointestinal disorders
Diarrhoea	58/411 (14.1%)	72	54/411 (13.1%)	65	21/338 (6.2%)	25
Nausea	60/411 (14.6%)	70	55/411 (13.4%)	66	3/338 (0.9%)	3
Abdominal pain	18/411 (4.4%)	21	16/411 (3.9%)	20	7/338 (2.1%)	7
Vomiting	16/411 (3.9%)	21	18/411 (4.4%)	19	5/338 (1.5%)	7
Constipation	15/411 (3.6%)	16	14/411 (3.4%)	17	1/338 (0.3%)	1
Abdominal pain upper	12/411 (2.9%)	13	12/411 (2.9%)	14	5/338 (1.5%)	5
Haemorrhoids	15/411 (3.6%)	15	9/411 (2.2%)	9	5/338 (1.5%)	6
Flatulence	12/411 (2.9%)	12	11/411 (2.7%)	11	1/338 (0.3%)	1
Dyspepsia	6/411 (1.5%)	6	11/411 (2.7%)	11	2/338 (0.6%)	3
Toothache	9/411 (2.2%)	10	3/411 (0.7%)	3	6/338 (1.8%)	6
Gastrooesophageal reflux disease	4/411 (1%)	4	12/411 (2.9%)	12	1/338 (0.3%)	1
Abdominal distension	6/411 (1.5%)	6	6/411 (1.5%)	7	4/338 (1.2%)	5
Proctitis	5/411 (1.2%)	5	5/411 (1.2%)	6	4/338 (1.2%)	4
Anogenital dysplasia	3/411 (0.7%)	3	4/411 (1%)	4	5/338 (1.5%)	5
Abdominal discomfort	10/411 (2.4%)	11	1/411 (0.2%)	1	0/338 (0%)	0
Anal fissure	3/411 (0.7%)	3	6/411 (1.5%)	6	2/338 (0.6%)	2
Gastritis	4/411 (1%)	4	1/411 (0.2%)	1	5/338 (1.5%)	5
Aphthous ulcer	3/411 (0.7%)	3	4/411 (1%)	6	2/338 (0.6%)	2
Odynophagia	3/411 (0.7%)	3	4/411 (1%)	4	1/338 (0.3%)	1
Rectal haemorrhage	2/411 (0.5%)	2	3/411 (0.7%)	3	2/338 (0.6%)	2
Dental caries	3/411 (0.7%)	3	3/411 (0.7%)	3	0/338 (0%)	0
Abdominal pain lower	1/411 (0.2%)	1	3/411 (0.7%)	3	1/338 (0.3%)	1
Enteritis	1/411 (0.2%)	1	2/411 (0.5%)	2	2/338 (0.6%)	2
Inguinal hernia	2/411 (0.5%)	2	2/411 (0.5%)	2	1/338 (0.3%)	1
Anal fistula	2/411 (0.5%)	2	1/411 (0.2%)	1	1/338 (0.3%)	1
Colitis	2/411 (0.5%)	2	0/411 (0%)	0	2/338 (0.6%)	2
Gastrointestinal disorder	1/411 (0.2%)	1	3/411 (0.7%)	3	0/338 (0%)	0
Hiatus hernia	0/411 (0%)	0	3/411 (0.7%)	3	1/338 (0.3%)	1
Proctalgia	2/411 (0.5%)	3	2/411 (0.5%)	2	0/338 (0%)	0
Anal haemorrhage	2/411 (0.5%)	2	1/411 (0.2%)	1	0/338 (0%)	0
Anal pruritus	3/411 (0.7%)	3	0/411 (0%)	0	0/338 (0%)	0
Dry mouth	1/411 (0.2%)	1	1/411 (0.2%)	1	1/338 (0.3%)	1
Mouth ulceration	2/411 (0.5%)	2	1/411 (0.2%)	1	0/338 (0%)	0
Oesophagitis	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Abdominal tenderness	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Abnormal faeces	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Anal ulcer	1/411 (0.2%)	2	1/411 (0.2%)	1	0/338 (0%)	0
Anorectal discomfort	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Cheilitis	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Dysphagia	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Food poisoning	0/411 (0%)	0	0/411 (0%)	0	2/338 (0.6%)	2
Gastrointestinal pain	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Haematochezia	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Haemorrhoidal haemorrhage	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Oesophageal spasm	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Oral disorder	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Abdominal rigidity	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Anal skin tags	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Anal spasm	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Anorectal disorder	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Chronic gastritis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Diverticulum	0/411 (0%)	0	1/411 (0.2%)	3	0/338 (0%)	0
Epigastric discomfort	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Erosive duodenitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Faeces pale	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Gastric ulcer	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Gastrointestinal haemorrhage	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Gingival hypertrophy	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Gingival pain	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Gingival swelling	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Haemorrhoids thrombosed	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Hyperchlorhydria	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Irritable bowel syndrome	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Large intestine polyp	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Lip haematoma	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Lip swelling	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Loose tooth	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Mouth cyst	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Oesophageal pain	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Oral pain	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Palatal disorder	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Palatal ulcer	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Pancreatitis acute	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	2
Paraesthesia oral	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Periodontal disease	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Rectal discharge	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Rectal fissure	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Saliva altered	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Salivary hypersecretion	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Stomatitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Tongue disorder	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Tooth disorder	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Tooth impacted	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Ulcerative gastritis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
General disorders
Fatigue	22/411 (5.4%)	26	24/411 (5.8%)	27	7/338 (2.1%)	7
Pyrexia	23/411 (5.6%)	30	24/411 (5.8%)	26	6/338 (1.8%)	7
Asthenia	14/411 (3.4%)	16	18/411 (4.4%)	19	7/338 (2.1%)	7
Influenza like illness	13/411 (3.2%)	15	9/411 (2.2%)	11	7/338 (2.1%)	8
Chest pain	5/411 (1.2%)	5	2/411 (0.5%)	2	3/338 (0.9%)	3
Feeling abnormal	2/411 (0.5%)	3	2/411 (0.5%)	2	0/338 (0%)	0
Malaise	3/411 (0.7%)	3	1/411 (0.2%)	1	0/338 (0%)	0
Local swelling	3/411 (0.7%)	3	0/411 (0%)	0	0/338 (0%)	0
Oedema peripheral	2/411 (0.5%)	2	1/411 (0.2%)	1	0/338 (0%)	0
Pain	0/411 (0%)	0	3/411 (0.7%)	3	0/338 (0%)	0
Peripheral swelling	0/411 (0%)	0	2/411 (0.5%)	2	1/338 (0.3%)	1
Chest discomfort	1/411 (0.2%)	1	1/411 (0.2%)	3	0/338 (0%)	0
Cyst	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Granuloma	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Ill-defined disorder	0/411 (0%)	0	0/411 (0%)	0	2/338 (0.6%)	2
Inflammation	0/411 (0%)	0	0/411 (0%)	0	2/338 (0.6%)	2
Mucosal dryness	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Nodule	0/411 (0%)	0	0/411 (0%)	0	2/338 (0.6%)	2
Suprapubic pain	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Axillary pain	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Chills	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Discomfort	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Facial pain	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Feeling cold	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Mucosal inflammation	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Non-cardiac chest pain	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Oedema mucosal	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Polyp	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Swelling	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Hepatobiliary disorders
Hepatic steatosis	2/411 (0.5%)	2	3/411 (0.7%)	3	1/338 (0.3%)	1
Cholelithiasis	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Hepatitis toxic	0/411 (0%)	0	2/411 (0.5%)	3	0/338 (0%)	0
Biliary colic	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Cholecystitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Drug-induced liver injury	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Gallbladder polyp	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Hepatic cyst	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Hepatic lesion	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Hepatitis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Hepatocellular injury	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Hepatomegaly	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Immune system disorders
Seasonal allergy	8/411 (1.9%)	8	7/411 (1.7%)	7	5/338 (1.5%)	7
Food allergy	0/411 (0%)	0	3/411 (0.7%)	3	1/338 (0.3%)	1
Drug hypersensitivity	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Immune reconstitution inflammatory syndrome	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Hypersensitivity	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Jarisch-Herxheimer reaction	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Infections and infestations
Viral upper respiratory tract infection	54/411 (13.1%)	73	54/411 (13.1%)	77	24/338 (7.1%)	27
Upper respiratory tract infection	34/411 (8.3%)	43	31/411 (7.5%)	38	27/338 (8%)	36
Syphilis	24/411 (5.8%)	25	28/411 (6.8%)	30	24/338 (7.1%)	30
Bronchitis	24/411 (5.8%)	33	22/411 (5.4%)	25	15/338 (4.4%)	16
Sinusitis	25/411 (6.1%)	36	16/411 (3.9%)	18	12/338 (3.6%)	19
Gastroenteritis	18/411 (4.4%)	21	18/411 (4.4%)	23	10/338 (3%)	11
Pharyngitis	23/411 (5.6%)	31	14/411 (3.4%)	16	9/338 (2.7%)	9
Influenza	16/411 (3.9%)	17	22/411 (5.4%)	23	7/338 (2.1%)	7
Respiratory tract infection	19/411 (4.6%)	19	12/411 (2.9%)	14	5/338 (1.5%)	9
Rhinitis	13/411 (3.2%)	20	13/411 (3.2%)	15	7/338 (2.1%)	8
Oral herpes	8/411 (1.9%)	9	13/411 (3.2%)	17	7/338 (2.1%)	8
Conjunctivitis	8/411 (1.9%)	8	11/411 (2.7%)	11	8/338 (2.4%)	9
Urinary tract infection	12/411 (2.9%)	14	7/411 (1.7%)	8	4/338 (1.2%)	4
Respiratory tract infection viral	11/411 (2.7%)	13	7/411 (1.7%)	8	4/338 (1.2%)	6
Urethritis	9/411 (2.2%)	10	8/411 (1.9%)	10	5/338 (1.5%)	6
Chlamydial infection	5/411 (1.2%)	6	9/411 (2.2%)	13	7/338 (2.1%)	8
Gonorrhoea	7/411 (1.7%)	8	6/411 (1.5%)	7	8/338 (2.4%)	9
Herpes zoster	9/411 (2.2%)	9	9/411 (2.2%)	9	2/338 (0.6%)	2
Gingivitis	8/411 (1.9%)	8	11/411 (2.7%)	11	0/338 (0%)	0
Tonsillitis	10/411 (2.4%)	10	4/411 (1%)	4	5/338 (1.5%)	8
Folliculitis	6/411 (1.5%)	7	8/411 (1.9%)	9	4/338 (1.2%)	4
Ear infection	7/411 (1.7%)	7	7/411 (1.7%)	11	2/338 (0.6%)	2
Genital herpes	5/411 (1.2%)	6	4/411 (1%)	5	5/338 (1.5%)	6
Pneumonia	8/411 (1.9%)	8	4/411 (1%)	4	2/338 (0.6%)	2
Tooth infection	7/411 (1.7%)	8	4/411 (1%)	4	3/338 (0.9%)	3
Nasopharyngitis	6/411 (1.5%)	7	4/411 (1%)	4	3/338 (0.9%)	3
Secondary syphilis	4/411 (1%)	4	4/411 (1%)	5	5/338 (1.5%)	5
Cellulitis	5/411 (1.2%)	5	4/411 (1%)	5	2/338 (0.6%)	2
Herpes simplex	1/411 (0.2%)	1	7/411 (1.7%)	8	3/338 (0.9%)	5
Herpes virus infection	3/411 (0.7%)	3	5/411 (1.2%)	8	3/338 (0.9%)	5
Onychomycosis	4/411 (1%)	5	4/411 (1%)	4	3/338 (0.9%)	3
Fungal skin infection	5/411 (1.2%)	5	5/411 (1.2%)	5	0/338 (0%)	0
Urethritis gonococcal	2/411 (0.5%)	2	5/411 (1.2%)	5	3/338 (0.9%)	3
Viral infection	6/411 (1.5%)	6	4/411 (1%)	4	0/338 (0%)	0
Furuncle	3/411 (0.7%)	3	4/411 (1%)	5	2/338 (0.6%)	2
Otitis externa	1/411 (0.2%)	1	5/411 (1.2%)	7	3/338 (0.9%)	3
Tooth abscess	4/411 (1%)	4	3/411 (0.7%)	3	2/338 (0.6%)	3
Tinea infection	5/411 (1.2%)	5	3/411 (0.7%)	3	0/338 (0%)	0
Anal chlamydia infection	3/411 (0.7%)	3	1/411 (0.2%)	1	3/338 (0.9%)	3
Lymphogranuloma venereum	0/411 (0%)	0	5/411 (1.2%)	5	2/338 (0.6%)	2
Otitis media	4/411 (1%)	4	2/411 (0.5%)	4	1/338 (0.3%)	1
Skin infection	2/411 (0.5%)	2	2/411 (0.5%)	2	3/338 (0.9%)	3
Tinea versicolour	3/411 (0.7%)	3	2/411 (0.5%)	2	2/338 (0.6%)	2
Acarodermatitis	1/411 (0.2%)	1	5/411 (1.2%)	5	0/338 (0%)	0
Laryngitis	2/411 (0.5%)	2	3/411 (0.7%)	3	1/338 (0.3%)	1
Anal abscess	2/411 (0.5%)	2	2/411 (0.5%)	3	1/338 (0.3%)	1
Erysipelas	2/411 (0.5%)	2	2/411 (0.5%)	2	1/338 (0.3%)	1
Genital infection fungal	1/411 (0.2%)	1	0/411 (0%)	0	4/338 (1.2%)	5
Infection	3/411 (0.7%)	3	2/411 (0.5%)	2	0/338 (0%)	0
Labyrinthitis	2/411 (0.5%)	2	2/411 (0.5%)	2	1/338 (0.3%)	1
Proctitis gonococcal	1/411 (0.2%)	1	2/411 (0.5%)	2	2/338 (0.6%)	2
Subcutaneous abscess	3/411 (0.7%)	3	1/411 (0.2%)	1	1/338 (0.3%)	1
Tinea cruris	1/411 (0.2%)	1	2/411 (0.5%)	2	2/338 (0.6%)	2
Fungal infection	1/411 (0.2%)	1	3/411 (0.7%)	3	0/338 (0%)	0
Lower respiratory tract infection	2/411 (0.5%)	2	0/411 (0%)	0	2/338 (0.6%)	4
Orchitis	1/411 (0.2%)	1	2/411 (0.5%)	2	1/338 (0.3%)	1
Pharyngitis streptococcal	1/411 (0.2%)	1	2/411 (0.5%)	2	1/338 (0.3%)	1
Rash pustular	0/411 (0%)	0	2/411 (0.5%)	2	2/338 (0.6%)	2
Staphylococcal infection	2/411 (0.5%)	2	2/411 (0.5%)	2	0/338 (0%)	0
Tinea pedis	2/411 (0.5%)	2	1/411 (0.2%)	1	1/338 (0.3%)	1
Abscess	2/411 (0.5%)	4	1/411 (0.2%)	1	0/338 (0%)	0
Acute hepatitis C	1/411 (0.2%)	1	1/411 (0.2%)	1	1/338 (0.3%)	1
Acute sinusitis	2/411 (0.5%)	2	1/411 (0.2%)	1	0/338 (0%)	0
Balanitis candida	1/411 (0.2%)	1	1/411 (0.2%)	1	1/338 (0.3%)	1
Cystitis	3/411 (0.7%)	3	0/411 (0%)	0	0/338 (0%)	0
Epididymitis	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Gastroenteritis viral	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Gastrointestinal infection	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Giardiasis	1/411 (0.2%)	1	1/411 (0.2%)	1	1/338 (0.3%)	1
Helicobacter infection	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Hordeolum	1/411 (0.2%)	1	2/411 (0.5%)	4	0/338 (0%)	0
Localised infection	0/411 (0%)	0	2/411 (0.5%)	2	1/338 (0.3%)	1
Lung infection	2/411 (0.5%)	3	0/411 (0%)	0	1/338 (0.3%)	1
Oral candidiasis	1/411 (0.2%)	1	1/411 (0.2%)	1	1/338 (0.3%)	1
Parotitis	2/411 (0.5%)	2	0/411 (0%)	0	1/338 (0.3%)	1
Pharyngotonsillitis	1/411 (0.2%)	1	0/411 (0%)	0	2/338 (0.6%)	2
Pilonidal cyst	2/411 (0.5%)	2	0/411 (0%)	0	1/338 (0.3%)	1
Primary syphilis	0/411 (0%)	0	1/411 (0.2%)	1	2/338 (0.6%)	2
Tracheitis	1/411 (0.2%)	1	1/411 (0.2%)	1	1/338 (0.3%)	1
Angular cheilitis	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Beta haemolytic streptococcal infection	0/411 (0%)	0	0/411 (0%)	0	2/338 (0.6%)	2
Cervicitis	0/411 (0%)	0	0/411 (0%)	0	2/338 (0.6%)	2
Chronic sinusitis	1/411 (0.2%)	1	1/411 (0.2%)	2	0/338 (0%)	0
Dermatophytosis	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Eye infection	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Gastroenteritis shigella	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Genital herpes simplex	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Genital infection bacterial	0/411 (0%)	0	0/411 (0%)	0	2/338 (0.6%)	2
Helicobacter gastritis	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Hepatitis A	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Hepatitis C	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Infected bite	0/411 (0%)	0	2/411 (0.5%)	3	0/338 (0%)	0
Infection parasitic	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Molluscum contagiosum	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Oral infection	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Parasitic gastroenteritis	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Paronychia	2/411 (0.5%)	3	0/411 (0%)	0	0/338 (0%)	0
Proctitis chlamydial	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Vulvovaginal mycotic infection	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Abscess oral	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Amoebiasis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Asymptomatic bacteriuria	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Bacterial disease carrier	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Bacterial infection	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Bacterial vaginosis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Bacteriuria	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Body tinea	0/411 (0%)	0	1/411 (0.2%)	2	0/338 (0%)	0
Campylobacter gastroenteritis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Campylobacter infection	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Carbuncle	1/411 (0.2%)	2	0/411 (0%)	0	0/338 (0%)	0
Cervicitis human papilloma virus	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Chronic hepatitis C	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Chronic tonsillitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Clostridium difficile colitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Conjunctivitis viral	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Dysentery	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Ear infection fungal	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Enterobiasis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Enterovirus infection	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Gastroenteritis clostridial	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Gastrointestinal viral infection	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Genitourinary chlamydia infection	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Genitourinary tract infection	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Groin abscess	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Hepatitis E	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Hepatitis viral	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Impetigo	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Infected cyst	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Latent syphilis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Latent tuberculosis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Lung abscess	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Nail infection	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Ophthalmic herpes simplex	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Oral viral infection	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Oropharyngeal gonococcal infection	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Papilloma viral infection	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Pericoronitis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Periorbital cellulitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Peritonsillar abscess	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Pharyngitis bacterial	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Pneumonia cytomegaloviral	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Post procedural infection	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Proctitis bacterial	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Pulpitis dental	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Pyelonephritis chronic	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Pyuria	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Scrotal abscess	0/411 (0%)	0	1/411 (0.2%)	2	0/338 (0%)	0
Sexually transmitted disease	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Sialoadenitis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Sinobronchitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Sycosis barbae	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Tonsillitis bacterial	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Tonsillitis streptococcal	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Urethritis chlamydial	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Urinary tract infection bacterial	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Vaginitis gardnerella	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Viral pharyngitis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Vulvovaginal candidiasis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Yersinia infection	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Injury, poisoning and procedural complications
Ligament sprain	6/411 (1.5%)	6	5/411 (1.2%)	5	6/338 (1.8%)	8
Muscle strain	7/411 (1.7%)	7	3/411 (0.7%)	3	3/338 (0.9%)	3
Limb injury	2/411 (0.5%)	2	5/411 (1.2%)	5	3/338 (0.9%)	3
Contusion	4/411 (1%)	4	2/411 (0.5%)	2	1/338 (0.3%)	2
Epicondylitis	4/411 (1%)	4	0/411 (0%)	0	3/338 (0.9%)	3
Laceration	4/411 (1%)	4	2/411 (0.5%)	2	0/338 (0%)	0
Arthropod bite	2/411 (0.5%)	2	2/411 (0.5%)	2	1/338 (0.3%)	1
Fall	1/411 (0.2%)	1	2/411 (0.5%)	2	2/338 (0.6%)	2
Rib fracture	2/411 (0.5%)	2	2/411 (0.5%)	3	1/338 (0.3%)	1
Skin abrasion	1/411 (0.2%)	1	3/411 (0.7%)	4	1/338 (0.3%)	1
Bone contusion	3/411 (0.7%)	3	1/411 (0.2%)	1	0/338 (0%)	0
Foot fracture	3/411 (0.7%)	3	1/411 (0.2%)	1	0/338 (0%)	0
Meniscus injury	2/411 (0.5%)	2	0/411 (0%)	0	1/338 (0.3%)	1
Back injury	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Concussion	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Exposure to communicable disease	1/411 (0.2%)	1	1/411 (0.2%)	2	0/338 (0%)	0
Hand fracture	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Injury	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Ligament rupture	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Post-traumatic neck syndrome	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Procedural pain	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Road traffic accident	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Scar	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Tendon rupture	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Thermal burn	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Upper limb fracture	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Accident	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Animal bite	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Ankle fracture	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Arthropod sting	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Bone fissure	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Burns second degree	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Cartilage injury	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Ear injury	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Excoriation	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Eye contusion	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Eye injury	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Fracture	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Head injury	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Human bite	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Joint dislocation	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Joint injury	1/411 (0.2%)	2	0/411 (0%)	0	0/338 (0%)	0
Lower limb fracture	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Neck injury	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Patella fracture	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Penis injury	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Poisoning	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Post lumbar puncture syndrome	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Post procedural discomfort	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Post-traumatic pain	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Scratch	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Subdural haematoma	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Tendon injury	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Traumatic haematoma	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Ulnar nerve injury	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Wound	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Investigations
Alanine aminotransferase increased	6/411 (1.5%)	8	4/411 (1%)	10	1/338 (0.3%)	1
Aspartate aminotransferase increased	3/411 (0.7%)	3	4/411 (1%)	9	2/338 (0.6%)	2
Weight increased	4/411 (1%)	4	5/411 (1.2%)	5	0/338 (0%)	0
Weight decreased	3/411 (0.7%)	4	3/411 (0.7%)	3	1/338 (0.3%)	1
Blood pressure increased	3/411 (0.7%)	3	3/411 (0.7%)	3	0/338 (0%)	0
Blood creatine phosphokinase increased	0/411 (0%)	0	2/411 (0.5%)	2	3/338 (0.9%)	3
Lipase increased	1/411 (0.2%)	1	3/411 (0.7%)	3	1/338 (0.3%)	1
Transaminases increased	1/411 (0.2%)	1	2/411 (0.5%)	2	1/338 (0.3%)	1
Blood creatinine increased	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Blood glucose increased	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Urinary sediment present	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Blood alkaline phosphatase increased	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Blood bilirubin increased	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Blood cholesterol increased	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Blood glucose decreased	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Blood phosphorus decreased	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Blood testosterone decreased	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Blood thyroid stimulating hormone increased	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Heart sounds abnormal	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Human papilloma virus test positive	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Liver function test increased	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Oestradiol increased	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Parasite stool test positive	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Protein urine present	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
QRS axis abnormal	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Shigella test positive	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Streptococcus test positive	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Urine analysis abnormal	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Vitamin D decreased	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Metabolism and nutrition disorders
Vitamin D deficiency	7/411 (1.7%)	7	6/411 (1.5%)	6	7/338 (2.1%)	7
Decreased appetite	6/411 (1.5%)	6	8/411 (1.9%)	9	1/338 (0.3%)	1
Hyperglycaemia	0/411 (0%)	0	0/411 (0%)	0	4/338 (1.2%)	4
Hypophosphataemia	1/411 (0.2%)	1	0/411 (0%)	0	3/338 (0.9%)	5
Gout	1/411 (0.2%)	1	1/411 (0.2%)	1	1/338 (0.3%)	1
Hypercholesterolaemia	2/411 (0.5%)	2	0/411 (0%)	0	1/338 (0.3%)	1
Hyperlipidaemia	2/411 (0.5%)	2	1/411 (0.2%)	1	0/338 (0%)	0
Iron deficiency	1/411 (0.2%)	1	1/411 (0.2%)	1	1/338 (0.3%)	1
Dyslipidaemia	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Increased appetite	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Alcohol intolerance	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Body fat disorder	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Dehydration	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Diabetes mellitus	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Diabetes mellitus inadequate control	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Folate deficiency	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Food intolerance	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Hyperlipasaemia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Hypertriglyceridaemia	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Hypovitaminosis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Lactase deficiency	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Obesity	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Polydipsia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Type 2 diabetes mellitus	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Vitamin B12 deficiency	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	24/411 (5.8%)	27	26/411 (6.3%)	29	10/338 (3%)	15
Arthralgia	11/411 (2.7%)	13	14/411 (3.4%)	17	7/338 (2.1%)	8
Tendonitis	7/411 (1.7%)	7	9/411 (2.2%)	9	5/338 (1.5%)	5
Myalgia	10/411 (2.4%)	10	7/411 (1.7%)	7	3/338 (0.9%)	3
Pain in extremity	7/411 (1.7%)	7	10/411 (2.4%)	11	1/338 (0.3%)	1
Musculoskeletal pain	5/411 (1.2%)	5	7/411 (1.7%)	7	2/338 (0.6%)	2
Osteopenia	2/411 (0.5%)	2	7/411 (1.7%)	7	5/338 (1.5%)	5
Neck pain	4/411 (1%)	4	5/411 (1.2%)	8	2/338 (0.6%)	2
Muscle spasms	3/411 (0.7%)	3	4/411 (1%)	4	2/338 (0.6%)	2
Musculoskeletal chest pain	5/411 (1.2%)	6	3/411 (0.7%)	3	1/338 (0.3%)	1
Bursitis	3/411 (0.7%)	3	2/411 (0.5%)	2	2/338 (0.6%)	2
Osteoarthritis	3/411 (0.7%)	3	1/411 (0.2%)	1	2/338 (0.6%)	3
Osteoporosis	1/411 (0.2%)	1	2/411 (0.5%)	2	3/338 (0.9%)	3
Flank pain	1/411 (0.2%)	2	3/411 (0.7%)	5	1/338 (0.3%)	1
Spinal osteoarthritis	2/411 (0.5%)	2	1/411 (0.2%)	1	1/338 (0.3%)	1
Intervertebral disc protrusion	1/411 (0.2%)	1	0/411 (0%)	0	2/338 (0.6%)	2
Joint swelling	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Muscle contracture	2/411 (0.5%)	2	0/411 (0%)	0	1/338 (0.3%)	1
Plantar fasciitis	0/411 (0%)	0	1/411 (0.2%)	1	2/338 (0.6%)	2
Synovial cyst	1/411 (0.2%)	1	0/411 (0%)	0	2/338 (0.6%)	2
Intervertebral disc disorder	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Limb discomfort	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Musculoskeletal discomfort	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Musculoskeletal stiffness	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Rotator cuff syndrome	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Spinal pain	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Arthritis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Bone erosion	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Bone pain	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Chondritis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Costochondritis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Dupuytren's contracture	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Enthesopathy	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Fasciitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Fistula	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Foot deformity	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Gouty arthritis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Groin pain	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Intervertebral disc degeneration	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Jaw disorder	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Joint stiffness	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Muscle fatigue	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Muscle tightness	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Muscle twitching	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Myosclerosis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Myositis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Osteochondrosis	0/411 (0%)	0	1/411 (0.2%)	3	0/338 (0%)	0
Osteonecrosis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Periarthritis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Plantar fascial fibromatosis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Psoriatic arthropathy	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Scoliosis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Torticollis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anogenital warts	16/411 (3.9%)	17	22/411 (5.4%)	24	8/338 (2.4%)	9
Skin papilloma	9/411 (2.2%)	10	8/411 (1.9%)	10	2/338 (0.6%)	2
Fibroma	1/411 (0.2%)	1	2/411 (0.5%)	2	1/338 (0.3%)	1
Lipoma	1/411 (0.2%)	1	2/411 (0.5%)	2	1/338 (0.3%)	1
Acrochordon	1/411 (0.2%)	2	1/411 (0.2%)	1	1/338 (0.3%)	2
Kaposi's sarcoma	2/411 (0.5%)	2	1/411 (0.2%)	1	0/338 (0%)	0
Melanocytic naevus	1/411 (0.2%)	1	0/411 (0%)	0	2/338 (0.6%)	2
Basal cell carcinoma	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Oral papilloma	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Seborrhoeic keratosis	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Anal neoplasm	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Cervix carcinoma	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Dysplastic naevus	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Eye haemangioma	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Fibroadenoma of breast	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Fibrous histiocytoma	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Haemangioma of liver	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Haemangioma of spleen	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Keratoacanthoma	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Papilloma	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Penile wart	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Schwannoma	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Uterine leiomyoma	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Nervous system disorders
Headache	56/411 (13.6%)	63	55/411 (13.4%)	70	9/338 (2.7%)	9
Dizziness	24/411 (5.8%)	25	24/411 (5.8%)	24	0/338 (0%)	0
Sciatica	4/411 (1%)	4	7/411 (1.7%)	9	4/338 (1.2%)	4
Migraine	4/411 (1%)	5	5/411 (1.2%)	10	1/338 (0.3%)	1
Lethargy	3/411 (0.7%)	3	6/411 (1.5%)	7	0/338 (0%)	0
Hypoaesthesia	4/411 (1%)	5	2/411 (0.5%)	2	2/338 (0.6%)	2
Paraesthesia	1/411 (0.2%)	1	5/411 (1.2%)	6	0/338 (0%)	0
Somnolence	4/411 (1%)	4	2/411 (0.5%)	2	0/338 (0%)	0
Disturbance in attention	1/411 (0.2%)	1	4/411 (1%)	5	0/338 (0%)	0
Dysgeusia	1/411 (0.2%)	1	4/411 (1%)	4	0/338 (0%)	0
Facial paralysis	2/411 (0.5%)	2	2/411 (0.5%)	2	1/338 (0.3%)	1
Amnesia	3/411 (0.7%)	3	1/411 (0.2%)	1	0/338 (0%)	0
Cervicobrachial syndrome	1/411 (0.2%)	2	1/411 (0.2%)	1	2/338 (0.6%)	2
Memory impairment	0/411 (0%)	0	1/411 (0.2%)	1	2/338 (0.6%)	2
Syncope	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Balance disorder	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Burning sensation	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Cognitive disorder	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Dysaesthesia	0/411 (0%)	0	1/411 (0.2%)	2	1/338 (0.3%)	1
Neuralgia	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Neuropathy peripheral	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Poor quality sleep	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Agnosia	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Anosmia	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Apraxia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Brain injury	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Cerebral haemorrhage	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Cervical radiculopathy	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Circadian rhythm sleep disorder	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Cluster headache	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Dizziness postural	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Dystonia	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Hyperaesthesia	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Morton's neuralgia	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Nerve compression	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Peripheral sensory neuropathy	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Peroneal nerve palsy	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Post herpetic neuralgia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Presyncope	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Sensory disturbance	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Trigeminal neuralgia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Vascular headache	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Psychiatric disorders
Insomnia	28/411 (6.8%)	28	19/411 (4.6%)	20	6/338 (1.8%)	6
Depression	26/411 (6.3%)	26	18/411 (4.4%)	18	8/338 (2.4%)	8
Anxiety	19/411 (4.6%)	19	22/411 (5.4%)	24	6/338 (1.8%)	7
Abnormal dreams	13/411 (3.2%)	14	8/411 (1.9%)	9	1/338 (0.3%)	1
Sleep disorder	7/411 (1.7%)	7	8/411 (1.9%)	8	1/338 (0.3%)	1
Libido decreased	3/411 (0.7%)	3	10/411 (2.4%)	10	1/338 (0.3%)	1
Stress	4/411 (1%)	4	4/411 (1%)	4	2/338 (0.6%)	2
Nightmare	6/411 (1.5%)	6	2/411 (0.5%)	2	0/338 (0%)	0
Depressed mood	4/411 (1%)	4	1/411 (0.2%)	1	1/338 (0.3%)	1
Panic attack	2/411 (0.5%)	2	2/411 (0.5%)	2	1/338 (0.3%)	1
Acute stress disorder	0/411 (0%)	0	2/411 (0.5%)	2	2/338 (0.6%)	2
Drug use disorder	1/411 (0.2%)	1	1/411 (0.2%)	1	2/338 (0.6%)	2
Burnout syndrome	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Disorientation	0/411 (0%)	0	3/411 (0.7%)	4	0/338 (0%)	0
Euphoric mood	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Irritability	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Suicidal ideation	2/411 (0.5%)	2	1/411 (0.2%)	1	0/338 (0%)	0
Agitation	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Emotional disorder	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Adjustment disorder	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Adjustment disorder with depressed mood	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Aggression	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Agoraphobia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Alcohol withdrawal syndrome	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Alcoholic psychosis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Anxiety disorder	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Apathy	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Attention deficit/hyperactivity disorder	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Confusional state	1/411 (0.2%)	2	0/411 (0%)	0	0/338 (0%)	0
Hallucination	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Major depression	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Mental disorder	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Mental fatigue	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Middle insomnia	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Mood swings	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Nervousness	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Panic reaction	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Persistent depressive disorder	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Phobia of flying	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Sleep-related eating disorder	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Somnambulism	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Substance-induced psychotic disorder	0/411 (0%)	0	1/411 (0.2%)	2	0/338 (0%)	0
Terminal insomnia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Thinking abnormal	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Withdrawal syndrome	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Renal and urinary disorders
Dysuria	4/411 (1%)	5	4/411 (1%)	5	0/338 (0%)	0
Urethral discharge	1/411 (0.2%)	1	3/411 (0.7%)	3	2/338 (0.6%)	2
Haematuria	2/411 (0.5%)	2	2/411 (0.5%)	2	0/338 (0%)	0
Micturition urgency	2/411 (0.5%)	2	1/411 (0.2%)	1	1/338 (0.3%)	1
Nephrolithiasis	1/411 (0.2%)	1	1/411 (0.2%)	1	2/338 (0.6%)	2
Leukocyturia	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Urethral pain	2/411 (0.5%)	2	0/411 (0%)	0	1/338 (0.3%)	1
Chronic kidney disease	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Pollakiuria	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Polyuria	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Proteinuria	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Renal colic	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Glycosuria	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Microalbuminuria	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Renal impairment	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Tubulointerstitial nephritis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Urethral haemorrhage	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Urethral stenosis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Urinary hesitation	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Urinary retention	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Urinary tract disorder	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Urine flow decreased	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Reproductive system and breast disorders
Erectile dysfunction	5/411 (1.2%)	5	6/411 (1.5%)	6	3/338 (0.9%)	3
Benign prostatic hyperplasia	2/411 (0.5%)	2	1/411 (0.2%)	1	2/338 (0.6%)	2
Cervical dysplasia	2/411 (0.5%)	2	0/411 (0%)	0	2/338 (0.6%)	2
Prostatitis	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Gynaecomastia	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Menorrhagia	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Sexual dysfunction	0/411 (0%)	0	2/411 (0.5%)	2	0/338 (0%)	0
Testicular pain	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Vaginal discharge	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Balanoposthitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Breast mass	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Breast pain	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Breast tenderness	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Endometriosis	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Epididymal tenderness	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Genital lesion	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Genital rash	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Hypospermia	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Menstruation irregular	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Ovarian cyst	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Pelvic discomfort	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Penile discharge	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Prostatomegaly	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Scrotal swelling	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Testicular oedema	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Testicular swelling	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Testis discomfort	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Varicocele	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Vulval ulceration	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	23/411 (5.6%)	27	22/411 (5.4%)	24	9/338 (2.7%)	9
Oropharyngeal pain	19/411 (4.6%)	22	16/411 (3.9%)	19	6/338 (1.8%)	7
Asthma	8/411 (1.9%)	10	4/411 (1%)	4	1/338 (0.3%)	1
Rhinitis allergic	2/411 (0.5%)	2	11/411 (2.7%)	13	0/338 (0%)	0
Nasal congestion	3/411 (0.7%)	3	5/411 (1.2%)	5	2/338 (0.6%)	2
Rhinorrhoea	2/411 (0.5%)	2	4/411 (1%)	4	2/338 (0.6%)	2
Sinus congestion	3/411 (0.7%)	3	3/411 (0.7%)	3	1/338 (0.3%)	1
Epistaxis	2/411 (0.5%)	2	2/411 (0.5%)	2	2/338 (0.6%)	2
Catarrh	0/411 (0%)	0	2/411 (0.5%)	2	1/338 (0.3%)	1
Allergic sinusitis	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Chronic obstructive pulmonary disease	0/411 (0%)	0	1/411 (0.2%)	2	1/338 (0.3%)	1
Dysphonia	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Lung disorder	1/411 (0.2%)	2	0/411 (0%)	0	1/338 (0.3%)	1
Productive cough	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Respiratory disorder	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Respiratory tract congestion	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Tonsillar hypertrophy	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Atelectasis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Dry throat	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Emphysema	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Laryngospasm	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Nasal dryness	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Nasal obstruction	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Nocturnal dyspnoea	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Pneumothorax	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Sleep apnoea syndrome	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Upper respiratory tract congestion	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Upper-airway cough syndrome	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Wheezing	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Skin and subcutaneous tissue disorders
Rash	18/411 (4.4%)	22	19/411 (4.6%)	23	1/338 (0.3%)	1
Pruritus	17/411 (4.1%)	18	10/411 (2.4%)	10	5/338 (1.5%)	5
Acne	9/411 (2.2%)	9	8/411 (1.9%)	9	2/338 (0.6%)	2
Eczema	7/411 (1.7%)	9	7/411 (1.7%)	10	1/338 (0.3%)	1
Night sweats	5/411 (1.2%)	5	8/411 (1.9%)	8	2/338 (0.6%)	2
Alopecia	5/411 (1.2%)	5	4/411 (1%)	4	4/338 (1.2%)	4
Seborrhoeic dermatitis	3/411 (0.7%)	3	8/411 (1.9%)	9	1/338 (0.3%)	1
Dry skin	5/411 (1.2%)	5	5/411 (1.2%)	5	1/338 (0.3%)	1
Dermatitis	3/411 (0.7%)	3	3/411 (0.7%)	3	2/338 (0.6%)	2
Dermatitis contact	4/411 (1%)	4	3/411 (0.7%)	3	1/338 (0.3%)	1
Skin lesion	2/411 (0.5%)	2	4/411 (1%)	5	1/338 (0.3%)	1
Hyperhidrosis	3/411 (0.7%)	3	3/411 (0.7%)	3	0/338 (0%)	0
Urticaria	3/411 (0.7%)	3	2/411 (0.5%)	2	1/338 (0.3%)	1
Intertrigo	4/411 (1%)	4	0/411 (0%)	0	0/338 (0%)	0
Photosensitivity reaction	2/411 (0.5%)	2	1/411 (0.2%)	1	1/338 (0.3%)	1
Rosacea	1/411 (0.2%)	1	3/411 (0.7%)	3	0/338 (0%)	0
Dermatitis acneiform	2/411 (0.5%)	2	0/411 (0%)	0	1/338 (0.3%)	1
Erythema	1/411 (0.2%)	1	2/411 (0.5%)	2	0/338 (0%)	0
Psoriasis	2/411 (0.5%)	2	1/411 (0.2%)	1	0/338 (0%)	0
Rash papular	2/411 (0.5%)	3	1/411 (0.2%)	1	0/338 (0%)	0
Actinic keratosis	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Dermatitis allergic	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Drug eruption	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Dyshidrotic eczema	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Eczema nummular	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Facial wasting	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Macule	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Neurodermatitis	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Pityriasis rosea	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Rash macular	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Rash pruritic	1/411 (0.2%)	1	1/411 (0.2%)	2	0/338 (0%)	0
Skin fissures	1/411 (0.2%)	1	0/411 (0%)	0	1/338 (0.3%)	1
Acne conglobata	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Acne cystic	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Alopecia areata	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Angioedema	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Cutaneous lupus erythematosus	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Dermal cyst	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Dermatosis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Eczema asteatotic	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Hidradenitis	1/411 (0.2%)	2	0/411 (0%)	0	0/338 (0%)	0
Hyperkeratosis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Lentigo	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Lipoatrophy	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Mechanical urticaria	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Nail discolouration	1/411 (0.2%)	2	0/411 (0%)	0	0/338 (0%)	0
Nail ridging	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Pain of skin	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Papule	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Penile ulceration	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Pityriasis	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Post inflammatory pigmentation change	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Pruritus generalised	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Rash erythematous	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Rash generalised	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Rash maculo-papular	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Scab	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Skin burning sensation	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Skin exfoliation	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Skin hyperpigmentation	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Skin irritation	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Skin mass	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Skin plaque	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Skin ulcer	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Spider naevus	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Swelling face	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Telangiectasia	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Toxic skin eruption	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Vitiligo	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Xeroderma	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Social circumstances
Stress at work	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Surgical and medical procedures
Tooth extraction	0/411 (0%)	0	0/411 (0%)	0	2/338 (0.6%)	2
Inguinal hernia repair	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Nasal septal operation	1/411 (0.2%)	1	0/411 (0%)	0	0/338 (0%)	0
Papilloma excision	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Tonsillectomy	0/411 (0%)	0	0/411 (0%)	0	1/338 (0.3%)	1
Vascular disorders
Hypertension	7/411 (1.7%)	7	12/411 (2.9%)	12	5/338 (1.5%)	6
Varicose vein	1/411 (0.2%)	1	1/411 (0.2%)	1	2/338 (0.6%)	2
Flushing	2/411 (0.5%)	2	0/411 (0%)	0	0/338 (0%)	0
Haematoma	0/411 (0%)	0	1/411 (0.2%)	1	1/338 (0.3%)	1
Hot flush	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Thrombophlebitis	1/411 (0.2%)	1	1/411 (0.2%)	1	0/338 (0%)	0
Circulatory collapse	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Deep vein thrombosis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0
Phlebitis	0/411 (0%)	0	1/411 (0.2%)	1	0/338 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.