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

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ClinicalTrials.gov Identifier: NCT01227824
Recruitment Status : Completed
First Posted : October 25, 2010
Results First Posted : June 23, 2014
Last Update Posted : October 8, 2018
Sponsor:
Collaborators:
Shionogi
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Infection, Human Immunodeficiency Virus I
Interventions Drug: GSK1349572 (dolutegravir)
Drug: raltegravir
Other: GSK1349572 Placebo
Other: ABC/3TC
Other: TDF/FTC
Other: raltegravir Placebo
Enrollment 828
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 Details 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)
Hide 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
Reason Not Completed
Adverse Event             12             7             0
Lack of Efficacy             22             25             0
Protocol Violation             18             16             0
Met Protocol-defined Stopping Criteria             6             3             0
Study Closed/Terminated             6             4             0
Lost to Follow-up             22             10             0
Withdrawal by Subject             18             14             0
Physician Decision             3             0             0
Period Title: Open-label Phase: Median of 1267 Days
Started 0 0 338 [1]
Completed 0 0 294
Not Completed 0 0 44
Reason Not Completed
Adverse Event             0             0             4
Lack of Efficacy             0             0             5
Protocol Violation             0             0             5
Met Protocol-defined Stopping Criteria             0             0             4
Lost to Follow-up             0             0             15
Withdrawal by Subject             0             0             8
Physician Decision             0             0             3
[1]
338 participants continued into the Open-label phase on completing the Double-blind Phase
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID Total
Hide 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 Number of Baseline Participants 411 411 822
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 411 participants 411 participants 822 participants
37.3  (9.19) 36.6  (10.02) 37.0  (9.61)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 411 participants 411 participants 822 participants
Female
63
  15.3%
56
  13.6%
119
  14.5%
Male
348
  84.7%
355
  86.4%
703
  85.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 411 participants 411 participants 822 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
   0.0%
2
   0.2%
Japanese/East Asian Her/South East Asian Her
4
   1.0%
10
   2.4%
14
   1.7%
Native Hawaiian or other Pacific Islander
2
   0.5%
0
   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
   0.0%
1
   0.1%
Asian and White
0
   0.0%
1
   0.2%
1
   0.1%
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
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT-E Population.
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 411 411
Measure Type: Number
Unit of Measure: Percentage of participants
88 85
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DTG 50 mg Once a Day, RTG 400 mg BID
Comments [Not Specified]
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%.
Method of Estimation Estimation Parameter Difference in percentage
Estimated Value 2.5
Confidence Interval (2-Sided) 95%
-2.2 to 7.1
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.
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT-E Population
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 411 411
Measure Type: Number
Unit of Measure: Participants
Week 48, genotypic 0 1
Week 48, phenotypic 1 2
Week 96, genotypic 0 1
Week 96, phenotypic 1 2
3.Secondary Outcome
Title Number of Participants With Plasma HIV-1 RNA <50 c/mL
Hide Description The number of participants with plasma HIV-1 RNA level <50 c/mL was assessed at Week 96.
Time Frame Week 96
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT-E Population
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 411 411
Measure Type: Number
Unit of Measure: Participants
332 314
4.Secondary Outcome
Title Number of Participants With Plasma HIV-1 RNA <400 c/mL
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT-E Population
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 411 411
Measure Type: Number
Unit of Measure: Participants
Week 48 369 356
Week 96 338 321
5.Secondary Outcome
Title Change From Baseline in Plasma HIV-1 RNA Over Time
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT-E Population.
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 411 411
Mean (Standard Deviation)
Unit of Measure: log10 c/mL
Baseline n=411, 411 Number Analyzed 411 participants 411 participants
4.538  (0.7258) 4.599  (0.7048)
Week 4, n=402, 406 Number Analyzed 402 participants 406 participants
-2.817  (0.6198) -2.801  (0.6041)
Week 8, n=397, 402 Number Analyzed 397 participants 402 participants
-2.897  (0.6837) -2.886  (0.6754)
Week 12, n=396, 395 Number Analyzed 396 participants 395 participants
-2.908  (0.6863) -2.918  (0.6834)
Week 16, n=395, 388 Number Analyzed 395 participants 388 participants
-2.917  (0.6949) -2.943  (0.6841)
Week 24, n=393, 390 Number Analyzed 393 participants 390 participants
-2.896  (0.7889) -2.933  (0.7398)
Week 32, n=386, 377 Number Analyzed 386 participants 377 participants
-2.907  (0.7609) -2.947  (0.7613)
Week 40, n=375, 358 Number Analyzed 375 participants 358 participants
-2.920  (0.7219) -2.946  (0.6700)
Week 48, n=374, 358 Number Analyzed 374 participants 358 participants
-2.915  (0.7237) -2.942  (0.6737)
Week 60, n=366, 355 Number Analyzed 366 participants 355 participants
-2.912  (0.7344) -2.937  (0.6685)
Week 72, n=361, 350 Number Analyzed 361 participants 350 participants
-2.917  (0.7261) -2.932  (0.6728)
Week 84, n=352, 338 Number Analyzed 352 participants 338 participants
-2.932  (0.7073) -2.916  (0.6646)
Week 96, n=342, 329 Number Analyzed 342 participants 329 participants
-2.938  (0.7004) -2.901  (0.7072)
6.Secondary Outcome
Title Absolute Values in Plasma HIV-1 RNA Over Time
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT-E Population.
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 411 411
Mean (Standard Deviation)
Unit of Measure: log10 c/mL
Baseline n=411, 411 Number Analyzed 411 participants 411 participants
4.538  (0.7258) 4.599  (0.7048)
Week 4, n=402, 406 Number Analyzed 402 participants 406 participants
1.718  (0.2593) 1.800  (0.4095)
Week 8, n=397, 402 Number Analyzed 397 participants 402 participants
1.646  (0.2006) 1.709  (0.3791)
Week 12, n=396, 395 Number Analyzed 396 participants 395 participants
1.626  (0.1323) 1.672  (0.3125)
Week 16, n=395, 388 Number Analyzed 395 participants 388 participants
1.620  (0.1252) 1.648  (0.2647)
Week 24, n=393, 390 Number Analyzed 393 participants 390 participants
1.643  (0.2950) 1.655  (0.3476)
Week 32, n=386, 377 Number Analyzed 386 participants 377 participants
1.620  (0.1917) 1.636  (0.2721)
Week 40, n=375, 358 Number Analyzed 375 participants 358 participants
1.603  (0.0821) 1.601  (0.0784)
Week 48, n=374, 358 Number Analyzed 374 participants 358 participants
1.606  (0.0866) 1.599  (0.0582)
Week 60, n=366, 355 Number Analyzed 366 participants 355 participants
1.605  (0.1134) 1.599  (0.0560)
Week 72, n=361, 350 Number Analyzed 361 participants 350 participants
1.601  (0.0803) 1.605  (0.0836)
Week 84, n=352, 338 Number Analyzed 352 participants 338 participants
1.607  (0.1337) 1.614  (0.1279)
Week 96, n=342, 329 Number Analyzed 342 participants 329 participants
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
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT-E Population.
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 411 411
Mean (Standard Deviation)
Unit of Measure: Cells per cubic millimeter (cells/mm^3)
Baseline n=411, 411 Number Analyzed 411 participants 411 participants
379.2  (178.32) 374.3  (163.37)
Week 4, n=398, 403 Number Analyzed 398 participants 403 participants
93.3  (116.27) 97.2  (129.35)
Week 8, n=398, 402 Number Analyzed 398 participants 402 participants
121.6  (127.97) 126.6  (134.59)
Week 12, n=392, 397 Number Analyzed 392 participants 397 participants
130.7  (131.49) 145.1  (144.08)
Week 16, n=394, 392 Number Analyzed 394 participants 392 participants
155.1  (137.23) 173.0  (159.10)
Week 24, n=392, 389 Number Analyzed 392 participants 389 participants
199.3  (161.23) 204.2  (162.28)
Week 32, n=384, 375 Number Analyzed 384 participants 375 participants
223.4  (165.30) 241.3  (167.64)
Week 40, n=371, 357 Number Analyzed 371 participants 357 participants
224.1  (173.59) 239.8  (173.33)
Week 48, n=374, 357 Number Analyzed 374 participants 357 participants
238.9  (171.81) 257.5  (178.69)
Week 60, n=367, 355 Number Analyzed 367 participants 355 participants
247.8  (184.11) 264.2  (188.63)
Week 72, n=360, 350 Number Analyzed 360 participants 350 participants
247.8  (168.37) 278.6  (182.76)
Week 84, n=351, 338 Number Analyzed 351 participants 338 participants
281.3  (175.07) 292.9  (199.42)
Week 96, n=343, 328 Number Analyzed 343 participants 328 participants
292.2  (195.70) 286.2  (192.45)
8.Secondary Outcome
Title Absolute Values in CD4+ Cell Counts Over Time
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT-E Population.
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 411 411
Mean (Standard Deviation)
Unit of Measure: cells/mm^3
Baseline n=411, 411 Number Analyzed 411 participants 411 participants
379.2  (172.32) 374.3  (163.37)
Week 4, n=398, 403 Number Analyzed 398 participants 403 participants
474.2  (199.06) 471.8  (191.02)
Week 8, n=398, 402 Number Analyzed 398 participants 402 participants
502.3  (205.15) 502.4  (187.99)
Week 12, n=392, 397 Number Analyzed 392 participants 397 participants
513.3  (218.75) 518.3  (195.59)
Week 16, n=394, 392 Number Analyzed 394 participants 392 participants
536.4  (219.47) 550.1  (221.77)
Week 24, n=392, 389 Number Analyzed 392 participants 389 participants
582.0  (232.93) 580.8  (218.76)
Week 32, n=384, 375 Number Analyzed 384 participants 375 participants
606.5  (242.95) 618.7  (237.56)
Week 40, n=371, 357 Number Analyzed 371 participants 357 participants
609.1  (239.11) 623.1  (234.82)
Week 48, n=374, 357 Number Analyzed 374 participants 357 participants
623.8  (247.82) 641.2  (241.75)
Week 60, n=367, 355 Number Analyzed 367 participants 355 participants
635.6  (241.27) 648.5  (238.99)
Week 72, n=360, 350 Number Analyzed 360 participants 350 participants
635.2  (237.78) 664.0  (239.86)
Week 84, n=351, 338 Number Analyzed 351 participants 338 participants
668.0  (246.50) 677.5  (249.64)
Week 96, n=343, 328 Number Analyzed 343 participants 328 participants
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
Hide 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
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Hide Analysis Population Description
ITT-E Population
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 411 411
Measure Type: Number
Unit of Measure: Participants
Any category condition 10 8
Any Category B condition 3 3
Any Category C condition 6 4
Any death 1 1
Progression from CAT A to CAT C 4 2
Progression from CAT B to CAT C 3 1
Progression from CAT C to new CAT C 0 1
Progression from CAT A, B, or C to death 1 1
10.Secondary Outcome
Title Number of Participants With the Indicated Grade 1 to 4 Clinical Chemistry and Hematology Toxicities/Laboratory Adverse Events (AEs)
Hide 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
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Hide Analysis Population Description
Safety Population.
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 411 411
Measure Type: Number
Unit of Measure: Participants
ALT 57 70
ALP 7 15
AST 67 75
CO2 content/bicarbonate 58 67
Cholesterol 90 73
CK 61 47
Creatinine 11 7
Hyperglycaemia 70 87
Hyperkalemia 7 4
Hypernatremia 4 6
Hypoglycaemia 17 27
Hypokalemia 10 15
Hyponatremia 34 48
LDL cholesterol calculation 74 49
Lipase 55 62
Phosphorus, inorganic 65 71
Total bilirubin 27 24
Triglycerides 7 8
Hemoglobin 10 5
Platelet count 19 19
Total neutrophils 54 48
White Blood Cell count 19 7
11.Secondary Outcome
Title Area Under the Plasma Concentration-time Curve From Time Zero to Time Tau [AUC(0-tau)] of DTG
Hide 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
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Hide Analysis Population Description
PK Concentration Population
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 403 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 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
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PK Concentration Population.
Arm/Group Title DTG 50 mg Once a Day RTG 400 mg BID
Hide 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.
Overall Number of Participants Analyzed 403 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Micrograms per milliliter (µg/mL)
Cmax
3.69
(19.6%)
Ctau
1.10
(46.5%)
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)
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/411 (0.24%)      1/411 (0.24%)      0/338 (0.00%)    
Show Serious Adverse Events Hide 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 (9.98%)      45/411 (10.95%)      21/338 (6.21%)    
Blood and lymphatic system disorders       
Anaemia  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Lymphadenopathy  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Cardiac disorders       
Arrhythmia  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Ear and labyrinth disorders       
Vertigo  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Gastrointestinal disorders       
Anal fissure  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Anal fistula  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Abdominal pain lower  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Anal inflammation  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Diarrhoea  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Inguinal hernia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Irritable bowel syndrome  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Pancreatic pseudocyst  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Peptic ulcer  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Proctitis ulcerative  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
General disorders       
Chest pain  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Polyserositis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Pyrexia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Hepatobiliary disorders       
Hepatitis  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Cholecystitis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Hepatotoxicity  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Portal vein thrombosis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Immune system disorders       
Drug hypersensitivity  1  3/411 (0.73%)  3 0/411 (0.00%)  0 1/338 (0.30%)  1
Hypersensitivity  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Immune reconstitution inflammatory syndrome  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Infections and infestations       
Appendicitis  1  2/411 (0.49%)  2 5/411 (1.22%)  5 1/338 (0.30%)  1
Pneumonia  1  0/411 (0.00%)  0 2/411 (0.49%)  2 1/338 (0.30%)  1
Anal abscess  1  0/411 (0.00%)  0 1/411 (0.24%)  1 1/338 (0.30%)  1
Arthritis bacterial  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Cellulitis  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Gastroenteritis  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Peritonsillar abscess  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Pneumonia bacterial  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Subcutaneous abscess  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Syphilis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 2/338 (0.59%)  2
Abscess  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Acute hepatitis C  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Atypical mycobacterial infection  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Bacteraemia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Corneal abscess  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Encephalitis viral  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Gastroenteritis bacterial  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Gastrointestinal infection  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Influenza  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Lung infection  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Lymphadenitis viral  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Meningitis tuberculous  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Neurosyphilis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Osteomyelitis chronic  1  1/411 (0.24%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Pneumocystis jirovecii pneumonia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Pneumonia cytomegaloviral  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Rhinitis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Secondary syphilis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Sepsis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Staphylococcal infection  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Urinary tract infection  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Viral infection  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Injury, poisoning and procedural complications       
Laceration  1  0/411 (0.00%)  0 2/411 (0.49%)  2 0/338 (0.00%)  0
Rib fracture  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Alcohol poisoning  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Intentional overdose  1  0/411 (0.00%)  0 1/411 (0.24%)  2 0/338 (0.00%)  0
Lower limb fracture  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Multiple fractures  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Penis injury  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Post procedural haemorrhage  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Tibia fracture  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Toxicity to various agents  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Upper limb fracture  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Investigations       
Blood creatine phosphokinase increased  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Metabolism and nutrition disorders       
Diabetes mellitus inadequate control  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Musculoskeletal and connective tissue disorders       
Arthritis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Back pain  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Costochondritis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Osteoarthritis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Lung neoplasm malignant  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Anogenital warts  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Breast cancer  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Malignant melanoma  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Metastatic malignant melanoma  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Papilloma  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Transitional cell carcinoma  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Nervous system disorders       
Seizure  1  0/411 (0.00%)  0 2/411 (0.49%)  2 0/338 (0.00%)  0
Aphasia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Cerebrovascular accident  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Cognitive disorder  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Sciatica  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Status epilepticus  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Psychiatric disorders       
Suicide attempt  1  2/411 (0.49%)  2 3/411 (0.73%)  4 1/338 (0.30%)  1
Suicidal ideation  1  0/411 (0.00%)  0 2/411 (0.49%)  2 0/338 (0.00%)  0
Completed suicide  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Depression  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Renal and urinary disorders       
Nephrolithiasis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  2
Renal colic  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Renal impairment  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Reproductive system and breast disorders       
Cervical dysplasia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Erectile dysfunction  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Menorrhagia  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Respiratory, thoracic and mediastinal disorders       
Chronic obstructive pulmonary disease  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Pneumonia aspiration  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Pneumothorax  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Social circumstances       
Homicide  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Surgical and medical procedures       
Keratoplasty  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Vascular disorders       
Thrombosis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
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 (85.89%)      344/411 (83.70%)      256/338 (75.74%)    
Blood and lymphatic system disorders       
Lymphadenopathy  1  9/411 (2.19%)  13 4/411 (0.97%)  4 3/338 (0.89%)  4
Anaemia  1  0/411 (0.00%)  0 4/411 (0.97%)  4 0/338 (0.00%)  0
Iron deficiency anaemia  1  1/411 (0.24%)  1 2/411 (0.49%)  2 1/338 (0.30%)  1
Neutropenia  1  1/411 (0.24%)  2 2/411 (0.49%)  2 0/338 (0.00%)  0
Lymphadenitis  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Eosinophilia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Granulocytopenia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Leukopenia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Polycythaemia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Red blood cell abnormality  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Thrombocytopenia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Thymus disorder  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Cardiac disorders       
Angina pectoris  1  1/411 (0.24%)  1 4/411 (0.97%)  4 1/338 (0.30%)  1
Palpitations  1  1/411 (0.24%)  1 2/411 (0.49%)  2 1/338 (0.30%)  1
Tachycardia  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Cardiomyopathy  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Myocarditis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Ventricular hypokinesia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Congenital, familial and genetic disorders       
Hereditary non-polyposis colorectal cancer syndrome  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Ichthyosis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Kidney duplex  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Odontogenic cyst  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Ear and labyrinth disorders       
Vertigo  1  6/411 (1.46%)  6 5/411 (1.22%)  5 1/338 (0.30%)  1
Tinnitus  1  5/411 (1.22%)  5 4/411 (0.97%)  5 0/338 (0.00%)  0
Ear pain  1  1/411 (0.24%)  1 0/411 (0.00%)  0 2/338 (0.59%)  2
Hypoacusis  1  2/411 (0.49%)  2 0/411 (0.00%)  0 1/338 (0.30%)  1
Deafness  1  0/411 (0.00%)  0 2/411 (0.49%)  2 0/338 (0.00%)  0
Ear disorder  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Eustachian tube obstruction  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Excessive cerumen production  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
External ear inflammation  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
External ear pain  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Middle ear effusion  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Tympanic membrane disorder  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Endocrine disorders       
Hypothyroidism  1  1/411 (0.24%)  1 1/411 (0.24%)  1 1/338 (0.30%)  1
Goitre  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Androgen deficiency  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Basedow's disease  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Hyperthyroidism  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Hypogonadism  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Thyroid mass  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Eye disorders       
Vision blurred  1  2/411 (0.49%)  2 5/411 (1.22%)  5 0/338 (0.00%)  0
Conjunctivitis allergic  1  1/411 (0.24%)  1 2/411 (0.49%)  2 1/338 (0.30%)  1
Ocular hyperaemia  1  3/411 (0.73%)  3 0/411 (0.00%)  0 0/338 (0.00%)  0
Visual acuity reduced  1  1/411 (0.24%)  1 1/411 (0.24%)  1 1/338 (0.30%)  1
Chalazion  1  0/411 (0.00%)  0 0/411 (0.00%)  0 2/338 (0.59%)  2
Conjunctival haemorrhage  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Conjunctival hyperaemia  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Dry eye  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Eye pruritus  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Blepharitis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Cataract  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Corneal erosion  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Diplopia  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Eye inflammation  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Eye pain  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Eyelids pruritus  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Hypermetropia  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Keratitis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Ocular discomfort  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Photophobia  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Retinal haemorrhage  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Retinal tear  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Scleritis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Gastrointestinal disorders       
Diarrhoea  1  58/411 (14.11%)  72 54/411 (13.14%)  65 21/338 (6.21%)  25
Nausea  1  60/411 (14.60%)  70 55/411 (13.38%)  66 3/338 (0.89%)  3
Abdominal pain  1  18/411 (4.38%)  21 16/411 (3.89%)  20 7/338 (2.07%)  7
Vomiting  1  16/411 (3.89%)  21 18/411 (4.38%)  19 5/338 (1.48%)  7
Constipation  1  15/411 (3.65%)  16 14/411 (3.41%)  17 1/338 (0.30%)  1
Abdominal pain upper  1  12/411 (2.92%)  13 12/411 (2.92%)  14 5/338 (1.48%)  5
Haemorrhoids  1  15/411 (3.65%)  15 9/411 (2.19%)  9 5/338 (1.48%)  6
Flatulence  1  12/411 (2.92%)  12 11/411 (2.68%)  11 1/338 (0.30%)  1
Dyspepsia  1  6/411 (1.46%)  6 11/411 (2.68%)  11 2/338 (0.59%)  3
Toothache  1  9/411 (2.19%)  10 3/411 (0.73%)  3 6/338 (1.78%)  6
Gastrooesophageal reflux disease  1  4/411 (0.97%)  4 12/411 (2.92%)  12 1/338 (0.30%)  1
Abdominal distension  1  6/411 (1.46%)  6 6/411 (1.46%)  7 4/338 (1.18%)  5
Proctitis  1  5/411 (1.22%)  5 5/411 (1.22%)  6 4/338 (1.18%)  4
Anogenital dysplasia  1  3/411 (0.73%)  3 4/411 (0.97%)  4 5/338 (1.48%)  5
Abdominal discomfort  1  10/411 (2.43%)  11 1/411 (0.24%)  1 0/338 (0.00%)  0
Anal fissure  1  3/411 (0.73%)  3 6/411 (1.46%)  6 2/338 (0.59%)  2
Gastritis  1  4/411 (0.97%)  4 1/411 (0.24%)  1 5/338 (1.48%)  5
Aphthous ulcer  1  3/411 (0.73%)  3 4/411 (0.97%)  6 2/338 (0.59%)  2
Odynophagia  1  3/411 (0.73%)  3 4/411 (0.97%)  4 1/338 (0.30%)  1
Rectal haemorrhage  1  2/411 (0.49%)  2 3/411 (0.73%)  3 2/338 (0.59%)  2
Dental caries  1  3/411 (0.73%)  3 3/411 (0.73%)  3 0/338 (0.00%)  0
Abdominal pain lower  1  1/411 (0.24%)  1 3/411 (0.73%)  3 1/338 (0.30%)  1
Enteritis  1  1/411 (0.24%)  1 2/411 (0.49%)  2 2/338 (0.59%)  2
Inguinal hernia  1  2/411 (0.49%)  2 2/411 (0.49%)  2 1/338 (0.30%)  1
Anal fistula  1  2/411 (0.49%)  2 1/411 (0.24%)  1 1/338 (0.30%)  1
Colitis  1  2/411 (0.49%)  2 0/411 (0.00%)  0 2/338 (0.59%)  2
Gastrointestinal disorder  1  1/411 (0.24%)  1 3/411 (0.73%)  3 0/338 (0.00%)  0
Hiatus hernia  1  0/411 (0.00%)  0 3/411 (0.73%)  3 1/338 (0.30%)  1
Proctalgia  1  2/411 (0.49%)  3 2/411 (0.49%)  2 0/338 (0.00%)  0
Anal haemorrhage  1  2/411 (0.49%)  2 1/411 (0.24%)  1 0/338 (0.00%)  0
Anal pruritus  1  3/411 (0.73%)  3 0/411 (0.00%)  0 0/338 (0.00%)  0
Dry mouth  1  1/411 (0.24%)  1 1/411 (0.24%)  1 1/338 (0.30%)  1
Mouth ulceration  1  2/411 (0.49%)  2 1/411 (0.24%)  1 0/338 (0.00%)  0
Oesophagitis  1  1/411 (0.24%)  1 2/411 (0.49%)  2 0/338 (0.00%)  0
Abdominal tenderness  1  0/411 (0.00%)  0 2/411 (0.49%)  2 0/338 (0.00%)  0
Abnormal faeces  1  0/411 (0.00%)  0 2/411 (0.49%)  2 0/338 (0.00%)  0
Anal ulcer  1  1/411 (0.24%)  2 1/411 (0.24%)  1 0/338 (0.00%)  0
Anorectal discomfort  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Cheilitis  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Dysphagia  1  0/411 (0.00%)  0 1/411 (0.24%)  1 1/338 (0.30%)  1
Food poisoning  1  0/411 (0.00%)  0 0/411 (0.00%)  0 2/338 (0.59%)  2
Gastrointestinal pain  1  0/411 (0.00%)  0 2/411 (0.49%)  2 0/338 (0.00%)  0
Haematochezia  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Haemorrhoidal haemorrhage  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Oesophageal spasm  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Oral disorder  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Abdominal rigidity  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Anal skin tags  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Anal spasm  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Anorectal disorder  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Chronic gastritis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Diverticulum  1  0/411 (0.00%)  0 1/411 (0.24%)  3 0/338 (0.00%)  0
Epigastric discomfort  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Erosive duodenitis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Faeces pale  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Gastric ulcer  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Gastrointestinal haemorrhage  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Gingival hypertrophy  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Gingival pain  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Gingival swelling  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Haemorrhoids thrombosed  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Hyperchlorhydria  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Irritable bowel syndrome  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Large intestine polyp  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Lip haematoma  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Lip swelling  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Loose tooth  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Mouth cyst  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Oesophageal pain  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Oral pain  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Palatal disorder  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Palatal ulcer  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Pancreatitis acute  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  2
Paraesthesia oral  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Periodontal disease  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Rectal discharge  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Rectal fissure  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Saliva altered  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Salivary hypersecretion  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Stomatitis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Tongue disorder  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Tooth disorder  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Tooth impacted  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Ulcerative gastritis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
General disorders       
Fatigue  1  22/411 (5.35%)  26 24/411 (5.84%)  27 7/338 (2.07%)  7
Pyrexia  1  23/411 (5.60%)  30 24/411 (5.84%)  26 6/338 (1.78%)  7
Asthenia  1  14/411 (3.41%)  16 18/411 (4.38%)  19 7/338 (2.07%)  7
Influenza like illness  1  13/411 (3.16%)  15 9/411 (2.19%)  11 7/338 (2.07%)  8
Chest pain  1  5/411 (1.22%)  5 2/411 (0.49%)  2 3/338 (0.89%)  3
Feeling abnormal  1  2/411 (0.49%)  3 2/411 (0.49%)  2 0/338 (0.00%)  0
Malaise  1  3/411 (0.73%)  3 1/411 (0.24%)  1 0/338 (0.00%)  0
Local swelling  1  3/411 (0.73%)  3 0/411 (0.00%)  0 0/338 (0.00%)  0
Oedema peripheral  1  2/411 (0.49%)  2 1/411 (0.24%)  1 0/338 (0.00%)  0
Pain  1  0/411 (0.00%)  0 3/411 (0.73%)  3 0/338 (0.00%)  0
Peripheral swelling  1  0/411 (0.00%)  0 2/411 (0.49%)  2 1/338 (0.30%)  1
Chest discomfort  1  1/411 (0.24%)  1 1/411 (0.24%)  3 0/338 (0.00%)  0
Cyst  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Granuloma  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Ill-defined disorder  1  0/411 (0.00%)  0 0/411 (0.00%)  0 2/338 (0.59%)  2
Inflammation  1  0/411 (0.00%)  0 0/411 (0.00%)  0 2/338 (0.59%)  2
Mucosal dryness  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Nodule  1  0/411 (0.00%)  0 0/411 (0.00%)  0 2/338 (0.59%)  2
Suprapubic pain  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Axillary pain  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Chills  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Discomfort  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Facial pain  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Feeling cold  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Mucosal inflammation  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Non-cardiac chest pain  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Oedema mucosal  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Polyp  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Swelling  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Hepatobiliary disorders       
Hepatic steatosis  1  2/411 (0.49%)  2 3/411 (0.73%)  3 1/338 (0.30%)  1
Cholelithiasis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Hepatitis toxic  1  0/411 (0.00%)  0 2/411 (0.49%)  3 0/338 (0.00%)  0
Biliary colic  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Cholecystitis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Drug-induced liver injury  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Gallbladder polyp  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Hepatic cyst  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Hepatic lesion  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Hepatitis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Hepatocellular injury  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Hepatomegaly  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Immune system disorders       
Seasonal allergy  1  8/411 (1.95%)  8 7/411 (1.70%)  7 5/338 (1.48%)  7
Food allergy  1  0/411 (0.00%)  0 3/411 (0.73%)  3 1/338 (0.30%)  1
Drug hypersensitivity  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Immune reconstitution inflammatory syndrome  1  0/411 (0.00%)  0 2/411 (0.49%)  2 0/338 (0.00%)  0
Hypersensitivity  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Jarisch-Herxheimer reaction  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Infections and infestations       
Viral upper respiratory tract infection  1  54/411 (13.14%)  73 54/411 (13.14%)  77 24/338 (7.10%)  27
Upper respiratory tract infection  1  34/411 (8.27%)  43 31/411 (7.54%)  38 27/338 (7.99%)  36
Syphilis  1  24/411 (5.84%)  25 28/411 (6.81%)  30 24/338 (7.10%)  30
Bronchitis  1  24/411 (5.84%)  33 22/411 (5.35%)  25 15/338 (4.44%)  16
Sinusitis  1  25/411 (6.08%)  36 16/411 (3.89%)  18 12/338 (3.55%)  19
Gastroenteritis  1  18/411 (4.38%)  21 18/411 (4.38%)  23 10/338 (2.96%)  11
Pharyngitis  1  23/411 (5.60%)  31 14/411 (3.41%)  16 9/338 (2.66%)  9
Influenza  1  16/411 (3.89%)  17 22/411 (5.35%)  23 7/338 (2.07%)  7
Respiratory tract infection  1  19/411 (4.62%)  19 12/411 (2.92%)  14 5/338 (1.48%)  9
Rhinitis  1  13/411 (3.16%)  20 13/411 (3.16%)  15 7/338 (2.07%)  8
Oral herpes  1  8/411 (1.95%)  9 13/411 (3.16%)  17 7/338 (2.07%)  8
Conjunctivitis  1  8/411 (1.95%)  8 11/411 (2.68%)  11 8/338 (2.37%)  9
Urinary tract infection  1  12/411 (2.92%)  14 7/411 (1.70%)  8 4/338 (1.18%)  4
Respiratory tract infection viral  1  11/411 (2.68%)  13 7/411 (1.70%)  8 4/338 (1.18%)  6
Urethritis  1  9/411 (2.19%)  10 8/411 (1.95%)  10 5/338 (1.48%)  6
Chlamydial infection  1  5/411 (1.22%)  6 9/411 (2.19%)  13 7/338 (2.07%)  8
Gonorrhoea  1  7/411 (1.70%)  8 6/411 (1.46%)  7 8/338 (2.37%)  9
Herpes zoster  1  9/411 (2.19%)  9 9/411 (2.19%)  9 2/338 (0.59%)  2
Gingivitis  1  8/411 (1.95%)  8 11/411 (2.68%)  11 0/338 (0.00%)  0
Tonsillitis  1  10/411 (2.43%)  10 4/411 (0.97%)  4 5/338 (1.48%)  8
Folliculitis  1  6/411 (1.46%)  7 8/411 (1.95%)  9 4/338 (1.18%)  4
Ear infection  1  7/411 (1.70%)  7 7/411 (1.70%)  11 2/338 (0.59%)  2
Genital herpes  1  5/411 (1.22%)  6 4/411 (0.97%)  5 5/338 (1.48%)  6
Pneumonia  1  8/411 (1.95%)  8 4/411 (0.97%)  4 2/338 (0.59%)  2
Tooth infection  1  7/411 (1.70%)  8 4/411 (0.97%)  4 3/338 (0.89%)  3
Nasopharyngitis  1  6/411 (1.46%)  7 4/411 (0.97%)  4 3/338 (0.89%)  3
Secondary syphilis  1  4/411 (0.97%)  4 4/411 (0.97%)  5 5/338 (1.48%)  5
Cellulitis  1  5/411 (1.22%)  5 4/411 (0.97%)  5 2/338 (0.59%)  2
Herpes simplex  1  1/411 (0.24%)  1 7/411 (1.70%)  8 3/338 (0.89%)  5
Herpes virus infection  1  3/411 (0.73%)  3 5/411 (1.22%)  8 3/338 (0.89%)  5
Onychomycosis  1  4/411 (0.97%)  5 4/411 (0.97%)  4 3/338 (0.89%)  3
Fungal skin infection  1  5/411 (1.22%)  5 5/411 (1.22%)  5 0/338 (0.00%)  0
Urethritis gonococcal  1  2/411 (0.49%)  2 5/411 (1.22%)  5 3/338 (0.89%)  3
Viral infection  1  6/411 (1.46%)  6 4/411 (0.97%)  4 0/338 (0.00%)  0
Furuncle  1  3/411 (0.73%)  3 4/411 (0.97%)  5 2/338 (0.59%)  2
Otitis externa  1  1/411 (0.24%)  1 5/411 (1.22%)  7 3/338 (0.89%)  3
Tooth abscess  1  4/411 (0.97%)  4 3/411 (0.73%)  3 2/338 (0.59%)  3
Tinea infection  1  5/411 (1.22%)  5 3/411 (0.73%)  3 0/338 (0.00%)  0
Anal chlamydia infection  1  3/411 (0.73%)  3 1/411 (0.24%)  1 3/338 (0.89%)  3
Lymphogranuloma venereum  1  0/411 (0.00%)  0 5/411 (1.22%)  5 2/338 (0.59%)  2
Otitis media  1  4/411 (0.97%)  4 2/411 (0.49%)  4 1/338 (0.30%)  1
Skin infection  1  2/411 (0.49%)  2 2/411 (0.49%)  2 3/338 (0.89%)  3
Tinea versicolour  1  3/411 (0.73%)  3 2/411 (0.49%)  2 2/338 (0.59%)  2
Acarodermatitis  1  1/411 (0.24%)  1 5/411 (1.22%)  5 0/338 (0.00%)  0
Laryngitis  1  2/411 (0.49%)  2 3/411 (0.73%)  3 1/338 (0.30%)  1
Anal abscess  1  2/411 (0.49%)  2 2/411 (0.49%)  3 1/338 (0.30%)  1
Erysipelas  1  2/411 (0.49%)  2 2/411 (0.49%)  2 1/338 (0.30%)  1
Genital infection fungal  1  1/411 (0.24%)  1 0/411 (0.00%)  0 4/338 (1.18%)  5
Infection  1  3/411 (0.73%)  3 2/411 (0.49%)  2 0/338 (0.00%)  0
Labyrinthitis  1  2/411 (0.49%)  2 2/411 (0.49%)  2 1/338 (0.30%)  1
Proctitis gonococcal  1  1/411 (0.24%)  1 2/411 (0.49%)  2 2/338 (0.59%)  2
Subcutaneous abscess  1  3/411 (0.73%)  3 1/411 (0.24%)  1 1/338 (0.30%)  1
Tinea cruris  1  1/411 (0.24%)  1 2/411 (0.49%)  2 2/338 (0.59%)  2
Fungal infection  1  1/411 (0.24%)  1 3/411 (0.73%)  3 0/338 (0.00%)  0
Lower respiratory tract infection  1  2/411 (0.49%)  2 0/411 (0.00%)  0 2/338 (0.59%)  4
Orchitis  1  1/411 (0.24%)  1 2/411 (0.49%)  2 1/338 (0.30%)  1
Pharyngitis streptococcal  1  1/411 (0.24%)  1 2/411 (0.49%)  2 1/338 (0.30%)  1
Rash pustular  1  0/411 (0.00%)  0 2/411 (0.49%)  2 2/338 (0.59%)  2
Staphylococcal infection  1  2/411 (0.49%)  2 2/411 (0.49%)  2 0/338 (0.00%)  0
Tinea pedis  1  2/411 (0.49%)  2 1/411 (0.24%)  1 1/338 (0.30%)  1
Abscess  1  2/411 (0.49%)  4 1/411 (0.24%)  1 0/338 (0.00%)  0
Acute hepatitis C  1  1/411 (0.24%)  1 1/411 (0.24%)  1 1/338 (0.30%)  1
Acute sinusitis  1  2/411 (0.49%)  2 1/411 (0.24%)  1 0/338 (0.00%)  0
Balanitis candida  1  1/411 (0.24%)  1 1/411 (0.24%)  1 1/338 (0.30%)  1
Cystitis  1  3/411 (0.73%)  3 0/411 (0.00%)  0 0/338 (0.00%)  0
Epididymitis  1  1/411 (0.24%)  1 2/411 (0.49%)  2 0/338 (0.00%)  0
Gastroenteritis viral  1  1/411 (0.24%)  1 2/411 (0.49%)  2 0/338 (0.00%)  0
Gastrointestinal infection  1  1/411 (0.24%)  1 2/411 (0.49%)  2 0/338 (0.00%)  0
Giardiasis  1  1/411 (0.24%)  1 1/411 (0.24%)  1 1/338 (0.30%)  1
Helicobacter infection  1  1/411 (0.24%)  1 2/411 (0.49%)  2 0/338 (0.00%)  0
Hordeolum  1  1/411 (0.24%)  1 2/411 (0.49%)  4 0/338 (0.00%)  0
Localised infection  1  0/411 (0.00%)  0 2/411 (0.49%)  2 1/338 (0.30%)  1
Lung infection  1  2/411 (0.49%)  3 0/411 (0.00%)  0 1/338 (0.30%)  1
Oral candidiasis  1  1/411 (0.24%)  1 1/411 (0.24%)  1 1/338 (0.30%)  1
Parotitis  1  2/411 (0.49%)  2 0/411 (0.00%)  0 1/338 (0.30%)  1
Pharyngotonsillitis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 2/338 (0.59%)  2
Pilonidal cyst  1  2/411 (0.49%)  2 0/411 (0.00%)  0 1/338 (0.30%)  1
Primary syphilis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 2/338 (0.59%)  2
Tracheitis  1  1/411 (0.24%)  1 1/411 (0.24%)  1 1/338 (0.30%)  1
Angular cheilitis  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Beta haemolytic streptococcal infection  1  0/411 (0.00%)  0 0/411 (0.00%)  0 2/338 (0.59%)  2
Cervicitis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 2/338 (0.59%)  2
Chronic sinusitis  1  1/411 (0.24%)  1 1/411 (0.24%)  2 0/338 (0.00%)  0
Dermatophytosis  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Eye infection  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Gastroenteritis shigella  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Genital herpes simplex  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Genital infection bacterial  1  0/411 (0.00%)  0 0/411 (0.00%)  0 2/338 (0.59%)  2
Helicobacter gastritis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Hepatitis A  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Hepatitis C  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Infected bite  1  0/411 (0.00%)  0 2/411 (0.49%)  3 0/338 (0.00%)  0
Infection parasitic  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Molluscum contagiosum  1  0/411 (0.00%)  0 2/411 (0.49%)  2 0/338 (0.00%)  0
Oral infection  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Parasitic gastroenteritis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Paronychia  1  2/411 (0.49%)  3 0/411 (0.00%)  0 0/338 (0.00%)  0
Proctitis chlamydial  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Vulvovaginal mycotic infection  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Abscess oral  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Amoebiasis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Asymptomatic bacteriuria  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Bacterial disease carrier  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Bacterial infection  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Bacterial vaginosis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Bacteriuria  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Body tinea  1  0/411 (0.00%)  0 1/411 (0.24%)  2 0/338 (0.00%)  0
Campylobacter gastroenteritis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Campylobacter infection  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Carbuncle  1  1/411 (0.24%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Cervicitis human papilloma virus  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Chronic hepatitis C  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Chronic tonsillitis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Clostridium difficile colitis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Conjunctivitis viral  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Dysentery  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Ear infection fungal  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Enterobiasis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Enterovirus infection  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Gastroenteritis clostridial  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Gastrointestinal viral infection  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Genitourinary chlamydia infection  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Genitourinary tract infection  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Groin abscess  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Hepatitis E  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Hepatitis viral  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Impetigo  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Infected cyst  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Latent syphilis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Latent tuberculosis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Lung abscess  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Nail infection  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Ophthalmic herpes simplex  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Oral viral infection  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Oropharyngeal gonococcal infection  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Papilloma viral infection  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Pericoronitis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Periorbital cellulitis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Peritonsillar abscess  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Pharyngitis bacterial  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Pneumonia cytomegaloviral  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Post procedural infection  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Proctitis bacterial  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Pulpitis dental  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Pyelonephritis chronic  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Pyuria  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Scrotal abscess  1  0/411 (0.00%)  0 1/411 (0.24%)  2 0/338 (0.00%)  0
Sexually transmitted disease  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Sialoadenitis  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Sinobronchitis  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Sycosis barbae  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Tonsillitis bacterial  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Tonsillitis streptococcal  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Urethritis chlamydial  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Urinary tract infection bacterial  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Vaginitis gardnerella  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Viral pharyngitis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Vulvovaginal candidiasis  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Yersinia infection  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Injury, poisoning and procedural complications       
Ligament sprain  1  6/411 (1.46%)  6 5/411 (1.22%)  5 6/338 (1.78%)  8
Muscle strain  1  7/411 (1.70%)  7 3/411 (0.73%)  3 3/338 (0.89%)  3
Limb injury  1  2/411 (0.49%)  2 5/411 (1.22%)  5 3/338 (0.89%)  3
Contusion  1  4/411 (0.97%)  4 2/411 (0.49%)  2 1/338 (0.30%)  2
Epicondylitis  1  4/411 (0.97%)  4 0/411 (0.00%)  0 3/338 (0.89%)  3
Laceration  1  4/411 (0.97%)  4 2/411 (0.49%)  2 0/338 (0.00%)  0
Arthropod bite  1  2/411 (0.49%)  2 2/411 (0.49%)  2 1/338 (0.30%)  1
Fall  1  1/411 (0.24%)  1 2/411 (0.49%)  2 2/338 (0.59%)  2
Rib fracture  1  2/411 (0.49%)  2 2/411 (0.49%)  3 1/338 (0.30%)  1
Skin abrasion  1  1/411 (0.24%)  1 3/411 (0.73%)  4 1/338 (0.30%)  1
Bone contusion  1  3/411 (0.73%)  3 1/411 (0.24%)  1 0/338 (0.00%)  0
Foot fracture  1  3/411 (0.73%)  3 1/411 (0.24%)  1 0/338 (0.00%)  0
Meniscus injury  1  2/411 (0.49%)  2 0/411 (0.00%)  0 1/338 (0.30%)  1
Back injury  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Concussion  1  0/411 (0.00%)  0 1/411 (0.24%)  1 1/338 (0.30%)  1
Exposure to communicable disease  1  1/411 (0.24%)  1 1/411 (0.24%)  2 0/338 (0.00%)  0
Hand fracture  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Injury  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Ligament rupture  1  1/411 (0.24%)  1 1/411 (0.24%)  1 0/338 (0.00%)  0
Post-traumatic neck syndrome  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Procedural pain  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Road traffic accident  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Scar  1  1/411 (0.24%)  1 0/411 (0.00%)  0 1/338 (0.30%)  1
Tendon rupture  1  0/411 (0.00%)  0 1/411 (0.24%)  1 1/338 (0.30%)  1
Thermal burn  1  2/411 (0.49%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Upper limb fracture  1  0/411 (0.00%)  0 2/411 (0.49%)  2 0/338 (0.00%)  0
Accident  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Animal bite  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Ankle fracture  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Arthropod sting  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Bone fissure  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Burns second degree  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Cartilage injury  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Ear injury  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Excoriation  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Eye contusion  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Eye injury  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Fracture  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Head injury  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Human bite  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Joint dislocation  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Joint injury  1  1/411 (0.24%)  2 0/411 (0.00%)  0 0/338 (0.00%)  0
Lower limb fracture  1  0/411 (0.00%)  0 0/411 (0.00%)  0 1/338 (0.30%)  1
Neck injury  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Patella fracture  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0
Penis injury  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Poisoning  1  1/411 (0.24%)  1 0/411 (0.00%)  0 0/338 (0.00%)  0
Post lumbar puncture syndrome  1  0/411 (0.00%)  0 1/411 (0.24%)  1 0/338 (0.00%)  0