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Safety and Pharmacokinetics (PK) of Raltegravir in HIV (Human Immunodeficiency Virus)-Infected Children and Adolescents

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ClinicalTrials.gov Identifier: NCT00485264
Recruitment Status : Completed
First Posted : June 12, 2007
Results First Posted : December 22, 2014
Last Update Posted : November 2, 2021
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV Infections
Interventions Drug: Raltegravir poloxamer film coated tablet
Drug: Raltegravir chewable tablet
Drug: Raltegravir oral granules for suspension (20 mg/mL)
Enrollment 153
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily. Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg. Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily. Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily. Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data. Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Period Title: Overall Study
Started 71 16 18 21 15 12
Completed Week 24 67 16 18 21 14 11
Completed 35 9 12 17 9 5
Not Completed 36 7 6 4 6 7
Reason Not Completed
Enrolled But Not Given Treatment             0             0             0             0             1             0
Death             1             0             0             0             1             0
Adverse Event             1             0             2             3             1             3
Pregnancy             4             0             0             0             0             0
Disallowed Medication             0             0             0             0             0             1
Number/Volume/Timing of Study Meds             2             1             1             0             0             0
Lack of Efficacy             0             1             0             0             0             0
Guardian Consent Withdrawn             1             0             0             0             1             0
Physician Decision             0             2             0             0             0             0
Intolerance/Unable to Tolerate Dose             0             0             1             0             0             0
Not Able to Attend Clinic             5             0             0             1             1             2
Non-Compliant             17             2             1             0             1             0
Lost to Follow-up             2             1             1             0             0             1
Other Reason             3             0             0             0             0             0
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V Total
Hide Arm/Group Description Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily. Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg. Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily. Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily. Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data. Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.. Total of all reporting groups
Overall Number of Baseline Participants 71 16 18 21 14 12 152
Hide Baseline Analysis Population Description
All Treated Population: All patients exposed to raltegravir (at any dose)
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
15  (2) 9.1  (1.6) 8.9  (1.6) 3.1  (1.2) 1.0  (0.5) 0.3  (0.1) 9.5  (6.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
Female
34
  47.9%
7
  43.8%
7
  38.9%
13
  61.9%
5
  35.7%
4
  33.3%
70
  46.1%
Male
37
  52.1%
9
  56.3%
11
  61.1%
8
  38.1%
9
  64.3%
8
  66.7%
82
  53.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
Hispanic or Latino
26
  36.6%
4
  25.0%
12
  66.7%
8
  38.1%
5
  35.7%
0
   0.0%
55
  36.2%
Not Hispanic or Latino
43
  60.6%
11
  68.8%
6
  33.3%
10
  47.6%
3
  21.4%
8
  66.7%
81
  53.3%
Unknown or Not Reported
2
   2.8%
1
   6.3%
0
   0.0%
3
  14.3%
6
  42.9%
4
  33.3%
16
  10.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
American Indian or Alaska Native
1
   1.4%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   0.7%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
42
  59.2%
12
  75.0%
7
  38.9%
14
  66.7%
10
  71.4%
12
 100.0%
97
  63.8%
White
25
  35.2%
3
  18.8%
10
  55.6%
5
  23.8%
2
  14.3%
0
   0.0%
45
  29.6%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.8%
1
   7.1%
0
   0.0%
2
   1.3%
Unknown or Not Reported
3
   4.2%
1
   6.3%
1
   5.6%
1
   4.8%
1
   7.1%
0
   0.0%
7
   4.6%
Plasma HIV RNA, continuous  
Mean (Standard Deviation)
Unit of measure:  Log10 copies/mL
Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
4.3  (0.6) 4.3  (0.6) 4.3  (0.5) 4.4  (0.8) 5.4  (1) 6  (1.2) 4.6  (0.9)
Plasma HIV RNA, categorical  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
0 to ≤4,000 copies/mL 10 2 2 2 1 0 16
>4,000 to ≤50,000 copies/mL 40 12 11 11 1 2 74
>50,000 to ≤100,000 copies/mL 14 1 4 4 3 1 23
>100,000 copies/mL 7 1 1 4 9 9 13
CD4 cell count  
Mean (Standard Deviation)
Unit of measure:  cells/µL
Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
410.7  (238.2) 652.3  (360.4) 545.4  (280.2) 1122.9  (537.1) 1647.5  (965.7) 1359.6  (1003.8) 744.3  (654.9)
CD4 percentage  
Mean (Standard Deviation)
Unit of measure:  Percentage of total lymphocytes
Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
19.9  (9.6) 25.4  (8.2) 26.7  (10.6) 27.9  (8.2) 22.6  (8.1) 18.4  (11.5) 23  (9.9)
CDC HIV Clinical Classification   [1] 
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
A 17 5 6 5 6 4 33
B 29 3 5 1 2 1 38
C 24 7 2 8 3 0 41
N 1 1 5 7 3 7 14
[1]
Measure Description: The CDC Classification System for HIV Infection is the medical classification system used by the United States Centers for Disease Control and Prevention (CDC) to classify HIV disease and infection. http://www.cdc.gov/mmwr/preview/mmwrhtml/00032890.htm
Number of antiretroviral (ARV) classes previously used  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
0 0 0 0 1 0 0 1
1 2 0 0 2 8 10 4
2 9 5 8 13 4 2 35
≥3 60 11 10 5 2 0 86
Duration of ARVs previously used  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
12  (3.8) 8.5  (2.3) 7.1  (3) 2.4  (1.4) 0.4  (0.5) 0.1  (0.1) 7.7  (5.6)
Prior use of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
Yes 60 14 15 10 8 11 118
No 11 2 3 11 6 1 34
Use of prior PIs  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
Yes 69 13 13 13 5 0 113
No 2 3 5 8 9 12 39
Phenotypic Sensitivity score   [1] 
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
0 5 1 0 0 0 0 6
1 15 4 7 2 0 1 29
2 25 2 8 8 2 5 50
≥3 21 7 2 6 9 4 49
Missing 5 2 1 5 3 2 18
[1]
Measure Description: The Phenotypic Sensitivity score (PSS) was defined as the total number of ARVs in optimized background therapy (OBT) to which the subject's viral isolate showed phenotypic sensitivity, based on pre-study resistance tests. The PSS score range is from 0 (meaning there was no ARV the subject was sensitive to) to >=3 (the subject was sensitive to >=3 of the ARVs in his/her OBT). If no resistance results were available for a drug, it was scored as one active drug in the PSS if there was history of prior use, and was considered not active if no prior use. Scoring did not include Raltegravir.
Genotypic sensitivity score   [1] 
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 71 participants 16 participants 18 participants 21 participants 14 participants 12 participants 152 participants
0 9 1 0 0 0 0 10
1 23 4 9 2 0 1 39
2 20 6 7 11 3 5 52
≥3 18 5 2 7 10 3 45
Missing 1 0 0 1 1 3 6
[1]
Measure Description: The Genotypic Sensitivity score (GSS) was defined as the total number of ARVs in OBT to which the subject's viral isolate showed genotypic sensitivity, based on pre-study resistance tests. The GSS score range is from 0 (meaning there was no ARV the subject was sensitive to) to >=3 (the subject was sensitive to >=3 of the ARVs in his/her OBT). If no resistance results were available for a drug, it was scored as one active drug in the GSS if there was history of prior use, and was considered not active if no prior use. Scoring did not include Raltegravir.
1.Primary Outcome
Title Percentage of Participants With Grade 3 or 4 Adverse Events (AEs)
Hide Description Adverse events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0. All grade 3 and higher signs, symptoms, and laboratory toxicities were included.
Time Frame From study entry through Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Final Dose Population: Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts were combined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts.
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Overall Number of Participants Analyzed 59 4 13 20 14 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
20.3
(11 to 32.8)
25
(0.6 to 80.6)
15.4
(1.9 to 45.4)
30
(11.9 to 54.3)
35.7
(12.8 to 64.9)
33.3
(9.9 to 65.1)
2.Primary Outcome
Title Number of Participants Terminated From Treatment Due to Suspected Adverse Drug Reaction (SADR) Attributable to the Study Medication
Hide Description The attribution of relationship of serious adverse events to study drug for the purposes of employing the start, stop and pause rules was by consensus among the site investigator, study team (which includes representatives from Merck) and the Division of AIDS medical officer; if unanimous agreement between them cannot be established, the attribution made by the majority of these 3 persons or entities will be used. Gradation of relationship will use the following terminology: Not related, Probably not related, Possibly related, Probably related or Definitely related.
Time Frame From study entry through Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Final Dose Population: Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts were combined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts.
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir granules for oral suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Overall Number of Participants Analyzed 59 4 13 20 14 12
Measure Type: Number
Unit of Measure: participants
0 0 0 0 0 0
3.Primary Outcome
Title Number of Participants Who Died
Hide Description Number of participants who died were summarized.
Time Frame From study entry through Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Final Dose Population: Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts were combined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts.
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data. .
Overall Number of Participants Analyzed 59 4 13 20 14 12
Measure Type: Number
Unit of Measure: participants
0 0 0 0 0 0
4.Primary Outcome
Title Pharmacokinetic (PK) Parameter: Area Under the Curve (AUC12h)
Hide Description Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). AUC12h (area-under-the-curve from 0 to 12 hours) were determined using the linear-log trapezoidal rule.
Time Frame Measured between days 5 and 12 of raltegravir initiation; Blood samples were drawn pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with intensive pharmacokinetic (PK) results at the final recommended dose (Stage I).
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Overall Number of Participants Analyzed 11 11 10 12 8 11
Mean (Standard Deviation)
Unit of Measure: hour*mg/L
10.2  (10.0) 13.4  (16.1) 10.5  (3.5) 9.5  (5.5) 9.3  (3.2) 10.9  (4.4)
5.Primary Outcome
Title PK Parameter: Maximum Plasma Concentration (Cmax)
Hide Description Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). Maximum plasma concentration (Cmax) was taken directly from the observed concentration-time data.
Time Frame Measured between days 5 and 12 of raltegravir initiation; Blood samples were drawn pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with intensive pharmacokinetic (PK) results at the final recommended dose (Stage I).
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Overall Number of Participants Analyzed 11 11 10 12 8 11
Mean (Standard Deviation)
Unit of Measure: ng/mL
2813.1  (2673.9) 4055.7  (5269.5) 5314.2  (2842.6) 5204.8  (2940.6) 5683.0  (3685.0) 4299.0  (1661.9)
6.Primary Outcome
Title PK Parameter: Time to Half of Maximum Plasma Concentration Cmax (T1/2)
Hide Description Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). Time to half of maximum plasma concentration Cmax (T1/2) was taken directly from the observed concentration-time data.
Time Frame Measured between days 5 and 12 of raltegravir initiation; Blood samples were drawn pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with intensive pharmacokinetic (PK) results at the final recommended dose (Stage I).
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Overall Number of Participants Analyzed 11 11 10 12 8 11
Mean (Standard Deviation)
Unit of Measure: hour
4.9  (3.6) 3.7  (1.4) 4.5  (4.2) 4.1  (3.2) 3.0  (1.8) 2.1  (1.5)
7.Primary Outcome
Title PK Parameter: Concentration at 12 Hours Postdose (C12h)
Hide Description Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). Plasma concentration at 12 hours postdose (C12h) was taken directly from the observed concentration-time data.
Time Frame Measured between days 5 and 12 of raltegravir initiation; Blood samples were drawn pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing.
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Participants with intensive pharmacokinetic (PK) results at the final recommended dose (Stage I).
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
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Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data..
Overall Number of Participants Analyzed 11 11 10 12 8 11
Mean (Standard Deviation)
Unit of Measure: ng/mL
197.0  (154.2) 399.4  (880.9) 78.7  (68.9) 39.5  (21.9) 56.4  (26.8) 99.6  (83.9)
8.Secondary Outcome
Title Percentage of Participants With Grade 3 or 4 Adverse Events (AEs)
Hide Description Adverse events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0. All grade 3 and higher signs, symptoms, and laboratory toxicities were included.
Time Frame From study entry through Week 48
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Final Dose Population: Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts were combined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts.
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Overall Number of Participants Analyzed 59 4 13 20 14 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
23.7
(13.6 to 36.6)
25
(0.6 to 80.6)
23.1
(5 to 53.8)
40
(19.1 to 63.9)
42.9
(17.7 to 71.1)
33.3
(9.9 to 65.1)
9.Secondary Outcome
Title Number of Participants Terminated From Treatment Due to Suspected Adverse Drug Reaction (SADR) Attributable to the Study Medication
Hide Description The attribution of relationship of serious adverse events to study drug for the purposes of employing the start, stop and pause rules was by consensus among the site investigator, study team (which includes representatives from Merck) and the Division of AIDS medical officer; if unanimous agreement between them cannot be established, the attribution made by the majority of these 3 persons or entities will be used. Gradation of relationship will use the following terminology: Not related, Probably not related, Possibly related, Probably related or Definitely related.
Time Frame From study entry through Week 48
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Final Dose Population: Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts were combined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts.
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV -Data Not Included in This Interim Analysis. Cohort V -Data Not Included in This Interim Analysis.
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Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Overall Number of Participants Analyzed 59 4 13 20 14 12
Measure Type: Number
Unit of Measure: participants
0 0 0 0 0 0
10.Secondary Outcome
Title Number of Participants Who Died
Hide Description Number of participants who died were summarized.
Time Frame From study entry through Week 48
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Final Dose Population: Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts were combined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts.
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data..
Overall Number of Participants Analyzed 59 4 13 20 14 12
Measure Type: Number
Unit of Measure: participants
0 0 0 0 0 0
11.Secondary Outcome
Title Percentage of Participants With ≥1 log10 Drop From Baseline in HIV RNA or HIV RNA <400 Copies/mL
Hide Description Plasma HIV RNA concentrations were determined at entry and at regular intervals using the HIV-1 MONITOR Test, version 1.5 (Roche Molecular Diagnostics) or RealTime HIV-1 (Abbott Molecular), and analyses used the Observed Failure Approach.
Time Frame Baseline, Week 24, 48
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Hide Analysis Population Description
Final Dose Population: Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts were combined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts.
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Overall Number of Participants Analyzed 59 4 13 20 14 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Baseline to Week 24
72.4
(59.1 to 83.3)
50
(6.8 to 93.2)
76.9
(46.2 to 95)
70
(45.7 to 88.1)
85.7
(57.2 to 98.2)
100
(71.5 to 100)
Baseline to Week 48
75
(61.6 to 85.6)
75
(19.4 to 99.4)
90.9
(58.7 to 99.8)
84.2
(60.4 to 96.6)
92.9
(66.1 to 99.8)
80
(44.4 to 97.5)
12.Secondary Outcome
Title Change of CD4 Count From Baseline
Hide Description Change in CD4 cell count from baseline was calculated as the value at later visit minus the value at baseline.
Time Frame Baseline, Week 24, 48
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Hide Analysis Population Description
Final Dose Population: Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts are combined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts.
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Overall Number of Participants Analyzed 59 4 13 20 14 12
Mean (95% Confidence Interval)
Unit of Measure: cells/µL
Baseline to Week 24
114.6
(73.9 to 155.4)
-35.8
(-348.8 to 277.3)
143.4
(-12.9 to 299.6)
147.2
(-2.7 to 297.1)
400.5
(60.3 to 740.6)
499.2
(-50.4 to 1048.7)
Baseline to Week 48
168.4
(117.7 to 219.1)
189.5
(-154.2 to 533.2)
76.8
(-85.3 to 238.9)
158.1
(11.7 to 304.4)
278.8
(-185.6 to 743.2)
876.0
(362.7 to 1389.3)
13.Secondary Outcome
Title Change of CD4 Percent From Baseline
Hide Description Change in CD4 percent from baseline was calculated as the value of the later visit minus the value at baseline.
Time Frame Baseline, Week 24, 48
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Hide Analysis Population Description
Final Dose Population: Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts are combined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts.
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description:
Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily.
Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg.
Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily.
Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
Overall Number of Participants Analyzed 59 4 13 20 14 12
Mean (95% Confidence Interval)
Unit of Measure: percentage of total lymphocytes
Baseline to Week 24
4.1
(2.8 to 5.3)
2.2
(-7.2 to 11.5)
0.8
(-3.6 to 5.2)
5.3
(2.9 to 7.7)
6.2
(1.3 to 11.2)
9.0
(4.6 to 13.4)
Baseline to Week 48
5.2
(3.9 to 6.6)
6.0
(-2.6 to 14.6)
1.6
(-2.7 to 5.9)
4.3
(1 to 7.6)
6.4
(1.4 to 11.3)
8.7
(2.7 to 14.8)
Time Frame From study entry to completion of the study at Week 240 or at 14 days after the premature study discontinuation.
Adverse Event Reporting Description Adverse event summary pertains to the Final Dose Population: participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts werecombined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts. The study protocol required reporting of all new diagnoses, signs/symptoms, and laboratory events of >=Grade 1; the protocol team assessed attribution to treatment for adverse events >=Grade 3.
 
Arm/Group Title Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Hide Arm/Group Description Participants between the ages of 12 and 18 years; receiving raltegravir poloxamer film coated tablet; final selected dose: 400-mg tablet taken orally twice daily. Participants between the ages of 6 and 11 years; receiving raltegravir poloxamer film coated tablet: final selected dose: 400-mg tablet taken orally twice daily for participants weighing at least 25 kg. Participants between the ages of 6 and 11 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily. Participants between the ages of 2 and 5 years; receiving raltegravir chewable tablet: final selected dose: Weight based dose of ~6 mg/kg to a maximum dose of 300 mg, taken orally twice daily. Participants between the ages of 6 and 23 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data. Participants between the ages of 4 weeks and 5 months; receiving raltegravir oral granules for suspension (20 mg/mL): Stage I starting dose of 6 mg/kg orally twice daily according to dosing table in protocol or the dose determined by review of all available data.
All-Cause Mortality
Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/59 (0.00%)   0/4 (0.00%)   0/13 (0.00%)   0/20 (0.00%)   1/14 (7.14%)   0/12 (0.00%) 
Hide Serious Adverse Events
Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   26/59 (44.07%)   2/4 (50.00%)   4/13 (30.77%)   7/20 (35.00%)   7/14 (50.00%)   4/12 (33.33%) 
Blood and lymphatic system disorders             
Anaemia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Haemolytic anaemia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Neutropenia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  2/14 (14.29%)  1/12 (8.33%) 
Thrombocytopenia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gastrointestinal disorders             
Abdominal pain † 1  5/59 (8.47%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Colitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gastric fistula † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gastritis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oesophagitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pancreatitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
General disorders             
Adverse drug reaction † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pyrexia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Hepatobiliary disorders             
Drug-induced liver injury † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Hyperbilirubinaemia † 1  1/59 (1.69%)  1/4 (25.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Infections and infestations             
Abdominal abscess † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Acute sinusitis † 1  0/59 (0.00%)  1/4 (25.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Appendicitis † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gastroenteritis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Herpes zoster † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Infection † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Lower respiratory tract infection † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Mastoiditis † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Meningitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Mycobacterium avium complex infection † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Periorbital cellulitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pneumocystis jirovecii pneumonia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Pneumonia † 1  6/59 (10.17%)  0/4 (0.00%)  0/13 (0.00%)  2/20 (10.00%)  0/14 (0.00%)  1/12 (8.33%) 
Pneumonia bacterial † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pneumonia viral † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Respiratory tract infection viral † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Sepsis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Septic shock † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Varicella † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Varicella zoster virus infection † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Viral diarrhoea † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Investigations             
Blood alkaline phosphatase increased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Blood bicarbonate decreased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Blood bilirubin increased † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Lipase abnormal † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Lipase increased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Liver function test increased † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Neutrophil count decreased † 1  6/59 (10.17%)  0/4 (0.00%)  0/13 (0.00%)  2/20 (10.00%)  0/14 (0.00%)  0/12 (0.00%) 
Transaminases increased † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Metabolism and nutrition disorders             
Cachexia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Diabetic ketoacidosis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Failure to thrive † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Hypoglycaemia † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Hypokalaemia † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  1/12 (8.33%) 
Metabolic acidosis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Musculoskeletal and connective tissue disorders             
Pain in extremity † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Nervous system disorders             
Febrile convulsion † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Nystagmus † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Seizure † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pregnancy, puerperium and perinatal conditions             
Foetal death † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Foetal growth restriction † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pregnancy † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Psychiatric disorders             
Abnormal behaviour † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Depression † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Mental disorder † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Suicidal behaviour † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Suicidal ideation † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Renal and urinary disorders             
Acute kidney injury † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Reproductive system and breast disorders             
Metrorrhagia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Vaginal haemorrhage † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Asthma † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Dyspnoea † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  2/14 (14.29%)  0/12 (0.00%) 
Pneumothorax † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Respiratory distress † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Skin and subcutaneous tissue disorders             
Dyshidrotic eczema † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Rash † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Rash erythematous † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Rash pruritic † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Social circumstances             
Treatment noncompliance † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Vascular disorders             
Hypovolaemic shock † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
1
Term from vocabulary, MedDRA 20.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Cohort I Cohort IIA Cohort IIB Cohort III Cohort IV Cohort V
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   57/59 (96.61%)   4/4 (100.00%)   13/13 (100.00%)   20/20 (100.00%)   14/14 (100.00%)   12/12 (100.00%) 
Blood and lymphatic system disorders             
Anaemia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Haemolytic anaemia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Iron deficiency anaemia † 1  3/59 (5.08%)  0/4 (0.00%)  1/13 (7.69%)  1/20 (5.00%)  4/14 (28.57%)  1/12 (8.33%) 
Lymph node pain † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Lymphadenitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Lymphadenopathy † 1  9/59 (15.25%)  0/4 (0.00%)  1/13 (7.69%)  7/20 (35.00%)  4/14 (28.57%)  5/12 (41.67%) 
Neutropenia † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pancytopenia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Splenomegaly † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Thrombocytopenia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Cardiac disorders             
Atrioventricular block first degree † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Congestive cardiomyopathy † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Left ventricular hypertrophy † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Palpitations † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Sinus bradycardia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Tachycardia † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Congenital, familial and genetic disorders             
Cerebral palsy † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Ear and labyrinth disorders             
Cerumen impaction † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Conductive deafness † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Deafness † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Ear canal erythema † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Ear congestion † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  2/12 (16.67%) 
Ear discomfort † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Ear pain † 1  14/59 (23.73%)  0/4 (0.00%)  4/13 (30.77%)  3/20 (15.00%)  2/14 (14.29%)  0/12 (0.00%) 
Ear pruritus † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Eustachian tube dysfunction † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Excessive cerumen production † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Hypoacusis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Middle ear effusion † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Noninfective myringitis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Otorrhoea † 1  4/59 (6.78%)  0/4 (0.00%)  1/13 (7.69%)  3/20 (15.00%)  0/14 (0.00%)  1/12 (8.33%) 
Tinnitus † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Tympanic membrane hyperaemia † 1  2/59 (3.39%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Tympanosclerosis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Eye disorders             
Conjunctival hyperaemia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Conjunctival pallor † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  2/14 (14.29%)  0/12 (0.00%) 
Eye discharge † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  3/20 (15.00%)  1/14 (7.14%)  0/12 (0.00%) 
Eye irritation † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Eye pain † 1  5/59 (8.47%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Eye pruritus † 1  3/59 (5.08%)  1/4 (25.00%)  1/13 (7.69%)  2/20 (10.00%)  1/14 (7.14%)  2/12 (16.67%) 
Eye swelling † 1  2/59 (3.39%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Eyelid oedema † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Eyelid thickening † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Keratitis † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Lacrimation increased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Ocular hyperaemia † 1  8/59 (13.56%)  0/4 (0.00%)  2/13 (15.38%)  2/20 (10.00%)  1/14 (7.14%)  1/12 (8.33%) 
Periorbital oedema † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Photophobia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Vision blurred † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gastrointestinal disorders             
Abdominal discomfort † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Abdominal distension † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  1/12 (8.33%) 
Abdominal hernia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Abdominal mass † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Abdominal pain † 1  12/59 (20.34%)  1/4 (25.00%)  1/13 (7.69%)  2/20 (10.00%)  3/14 (21.43%)  0/12 (0.00%) 
Abdominal pain lower † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Abdominal pain upper † 1  8/59 (13.56%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Abdominal tenderness † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Anal pruritus † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Anorectal discomfort † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Aphthous ulcer † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Breath odour † 1  1/59 (1.69%)  0/4 (0.00%)  2/13 (15.38%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Cheilitis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Colitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Constipation † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  1/12 (8.33%) 
Dental caries † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Diarrhoea † 1  18/59 (30.51%)  1/4 (25.00%)  3/13 (23.08%)  7/20 (35.00%)  9/14 (64.29%)  7/12 (58.33%) 
Dysphagia † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Flatulence † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  1/12 (8.33%) 
Food poisoning † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gastrointestinal haemorrhage † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gastrooesophageal reflux disease † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gingival erythema † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gingival pain † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Infantile spitting up † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Infantile vomiting † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Inflammatory bowel disease † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Lip discolouration † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Lip ulceration † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Mouth ulceration † 1  3/59 (5.08%)  0/4 (0.00%)  1/13 (7.69%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Nausea † 1  20/59 (33.90%)  0/4 (0.00%)  2/13 (15.38%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Noninfective gingivitis † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oral discharge † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oral disorder † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  2/20 (10.00%)  1/14 (7.14%)  2/12 (16.67%) 
Oral mucosal blistering † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oral mucosal erythema † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Rectal haemorrhage † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Stomatitis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  2/14 (14.29%)  0/12 (0.00%) 
Toothache † 1  5/59 (8.47%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Vomiting † 1  21/59 (35.59%)  0/4 (0.00%)  4/13 (30.77%)  9/20 (45.00%)  6/14 (42.86%)  3/12 (25.00%) 
General disorders             
Adverse event † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Asthenia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Chest discomfort † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Chest pain † 1  7/59 (11.86%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Chills † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Crepitations † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Crying † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Cyst † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Fatigue † 1  7/59 (11.86%)  0/4 (0.00%)  2/13 (15.38%)  2/20 (10.00%)  0/14 (0.00%)  0/12 (0.00%) 
Influenza like illness † 1  5/59 (8.47%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Local swelling † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Localised oedema † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Malaise † 1  5/59 (8.47%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Mass † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Nodule † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Non-cardiac chest pain † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oedema peripheral † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pain † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Peripheral swelling † 1  2/59 (3.39%)  1/4 (25.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Puncture site discharge † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pyrexia † 1  28/59 (47.46%)  3/4 (75.00%)  8/13 (61.54%)  9/20 (45.00%)  8/14 (57.14%)  6/12 (50.00%) 
Secretion discharge † 1  1/59 (1.69%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Tenderness † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Hepatobiliary disorders             
Hepatomegaly † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  3/20 (15.00%)  2/14 (14.29%)  0/12 (0.00%) 
Ocular icterus † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Immune system disorders             
Anaphylactic reaction † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Immune reconstitution inflammatory syndrome † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Infections and infestations             
Abscess limb † 1  0/59 (0.00%)  1/4 (25.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Acarodermatitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Acute sinusitis † 1  4/59 (6.78%)  0/4 (0.00%)  1/13 (7.69%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Bacterial sepsis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Bacterial vaginosis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Body tinea † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  2/14 (14.29%)  3/12 (25.00%) 
Bronchiolitis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  1/12 (8.33%) 
Bronchitis † 1  4/59 (6.78%)  1/4 (25.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  1/12 (8.33%) 
Candida infection † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Cellulitis † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Cervicitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Cervicitis human papilloma virus † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Cervicitis trichomonal † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Chlamydial cervicitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Chronic sinusitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Clostridium difficile colitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Conjunctivitis † 1  4/59 (6.78%)  0/4 (0.00%)  2/13 (15.38%)  4/20 (20.00%)  1/14 (7.14%)  0/12 (0.00%) 
Conjunctivitis bacterial † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Coxsackie viral infection † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Dysentery † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Epididymitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Escherichia urinary tract infection † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  1/12 (8.33%) 
Fungal skin infection † 1  1/59 (1.69%)  0/4 (0.00%)  2/13 (15.38%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gastroenteritis † 1  4/59 (6.78%)  0/4 (0.00%)  3/13 (23.08%)  6/20 (30.00%)  6/14 (42.86%)  3/12 (25.00%) 
Gastroenteritis rotavirus † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Gingivitis † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
H1N1 influenza † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
HIV associated nephropathy † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
HIV wasting syndrome † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Hand-foot-and-mouth disease † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Herpes simplex † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Herpes zoster † 1  5/59 (8.47%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Hymenolepiasis † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Impetigo † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  9/20 (45.00%)  1/14 (7.14%)  1/12 (8.33%) 
Infection parasitic † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Influenza † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Laryngitis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Latent tuberculosis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Lice infestation † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  2/20 (10.00%)  0/14 (0.00%)  0/12 (0.00%) 
Lower respiratory tract infection viral † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Meningitis bacterial † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Molluscum contagiosum † 1  1/59 (1.69%)  0/4 (0.00%)  1/13 (7.69%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Mycoplasma infection † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oesophageal candidiasis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Onychomycosis † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oral candidiasis † 1  6/59 (10.17%)  0/4 (0.00%)  0/13 (0.00%)  2/20 (10.00%)  2/14 (14.29%)  1/12 (8.33%) 
Oral hairy leukoplakia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oral herpes † 1  1/59 (1.69%)  2/4 (50.00%)  2/13 (15.38%)  3/20 (15.00%)  1/14 (7.14%)  0/12 (0.00%) 
Orchitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oropharyngeal candidiasis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oropharyngeal gonococcal infection † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Otitis externa † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Otitis media † 1  8/59 (13.56%)  0/4 (0.00%)  3/13 (23.08%)  9/20 (45.00%)  4/14 (28.57%)  2/12 (16.67%) 
Otitis media acute † 1  3/59 (5.08%)  0/4 (0.00%)  1/13 (7.69%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Otitis media chronic † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pancreatitis viral † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Parotitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Persistent generalised lymphadenopathy † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  1/12 (8.33%) 
Pharyngeal chlamydia infection † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pharyngitis † 1  4/59 (6.78%)  0/4 (0.00%)  2/13 (15.38%)  2/20 (10.00%)  6/14 (42.86%)  4/12 (33.33%) 
Pharyngitis streptococcal † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pneumocystis jirovecii pneumonia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pneumonia † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  2/14 (14.29%)  0/12 (0.00%) 
Pneumonia bacterial † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  1/12 (8.33%) 
Pneumonia pneumococcal † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pneumonia respiratory syncytial viral † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pneumonia streptococcal † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Proctitis chlamydial † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Proctitis gonococcal † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pulmonary tuberculosis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Purulent discharge † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  2/20 (10.00%)  0/14 (0.00%)  0/12 (0.00%) 
Rash pustular † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Rhinitis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  2/20 (10.00%)  1/14 (7.14%)  0/12 (0.00%) 
Rubella † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Sinusitis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Sinusitis bacterial † 1  2/59 (3.39%)  2/4 (50.00%)  3/13 (23.08%)  5/20 (25.00%)  2/14 (14.29%)  0/12 (0.00%) 
Skin candida † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  2/20 (10.00%)  1/14 (7.14%)  1/12 (8.33%) 
Skin infection † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Staphylococcal abscess † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Subcutaneous abscess † 1  0/59 (0.00%)  1/4 (25.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Tinea capitis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  4/20 (20.00%)  2/14 (14.29%)  2/12 (16.67%) 
Tinea faciei † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  2/14 (14.29%)  0/12 (0.00%) 
Tinea infection † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  2/20 (10.00%)  1/14 (7.14%)  0/12 (0.00%) 
Tinea pedis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Tinea versicolour † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Tonsillitis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  3/20 (15.00%)  3/14 (21.43%)  1/12 (8.33%) 
Tooth abscess † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Upper respiratory tract infection † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Urethritis chlamydial † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Urethritis gonococcal † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Urinary tract infection † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  1/12 (8.33%) 
Urinary tract infection bacterial † 1  1/59 (1.69%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Urinary tract infection staphylococcal † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Vaginitis chlamydial † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Varicella † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Viral upper respiratory tract infection † 1  0/59 (0.00%)  0/4 (0.00%)  2/13 (15.38%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Virologic failure † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Vulvovaginal candidiasis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Vulvovaginitis † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Vulvovaginitis gonococcal † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Injury, poisoning and procedural complications             
Ankle fracture † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Arthropod bite † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  1/12 (8.33%) 
Clavicle fracture † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Contusion † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  2/14 (14.29%)  0/12 (0.00%) 
Genital injury † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Hand fracture † 1  5/59 (8.47%)  0/4 (0.00%)  2/13 (15.38%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Laceration † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Ligament sprain † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Post procedural swelling † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Post-traumatic pain † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Procedural pain † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Skin abrasion † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Stoma site rash † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Wrist fracture † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Investigations             
Alanine aminotransferase increased † 1  19/59 (32.20%)  1/4 (25.00%)  4/13 (30.77%)  3/20 (15.00%)  5/14 (35.71%)  4/12 (33.33%) 
Aspartate aminotransferase increased † 1  15/59 (25.42%)  2/4 (50.00%)  4/13 (30.77%)  4/20 (20.00%)  8/14 (57.14%)  4/12 (33.33%) 
Blood albumin decreased † 1  12/59 (20.34%)  0/4 (0.00%)  0/13 (0.00%)  3/20 (15.00%)  2/14 (14.29%)  4/12 (33.33%) 
Blood alkaline phosphatase increased † 1  11/59 (18.64%)  1/4 (25.00%)  1/13 (7.69%)  3/20 (15.00%)  0/14 (0.00%)  1/12 (8.33%) 
Blood bicarbonate decreased † 1  24/59 (40.68%)  0/4 (0.00%)  4/13 (30.77%)  11/20 (55.00%)  8/14 (57.14%)  5/12 (41.67%) 
Blood bilirubin increased † 1  13/59 (22.03%)  1/4 (25.00%)  4/13 (30.77%)  0/20 (0.00%)  2/14 (14.29%)  1/12 (8.33%) 
Blood calcium decreased † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Blood calcium increased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Blood cholesterol increased † 1  9/59 (15.25%)  0/4 (0.00%)  3/13 (23.08%)  9/20 (45.00%)  1/14 (7.14%)  0/12 (0.00%) 
Blood creatinine increased † 1  7/59 (11.86%)  0/4 (0.00%)  1/13 (7.69%)  1/20 (5.00%)  2/14 (14.29%)  0/12 (0.00%) 
Blood glucose decreased † 1  22/59 (37.29%)  1/4 (25.00%)  7/13 (53.85%)  8/20 (40.00%)  5/14 (35.71%)  1/12 (8.33%) 
Blood glucose increased † 1  14/59 (23.73%)  1/4 (25.00%)  1/13 (7.69%)  3/20 (15.00%)  9/14 (64.29%)  4/12 (33.33%) 
Blood lactate dehydrogenase increased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Blood lactic acid increased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Blood magnesium decreased † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Blood pH increased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Blood phosphorus decreased † 1  14/59 (23.73%)  2/4 (50.00%)  3/13 (23.08%)  1/20 (5.00%)  4/14 (28.57%)  2/12 (16.67%) 
Blood potassium decreased † 1  15/59 (25.42%)  2/4 (50.00%)  1/13 (7.69%)  2/20 (10.00%)  5/14 (35.71%)  2/12 (16.67%) 
Blood potassium increased † 1  0/59 (0.00%)  1/4 (25.00%)  0/13 (0.00%)  4/20 (20.00%)  7/14 (50.00%)  9/12 (75.00%) 
Blood pressure decreased † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Blood pressure diastolic increased † 1  0/59 (0.00%)  1/4 (25.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  2/12 (16.67%) 
Blood pressure increased † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Blood pressure systolic increased † 1  0/59 (0.00%)  1/4 (25.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Blood sodium abnormal † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Blood sodium decreased † 1  28/59 (47.46%)  2/4 (50.00%)  6/13 (46.15%)  14/20 (70.00%)  9/14 (64.29%)  10/12 (83.33%) 
Blood sodium increased † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Blood uric acid increased † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Blood urine present † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Breath sounds abnormal † 1  3/59 (5.08%)  0/4 (0.00%)  2/13 (15.38%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Electrocardiogram abnormal † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gamma-glutamyltransferase abnormal † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Gamma-glutamyltransferase increased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Haemoglobin decreased † 1  8/59 (13.56%)  0/4 (0.00%)  1/13 (7.69%)  2/20 (10.00%)  6/14 (42.86%)  9/12 (75.00%) 
Helicobacter test positive † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Lipase increased † 1  9/59 (15.25%)  0/4 (0.00%)  1/13 (7.69%)  2/20 (10.00%)  2/14 (14.29%)  3/12 (25.00%) 
Low density lipoprotein increased † 1  8/59 (13.56%)  0/4 (0.00%)  1/13 (7.69%)  8/20 (40.00%)  0/14 (0.00%)  0/12 (0.00%) 
Neutrophil count decreased † 1  18/59 (30.51%)  1/4 (25.00%)  5/13 (38.46%)  8/20 (40.00%)  11/14 (78.57%)  2/12 (16.67%) 
Platelet count decreased † 1  7/59 (11.86%)  0/4 (0.00%)  3/13 (23.08%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Transaminases increased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Viral load increased † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Weight decreased † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  3/14 (21.43%)  1/12 (8.33%) 
White blood cell count decreased † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Metabolism and nutrition disorders             
Abnormal loss of weight † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Acidosis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  1/12 (8.33%) 
Body fat disorder † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Decreased appetite † 1  6/59 (10.17%)  0/4 (0.00%)  3/13 (23.08%)  3/20 (15.00%)  4/14 (28.57%)  3/12 (25.00%) 
Dehydration † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  1/12 (8.33%) 
Failure to thrive † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  3/14 (21.43%)  3/12 (25.00%) 
Hyperlactacidaemia † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  2/20 (10.00%)  0/14 (0.00%)  0/12 (0.00%) 
Hyperlipidaemia † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Hypertriglyceridaemia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Lactic acidosis † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Malnutrition † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Metabolic syndrome † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Obesity † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Musculoskeletal and connective tissue disorders             
Arthralgia † 1  9/59 (15.25%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Back pain † 1  12/59 (20.34%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Costochondritis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Facial asymmetry † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Flank pain † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Head deformity † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Joint stiffness † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Joint swelling † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Kyphosis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Limb discomfort † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Muscle spasms † 1  4/59 (6.78%)  0/4 (0.00%)  1/13 (7.69%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Muscle twitching † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Musculoskeletal chest pain † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Musculoskeletal pain † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Myalgia † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Neck pain † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pain in extremity † 1  7/59 (11.86%)  1/4 (25.00%)  2/13 (15.38%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Pain in jaw † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pathological fracture † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Spinal pain † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Anogenital warts † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Skin papilloma † 1  4/59 (6.78%)  0/4 (0.00%)  2/13 (15.38%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Uterine leiomyoma † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Nervous system disorders             
Disturbance in attention † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Dizziness † 1  9/59 (15.25%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Dysarthria † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Dyscalculia † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Dysgraphia † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Dyslalia † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Epilepsy † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Facial paralysis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Facial paresis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Headache † 1  25/59 (42.37%)  4/4 (100.00%)  2/13 (15.38%)  1/20 (5.00%)  1/14 (7.14%)  0/12 (0.00%) 
Hyperreflexia † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Hypersomnia † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Hypertonia † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Hypoaesthesia † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Language disorder † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Meningeal disorder † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Migraine † 1  1/59 (1.69%)  1/4 (25.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Monoparesis † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Muscle spasticity † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Neuropathy peripheral † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Paraesthesia † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Posterior reversible encephalopathy syndrome † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Psychomotor hyperactivity † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Seizure † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  1/12 (8.33%) 
Speech disorder † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Syncope † 1  4/59 (6.78%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Thrombotic stroke † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Unresponsive to stimuli † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pregnancy, puerperium and perinatal conditions             
First trimester pregnancy † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Pregnancy † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Psychiatric disorders             
Abnormal behaviour † 1  1/59 (1.69%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Adjustment disorder † 1  1/59 (1.69%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Agitation † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Anger † 1  2/59 (3.39%)  1/4 (25.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Anxiety † 1  1/59 (1.69%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Attention deficit/hyperactivity disorder † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Depression † 1  6/59 (10.17%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Generalised anxiety disorder † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Hallucination, auditory † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Initial insomnia † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Insomnia † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Learning disorder † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Major depression † 1  2/59 (3.39%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Mood swings † 1  0/59 (0.00%)  1/4 (25.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Oppositional defiant disorder † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Reading disorder † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Restlessness † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Sexually inappropriate behaviour † 1  0/59 (0.00%)  0/4 (0.00%)  0/13 (0.00%)  1/20 (5.00%)  0/14 (0.00%)  0/12 (0.00%) 
Sleep terror † 1  0/59 (0.00%)  0/4 (0.00%)  1/13 (7.69%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Renal and urinary disorders             
Acute kidney injury † 1  1/59 (1.69%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  0/14 (0.00%)  0/12 (0.00%) 
Dysuria † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)  1/14 (7.14%)  0/12 (0.00%) 
Haematuria † 1  3/59 (5.08%)  0/4 (0.00%)  0/13 (0.00%)  0/20 (0.00%)