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A Study in Men With Low Testosterone to Measure the Effects of Testosterone Solution on Testosterone Levels, Sex Drive and Energy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01816295
Recruitment Status : Completed
First Posted : March 22, 2013
Results First Posted : October 2, 2015
Last Update Posted : December 28, 2015
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Hypogonadism
Interventions Drug: Testosterone Solution
Drug: Placebo Solution
Enrollment 715
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Solution Testosterone Solution
Hide Arm/Group Description Placebo solution applied topically to axillae once daily for 12 week double-blind treatment period. In optional open label extension (OLE) period, 60 milligram (mg) testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 24 weeks. Sixty mg testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 12 week double-blind treatment period. Optional OLE period starting at 60 mg/day with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Period Title: Double Blind Phase
Started 357 358
Received Study Drug 356 354
Completed 294 302
Not Completed 63 56
Reason Not Completed
Adverse Event             11             8
Entry Criteria Not Met             0             2
Lost to Follow-up             3             5
Physician Decision             2             2
Protocol Violation             17             11
Sponsor Decision             8             8
Withdrawal by Subject             22             20
Period Title: OLE Phase
Started 275 [1] 283 [1]
Completed 222 227
Not Completed 53 56
Reason Not Completed
Adverse Event             17             15
Death             1             0
Entry Criteria Not Met             3             5
Lost to Follow-up             5             5
Physician Decision             3             1
Protocol Violation             4             4
Sponsor Decision             7             9
Withdrawal by Subject             10             10
Lack of Efficacy             3             7
[1]
Participants who completed the DBP and still met eligibility criteria had option to enroll in OLE.
Arm/Group Title Placebo Solution Testosterone Solution Total
Hide Arm/Group Description Placebo solution applied topically to axillae once daily for 12 week double-blind treatment period. In optional open label extension (OLE) period, 60 milligram (mg) testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 24 weeks. Sixty mg testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 12 week double-blind treatment period. Optional OLE period starting at 60 mg/day with possible down/up titration (30 - 120 mg/day) for 24 weeks. Total of all reporting groups
Overall Number of Baseline Participants 357 358 715
Hide Baseline Analysis Population Description
All randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 357 participants 358 participants 715 participants
55.9  (11.35) 54.7  (10.58) 55.3  (10.98)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 357 participants 358 participants 715 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
357
 100.0%
358
 100.0%
715
 100.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 357 participants 358 participants 715 participants
Hispanic or Latino
51
  14.3%
57
  15.9%
108
  15.1%
Not Hispanic or Latino
280
  78.4%
279
  77.9%
559
  78.2%
Unknown or Not Reported
26
   7.3%
22
   6.1%
48
   6.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 357 participants 358 participants 715 participants
American Indian or Alaska Native
3
   0.8%
1
   0.3%
4
   0.6%
Asian
38
  10.6%
45
  12.6%
83
  11.6%
Native Hawaiian or Other Pacific Islander
2
   0.6%
0
   0.0%
2
   0.3%
Black or African American
26
   7.3%
24
   6.7%
50
   7.0%
White
282
  79.0%
281
  78.5%
563
  78.7%
More than one race
6
   1.7%
7
   2.0%
13
   1.8%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 357 participants 358 participants 715 participants
East Asia 34 40 74
Europe 63 57 120
South America 28 30 58
North America 232 231 463
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kilogram per square meter (kg/m²)
Number Analyzed 357 participants 358 participants 715 participants
30.9  (4.21) 30.3  (4.06) 30.6  (4.14)
[1]
Measure Description: BMI is an estimate of body fat based on body weight divided by height squared.
Symptoms of Hypogonadism  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 357 participants 358 participants 715 participants
Only Low Energy 49 47 96
Only Decreased Sexual Drive 39 40 79
Both Symptoms Present 269 271 540
1.Primary Outcome
Title Number of Participants With Total Serum Testosterone Concentration Within Normal Range at Week 12
Hide Description Normal range for total serum testosterone was defined as 300 to 1050 nanograms per deciliter (ng/dL).
Time Frame Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who completed 12 weeks of treatment and had non-missing testosterone concentration at week 12.
Arm/Group Title Placebo Solution Testosterone Solution
Hide Arm/Group Description:
Placebo solution applied topically to axillae once daily for 12 week double-blind treatment period. In optional open label extension (OLE) period, 60 milligram (mg) testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Sixty mg testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 12 week double-blind treatment period. Optional OLE period starting at 60 mg/day with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Overall Number of Participants Analyzed 287 297
Measure Type: Number
Unit of Measure: participants
43 217
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Solution, Testosterone Solution
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline to Week 12 in Sexual Arousal, Interest, and Drive (SAID) Scale Scores
Hide Description The SAID Scale is a self-administered instrument used to assess sexual arousal, interest, and sex drive in men with symptomatic hypogonadism. The SAID consists of 5 questions that were scored on a scale from 1 to 5, with "5" corresponding to greater levels of sexual arousal, interest, or drive. The SAID Scale total score was computed by summing the item scores and linearly transforming the sum to a 0 to 100 scale, with higher scores corresponding to greater sexual arousal, interest, and drive. Least squares (LS) mean change from baseline was calculated using an analysis of covariance (ANCOVA) with treatment group and the baseline value as covariates.
Time Frame Baseline, Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who reported low sex drive at baseline with non-missing SAID Scale data at baseline and at least one post baseline visit. Missing data endpoints were imputed using last observation carried forward (LOCF).
Arm/Group Title Placebo Solution Testosterone Solution
Hide Arm/Group Description:
Placebo solution applied topically to axillae once daily for 12 week double-blind treatment period. In optional open label extension (OLE) period, 60 milligram (mg) testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Sixty mg testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 12 week double-blind treatment period. Optional OLE period starting at 60 mg/day with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Overall Number of Participants Analyzed 257 244
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
6.3  (0.99) 11.4  (1.02)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Solution, Testosterone Solution
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 5.1
Confidence Interval (2-Sided) 99.5%
1.05 to 9.07
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.42
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline to Week 12 in Hypogonadism Energy Diary (HED) Scores
Hide Description The HED is a self-administered instrument used to assess real-time energy levels in men with symptomatic hypogonadism. It consists of 2 questions that were scored on a scale from 0 to 10, with "10" corresponding to "Full of Energy" or "Not Tired at All" (The Tiredness scale was reverse-mapped, as it was collected with "10" corresponding to "Extreme Tiredness"). The questionnaire was completed 3 times daily (forming 6 unique items) for 7 consecutive days. Item scores were computed by averaging the values for each item across 7 days. If more than 2 days were missing for an item, the item score was missing. The total score was computed by summing the item scores and linearly transforming the sum to a 0 to 100 scale, with higher scores corresponding to greater energy. If any item score was missing, the total score was missing. LS mean change from baseline was calculated using ANCOVA with treatment group and the baseline value as covariates.
Time Frame Baseline, Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who reported low energy at baseline with non-missing HED questionnaire at baseline and at least one post baseline visit. Missing data endpoints were imputed using LOCF.
Arm/Group Title Placebo Solution Testosterone Solution
Hide Arm/Group Description:
Placebo solution applied topically to axillae once daily for 12 week double-blind treatment period. In optional open label extension (OLE) period, 60 milligram (mg) testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Sixty mg testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 12 week double-blind treatment period. Optional OLE period starting at 60 mg/day with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Overall Number of Participants Analyzed 243 230
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
7.5  (0.87) 10.5  (0.89)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Solution, Testosterone Solution
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.019
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 2.9
Confidence Interval (2-Sided) 99.5%
-0.59 to 6.45
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.25
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Number of Participants With Prostate Specific Antigen (PSA) >4 Nanogram/Milliliter (ng/mL)
Hide Description [Not Specified]
Time Frame Double Blind Baseline, Week 12, Open Label Baseline, Week 36
Hide Outcome Measure Data
Hide Analysis Population Description
All participants with non-missing PSA result at the specified time point.
Arm/Group Title Placebo Solution Testosterone Solution
Hide Arm/Group Description:
Placebo solution applied topically to axillae once daily for 12 week double-blind treatment period. In optional open label extension (OLE) period, 60 milligram (mg) testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Sixty mg testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 12 week double-blind treatment period. Optional OLE period starting at 60 mg/day with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Overall Number of Participants Analyzed 350 347
Measure Type: Number
Unit of Measure: participants
Double-Blind Baseline (n=350, 347) 1 0
Week 12 (n=289, 299) 3 4
Open Label Baseline (n=269, 278) 0 0
Week 36 (n=219, 223) 4 4
5.Other Pre-specified Outcome
Title Change From Baseline in Total International Prostate Symptom Score (IPSS)
Hide Description The IPSS is a self-administered instrument used to assess for the severity of lower urinary tract symptoms. The IPSS consists of 7 questions that were scored on a scale from 0 (none/no symptoms) to 5 (frequent symptoms), for a total score range of 0 to 35. Higher numerical scores from the IPSS questionnaire represent greater severity of symptoms. LS mean change from baseline was calculated using ANCOVA with treatment group and the baseline value as covariates.
Time Frame Baseline, Week 12, Week 36
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with non-missing baseline IPSS measurement and at least one non-missing post baseline IPSS measurement. Missing data endpoints were imputed using LOCF.
Arm/Group Title Placebo Solution Testosterone Solution
Hide Arm/Group Description:
Placebo solution applied topically to axillae once daily for 12 week double-blind treatment period. In optional open label extension (OLE) period, 60 milligram (mg) testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Sixty mg testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 12 week double-blind treatment period. Optional OLE period starting at 60 mg/day with possible down/up titration (30 - 120 mg/day) for 24 weeks.
Overall Number of Participants Analyzed 320 324
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Change from Baseline to Week 12 -0.7  (0.24) -0.9  (0.24)
Change from Baseline to Week 36 (n=247, 255) -0.7  (0.28) -0.7  (0.27)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Solution, Testosterone Solution
Comments Change from Baseline to Week 12
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.442
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-0.94 to 0.41
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.34
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo Solution, Testosterone Solution
Comments Change from Baseline to Week 36
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.905
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-0.82 to 0.72
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.39
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description Analysis population includes all evaluable, randomized patients who received at least one dose of study drug.
 
Arm/Group Title Placebo Solution - Double Blind Testosterone Solution - Double Blind Testosterone Solution - OLE
Hide Arm/Group Description Placebo solution applied topically to axillae once daily for 12 week double-blind treatment period. Sixty mg testosterone solution applied topically to axillae once daily with possible down/up titration (30 - 120 mg/day) for 12 week double-blind treatment period. Sixty mg testosterone solution applied topically to axillae once daily at 60 mg/day with possible down/up titration (30 - 120 mg/day) for 24 weeks in optional OLE period.
All-Cause Mortality
Placebo Solution - Double Blind Testosterone Solution - Double Blind Testosterone Solution - OLE
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Hide Serious Adverse Events
Placebo Solution - Double Blind Testosterone Solution - Double Blind Testosterone Solution - OLE
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   8/356 (2.25%)      4/354 (1.13%)      24/558 (4.30%)    
Cardiac disorders       
Acute myocardial infarction  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Angina pectoris  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Angina unstable  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Gastrointestinal disorders       
Gastrooesophageal reflux disease  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Nausea  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Pancreatitis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
General disorders       
Non-cardiac chest pain  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  2
Pyrexia  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Hepatobiliary disorders       
Cholelithiasis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Infections and infestations       
Bacterial disease carrier  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Clostridium difficile colitis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Endocarditis enterococcal  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Influenza  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Meningitis viral  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Septic embolus  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Injury, poisoning and procedural complications       
Brachial plexus injury  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Chest injury  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Craniocerebral injury  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Fall  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Foreign body  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Haematuria traumatic  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Overdose  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Rib fracture  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Scapula fracture  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Upper limb fracture  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Musculoskeletal and connective tissue disorders       
Back pain  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Intervertebral disc protrusion  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Musculoskeletal pain  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Basal cell carcinoma  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Brain neoplasm  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Cholangiocarcinoma  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Lentigo maligna  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Lung carcinoma cell type unspecified stage iv  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Lung neoplasm malignant  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Squamous cell carcinoma  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Nervous system disorders       
Cerebrovascular accident  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Ischaemic stroke  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Seizure  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Transient ischaemic attack  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Psychiatric disorders       
Suicidal ideation  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Suicide attempt  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Renal and urinary disorders       
Nephrolithiasis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Respiratory, thoracic and mediastinal disorders       
Pneumothorax  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Pulmonary embolism  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Respiratory failure  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Vascular disorders       
Deep vein thrombosis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Venous thrombosis limb  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Placebo Solution - Double Blind Testosterone Solution - Double Blind Testosterone Solution - OLE
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   143/356 (40.17%)      148/354 (41.81%)      252/558 (45.16%)    
Blood and lymphatic system disorders       
Anaemia  1  1/356 (0.28%)  1 1/354 (0.28%)  2 0/558 (0.00%)  0
Leukocytosis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Lymphadenopathy  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Polycythaemia  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Cardiac disorders       
Angina pectoris  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Atrial fibrillation  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Atrial flutter  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Atrioventricular block first degree  1  1/356 (0.28%)  1 1/354 (0.28%)  1 0/558 (0.00%)  0
Bradycardia  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Bundle branch block left  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Bundle branch block right  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Cardiac failure congestive  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Coronary artery disease  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Palpitations  1  2/356 (0.56%)  2 1/354 (0.28%)  1 1/558 (0.18%)  1
Sinus bradycardia  1  1/356 (0.28%)  1 1/354 (0.28%)  1 0/558 (0.00%)  0
Sinus tachycardia  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Supraventricular extrasystoles  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Supraventricular tachycardia  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Tachycardia  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Ventricular extrasystoles  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Ear and labyrinth disorders       
Cerumen impaction  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Deafness neurosensory  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Middle ear effusion  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Tinnitus  1  1/356 (0.28%)  1 0/354 (0.00%)  0 2/558 (0.36%)  2
Vertigo  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Eye disorders       
Blepharospasm  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Dry eye  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Gastrointestinal disorders       
Abdominal discomfort  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Abdominal pain  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Abdominal pain lower  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Abdominal pain upper  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Chronic gastritis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Constipation  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Diarrhoea  1  4/356 (1.12%)  4 1/354 (0.28%)  1 5/558 (0.90%)  5
Diverticulum  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Dyspepsia  1  0/356 (0.00%)  0 2/354 (0.56%)  2 0/558 (0.00%)  0
Food poisoning  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Gastritis  1  1/356 (0.28%)  1 1/354 (0.28%)  1 1/558 (0.18%)  1
Gastrooesophageal reflux disease  1  1/356 (0.28%)  1 2/354 (0.56%)  2 1/558 (0.18%)  1
Gingival cyst  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Gingival pain  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Haemorrhoidal haemorrhage  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Haemorrhoids  1  0/356 (0.00%)  0 2/354 (0.56%)  2 0/558 (0.00%)  0
Hypoaesthesia oral  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Inguinal hernia  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Intestinal mass  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Irritable bowel syndrome  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Large intestine polyp  1  0/356 (0.00%)  0 1/354 (0.28%)  1 2/558 (0.36%)  2
Nausea  1  1/356 (0.28%)  1 2/354 (0.56%)  2 1/558 (0.18%)  1
Oral pain  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Paraesthesia oral  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Rectal fissure  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Salivary duct obstruction  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Tooth impacted  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  2
Toothache  1  0/356 (0.00%)  0 0/354 (0.00%)  0 4/558 (0.72%)  4
Umbilical hernia  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Vomiting  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
General disorders       
Application site acne  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Application site dryness  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Application site eczema  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Application site erythema  1  3/356 (0.84%)  3 1/354 (0.28%)  1 4/558 (0.72%)  4
Application site irritation  1  0/356 (0.00%)  0 2/354 (0.56%)  2 3/558 (0.54%)  3
Application site pain  1  7/356 (1.97%)  7 6/354 (1.69%)  6 2/558 (0.36%)  2
Application site pruritus  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Application site rash  1  0/356 (0.00%)  0 0/354 (0.00%)  0 4/558 (0.72%)  4
Application site reaction  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Application site warmth  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Asthenia  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Axillary pain  1  0/356 (0.00%)  0 2/354 (0.56%)  2 0/558 (0.00%)  0
Chills  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Cyst  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Cyst rupture  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Effusion  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Fatigue  1  0/356 (0.00%)  0 4/354 (1.13%)  4 2/558 (0.36%)  2
Haemorrhagic cyst  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Influenza like illness  1  2/356 (0.56%)  2 0/354 (0.00%)  0 2/558 (0.36%)  2
Local swelling  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Non-cardiac chest pain  1  1/356 (0.28%)  1 0/354 (0.00%)  0 3/558 (0.54%)  3
Oedema  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Oedema peripheral  1  0/356 (0.00%)  0 3/354 (0.85%)  3 3/558 (0.54%)  3
Pain  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Peripheral swelling  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Pyrexia  1  0/356 (0.00%)  0 2/354 (0.56%)  2 1/558 (0.18%)  1
Therapeutic response unexpected  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Hepatobiliary disorders       
Cholecystitis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Gallbladder polyp  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Hepatic cyst  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Immune system disorders       
Allergy to arthropod sting  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Drug hypersensitivity  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Multiple allergies  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Infections and infestations       
Abscess limb  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Acute sinusitis  1  1/356 (0.28%)  1 1/354 (0.28%)  1 1/558 (0.18%)  1
Application site pustules  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Arthritis infective  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Bronchitis  1  3/356 (0.84%)  4 1/354 (0.28%)  1 7/558 (1.25%)  7
Candida infection  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Cellulitis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 3/558 (0.54%)  3
Chest wall abscess  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Conjunctivitis  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Diarrhoea infectious  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Diverticulitis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Ear infection  1  6/356 (1.69%)  6 0/354 (0.00%)  0 0/558 (0.00%)  0
Erythema induratum  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Folliculitis  1  1/356 (0.28%)  1 1/354 (0.28%)  1 2/558 (0.36%)  2
Fungal infection  1  1/356 (0.28%)  1 0/354 (0.00%)  0 2/558 (0.36%)  2
Fungal skin infection  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Furuncle  1  2/356 (0.56%)  2 0/354 (0.00%)  0 0/558 (0.00%)  0
Gastroenteritis  1  3/356 (0.84%)  3 0/354 (0.00%)  0 1/558 (0.18%)  1
Gastroenteritis viral  1  0/356 (0.00%)  0 2/354 (0.56%)  2 5/558 (0.90%)  5
Helicobacter infection  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Herpes zoster  1  1/356 (0.28%)  1 1/354 (0.28%)  1 1/558 (0.18%)  1
Hordeolum  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Influenza  1  3/356 (0.84%)  3 3/354 (0.85%)  3 10/558 (1.79%)  10
Kidney infection  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Laryngitis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Localised infection  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Nasal vestibulitis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Nasopharyngitis  1  11/356 (3.09%)  11 8/354 (2.26%)  8 19/558 (3.41%)  21
Oesophageal candidiasis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Onychomycosis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Ophthalmic herpes zoster  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Oral candidiasis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Otitis media acute  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Paronychia  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Periodontitis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Pharyngitis  1  1/356 (0.28%)  1 2/354 (0.56%)  2 3/558 (0.54%)  3
Pharyngitis streptococcal  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Pneumonia  1  0/356 (0.00%)  0 0/354 (0.00%)  0 4/558 (0.72%)  4
Pneumonia mycoplasmal  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Rhinitis  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Sinusitis  1  2/356 (0.56%)  2 3/354 (0.85%)  3 5/558 (0.90%)  6
Tinea cruris  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Tinea pedis  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Tooth abscess  1  1/356 (0.28%)  1 1/354 (0.28%)  1 2/558 (0.36%)  2
Tooth infection  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Upper respiratory tract infection  1  6/356 (1.69%)  6 8/354 (2.26%)  9 19/558 (3.41%)  20
Urethritis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Urinary tract infection  1  1/356 (0.28%)  1 2/354 (0.56%)  2 3/558 (0.54%)  3
Viral upper respiratory tract infection  1  1/356 (0.28%)  1 1/354 (0.28%)  1 2/558 (0.36%)  2
Injury, poisoning and procedural complications       
Ankle fracture  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Contusion  1  1/356 (0.28%)  1 1/354 (0.28%)  1 0/558 (0.00%)  0
Epicondylitis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Fall  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Fibula fracture  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Foot fracture  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Hand fracture  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Human bite  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Joint dislocation  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Joint injury  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Laceration  1  1/356 (0.28%)  1 1/354 (0.28%)  1 1/558 (0.18%)  1
Ligament rupture  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Ligament sprain  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Limb injury  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Meniscus injury  1  1/356 (0.28%)  1 2/354 (0.56%)  2 1/558 (0.18%)  2
Muscle strain  1  0/356 (0.00%)  0 0/354 (0.00%)  0 3/558 (0.54%)  3
Procedural pain  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Rib fracture  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Skin abrasion  1  1/356 (0.28%)  1 0/354 (0.00%)  0 2/558 (0.36%)  2
Stress fracture  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Tendon injury  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Thermal burn  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Tibia fracture  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Tooth fracture  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Wound  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Investigations       
Alanine aminotransferase increased  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Aspartate aminotransferase increased  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Blood creatine phosphokinase abnormal  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Blood creatine phosphokinase increased  1  1/356 (0.28%)  1 1/354 (0.28%)  1 0/558 (0.00%)  0
Blood creatinine increased  1  1/356 (0.28%)  1 1/354 (0.28%)  1 1/558 (0.18%)  1
Blood follicle stimulating hormone increased  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Blood glucose decreased  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Blood glucose increased  1  3/356 (0.84%)  3 0/354 (0.00%)  0 1/558 (0.18%)  1
Blood insulin increased  1  2/356 (0.56%)  2 0/354 (0.00%)  0 0/558 (0.00%)  0
Blood luteinising hormone increased  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Blood pressure increased  1  2/356 (0.56%)  2 0/354 (0.00%)  0 2/558 (0.36%)  2
Blood testosterone increased  1  0/356 (0.00%)  0 0/354 (0.00%)  0 3/558 (0.54%)  3
Blood triglycerides increased  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Blood urea increased  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Electrocardiogram abnormal  1  0/356 (0.00%)  0 2/354 (0.56%)  2 0/558 (0.00%)  0
Electrocardiogram p wave abnormal  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Electrocardiogram repolarisation abnormality  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Gamma-glutamyltransferase increased  1  2/356 (0.56%)  2 0/354 (0.00%)  0 0/558 (0.00%)  0
Glycosylated haemoglobin increased  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Haematocrit increased  1  2/356 (0.56%)  2 9/354 (2.54%)  9 28/558 (5.02%)  28
Haemoglobin increased  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Hepatic enzyme increased  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
High density lipoprotein increased  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Liver function test abnormal  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Low density lipoprotein increased  1  0/356 (0.00%)  0 1/354 (0.28%)  1 3/558 (0.54%)  3
Lymph node palpable  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Mean cell volume increased  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Prostatic specific antigen  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Prostatic specific antigen abnormal  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Prostatic specific antigen increased  1  2/356 (0.56%)  2 4/354 (1.13%)  4 6/558 (1.08%)  6
Red blood cell count decreased  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Red blood cell count increased  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Weight decreased  1  0/356 (0.00%)  0 2/354 (0.56%)  2 1/558 (0.18%)  1
Weight increased  1  1/356 (0.28%)  1 1/354 (0.28%)  1 0/558 (0.00%)  0
Metabolism and nutrition disorders       
Decreased appetite  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Diabetes mellitus  1  1/356 (0.28%)  1 1/354 (0.28%)  1 1/558 (0.18%)  1
Dyslipidaemia  1  2/356 (0.56%)  2 0/354 (0.00%)  0 0/558 (0.00%)  0
Fluid retention  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Glucose tolerance impaired  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Gout  1  1/356 (0.28%)  2 1/354 (0.28%)  1 4/558 (0.72%)  5
Hypercalcaemia  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Hyperlipidaemia  1  3/356 (0.84%)  3 3/354 (0.85%)  3 0/558 (0.00%)  0
Hypertriglyceridaemia  1  1/356 (0.28%)  1 2/354 (0.56%)  2 2/558 (0.36%)  2
Hyperuricaemia  1  0/356 (0.00%)  0 1/354 (0.28%)  1 2/558 (0.36%)  2
Hypoglycaemia  1  1/356 (0.28%)  1 0/354 (0.00%)  0 2/558 (0.36%)  2
Increased appetite  1  0/356 (0.00%)  0 0/354 (0.00%)  0 3/558 (0.54%)  3
Type 2 diabetes mellitus  1  2/356 (0.56%)  2 1/354 (0.28%)  1 1/558 (0.18%)  1
Vitamin b complex deficiency  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Vitamin d deficiency  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Musculoskeletal and connective tissue disorders       
Arthralgia  1  4/356 (1.12%)  4 8/354 (2.26%)  8 6/558 (1.08%)  7
Axillary mass  1  0/356 (0.00%)  0 1/354 (0.28%)  2 0/558 (0.00%)  0
Back pain  1  5/356 (1.40%)  5 5/354 (1.41%)  5 16/558 (2.87%)  16
Exostosis  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Foot deformity  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Intervertebral disc degeneration  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Joint swelling  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Lumbar spinal stenosis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Muscle spasms  1  1/356 (0.28%)  1 2/354 (0.56%)  2 2/558 (0.36%)  2
Musculoskeletal chest pain  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Musculoskeletal pain  1  0/356 (0.00%)  0 1/354 (0.28%)  1 3/558 (0.54%)  3
Musculoskeletal stiffness  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Myalgia  1  1/356 (0.28%)  1 1/354 (0.28%)  1 2/558 (0.36%)  2
Neck mass  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Neck pain  1  0/356 (0.00%)  0 2/354 (0.56%)  2 2/558 (0.36%)  2
Pain in extremity  1  1/356 (0.28%)  1 2/354 (0.56%)  2 2/558 (0.36%)  2
Plantar fasciitis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Rotator cuff syndrome  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Spinal osteoarthritis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Tendonitis  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Acoustic neuroma  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Acrochordon  1  2/356 (0.56%)  2 0/354 (0.00%)  0 0/558 (0.00%)  0
Infected neoplasm  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Melanocytic naevus  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Neoplasm prostate  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Squamous cell carcinoma  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Nervous system disorders       
Burning sensation  1  4/356 (1.12%)  5 6/354 (1.69%)  7 0/558 (0.00%)  0
Carpal tunnel syndrome  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Cognitive disorder  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Diabetic neuropathy  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Dizziness  1  4/356 (1.12%)  4 0/354 (0.00%)  0 4/558 (0.72%)  4
Dysgeusia  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Epilepsy  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Headache  1  8/356 (2.25%)  8 3/354 (0.85%)  3 7/558 (1.25%)  7
Hypoaesthesia  1  0/356 (0.00%)  0 2/354 (0.56%)  2 1/558 (0.18%)  1
Lumbar radiculopathy  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Memory impairment  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Mental impairment  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Neuropathy peripheral  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Paraesthesia  1  0/356 (0.00%)  0 2/354 (0.56%)  2 1/558 (0.18%)  1
Paralysis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Presyncope  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Sciatica  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Sensory disturbance  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Sleep phase rhythm disturbance  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Syncope  1  0/356 (0.00%)  0 0/354 (0.00%)  0 3/558 (0.54%)  3
Trigeminal nerve disorder  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Writer's cramp  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Psychiatric disorders       
Aggression  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Agitation  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Anger  1  1/356 (0.28%)  1 1/354 (0.28%)  1 3/558 (0.54%)  4
Anxiety  1  2/356 (0.56%)  2 2/354 (0.56%)  2 6/558 (1.08%)  6
Bipolar disorder  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Depression  1  0/356 (0.00%)  0 2/354 (0.56%)  2 3/558 (0.54%)  3
Drug dependence  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Eating disorder  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Insomnia  1  2/356 (0.56%)  2 3/354 (0.85%)  3 3/558 (0.54%)  3
Irritability  1  0/356 (0.00%)  0 1/354 (0.28%)  1 2/558 (0.36%)  2
Libido decreased  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Libido increased  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Loss of libido  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Middle insomnia  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Mood swings  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Nervousness  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Personality disorder  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Premature ejaculation  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Restlessness  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Sleep disorder  1  3/356 (0.84%)  3 0/354 (0.00%)  0 0/558 (0.00%)  0
Renal and urinary disorders       
Calculus urinary  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Diabetic nephropathy  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Dysuria  1  0/356 (0.00%)  0 1/354 (0.28%)  1 2/558 (0.36%)  2
Haematuria  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Lower urinary tract symptoms  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Micturition disorder  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Nephrolithiasis  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Nocturia  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Pollakiuria  1  1/356 (0.28%)  1 1/354 (0.28%)  1 3/558 (0.54%)  3
Polyuria  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Urinary incontinence  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Urinary retention  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Urinary tract obstruction  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Reproductive system and breast disorders       
Balanoposthitis  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Benign prostatic hyperplasia  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Breast mass  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Breast tenderness  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Erectile dysfunction  1  0/356 (0.00%)  0 1/354 (0.28%)  1 3/558 (0.54%)  3
Genital paraesthesia  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Gynaecomastia  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Nipple disorder  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Nipple pain  1  0/356 (0.00%)  0 3/354 (0.85%)  3 1/558 (0.18%)  1
Painful erection  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Prostatomegaly  1  2/356 (0.56%)  2 1/354 (0.28%)  1 1/558 (0.18%)  1
Pruritus genital  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Spermatic cord pain  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Testicular atrophy  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Testicular pain  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Testicular swelling  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Cough  1  2/356 (0.56%)  2 4/354 (1.13%)  4 7/558 (1.25%)  7
Dyspnoea  1  4/356 (1.12%)  4 1/354 (0.28%)  1 3/558 (0.54%)  3
Epistaxis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Nasal congestion  1  0/356 (0.00%)  0 1/354 (0.28%)  1 3/558 (0.54%)  3
Oropharyngeal pain  1  1/356 (0.28%)  1 1/354 (0.28%)  1 4/558 (0.72%)  5
Respiratory tract congestion  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Rhinitis allergic  1  1/356 (0.28%)  1 1/354 (0.28%)  1 1/558 (0.18%)  1
Rhinorrhoea  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Sinus congestion  1  0/356 (0.00%)  0 1/354 (0.28%)  1 2/558 (0.36%)  2
Sleep apnoea syndrome  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Upper-airway cough syndrome  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Skin and subcutaneous tissue disorders       
Acne  1  3/356 (0.84%)  3 2/354 (0.56%)  2 10/558 (1.79%)  11
Actinic keratosis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Dermatitis  1  2/356 (0.56%)  2 2/354 (0.56%)  2 2/558 (0.36%)  3
Dermatitis atopic  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Dermatitis contact  1  1/356 (0.28%)  1 2/354 (0.56%)  2 2/558 (0.36%)  2
Dry skin  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Eczema  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Erythema  1  0/356 (0.00%)  0 4/354 (1.13%)  4 0/558 (0.00%)  0
Haemorrhage subcutaneous  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Hair growth abnormal  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Hyperhidrosis  1  1/356 (0.28%)  1 1/354 (0.28%)  1 0/558 (0.00%)  0
Night sweats  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Pruritus  1  4/356 (1.12%)  4 3/354 (0.85%)  3 3/558 (0.54%)  3
Rash  1  10/356 (2.81%)  11 4/354 (1.13%)  4 2/558 (0.36%)  2
Rash erythematous  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Rash papular  1  1/356 (0.28%)  1 2/354 (0.56%)  3 0/558 (0.00%)  0
Skin burning sensation  1  1/356 (0.28%)  1 1/354 (0.28%)  1 0/558 (0.00%)  0
Skin irritation  1  9/356 (2.53%)  9 4/354 (1.13%)  5 0/558 (0.00%)  0
Skin lesion  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Skin reaction  1  1/356 (0.28%)  1 1/354 (0.28%)  1 0/558 (0.00%)  0
Skin ulcer  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Urticaria  1  0/356 (0.00%)  0 1/354 (0.28%)  1 1/558 (0.18%)  1
Social circumstances       
Alcohol use  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Sexual activity increased  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Substance use  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Surgical and medical procedures       
Arthrodesis  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Cataract operation  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Corneal transplant  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Endodontic procedure  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
High frequency ablation  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Inguinal hernia repair  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Knee arthroplasty  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Knee operation  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Meniscus operation  1  0/356 (0.00%)  0 1/354 (0.28%)  1 2/558 (0.36%)  2
Orthodontic procedure  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Posterior lens capsulotomy  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Rotator cuff repair  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Suture insertion  1  1/356 (0.28%)  1 0/354 (0.00%)  0 0/558 (0.00%)  0
Umbilical hernia repair  1  0/356 (0.00%)  0 0/354 (0.00%)  0 2/558 (0.36%)  2
Vasectomy  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Vitrectomy  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Wisdom teeth removal  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Vascular disorders       
Aortic aneurysm  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Flushing  1  0/356 (0.00%)  0 2/354 (0.56%)  2 1/558 (0.18%)  1
Hot flush  1  1/356 (0.28%)  1 0/354 (0.00%)  0 1/558 (0.18%)  1
Hypertension  1  4/356 (1.12%)  4 4/354 (1.13%)  4 4/558 (0.72%)  4
Hypertensive crisis  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Hypotension  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Peripheral vascular disorder  1  0/356 (0.00%)  0 1/354 (0.28%)  1 0/558 (0.00%)  0
Varicose vein  1  0/356 (0.00%)  0 0/354 (0.00%)  0 1/558 (0.18%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
Phone: 800-545-5979
Layout table for additonal information
Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01816295    
Other Study ID Numbers: 14396
I5E-MC-TSAT ( Other Identifier: Eli Lilly and Company )
2012-004866-16 ( EudraCT Number )
First Submitted: March 19, 2013
First Posted: March 22, 2013
Results First Submitted: September 1, 2015
Results First Posted: October 2, 2015
Last Update Posted: December 28, 2015