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Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis (POISE)

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: NCT01473524
Recruitment Status : Completed
First Posted : November 17, 2011
Results First Posted : February 13, 2017
Last Update Posted : October 6, 2020
Sponsor:
Information provided by (Responsible Party):
Intercept Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Primary Biliary Cirrhosis
Interventions Drug: Obeticholic Acid (OCA)
Drug: Placebo
Enrollment 217
Recruitment Details Recruitment into hospitals and physicians' clinics started January 2012 and completed December 2012.
Pre-assignment Details

Screening interim allowed for pre-randomization eligibility assessment of 1 to 8 weeks.

A total of 217 participants were randomized into the double-blind phase of the study, however, 216 received treatment with study drug. One randomized participant discontinued prior to receiving any study drug.
Arm/Group Title DB OCA 5-10 mg DB OCA 10 mg DB Placebo LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB OCA 10 mg) LTSE OCA (DB Placebo)
Hide Arm/Group Description Obeticholic acid (OCA) 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the double-blind (DB) phase. OCA 10 mg for 12 months during DB phase. Matching placebo for 12 months in the DB phase. Participants previously receiving OCA 5 to 10 mg in the DB phase received OCA in the open-label long-term safety extension (LTSE) phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. Participants previously receiving OCA 10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. Participants previously receiving placebo in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
Period Title: DB Phase
Started 71 73 73 0 0 0
Received at Least 1 Dose of Study Drug 70 73 73 0 0 0
Completed 64 64 70 0 0 0
Not Completed 7 9 3 0 0 0
Reason Not Completed
Adverse Event             4             8             2             0             0             0
Death             1             0             0             0             0             0
Withdrawal by Subject             2             1             1             0             0             0
Period Title: LTSE Phase
Started 0 0 0 63 [1] 64 66 [2]
Received at Least 1 Dose of OCA in LTSE 0 0 0 63 64 66
Completed 0 0 0 54 47 45
Not Completed 0 0 0 9 17 21
Reason Not Completed
Withdrawal by Subject             0             0             0             3             3             6
Death             0             0             0             0             1             0
Adverse Event of Pruritus             0             0             0             1             5             2
Other Clinical/ Laboratory Adverse Event             0             0             0             2             4             6
Lost to Follow-up             0             0             0             1             3             2
Principal Investigator Decision             0             0             0             1             1             3
Liver Transplantation             0             0             0             0             0             1
Pregnancy             0             0             0             1             0             0
Protocol Violation             0             0             0             0             0             1
[1]
One participant in the double-blind OCA 5-10 mg group did not enroll in the LTSE phase.
[2]
Four participants in the double-blind placebo group did not enroll in the LTSE phase.
Arm/Group Title DB OCA 5-10 mg DB OCA 10 mg DB Placebo Total
Hide Arm/Group Description

OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.

After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.

 OCA 10 mg 12 months during the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. Matching placebo for 12 months during the DB phase. After completion of the 12-month DB phase participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. Total of all reporting groups
Overall Number of Baseline Participants 70 73 73 216
Hide Baseline Analysis Population Description
Intent-to-treat Population: All participants who were randomized and received at least 1 dose of study drug.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 70 participants 73 participants 73 participants 216 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
60
  85.7%
56
  76.7%
60
  82.2%
176
  81.5%
>=65 years
10
  14.3%
17
  23.3%
13
  17.8%
40
  18.5%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 70 participants 73 participants 73 participants 216 participants
55.8  (10.53) 56.2  (11.00) 55.5  (10.03) 55.8  (10.48)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 70 participants 73 participants 73 participants 216 participants
Female
65
  92.9%
63
  86.3%
68
  93.2%
196
  90.7%
Male
5
   7.1%
10
  13.7%
5
   6.8%
20
   9.3%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 70 participants 73 participants 73 participants 216 participants
Asian 1 1 1 3
Black or African American 1 1 1 3
Other 1 1 5 7
White 67 70 66 203
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 70 participants 73 participants 73 participants 216 participants
United States 18 19 17 54
United Kingdom 8 5 9 22
Spain 4 2 3 9
Canada 2 2 4 8
Austria 2 0 1 3
Netherlands 3 7 6 16
Sweden 3 1 0 4
Belgium 2 9 5 16
Poland 4 6 4 14
Italy 11 10 11 32
Australia 5 1 3 9
France 0 0 1 1
Germany 8 11 9 28
Alkaline Phosphatase (U/L)  
Mean (Standard Deviation)
Unit of measure:  U/L
Number Analyzed 70 participants 73 participants 73 participants 216 participants
325.87  (116.238) 316.34  (103.881) 327.49  (115.014) 323.19  (111.375)
Total Bilirubin (umol/L)  
Mean (Standard Deviation)
Unit of measure:  umol/L
Number Analyzed 70 participants 73 participants 73 participants 216 participants
10.192  (5.549) 11.278  (6.634) 11.757  (7.227) 11.088  (6.522)
Direct Bilirubin (umol/L)  
Mean (Standard Deviation)
Unit of measure:  umol/L
Number Analyzed 70 participants 73 participants 73 participants 216 participants
4.398  (4.528) 4.868  (4.473) 5.469  (6.214) 4.919  (5.138)
Alanine Aminotransferase (ALT) (U/L)  
Mean (Standard Deviation)
Unit of measure:  U/L
Number Analyzed 70 participants 73 participants 73 participants 216 participants
61.56  (39.037) 56.31  (39.741) 55.99  (30.312) 57.9  (36.498)
Aspartate Aminotransferase (AST) (U/L)  
Mean (Standard Deviation)
Unit of measure:  U/L
Number Analyzed 70 participants 73 participants 73 participants 216 participants
52.25  (25.289) 50.49  (31.100) 48.79  (22.449) 50.49  (26.456)
Gamma-Glutamyltransferase (GGT) (U/L)  
Mean (Standard Deviation)
Unit of measure:  U/L
Number Analyzed 70 participants 73 participants 73 participants 216 participants
252.83  (167.038) 261.07  (207.396) 309.58  (449.356) 274.79  (302.673)
1.Primary Outcome
Title DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo
Hide Description Percentage of participants at Month 12 with ALP < 1.67 x upper limit of normal (ULN) and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
Time Frame DB Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug.
Arm/Group Title DB OCA 10 mg DB Placebo
Hide Arm/Group Description:
OCA 10 mg for 12 months during the DB phase.
Matching placebo for 12 months during the DB phase.
Overall Number of Participants Analyzed 73 73
Measure Type: Number
Unit of Measure: percentage of participants
47 10
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DB OCA 10 mg, DB Placebo
Comments H0: The response rates are equal between placebo and 10 mg OCA. H1: The response rates are different between placebo and 10 mg OCA.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel (CMH) General Association test stratified by randomization strata factor.
2.Primary Outcome
Title LTSE Phase: Composite Endpoint ALP And Total Bilirubin
Hide Description Percentage of participants at Months 24, 36, 48, and 60 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline. DB Month 12 is the baseline for the LTSE phase.
Time Frame Baseline (DB Month 12), LTSE Months 24, 36, 48, and 60
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least 1 dose of OCA in the open-label safety extension phase and had an assessment at the specified timepoint.
Arm/Group Title LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB OCA 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
Hide Arm/Group Description:
Participants previously receiving OCA 5-10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
Participants previously receiving OCA 10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
Participants previously receiving placebo in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
After completion of the 12-month DB phase all participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
Overall Number of Participants Analyzed 63 64 66 193
Measure Type: Number
Unit of Measure: percentage of participants
Baseline (Double-blind Month 12) Number Analyzed 63 participants 63 participants 66 participants 192 participants
51 56 9 38
LTSE Month 12 Number Analyzed 60 participants 59 participants 59 participants 178 participants
55 58 41 51
LTSE Month 24 Number Analyzed 57 participants 57 participants 52 participants 166 participants
60 61 54 58
LTSE Month 36 Number Analyzed 56 participants 55 participants 49 participants 160 participants
48 51 49 49
LTSE Month 48 Number Analyzed 50 participants 53 participants 48 participants 151 participants
52 55 60 56
LTSE Month 60 Number Analyzed 31 participants 21 participants 24 participants 76 participants
48 52 50 50
3.Secondary Outcome
Title DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo
Hide Description Percentage of participants at Month 6 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
Time Frame DB Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug.
Arm/Group Title Double-blind OCA 10 mg Double-blind Placebo
Hide Arm/Group Description:
OCA 10 mg for 12 months during the DB phase.
Matching placebo for 12 months during the DB phase.
Overall Number of Participants Analyzed 73 73
Measure Type: Number
Unit of Measure: percentage of participants
51 7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind OCA 10 mg, Double-blind Placebo
Comments H0: The response rates are equal between placebo and 10 mg OCA. H1: The response rates are different between placebo and 10 mg OCA.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel (CMH) General Association test stratified by randomization strata factor.
4.Secondary Outcome
Title DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo
Hide Description Percentage of participants at Month 12 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
Time Frame DB Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug.
Arm/Group Title DB OCA 5-10 mg DB Placebo
Hide Arm/Group Description:
OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.
Matching placebo for 12 months during the DB phase.
Overall Number of Participants Analyzed 70 73
Measure Type: Number
Unit of Measure: percentage of participants
46 10
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DB OCA 5-10 mg, DB Placebo
Comments H0: The response rates are equal between placebo and 5-10 mg OCA. H1: The response rates are different between placebo and 5-10 mg OCA.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel (CMH) General Association test stratified by randomization strata factor.
5.Secondary Outcome
Title DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo
Hide Description Percentage of participants at Month 6 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.
Time Frame DB Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug.
Arm/Group Title DB OCA 5-10 mg DB Placebo
Hide Arm/Group Description:
OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.
Matching placebo for 12 months during the DB phase.
Overall Number of Participants Analyzed 70 73
Measure Type: Number
Unit of Measure: percentage of participants
34 7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DB OCA 5-10 mg, DB Placebo
Comments H0: The response rates are equal between placebo and 5-10 mg OCA. H1: The response rates are different between placebo and 5-10 mg OCA.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel (CMH) General Association test stratified by randomization strata factor.
6.Secondary Outcome
Title DB Phase: ALP Absolute Change From Baseline To Month 12
Hide Description Blood samples were evaluated for ALP levels. ALP Absolute Change From Baseline (ALP at Month 12 - ALP at Baseline) is presented.
Time Frame Baseline, DB Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
Arm/Group Title DB OCA 5-10 mg DB OCA 10 mg DB Placebo
Hide Arm/Group Description:
OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.
OCA 10 mg for 12 months during the DB phase.
Matching placebo during the DB phase.
Overall Number of Participants Analyzed 64 62 70
Least Squares Mean (Standard Error)
Unit of Measure: U/L
-112.51  (14.36) -129.90  (14.60) -14.42  (14.74)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DB OCA 5-10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection DB OCA 10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
7.Secondary Outcome
Title DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12
Hide Description Blood samples were evaluated for bilirubin levels. Total bilirubin absolute change from baseline (total bilirubin at Month 12 - total bilirubin at Baseline) is presented.
Time Frame Baseline, DB Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
Arm/Group Title DB OCA 5-10 mg DB OCA 10 mg DB Placebo
Hide Arm/Group Description:
OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.
OCA 10 mg for 12 months during the DB phase.
Matching placebo for 12 months during the DB phase.
Overall Number of Participants Analyzed 64 62 70
Least Squares Mean (Standard Error)
Unit of Measure: umol/L
-0.33  (0.68) -0.90  (0.71) 1.98  (0.70)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DB OCA 5-10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection DB OCA 10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
8.Secondary Outcome
Title DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12
Hide Description Blood samples were evaluated for bilirubin levels. Direct bilirubin absolute change from baseline (direct bilirubin at Month 12 - direct bilirubin at Baseline) is presented.
Time Frame Baseline, DB Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
Arm/Group Title DB OCA 5-10 mg DB OCA 10 mg DB Placebo
Hide Arm/Group Description:
OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.
OCA 10 mg for 12 months during the DB phase.
Matching placebo for 12 months during the DB phase.
Overall Number of Participants Analyzed 64 62 70
Least Squares Mean (Standard Error)
Unit of Measure: umol/L
-0.13  (0.52) -0.49  (0.54) 1.89  (0.53)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DB OCA 5-10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection DB OCA 10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
9.Secondary Outcome
Title DB Phase: Alanine Aminotransferase (ALT) Absolute Change From Baseline To Month 12
Hide Description Blood samples were evaluated for ALT levels. ALT absolute change from baseline (ALT at Month 12 - ALT at Baseline) is presented.
Time Frame Baseline, DB Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
Arm/Group Title DB OCA 5-10 mg DB OCA 10 mg DB Placebo
Hide Arm/Group Description:
OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.
OCA 10 mg for 12 months during the DB phase.
Matching placebo for 12 months during the DB phase.
Overall Number of Participants Analyzed 64 62 70
Least Squares Mean (Standard Error)
Unit of Measure: U/L
-21.26  (3.27) -25.31  (3.35) -4.95  (3.32)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DB OCA 5-10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection DB OCA 10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
10.Secondary Outcome
Title DB Phase: Aspartate Aminotransferase (AST) Absolute Change From Baseline To Month 12
Hide Description Blood samples were evaluated for AST levels. AST absolute change from baseline (AST at Month 12 - AST at Baseline) is presented.
Time Frame Baseline, DB Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
Arm/Group Title DB OCA 5-10 mg DB OCA 10 mg DB Placebo
Hide Arm/Group Description:
OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 12 months of the DB phase.
OCA 10 mg for 12 months during the DB phase.
Matching placebo for 12 months during the DB phase.
Overall Number of Participants Analyzed 64 62 70
Least Squares Mean (Standard Error)
Unit of Measure: U/L
-13.03  (4.17) -15.00  (4.28) 1.04  (4.22)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DB OCA 5-10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection DB OCA 10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor
11.Secondary Outcome
Title DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12
Hide Description Blood samples were evaluated for GGT levels. GGT absolute change from baseline (GGT at Month 12 - GGT at Baseline) is presented.
Time Frame Baseline, DB Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population: All participants who were randomized and received at least 1 dose of study drug and had an assessment at the specified timepoint.
Arm/Group Title DB OCA 5-10 mg DB OCA 10 mg DB Placebo
Hide Arm/Group Description:
OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.
OCA 10 mg for 12 months during the DB phase.
Matching placebo for 12 months during the DB phase.
Overall Number of Participants Analyzed 64 62 70
Least Squares Mean (Standard Error)
Unit of Measure: U/L
-140.83  (24.70) -176.66  (25.58) 6.70  (25.56)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DB OCA 5-10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection DB OCA 10 mg, DB Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.
12.Secondary Outcome
Title LTSE Phase: ALP Levels
Hide Description Blood samples were evaluated for ALP levels.
Time Frame LTSE Day 0 and LTSE Months 12, 24, 36, 48, and 60
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least 1 dose of OCA in the open-label safety extension phase and had an assessment at the specified timepoint.
Arm/Group Title LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB OCA 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
Hide Arm/Group Description:
Participants previously receiving OCA 5-10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
Participants previously receiving OCA 10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
Participants previously receiving placebo in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
After completion of the 12-month DB phase all participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
Overall Number of Participants Analyzed 63 64 66 193
Mean (Standard Deviation)
Unit of Measure: U/L
LTSE Day 0 Number Analyzed 63 participants 63 participants 66 participants 192 participants
218.69  (100.328) 191.24  (61.381) 317.79  (139.666) 243.75  (118.910)
LTSE Month 12 Number Analyzed 60 participants 59 participants 59 participants 178 participants
209.49  (93.157) 198.68  (75.799) 226.28  (105.404) 211.47  (92.439)
LTSE Month 24 Number Analyzed 57 participants 57 participants 52 participants 166 participants
195.14  (80.361) 194.57  (66.593) 215.99  (83.469) 201.47  (77.117)
LTSE Month 36 Number Analyzed 56 participants 55 participants 49 participants 160 participants
204.52  (68.019) 214.66  (158.831) 205.37  (65.206) 208.27  (107.114)
LTSE Month 48 Number Analyzed 50 participants 53 participants 48 participants 151 participants
189.75  (55.929) 192.00  (59.761) 198.70  (65.551) 193.38  (60.170)
LTSE Month 60 Number Analyzed 31 participants 21 participants 24 participants 76 participants
200.90  (97.475) 191.37  (62.404) 209.38  (82.240) 200.94  (83.436)
13.Secondary Outcome
Title LTSE Phase: ALP Change From DB Baseline
Hide Description Blood samples were evaluated for ALP levels. ALP Change From Baseline (ALP at LTSE Months 12, 24, 36, 48, and 60 - ALP at Baseline) is presented. DB baseline is the mean of all available evaluations prior to DB treatment.
Time Frame DB Baseline, LTSE Months 12, 24, 36, 48, and 60
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least 1 dose of OCA in the open-label safety extension phase and had an assessment at the specified timepoint.
Arm/Group Title LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB OCA 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
Hide Arm/Group Description:
Participants previously receiving OCA 5-10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
Participants previously receiving OCA 10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
Participants previously receiving placebo in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
After completion of the 12-month DB phase all participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
Overall Number of Participants Analyzed 63 64 66 193
Mean (Standard Deviation)
Unit of Measure: U/L
Month 12 Number Analyzed 60 participants 59 participants 59 participants 178 participants
-106.63  (98.448) -104.39  (82.496) -104.36  (83.074) -105.13  (87.882)
Month 24 Number Analyzed 57 participants 57 participants 52 participants 166 participants
-120.86  (96.614) -102.52  (79.413) -100.99  (87.181) -108.34  (87.980)
Month 36 Number Analyzed 56 participants 55 participants 49 participants 160 participants
-100.98  (109.952) -84.65  (137.293) -112.73  (89.661) -98.96  (114.635)
Month 48 Number Analyzed 50 participants 53 participants 48 participants 151 participants
-118.23  (101.527) -101.50  (91.335) -115.51  (106.774) -111.49  (99.433)
Month 60 Number Analyzed 31 participants 21 participants 24 participants 60 participants
-118.99  (147.126) -117.49  (95.587) -119.52  (108.949) -118.74  (121.391)
Time Frame DB Phase: Baseline up to 12 months (1 year). LTSE phase: Baseline (DB Month 12) up to 60 months (5 years).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title DB 5-10 mg DB OCA 10 mg DB Placebo LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
Hide Arm/Group Description OCA 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase. OCA 10 mg for 12 months during the DB phase. Matching placebo for 12 months during the DB phase. Participants previously receiving OCA 5 to 10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. Participants previously receiving OCA 10 mg in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. Participants previously receiving placebo in the DB phase received OCA in the open-label LTSE phase for up to 5 years beginning at 5 mg, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. After completion of the 12-month DB phase, all participants were offered the opportunity to enter an open-label LTSE for up to 5 years beginning at 5 mg OCA, and then the dose could be titrated up. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg.
All-Cause Mortality
DB 5-10 mg DB OCA 10 mg DB Placebo LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--      --/--    
Hide Serious Adverse Events
DB 5-10 mg DB OCA 10 mg DB Placebo LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   11/70 (15.71%)      8/73 (10.96%)      3/73 (4.11%)      30/63 (47.62%)      19/64 (29.69%)      20/66 (30.30%)      69/193 (35.75%)    
Blood and lymphatic system disorders               
Anaemia † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 2/63 (3.17%)  4 0/64 (0.00%)  0 0/66 (0.00%)  0 2/193 (1.04%)  4
Splenic infarction † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Cardiac disorders               
Aortic valve stenosis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Atrial fibrillation † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 2/64 (3.13%)  2 0/66 (0.00%)  0 2/193 (1.04%)  2
Cardiac failure † 1  1/70 (1.43%)  2 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Cardiac failure congestive † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Cardiomyopathy † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Myocardial infarction † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Sick sinus syndrome † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 1/73 (1.37%)  1 0/63 (0.00%)  0 0/64 (0.00%)  0 0/66 (0.00%)  0 0/193 (0.00%)  0
Ventricular fibrillation † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Eye disorders               
Cataract † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Gastrointestinal disorders               
Abdominal distension † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Abdominal pain † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Abdominal pain lower † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Abdominal wall haematoma † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 1/64 (1.56%)  1 0/66 (0.00%)  0 2/193 (1.04%)  2
Ascites † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Constipation † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Haematemesis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Lower gastrointestinal haemorrhage † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Oedematous pancreatitis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Oesophageal varices haemorrhage † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 2/63 (3.17%)  2 1/64 (1.56%)  1 1/66 (1.52%)  1 4/193 (2.07%)  4
Pancreatitis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 2/66 (3.03%)  2 2/193 (1.04%)  2
Rectal prolapse † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Splenic artery aneurysm † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  3 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  3
Upper gastrointestinal haemorrhage † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 1/73 (1.37%)  1 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Varices oesophageal † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 1/73 (1.37%)  2 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Volvulus † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
General disorders               
Chest pain † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 1/73 (1.37%)  1 0/63 (0.00%)  0 0/64 (0.00%)  0 0/66 (0.00%)  0 0/193 (0.00%)  0
Non-cardiac chest pain † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 1/73 (1.37%)  1 0/63 (0.00%)  0 0/64 (0.00%)  0 0/66 (0.00%)  0 0/193 (0.00%)  0
Oedema † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 0/66 (0.00%)  0 0/193 (0.00%)  0
Polyserositis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Hepatobiliary disorders               
Cholecystitis acute † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Cholelithiasis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Hepatic failure † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Hyperplastic cholecystopathy † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Jaundice † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Infections and infestations               
Appendicitis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Bacterial sepsis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Cellulitis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Endocarditis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Erysipelas † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 0/66 (0.00%)  0 0/193 (0.00%)  0
Parotitis † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  3 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  3
Pneumonia † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 3/63 (4.76%)  3 1/64 (1.56%)  1 0/66 (0.00%)  0 4/193 (2.07%)  4
Postoperative wound infection † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Pyelonephritis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Pyelonephritis chronic † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Sepsis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Urosepsis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Vaginal infection † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Injury, poisoning and procedural complications               
Anastomotic ulcer † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Ankle fracture † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Clavicle fracture † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Foot fracture † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Ligament rupture † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Lower limb fracture † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Meniscus lesion † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Post procedural haemorrhage † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 1/66 (1.52%)  1 2/193 (1.04%)  2
Procedural pain † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 1/66 (1.52%)  1 2/193 (1.04%)  2
Radius fracture † 1  0/70 (0.00%)  0 1/73 (1.37%)  2 0/73 (0.00%)  0 2/63 (3.17%)  2 2/64 (3.13%)  3 0/66 (0.00%)  0 4/193 (2.07%)  5
Rib fracture † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  2 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  2
Spinal compression fracture † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Tibia fracture † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 1/73 (1.37%)  1 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Wrist fracture † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Investigations               
Medical observation † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Metabolism and nutrition disorders               
Hypoglycaemia † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Hyponatraemia † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Musculoskeletal and connective tissue disorders               
Haemarthrosis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Intervertebral disc protrusion † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Osteoarthritis † 1  0/70 (0.00%)  0 2/73 (2.74%)  2 0/73 (0.00%)  0 2/63 (3.17%)  2 5/64 (7.81%)  6 0/66 (0.00%)  0 7/193 (3.63%)  8
Rotator cuff syndrome † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Spondylolisthesis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Systemic sclerosis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Basal cell carcinoma † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Breast cancer † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Chronic myeloid leukaemia † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Chronic obstructive pulmonary disease † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Colorectal cancer † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Hepatic neoplasm malignant † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Hepatic neoplasm malignant recurrent † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Lip neoplasm malignant stage unspecified † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Renal oncocytoma † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Uterine leiomyoma † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Nervous system disorders               
Carpal tunnel syndrome † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Hepatic encephalopathy † 1  1/70 (1.43%)  2 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 0/66 (0.00%)  0 0/193 (0.00%)  0
Ischaemic stroke † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Loss of consciousness † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Syncope † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 1/64 (1.56%)  1 0/66 (0.00%)  0 2/193 (1.04%)  2
Transient ischaemic attack † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Psychiatric disorders               
Depression † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Major depression † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Renal and urinary disorders               
Nephrolithiasis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Nephropathy toxic † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Renal atrophy † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Renal failure † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 1/66 (1.52%)  1 1/193 (0.52%)  1
Renal failure acute † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Respiratory, thoracic and mediastinal disorders               
Dyspnoea † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 1/73 (1.37%)  1 0/63 (0.00%)  0 0/64 (0.00%)  0 0/66 (0.00%)  0 0/193 (0.00%)  0
Interstitial lung disease † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 0/66 (0.00%)  0 0/193 (0.00%)  0
Skin and subcutaneous tissue disorders               
Neurodermatitis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Vascular disorders               
Hypertension † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 0/64 (0.00%)  0 0/66 (0.00%)  0 1/193 (0.52%)  1
Intra-abdominal haematoma † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Temporal arteritis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 0/66 (0.00%)  0 1/193 (0.52%)  1
Varicose vein † 1  2/70 (2.86%)  2 0/73 (0.00%)  0 0/73 (0.00%)  0 2/63 (3.17%)  2 0/64 (0.00%)  0 0/66 (0.00%)  0 2/193 (1.04%)  2
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
DB 5-10 mg DB OCA 10 mg DB Placebo LTSE OCA (DB OCA 5-10 mg) LTSE OCA (DB 10 mg) LTSE OCA (DB Placebo) Overall LTSE OCA
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   64/70 (91.43%)      64/73 (87.67%)      62/73 (84.93%)      61/63 (96.83%)      62/64 (96.88%)      64/66 (96.97%)      187/193 (96.89%)    
Blood and lymphatic system disorders               
Anaemia † 1  2/70 (2.86%)  2 3/73 (4.11%)  3 4/73 (5.48%)  5 8/63 (12.70%)  12 7/64 (10.94%)  8 4/66 (6.06%)  5 19/193 (9.84%)  25
Iron deficiency anaemia † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 1/63 (1.59%)  4 1/64 (1.56%)  1 3/66 (4.55%)  4 5/193 (2.59%)  9
Thrombocytopenia † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 3/64 (4.69%)  3 2/66 (3.03%)  2 5/193 (2.59%)  5
Splenomegaly † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 4/63 (6.35%)  5 2/64 (3.13%)  2 1/66 (1.52%)  1 7/193 (3.63%)  8
Cardiac disorders               
Palpitations † 1  2/70 (2.86%)  3 5/73 (6.85%)  5 1/73 (1.37%)  1 4/63 (6.35%)  6 5/64 (7.81%)  5 2/66 (3.03%)  2 11/193 (5.70%)  13
Bradycardia † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 3/63 (4.76%)  3 0/64 (0.00%)  0 1/66 (1.52%)  1 4/193 (2.07%)  4
Cardiac murmur † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 3/63 (4.76%)  3 2/64 (3.13%)  2 2/66 (3.03%)  2 7/193 (3.63%)  7
Atrial fibrillation † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 3/64 (4.69%)  7 2/66 (3.03%)  2 6/193 (3.11%)  10
Ear and labyrinth disorders               
Vertigo † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 4/63 (6.35%)  7 2/64 (3.13%)  2 2/66 (3.03%)  2 8/193 (4.15%)  11
Ear pain † 1  2/70 (2.86%)  2 0/73 (0.00%)  0 1/73 (1.37%)  1 2/63 (3.17%)  3 3/64 (4.69%)  3 1/66 (1.52%)  1 6/193 (3.11%)  7
Endocrine disorders               
Hypothyroidism † 1  4/70 (5.71%)  4 1/73 (1.37%)  1 1/73 (1.37%)  1 4/63 (6.35%)  4 3/64 (4.69%)  3 3/66 (4.55%)  3 10/193 (5.18%)  10
Eye disorders               
Dry eye † 1  2/70 (2.86%)  3 4/73 (5.48%)  4 4/73 (5.48%)  4 3/63 (4.76%)  4 10/64 (15.63%)  11 2/66 (3.03%)  2 15/193 (7.77%)  17
Conjunctivitis † 1  1/70 (1.43%)  1 2/73 (2.74%)  2 2/73 (2.74%)  2 2/63 (3.17%)  4 5/64 (7.81%)  6 1/66 (1.52%)  1 8/193 (4.15%)  11
Cataract † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 2/63 (3.17%)  2 3/64 (4.69%)  4 1/66 (1.52%)  1 6/193 (3.11%)  7
Gastrointestinal disorders               
Nausea † 1  4/70 (5.71%)  5 8/73 (10.96%)  10 9/73 (12.33%)  18 14/63 (22.22%)  20 13/64 (20.31%)  19 10/66 (15.15%)  15 37/193 (19.17%)  54
Diarrhoea † 1  2/70 (2.86%)  3 8/73 (10.96%)  10 8/73 (10.96%)  13 8/63 (12.70%)  15 11/64 (17.19%)  17 14/66 (21.21%)  26 33/193 (17.10%)  58
Abdominal pain upper † 1  5/70 (7.14%)  5 4/73 (5.48%)  5 5/73 (6.85%)  8 9/63 (14.29%)  12 10/64 (15.63%)  11 12/66 (18.18%)  13 31/193 (16.06%)  36
Constipation † 1  5/70 (7.14%)  5 5/73 (6.85%)  5 4/73 (5.48%)  7 12/63 (19.05%)  12 9/64 (14.06%)  9 7/66 (10.61%)  8 28/193 (14.51%)  29
Abdominal distension † 1  3/70 (4.29%)  3 3/73 (4.11%)  3 7/73 (9.59%)  7 5/63 (7.94%)  7 7/64 (10.94%)  7 5/66 (7.58%)  5 17/193 (8.81%)  19
Dyspepsia † 1  4/70 (5.71%)  4 0/73 (0.00%)  0 8/73 (10.96%)  11 7/63 (11.11%)  12 8/64 (12.50%)  8 5/66 (7.58%)  5 20/193 (10.36%)  25
Vomiting † 1  3/70 (4.29%)  3 3/73 (4.11%)  3 5/73 (6.85%)  8 5/63 (7.94%)  7 7/64 (10.94%)  9 2/66 (3.03%)  2 14/193 (7.25%)  18
Gastrooesophageal reflux disease † 1  2/70 (2.86%)  2 4/73 (5.48%)  5 4/73 (5.48%)  6 7/63 (11.11%)  7 9/64 (14.06%)  12 4/66 (6.06%)  4 20/193 (10.36%)  23
Abdominal pain † 1  3/70 (4.29%)  3 1/73 (1.37%)  1 6/73 (8.22%)  6 11/63 (17.46%)  15 7/64 (10.94%)  9 8/66 (12.12%)  8 26/193 (13.47%)  32
Abdominal discomfort † 1  5/70 (7.14%)  5 0/73 (0.00%)  0 1/73 (1.37%)  5 5/63 (7.94%)  5 0/64 (0.00%)  0 2/66 (3.03%)  2 7/193 (3.63%)  7
Dry mouth † 1  2/70 (2.86%)  2 3/73 (4.11%)  3 2/73 (2.74%)  2 3/63 (4.76%)  4 5/64 (7.81%)  5 3/66 (4.55%)  3 11/193 (5.70%)  12
Gastritis † 1  1/70 (1.43%)  1 1/73 (1.37%)  1 0/73 (0.00%)  0 2/63 (3.17%)  2 6/64 (9.38%)  7 3/66 (4.55%)  3 11/193 (5.70%)  12
Haemorrhoids † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 2/73 (2.74%)  2 5/63 (7.94%)  6 1/64 (1.56%)  1 5/66 (7.58%)  5 11/193 (5.70%)  12
Varices oesophageal † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 8/63 (12.70%)  8 2/64 (3.13%)  3 1/66 (1.52%)  1 11/193 (5.70%)  12
Ascites † 1  1/70 (1.43%)  1 1/73 (1.37%)  1 0/73 (0.00%)  0 6/63 (9.52%)  9 1/64 (1.56%)  1 3/66 (4.55%)  4 10/193 (5.18%)  14
Toothache † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 1/73 (1.37%)  1 2/63 (3.17%)  2 5/64 (7.81%)  6 3/66 (4.55%)  3 10/193 (5.18%)  11
Dental caries † 1  2/70 (2.86%)  2 0/73 (0.00%)  0 0/73 (0.00%)  0 4/63 (6.35%)  5 1/64 (1.56%)  1 4/66 (6.06%)  6 9/193 (4.66%)  12
Hiatus hernia † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 3/64 (4.69%)  3 1/66 (1.52%)  1 5/193 (2.59%)  5
Portal hypertensive gastropathy † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 3/63 (4.76%)  3 0/64 (0.00%)  0 2/66 (3.03%)  2 5/193 (2.59%)  5
Gastric polyps † 1  0/70 (0.00%)  0 2/73 (2.74%)  2 0/73 (0.00%)  0 1/63 (1.59%)  1 3/64 (4.69%)  4 0/66 (0.00%)  0 4/193 (2.07%)  5
Rectal haemorrhage † 1  0/70 (0.00%)  0 2/73 (2.74%)  2 0/73 (0.00%)  0 1/63 (1.59%)  1 2/64 (3.13%)  2 4/66 (6.06%)  4 7/193 (3.63%)  7
Abdominal pain lower † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 3/63 (4.76%)  4 1/64 (1.56%)  1 1/66 (1.52%)  1 5/193 (2.59%)  6
General disorders               
Fatigue † 1  11/70 (15.71%)  13 17/73 (23.29%)  25 10/73 (13.70%)  12 24/63 (38.10%)  46 24/64 (37.50%)  43 15/66 (22.73%)  20 63/193 (32.64%)  109
Oedema peripheral † 1  2/70 (2.86%)  2 5/73 (6.85%)  7 2/73 (2.74%)  3 10/63 (15.87%)  15 8/64 (12.50%)  12 8/66 (12.12%)  10 26/193 (13.47%)  37
Pyrexia † 1  0/70 (0.00%)  0 5/73 (6.85%)  6 1/73 (1.37%)  1 5/63 (7.94%)  6 6/64 (9.38%)  8 5/66 (7.58%)  5 16/193 (8.29%)  19
Asthenia † 1  2/70 (2.86%)  2 1/73 (1.37%)  1 1/73 (1.37%)  1 2/63 (3.17%)  2 3/64 (4.69%)  7 6/66 (9.09%)  6 11/193 (5.70%)  15
Influenza like illness † 1  1/70 (1.43%)  1 3/73 (4.11%)  4 1/73 (1.37%)  1 4/63 (6.35%)  4 6/64 (9.38%)  9 1/66 (1.52%)  1 11/193 (5.70%)  14
Hepatobiliary disorders               
Cholelithiasis † 1  2/70 (2.86%)  2 0/73 (0.00%)  0 0/73 (0.00%)  0 5/63 (7.94%)  6 4/64 (6.25%)  4 1/66 (1.52%)  1 10/193 (5.18%)  11
Hepatomegaly † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 3/63 (4.76%)  3 0/64 (0.00%)  0 1/66 (1.52%)  1 4/193 (2.07%)  4
Hepatic cirrhosis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 2/64 (3.13%)  2 4/66 (6.06%)  4 7/193 (3.63%)  7
Immune system disorders               
Seasonal allergy † 1  2/70 (2.86%)  2 1/73 (1.37%)  1 2/73 (2.74%)  2 4/63 (6.35%)  4 2/64 (3.13%)  2 1/66 (1.52%)  1 7/193 (3.63%)  7
Infections and infestations               
Nasopharyngitis † 1  17/70 (24.29%)  27 13/73 (17.81%)  15 13/73 (17.81%)  19 23/63 (36.51%)  66 23/64 (35.94%)  39 11/66 (16.67%)  22 57/193 (29.53%)  127
Urinary tract infection † 1  4/70 (5.71%)  6 4/73 (5.48%)  6 8/73 (10.96%)  15 17/63 (26.98%)  31 19/64 (29.69%)  27 15/66 (22.73%)  23 51/193 (26.42%)  81
Upper respiratory tract infection † 1  4/70 (5.71%)  4 4/73 (5.48%)  4 8/73 (10.96%)  8 12/63 (19.05%)  21 11/64 (17.19%)  17 11/66 (16.67%)  16 34/193 (17.62%)  54
Influenza † 1  5/70 (7.14%)  5 4/73 (5.48%)  4 4/73 (5.48%)  5 12/63 (19.05%)  17 12/64 (18.75%)  17 10/66 (15.15%)  17 34/193 (17.62%)  51
Sinusitis † 1  1/70 (1.43%)  1 4/73 (5.48%)  5 0/73 (0.00%)  0 7/63 (11.11%)  7 9/64 (14.06%)  11 8/66 (12.12%)  11 24/193 (12.44%)  29
Bronchitis † 1  4/70 (5.71%)  4 1/73 (1.37%)  1 0/73 (0.00%)  0 7/63 (11.11%)  7 7/64 (10.94%)  7 6/66 (9.09%)  10 20/193 (10.36%)  24
Respiratory tract infection † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 3/73 (4.11%)  3 5/63 (7.94%)  6 4/64 (6.25%)  5 4/66 (6.06%)  5 13/193 (6.74%)  16
Cystitis † 1  1/70 (1.43%)  2 2/73 (2.74%)  2 0/73 (0.00%)  0 5/63 (7.94%)  12 5/64 (7.81%)  15 2/66 (3.03%)  3 12/193 (6.22%)  30
Herpes zoster † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 1/63 (1.59%)  1 7/64 (10.94%)  8 4/66 (6.06%)  4 12/193 (6.22%)  13
Pneumonia † 1  0/70 (0.00%)  0 2/73 (2.74%)  2 0/73 (0.00%)  0 2/63 (3.17%)  2 5/64 (7.81%)  8 5/66 (7.58%)  6 12/193 (6.22%)  16
Gastroenteritis † 1  3/70 (4.29%)  3 1/73 (1.37%)  1 0/73 (0.00%)  0 4/63 (6.35%)  4 1/64 (1.56%)  1 5/66 (7.58%)  6 10/193 (5.18%)  11
Diverticulum † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 2/63 (3.17%)  2 3/64 (4.69%)  3 0/66 (0.00%)  0 5/193 (2.59%)  5
Ear infection † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 1/73 (1.37%)  1 1/63 (1.59%)  1 1/64 (1.56%)  2 3/66 (4.55%)  3 5/193 (2.59%)  6
Oral herpes † 1  1/70 (1.43%)  1 1/73 (1.37%)  1 1/73 (1.37%)  1 3/63 (4.76%)  4 1/64 (1.56%)  1 1/66 (1.52%)  1 5/193 (2.59%)  6
Tooth infection † 1  1/70 (1.43%)  2 0/73 (0.00%)  0 0/73 (0.00%)  0 2/63 (3.17%)  3 3/64 (4.69%)  3 2/66 (3.03%)  2 7/193 (3.63%)  8
Lower respiratory tract infection † 1  2/70 (2.86%)  2 0/73 (0.00%)  0 1/73 (1.37%)  1 4/63 (6.35%)  8 1/64 (1.56%)  2 1/66 (1.52%)  5 6/193 (3.11%)  15
Pharyngitis † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 1/73 (1.37%)  1 1/63 (1.59%)  1 3/64 (4.69%)  6 2/66 (3.03%)  2 6/193 (3.11%)  9
Injury, poisoning and procedural complications               
Procedural pain † 1  4/70 (5.71%)  4 1/73 (1.37%)  1 1/73 (1.37%)  3 8/63 (12.70%)  9 4/64 (6.25%)  5 4/66 (6.06%)  7 16/193 (8.29%)  21
Contusion † 1  3/70 (4.29%)  3 2/73 (2.74%)  3 2/73 (2.74%)  2 2/63 (3.17%)  2 5/64 (7.81%)  5 3/66 (4.55%)  3 10/193 (5.18%)  10
Rib fracture † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 3/63 (4.76%)  3 2/64 (3.13%)  2 0/66 (0.00%)  0 5/193 (2.59%)  5
Arthropod bite † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 1/73 (1.37%)  1 0/63 (0.00%)  0 0/64 (0.00%)  0 4/66 (6.06%)  4 4/193 (2.07%)  4
Excoriation † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 1/63 (1.59%)  1 3/64 (4.69%)  3 0/66 (0.00%)  0 4/193 (2.07%)  4
Ligament rupture † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 3/66 (4.55%)  3 3/193 (1.55%)  3
Tendon rupture † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 3/64 (4.69%)  3 0/66 (0.00%)  0 3/193 (1.55%)  3
Scratch † 1  1/70 (1.43%)  1 3/73 (4.11%)  4 0/73 (0.00%)  0 1/63 (1.59%)  1 6/64 (9.38%)  7 2/66 (3.03%)  3 9/193 (4.66%)  11
Fall † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 4/63 (6.35%)  4 0/64 (0.00%)  0 4/66 (6.06%)  4 8/193 (4.15%)  8
Meniscus lesion † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  2 5/64 (7.81%)  5 1/66 (1.52%)  1 7/193 (3.63%)  8
Investigations               
Hepatic enzyme increased † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 1/63 (1.59%)  1 3/64 (4.69%)  5 1/66 (1.52%)  1 5/193 (2.59%)  7
Low density lipoprotein increased † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 0/63 (0.00%)  0 1/64 (1.56%)  1 3/66 (4.55%)  4 4/193 (2.07%)  5
Gamma-glutamyltransferase increased † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 0/64 (0.00%)  0 3/66 (4.55%)  3 3/193 (1.55%)  3
Weight decreased † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 3/63 (4.76%)  3 2/64 (3.13%)  2 1/66 (1.52%)  1 6/193 (3.11%)  6
Metabolism and nutrition disorders               
Hypercholesterolaemia † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 2/73 (2.74%)  2 3/63 (4.76%)  4 2/64 (3.13%)  2 3/66 (4.55%)  3 8/193 (4.15%)  9
Vitamin D deficiency † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 1/73 (1.37%)  1 2/63 (3.17%)  2 3/64 (4.69%)  3 3/66 (4.55%)  3 8/193 (4.15%)  8
Diabetes mellitus † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 0/63 (0.00%)  0 3/64 (4.69%)  3 3/66 (4.55%)  5 6/193 (3.11%)  8
Musculoskeletal and connective tissue disorders               
Back pain † 1  4/70 (5.71%)  4 4/73 (5.48%)  5 8/73 (10.96%)  8 10/63 (15.87%)  13 11/64 (17.19%)  15 10/66 (15.15%)  10 31/193 (16.06%)  38
Arthralgia † 1  4/70 (5.71%)  5 7/73 (9.59%)  7 3/73 (4.11%)  3 14/63 (22.22%)  17 17/64 (26.56%)  23 15/66 (22.73%)  18 46/193 (23.83%)  58
Muscle spasms † 1  2/70 (2.86%)  2 2/73 (2.74%)  2 4/73 (5.48%)  5 4/63 (6.35%)  4 4/64 (6.25%)  7 3/66 (4.55%)  3 11/193 (5.70%)  14
Osteopenia † 1  1/70 (1.43%)  1 1/73 (1.37%)  1 0/73 (0.00%)  0 9/63 (14.29%)  9 6/64 (9.38%)  6 6/66 (9.09%)  7 21/193 (10.88%)  22
Pain in extremity † 1  3/70 (4.29%)  3 1/73 (1.37%)  1 3/73 (4.11%)  3 7/63 (11.11%)  11 5/64 (7.81%)  5 8/66 (12.12%)  9 20/193 (10.36%)  25
Osteoarthritis † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 1/73 (1.37%)  1 4/63 (6.35%)  5 6/64 (9.38%)  8 5/66 (7.58%)  7 15/193 (7.77%)  20
Myalgia † 1  1/70 (1.43%)  1 3/73 (4.11%)  3 0/73 (0.00%)  0 4/63 (6.35%)  5 7/64 (10.94%)  9 2/66 (3.03%)  2 13/193 (6.74%)  16
Musculoskeletal pain † 1  1/70 (1.43%)  1 1/73 (1.37%)  1 1/73 (1.37%)  1 4/63 (6.35%)  5 5/64 (7.81%)  6 3/66 (4.55%)  3 12/193 (6.22%)  14
Neck pain † 1  1/70 (1.43%)  1 2/73 (2.74%)  2 1/73 (1.37%)  2 3/63 (4.76%)  3 4/64 (6.25%)  4 5/66 (7.58%)  5 12/193 (6.22%)  12
Osteoporosis † 1  1/70 (1.43%)  1 1/73 (1.37%)  1 2/73 (2.74%)  2 2/63 (3.17%)  2 4/64 (6.25%)  5 5/66 (7.58%)  6 11/193 (5.70%)  13
Bone pain † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 1/63 (1.59%)  1 3/64 (4.69%)  3 1/66 (1.52%)  1 5/193 (2.59%)  5
Plantar fasciitis † 1  0/70 (0.00%)  0 2/73 (2.74%)  2 0/73 (0.00%)  0 0/63 (0.00%)  0 3/64 (4.69%)  4 1/66 (1.52%)  1 4/193 (2.07%)  5
Joint swelling † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 3/63 (4.76%)  3 1/64 (1.56%)  1 4/66 (6.06%)  4 8/193 (4.15%)  8
Nervous system disorders               
Headache † 1  12/70 (17.14%)  26 6/73 (8.22%)  7 13/73 (17.81%)  16 20/63 (31.75%)  43 15/64 (23.44%)  22 9/66 (13.64%)  10 44/193 (22.80%)  75
Dizziness † 1  3/70 (4.29%)  5 2/73 (2.74%)  2 2/73 (2.74%)  2 5/63 (7.94%)  9 7/64 (10.94%)  7 2/66 (3.03%)  2 14/193 (7.25%)  18
Sciatica † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 0/73 (0.00%)  0 3/63 (4.76%)  3 3/64 (4.69%)  4 3/66 (4.55%)  4 9/193 (4.66%)  11
Hypoaesthesia † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 3/63 (4.76%)  5 0/64 (0.00%)  0 0/66 (0.00%)  0 3/193 (1.55%)  5
Paraesthesia † 1  1/70 (1.43%)  1 1/73 (1.37%)  1 1/73 (1.37%)  1 2/63 (3.17%)  3 2/64 (3.13%)  2 3/66 (4.55%)  3 7/193 (3.63%)  8
Psychiatric disorders               
Insomnia † 1  2/70 (2.86%)  2 3/73 (4.11%)  3 7/73 (9.59%)  8 6/63 (9.52%)  6 7/64 (10.94%)  7 7/66 (10.61%)  11 20/193 (10.36%)  24
Depression † 1  1/70 (1.43%)  1 1/73 (1.37%)  1 0/73 (0.00%)  0 5/63 (7.94%)  6 5/64 (7.81%)  6 3/66 (4.55%)  4 13/193 (6.74%)  16
Depressed mood † 1  0/70 (0.00%)  0 1/73 (1.37%)  2 0/73 (0.00%)  0 0/63 (0.00%)  0 4/64 (6.25%)  5 1/66 (1.52%)  2 5/193 (2.59%)  7
Anxiety † 1  2/70 (2.86%)  3 0/73 (0.00%)  0 2/73 (2.74%)  3 3/63 (4.76%)  5 1/64 (1.56%)  1 3/66 (4.55%)  3 7/193 (3.63%)  9
Sleep disorder † 1  3/70 (4.29%)  7 0/73 (0.00%)  0 0/73 (0.00%)  0 3/63 (4.76%)  8 1/64 (1.56%)  1 2/66 (3.03%)  2 6/193 (3.11%)  11
Renal and urinary disorders               
Renal cyst † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 0/73 (0.00%)  0 2/63 (3.17%)  2 3/64 (4.69%)  3 1/66 (1.52%)  1 6/193 (3.11%)  6
Respiratory, thoracic and mediastinal disorders               
Cough † 1  4/70 (5.71%)  5 6/73 (8.22%)  6 5/73 (6.85%)  9 12/63 (19.05%)  23 11/64 (17.19%)  16 12/66 (18.18%)  16 35/193 (18.13%)  55
Oropharyngeal pain † 1  5/70 (7.14%)  5 6/73 (8.22%)  8 1/73 (1.37%)  1 6/63 (9.52%)  6 8/64 (12.50%)  11 4/66 (6.06%)  6 18/193 (9.33%)  23
Nasal congestion † 1  0/70 (0.00%)  0 2/73 (2.74%)  2 0/73 (0.00%)  0 3/63 (4.76%)  3 2/64 (3.13%)  2 0/66 (0.00%)  0 5/193 (2.59%)  5
Epistaxis † 1  2/70 (2.86%)  3 0/73 (0.00%)  0 3/73 (4.11%)  4 3/63 (4.76%)  4 2/64 (3.13%)  3 3/66 (4.55%)  5 8/193 (4.15%)  12
Dyspnoea † 1  1/70 (1.43%)  1 1/73 (1.37%)  1 3/73 (4.11%)  3 1/63 (1.59%)  1 4/64 (6.25%)  6 2/66 (3.03%)  2 7/193 (3.63%)  9
Skin and subcutaneous tissue disorders               
Pruritus † 1  39/70 (55.71%)  93 50/73 (68.49%)  99 28/73 (38.36%)  49 49/63 (77.78%)  249 51/64 (79.69%)  198 50/66 (75.76%)  180 150/193 (77.72%)  627
Rash † 1  3/70 (4.29%)  3 4/73 (5.48%)  4 3/73 (4.11%)  3 7/63 (11.11%)  9 5/64 (7.81%)  5 2/66 (3.03%)  2 14/193 (7.25%)  16
Eczema † 1  4/70 (5.71%)  4 2/73 (2.74%)  2 0/73 (0.00%)  0 5/63 (7.94%)  5 4/64 (6.25%)  4 5/66 (7.58%)  7 14/193 (7.25%)  16
Skin lesion † 1  0/70 (0.00%)  0 1/73 (1.37%)  1 3/73 (4.11%)  3 3/63 (4.76%)  5 5/64 (7.81%)  7 6/66 (9.09%)  8 14/193 (7.25%)  20
Dry skin † 1  1/70 (1.43%)  1 2/73 (2.74%)  2 1/73 (1.37%)  1 1/63 (1.59%)  1 3/64 (4.69%)  3 5/66 (7.58%)  5 9/193 (4.66%)  9
Dermatitis † 1  1/70 (1.43%)  1 0/73 (0.00%)  0 0/73 (0.00%)  0 3/63 (4.76%)  5 0/64 (0.00%)  0 2/66 (3.03%)  7 5/193 (2.59%)  12
Urticaria † 1  0/70 (0.00%)  0 0/73 (0.00%)  0 2/73 (2.74%)  3 1/63 (1.59%)  1 3/64 (4.69%)  4 1/66 (1.52%)  4 5/193 (2.59%)  9
Night sweats † 1  3/70 (4.29%)  3 0/73 (0.00%)  0 0/73 (0.00%)  0 3/63 (4.76%)  3 0/64 (0.00%)  0 1/66 (1.52%)  1