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

• Sponsor: Intercept Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01473524
• Collaborator: (none)
• Enrollment: 217
• Locations: 59
• Arms: 4
• Duration (Months): 83.5
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The main objectives of the study were to assess the effects of Obeticholic Acid (OCA) on serum alkaline phosphatase (ALP) and total bilirubin, together as a composite endpoint and on safety in participants with primary biliary cirrhosis (PBC).

Condition or Disease	Intervention/Treatment	Phase
Primary Biliary Cirrhosis	Drug: Obeticholic Acid (OCA); Drug: Placebo	Phase 3

Detailed Description

The study included 2 phases: a 12-month randomized, double-blind (DB), placebo-controlled, parallel group phase, followed by a long-term safety extension (LTSE) phase up to 5 years. Participants from the 12-month DB phase, including those who received placebo, were eligible to participate in the open-label LTSE phase. The Month 12 visit from the DB phase served as the Day 1 visit of the LTSE phase. 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.

Data for the LTSE phase is reported by the randomized dose group assigned in the DB phase.

Study Design

• Study Type: Interventional
• Actual Enrollment: 217 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Double-Blind, Placebo-Controlled Trial and Long-Term Safety Extension of Obeticholic Acid in Patients With Primary Biliary Cirrhosis
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 17, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DB OCA 5-10 mg OCA 5 milligram (mg) for 6 months and then titrating up to 10 mg based on tolerability and response for remaining 6 months of the DB phase.	Drug: Obeticholic Acid (OCA); OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.; Other Names: 6α-ethyl chenodeoxycholic acid (6-ECDCA) INT-747
Experimental: DB OCA 10 mg OCA 10 mg for 12 months during the DB phase.	Drug: Obeticholic Acid (OCA); OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.; Other Names: 6α-ethyl chenodeoxycholic acid (6-ECDCA) INT-747
Placebo Comparator: DB Placebo Matching placebo for 12 months during the DB phase.	Drug: Placebo; Matching placebo tablets were administered orally once daily.
Experimental: LTSE OCA 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. Initially, participants were allowed to titrate to doses up to 25 mg, however, the maximum dose was then limited to 10 mg. Participants who were previously titrated above 10 mg OCA daily were down-titrated to ≤10 mg OCA daily.	Drug: Obeticholic Acid (OCA); OCA was administered orally once daily and provided in tablet form in 2 strengths: 5 mg and 10 mg.; Other Names: 6α-ethyl chenodeoxycholic acid (6-ECDCA) INT-747

Outcome Measures

Primary Outcome Measures

1. DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo [DB Month 12]

   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.

2. LTSE Phase: Composite Endpoint ALP And Total Bilirubin [Baseline (DB Month 12), LTSE Months 24, 36, 48, and 60]

   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.

Secondary Outcome Measures

1. DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo [DB Month 6]

   Percentage of participants at Month 6 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.

2. DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo [DB Month 12]

   Percentage of participants at Month 12 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.

3. DB Phase: Composite Endpoint ALP And Total Bilirubin, 5-10 mg Versus Placebo [DB Month 6]

   Percentage of participants at Month 6 with ALP < 1.67x ULN and total bilirubin ≤ ULN and ALP decrease of ≥ 15% from baseline.

4. DB Phase: ALP Absolute Change From Baseline To Month 12 [Baseline, DB Month 12]

   Blood samples were evaluated for ALP levels. ALP Absolute Change From Baseline (ALP at Month 12 - ALP at Baseline) is presented.

5. DB Phase: Total Bilirubin Absolute Change From Baseline To Month 12 [Baseline, DB Month 12]

   Blood samples were evaluated for bilirubin levels. Total bilirubin absolute change from baseline (total bilirubin at Month 12 - total bilirubin at Baseline) is presented.

6. DB Phase: Direct Bilirubin Absolute Change From Baseline To Month 12 [Baseline, DB Month 12]

   Blood samples were evaluated for bilirubin levels. Direct bilirubin absolute change from baseline (direct bilirubin at Month 12 - direct bilirubin at Baseline) is presented.

7. DB Phase: Alanine Aminotransferase (ALT) Absolute Change From Baseline To Month 12 [Baseline, DB Month 12]

   Blood samples were evaluated for ALT levels. ALT absolute change from baseline (ALT at Month 12 - ALT at Baseline) is presented.

8. DB Phase: Aspartate Aminotransferase (AST) Absolute Change From Baseline To Month 12 [Baseline, DB Month 12]

   Blood samples were evaluated for AST levels. AST absolute change from baseline (AST at Month 12 - AST at Baseline) is presented.

9. DB Phase: Gamma-glutamyltransferase (GGT) Absolute Change From Baseline To Month 12 [Baseline, DB Month 12]

   Blood samples were evaluated for GGT levels. GGT absolute change from baseline (GGT at Month 12 - GGT at Baseline) is presented.

10. LTSE Phase: ALP Levels [LTSE Day 0 and LTSE Months 12, 24, 36, 48, and 60]

    Blood samples were evaluated for ALP levels.

11. LTSE Phase: ALP Change From DB Baseline [DB Baseline, LTSE Months 12, 24, 36, 48, and 60]

    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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Disease [AASLD] and European Association for Study of the Liver [EASL] Practice Guidelines; [Lindor 2009; EASL 2009]), as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors:

• History of elevated alkaline phosphatase (ALP) levels for at least 6 months

• Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in low titer (<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components (pyruvate dehydrogenase complex-E2 [PDC-E2], 2-oxo-glutaric acid dehydrogenase complex)

• Liver biopsy consistent with PBC

1. At least 1 of the following qualifying biochemistry values:

• ALP ≥ 1.67x upper limit of normal (ULN)

• Total bilirubin > ULN but < 2x ULN

1. Age ≥ 18 years

2. Taking ursodeoxycholic acid (UDCA) for at least 12 months (stable dose for ≥ 3 months) prior to Day 0, or unable to tolerate UDCA (no UDCA for ≥ 3 months) prior to Day 0.

3. Contraception: Female participants must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use ≥ 1 effective (≤ 1% failure rate) method of contraception during the trial and for 30 days after the end of treatment (EOT) visit.

Effective methods of contraception are considered to be:

• Hormonal (for example, contraceptive pill, patch, intramuscular implant or injection); or

• Double barrier method, that is, (a) condom (male or female) or (b) diaphragm, with spermicide; or

• Intrauterine device (IUD); or

• Vasectomy (partner); or

• Sexual abstinence

1. Must provide written informed consent and agree to comply with the trial protocol.

Exclusion Criteria:

1. History or presence of other concomitant liver diseases including:

• Hepatitis C virus (HCV) infection; participants with active hepatitis B (HBV) infection will be excluded, however, participants who have seroconverted (hepatitis B surface antigen [Hbs Ag] and hepatitis B e antigen [Hbe Ag] negative) may be included after consultation with the medical monitor.

• Primary sclerosing cholangitis (PSC)

• Alcoholic liver disease

• Definite autoimmune liver disease or overlap hepatitis

• Nonalcoholic steatohepatitis (NASH)

• Gilbert's Syndrome (due to interpretability of bilirubin levels)

1. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:

• History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15

• Portal hypertension with complications, including: known gastric or large esophageal varices, poorly controlled or diuretic resistant ascites, history of variceal bleeds or related therapeutic or prophylactic interventions (for example, beta blockers, insertion of variceal bands or transjugular intrahepatic portosystemic shunt [TIPS]), or hepatic encephalopathy

• Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, bilirubin > 2x ULN

• Hepatorenal syndrome (type I or II) or Screening serum creatinine > 2 mg/deciliter dL) (178 micromole [µmol])/liter [L])

1. Participants with severe pruritus or those requiring systemic treatment for pruritus (for example, with bile acid sequestrants [BAS] or rifampicin) within 2 months of Day 0 will be excluded

2. Administration of the following medications is prohibited as specified below:

• Prohibited 6 months prior to Day 0 and throughout the trial (that is, to last dose and/or EOT): azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; fenofibrate or other fibrates; budesonide and other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)

• Prohibited 12 months prior to Day 0 and throughout the trial (that is, to last dose and/or EOT): antibodies or immunotherapy directed against interleukins or other cytokines or chemokines

1. Participants who have previously participated in a clinical trial of OCA will not be allowed to participate

2. History or presence of clinically concerning cardiac arrhythmias likely to affect survival during the trial, or prolongation of Screening (pretreatment) QT or QTc interval of > 500 milliseconds (msec)

3. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating

4. Known history of human immunodeficiency virus (HIV) infection

5. Presence of any other disease or condition that is interfering with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the intestine. Participants with inflammatory bowel disease or who have undergone gastric bypass procedures will be excluded (gastric lap band is acceptable).

6. Medical conditions that may cause nonhepatic increases in ALP (for example, Paget's disease) or which may diminish life expectancy to < 2 years, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such as chronic lymphatic leukemia)

7. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the trial

8. Anticipated changes to current concomitant medications during the course of the trial

9. History of alcohol abuse, defined as consumption of more than 210 mL of alcohol per week (that is, the equivalent of fourteen 4-ounce (125 mL) glasses of wine or fourteen 12 ounce cans/bottles of beer), or other substance abuse within 1 year prior to Day 0

10. Participation in another investigational drug, biologic, or medical device trial within 30 days prior to Screening

11. History of noncompliance with medical regimens, or participants who are considered to be potentially unreliable

12. Blood or plasma donation within 30 days prior to Day 0

13. Mental instability or incompetence, such that the validity of informed consent or compliance with the trial is uncertain

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC Davis Medical Center	Sacramento	California	United States	95817
2	Scripps Clinic	San Diego	California	United States	92037
3	University of Colorado, Denver	Aurora	Colorado	United States	80045
4	University of Chicago	Chicago	Illinois	United States	60637
5	Indiana University School of Medicine	Indianapolis	Indiana	United States	46202
6	Henry Ford Health System	Detroit	Michigan	United States	48377
7	St. Louis University	Saint Louis	Missouri	United States	63104
8	Beth Israel Medical Center	New York	New York	United States	10003
9	Duke University Medical Center	Durham	North Carolina	United States	27710
10	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
11	Baylor College of Medicine	Houston	Texas	United States	77030
12	Liver Institute of Virginia	Newport News	Virginia	United States	23602
13	Liver Institute of Virginia	Richmond	Virginia	United States	23226
14	Virginia Commonwealth University/McGuire DVAMC	Richmond	Virginia	United States	23249
15	Swedish Medical Center	Seattle	Washington	United States	98101
16	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia	2050
17	Austin Hospital	Heidelberg	Victoria	Australia	3084
18	The Alfred Hospital	Melbourne	Victoria	Australia	3004
19	Medizinische Universität Innsbruck	Innsbruck		Austria	6020
20	Medizinische Universität Wien	Wien		Austria	1090
21	UZ Leuven	Leuven		Belgium	B-3000
22	Toronto Western Hospital Liver Centre	Toronto	Ontario	Canada	M5T 2S8
23	CHUM Hôpital St-Luc	Montreal	Quebec	Canada	H2X 3J4
24	Hopital Haut-Leveque	Pessac		France	33604
25	Universitätsklinikum Aachen	Aachen		Germany	D-52074
26	Friedrich-Alexander-Universität Erlangen	Erlangen		Germany	D-91054
27	Klinikum der Johann-Wolfgang Goethe Universität Frankfurt am Main	Frankfurt am Main		Germany	60590
28	Universitätsklinikum Hamburg Eppendorf	Hamburg		Germany	20246
29	Medizinische Hochschule Hannover	Hannover		Germany	D-30625
30	Medizinische Universitätsklinik	Heidelberg		Germany	D-69120
31	Gastroenterologische Gemeinschaftspraxis, Dres. Felten / Hartmann / Hüppe	Herne		Germany	D-44623
32	Universitätsklinikum des Saarlandes	Homburg		Germany	66421
33	Universitätsklinikum Leipzig	Leipzig		Germany	04103
34	LMU Klinikum der Universität München	München		Germany	D-81377
35	Dip. Medicina Clinica - Università di Bologna	Bologna		Italy	40138
36	Dip. Medicina Clinica- Università di Bologna	Bologna		Italy	40138
37	Azienda Ospedaliera di Padova - Gastroenterologia	Padova		Italy	35128
38	Istituto Clinico Humanitas	Rozzano (MI)		Italy	20089
39	VUmc Amsterdam	Amsterdam		Netherlands	1081 HV
40	AMC Amsterdam	Amsterdam		Netherlands	1105 AZ
41	UMC St. Radboud, Nijmegen	Nijmegen		Netherlands	6525
42	UMC Utrecht	Utrecht		Netherlands	3508 GA
43	All-Medicus	Katowice		Poland	40-660
44	Klinika Gastroenterologii i Hepatologii SP CSK im. prof. K. Gibinskiego SUM	Katowice		Poland	40-752
45	Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie	Lublin		Poland	20-954
46	Niepubliczny Zakład Opieki Zdrowotnej "SONOMED"	Szczecin		Poland	70-361
47	Centrum Onkologii - Instytut im. Marii Skłodowskiej - Curie, Klinika Gastroenterologii	Warszawa		Poland	02-781
48	Hospital Vall d'Hebron	Barcelona		Spain	08035
49	Hospital Clinic de Barcelona	Barcelona		Spain	08036
50	Sahlgrenska University Hospital	Gothenburg		Sweden	SE-41345
51	Queen Elizabeth Hospital	Birmingham		United Kingdom	B15 2TH
52	Bristol Royal Infirmary	Bristol		United Kingdom	BS2 8HW
53	Ninewells Hospital Dundee	Dundee		United Kingdom	DD1 9SY
54	Forth Valley Royal Hospital	Larbert		United Kingdom	FK5 4WR
55	The Royal Free Hospital	London		United Kingdom	NW3 2QG
56	Manchester Royal Infirmary	Manchester		United Kingdom	M13 9WL
57	Institute of Cellular Medicine, Newcastle University	Newcastle Upon Tyne		United Kingdom	NE2 4 HH
58	Nottingham University Hospitals NHS Trust	Nottingham		United Kingdom	NG7 2UH
59	Oxford University Hospitals Trust	Oxford		United Kingdom	OX3 9DU

Sponsors and Collaborators

• Intercept Pharmaceuticals

Investigators

• Study Chair: Christian Weyer, MD, Intercept Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology. 2009 Jul;50(1):291-308. doi: 10.1002/hep.22906.

• Responsible Party: Intercept Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01473524
• Other Study ID Numbers: 747-301
• First Posted: Nov 17, 2011
• Last Update Posted: May 6, 2021
• Last Verified: Apr 1, 2021

• Keywords provided by Intercept Pharmaceuticals: Primary Biliary Cholangitis; Primary Biliary Cirrhosis; PBC; Cirrhosis; Liver
• Additional relevant MeSH terms: Liver Cirrhosis; Liver Cirrhosis, Biliary; Fibrosis; Chenodeoxycholic Acid

Study Results

Participant Flow

Recruitment Details	Recruitment into hospitals and physicians' clinics started January 2012 and completed December 2012.
Pre-assignment Detail	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)
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
Period Title: DB Phase
STARTED	0	0	0	63	64	66
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

Baseline Characteristics

Arm/Group Title	DB OCA 5-10 mg	DB OCA 10 mg	DB Placebo	Total
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 Participants	70	73	73	216
Age (Count of Participants)
<=18 years	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 (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.8 (10.53)	56.2 (11.00)	55.5 (10.03)	55.8 (10.48)
Sex: Female, Male (Count of 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 (participants) [Number]
Asian	1 1.4%	1 1.4%	1 1.4%	3 1.4%
Black or African American	1 1.4%	1 1.4%	1 1.4%	3 1.4%
Other	1 1.4%	1 1.4%	5 6.8%	7 3.2%
White	67 95.7%	70 95.9%	66 90.4%	203 94%
Region of Enrollment (participants) [Number]
United States	18 25.7%	19 26%	17 23.3%	54 25%
United Kingdom	8 11.4%	5 6.8%	9 12.3%	22 10.2%
Spain	4 5.7%	2 2.7%	3 4.1%	9 4.2%
Canada	2 2.9%	2 2.7%	4 5.5%	8 3.7%
Austria	2 2.9%	0 0%	1 1.4%	3 1.4%
Netherlands	3 4.3%	7 9.6%	6 8.2%	16 7.4%
Sweden	3 4.3%	1 1.4%	0 0%	4 1.9%
Belgium	2 2.9%	9 12.3%	5 6.8%	16 7.4%
Poland	4 5.7%	6 8.2%	4 5.5%	14 6.5%
Italy	11 15.7%	10 13.7%	11 15.1%	32 14.8%
Australia	5 7.1%	1 1.4%	3 4.1%	9 4.2%
France	0 0%	0 0%	1 1.4%	1 0.5%
Germany	8 11.4%	11 15.1%	9 12.3%	28 13%
Alkaline Phosphatase (U/L) (U/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/L]	325.87 (116.238)	316.34 (103.881)	327.49 (115.014)	323.19 (111.375)
Total Bilirubin (umol/L) (umol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [umol/L]	10.192 (5.549)	11.278 (6.634)	11.757 (7.227)	11.088 (6.522)
Direct Bilirubin (umol/L) (umol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [umol/L]	4.398 (4.528)	4.868 (4.473)	5.469 (6.214)	4.919 (5.138)
Alanine Aminotransferase (ALT) (U/L) (U/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/L]	61.56 (39.037)	56.31 (39.741)	55.99 (30.312)	57.9 (36.498)
Aspartate Aminotransferase (AST) (U/L) (U/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/L]	52.25 (25.289)	50.49 (31.100)	48.79 (22.449)	50.49 (26.456)
Gamma-Glutamyltransferase (GGT) (U/L) (U/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/L]	252.83 (167.038)	261.07 (207.396)	309.58 (449.356)	274.79 (302.673)

Outcome Measures

1. Primary Outcome

Title	DB Phase: Composite Endpoint Alkaline Phosphatase (ALP) And Total Bilirubin, 10 mg OCA Versus Placebo
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

Outcome Measure Data

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
Arm/Group Description	OCA 10 mg for 12 months during the DB phase.	Matching placebo for 12 months during the DB phase.
Measure Participants	73	73
Number [percentage of participants]	47 67.1%	10 13.7%

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
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	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
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

Outcome Measure Data

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
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.
Measure Participants	63	64	66	193
Baseline (Double-blind Month 12)	51 72.9%	56 76.7%	9 12.3%	38 17.6%
LTSE Month 12	55 78.6%	58 79.5%	41 56.2%	51 23.6%
LTSE Month 24	60 85.7%	61 83.6%	54 74%	58 26.9%
LTSE Month 36	48 68.6%	51 69.9%	49 67.1%	49 22.7%
LTSE Month 48	52 74.3%	55 75.3%	60 82.2%	56 25.9%
LTSE Month 60	48 68.6%	52 71.2%	50 68.5%	50 23.1%

3. Secondary Outcome

Title	DB Phase: Composite Endpoint ALP And Total Bilirubin, 10 mg Versus Placebo
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

Outcome Measure Data

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
Arm/Group Description	OCA 10 mg for 12 months during the DB phase.	Matching placebo for 12 months during the DB phase.
Measure Participants	73	73
Number [percentage of participants]	51 72.9%	7 9.6%

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
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	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
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

Outcome Measure Data

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
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.
Measure Participants	70	73
Number [percentage of participants]	46 65.7%	10 13.7%

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 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
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	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
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

Outcome Measure Data

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
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.
Measure Participants	70	73
Number [percentage of participants]	34 48.6%	7 9.6%

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 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
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	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
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

Outcome Measure Data

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
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.
Measure Participants	64	62	70
Least Squares Mean (Standard Error) [U/L]	-112.51 (14.36)	-129.90 (14.60)	-14.42 (14.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DB OCA 10 mg, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DB Placebo, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	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
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

Outcome Measure Data

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
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.
Measure Participants	64	62	70
Least Squares Mean (Standard Error) [umol/L]	-0.33 (0.68)	-0.90 (0.71)	1.98 (0.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DB OCA 10 mg, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DB Placebo, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	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
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

Outcome Measure Data

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
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.
Measure Participants	64	62	70
Least Squares Mean (Standard Error) [umol/L]	-0.13 (0.52)	-0.49 (0.54)	1.89 (0.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DB OCA 10 mg, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DB Placebo, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	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
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

Outcome Measure Data

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
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.
Measure Participants	64	62	70
Least Squares Mean (Standard Error) [U/L]	-21.26 (3.27)	-25.31 (3.35)	-4.95 (3.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DB OCA 10 mg, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DB Placebo, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	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
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

Outcome Measure Data

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
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.
Measure Participants	64	62	70
Least Squares Mean (Standard Error) [U/L]	-13.03 (4.17)	-15.00 (4.28)	1.04 (4.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DB OCA 10 mg, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DB Placebo, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	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
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

Outcome Measure Data

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
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.
Measure Participants	64	62	70
Least Squares Mean (Standard Error) [U/L]	-140.83 (24.70)	-176.66 (25.58)	6.70 (25.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DB OCA 10 mg, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DB Placebo, LTSE OCA (DB Placebo)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	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
Description	Blood samples were evaluated for ALP levels.
Time Frame	LTSE Day 0 and LTSE Months 12, 24, 36, 48, and 60

Outcome Measure Data

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
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.
Measure Participants	63	64	66	193
LTSE Day 0	218.69 (100.328)	191.24 (61.381)	317.79 (139.666)	243.75 (118.910)
LTSE Month 12	209.49 (93.157)	198.68 (75.799)	226.28 (105.404)	211.47 (92.439)
LTSE Month 24	195.14 (80.361)	194.57 (66.593)	215.99 (83.469)	201.47 (77.117)
LTSE Month 36	204.52 (68.019)	214.66 (158.831)	205.37 (65.206)	208.27 (107.114)
LTSE Month 48	189.75 (55.929)	192.00 (59.761)	198.70 (65.551)	193.38 (60.170)
LTSE Month 60	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
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

Outcome Measure Data

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
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.
Measure Participants	63	64	66	193
Month 12	-106.63 (98.448)	-104.39 (82.496)	-104.36 (83.074)	-105.13 (87.882)
Month 24	-120.86 (96.614)	-102.52 (79.413)	-100.99 (87.181)	-108.34 (87.980)
Month 36	-100.98 (109.952)	-84.65 (137.293)	-112.73 (89.661)	-98.96 (114.635)
Month 48	-118.23 (101.527)	-101.50 (91.335)	-115.51 (106.774)	-111.49 (99.433)
Month 60	-118.99 (147.126)	-117.49 (95.587)	-119.52 (108.949)	-118.74 (121.391)

Adverse Events

Time Frame	DB Phase: Baseline up to 12 months (1 year). LTSE phase: Baseline (DB Month 12) up to 60 months (5 years).
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
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 (%)	# 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	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
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 (15.7%)		8/73 (11%)		3/73 (4.1%)		30/63 (47.6%)		19/64 (29.7%)		20/66 (30.3%)		69/193 (35.8%)
Blood and lymphatic system disorders
Anaemia	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	2/63 (3.2%)	4	0/64 (0%)	0	0/66 (0%)	0	2/193 (1%)	4
Splenic infarction	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Cardiac disorders
Aortic valve stenosis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Atrial fibrillation	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	2/64 (3.1%)	2	0/66 (0%)	0	2/193 (1%)	2
Cardiac failure	1/70 (1.4%)	2	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Cardiac failure congestive	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Cardiomyopathy	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Myocardial infarction	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Sick sinus syndrome	0/70 (0%)	0	0/73 (0%)	0	1/73 (1.4%)	1	0/63 (0%)	0	0/64 (0%)	0	0/66 (0%)	0	0/193 (0%)	0
Ventricular fibrillation	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Eye disorders
Cataract	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Gastrointestinal disorders
Abdominal distension	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Abdominal pain	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Abdominal pain lower	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Abdominal wall haematoma	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	1/64 (1.6%)	1	0/66 (0%)	0	2/193 (1%)	2
Ascites	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Constipation	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Haematemesis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Lower gastrointestinal haemorrhage	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Oedematous pancreatitis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Oesophageal varices haemorrhage	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	2/63 (3.2%)	2	1/64 (1.6%)	1	1/66 (1.5%)	1	4/193 (2.1%)	4
Pancreatitis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	2/66 (3%)	2	2/193 (1%)	2
Rectal prolapse	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Splenic artery aneurysm	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	3	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	3
Upper gastrointestinal haemorrhage	1/70 (1.4%)	1	0/73 (0%)	0	1/73 (1.4%)	1	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Varices oesophageal	0/70 (0%)	0	0/73 (0%)	0	1/73 (1.4%)	2	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Volvulus	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
General disorders
Chest pain	0/70 (0%)	0	0/73 (0%)	0	1/73 (1.4%)	1	0/63 (0%)	0	0/64 (0%)	0	0/66 (0%)	0	0/193 (0%)	0
Non-cardiac chest pain	0/70 (0%)	0	0/73 (0%)	0	1/73 (1.4%)	1	0/63 (0%)	0	0/64 (0%)	0	0/66 (0%)	0	0/193 (0%)	0
Oedema	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	0/66 (0%)	0	0/193 (0%)	0
Polyserositis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Hepatobiliary disorders
Cholecystitis acute	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Cholelithiasis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Hepatic failure	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Hyperplastic cholecystopathy	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Jaundice	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Infections and infestations
Appendicitis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Bacterial sepsis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Cellulitis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Endocarditis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Erysipelas	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	0/66 (0%)	0	0/193 (0%)	0
Parotitis	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	3	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	3
Pneumonia	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	3/63 (4.8%)	3	1/64 (1.6%)	1	0/66 (0%)	0	4/193 (2.1%)	4
Postoperative wound infection	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Pyelonephritis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Pyelonephritis chronic	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Sepsis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Urosepsis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Vaginal infection	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Injury, poisoning and procedural complications
Anastomotic ulcer	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Ankle fracture	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Clavicle fracture	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Foot fracture	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Ligament rupture	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Lower limb fracture	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Meniscus lesion	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Post procedural haemorrhage	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	1/66 (1.5%)	1	2/193 (1%)	2
Procedural pain	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	1/66 (1.5%)	1	2/193 (1%)	2
Radius fracture	0/70 (0%)	0	1/73 (1.4%)	2	0/73 (0%)	0	2/63 (3.2%)	2	2/64 (3.1%)	3	0/66 (0%)	0	4/193 (2.1%)	5
Rib fracture	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	2	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	2
Spinal compression fracture	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Tibia fracture	0/70 (0%)	0	0/73 (0%)	0	1/73 (1.4%)	1	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Wrist fracture	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Investigations
Medical observation	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Metabolism and nutrition disorders
Hypoglycaemia	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Hyponatraemia	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Musculoskeletal and connective tissue disorders
Haemarthrosis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Intervertebral disc protrusion	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Osteoarthritis	0/70 (0%)	0	2/73 (2.7%)	2	0/73 (0%)	0	2/63 (3.2%)	2	5/64 (7.8%)	6	0/66 (0%)	0	7/193 (3.6%)	8
Rotator cuff syndrome	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Spondylolisthesis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Systemic sclerosis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Breast cancer	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Chronic myeloid leukaemia	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Chronic obstructive pulmonary disease	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Colorectal cancer	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Hepatic neoplasm malignant	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Hepatic neoplasm malignant recurrent	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Lip neoplasm malignant stage unspecified	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Renal oncocytoma	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Uterine leiomyoma	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Nervous system disorders
Carpal tunnel syndrome	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Hepatic encephalopathy	1/70 (1.4%)	2	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	0/66 (0%)	0	0/193 (0%)	0
Ischaemic stroke	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Loss of consciousness	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Syncope	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	1/64 (1.6%)	1	0/66 (0%)	0	2/193 (1%)	2
Transient ischaemic attack	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Psychiatric disorders
Depression	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Major depression	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Renal and urinary disorders
Nephrolithiasis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Nephropathy toxic	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Renal atrophy	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Renal failure	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	1/66 (1.5%)	1	1/193 (0.5%)	1
Renal failure acute	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/70 (0%)	0	0/73 (0%)	0	1/73 (1.4%)	1	0/63 (0%)	0	0/64 (0%)	0	0/66 (0%)	0	0/193 (0%)	0
Interstitial lung disease	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	0/66 (0%)	0	0/193 (0%)	0
Skin and subcutaneous tissue disorders
Neurodermatitis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Vascular disorders
Hypertension	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	0/64 (0%)	0	0/66 (0%)	0	1/193 (0.5%)	1
Intra-abdominal haematoma	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Temporal arteritis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	0/66 (0%)	0	1/193 (0.5%)	1
Varicose vein	2/70 (2.9%)	2	0/73 (0%)	0	0/73 (0%)	0	2/63 (3.2%)	2	0/64 (0%)	0	0/66 (0%)	0	2/193 (1%)	2
Other (Not Including 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	64/70 (91.4%)		64/73 (87.7%)		62/73 (84.9%)		61/63 (96.8%)		62/64 (96.9%)		64/66 (97%)		187/193 (96.9%)
Blood and lymphatic system disorders
Anaemia	2/70 (2.9%)	2	3/73 (4.1%)	3	4/73 (5.5%)	5	8/63 (12.7%)	12	7/64 (10.9%)	8	4/66 (6.1%)	5	19/193 (9.8%)	25
Iron deficiency anaemia	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	1/63 (1.6%)	4	1/64 (1.6%)	1	3/66 (4.5%)	4	5/193 (2.6%)	9
Thrombocytopenia	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	3/64 (4.7%)	3	2/66 (3%)	2	5/193 (2.6%)	5
Splenomegaly	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	4/63 (6.3%)	5	2/64 (3.1%)	2	1/66 (1.5%)	1	7/193 (3.6%)	8
Cardiac disorders
Palpitations	2/70 (2.9%)	3	5/73 (6.8%)	5	1/73 (1.4%)	1	4/63 (6.3%)	6	5/64 (7.8%)	5	2/66 (3%)	2	11/193 (5.7%)	13
Bradycardia	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	3/63 (4.8%)	3	0/64 (0%)	0	1/66 (1.5%)	1	4/193 (2.1%)	4
Cardiac murmur	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	3/63 (4.8%)	3	2/64 (3.1%)	2	2/66 (3%)	2	7/193 (3.6%)	7
Atrial fibrillation	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	3/64 (4.7%)	7	2/66 (3%)	2	6/193 (3.1%)	10
Ear and labyrinth disorders
Vertigo	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	4/63 (6.3%)	7	2/64 (3.1%)	2	2/66 (3%)	2	8/193 (4.1%)	11
Ear pain	2/70 (2.9%)	2	0/73 (0%)	0	1/73 (1.4%)	1	2/63 (3.2%)	3	3/64 (4.7%)	3	1/66 (1.5%)	1	6/193 (3.1%)	7
Endocrine disorders
Hypothyroidism	4/70 (5.7%)	4	1/73 (1.4%)	1	1/73 (1.4%)	1	4/63 (6.3%)	4	3/64 (4.7%)	3	3/66 (4.5%)	3	10/193 (5.2%)	10
Eye disorders
Dry eye	2/70 (2.9%)	3	4/73 (5.5%)	4	4/73 (5.5%)	4	3/63 (4.8%)	4	10/64 (15.6%)	11	2/66 (3%)	2	15/193 (7.8%)	17
Conjunctivitis	1/70 (1.4%)	1	2/73 (2.7%)	2	2/73 (2.7%)	2	2/63 (3.2%)	4	5/64 (7.8%)	6	1/66 (1.5%)	1	8/193 (4.1%)	11
Cataract	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	2/63 (3.2%)	2	3/64 (4.7%)	4	1/66 (1.5%)	1	6/193 (3.1%)	7
Gastrointestinal disorders
Nausea	4/70 (5.7%)	5	8/73 (11%)	10	9/73 (12.3%)	18	14/63 (22.2%)	20	13/64 (20.3%)	19	10/66 (15.2%)	15	37/193 (19.2%)	54
Diarrhoea	2/70 (2.9%)	3	8/73 (11%)	10	8/73 (11%)	13	8/63 (12.7%)	15	11/64 (17.2%)	17	14/66 (21.2%)	26	33/193 (17.1%)	58
Abdominal pain upper	5/70 (7.1%)	5	4/73 (5.5%)	5	5/73 (6.8%)	8	9/63 (14.3%)	12	10/64 (15.6%)	11	12/66 (18.2%)	13	31/193 (16.1%)	36
Constipation	5/70 (7.1%)	5	5/73 (6.8%)	5	4/73 (5.5%)	7	12/63 (19%)	12	9/64 (14.1%)	9	7/66 (10.6%)	8	28/193 (14.5%)	29
Abdominal distension	3/70 (4.3%)	3	3/73 (4.1%)	3	7/73 (9.6%)	7	5/63 (7.9%)	7	7/64 (10.9%)	7	5/66 (7.6%)	5	17/193 (8.8%)	19
Dyspepsia	4/70 (5.7%)	4	0/73 (0%)	0	8/73 (11%)	11	7/63 (11.1%)	12	8/64 (12.5%)	8	5/66 (7.6%)	5	20/193 (10.4%)	25
Vomiting	3/70 (4.3%)	3	3/73 (4.1%)	3	5/73 (6.8%)	8	5/63 (7.9%)	7	7/64 (10.9%)	9	2/66 (3%)	2	14/193 (7.3%)	18
Gastrooesophageal reflux disease	2/70 (2.9%)	2	4/73 (5.5%)	5	4/73 (5.5%)	6	7/63 (11.1%)	7	9/64 (14.1%)	12	4/66 (6.1%)	4	20/193 (10.4%)	23
Abdominal pain	3/70 (4.3%)	3	1/73 (1.4%)	1	6/73 (8.2%)	6	11/63 (17.5%)	15	7/64 (10.9%)	9	8/66 (12.1%)	8	26/193 (13.5%)	32
Abdominal discomfort	5/70 (7.1%)	5	0/73 (0%)	0	1/73 (1.4%)	5	5/63 (7.9%)	5	0/64 (0%)	0	2/66 (3%)	2	7/193 (3.6%)	7
Dry mouth	2/70 (2.9%)	2	3/73 (4.1%)	3	2/73 (2.7%)	2	3/63 (4.8%)	4	5/64 (7.8%)	5	3/66 (4.5%)	3	11/193 (5.7%)	12
Gastritis	1/70 (1.4%)	1	1/73 (1.4%)	1	0/73 (0%)	0	2/63 (3.2%)	2	6/64 (9.4%)	7	3/66 (4.5%)	3	11/193 (5.7%)	12
Haemorrhoids	0/70 (0%)	0	0/73 (0%)	0	2/73 (2.7%)	2	5/63 (7.9%)	6	1/64 (1.6%)	1	5/66 (7.6%)	5	11/193 (5.7%)	12
Varices oesophageal	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	8/63 (12.7%)	8	2/64 (3.1%)	3	1/66 (1.5%)	1	11/193 (5.7%)	12
Ascites	1/70 (1.4%)	1	1/73 (1.4%)	1	0/73 (0%)	0	6/63 (9.5%)	9	1/64 (1.6%)	1	3/66 (4.5%)	4	10/193 (5.2%)	14
Toothache	0/70 (0%)	0	1/73 (1.4%)	1	1/73 (1.4%)	1	2/63 (3.2%)	2	5/64 (7.8%)	6	3/66 (4.5%)	3	10/193 (5.2%)	11
Dental caries	2/70 (2.9%)	2	0/73 (0%)	0	0/73 (0%)	0	4/63 (6.3%)	5	1/64 (1.6%)	1	4/66 (6.1%)	6	9/193 (4.7%)	12
Hiatus hernia	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	3/64 (4.7%)	3	1/66 (1.5%)	1	5/193 (2.6%)	5
Portal hypertensive gastropathy	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	3/63 (4.8%)	3	0/64 (0%)	0	2/66 (3%)	2	5/193 (2.6%)	5
Gastric polyps	0/70 (0%)	0	2/73 (2.7%)	2	0/73 (0%)	0	1/63 (1.6%)	1	3/64 (4.7%)	4	0/66 (0%)	0	4/193 (2.1%)	5
Rectal haemorrhage	0/70 (0%)	0	2/73 (2.7%)	2	0/73 (0%)	0	1/63 (1.6%)	1	2/64 (3.1%)	2	4/66 (6.1%)	4	7/193 (3.6%)	7
Abdominal pain lower	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	3/63 (4.8%)	4	1/64 (1.6%)	1	1/66 (1.5%)	1	5/193 (2.6%)	6
General disorders
Fatigue	11/70 (15.7%)	13	17/73 (23.3%)	25	10/73 (13.7%)	12	24/63 (38.1%)	46	24/64 (37.5%)	43	15/66 (22.7%)	20	63/193 (32.6%)	109
Oedema peripheral	2/70 (2.9%)	2	5/73 (6.8%)	7	2/73 (2.7%)	3	10/63 (15.9%)	15	8/64 (12.5%)	12	8/66 (12.1%)	10	26/193 (13.5%)	37
Pyrexia	0/70 (0%)	0	5/73 (6.8%)	6	1/73 (1.4%)	1	5/63 (7.9%)	6	6/64 (9.4%)	8	5/66 (7.6%)	5	16/193 (8.3%)	19
Asthenia	2/70 (2.9%)	2	1/73 (1.4%)	1	1/73 (1.4%)	1	2/63 (3.2%)	2	3/64 (4.7%)	7	6/66 (9.1%)	6	11/193 (5.7%)	15
Influenza like illness	1/70 (1.4%)	1	3/73 (4.1%)	4	1/73 (1.4%)	1	4/63 (6.3%)	4	6/64 (9.4%)	9	1/66 (1.5%)	1	11/193 (5.7%)	14
Hepatobiliary disorders
Cholelithiasis	2/70 (2.9%)	2	0/73 (0%)	0	0/73 (0%)	0	5/63 (7.9%)	6	4/64 (6.3%)	4	1/66 (1.5%)	1	10/193 (5.2%)	11
Hepatomegaly	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	3/63 (4.8%)	3	0/64 (0%)	0	1/66 (1.5%)	1	4/193 (2.1%)	4
Hepatic cirrhosis	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	2/64 (3.1%)	2	4/66 (6.1%)	4	7/193 (3.6%)	7
Immune system disorders
Seasonal allergy	2/70 (2.9%)	2	1/73 (1.4%)	1	2/73 (2.7%)	2	4/63 (6.3%)	4	2/64 (3.1%)	2	1/66 (1.5%)	1	7/193 (3.6%)	7
Infections and infestations
Nasopharyngitis	17/70 (24.3%)	27	13/73 (17.8%)	15	13/73 (17.8%)	19	23/63 (36.5%)	66	23/64 (35.9%)	39	11/66 (16.7%)	22	57/193 (29.5%)	127
Urinary tract infection	4/70 (5.7%)	6	4/73 (5.5%)	6	8/73 (11%)	15	17/63 (27%)	31	19/64 (29.7%)	27	15/66 (22.7%)	23	51/193 (26.4%)	81
Upper respiratory tract infection	4/70 (5.7%)	4	4/73 (5.5%)	4	8/73 (11%)	8	12/63 (19%)	21	11/64 (17.2%)	17	11/66 (16.7%)	16	34/193 (17.6%)	54
Influenza	5/70 (7.1%)	5	4/73 (5.5%)	4	4/73 (5.5%)	5	12/63 (19%)	17	12/64 (18.8%)	17	10/66 (15.2%)	17	34/193 (17.6%)	51
Sinusitis	1/70 (1.4%)	1	4/73 (5.5%)	5	0/73 (0%)	0	7/63 (11.1%)	7	9/64 (14.1%)	11	8/66 (12.1%)	11	24/193 (12.4%)	29
Bronchitis	4/70 (5.7%)	4	1/73 (1.4%)	1	0/73 (0%)	0	7/63 (11.1%)	7	7/64 (10.9%)	7	6/66 (9.1%)	10	20/193 (10.4%)	24
Respiratory tract infection	0/70 (0%)	0	0/73 (0%)	0	3/73 (4.1%)	3	5/63 (7.9%)	6	4/64 (6.3%)	5	4/66 (6.1%)	5	13/193 (6.7%)	16
Cystitis	1/70 (1.4%)	2	2/73 (2.7%)	2	0/73 (0%)	0	5/63 (7.9%)	12	5/64 (7.8%)	15	2/66 (3%)	3	12/193 (6.2%)	30
Herpes zoster	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	1/63 (1.6%)	1	7/64 (10.9%)	8	4/66 (6.1%)	4	12/193 (6.2%)	13
Pneumonia	0/70 (0%)	0	2/73 (2.7%)	2	0/73 (0%)	0	2/63 (3.2%)	2	5/64 (7.8%)	8	5/66 (7.6%)	6	12/193 (6.2%)	16
Gastroenteritis	3/70 (4.3%)	3	1/73 (1.4%)	1	0/73 (0%)	0	4/63 (6.3%)	4	1/64 (1.6%)	1	5/66 (7.6%)	6	10/193 (5.2%)	11
Diverticulum	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	2/63 (3.2%)	2	3/64 (4.7%)	3	0/66 (0%)	0	5/193 (2.6%)	5
Ear infection	0/70 (0%)	0	1/73 (1.4%)	1	1/73 (1.4%)	1	1/63 (1.6%)	1	1/64 (1.6%)	2	3/66 (4.5%)	3	5/193 (2.6%)	6
Oral herpes	1/70 (1.4%)	1	1/73 (1.4%)	1	1/73 (1.4%)	1	3/63 (4.8%)	4	1/64 (1.6%)	1	1/66 (1.5%)	1	5/193 (2.6%)	6
Tooth infection	1/70 (1.4%)	2	0/73 (0%)	0	0/73 (0%)	0	2/63 (3.2%)	3	3/64 (4.7%)	3	2/66 (3%)	2	7/193 (3.6%)	8
Lower respiratory tract infection	2/70 (2.9%)	2	0/73 (0%)	0	1/73 (1.4%)	1	4/63 (6.3%)	8	1/64 (1.6%)	2	1/66 (1.5%)	5	6/193 (3.1%)	15
Pharyngitis	0/70 (0%)	0	0/73 (0%)	0	1/73 (1.4%)	1	1/63 (1.6%)	1	3/64 (4.7%)	6	2/66 (3%)	2	6/193 (3.1%)	9
Injury, poisoning and procedural complications
Procedural pain	4/70 (5.7%)	4	1/73 (1.4%)	1	1/73 (1.4%)	3	8/63 (12.7%)	9	4/64 (6.3%)	5	4/66 (6.1%)	7	16/193 (8.3%)	21
Contusion	3/70 (4.3%)	3	2/73 (2.7%)	3	2/73 (2.7%)	2	2/63 (3.2%)	2	5/64 (7.8%)	5	3/66 (4.5%)	3	10/193 (5.2%)	10
Rib fracture	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	3/63 (4.8%)	3	2/64 (3.1%)	2	0/66 (0%)	0	5/193 (2.6%)	5
Arthropod bite	1/70 (1.4%)	1	0/73 (0%)	0	1/73 (1.4%)	1	0/63 (0%)	0	0/64 (0%)	0	4/66 (6.1%)	4	4/193 (2.1%)	4
Excoriation	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	1/63 (1.6%)	1	3/64 (4.7%)	3	0/66 (0%)	0	4/193 (2.1%)	4
Ligament rupture	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	3/66 (4.5%)	3	3/193 (1.6%)	3
Tendon rupture	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	3/64 (4.7%)	3	0/66 (0%)	0	3/193 (1.6%)	3
Scratch	1/70 (1.4%)	1	3/73 (4.1%)	4	0/73 (0%)	0	1/63 (1.6%)	1	6/64 (9.4%)	7	2/66 (3%)	3	9/193 (4.7%)	11
Fall	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	4/63 (6.3%)	4	0/64 (0%)	0	4/66 (6.1%)	4	8/193 (4.1%)	8
Meniscus lesion	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	2	5/64 (7.8%)	5	1/66 (1.5%)	1	7/193 (3.6%)	8
Investigations
Hepatic enzyme increased	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	1/63 (1.6%)	1	3/64 (4.7%)	5	1/66 (1.5%)	1	5/193 (2.6%)	7
Low density lipoprotein increased	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	0/63 (0%)	0	1/64 (1.6%)	1	3/66 (4.5%)	4	4/193 (2.1%)	5
Gamma-glutamyltransferase increased	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	0/64 (0%)	0	3/66 (4.5%)	3	3/193 (1.6%)	3
Weight decreased	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	3/63 (4.8%)	3	2/64 (3.1%)	2	1/66 (1.5%)	1	6/193 (3.1%)	6
Metabolism and nutrition disorders
Hypercholesterolaemia	0/70 (0%)	0	0/73 (0%)	0	2/73 (2.7%)	2	3/63 (4.8%)	4	2/64 (3.1%)	2	3/66 (4.5%)	3	8/193 (4.1%)	9
Vitamin D deficiency	0/70 (0%)	0	0/73 (0%)	0	1/73 (1.4%)	1	2/63 (3.2%)	2	3/64 (4.7%)	3	3/66 (4.5%)	3	8/193 (4.1%)	8
Diabetes mellitus	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	0/63 (0%)	0	3/64 (4.7%)	3	3/66 (4.5%)	5	6/193 (3.1%)	8
Musculoskeletal and connective tissue disorders
Back pain	4/70 (5.7%)	4	4/73 (5.5%)	5	8/73 (11%)	8	10/63 (15.9%)	13	11/64 (17.2%)	15	10/66 (15.2%)	10	31/193 (16.1%)	38
Arthralgia	4/70 (5.7%)	5	7/73 (9.6%)	7	3/73 (4.1%)	3	14/63 (22.2%)	17	17/64 (26.6%)	23	15/66 (22.7%)	18	46/193 (23.8%)	58
Muscle spasms	2/70 (2.9%)	2	2/73 (2.7%)	2	4/73 (5.5%)	5	4/63 (6.3%)	4	4/64 (6.3%)	7	3/66 (4.5%)	3	11/193 (5.7%)	14
Osteopenia	1/70 (1.4%)	1	1/73 (1.4%)	1	0/73 (0%)	0	9/63 (14.3%)	9	6/64 (9.4%)	6	6/66 (9.1%)	7	21/193 (10.9%)	22
Pain in extremity	3/70 (4.3%)	3	1/73 (1.4%)	1	3/73 (4.1%)	3	7/63 (11.1%)	11	5/64 (7.8%)	5	8/66 (12.1%)	9	20/193 (10.4%)	25
Osteoarthritis	0/70 (0%)	0	1/73 (1.4%)	1	1/73 (1.4%)	1	4/63 (6.3%)	5	6/64 (9.4%)	8	5/66 (7.6%)	7	15/193 (7.8%)	20
Myalgia	1/70 (1.4%)	1	3/73 (4.1%)	3	0/73 (0%)	0	4/63 (6.3%)	5	7/64 (10.9%)	9	2/66 (3%)	2	13/193 (6.7%)	16
Musculoskeletal pain	1/70 (1.4%)	1	1/73 (1.4%)	1	1/73 (1.4%)	1	4/63 (6.3%)	5	5/64 (7.8%)	6	3/66 (4.5%)	3	12/193 (6.2%)	14
Neck pain	1/70 (1.4%)	1	2/73 (2.7%)	2	1/73 (1.4%)	2	3/63 (4.8%)	3	4/64 (6.3%)	4	5/66 (7.6%)	5	12/193 (6.2%)	12
Osteoporosis	1/70 (1.4%)	1	1/73 (1.4%)	1	2/73 (2.7%)	2	2/63 (3.2%)	2	4/64 (6.3%)	5	5/66 (7.6%)	6	11/193 (5.7%)	13
Bone pain	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	1/63 (1.6%)	1	3/64 (4.7%)	3	1/66 (1.5%)	1	5/193 (2.6%)	5
Plantar fasciitis	0/70 (0%)	0	2/73 (2.7%)	2	0/73 (0%)	0	0/63 (0%)	0	3/64 (4.7%)	4	1/66 (1.5%)	1	4/193 (2.1%)	5
Joint swelling	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	3/63 (4.8%)	3	1/64 (1.6%)	1	4/66 (6.1%)	4	8/193 (4.1%)	8
Nervous system disorders
Headache	12/70 (17.1%)	26	6/73 (8.2%)	7	13/73 (17.8%)	16	20/63 (31.7%)	43	15/64 (23.4%)	22	9/66 (13.6%)	10	44/193 (22.8%)	75
Dizziness	3/70 (4.3%)	5	2/73 (2.7%)	2	2/73 (2.7%)	2	5/63 (7.9%)	9	7/64 (10.9%)	7	2/66 (3%)	2	14/193 (7.3%)	18
Sciatica	0/70 (0%)	0	1/73 (1.4%)	1	0/73 (0%)	0	3/63 (4.8%)	3	3/64 (4.7%)	4	3/66 (4.5%)	4	9/193 (4.7%)	11
Hypoaesthesia	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	3/63 (4.8%)	5	0/64 (0%)	0	0/66 (0%)	0	3/193 (1.6%)	5
Paraesthesia	1/70 (1.4%)	1	1/73 (1.4%)	1	1/73 (1.4%)	1	2/63 (3.2%)	3	2/64 (3.1%)	2	3/66 (4.5%)	3	7/193 (3.6%)	8
Psychiatric disorders
Insomnia	2/70 (2.9%)	2	3/73 (4.1%)	3	7/73 (9.6%)	8	6/63 (9.5%)	6	7/64 (10.9%)	7	7/66 (10.6%)	11	20/193 (10.4%)	24
Depression	1/70 (1.4%)	1	1/73 (1.4%)	1	0/73 (0%)	0	5/63 (7.9%)	6	5/64 (7.8%)	6	3/66 (4.5%)	4	13/193 (6.7%)	16
Depressed mood	0/70 (0%)	0	1/73 (1.4%)	2	0/73 (0%)	0	0/63 (0%)	0	4/64 (6.3%)	5	1/66 (1.5%)	2	5/193 (2.6%)	7
Anxiety	2/70 (2.9%)	3	0/73 (0%)	0	2/73 (2.7%)	3	3/63 (4.8%)	5	1/64 (1.6%)	1	3/66 (4.5%)	3	7/193 (3.6%)	9
Sleep disorder	3/70 (4.3%)	7	0/73 (0%)	0	0/73 (0%)	0	3/63 (4.8%)	8	1/64 (1.6%)	1	2/66 (3%)	2	6/193 (3.1%)	11
Renal and urinary disorders
Renal cyst	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	2/63 (3.2%)	2	3/64 (4.7%)	3	1/66 (1.5%)	1	6/193 (3.1%)	6
Respiratory, thoracic and mediastinal disorders
Cough	4/70 (5.7%)	5	6/73 (8.2%)	6	5/73 (6.8%)	9	12/63 (19%)	23	11/64 (17.2%)	16	12/66 (18.2%)	16	35/193 (18.1%)	55
Oropharyngeal pain	5/70 (7.1%)	5	6/73 (8.2%)	8	1/73 (1.4%)	1	6/63 (9.5%)	6	8/64 (12.5%)	11	4/66 (6.1%)	6	18/193 (9.3%)	23
Nasal congestion	0/70 (0%)	0	2/73 (2.7%)	2	0/73 (0%)	0	3/63 (4.8%)	3	2/64 (3.1%)	2	0/66 (0%)	0	5/193 (2.6%)	5
Epistaxis	2/70 (2.9%)	3	0/73 (0%)	0	3/73 (4.1%)	4	3/63 (4.8%)	4	2/64 (3.1%)	3	3/66 (4.5%)	5	8/193 (4.1%)	12
Dyspnoea	1/70 (1.4%)	1	1/73 (1.4%)	1	3/73 (4.1%)	3	1/63 (1.6%)	1	4/64 (6.3%)	6	2/66 (3%)	2	7/193 (3.6%)	9
Skin and subcutaneous tissue disorders
Pruritus	39/70 (55.7%)	93	50/73 (68.5%)	99	28/73 (38.4%)	49	49/63 (77.8%)	249	51/64 (79.7%)	198	50/66 (75.8%)	180	150/193 (77.7%)	627
Rash	3/70 (4.3%)	3	4/73 (5.5%)	4	3/73 (4.1%)	3	7/63 (11.1%)	9	5/64 (7.8%)	5	2/66 (3%)	2	14/193 (7.3%)	16
Eczema	4/70 (5.7%)	4	2/73 (2.7%)	2	0/73 (0%)	0	5/63 (7.9%)	5	4/64 (6.3%)	4	5/66 (7.6%)	7	14/193 (7.3%)	16
Skin lesion	0/70 (0%)	0	1/73 (1.4%)	1	3/73 (4.1%)	3	3/63 (4.8%)	5	5/64 (7.8%)	7	6/66 (9.1%)	8	14/193 (7.3%)	20
Dry skin	1/70 (1.4%)	1	2/73 (2.7%)	2	1/73 (1.4%)	1	1/63 (1.6%)	1	3/64 (4.7%)	3	5/66 (7.6%)	5	9/193 (4.7%)	9
Dermatitis	1/70 (1.4%)	1	0/73 (0%)	0	0/73 (0%)	0	3/63 (4.8%)	5	0/64 (0%)	0	2/66 (3%)	7	5/193 (2.6%)	12
Urticaria	0/70 (0%)	0	0/73 (0%)	0	2/73 (2.7%)	3	1/63 (1.6%)	1	3/64 (4.7%)	4	1/66 (1.5%)	4	5/193 (2.6%)	9
Night sweats	3/70 (4.3%)	3	0/73 (0%)	0	0/73 (0%)	0	3/63 (4.8%)	3	0/64 (0%)	0	1/66 (1.5%)	1	4/193 (2.1%)	4
Rash pruritic	0/70 (0%)	0	2/73 (2.7%)	2	0/73 (0%)	0	0/63 (0%)	0	3/64 (4.7%)	3	1/66 (1.5%)	1	4/193 (2.1%)	4
Hyperhidrosis	1/70 (1.4%)	1	0/73 (0%)	0	2/73 (2.7%)	2	3/63 (4.8%)	3	0/64 (0%)	0	0/66 (0%)	0	3/193 (1.6%)	3
Erythema	1/70 (1.4%)	1	3/73 (4.1%)	3	0/73 (0%)	0	2/63 (3.2%)	4	3/64 (4.7%)	4	3/66 (4.5%)	4	8/193 (4.1%)	12
Vascular disorders
Hypertension	0/70 (0%)	0	2/73 (2.7%)	2	1/73 (1.4%)	1	5/63 (7.9%)	6	6/64 (9.4%)	7	8/66 (12.1%)	8	19/193 (9.8%)	21
Hypotension	0/70 (0%)	0	0/73 (0%)	0	0/73 (0%)	0	2/63 (3.2%)	2	2/64 (3.1%)	3	4/66 (6.1%)	4	8/193 (4.1%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Principal Investigators must wait 18 months after the study ends to publish their results and a multi-center publication must come first. The sponsor has a 45 day review period with the option to extend to an additional 90 days.