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Clinical Trial Results:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in Combination with Ursodeoxycholic Acid (UDCA) in Patients with Primary Biliary Cirrhosis

Summary
EudraCT number	2013-000482-36
Trial protocol	GB
Global end of trial date	09 Apr 2015

Results information
Results version number	v1(current)
This version publication date	21 Apr 2016
First version publication date	21 Apr 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

LUM001-201

ISRCTN number

US NCT number

NCT01904058

WHO universal trial number (UTN)

Sponsor organisation name

Lumena Pharmaceuticals, LLC

Sponsor organisation address

300 Shire Way, Lexington, MA, United States, 02421

Public contact

Study Physician, Shire, 1 866 842 5335,

Scientific contact

Study Physician, Shire, 1 866 842 5335,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

09 Apr 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Apr 2015

Was the trial ended prematurely?

Main objective of the trial

To evaluate the effect of LUM001 in combination with ursodeoxycholic acid (UDCA) versus UDCA alone on the reduction of pruritus associated with primary biliary cirrhosis (PBC).

Protection of trial subjects

The study was conducted in accordance with the Declaration of Helsinki and its revisions as well as with the valid national law(s) of the participating countries, with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline for Good Clinical Practice (GCP).

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Aug 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

United Kingdom: 18

Country: Number of subjects enrolled

United States: 47

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 24 centers in the United Kingdom, Canada, and the United States between 19 August 2013 and 09 April 2015.

Screening details

A total of 87 subjects were screened out of which 66 subjects were randomized into the study and the remaining 21 were screen failures.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

LUM001 10 mg + UDCA (Cohort A)

Arm description

In Cohort A, subjects received LUM001 tablet in combination with ursodeoxycholic acid (UDCA) orally once daily at a dosage of 2.5 up to a maximum of 10 milligram (mg) during the dose-escalation period over a 3 week period. Thereafter, subjects received LUM001 10 mg tablet along with one placebo matched to LUM001 orally once daily for another 10 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Arm type

Experimental

Investigational medicinal product name

LUM001

Investigational medicinal product code

SHP625

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received LUM001 tablet in combination with UDCA orally once daily at a dosage of 2.5 up to a maximum of 10 mg during the dose-escalation period over a 3 week period. Thereafter, subjects received LUM001 10 mg tablet along with one placebo matched to LUM001 orally once daily for another 10 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

LUM001 20 mg + UDCA (Cohort B)

Arm description

In Cohort B, subjects received LUM001 tablets in combination with UDCA orally once daily at a dosage of 2.5 mg up to a maximum of 20 mg during the dose-escalation period over a 4 week period. Thereafter, subjects received LUM001 20 mg (2x10 mg) tablet orally once daily for another 9 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Arm type

Experimental

Investigational medicinal product name

LUM001

Investigational medicinal product code

SHP625

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received LUM001 tablets in combination with UDCA orally once daily at a dosage of 2.5 mg up to a maximum of 20 mg during the dose-escalation period over a 4 week period. Thereafter, subjects received LUM001 20 mg (2x10 mg) tablet orally once daily for another 9 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Placebo + UDCA (Cohort A)

Arm description

In Cohort A, subjects received placebo (matched to LUM001) once daily for a period of 13 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo (matched to LUM001) once daily for a period of 13 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Placebo + UDCA (Cohort B)

Arm description

In Cohort B, subjects received placebo (matched to LUM001) for a period of 13 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo (matched to LUM001) for a period of 13 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Number of subjects in period 1	LUM001 10 mg + UDCA (Cohort A)	LUM001 20 mg + UDCA (Cohort B)	Placebo + UDCA (Cohort A)	Placebo + UDCA (Cohort B)
Started	21	21	11	13
Completed	18	21	10	12
Not completed	3	0	1	1
Consent withdrawn by subject	1	-	1	-
Adverse event, non-fatal	2	-	-	-
Pregnancy	-	-	-	1

Baseline characteristics

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Reporting group title

LUM001 10 mg + UDCA (Cohort A)

Reporting group description

Reporting group title

LUM001 20 mg + UDCA (Cohort B)

Reporting group description

Reporting group title

Placebo + UDCA (Cohort A)

Reporting group description

In Cohort A, subjects received placebo (matched to LUM001) once daily for a period of 13 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Reporting group title

Placebo + UDCA (Cohort B)

Reporting group description

In Cohort B, subjects received placebo (matched to LUM001) for a period of 13 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Reporting group values	LUM001 10 mg + UDCA (Cohort A)	LUM001 20 mg + UDCA (Cohort B)	Placebo + UDCA (Cohort A)	Placebo + UDCA (Cohort B)	Total
Number of subjects	21	21	11	13
Age categorical
Units: Subjects
Age continuous
Age continuous description
Units: years
arithmetic mean (standard deviation)	54.7 ( 12.74 )	53.5 ( 10.53 )	47.5 ( 8.14 )	55.8 ( 8.73 )	-
Gender categorical
Gender categorical description
Units: Subjects
Female	20	17	11	12	60
Male	1	4	0	1	6

End points

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Reporting group title

LUM001 10 mg + UDCA (Cohort A)

Reporting group description

Reporting group title

LUM001 20 mg + UDCA (Cohort B)

Reporting group description

Reporting group title

Placebo + UDCA (Cohort A)

Reporting group description

In Cohort A, subjects received placebo (matched to LUM001) once daily for a period of 13 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Reporting group title

Placebo + UDCA (Cohort B)

Reporting group description

In Cohort B, subjects received placebo (matched to LUM001) for a period of 13 weeks, in combination with UDCA. Subjects continued UDCA alone for an additional period of 4 weeks.

Subject analysis set title

LUM001 5 mg + UDCA

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received LUM001 5 mg tablet orally once daily for a period of 13 weeks in combination with UDCA.

Subject analysis set title

LUM001 10 mg + UDCA

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received LUM001 10 mg tablet orally once daily for a period of 13 weeks in combination with UDCA.

Subject analysis set title

LUM001 20 mg + UDCA

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received LUM001 20 mg (2x 10 mg) tablet for 20 mg daily dose in combination with UDCA orally once daily for a period of 13 weeks.

Subject analysis set title

Placebo + UDCA

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received placebo matched to LUM001 tablet orally once daily for a period of 13 weeks in combination with UDCA.

Primary: Change From Baseline in Pruritus Using Adult Itch Reported Outcome (ItchRO) Weekly Sum Score at Week 13/ Early Termination (ET)

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End point title

Change From Baseline in Pruritus Using Adult Itch Reported Outcome (ItchRO) Weekly Sum Score at Week 13/ Early Termination (ET)

End point description

Pruritus was assessed using ItchRO measure, administered as an electronic diary (eDiary) which was completed by the subjects twice daily (morning and evening). (ItchRO) scores ranged from 0 to 10, with 0 representing no itch and 10 representing very severe itching. The highest score between the morning and evening ItchRO reports represented the daily score: a measure of the worst itching over the previous 24-hour period. The weekly sum score was calculated as the sum of the daily scores for the 7 days prior to the time point being reported:7 days prior to randomization or 7 days prior to Week 13/ET visit. The mITT population included all subjects who were randomized, received at least 1 dose of treatment, and had at least 1 post-baseline ItchRO assessment.

End point type

Primary

End point timeframe

Baseline and Week 13/ET

End point values	LUM001 10 mg + UDCA (Cohort A)	LUM001 20 mg + UDCA (Cohort B)	Placebo + UDCA (Cohort A)	Placebo + UDCA (Cohort B)
Number of subjects analysed	21	21	11	13
Units: units on a scale
arithmetic mean (standard deviation)
Baseline	48.11 ( 13.363 )	52.1 ( 13.78 )	54.64 ( 9.157 )	49.46 ( 14.11 )
Change at Week 13/ET	-24.59 ( 15.24 )	-27.67 ( 19.888 )	-26.18 ( 18.313 )	-22.77 ( 17.123 )

Statistical analysis 1

Statistical analysis description

The difference between treatment groups in change from Baseline to Week 13/ET in ItchRO weekly sum score evaluated by analysis of covariance (ANCOVA) using generalized linear model (GLM). The model included terms for treatment group, alkaline phosphatase (ALP) level (strata), treatment group by ALP level interaction and Baseline ItchRO weekly sum score as a covariate. Least squares mean change from Baseline to Week 13/ET, along with 95 percentage (%) confidence interval for mean were presented.

Comparison groups

LUM001 10 mg + UDCA (Cohort A) v Placebo + UDCA (Cohort A) v Placebo + UDCA (Cohort B)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6603 ^[1]

Method

ANCOVA

Parameter type

Least squares mean difference

Point estimate

-2.28

Confidence interval

level

95%

sides

2-sided

lower limit

-12.59

upper limit

8.03

Notes
[1] - p-value (LUM001 LS Mean = Placebo LS Mean).

Statistical analysis 2

Statistical analysis description

The difference between treatment groups in change from Baseline to Week 13/ET in ItchRO weekly sum score was evaluated by ANCOVA using a GLM. The model included terms for treatment group, ALP level (strata), treatment group by ALP level interaction, and Baseline ItchRO weekly sum score as a covariate. Least squares mean change from Baseline to Week 13/ET, along with 95% confidence interval for the mean, were presented.

Comparison groups

LUM001 20 mg + UDCA (Cohort B) v Placebo + UDCA (Cohort A) v Placebo + UDCA (Cohort B)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.438 ^[2]

Method

ANCOVA

Parameter type

Least squares mean difference

Point estimate

-3.99

Confidence interval

level

95%

sides

2-sided

lower limit

-14.2

upper limit

6.23

Notes
[2] - p-value (LUM001 LS Mean = Placebo LS Mean).

Secondary: Change From Baseline in Pruritus Using Adult ItchRO Weekly Sum Scores at Weeks 4, 8 and 13

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End point title

Change From Baseline in Pruritus Using Adult ItchRO Weekly Sum Scores at Weeks 4, 8 and 13

End point description

ItchRO scores had a range from 0 to 10, with 0 representing no itch and 10 representing very severe itching. The highest score between the morning and evening ItchRO reports represented the daily score: a measure of the worst itching over the previous 24-hour period. The weekly sum score was calculated as the sum of the daily scores for the 7 days prior to the time point being reported:7 days prior to randomization or 7 days prior to Week 13/ET visit. Here, “n” signifies the number of subjects evaluable for the respective time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 4, 8 and 13

End point values	LUM001 10 mg + UDCA (Cohort A)	LUM001 20 mg + UDCA (Cohort B)	Placebo + UDCA (Cohort A)	Placebo + UDCA (Cohort B)
Number of subjects analysed	21	21	11	13
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=21, 21, 11, 13)	48.11 ( 13.363 )	52.1 ( 13.78 )	54.64 ( 9.157 )	49.46 ( 14.11 )
Change at Week 4 (n=20, 21, 11, 13)	-15.62 ( 13.708 )	-22.19 ( 18.101 )	-10.55 ( 11.103 )	-16.23 ( 12.749 )
Change at Week 8 (n=20, 21, 10, 13)	-21.92 ( 13.089 )	-23.97 ( 20.398 )	-23.5 ( 18.585 )	-19.15 ( 15.302 )
Change at Week 13 (n=18, 21, 10, 12)	-27.41 ( 14.346 )	-27.67 ( 19.888 )	-28.5 ( 17.52 )	-22.92 ( 17.876 )

No statistical analyses for this end point

Secondary: Change from Baseline in Pruritus Using Adult ItchRO Average Daily Scores at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

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End point title

Change from Baseline in Pruritus Using Adult ItchRO Average Daily Scores at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

End point description

ItchRO scores had a range from 0 to 10, with 0 representing no itch and 10 representing very severe itching. The highest score between the morning and evening ItchRO reports represented the daily score: a measure of the worst itching over the previous 24-hour period. Adult ItchRO average daily score was the sum of daily scores divided by the number of days adult ItchRO was completed, using the 7 days prior to the reported visit date. mITT Population. Here, “n” signifies the number of subjects evaluable for the respective time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 4, 8, 13 and Last Post-baseline visit (Week 13/ET)

End point values	LUM001 10 mg + UDCA (Cohort A)	LUM001 20 mg + UDCA (Cohort B)	Placebo + UDCA (Cohort A)	Placebo + UDCA (Cohort B)
Number of subjects analysed	21	21	11	13
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=21, 21, 11, 13)	6.873 ( 1.9091 )	7.442 ( 1.9686 )	7.805 ( 1.3082 )	7.066 ( 2.0158 )
Change at Week 4 (n=20, 21, 11, 13)	-2.231 ( 1.9587 )	-3.17 ( 2.5859 )	-1.506 ( 1.5861 )	-2.319 ( 1.8212 )
Change at Week 8 (n=20, 21, 10, 13)	-3.131 ( 1.8703 )	-3.424 ( 2.9139 )	-3.357 ( 2.6549 )	-2.736 ( 2.186 )
Change at Week 13 (n=18, 21, 10, 12)	-3.915 ( 2.0496 )	-3.952 ( 2.8411 )	-4.071 ( 2.5028 )	-3.274 ( 2.5537 )
Change at Week 13/ET (n=21, 21, 11, 13)	-3.512 ( 2.1774 )	-3.952 ( 2.8411 )	-3.74 ( 2.6161 )	-3.253 ( 2.4461 )

No statistical analyses for this end point

Secondary: Change From Baseline in Alkaline Phosphatase (ALP) at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

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End point title

Change From Baseline in Alkaline Phosphatase (ALP) at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

End point description

Laboratory serum ALP enzyme levels were evaluated using blood samples collected. mITT Population. Here, “n” signifies the number of subjects evaluable for the respective time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 4, 8, 13 and Last Post-baseline (Week 13/ET)

End point values	LUM001 10 mg + UDCA (Cohort A)	LUM001 20 mg + UDCA (Cohort B)	Placebo + UDCA (Cohort A)	Placebo + UDCA (Cohort B)
Number of subjects analysed	21	21	11	13
Units: units per liter (U/L)
arithmetic mean (standard deviation)
Baseline (n=21, 21, 11, 13)	288.2 ( 193.91 )	257.6 ( 190.38 )	253.9 ( 96.83 )	274.2 ( 190.85 )
Change at Week 4 (n=20, 21, 10, 13)	-22.1 ( 54.94 )	13.2 ( 47.76 )	20.3 ( 49.68 )	-0.7 ( 39.69 )
Change at Week 8 (n=20, 21, 10, 12	2.6 ( 53.95 )	1.1 ( 41.98 )	8.8 ( 38.72 )	-4.8 ( 55.7 )
Change at Week 13 (n=17, 20, 10, 12)	-15.2 ( 97.19 )	18.5 ( 56.21 )	24.3 ( 76.48 )	-7.2 ( 83.7 )
Change at Week 13/ET (n=21, 21, 11, 13)	-8 ( 93.02 )	16.4 ( 55.6 )	22.9 ( 72.7 )	-7.9 ( 80.19 )

No statistical analyses for this end point

Secondary: Change from Baseline in 5-D Itch Score at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

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End point title

Change from Baseline in 5-D Itch Score at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

End point description

The 5-D itch (validated instrument to measure pruritus) scale was developed for the multidimensional quantification of pruritus that is sensitive to change over time. The 5-D itch scale included 5 domains (duration, degree, direction, disability, and distribution of pruritus). The total 5-D score was obtained by scoring each of the domains separately and then summing them together. 5-D total scores ranged between 5 (no pruritus) and 25 (most severe pruritus). mITT Population. Here, “n” signifies the number of subjects evaluable for the respective time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 4, 8, 13 and Last Post-baseline visit (Week 13/ET)

End point values	LUM001 10 mg + UDCA (Cohort A)	LUM001 20 mg + UDCA (Cohort B)	Placebo + UDCA (Cohort A)	Placebo + UDCA (Cohort B)
Number of subjects analysed	21	21	11	13
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=21, 21, 11, 13)	18.7 ( 3.47 )	19.4 ( 3.49 )	19.6 ( 2.94 )	19.2 ( 3.32 )
Change at Week 4 (n=20, 21, 10, 13)	-4.8 ( 3.91 )	-6.3 ( 4.96 )	-3.4 ( 3.89 )	-4.2 ( 3.81 )
Change at Week 8 (n=20, 21, 10, 12)	-6.8 ( 3.16 )	-5.9 ( 5.62 )	-6.4 ( 6.2 )	-4.4 ( 4.27 )
Change at Week 13 (n=18, 21, 10, 12)	-7.4 ( 3.68 )	-7 ( 5.89 )	-7.8 ( 5.94 )	-6.1 ( 4.68 )
Change at Week 13/ET (n=21, 21, 10, 13)	-6.5 ( 4.11 )	-7 ( 5.89 )	-7.8 ( 5.94 )	-5.6 ( 4.79 )

No statistical analyses for this end point

Secondary: Change From Baseline in Fasting Serum Bile Acid Level at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

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End point title

Change From Baseline in Fasting Serum Bile Acid Level at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

End point description

Laboratory serum bile acid level levels were evaluated using blood samples collected. mITT Population. Here, “n” signifies the number of subjects evaluable for the respective time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 4, 8, 13 and Last Post-baseline visit (Week 13/ET)

End point values	LUM001 10 mg + UDCA (Cohort A)	LUM001 20 mg + UDCA (Cohort B)	Placebo + UDCA (Cohort A)	Placebo + UDCA (Cohort B)
Number of subjects analysed	21	21	11	13
Units: micromoles per liter
arithmetic mean (standard deviation)
Baseline (n=21, 21, 11, 13)	33.11 ( 30.5943 )	52.46 ( 94.3892 )	52.615 ( 64.6162 )	58.434 ( 73.9895 )
Change at Week 4 (n=20, 21, 10, 13)	-11.204 ( 31.6132 )	-14.465 ( 58.5891 )	-10.221 ( 50.0398 )	14.317 ( 75.1092 )
Change at Week 8 (n=20, 21, 10, 12)	-3.968 ( 45.7388 )	-21.983 ( 78.6134 )	-3.585 ( 52.4398 )	34.893 ( 67.7189 )
Change at Week 13 (n=18, 21, 10, 12)	-8.122 ( 48.129 )	-19.098 ( 81.8452 )	11.481 ( 44.0465 )	4.123 ( 46.217 )
Change at Week 13/ET (n=21, 21, 10, 13)	-4.504 ( 45.7595 )	-19.098 ( 81.8452 )	11.481 ( 44.0465 )	3.69 ( 44.277 )

No statistical analyses for this end point

Secondary: Change From Baseline in Bile Acid Synthesis as Measured by Serum 7 Alpha-Hydroxy-4-Cholesten-3-One C4 Level [7 Alpha C4]) at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

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End point title

Change From Baseline in Bile Acid Synthesis as Measured by Serum 7 Alpha-Hydroxy-4-Cholesten-3-One C4 Level [7 Alpha C4]) at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

End point description

C4 7 alpha-hydroxy-4-cholesten-3-one is an intermediate in the biochemical synthesis of bile acids from cholesterol and its concentrations reflect the activity of the bile acid synthetic pathway. Elevated levels of C4 indicate bile acid malabsorption. Laboratory C4 levels were evaluated using blood samples collected. mITT Population. Here, “n” signifies the number of subjects evaluable for the respective time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 4, 8, 13 and Last Post-baseline Visit (Week 13/ET)

End point values	LUM001 10 mg + UDCA (Cohort A)	LUM001 20 mg + UDCA (Cohort B)	Placebo + UDCA (Cohort A)	Placebo + UDCA (Cohort B)
Number of subjects analysed	21	21	11	13
Units: nanogram per milliliter (ng/mL)
arithmetic mean (standard deviation)
Baseline (n=21, 21, 10, 13)	18.74 ( 16.18 )	13.17 ( 11.851 )	22.31 ( 20.769 )	16.98 ( 33.093 )
Change at Week 4 (n=20, 21, 9, 13)	8.66 ( 23.422 )	17.03 ( 18.38 )	-6.8 ( 6.783 )	-0.19 ( 8.856 )
Change at Week 8 (n=20, 21, 9, 12)	13.04 ( 17.895 )	15.03 ( 31.12 )	-12.57 ( 14.63 )	3.43 ( 16.666 )
Change at Week 13 (n=18, 21, 9, 12)	24.38 ( 38.105 )	6.62 ( 10.116 )	-12.72 ( 10.374 )	4.56 ( 13.61 )
Change at Week 13/ET (n=21, 21, 9, 13)	20.56 ( 37.312 )	6.62 ( 10.116 )	-12.72 ( 10.374 )	4.74 ( 13.047 )

No statistical analyses for this end point

Other pre-specified: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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End point title

Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

End point description

An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the product. A serious adverse event (SAE) was defined as an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly or birth defect; an important medical event that did not meet any of the above criteria but jeopardized the subject or required medical or surgical intervention to prevent one of the outcomes listed above. A TEAE was defined as any AE that occurred during the study, from the start of investigational product dosing through the end of the study [13 weeks of treatment period (or ET) + 14 days], or that worsened since the start of dosing.

End point type

Other pre-specified

End point timeframe

From the first dose of study drug until the 13 weeks of treatment period (or ET) + 14 days (approximately 15 weeks)

End point values	LUM001 5 mg + UDCA	LUM001 10 mg + UDCA	LUM001 20 mg + UDCA	Placebo + UDCA
Number of subjects analysed	1 ^[3]	20 ^[4]	21 ^[5]	24 ^[6]
Units: subjects
TEAEs	1	19	21	17
TESAEs	0	2	1	0

Notes
[3] - The Safety Population included all subjects who randomized, received at least 1dose of study drug.
[4] - The Safety Population included all subjects who randomized, received at least 1dose of study drug.
[5] - The Safety Population included all subjects who randomized, received at least 1dose of study drug.
[6] - The Safety Population included all subjects who randomized, received at least 1dose of study drug.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first dose of study drug until the 13 weeks of treatment period (or ET) + 14 days (approximately 15 weeks)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

LUM001 10 mg + UDCA

Reporting group description

Subjects received LUM001 10 mg tablet orally once daily for a period of 13 weeks in combination with UDCA.

Reporting group title

LUM001 5 mg + UDCA

Reporting group description

Subjects received LUM001 5 mg tablet orally once daily for a period of 13 weeks in combination with UDCA.

Reporting group title

Placebo + UDCA

Reporting group description

Subjects received placebo matched to LUM001 tablet orally once daily for a period of 13 weeks in combination with UDCA.

Reporting group title

LUM001 20 mg + UDCA

Reporting group description

Subjects received LUM001 20 mg (2x 10 mg) tablet for 20 mg daily dose in combination with UDCA orally once daily for a period of 13 weeks.

Serious adverse events	LUM001 10 mg + UDCA	LUM001 5 mg + UDCA	Placebo + UDCA	LUM001 20 mg + UDCA
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 20 (10.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	1 / 21 (4.76%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Cardiac disorders
Myocardial Infarction
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal Haemorrhage
subjects affected / exposed	0 / 20 (0.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	1 / 21 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	LUM001 10 mg + UDCA	LUM001 5 mg + UDCA	Placebo + UDCA	LUM001 20 mg + UDCA
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 20 (90.00%)	1 / 1 (100.00%)	16 / 24 (66.67%)	20 / 21 (95.24%)
Injury, poisoning and procedural complications
Anal Injury
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Excoriation
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Surgical and medical procedures
Sinus Operation
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 20 (0.00%)	1 / 1 (100.00%)	1 / 24 (4.17%)	1 / 21 (4.76%)
occurrences all number	0	1	1	1
Headache
subjects affected / exposed	3 / 20 (15.00%)	0 / 1 (0.00%)	8 / 24 (33.33%)	2 / 21 (9.52%)
occurrences all number	3	0	10	2
Paraesthesia
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Blood and lymphatic system disorders
Pancytopenia
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Chills
subjects affected / exposed	2 / 20 (10.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	2	0	0	0
Fatigue
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	1 / 24 (4.17%)	2 / 21 (9.52%)
occurrences all number	1	0	1	2
Influenza Like Illness
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Pain
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Pyrexia
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	1 / 21 (4.76%)
occurrences all number	1	0	0	1
Eye disorders
Dry Eye
subjects affected / exposed	2 / 20 (10.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	2	0	0	0
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	3 / 20 (15.00%)	0 / 1 (0.00%)	3 / 24 (12.50%)	0 / 21 (0.00%)
occurrences all number	3	0	4	0
Abdominal Pain
subjects affected / exposed	4 / 20 (20.00%)	1 / 1 (100.00%)	1 / 24 (4.17%)	5 / 21 (23.81%)
occurrences all number	4	3	1	6
Abdominal Pain Upper
subjects affected / exposed	4 / 20 (20.00%)	0 / 1 (0.00%)	2 / 24 (8.33%)	6 / 21 (28.57%)
occurrences all number	6	0	2	9
Constipation
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	1 / 24 (4.17%)	1 / 21 (4.76%)
occurrences all number	1	0	1	1
Diarrhoea
subjects affected / exposed	14 / 20 (70.00%)	1 / 1 (100.00%)	6 / 24 (25.00%)	11 / 21 (52.38%)
occurrences all number	16	3	7	19
Dry Mouth
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	1 / 21 (4.76%)
occurrences all number	1	0	0	1
Dyspepsia
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	2 / 24 (8.33%)	1 / 21 (4.76%)
occurrences all number	1	0	2	1
Faeces Discoloured
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	1 / 24 (4.17%)	0 / 21 (0.00%)
occurrences all number	1	0	2	0
Flatulence
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	1 / 24 (4.17%)	0 / 21 (0.00%)
occurrences all number	1	0	1	0
Gastrooesophageal Reflux Disease
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	2 / 21 (9.52%)
occurrences all number	1	0	0	2
Gingival Pain
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Mouth Ulceration
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	1 / 24 (4.17%)	0 / 21 (0.00%)
occurrences all number	1	0	1	0
Nausea
subjects affected / exposed	5 / 20 (25.00%)	1 / 1 (100.00%)	4 / 24 (16.67%)	4 / 21 (19.05%)
occurrences all number	6	2	4	5
Toothache
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Vomiting
subjects affected / exposed	0 / 20 (0.00%)	1 / 1 (100.00%)	2 / 24 (8.33%)	1 / 21 (4.76%)
occurrences all number	0	1	2	1
Reproductive system and breast disorders
Vaginal Discharge
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 20 (20.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	1 / 21 (4.76%)
occurrences all number	4	0	0	1
Laryngeal Inflammation
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Nasal Congestion
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Oropharyngeal Pain
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	2	0	0	0
Pharyngeal Erythema
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 20 (0.00%)	0 / 1 (0.00%)	3 / 24 (12.50%)	1 / 21 (4.76%)
occurrences all number	0	0	3	1
Rash
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	1 / 24 (4.17%)	0 / 21 (0.00%)
occurrences all number	1	0	2	0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	2 / 20 (10.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	2	0	0	0
Muscle Spasms
subjects affected / exposed	2 / 20 (10.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	2	0	0	0
Muscular Weakness
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal Chest Pain
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Myalgia
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	1 / 24 (4.17%)	0 / 21 (0.00%)
occurrences all number	1	0	1	0
Pain In Extremity
subjects affected / exposed	0 / 20 (0.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	3 / 21 (14.29%)
occurrences all number	0	0	0	3
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Sinusitis
subjects affected / exposed	1 / 20 (5.00%)	0 / 1 (0.00%)	0 / 24 (0.00%)	0 / 21 (0.00%)
occurrences all number	1	0	0	0
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 20 (0.00%)	0 / 1 (0.00%)	1 / 24 (4.17%)	2 / 21 (9.52%)
occurrences all number	0	0	1	2
Urinary Tract Infection
subjects affected / exposed	0 / 20 (0.00%)	0 / 1 (0.00%)	1 / 24 (4.17%)	2 / 21 (9.52%)
occurrences all number	0	0	1	2

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Were there any global substantial amendments to the protocol? Yes

03 Jun 2013

- Clarified inclusion criterion, effective barrier method of contraception, as the combination of condom or diaphragm plus a spermicide. - Clarified excluded screening serum creatinine conventional reference level to 2 decimals 2.00 milligram per deciliter (mg/dL) and corrected reference level 177 micromole per liter (mmoL/L). - Added cholestyramine as example of excluded bile acid resins. - Revised tolerability assessment to be consistent with protocol body. - Added 8-week time point for serum bile acid level and 7alpha-hydroxy-4-cholesten-3-one (7aC4). - Modified section to provide instructions to investigator for unblinding in the event of an emergency situation when knowledge of the treatment assignment will impact the clinical management of the subject. - Added safety monitoring for any subject with an increase in ALP >1.5 x Baseline at any time during the study. - Added stopping rule for any subject with an increase in ALP >2 x baseline at any time during the study. - Added study stopping rules in the event that 10 subjects discontinue dosing for any of the criteria. - Added collection of blood sample for cholestasis biomarkers at Week 8. - Corrected typographical errors in protocol.

28 Feb 2014

- Revised inclusion criterion, to allow for inclusion of subjects who are on a stable dose of UDCA for greater than equal to (>=) 3 months or are intolerant of UDCA (no UDCA for >=3 months). - Revised Inclusion Criterion, to also include subjects with ability to read and understand Spanish. - Screening period increased to “up to 5 weeks” (was “up to 4 weeks”) and total study duration increased to approximately 22 weeks (was approximately 21 weeks). - Corrected time points for evaluation of pruritus using the average daily Adult ItchRO score (4, 8, and 13 weeks) to be consistent with protocol text.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in Combination with Ursodeoxycholic Acid (UDCA) in Patients with Primary Biliary Cirrhosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Pruritus Using Adult Itch Reported Outcome (ItchRO) Weekly Sum Score at Week 13/ Early Termination (ET)

Primary: Change From Baseline in Pruritus Using Adult Itch Reported Outcome (ItchRO) Weekly Sum Score at Week 13/ Early Termination (ET)

Secondary: Change From Baseline in Pruritus Using Adult ItchRO Weekly Sum Scores at Weeks 4, 8 and 13

Secondary: Change From Baseline in Pruritus Using Adult ItchRO Weekly Sum Scores at Weeks 4, 8 and 13

Secondary: Change from Baseline in Pruritus Using Adult ItchRO Average Daily Scores at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

Secondary: Change from Baseline in Pruritus Using Adult ItchRO Average Daily Scores at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Alkaline Phosphatase (ALP) at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Alkaline Phosphatase (ALP) at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

Secondary: Change from Baseline in 5-D Itch Score at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Secondary: Change from Baseline in 5-D Itch Score at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Fasting Serum Bile Acid Level at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Fasting Serum Bile Acid Level at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Bile Acid Synthesis as Measured by Serum 7 Alpha-Hydroxy-4-Cholesten-3-One C4 Level [7 Alpha C4]) at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Bile Acid Synthesis as Measured by Serum 7 Alpha-Hydroxy-4-Cholesten-3-One C4 Level [7 Alpha C4]) at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Other pre-specified: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Other pre-specified: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in Combination with Ursodeoxycholic Acid (UDCA) in Patients with Primary Biliary Cirrhosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Pruritus Using Adult Itch Reported Outcome (ItchRO) Weekly Sum Score at Week 13/ Early Termination (ET)

Primary: Change From Baseline in Pruritus Using Adult Itch Reported Outcome (ItchRO) Weekly Sum Score at Week 13/ Early Termination (ET)

Secondary: Change From Baseline in Pruritus Using Adult ItchRO Weekly Sum Scores at Weeks 4, 8 and 13

Secondary: Change From Baseline in Pruritus Using Adult ItchRO Weekly Sum Scores at Weeks 4, 8 and 13

Secondary: Change from Baseline in Pruritus Using Adult ItchRO Average Daily Scores at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

Secondary: Change from Baseline in Pruritus Using Adult ItchRO Average Daily Scores at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Alkaline Phosphatase (ALP) at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Alkaline Phosphatase (ALP) at Weeks 4, 8, 13, and Last Post-baseline Visit (Week 13/ET)

Secondary: Change from Baseline in 5-D Itch Score at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Secondary: Change from Baseline in 5-D Itch Score at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Fasting Serum Bile Acid Level at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Fasting Serum Bile Acid Level at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Bile Acid Synthesis as Measured by Serum 7 Alpha-Hydroxy-4-Cholesten-3-One C4 Level [7 Alpha C4]) at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Secondary: Change From Baseline in Bile Acid Synthesis as Measured by Serum 7 Alpha-Hydroxy-4-Cholesten-3-One C4 Level [7 Alpha C4]) at Weeks 4, 8, 13, and Last Post -baseline Visit (Week 13/ET)

Other pre-specified: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Other pre-specified: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in Combination with Ursodeoxycholic Acid (UDCA) in Patients with Primary Biliary Cirrhosis