Download PDF

Clinical Trial Results:
A Multicentre Extension Study to Evaluate the Long-Term Safety and Durability of the Therapeutic Effect of LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric Subjects with Alagille Syndrome

Summary
EudraCT number	2013-003832-54
Trial protocol	GB
Global end of trial date	17 Jun 2020

Results information
Results version number	v1(current)
This version publication date	27 Dec 2020
First version publication date	27 Dec 2020
Other versions
Summary report(s)	Synoptic Clinical Study Report Interim Clinical Study Report Synopsis

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

LUM001-303

ISRCTN number

US NCT number

NCT02047318

WHO universal trial number (UTN)

Sponsor organisation name

Mirum Pharmaceuticals, Inc.

Sponsor organisation address

950 Tower Lane, Suite 1050, Foster City, United States, CA 94404

Public contact

Medical Information Mirum, Mirum Pharmaceuticals, Inc., 1 6506674085, medinfo@mirumpharma.com

Scientific contact

Medical Information Mirum, Mirum Pharmaceuticals, Inc., 1 6506674085, medinfo@mirumpharma.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001475-PIP03-17

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

17 Sep 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

09 Oct 2015

Global end of trial reached?

Yes

Global end of trial date

17 Jun 2020

Was the trial ended prematurely?

Main objective of the trial

The primary objective (up to and including Week 72) was to evaluate the long-term safety and tolerability of maralixibat (MRX) in pediatric patients with Alagille Syndrome. The secondary objectives (up to and including Week 72) were to evaluate the long-term effects of MRX on serum bile acids, pruritus, and xanthomas; and to explore the long-term effects of MRX on other biochemical markers of cholestasis and liver disease, and an expanded dosing range to identify doses necessary to achieve the optimal benefit-to-risk ratio for this patient population. The objectives of the long-term follow-up treatment period for participants who were eligible for Protocol Amendment 5 were to offer eligible participants in the LUM001-303 study continued study treatment; explore a twice daily (BID) dosing regimen and higher daily dosing of MRX; obtain safety and efficacy data in participants treated long-term on MRX; assess the level of alpha-fetoprotein; assess palatability of the MRX formulation.

Protection of trial subjects

All study participants (caregivers as applicable) were required to read and sign an Informed Consent Form (ICF). Participants were re-consented to the most current version of the ICF(s) during their participation in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Dec 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 19

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

Top of page

Recruitment details

A total of 19 participants were enrolled in the core study (Day 1 to Week 72) and treated in the study. Completion of participation in Study LUM001-302 was an inclusion criterion for this study: 5 of the 19 participants had received placebo in Study LUM001-302; and 14 of the 19 participants had received any dose level of MRX in Study LUM001-302.

Screening details

All patients who were screened for the study were enrolled. One subject who completed participation in Study LUM001-302 (and received placebo) did not enter Study LUM001-303.

Period 1 title

Core study period

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Although all participants were treated with MRX, dose optimization occurred in a blinded, titrated manner based on randomization in the LUM001-302 core study. This represented a real dose escalation for participants previously randomized to placebo and a mock dose escalation for participants previously randomized to active study treatment in the LUM001-302 core study.

Core study period

Arm description

In the lead-in Study LUM001-302, participants were randomized to receive either placebo or active drug (MRX). The last observation obtained before first dose of MRX (either for participants who received MRX in Study LUM001-302 or in Study LUM001-303 for participants who received placebo in Study LUM001-302) was used as the MRX baseline observation for all calculations of change from MRX baseline. For participants who were assigned MRX in Study LUM001-302, results at each post-baseline analysis visit included up to 13 more weeks of treatment than participants who were assigned placebo in Study LUM001-302. The core study period of Study LUM001-303 was from Day 1 to Week 72. It encompassed: - a 4-week double-blind dose-escalation period - an 8-week dose-optimization period - a 60-week stable dosing period All participants received MRX.

Arm type

Experimental

Investigational medicinal product name

Maralixibat chloride

Investigational medicinal product code

Other name

LUM001

Pharmaceutical forms

Powder and solvent for oral solution

Routes of administration

Oral use

Dosage and administration details

During the 4-week double-blind dose-escalation period participants who received placebo during Study LUM001-302 received weekly dose increases of MRX up to a target dose of 140 μg/kg once daily (QD); and participants who received MRX during Study LUM001-302 continued to receive the dose of MRX that they were taking at Week 13 of Study LUM001-302. During the 8-week dose-optimization period MRX dosing could be adjusted by the investigator to achieve optimal control of pruritus at a dose level tolerated by the participant up to a maximum dose of MRX 280 μg/kg QD. Dose levels during the period were 35, 70, 140, or 280 μg/kg QD. During the 60-week stable dosing period participants were dosed with the Week 12 dose, or the highest tolerated dose below the Week 12 dose.

Number of subjects in period 1	Core study period
Started	19
Completed	7
Not completed	12
Withdrawal by caregiver	3
Adverse event, serious non-fatal	1
Did not consent to 52-week follow- up	8

Period 2 title

52-week follow-up treatment period

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Blinding implementation details

All participants continued to receive MRX. Participants, investigators, and study site personnel remained blinded to all participants' treatment assignments from the LUM001-302 core study.

52-week follow-up treatment period

Arm description

At Week 72, participants were assessed by the investigator to determine their willingness and eligibility to roll over into the 52-week follow-up treatment period to receive MRX at the doses they were receiving at Week 72. Note: one subject who completed the original study through Week 72 did not consent to protocol amendment 4, and so did not participate in the 52-week follow-up treatment period.

Arm type

Experimental

Investigational medicinal product name

Maralixibat chloride

Investigational medicinal product code

Other name

LUM001

Pharmaceutical forms

Powder and solvent for oral solution

Routes of administration

Oral use

Dosage and administration details

For participants whose caregivers did not wish the participants to enter the follow-up treatment period, or who were not eligible to enter the follow-up treatment period, a safety follow-up phone call was made by the study site 30 days after the last dose of MRX. If any participant experienced intolerance, the investigator, in consultation with the medical monitor, could lower the dose to a previously tolerated dose at any time during the entire follow-up treatment period.

Number of subjects in period 2 ^[1]	52-week follow-up treatment period
Started	6
Completed	6

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: One subject completed the original study, through Week 72, and reconsented only to protocol amendment 5, the long-term follow-up treatment period. This subject did not participate in the 52-week follow-up treatment period.

Period 3 title

Long-term follow-up treatment period

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Blinding implementation details

All participants continued to receive MRX. Participants, investigators, and study site personnel remained blinded to all participants' treatment assignments from Study LUM001-302.

Long-term follow-up treatment period

Arm description

The long-term follow-up treatment period was for eligible participants who chose to stay on treatment with MRX. Participants were considered eligible if they: - completed the protocol through either the Week 124 or the Early Termination visit - completed the protocol with no major safety concerns - discontinued due to safety reasons judged unrelated to the MRX - laboratory results returned to levels acceptable for this patient population - did not meet any of the protocol’s stopping rules at the time of entry into the follow-up period Participation in the long-term follow-up treatment period continued until either: 1) the participants were eligible to enter another MRX study; 2) MRX was available commercially; or 3) the sponsor stopped the program or development in this indication. Note: one participant who completed the core study period did not consent to the 52-week follow-up treatment period. They reconsented to protocol amendment 5 and joined the long-term follow-up.

Arm type

Experimental

Investigational medicinal product name

Maralixibat chloride

Investigational medicinal product code

Other name

LUM001

Pharmaceutical forms

Powder and solvent for oral solution

Routes of administration

Oral use

Dosage and administration details

During the long-term follow-up treatment period, participants could have their dose of MRX increased to a maximum of 560 μg/kg QD (280 μg/kg twice daily [BID]), based on efficacy (sBA and ItchRO score) and safety assessment results. If any participant experienced intolerance, the investigator, in consultation with the medical monitor, could lower the dose to a previously tolerated dose at any time during the entire follow-up treatment period.

Number of subjects in period 3	Long-term follow-up treatment period
Started	6
Completed	6
Not completed	1
Consent withdrawn by subject	1
Joined	1
Consented to long-term follow-up but not 52-week	1

Baseline characteristics

Top of page

Reporting group title

Core study period

Reporting group description

Reporting group values	Core study period	Total
Number of subjects	19	19
Age categorical
The last observation obtained before the first dose of MRX (whether before receiving MRX in Study LUM001-302 for participants who received MRX in Study LUM001-302, or in Study LUM001-303 for participants who received placebo in Study LUM001-302) was used as the MRX baseline observation. In the overall population, the mean (SD) age at MRX baseline was 6.0 (5.02) years, and participants ranged from 1 to 16 years of age.
Units: Subjects
<2 years	3	3
2 to 4 years	6	6
5 to 8 years	5	5
9 to 12 years	2	2
13 to 18 years	3	3
Gender categorical
Units: Subjects
Female	9	9
Male	10	10
Race
Units: Subjects
Asian	1	1
Black or African American	1	1
White	16	16
More than one race	1	1
Height z-score
The last observation obtained before the first dose of MRX (whether before receiving MRX in Study LUM001-302 for participants who received MRX in Study LUM001-302, or in Study LUM001-303 for participants who received placebo in Study LUM001-302) was used as the MRX baseline observation.
Units: z-score
arithmetic mean (standard deviation)	-1.850 ± 1.3095	-
Weight z-score
The last observation obtained before the first dose of MRX (whether before receiving MRX in Study LUM001-302 for participants who received MRX in Study LUM001-302, or in Study LUM001-303 for participants who received placebo in Study LUM001-302) was used as the MRX baseline observation.
Units: z-score
arithmetic mean (standard deviation)	-1.565 ± 1.0221	-

End points

Top of page

Reporting group title

Core study period

Reporting group description

Reporting group title

52-week follow-up treatment period

Reporting group description

Reporting group title

Long-term follow-up treatment period

Reporting group description

Subject analysis set title

Core study period: MRX baseline values

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the MRX baseline values for participants. The last observation obtained before the first dose of MRX (whether before receiving MRX in Study LUM001-302 for participants who received MRX in Study LUM001-302, or in Study LUM001-303 for participants who received placebo in Study LUM001-302) was used as the MRX baseline observation for all calculations of change from MRX baseline. For participants who were assigned MRX in Study LUM001-302, results at each post-baseline analysis visit included up to 13 more weeks of treatment than participants who were assigned placebo in Study LUM001-302.

Subject analysis set title

Core study period: Week 48 values

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the Week 48 values for participants. These participants are also represented in the Core study period: MRX baseline values group; the analyses look at the change from MRX baseline to Week 48 in the same participants.

Subject analysis set title

Week 252 values

Subject analysis set type

Sub-group analysis

Subject analysis set description

Week 252 values for participants continuing in the study. These participants are also represented in the Core study period: MRX baseline values group; the analyses look at the change from MRX baseline to Week 252 in the same participants.

Subject analysis set title

Week 158 values

Subject analysis set type

Sub-group analysis

Subject analysis set description

Week 158 values for participants continuing in the study. These participants are also represented in the Core study period: MRX baseline values group; the analyses look at the change from MRX baseline to Week 158 in the same participants.

Primary: Change from MRX baseline to Week 48 in fasting sBA levels

Top of page

End point title

Change from MRX baseline to Week 48 in fasting sBA levels

End point description

The primary endpoint of this study was the mean change from MRX baseline to Week 48 in fasting sBA level. The primary objective was defined as “up to and including Week 72” while the primary endpoint evaluated the change from baseline to Week 48. Results reported here are for the Week 48 endpoint.

End point type

Primary

End point timeframe

MRX baseline to Week 48

End point values	Core study period: MRX baseline values	Core study period: Week 48 values
Number of subjects analysed	19 ^[1]	17 ^[2]
Units: μmol/L
arithmetic mean (standard deviation)	261.96 ± 206.839	128.32 ± 101.742

Notes
[1] - Data collected from 19 participants at MRX baseline.
[2] - Data collected at Week 48 from 17 of the 19 participants who contributed values at MRX baseline.

Change from MRX baseline to Week 48 in sBA

Statistical analysis description

This analysis investigated whether a statistically significant change in sBA levels was observed when comparing MRX baseline to Week 48. The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Core study period: Week 48 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[3]

P-value

= 0.0012 ^[4]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

-94.4

Confidence interval

level

95%

sides

2-sided

lower limit

-145.26

upper limit

-43.55

Variability estimate

Standard deviation

Dispersion value

98.915

Notes
[3] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in sBA levels between MRX baseline and Week 48 was statistically significant.
[4] - Data for this analysis were obtained from 19 participants at MRX baseline; 17 of those participants contributed Week 48 data.

Secondary: Change from MRX baseline over time in fasting sBA levels

Top of page

End point title

Change from MRX baseline over time in fasting sBA levels

End point description

This secondary efficacy endpoint is the mean change from MRX baseline over time in fasting sBA levels. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluated the change from baseline to Week 48. Results reported here are the long-term results, including Week 72 and subsequent visits.

End point type

Secondary

End point timeframe

MRX baseline to EOT

End point values	Core study period: MRX baseline values	Week 252 values
Number of subjects analysed	19 ^[5]	6 ^[6]
Units: μmol/L
arithmetic mean (standard deviation)	261.96 ± 206.839	118.32 ± 76.140

Notes
[5] - Data collected from 19 participants at MRX baseline.
[6] - Data collected at Week 252 from all 6 participants who contributed values at MRX baseline.

Change from MRX baseline over time in sBA

Statistical analysis description

This analysis investigated whether a statistically significant change in sBA levels was observed over time (with Week 252 chosen as the end point, as the last analysis visit with at least 6 participants). The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Week 252 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[7]

P-value

= 0.032 ^[8]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

-141.94

Confidence interval

level

95%

sides

2-sided

lower limit

-265.77

upper limit

-18.12

Variability estimate

Standard deviation

Dispersion value

117.992

Notes
[7] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in sBA levels from baseline over time (to Week 252) was statistically significant.
[8] - Data for this analysis were obtained from 19 participants at MRX baseline; 6 of those participants contributed Week 252 data.

Secondary: Change from MRX baseline to Week 48 in pruritus

Top of page

End point title

Change from MRX baseline to Week 48 in pruritus

End point description

This secondary efficacy endpoint is the change from MRX baseline to Week 48 in pruritus as measured by ItchRO(Obs) weekly average morning severity score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe). The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluate the change from baseline to Week 48. Results reported here are for the Week 48 endpoint.

End point type

Secondary

End point timeframe

MRX baseline to Week 48

End point values	Core study period: MRX baseline values	Core study period: Week 48 values
Number of subjects analysed	19 ^[9]	17 ^[10]
Units: Points (0-4)
arithmetic mean (standard deviation)	2.435 ± 0.7952	1.307 ± 0.6995

Notes
[9] - Values were collected from 19 participants at MRX baseline.
[10] - Data collected at Week 48 from 17 of the 19 participants who contributed values at MRX baseline.

Change from MRX baseline to Week 48 in ItchRO(Obs)

Statistical analysis description

This analysis investigated whether a statistically significant change in ItchRO(Obs) scores was observed when comparing MRX baseline to Week 48. The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Core study period: Week 48 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[11]

P-value

< 0.0001 ^[12]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

-1.095

Confidence interval

level

95%

sides

2-sided

lower limit

-1.464

upper limit

-0.726

Variability estimate

Standard deviation

Dispersion value

0.7173

Notes
[11] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in sBA levels between MRX baseline and Week 48 was statistically significant.
[12] - Data for this analysis were obtained from 19 participants at MRX baseline; 17 of those participants contributed Week 48 data.

Secondary: Change from MRX baseline over time in pruritus

Top of page

End point title

Change from MRX baseline over time in pruritus

End point description

This secondary efficacy endpoint is the change from MRX baseline over time in pruritus as measured by ItchRO(Obs) weekly average morning severity score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe). The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluated the change from baseline to Week 48. Results reported here are the long-term results, including Week 72 and subsequent visits.

End point type

Secondary

End point timeframe

MRX baseline to EOT

End point values	Core study period: MRX baseline values	Week 158 values
Number of subjects analysed	19 ^[13]	6 ^[14]
Units: Points (0-4)
arithmetic mean (standard deviation)	2.435 ± 0.7952	0.952 ± 0.4302

Notes
[13] - Data collected from 19 participants at MRX baseline
[14] - Data collected at Week 158 from all 6 participants who contributed values at MRX baseline.

Change from MRX baseline over time in ItchRO(Obs)

Statistical analysis description

This analysis investigated whether a statistically significant change in ItchRO(Obs) scores was observed over time (with Week 158 chosen as the end point, as the last analysis visit with at least 6 participants). The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Week 158 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[15]

P-value

= 0.0307 ^[16]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

-0.958

Confidence interval

level

95%

sides

2-sided

lower limit

-1.784

upper limit

-0.132

Variability estimate

Standard deviation

Dispersion value

0.7868

Notes
[15] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in ItchRO(Obs) scores from baseline over time (to Week 158) was statistically significant.
[16] - Data for this analysis were obtained from 19 participants at MRX baseline; 6 of those participants contributed Week 158 data.

Secondary: Change from MRX baseline to Week 48 in clinician xanthoma severity score

Top of page

End point title

Change from MRX baseline to Week 48 in clinician xanthoma severity score

End point description

This secondary efficacy endpoint is the mean change from MRX baseline to Week 48 in clinician xanthoma severity scores. It is based on a 0-4 scale to rate the number of lesions present and the degree to which the participant's lesions interfere or limit his or her activities. Clinician xanthoma severity scores range from 0 to 4, with a xanthoma score of zero representing no evidence of xanthomatosis and a score of 4 representing xanthoma so severe that it is disabling. Clinician xanthoma severity scores were not assessed in Study LUM001-302 so mean clinician xanthoma severity score at MRX baseline was calculated from the 5 participants who were assigned to placebo in Study LUM001-302, and analysis of change from MRX baseline is not presented. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluate the change from baseline to Week 48. Results reported here are for the Week 48 endpoint.

End point type

Secondary

End point timeframe

MRX baseline to Week 48

End point values	Core study period: MRX baseline values	Core study period: Week 48 values
Number of subjects analysed	5 ^[17]	17 ^[18]
Units: Points (0-4)
arithmetic mean (standard deviation)	0.4 ± 0.55	0.2 ± 0.73

Notes
[17] - Mean MRX baseline scores were calculated from the 5 participants assigned placebo in LUM001-302.
[18] - Mean MRX Week 48 scores were calculated from 17 participants.

No statistical analyses for this end point

Secondary: Change from MRX baseline over time in clinician xanthoma severity score

Top of page

End point title

Change from MRX baseline over time in clinician xanthoma severity score

End point description

This secondary efficacy endpoint is the mean change from MRX baseline over time (with Week 252 chosen as the end point, as the last analysis visit with at least 6 participants) in clinician xanthoma severity scores. It is based on a 0-4 scale to rate the number of lesions present and the degree to which the lesions interfere or limit activities. Clinician xanthoma severity scores range from 0 to 4, with a score of zero representing no evidence of xanthomatosis and a score of 4 representing xanthoma so severe that it is disabling. Clinician xanthoma severity scores were not assessed in Study LUM001-302 so mean clinician xanthoma severity score at MRX baseline was calculated from the 5 participants assigned to placebo in Study LUM001-302, and analysis of change from MRX baseline is not presented. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluated the change from baseline to Week 48. Results reported here are the long-term results.

End point type

Secondary

End point timeframe

MRX baseline to EOT

End point values	Core study period: MRX baseline values	Week 252 values
Number of subjects analysed	5 ^[19]	6 ^[20]
Units: Points (0-4)
arithmetic mean (standard deviation)	0.4 ± 0.55	0.2 ± 0.41

Notes
[19] - Mean MRX baseline scores were calculated from the 5 participants assigned placebo in LUM001-302.
[20] - Mean Week 252 scores were calculated from 6 participants.

No statistical analyses for this end point

Secondary: Change from MRX baseline to Week 48 in alkaline phosphatase

Top of page

End point title

Change from MRX baseline to Week 48 in alkaline phosphatase

End point description

This secondary efficacy endpoint is the mean change from MRX baseline to Week 48 in ALP. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluate the change from baseline to Week 48. Results reported here are for the Week 48 endpoint.

End point type

Secondary

End point timeframe

MRX baseline to Week 48

End point values	Core study period: MRX baseline values	Core study period: Week 48 values
Number of subjects analysed	19 ^[21]	17 ^[22]
Units: U/L
arithmetic mean (standard deviation)	601.5 ± 232.54	596.2 ± 185.20

Notes
[21] - Data collected from 19 participants at MRX baseline.
[22] - Data collected at Week 48 from 17 of the 19 participants who contributed values at MRX baseline.

Change from MRX baseline to Week 48 in ALP

Statistical analysis description

This analysis investigated whether a statistically significant change in ALP levels was observed when comparing MRX baseline to Week 48. The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Core study period: Week 48 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[23]

P-value

= 0.8863 ^[24]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

7.4

Confidence interval

level

95%

sides

2-sided

lower limit

-100.7

upper limit

115.6

Variability estimate

Standard deviation

Dispersion value

210.32

Notes
[23] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in ALP levels between MRX baseline and Week 48 was statistically significant.
[24] - Data for this analysis were obtained from 19 participants at MRX baseline; 17 of those participants contributed Week 48 data.

Secondary: Change from MRX baseline over time in alkaline phosphatase

Top of page

End point title

Change from MRX baseline over time in alkaline phosphatase

End point description

This secondary efficacy endpoint is the mean change from MRX baseline over time in ALP. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluated the change from baseline to Week 48. Results reported here are the long-term results, including Week 72 and subsequent visits.

End point type

Secondary

End point timeframe

MRX baseline to EOT

End point values	Core study period: MRX baseline values	Week 252 values
Number of subjects analysed	19 ^[25]	6 ^[26]
Units: U/L
arithmetic mean (standard deviation)	601.5 ± 232.54	430.5 ± 223.56

Notes
[25] - Data collected from 19 participants at MRX baseline.
[26] - Data collected at Week 252 from 6 participants who contributed values at MRX baseline.

Change from MRX baseline over time in ALP

Statistical analysis description

This analysis investigated whether a statistically significant change in ALP levels was observed over time (with Week 252 chosen as the end point as the last analysis visit with at least 6 participants). The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Week 252 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[27]

P-value

= 0.22 ^[28]

Method

Student’s t-test

Parameter type

Mean difference (net)

Point estimate

-184.3

Confidence interval

level

95%

sides

2-sided

lower limit

-522.5

upper limit

153.8

Variability estimate

Standard deviation

Dispersion value

322.22

Notes
[27] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in ALP levels from baseline over time (to Week 252) was statistically significant.
[28] - Data for this analysis were obtained from 19 participants at MRX baseline; 6 of those participants contributed Week 252 data.

Secondary: Change from MRX baseline to Week 48 in alanine aminotransferase

Top of page

End point title

Change from MRX baseline to Week 48 in alanine aminotransferase

End point description

This secondary efficacy endpoint is the mean change from MRX baseline to Week 48 in ALT. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluate the change from baseline to Week 48. Results reported here are for the Week 48 endpoint.

End point type

Secondary

End point timeframe

MRX baseline to Week 48

End point values	Core study period: MRX baseline values	Core study period: Week 48 values
Number of subjects analysed	19 ^[29]	17 ^[30]
Units: U/L
arithmetic mean (standard deviation)	130.7 ± 59.12	174.5 ± 97.28

Notes
[29] - Data collected from 19 participants at MRX baseline.
[30] - Data collected at Week 48 from 17 of the 19 participants who contributed values at MRX baseline.

Change from MRX baseline to Week 48 in ALT

Statistical analysis description

This analysis investigated whether a statistically significant change in ALT levels was observed when comparing MRX baseline to Week 48. The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Core study period: Week 48 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[31]

P-value

= 0.0307 ^[32]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

51.6

Confidence interval

level

95%

sides

2-sided

lower limit

5.4

upper limit

97.7

Variability estimate

Standard deviation

Dispersion value

89.77

Notes
[31] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in ALT levels between MRX baseline and Week 48 was statistically significant.
[32] - Data for this analysis were obtained from 19 participants at MRX baseline; 17 of those participants contributed Week 48 data.

Secondary: Change from MRX baseline over time in alanine aminotransferase

Top of page

End point title

Change from MRX baseline over time in alanine aminotransferase

End point description

This secondary efficacy endpoint is the mean change from MRX baseline over time in ALT levels. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluated the change from baseline to Week 48. Results reported here are the long-term results, including Week 72 and subsequent visits.

End point type

Secondary

End point timeframe

MRX baseline to EOT

End point values	Core study period: MRX baseline values	Week 252 values
Number of subjects analysed	19 ^[33]	6 ^[34]
Units: U/L
arithmetic mean (standard deviation)	130.7 ± 59.12	175.3 ± 101.17

Notes
[33] - Data collected from 19 participants at MRX baseline.
[34] - Data collected at Week 252 from all 6 participants who contributed values at MRX baseline.

Change from MRX baseline over time in ALT

Statistical analysis description

This analysis investigated whether a statistically significant change in ALT levels was observed over time (with Week 252 chosen as the end point, as the last analysis visit with at least 6 participants). The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Week 252 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[35]

P-value

= 0.4934 ^[36]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

42.3

Confidence interval

level

95%

sides

2-sided

lower limit

-105

upper limit

189.7

Variability estimate

Standard deviation

Dispersion value

140.41

Notes
[35] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in ALT levels from baseline over time (to Week 252) was statistically significant.
[36] - Data for this analysis were obtained from 19 participants at MRX baseline; 6 of those participants contributed Week 252 data.

Secondary: Change from MRX baseline to Week 48 in aspartate aminotransferase

Top of page

End point title

Change from MRX baseline to Week 48 in aspartate aminotransferase

End point description

This secondary efficacy endpoint is the mean change from MRX baseline to Week 48 in AST levels. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluate the change from baseline to Week 48. Results reported here are for the Week 48 endpoint.

End point type

Secondary

End point timeframe

MRX baseline to Week 48

End point values	Core study period: MRX baseline values	Core study period: Week 48 values
Number of subjects analysed	19 ^[37]	17 ^[38]
Units: U/L
arithmetic mean (standard deviation)	127.6 ± 60.03	142.4 ± 78.94

Notes
[37] - Data collected from 19 participants at MRX baseline.
[38] - Data collected at Week 48 from 17 of the 19 participants who contributed values at MRX baseline.

Change from MRX baseline to Week 48 in AST

Statistical analysis description

This analysis investigated whether a statistically significant change in AST levels was observed when comparing MRX baseline to Week 48. The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Core study period: Week 48 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[39]

P-value

= 0.1571 ^[40]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

21.2

Confidence interval

level

95%

sides

2-sided

lower limit

-9.1

upper limit

51.6

Variability estimate

Standard deviation

Dispersion value

58.98

Notes
[39] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in AST levels between MRX baseline and Week 48 was statistically significant.
[40] - Data for this analysis were obtained from 19 participants at MRX baseline; 17 of those participants contributed Week 48 data.

Secondary: Change from MRX baseline over time in aspartate aminotransferase

Top of page

End point title

Change from MRX baseline over time in aspartate aminotransferase

End point description

This secondary efficacy endpoint is the mean change from MRX baseline over time in AST levels. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluated the change from baseline to Week 48. Results reported here are the long-term results, including Week 72 and subsequent visits.

End point type

Secondary

End point timeframe

MRX baseline to EOT

End point values	Core study period: MRX baseline values	Week 252 values
Number of subjects analysed	19 ^[41]	6 ^[42]
Units: U/L
arithmetic mean (standard deviation)	127.6 ± 60.03	145.0 ± 56.50

Notes
[41] - Data collected from 19 participants at MRX baseline.
[42] - Data collected at Week 252 from 6 participants who contributed values at MRX baseline.

Change from MRX baseline over time in AST

Statistical analysis description

This analysis investigated whether a statistically significant change in AST levels was observed over time (with Week 252 chosen as the end point as the last analysis visit with at least 6 participants). The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Week 252 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[43]

P-value

= 0.7815 ^[44]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

12.2

Confidence interval

level

95%

sides

2-sided

lower limit

-94.7

upper limit

119

Variability estimate

Standard deviation

Dispersion value

101.84

Notes
[43] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in AST levels from baseline over time (to Week 252) was statistically significant.
[44] - Data for this analysis were obtained from 19 participants at MRX baseline; 6 of those participants contributed Week 252 data.

Secondary: Change from MRX baseline to Week 48 in gamma glutamyltransferase

Top of page

End point title

Change from MRX baseline to Week 48 in gamma glutamyltransferase

End point description

This secondary efficacy endpoint is the mean change from MRX baseline to Week 48 in GGT. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluate the change from baseline to Week 48. Results reported here are for the Week 48 endpoint.

End point type

Secondary

End point timeframe

MRX baseline to Week 48

End point values	Core study period: MRX baseline values	Core study period: Week 48 values
Number of subjects analysed	19 ^[45]	17 ^[46]
Units: U/L
arithmetic mean (standard deviation)	476.9 ± 376.85	440.5 ± 230.60

Notes
[45] - Data collected from 19 participants at MRX baseline.
[46] - Data collected at Week 48 from 17 of the 19 participants who contributed values at MRX baseline.

Change from MRX baseline to Week 48 in GGT

Statistical analysis description

This analysis investigated whether a statistically significant change in GGT levels was observed when comparing MRX baseline to Week 48. The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Core study period: Week 48 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[47]

P-value

= 0.9513 ^[48]

Method

Student's t-test

Parameter type

Mean difference (final values)

Point estimate

-3.9

Confidence interval

level

95%

sides

2-sided

lower limit

-136.4

upper limit

128.7

Variability estimate

Standard deviation

Dispersion value

257.78

Notes
[47] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in GGT levels between MRX baseline and Week 48 was statistically significant.
[48] - Data for this analysis were obtained from 19 participants at MRX baseline; 17 of those participants contributed Week 48 data.

Secondary: Change from MRX baseline over time in gamma glutamyltransferase

Top of page

End point title

Change from MRX baseline over time in gamma glutamyltransferase

End point description

This secondary efficacy endpoint is the mean change from MRX baseline over time in GGT. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluated the change from baseline to Week 48. Results reported here are the long-term results, including Week 72 and subsequent visits.

End point type

Secondary

End point timeframe

MRX baseline to EOT

End point values	Core study period: MRX baseline values	Week 252 values
Number of subjects analysed	19 ^[49]	6 ^[50]
Units: U/L
arithmetic mean (standard deviation)	476.9 ± 376.85	377.5 ± 163.10

Notes
[49] - Data collected from 19 participants at MRX baseline.
[50] - Data collected at Week 252 from 6 participants who contributed values at MRX baseline.

Change from MRX baseline over time in GGT

Statistical analysis description

This analysis investigated whether a statistically significant change in GGT levels was observed over time (with Week 252 chosen as the end point as the last analysis visit with at least 6 participants). The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Week 252 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[51]

P-value

= 0.7133 ^[52]

Method

Student’s t-test

Parameter type

Mean difference (net)

Point estimate

-56.7

Confidence interval

level

95%

sides

2-sided

lower limit

-431.2

upper limit

317.9

Variability estimate

Standard deviation

Dispersion value

356.88

Notes
[51] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in GGT levels from baseline over time (to Week 252) was statistically significant.
[52] - Data for this analysis were obtained from 19 participants at MRX baseline; 6 of those participants contributed Week 252 data.

Secondary: Change from MRX baseline to Week 48 in total and direct bilirubin

Top of page

End point title

Change from MRX baseline to Week 48 in total and direct bilirubin

End point description

This secondary efficacy endpoint is the mean change from MRX baseline to Week 48 in total bilirubin and direct bilirubin. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluate the change from baseline to Week 48. Results reported here are for the Week 48 endpoint.

End point type

Secondary

End point timeframe

MRX baseline to Week 48

End point values	Core study period: MRX baseline values	Core study period: Week 48 values
Number of subjects analysed	19 ^[53]	17 ^[54]
Units: mg/dL
arithmetic mean (standard deviation)
Total bilirubin	4.47 ± 4.837	4.25 ± 5.384
Direct bilirubin	3.80 ± 3.858	3.21 ± 3.656

Notes
[53] - Data collected from 19 participants at MRX baseline.
[54] - Data collected at Week 48 from 17 of the 19 participants who contributed values at MRX baseline.

Change from MRX baseline to W48 in tot. bilirubin

Statistical analysis description

This analysis investigated whether a statistically significant change in total bilirubin levels was observed when comparing MRX baseline to Week 48. The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Core study period: Week 48 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[55]

P-value

= 0.7839 ^[56]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-1.05

upper limit

1.37

Variability estimate

Standard deviation

Dispersion value

2.348

Notes
[55] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in total bilirubin levels between MRX baseline and Week 48 was statistically significant.
[56] - Data for this analysis were obtained from 19 participants at MRX baseline; 17 of those participants contributed Week 48 data.

Change from MRX baseline to W48 in dir. bilirubin

Statistical analysis description

This analysis investigated whether a statistically significant change in direct bilirubin levels was observed when comparing MRX baseline to Week 48. The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Core study period: Week 48 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[57]

P-value

= 0.5298 ^[58]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.66

upper limit

0.35

Variability estimate

Standard deviation

Dispersion value

0.982

Notes
[57] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in direct bilirubin levels between MRX baseline and Week 48 was statistically significant.
[58] - Data for this analysis were obtained from 19 participants at MRX baseline; 17 of those participants contributed Week 48 data.

Secondary: Change from MRX baseline over time in total and direct bilirubin

Top of page

End point title

Change from MRX baseline over time in total and direct bilirubin

End point description

This secondary efficacy endpoint is the mean change from MRX baseline over time in total bilirubin and direct bilirubin. The secondary objectives were defined as “up to and including Week 72” while the endpoints evaluated the change from baseline to Week 48. Results reported here are the long-term results, including Week 72 and subsequent visits.

End point type

Secondary

End point timeframe

MRX baseline to EOT

End point values	Core study period: MRX baseline values	Week 252 values
Number of subjects analysed	19 ^[59]	6 ^[60]
Units: mg/dL
arithmetic mean (standard deviation)
Total bilirubin	4.47 ± 4.837	5.05 ± 6.449
Direct bilirubin	3.80 ± 3.858	3.53 ± 3.727

Notes
[59] - Data collected from 19 participants at MRX baseline.
[60] - Data collected at Week 252 from 6 participants who contributed values at MRX baseline.

Change from MRX baseline in total bilirubin

Statistical analysis description

This analysis investigated whether a statistically significant change in total bilirubin levels was observed over time (with Week 252 chosen as the end point as the last analysis visit with at least 6 participants). The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Week 252 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[61]

P-value

= 0.8218 ^[62]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

-0.53

Confidence interval

level

95%

sides

2-sided

lower limit

-6.31

upper limit

5.24

Variability estimate

Standard deviation

Dispersion value

5.505

Notes
[61] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in total bilirubin levels from baseline over time (to Week 252) was statistically significant.
[62] - Data for this analysis were obtained from 19 participants at MRX baseline; 6 of those participants contributed Week 252 data.

Change from MRX baseline in direct bilirubin

Statistical analysis description

This analysis investigated whether a statistically significant change in direct bilirubin levels was observed over time (with Week 252 chosen as the end point as the last analysis visit with at least 6 participants). The analysis was based on the safety population.

Comparison groups

Core study period: MRX baseline values v Week 252 values

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[63]

P-value

= 0.5549 ^[64]

Method

Student's t-test

Parameter type

Mean difference (net)

Point estimate

-0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-2.62

upper limit

1.58

Variability estimate

Standard deviation

Dispersion value

2.001

Notes
[63] - The null hypothesis that the mean change was equal to zero was tested using the Student’s t-test to determine if the mean change in direct bilirubin levels from baseline over time (to Week 252) was statistically significant.
[64] - Data for this analysis were obtained from 19 participants at MRX baseline; 6 of those participants contributed Week 252 data.

Adverse events

Top of page

Timeframe for reporting adverse events

Treatment-emergent adverse events are AEs with a start date on or after the first dose of study drug and started prior to the last dose of study drug plus 14 days.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Safety population

Reporting group description

Serious adverse events	Safety population
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 19 (31.58%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Gastrointestinal stoma output decreased
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
International normalised ratio increased
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Injury, poisoning and procedural complications
Forearm fracture
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Humerus fracture
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Procedural haemorrhage
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Cardiac disorders
Bradycardia
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Right ventricular failure
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Surgical and medical procedures
Medical device change
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Ear and labyrinth disorders
Ear haemorrhage
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Vomiting
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Respiratory, thoracic and mediastinal disorders
Fibrinous bronchitis
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Hypoxia
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Musculoskeletal and connective tissue disorders
Pathological fracture
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Infections and infestations
Gastrointestinal infection
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 19 (5.26%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Safety population
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 19 (94.74%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Hypotension
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Thrombosis
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
General disorders and administration site conditions
Chest pain
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	2
Fatigue
subjects affected / exposed	3 / 19 (15.79%)
occurrences all number	4
Feeling abnormal
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Feeling hot
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Influenza like illness
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Pyrexia
subjects affected / exposed	8 / 19 (42.11%)
occurrences all number	15
Immune system disorders
Seasonal allergy
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	3
Reproductive system and breast disorders
Amenorrhoea
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	10 / 19 (52.63%)
occurrences all number	21
Epistaxis
subjects affected / exposed	3 / 19 (15.79%)
occurrences all number	16
Fibrinous bronchitis
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	2
Nasal congestion
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	3
Oropharyngeal pain
subjects affected / exposed	7 / 19 (36.84%)
occurrences all number	18
Pleural effusion
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Pulmonary hypertension
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Rhinorrhoea
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	3
Sneezing
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Psychiatric disorders
Breath holding
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	2
Enuresis
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Restlessness
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Sleep disorder
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Product issues
Device occlusion
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	2
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Bilirubin urine present
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Blood bilirubin increased
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Blood parathyroid hormone increased
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Body temperature increased
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
International normalised ratio increased
subjects affected / exposed	3 / 19 (15.79%)
occurrences all number	6
Intracardiac pressure increased
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Urobilinogen urine increased
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Vitamin D decreased
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	2
Vitamin E decreased
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Injury, poisoning and procedural complications
Anaemia postoperative
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Clavicle fracture
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Concussion
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Contusion
subjects affected / exposed	3 / 19 (15.79%)
occurrences all number	3
Drain site complication
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Fall
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Hand fracture
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Head injury
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Joint injury
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Limb crushing injury
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Limb injury
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Post procedural fever
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	2
Procedural pain
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Scratch
subjects affected / exposed	3 / 19 (15.79%)
occurrences all number	4
Skin abrasion
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Stoma site erythema
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Stoma site pain
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Stress fracture
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	2
Vaccination complication
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Wound haemorrhage
subjects affected / exposed	4 / 19 (21.05%)
occurrences all number	10
Nervous system disorders
Disturbance in attention
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Dizziness
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	2
Headache
subjects affected / exposed	6 / 19 (31.58%)
occurrences all number	13
Lethargy
subjects affected / exposed	4 / 19 (21.05%)
occurrences all number	6
Poor quality sleep
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Seizure
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Somnolence
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Taste disorder
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Lymphadenopathy
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	4 / 19 (21.05%)
occurrences all number	5
Ear pruritus
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Abdominal distension
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Abdominal pain
subjects affected / exposed	11 / 19 (57.89%)
occurrences all number	40
Abdominal pain upper
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	3
Abnormal faeces
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Chapped lips
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Constipation
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	2
Dental caries
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	2
Diarrhoea
subjects affected / exposed	11 / 19 (57.89%)
occurrences all number	18
Faeces discoloured
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	2
Flatulence
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Frequent bowel movements
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Gingival bleeding
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Haematochezia
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	2
Inguinal hernia
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Lip haemorrhage
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Malabsorption
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Melaena
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Mouth haemorrhage
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Nausea
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	2
Teething
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Vomiting
subjects affected / exposed	5 / 19 (26.32%)
occurrences all number	7
Hepatobiliary disorders
Biliary tract disorder
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	2
Hepatic lesion
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Jaundice
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Drug eruption
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Dry skin
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Eczema
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Pruritus
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	2
Rash
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Rash maculo-papular
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	2
Skin discolouration
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Skin lesion
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Skin ulcer
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Urticaria
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Xanthelasma
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Pollakiuria
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Urinary incontinence
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	5
Back pain
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	2
Bone metabolism disorder
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Bone pain
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	2
Pain in extremity
subjects affected / exposed	4 / 19 (21.05%)
occurrences all number	8
Infections and infestations
Clostridium difficile infection
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Ear infection
subjects affected / exposed	5 / 19 (26.32%)
occurrences all number	9
Epstein-Barr virus infection
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Gastroenteritis
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Gastrointestinal infection
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Hepatitis infectious mononucleosis
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Impetigo
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	1
Nasopharyngitis
subjects affected / exposed	8 / 19 (42.11%)
occurrences all number	36
Oral herpes
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	4
Otitis media
subjects affected / exposed	1 / 19 (5.26%)
occurrences all number	2
Tonsillitis
subjects affected / exposed	4 / 19 (21.05%)
occurrences all number	8
Upper respiratory tract infection
subjects affected / exposed	11 / 19 (57.89%)
occurrences all number	28
Varicella
subjects affected / exposed	3 / 19 (15.79%)
occurrences all number	3
Viral upper respiratory tract infection
subjects affected / exposed	3 / 19 (15.79%)
occurrences all number	5
Metabolism and nutrition disorders
Vitamin D deficiency
subjects affected / exposed	2 / 19 (10.53%)
occurrences all number	2

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

05 Nov 2013

Protocol Amendment 1 Updates were made to add exclusion of participants with a history or presence of gallstones or kidney stones.

28 Feb 2014

Protocol Amendment 2 Updates were made to: - Lower eligibility age from 2 years of age to 12 months - Alter the number of participants planned for enrollment from 60 to 42 - Revise text to indicate that participants who weighed 10 kg or more would receive a 1.0 mL solution containing MRX or placebo. Participants who weighed less than 10 kg would receive a 0.5 mL solution containing MRX or placebo. The volume administered would not change during the course of the study - Correct maximum MRX dose - Add PedsQL for infants

17 Sep 2014

Protocol Amendment 3 Updates were made to: - Change treatment (duration) period to collect additional long-term safety data from 48 weeks to 76 weeks, including a 4-week follow-up. The treatment period was changed from 48 weeks to 72 weeks - Change stable dosing period from 36 weeks to 60 weeks and study duration to 76 weeks, including a 4-week follow-up - Add study visits at Weeks 60 and 72 - Change Study Termination (End of Study) from Week 48 to Week 72 - Add PedsQL evaluation at Week 72 - Add Caregiver Impression of Change evaluation at Week 72 - Change Study Termination from Week 48 to Week 72 - Change the number of participants planned for enrollment from 42 to 18 - Modify biochemical markers of cholestasis and liver disease to include deletion of ALP and modification of bilirubin (total and direct) to total bilirubin in secondary evaluations for the durability of the therapeutic effect as mean change from Baseline (Day 0) to Week 48 and the change from Week 12 to Week 48 - Change the number of study centers from 14 to 3 - Add drug level evaluations at Week 72

04 Nov 2015

Protocol Amendment 4 Updates were made to include a follow-up treatment period (after Week 72) that was intended to offer the opportunity to eligible participants treated in Study LUM001-303 to continue on treatment after Week 72 until the first of the following occurred: (i) up to 52 weeks of additional treatment (Week 124), or (ii) in the event that a new study opened to enrollment.

16 May 2017

Protocol Amendment 5 Updates were made to: - Allow continued participation in the long-term follow-up treatment, beyond what was previously described in Protocol Amendment 4 - Clarify that study treatment in the follow-up treatment period could continue until the first of the following occurred: (i) the participants were eligible to enter another MRX study; (ii) MRX was available commercially; or (iii) the sponsor stopped the program or development in this indication - Clarify that eligible participants who had previously discontinued from the study could re-enter and receive study treatment in the follow-up treatment period (after Week 124) - Add additional objectives for the long-term follow-up treatment period as follows: exploration of a BID dosing regimen and higher daily dosing of MRX, assessment of AFP levels, assessment of the palatability of the MRX formulation in all participants, obtain safety and efficacy data in participants treated long term on MRX - Align the contraceptive requirements with the Heads of Medicine Clinical Trials Facilitation Group Recommendations Related to Contraception and Pregnancy Testing

08 Feb 2019

Protocol Amendment 5.1 Updates were made to: - Change the sponsorship from Lumena Pharmaceuticals LLC to Mirum Pharmaceuticals, Inc. - Add drug compliance at Week 4 - Add Afternoon Dose Escalation eligibility assessment at Week 12 starting at Repeating Period 2 - Add Caregiver Global Therapeutic Benefit Questionnaire

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Multicentre Extension Study to Evaluate the Long-Term Safety and Durability of the Therapeutic Effect of LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric Subjects with Alagille Syndrome

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from MRX baseline to Week 48 in fasting sBA levels

Primary: Change from MRX baseline to Week 48 in fasting sBA levels

Secondary: Change from MRX baseline over time in fasting sBA levels

Secondary: Change from MRX baseline over time in fasting sBA levels

Secondary: Change from MRX baseline to Week 48 in pruritus

Secondary: Change from MRX baseline to Week 48 in pruritus

Secondary: Change from MRX baseline over time in pruritus

Secondary: Change from MRX baseline over time in pruritus

Secondary: Change from MRX baseline to Week 48 in clinician xanthoma severity score

Secondary: Change from MRX baseline to Week 48 in clinician xanthoma severity score

Secondary: Change from MRX baseline over time in clinician xanthoma severity score

Secondary: Change from MRX baseline over time in clinician xanthoma severity score

Secondary: Change from MRX baseline to Week 48 in alkaline phosphatase

Secondary: Change from MRX baseline to Week 48 in alkaline phosphatase

Secondary: Change from MRX baseline over time in alkaline phosphatase

Secondary: Change from MRX baseline over time in alkaline phosphatase

Secondary: Change from MRX baseline to Week 48 in alanine aminotransferase

Secondary: Change from MRX baseline to Week 48 in alanine aminotransferase

Secondary: Change from MRX baseline over time in alanine aminotransferase

Secondary: Change from MRX baseline over time in alanine aminotransferase

Secondary: Change from MRX baseline to Week 48 in aspartate aminotransferase

Secondary: Change from MRX baseline to Week 48 in aspartate aminotransferase

Secondary: Change from MRX baseline over time in aspartate aminotransferase

Secondary: Change from MRX baseline over time in aspartate aminotransferase

Secondary: Change from MRX baseline to Week 48 in gamma glutamyltransferase

Secondary: Change from MRX baseline to Week 48 in gamma glutamyltransferase

Secondary: Change from MRX baseline over time in gamma glutamyltransferase

Secondary: Change from MRX baseline over time in gamma glutamyltransferase

Secondary: Change from MRX baseline to Week 48 in total and direct bilirubin

Secondary: Change from MRX baseline to Week 48 in total and direct bilirubin

Secondary: Change from MRX baseline over time in total and direct bilirubin

Secondary: Change from MRX baseline over time in total and direct bilirubin

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicentre Extension Study to Evaluate the Long-Term Safety and Durability of the Therapeutic Effect of LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric Subjects with Alagille Syndrome