Alagille Syndrome
Conditions
Brief summary
This is a long-term, open-label study with a double-blind, placebo-controlled, randomized drug withdrawal period in children with Alagille Syndrome (ALGS) designed to evaluate the safety and efficacy of LUM001 (Also known as maralixibat or MRX).
Detailed description
The study is divided into 6 parts: a 6-week open-label, dose escalation period, a 12-week open-label stable dosing period, a 4-week randomized, double-blind, placebo-controlled drug withdrawal period, a 26-week long-term stable dosing period, and an a 52-week optional follow-up treatment period, and a long-term optional follow-up treatment period for eligible participants who choose to stay on treatment with LUM001.
Interventions
LUM001, also known as Maralixibat (MRX) will be administered orally Once Daily (OD). To be administered Twice Daily (BID) for patients who are eligible.
DRUGPlacebo
Placebo will be administered orally once daily during randomized withdrawal period
Sponsors
Mirum Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Open-label single arm study with a randomized placebo-controlled parallel group period
Eligibility
Sex/Gender
ALL
Age
12 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
* Male or female between the ages of 12 months and 18 years inclusive. * Diagnosis of ALGS. * Evidence of cholestasis (one or more of the following): 1. Total serum bile acid \> 3x ULN for age. 2. Conjugated bilirubin \> 1 mg/dL. 3. Fat soluble vitamin deficiency otherwise unexplainable. 4. GGT \> 3x ULN for age. 5. Intractable pruritus explainable only by liver disease. * Females of childbearing potential must have a negative serum pregnancy test during Screening. * Males and females of child-bearing potential who are sexually active, or are not currently sexually active during the study, but become sexually active during the period of the study and 30 days following the last dose of study drug, must agree and use acceptable contraception during the trial. * Participant is expected to have a consistent caregiver(s) for the duration of the study. * Informed consent and assent (per IRB/IEC) as appropriate. * Access to phone for scheduled calls from study site. * Caregivers (and age-appropriate participants) must be willing and able to use an eDiary device during the study. * Caregivers (and age-appropriate participants) must digitally accept the licensing agreement in the eDiary software. * Caregivers (and age-appropriate participants) must complete at least 10 eDiary reports (morning or evening) during each of two consecutive weeks of the screening period (maximum possible reports = 14 per week). * Average daily score \>2 on the Itch Reported Outcome (ItchRO™) questionnaire (maximum possible daily score of 4) for two consecutive weeks in the screening period, prior to dosing. A daily score is the higher of the scores for the morning and evening ItchRO. The average daily score is the sum of all daily scores divided by the number of days the ItchRO was completed. Inclusion Criteria for participants to be eligible for the 52-week optional follow-up treatment period: * Completed the protocol through the Week 48 visit with no safety concerns. Participants who were discontinued due to safety reasons can be rechallenged if blood tests are back to relatively normal values for this patient population and participant does not meet any of the protocol's stopping rules. The decision will be made by the investigator in consultation with the sponsor medical monitor. * Participants who have undergone a surgical disruption of the enterohepatic circulation will not be eligible to enter into the follow up treatment period. * Participants who were discontinued for other reasons will be considered for the 52-week optional follow-up treatment period on an individual basis. The decision will be made by the investigator in consultation with the sponsor medical monitor. Inclusion Criteria for participants with LUM001dosing interruption \<7 days, or \>=7 days: * The Participant has either: completed the protocol through the Week 48 visit with no major safety concerns OR discontinued due to safety reasons judged unrelated to the study drug, and laboratory results have returned to levels acceptable for this patient population or individual and participant does not meet any of the protocol's stopping rules at the time of entry into the follow-up period. The decision will be made by the investigator in consultation with the sponsor medical monitor. \[Participants who were discontinued for other reasons will be considered on an individual basis.\] * Females of childbearing potential must have a negative urine or serum pregnancy test (beta- human chorionic gonadotropin \[β-hCG\]) at the time of entry into the long-term optional follow-up treatment period. * Males and females of child-bearing potential who are sexually active, or are not currently sexually active during the study, but become sexually active during the period of the study and 30 days following the last dose of study drug, must agree and use acceptable contraception during the trial. * Informed consent and assent (per IRB/EC) as appropriate. * Access to phone for scheduled calls from study site. * Caregivers (and age-appropriate participants) must be willing and able to use an eDiary device during the study.
Exclusion criteria
* Chronic diarrhea requiring ongoing intravenous fluid or nutritional intervention. * Surgical interruption of the enterohepatic circulation. * Previous liver transplant * Decompensated cirrhosis (ALT \>15 x ULN, INR \>1.5 \[unresponsive to vitamin K therapy\], albumin \<3.0 g/dL, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy). * History or presence of other concomitant liver disease. * History or presence of any other disease or condition known to interfere with the absorption, distribution, metabolism or excretion of drugs, including bile salt metabolism in the intestine (eg, inflammatory bowel disease). * History or presence of gallstones or kidney stones. * Known diagnosis of human immunodeficiency virus (HIV) infection. * Cancers, except for in situ carcinoma, or cancers treated at least 5 years prior to Screening with no evidence of recurrence. * Recent medical history or current status that suggests that the participant may be unable to complete the study. * Any female who is pregnant or lactating or who is planning to become pregnant during the study period. * Known history of alcohol or substance abuse. * Administration of bile acid or lipid binding resins within 28 days prior to screening and throughout the trial. * Known hypersensitivity to LUM001 or any of its components. * Receipt of investigational drug, biologic, or medical device within 28 days prior to screening, or 5 half-lives of the study agent, whichever is longer. * History of non-adherence to medical regimens, unreliability, mental instability or incompetence that could compromise the validity of informed consent or lead to nonadherence with the study protocol based upon investigator judgment. * Any other conditions or abnormalities which, in the opinion of the investigator or sponsor medical monitor, may compromise the safety of the participant, or interfere with the participant participating in or completing the study. * Participants weighing over 50 kg at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Week 18 to Week 22 in Fasting sBA Levels in Participants Who Had a Reduction in sBA ≥50% From Baseline to Week 12 or Week 18 | Week 18 to Week 22 | The primary efficacy endpoint of this study was the mean change from Week 18 to Week 22 (the RWD period) of fasting sBA levels in participants who had a reduction in sBA ≥50% from baseline to Week 12 or Week 18 (Modified Intent-to-Treat \[MITT\] Population). Five participants in the MRX group and 10 participants in the placebo group met the prespecified sBA reduction criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 18 in Pruritus as Measured by ItchRO (Obs) | Baseline to Week 18 | This secondary efficacy endpoint is the change from baseline to Week 18 in pruritus as measured by ItchRO(Obs) weekly average morning score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe). |
| Change From Baseline to Week 18 in Pruritus as Measured by ItchRO (Pt) | Baseline to Week 18 | This secondary efficacy endpoint is the change from baseline to Week 18 in pruritus as measured by ItchRO(Pt) weekly average morning score |
| Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO(Obs) | Week 18 to Week 22 | This secondary efficacy endpoint is the change from Week 18 to Week 22 in pruritus as measured by ItchRO(Obs) weekly average morning score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe). |
| Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO(Pt) | Week 18 to Week 22 | This secondary efficacy endpoint is the change from Week 18 to Week 22 in pruritus as measured by ItchRO(Pt) weekly average morning score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe). |
| Change From Baseline to Week 18 in Alkaline Phosphatase | Baseline to Week 18 | This secondary efficacy endpoint is the mean change from baseline to Week 18 in ALP |
| Change From Week 18 to Week 22 in Alkaline Phosphatase | Week 18 to Week 22 | This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in ALP |
| Change From Baseline to Week 18 in Fasting sBA Levels | Baseline to Week 18 | This secondary efficacy endpoint is the mean change from baseline to Week 18 in fasting sBA levels |
| Change From Week 18 to Week 22 in Alanine Aminotransferase | Week 18 to Week 22 | This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in alanine aminotransferase (ALT) |
| Change From Baseline to Week 18 in Total Bilirubin | Baseline to Week 18 | This secondary efficacy endpoint is the mean change from baseline to Week 18 in total bilirubin |
| Change From Week 18 to Week 22 in Total Bilirubin | Week 18 to Week 22 | This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in total bilirubin |
| Change From Baseline to Week 18 in Direct Bilirubin | Baseline to Week 18 | This secondary efficacy endpoint is the mean change from baseline to Week 18 in direct bilirubin |
| Change From Week 18 to Week 22 in Direct Bilirubin | Week 18 to Week 22 | This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in direct bilirubin |
| Change From Baseline to Week 18 in Alanine Aminotransferase | Baseline to Week 18 | This secondary efficacy endpoint is the mean change from baseline to Week 18 in ALT |
Countries
Australia, Belgium, France, Poland, Spain, United Kingdom
Participant flow
Recruitment details
The participants were enrolled at 9 sites in 6 countries (Australia, UK, France, Poland, Spain and Belgium) between 28 October 2014 and 11 September 2015
Pre-assignment details
A total of 36 patients were screened for the study. 31 patients were enrolled, while 5 patients were screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Open-label Period: Maralixibat All participants received MRX at doses of up to 400 μg/kg once daily (QD) during a 6-week open-label dose-escalation period, followed by a 12-week open-label stable-dosing period. All participants reached 400 μg/kg QD for this period. | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| After Randomized Withdrawal: Maralixibat | Adverse Event | 0 | 0 | 0 | 1 | 0 |
| After Randomized Withdrawal: Maralixibat | Did not consent to protocol amendment for long term extension | 0 | 0 | 0 | 5 | 0 |
| Long-term Extension Period: Maralixibat | Adverse Event | 0 | 0 | 0 | 0 | 3 |
| Long-term Extension Period: Maralixibat | Did not consent to protocol amendment | 0 | 0 | 0 | 0 | 4 |
| Long-term Extension Period: Maralixibat | Physician Decision | 0 | 0 | 0 | 0 | 1 |
| Long-term Extension Period: Maralixibat | Withdrawal by caregiver | 0 | 0 | 0 | 0 | 1 |
| Open-label Period: Maralixibat | Adverse Event | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Open-label Period: Maralixibat |
|---|---|
| Age, Continuous | 5.4 years of age STANDARD_DEVIATION 4.25 |
| Age, Customized 13 to 18 years | 3 Participants |
| Age, Customized 2 to 4 years | 9 Participants |
| Age, Customized <2 years | 6 Participants |
| Age, Customized 5 to 8 years | 9 Participants |
| Age, Customized 9 to 12 years | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | NA Participants |
| Race (NIH/OMB) Asian | NA Participants |
| Race (NIH/OMB) Black or African American | NA Participants |
| Race (NIH/OMB) More than one race | NA Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | NA Participants |
| Race (NIH/OMB) Unknown or Not Reported | NA Participants |
| Race (NIH/OMB) White | NA Participants |
| Region of Enrollment Australia | 9 participants |
| Region of Enrollment Belgium | 5 participants |
| Region of Enrollment France | 9 participants |
| Region of Enrollment Poland | 3 participants |
| Region of Enrollment Spain | 2 participants |
| Region of Enrollment United Kingdom | 3 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 13 | 0 / 16 | 0 / 29 | 0 / 23 | 0 / 31 |
| other Total, other adverse events | 29 / 31 | 7 / 13 | 12 / 16 | 25 / 29 | 23 / 23 | 31 / 31 |
| serious Total, serious adverse events | 4 / 31 | 1 / 13 | 1 / 16 | 5 / 29 | 6 / 23 | 13 / 31 |
Outcome results
Primary
Change From Week 18 to Week 22 in Fasting sBA Levels in Participants Who Had a Reduction in sBA ≥50% From Baseline to Week 12 or Week 18
The primary efficacy endpoint of this study was the mean change from Week 18 to Week 22 (the RWD period) of fasting sBA levels in participants who had a reduction in sBA ≥50% from baseline to Week 12 or Week 18 (Modified Intent-to-Treat \[MITT\] Population). Five participants in the MRX group and 10 participants in the placebo group met the prespecified sBA reduction criteria.
Time frame: Week 18 to Week 22
Population: Primary outcome used the (Modified Intent-to-Treat \[MITT\]Population. The MITT population is defined as participants who had a reduction in sBA ≥50% from baseline to Week 12 or Week 18. Five participants in the MRX group and 10 participants in the placebo group met the prespecified sBA reduction criteria.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Week 18 to Week 22 in Fasting sBA Levels in Participants Who Had a Reduction in sBA ≥50% From Baseline to Week 12 or Week 18 | -21.73 μmol/L | Standard Error 43.125 |
| Randomized Withdrawal Period: Placebo | Change From Week 18 to Week 22 in Fasting sBA Levels in Participants Who Had a Reduction in sBA ≥50% From Baseline to Week 12 or Week 18 | 95.55 μmol/L | Standard Error 30.488 |
Comparison: The difference between treatment groups in change from Week 18 to Week 22 in fasting sBA levels was evaluated using an analysis of covariance (ANCOVA) model with treatment group as a factor, and Week 18 sBA as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the MITT population, which included all participants who were enrolled, received study drug through Week 18, and had a reduction from baseline in sBA of ≥50% at the Week 12 or Week 18 measurement.p-value: 0.046495% CI: [-232.38, -2.18]ANCOVA
Secondary
Change From Baseline to Week 18 in Alanine Aminotransferase
This secondary efficacy endpoint is the mean change from baseline to Week 18 in ALT
Time frame: Baseline to Week 18
Population: Values were collected from 31 participants at baseline. Values were collected at Week 18 from 29 of the 31 participants who contributed values at baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Baseline to Week 18 in Alanine Aminotransferase | 181.0 U/L | Standard Deviation 108.56 |
| Randomized Withdrawal Period: Placebo | Change From Baseline to Week 18 in Alanine Aminotransferase | 177.4 U/L | Standard Deviation 92.08 |
Comparison: This analysis investigated whether a statistically significant change in ALT levels was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population.p-value: 0.935895% CI: [-33.4, 30.9]Student's t-test
Secondary
Change From Baseline to Week 18 in Alkaline Phosphatase
This secondary efficacy endpoint is the mean change from baseline to Week 18 in ALP
Time frame: Baseline to Week 18
Population: Values were collected from 31 participants at baseline. Values were collected at Week 18 from 29 of the 31 participants who contributed values at baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Baseline to Week 18 in Alkaline Phosphatase | 601.3 U/L | Standard Deviation 274.77 |
| Randomized Withdrawal Period: Placebo | Change From Baseline to Week 18 in Alkaline Phosphatase | 580.8 U/L | Standard Deviation 215.5 |
Comparison: This analysis investigated whether a statistically significant change in ALP levels was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population.p-value: 0.216395% CI: [-72.8, 17.2]Student's t-test
Secondary
Change From Baseline to Week 18 in Direct Bilirubin
This secondary efficacy endpoint is the mean change from baseline to Week 18 in direct bilirubin
Time frame: Baseline to Week 18
Population: Values from the open-label period were collected from 31 participants at baseline. Values were collected at Week 18 from 28 of the 31 participants who contributed values at baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Baseline to Week 18 in Direct Bilirubin | 4.57 mg/dL | Standard Deviation 3.666 |
| Randomized Withdrawal Period: Placebo | Change From Baseline to Week 18 in Direct Bilirubin | 3.98 mg/dL | Standard Deviation 3.369 |
p-value: 0.013995% CI: [-0.9, -0.11]Student's t-test
Secondary
Change From Baseline to Week 18 in Fasting sBA Levels
This secondary efficacy endpoint is the mean change from baseline to Week 18 in fasting sBA levels
Time frame: Baseline to Week 18
Population: Values were collected from 31 participants at baseline. Values were collected at Week 18 from 29 of the 31 participants who contributed values at baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Baseline to Week 18 in Fasting sBA Levels | 283.43 μmol/L | Standard Deviation 210.569 |
| Randomized Withdrawal Period: Placebo | Change From Baseline to Week 18 in Fasting sBA Levels | 192.50 μmol/L | Standard Deviation 161.278 |
Comparison: This analysis investigated whether a statistically significant change in sBA levels was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population.p-value: 0.000595% CI: [-133.37, -42.09]Student's t-test
Secondary
Change From Baseline to Week 18 in Pruritus as Measured by ItchRO (Obs)
This secondary efficacy endpoint is the change from baseline to Week 18 in pruritus as measured by ItchRO(Obs) weekly average morning score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe).
Time frame: Baseline to Week 18
Population: Values were collected from 31 participants at baseline. Values were collected at Week 18 from 29 of the 31 participants who contributed values at baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Baseline to Week 18 in Pruritus as Measured by ItchRO (Obs) | 2.909 Points | Standard Deviation 0.548 |
| Randomized Withdrawal Period: Placebo | Change From Baseline to Week 18 in Pruritus as Measured by ItchRO (Obs) | 1.203 Points | Standard Deviation 0.8446 |
Comparison: This analysis investigated whether a statistically significant change in ItchRO(Obs) score was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity.p-value: <0.000195% CI: [-2.051, -1.357]Student's t-test
Secondary
Change From Baseline to Week 18 in Pruritus as Measured by ItchRO (Pt)
This secondary efficacy endpoint is the change from baseline to Week 18 in pruritus as measured by ItchRO(Pt) weekly average morning score
Time frame: Baseline to Week 18
Population: NOTE: 2 participants discontinued prior week 18 and did not provide data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Baseline to Week 18 in Pruritus as Measured by ItchRO (Pt) | 2.903 Points | Standard Deviation 0.6616 |
| Randomized Withdrawal Period: Placebo | Change From Baseline to Week 18 in Pruritus as Measured by ItchRO (Pt) | 0.831 Points | Standard Deviation 0.8122 |
Comparison: This analysis investigated whether a statistically significant change in ItchRO(Pt) score was observed when comparing baseline to Week 18 (the open-label period, during which all participants received MRX). The analysis was based on the ITT population. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity.p-value: <0.000195% CI: [-2.645, -1.498]Student's t-test
Secondary
Change From Baseline to Week 18 in Total Bilirubin
This secondary efficacy endpoint is the mean change from baseline to Week 18 in total bilirubin
Time frame: Baseline to Week 18
Population: Open-label period: MRX baseline v Open-label period: MRX Week 18
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Baseline to Week 18 in Total Bilirubin | 6.09 mg/dL | Standard Deviation 5.781 |
| Randomized Withdrawal Period: Placebo | Change From Baseline to Week 18 in Total Bilirubin | 5.12 mg/dL | Standard Deviation 5.337 |
p-value: 0.089395% CI: [-1.01, 0.08]Student's t-test
Secondary
Change From Week 18 to Week 22 in Alanine Aminotransferase
This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in alanine aminotransferase (ALT)
Time frame: Week 18 to Week 22
Population: The difference between treatment groups in change from Week 18 to Week 22 in ALT levels was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 ALT as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Week 18 to Week 22 in Alanine Aminotransferase | 34.5 U/L | Standard Error 14.04 |
| Randomized Withdrawal Period: Placebo | Change From Week 18 to Week 22 in Alanine Aminotransferase | 19.4 U/L | Standard Error 12.56 |
Comparison: The difference between treatment groups in change from Week 18 to Week 22 in ALT levels was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 ALT as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.p-value: 0.447295% CI: [-25.1, 55.2]ANCOVA
Secondary
Change From Week 18 to Week 22 in Alkaline Phosphatase
This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in ALP
Time frame: Week 18 to Week 22
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Week 18 to Week 22 in Alkaline Phosphatase | 2.8 U/L | Standard Error 22.55 |
| Randomized Withdrawal Period: Placebo | Change From Week 18 to Week 22 in Alkaline Phosphatase | -7.2 U/L | Standard Error 20.31 |
Comparison: The difference between treatment groups in change from Week 18 to Week 22 in ALP levels was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 ALP as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.p-value: 0.745595% CI: [-52.6, 72.6]ANCOVA
Secondary
Change From Week 18 to Week 22 in Direct Bilirubin
This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in direct bilirubin
Time frame: Week 18 to Week 22
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Week 18 to Week 22 in Direct Bilirubin | 0.13 mg/dL | Standard Error 0.195 |
| Randomized Withdrawal Period: Placebo | Change From Week 18 to Week 22 in Direct Bilirubin | 0.14 mg/dL | Standard Error 0.174 |
Comparison: The difference between treatment groups in change from Week 18 to Week 22 in direct bilirubin levels was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 direct bilirubin as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.p-value: 0.951795% CI: [-0.56, 0.53]ANCOVA
Secondary
Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO(Obs)
This secondary efficacy endpoint is the change from Week 18 to Week 22 in pruritus as measured by ItchRO(Obs) weekly average morning score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe).
Time frame: Week 18 to Week 22
Population: For Maralixibat, n=12 for ItchRO(Obs) weekly average morning score For Placebo, n=16 for ItchRO(Obs) weekly average morning score
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO(Obs) | 0.217 Points | Standard Error 0.2345 |
| Randomized Withdrawal Period: Placebo | Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO(Obs) | 1.700 Points | Standard Error 0.2031 |
Comparison: The difference between treatment groups in change from Week 18 to Week 22 in ItchRO(Obs) was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 ItchRO(Obs) as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.p-value: <0.000195% CI: [-2.122, -0.844]ANCOVA
Secondary
Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO(Pt)
This secondary efficacy endpoint is the change from Week 18 to Week 22 in pruritus as measured by ItchRO(Pt) weekly average morning score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe).
Time frame: Week 18 to Week 22
Population: ItchRO(Pt) was completed independently in participants 9 years old or older. Children between the ages of 5 and 8 years old completed the patient instrument with the assistance of their caregiver, if needed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO(Pt) | -0.149 Points | Standard Error 0.3719 |
| Randomized Withdrawal Period: Placebo | Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO(Pt) | 1.839 Points | Standard Error 0.2771 |
Comparison: The difference between treatment groups in change from Week 18 to Week 22 in ItchRO (Pt) was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 ItchRO(Pt) as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.p-value: 0.001395% CI: [-3.009, -0.967]ANCOVA
Secondary
Change From Week 18 to Week 22 in Total Bilirubin
This secondary efficacy endpoint is the mean change from Week 18 to Week 22 in total bilirubin
Time frame: Week 18 to Week 22
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal Period: MRX | Change From Week 18 to Week 22 in Total Bilirubin | 0.32 mg/dL | Standard Error 0.265 |
| Randomized Withdrawal Period: Placebo | Change From Week 18 to Week 22 in Total Bilirubin | 0.46 mg/dL | Standard Error 0.238 |
Comparison: The difference between treatment groups in change from Week 18 to Week 22 in total bilirubin was evaluated using an ANCOVA model with treatment group as a factor, and Week 18 total bilirubin as a covariate. The analysis used a tabulation of fitted summary statistics from ANCOVA in the intent-to-treat population, which included all participants who were enrolled, and received at least one dose of study drug.p-value: 0.795% CI: [-0.88, 0.6]ANCOVA