Alagille Syndrome
Conditions
Brief summary
The study is a randomized, double-blind, placebo-controlled study in children with Alagille Syndrome (ALGS). The study will investigate the effects of LUM001, compared to placebo, on pruritus, serum bile acids, liver enzymes, and other biochemical markers in patients with ALGS.
Interventions
DRUGLUM001
LUM001 administered orally
DRUGPlacebo
Placebo administered orally
Sponsors
Childhood Liver Disease Research and Education Network
Mirum Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Alagille Syndrome 2. Evidence of cholestasis 3. Moderate to severe pruritus 4. Ability to understand and willingness to sign informed consent/assent prior to initiation of any study procedures
Exclusion criteria
1. Surgical disruption of the enterohepatic circulation 2. Liver transplant 3. History or presence of other concomitant liver disease 4. Females who are pregnant or lactating 5. Known HIV infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Endpoint (Week 13/Early Termination) in Pruritus | Baseline, Week 13/Early Termination | Pruritus was assessed using Itch report outcome measure (ItchRO\[Obs\]), administered as an electronic diary (eDiary) which was completed by the participants twice daily (morning and evening). ItchRO(Obs) score ranged from 0 to 4, with the higher score indicating increasing itch severity. The highest score between the morning and evening ItchRO(Obs) reports represented the daily score: a measure of the worst itching over the previous 24-hour period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Endpoint (Week 13/Early Termination) in Fasting Serum Bile Acid (sBA) Level | Baseline, Week 13/Early Termination | Fasting sBA level was measured by using a liquid chromatography mass spectrometry method. |
| Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Baseline, Week 13/Early Termination | Liver enzyme levels of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase and gamma glutamyl transferase were reported here. |
| Change From Baseline to Endpoint (Week 13/Early Termination) in Total and Direct Bilirubin Concentrations | Baseline, Week 13/Early Termination | Liver enzyme levels of total bilirubin and direct bilirubin were reported here. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | From the start of study drug administration up to Week 17 | An AE was any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life -threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.TEAEs were defined as AEs/SAEs that started or worsened after the study drug treatment. |
Countries
Canada, United States
Participant flow
Recruitment details
Study was conducted at 13 study centers in the United States and Canada, between 24 November 2014 (first participant first visit) and 16 November 2016 (last participant last visit).
Pre-assignment details
Overall, 37 participants were enrolled to dose escalation phase started with 14 microgram per kilogram per day (mcg/kg/day) per week on Week 1 up to 280 mcg/kg/day for a maximum up to 5 weeks, until they reached the planned stable dose of 70, 140 and 280 mcg/kg/day and continued up to Week 13.
Participants by arm
| Arm | Count |
|---|---|
| Maralixibat 70 mcg/kg/Day Participants received low dose maralixibat 70 mcg/kg/day oral solution for 10 weeks during the stable dosing period, which was administered after a dose escalation period, in which participants received 14, 35 and 70 mcg/kg/day dose per each week respectively up to 3 weeks. | 8 |
| Maralixibat 140 mcg/kg/Day Participants received mid dose maralixibat 140 mcg/kg/day oral solution for 9 weeks during the stable dosing period, which was administered after a dose escalation period, in which participants received 14, 35, 70 and 140 mcg/kg/day dose per each week respectively up to 4 weeks. | 11 |
| Maralixibat 280 mcg/kg/Day Participants received high dose maralixibat 280 mcg/kg/day oral solution for 8 weeks during the stable dosing period, which was administered after a dose escalation period, in which participants received 14, 35, 70, 140 and 280 mcg/kg/day dose per each week respectively up to 5 weeks. | 6 |
| Placebo Participants received placebo matched to maralixibat oral solution for 13 weeks (dose escalation and stable dosing period). | 12 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Maralixibat 70 mcg/kg/Day | Maralixibat 140 mcg/kg/Day | Maralixibat 280 mcg/kg/Day | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 7.4 Years STANDARD_DEVIATION 4.75 | 8.6 Years STANDARD_DEVIATION 4.32 | 5.5 Years STANDARD_DEVIATION 4.76 | 5.5 Years STANDARD_DEVIATION 4.19 | 6.8 Years STANDARD_DEVIATION 4.48 |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 4 Participants | 6 Participants | 16 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 2 Participants | 6 Participants | 21 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 7 | 0 / 11 | 0 / 6 | 0 / 12 |
| other Total, other adverse events | 1 / 1 | 7 / 7 | 9 / 11 | 5 / 6 | 12 / 12 |
| serious Total, serious adverse events | 0 / 1 | 1 / 7 | 0 / 11 | 0 / 6 | 0 / 12 |
Outcome results
Primary
Change From Baseline to Endpoint (Week 13/Early Termination) in Pruritus
Pruritus was assessed using Itch report outcome measure (ItchRO\[Obs\]), administered as an electronic diary (eDiary) which was completed by the participants twice daily (morning and evening). ItchRO(Obs) score ranged from 0 to 4, with the higher score indicating increasing itch severity. The highest score between the morning and evening ItchRO(Obs) reports represented the daily score: a measure of the worst itching over the previous 24-hour period.
Time frame: Baseline, Week 13/Early Termination
Population: Modified Intent-to-Treat Population (mITT) population included all participants randomly assigned to study treatment, receiving at least 1 dose of treatment, and having at least 1 post baseline observer itch reported outcome (ItchRO\[Obs\]) average daily score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Maralixibat 70 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Pruritus | -1.470 Score on a scale | Standard Error 0.3034 |
| Maralixibat 140 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Pruritus | -1.486 Score on a scale | Standard Error 0.2597 |
| Maralixibat 280 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Pruritus | -0.620 Score on a scale | Standard Error 0.3575 |
| Placebo | Change From Baseline to Endpoint (Week 13/Early Termination) in Pruritus | -0.580 Score on a scale | Standard Error 0.2453 |
Comparison: The primary analysis of change from baseline to endpoint (Week 13/ET) average daily ItchRO(Obs) was evaluated by analysis of covariance (ANCOVA) using a PROC MIXED procedure. Least-squares (LS) mean change from baseline to Endpoint (Week 13/ET), along with associated 95% confidence interval (CI) for the LS mean, and pair-wise treatment P-values were calculated for each treatment group.p-value: 0.032195% CI: [-1.698, 0.081]ANCOVA
Comparison: The primary analysis of change from baseline to endpoint (Week 13/ET) average daily ItchRO(Obs) was evaluated by ANCOVA using a PROC MIXED procedure. LS mean change from baseline to Endpoint (Week 13/ET), along with associated 95% CI for the LS mean, and pair-wise treatment P-values were calculated for each treatment group.p-value: 0.014595% CI: [-1.62, -0.192]ANCOVA
Comparison: The primary analysis of change from baseline to endpoint (Week 13/ET) average daily ItchRO(Obs) was evaluated by ANCOVA using a PROC MIXED procedure. LS mean change from baseline to Endpoint (Week 13/ET), along with associated 95% confidence interval (CI) for the LS mean, and pair-wise treatment P-values were calculated for each treatment group.p-value: 0.929895% CI: [-0.942, 0.863]ANCOVA
Secondary
Change From Baseline to Endpoint (Week 13/Early Termination) in Fasting Serum Bile Acid (sBA) Level
Fasting sBA level was measured by using a liquid chromatography mass spectrometry method.
Time frame: Baseline, Week 13/Early Termination
Population: mITT population included all participants randomly assigned to study treatment, receiving at least 1 dose of treatment, and having at least 1 post baseline observer itch reported outcome (ItchRO\[Obs\]) average daily score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Maralixibat 70 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Fasting Serum Bile Acid (sBA) Level | -117.401 Micro moles per liter (mcmol/L) | Standard Error 46.2353 |
| Maralixibat 140 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Fasting Serum Bile Acid (sBA) Level | -40.358 Micro moles per liter (mcmol/L) | Standard Error 34.865 |
| Maralixibat 280 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Fasting Serum Bile Acid (sBA) Level | -27.437 Micro moles per liter (mcmol/L) | Standard Error 46.2823 |
| Placebo | Change From Baseline to Endpoint (Week 13/Early Termination) in Fasting Serum Bile Acid (sBA) Level | -10.442 Micro moles per liter (mcmol/L) | Standard Error 32.6776 |
Secondary
Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels
Liver enzyme levels of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase and gamma glutamyl transferase were reported here.
Time frame: Baseline, Week 13/Early Termination
Population: mITT population included all participants randomly assigned to study treatment, receiving at least 1 dose of treatment, and having at least 1 post baseline observer itch reported outcome (ItchRO\[Obs\]) average daily score.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Maralixibat 70 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Alanine Aminotransferase | 14.616 Unit per liter (U/L) | Standard Error 17.9442 |
| Maralixibat 70 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Aspartate Aminotransferase | 20.241 Unit per liter (U/L) | Standard Error 16.8467 |
| Maralixibat 70 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Alkaline Phosphatase | 46.276 Unit per liter (U/L) | Standard Error 38.9056 |
| Maralixibat 70 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Gamma Glutamyl Transferase | -48.124 Unit per liter (U/L) | Standard Error 46.2867 |
| Maralixibat 140 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Alkaline Phosphatase | -9.570 Unit per liter (U/L) | Standard Error 30.8065 |
| Maralixibat 140 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Alanine Aminotransferase | 13.236 Unit per liter (U/L) | Standard Error 14.9424 |
| Maralixibat 140 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Gamma Glutamyl Transferase | 48.053 Unit per liter (U/L) | Standard Error 36.1507 |
| Maralixibat 140 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Aspartate Aminotransferase | 11.851 Unit per liter (U/L) | Standard Error 13.9367 |
| Maralixibat 280 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Alkaline Phosphatase | -3.280 Unit per liter (U/L) | Standard Error 42.1582 |
| Maralixibat 280 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Aspartate Aminotransferase | 16.539 Unit per liter (U/L) | Standard Error 18.3472 |
| Maralixibat 280 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Alanine Aminotransferase | 29.539 Unit per liter (U/L) | Standard Error 19.6083 |
| Maralixibat 280 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Gamma Glutamyl Transferase | -10.937 Unit per liter (U/L) | Standard Error 48.8614 |
| Placebo | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Alkaline Phosphatase | 32.502 Unit per liter (U/L) | Standard Error 29.9885 |
| Placebo | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Alanine Aminotransferase | -11.928 Unit per liter (U/L) | Standard Error 13.9736 |
| Placebo | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Gamma Glutamyl Transferase | -37.757 Unit per liter (U/L) | Standard Error 34.7766 |
| Placebo | Change From Baseline to Endpoint (Week 13/Early Termination) in Liver Enzyme Levels | Aspartate Aminotransferase | -3.691 Unit per liter (U/L) | Standard Error 13.0114 |
Secondary
Change From Baseline to Endpoint (Week 13/Early Termination) in Total and Direct Bilirubin Concentrations
Liver enzyme levels of total bilirubin and direct bilirubin were reported here.
Time frame: Baseline, Week 13/Early Termination
Population: mITT population included all participants randomly assigned to study treatment, receiving at least 1 dose of treatment, and having at least 1 post baseline observer itch reported outcome (ItchRO\[Obs\]) average daily score.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Maralixibat 70 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Total and Direct Bilirubin Concentrations | Total Bilirubin | -0.291 Milligrams per deciliter (mg/dL) | Standard Error 0.3777 |
| Maralixibat 70 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Total and Direct Bilirubin Concentrations | Direct Bilirubin | -0.333 Milligrams per deciliter (mg/dL) | Standard Error 0.2086 |
| Maralixibat 140 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Total and Direct Bilirubin Concentrations | Direct Bilirubin | -0.305 Milligrams per deciliter (mg/dL) | Standard Error 0.1672 |
| Maralixibat 140 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Total and Direct Bilirubin Concentrations | Total Bilirubin | -0.353 Milligrams per deciliter (mg/dL) | Standard Error 0.3014 |
| Maralixibat 280 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Total and Direct Bilirubin Concentrations | Total Bilirubin | -0.804 Milligrams per deciliter (mg/dL) | Standard Error 0.4021 |
| Maralixibat 280 mcg/kg/Day | Change From Baseline to Endpoint (Week 13/Early Termination) in Total and Direct Bilirubin Concentrations | Direct Bilirubin | -0.508 Milligrams per deciliter (mg/dL) | Standard Error 0.2243 |
| Placebo | Change From Baseline to Endpoint (Week 13/Early Termination) in Total and Direct Bilirubin Concentrations | Total Bilirubin | 0.104 Milligrams per deciliter (mg/dL) | Standard Error 0.2847 |
| Placebo | Change From Baseline to Endpoint (Week 13/Early Termination) in Total and Direct Bilirubin Concentrations | Direct Bilirubin | 0.011 Milligrams per deciliter (mg/dL) | Standard Error 0.1591 |
Other Pre-specified
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
An AE was any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life -threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.TEAEs were defined as AEs/SAEs that started or worsened after the study drug treatment.
Time frame: From the start of study drug administration up to Week 17
Population: The Safety Population included all participants who were randomly assigned to study treatment and received at least one dose of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Maralixibat 70 mcg/kg/Day | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAE | 1 Participants |
| Maralixibat 70 mcg/kg/Day | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Serious TEAE | 0 Participants |
| Maralixibat 140 mcg/kg/Day | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Serious TEAE | 1 Participants |
| Maralixibat 140 mcg/kg/Day | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAE | 7 Participants |
| Maralixibat 280 mcg/kg/Day | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Serious TEAE | 0 Participants |
| Maralixibat 280 mcg/kg/Day | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAE | 9 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAE | 5 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Serious TEAE | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Serious TEAE | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | TEAE | 12 Participants |