Alagille Syndrome
Conditions
Brief summary
The study is a randomized, double-blind, placebo-controlled study to evaluate the safety and tolerability of LUM001. Efficacy will be assessed by evaluating the effect of LUM001 versus placebo on the biochemical markers and pruritus associated with Alagille Syndrome.
Interventions
DRUGLUM001
DRUGPlacebo
Sponsors
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 Week 13 (End of Treatment) in Fasting Serum Bile Acid Level | Baseline to 13 weeks or end of treatment | Participants were required to fast for at least 4 hours; only water was permitted prior to collection. A negative change from baseline indicates that the level of bile acid decreased. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | Baseline to 13 weeks or end of treatment | Analysis of liver enzymes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). A negative change from baseline indicates that the level of that enzyme decreased. |
| Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores | Baseline to 13 weeks or end of treatment | The ItchRO was administered as a twice daily electronic diary (eDiary). Children ≥9 years of age completed the patient ItchRO; those between the ages of 5 and 8 completed the patient ItchRO with the assistance of their caregiver. There was no patient report for subjects under the age of 5. ItchRO scores range from 0 to 4, with the higher score indicating increasing itch severity. ItchRO average daily scores were calculated as the sum of daily scores (ie, the maximum of morning and evening scores) divided by the number of days. The average daily score was calculated by using the 7 days pre-treatment for baseline, and the last 7 days of treatment for Week 13. A negative change from Baseline indicates that itch severity decreased. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LUM001 140ug/kg/Day Participants received an escalating dose of LUM001 over 3 to 5 weeks, from 14ug/kg/day to 140ug/kg/day, then received 8 to 10 weeks of treatment at either 140ug/kg/day or the highest tolerated dose below 140ug/kg/day. Participants were then followed for 4 weeks after treatment. | 6 |
| LUM001 280ug/kg/Day Participants received an escalating dose of LUM001 over 3 to 5 weeks, from 14ug/kg/day to 280ug/kg/day, then received 8 to 10 weeks of treatment at either 280ug/kg/day or the highest tolerated dose below 280ug/kg/day. Participants were then followed for 4 weeks after treatment. | 8 |
| Placebo Cohort A Participants received LUM001-matching placebo for up to 13 weeks, then were followed for 4 weeks after treatment. | 3 |
| Placebo Cohort B Participants received LUM001-matching placebo for up to 13 weeks, then were followed for 4 weeks after treatment. | 3 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo Cohort B | LUM001 140ug/kg/Day | Placebo Cohort A | LUM001 280ug/kg/Day |
|---|---|---|---|---|---|
| Age, Continuous | 5.9 years STANDARD_DEVIATION 4.93 | 4.3 years STANDARD_DEVIATION 3.21 | 5.8 years STANDARD_DEVIATION 4.49 | 5.0 years STANDARD_DEVIATION 2 | 6.8 years STANDARD_DEVIATION 6.73 |
| Age, Customized 13 to 18 years | 3 participants | 0 participants | 0 participants | 0 participants | 3 participants |
| Age, Customized 2 to 4 years | 7 participants | 2 participants | 3 participants | 1 participants | 1 participants |
| Age, Customized < 2 years | 3 participants | 0 participants | 0 participants | 0 participants | 3 participants |
| Age, Customized 5 to 8 years | 5 participants | 1 participants | 1 participants | 2 participants | 1 participants |
| Age, Customized 9 to 12 years | 2 participants | 0 participants | 2 participants | 0 participants | 0 participants |
| Region of Enrollment United Kingdom | 20 participants | 3 participants | 6 participants | 3 participants | 8 participants |
| Sex: Female, Male Female | 10 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 10 Participants | 1 Participants | 4 Participants | 0 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 7 / 8 | 4 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 8 | 0 / 6 |
Outcome results
Primary
Change From Baseline to Week 13 (End of Treatment) in Fasting Serum Bile Acid Level
Participants were required to fast for at least 4 hours; only water was permitted prior to collection. A negative change from baseline indicates that the level of bile acid decreased.
Time frame: Baseline to 13 weeks or end of treatment
Population: The modified Intent-to-Treat (mITT) population, defined as all participants in the Safety population who had at least 1 post-baseline efficacy assessment. The Safety population was defined as all participants who were randomly assigned to study treatment and who received any amount of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LUM001 140ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Fasting Serum Bile Acid Level | -82.864 umol/L | Standard Error 50.1513 |
| LUM001 280ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Fasting Serum Bile Acid Level | -49.388 umol/L | Standard Error 43.4732 |
| LUM001 Overall | Change From Baseline to Week 13 (End of Treatment) in Fasting Serum Bile Acid Level | -66.126 umol/L | Standard Error 33.1208 |
| Placebo Overall | Change From Baseline to Week 13 (End of Treatment) in Fasting Serum Bile Acid Level | -42.157 umol/L | Standard Error 50.0903 |
Comparison: Analysis of LUM001 140ug/kg/dayp-value: 0.57495% CI: [-191.679, 110.265]ANCOVA
Comparison: Analysis of LUM001 280ug/kg/dayp-value: 0.914795% CI: [-148.726, 134.264]ANCOVA
Comparison: Analysis of all doses of LUM001p-value: 0.695495% CI: [-151.969, 104.031]ANCOVA
Secondary
Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes
Analysis of liver enzymes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). A negative change from baseline indicates that the level of that enzyme decreased.
Time frame: Baseline to 13 weeks or end of treatment
Population: The mITT population, defined as all participants in the Safety population who had at least 1 post-baseline efficacy assessment. The Safety population was defined as all participants who were randomly assigned to study treatment and who received any amount of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LUM001 140ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | ALT | 59.3 U/L | Standard Error 20.99 |
| LUM001 140ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | ALP | 71.4 U/L | Standard Error 53.35 |
| LUM001 140ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | AST | 37.2 U/L | Standard Error 13.64 |
| LUM001 280ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | ALT | 10.5 U/L | Standard Error 18.06 |
| LUM001 280ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | ALP | 31.6 U/L | Standard Error 43.59 |
| LUM001 280ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | AST | -2.7 U/L | Standard Error 11.7 |
| LUM001 Overall | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | AST | 17.3 U/L | Standard Error 8.98 |
| LUM001 Overall | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | ALT | 34.9 U/L | Standard Error 13.86 |
| LUM001 Overall | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | ALP | 51.5 U/L | Standard Error 36.13 |
| Placebo Overall | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | ALT | 2.7 U/L | Standard Error 21.06 |
| Placebo Overall | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | ALP | 19.7 U/L | Standard Error 60.76 |
| Placebo Overall | Change From Baseline to Week 13 (End of Treatment) in Liver Enzymes | AST | 13.2 U/L | Standard Error 13.63 |
Comparison: Analysis of LUM001 140ug/kg/day for ALTp-value: 0.078395% CI: [-7.2, 120.6]ANCOVA
Comparison: Analysis of LUM001 280ug/kg/day for ALTp-value: 0.782795% CI: [-51.4, 67]ANCOVA
Comparison: Analysis of all doses of LUM001 for ALTp-value: 0.223595% CI: [-21.9, 86.3]ANCOVA
Comparison: Analysis of LUM001 140ug/kg/day for ASTp-value: 0.237295% CI: [-17.5, 65.5]ANCOVA
Comparison: Analysis of LUM001 280ug/kg/day for ASTp-value: 0.391495% CI: [-54.1, 22.4]ANCOVA
Comparison: Analysis of all doses of LUM001 for ASTp-value: 0.808195% CI: [-31, 39.1]ANCOVA
Comparison: Analysis of LUM001 140ug/kg/day for ALPp-value: 0.574895% CI: [-140.3, 243.7]ANCOVA
Comparison: Analysis of LUM001 280ug/kg/day for ALPp-value: 0.883595% CI: [-158.4, 182.2]ANCOVA
Comparison: Analysis of all doses of LUM001 for ALPp-value: 0.691795% CI: [-135.8, 199.4]ANCOVA
Secondary
Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores
The ItchRO was administered as a twice daily electronic diary (eDiary). Children ≥9 years of age completed the patient ItchRO; those between the ages of 5 and 8 completed the patient ItchRO with the assistance of their caregiver. There was no patient report for subjects under the age of 5. ItchRO scores range from 0 to 4, with the higher score indicating increasing itch severity. ItchRO average daily scores were calculated as the sum of daily scores (ie, the maximum of morning and evening scores) divided by the number of days. The average daily score was calculated by using the 7 days pre-treatment for baseline, and the last 7 days of treatment for Week 13. A negative change from Baseline indicates that itch severity decreased.
Time frame: Baseline to 13 weeks or end of treatment
Population: The mITT population, defined as all participants in the Safety population who had at least 1 post-baseline efficacy assessment. The Safety population was defined as all participants who were randomly assigned to study treatment and who received any amount of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LUM001 140ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores | Observer ItchRO | -0.802 units on a scale | Standard Error 0.2732 |
| LUM001 140ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores | Patient ItchRO | -1.159 units on a scale | Standard Error 0.5396 |
| LUM001 280ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores | Observer ItchRO | -0.419 units on a scale | Standard Error 0.2318 |
| LUM001 280ug/kg/Day | Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores | Patient ItchRO | -0.608 units on a scale | Standard Error 0.4399 |
| LUM001 Overall | Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores | Patient ItchRO | -0.883 units on a scale | Standard Error 0.3484 |
| LUM001 Overall | Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores | Observer ItchRO | -0.610 units on a scale | Standard Error 0.1776 |
| Placebo Overall | Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores | Observer ItchRO | -0.592 units on a scale | Standard Error 0.269 |
| Placebo Overall | Change From Baseline to Week 13 (End of Treatment) in Pruritus as Measured by The Patient And Observer Itch Reported Outcome (ItchRO) Average Daily Scores | Patient ItchRO | -0.811 units on a scale | Standard Error 0.5684 |
Comparison: Analysis of LUM001 140ug/kg/day for Patient ItchROp-value: 0.690795% CI: [-2.468, 1.772]ANCOVA
Comparison: Analysis of LUM001 280ug/kg/day for Patient ItchROp-value: 0.789795% CI: [-1.647, 2.052]ANCOVA
Comparison: Analysis of all doses of LUM001 for Patient ItchROp-value: 0.920395% CI: [-1.85, 1.705]ANCOVA
Comparison: Analysis of LUM001 140ug/kg/day for Observer ItchROp-value: 0.596695% CI: [-1.038, 0.618]ANCOVA
Comparison: Analysis of LUM001 280ug/kg/day for Observer ItchROp-value: 0.63295% CI: [-0.58, 0.926]ANCOVA
Comparison: Analysis of all doses of LUM001 for Observer ItchROp-value: 0.954795% CI: [-0.71, 0.673]ANCOVA