Alagille Syndrome
Conditions
Brief summary
This is a multicentre, extension study of LUM001 in children diagnosed with Alagille Syndrome who have completed participation in a core LUM001 treatment protocol. The primary objective is to evaluate long-term safety and tolerability of LUM001. Efficacy will be assessed by evaluating the effect of LUM001 on the biochemical markers and pruritus associated with Alagille Syndrome.
Interventions
Dosing of LUM001 also known as Maralixibat (MRX) with the objective of achieving optimal control of pruritus at a dose level that is tolerated by the participant and up to a maximum daily dose of 280 micrograms per kilogram (mcg/kg).
Sponsors
Lumena Pharmaceuticals, Inc.
Childhood Liver Disease Research and Education Network
Mirum Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, 12 months to 18 years of age. 2. Competent to provide informed consent and assent (per institutional review board/Ethics Committee \[IRB/EC\]), as appropriate. 3. Completed participation in the LUM001-301 protocol. 4. Females of childbearing potential must have a negative urine pregnancy test \[beta human chorionic gonadotropin (beta-hCG)\] at the Baseline Visit. 5. Sexually active females must be prepared to use an effective method of contraception during the trial. Effective methods of contraception are considered to be: 1. Hormonal (for example, contraceptive pill, patch, intramuscular implant or injection); or 2. Barrier method, for example, (a) condom with spermicide, or (b) diaphragm, with spermicide; or 3. Intrauterine device (IUD). 6. Participants above the age of assent and caregivers and children must be able to read and understand English or Spanish. 7. Caregivers (and age appropriate participants) must have access to phone for scheduled calls from study site. 8. Caregivers (and age appropriate participants) must be willing and able to complete a daily electronic diary (ItchRO) during the first consecutive 12 weeks of the study and then for 4 consecutive weeks following the Week 24 and Week 44 visits. 9. Caregivers (and age appropriate participants) must digitally accept the licensing agreement in the ItchRO electronic diary software at the outset of the study. 10. Eligible participants must be able to adhere to local Ethics Committee or Institutional Review Board (IRB) blood volume limits for laboratory testing. 11. The participant has completed the protocol either through Week 144, or the End of Trial visit, or has received permission from the sponsor and the Premier Medical monitor to re-enter the study in the long-term, optional follow-up treatment period 2. 12. Females of child-bearing potential must have a negative urine or serum pregnancy test (beta-HCG\]) at the time of entry into the long-term optional follow-up treatment period 2. 13. Male and female participants of child-bearing potential who are sexually active, or are not currently sexually active, but become sexually active during the study or for 30 days following the last dose of study drug, must agree to use acceptable contraception during the study. 14. Informed consent and assent (per IRB/EC) as appropriate. 15. Caregivers (and age appropriate participants) must have access to phone for scheduled calls from study site. 16. Caregivers (and age appropriate participants) must be willing to follow the rules of eDiary completion.
Exclusion criteria
1. Experienced an adverse event or serious adverse event (SAE) related to the study drug during the LUM001-301 protocol that led to the discontinuation of the participant from the core study. 2. Any conditions or abnormalities (including laboratory abnormalities) which in the opinion of the Investigator, Medical Monitor or ChiLDReN Protocol Chair, may compromise the safety of the participant, or interfere with the participant participating in or completing the study. 3. History or known presence of gallstones or kidney stones. 4. History of non-adherence during the participant's participation in the LUM001-301 protocol. Non-adherence is defined by dosing compliance (dosing compliance is calculated by \[the total number of doses that were actually taken by the participant\] divided by \[the total number of doses that should have been taken by the participant\] multiplied by 100) of less than 80% in the LUM001-301 protocol. 5. Unlikely to comply with the study protocol, or unsuitable for any other reason, as judged by the investigator. 6. All above
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From MRX Baseline to Week 48 in Fasting Serum Bile Acid (sBA) | Baseline to Week 48 | This primacy efficacy endpoint is the mean change from MRX baseline to week 48 in fasting sBA levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 218 in Pruritus | Baseline to Week 218 | This secondary efficacy endpoint is the mean change from MRX baseline over time to week 218 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). Results reported here are the long-term results. |
| Change From Baseline to Week 216 in Alanine Aminotransferase | Baseline to week 216 | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALT levels. |
| Change From Baseline to End of Treatment in Alkaline Phosphatase | Baseline to Week 216 | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALP levels. |
| Change From MRX Baseline to Week 216 in Aspartate Aminotransferase | Baseline to week 216 | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in AST levels. |
| Change From MRX Baseline to Week 216 in Fasting Serum Bile Acid (sBA) | Baseline to week 216 | The secondary endpoint of this study was the mean change from MRX baseline to week 216 fasting in sBA levels. |
| Change From Baseline to Week 216/LOFC Clinician Scratch Scale (CSS) Score | Baseline to Week 216 | This secondary efficacy endpoint is the mean change from MRX baseline over time to week 216/LOCF in pruritus as measured by the Clinician Scratch Scale (CSS). The Clinician Scratch Scale uses a 5-point scale, where 0 = none; 1 = rubbing or mild scratching when undistracted; 2 = active scratching without evident skin abrasions; 3 = abrasion evident; 4 = cutaneous mutilation, haemorrhage and scarring evident. |
| Change From MRX Baseline to Week 216 in Gamma Glutamyltransferase | Baseline to Week 216 | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in GGT. |
| Mean Change From MRX Baseline to Week 216 in Total Bilirubin | Baseline to week 216 | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in total bilirubin. |
| Mean Change From MRX Baseline to Week 216 in Direct Bilirubin | Baseline to week 216 | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in direct bilirubin. |
| Change From MRX Baseline to Week 216 in Clinician Xanthoma Severity Score | Baseline to week 216 | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Core Study Period Participant received LUM001 also known as Maralixibat (MRX) administered orally once per day. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Long Term Follow-up Treatment | Adverse Event | 3 |
| Long Term Follow-up Treatment | Non-Compliance with study drug | 1 |
| Long Term Follow-up Treatment | Progressive Disease | 2 |
| Week 48 | Adverse Event | 4 |
| Week 48 | Did not consent to Protocol Amendment 4 | 2 |
| Week 48 | Withdrawal by caregiver | 2 |
Baseline characteristics
| Characteristic | Core Study Period |
|---|---|
| Age, Continuous | 7 years of age STANDARD_DEVIATION 4.55 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Region of Enrollment Canada | 4 participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 34 |
| other Total, other adverse events | 34 / 34 |
| serious Total, serious adverse events | 6 / 34 |
Outcome results
Primary
Change From MRX Baseline to Week 48 in Fasting Serum Bile Acid (sBA)
This primacy efficacy endpoint is the mean change from MRX baseline to week 48 in fasting sBA levels.
Time frame: Baseline to Week 48
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Change From MRX Baseline to Week 48 in Fasting Serum Bile Acid (sBA) | 223.62 μmol/L | Standard Deviation 205.041 |
| Maralixibat Week 48 Values | Change From MRX Baseline to Week 48 in Fasting Serum Bile Acid (sBA) | 157.35 μmol/L | Standard Deviation 178.538 |
p-value: 0.115795% CI: [-64.72, 7.54]Student's t-test
Secondary
Change From Baseline to End of Treatment in Alkaline Phosphatase
This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALP levels.
Time frame: Baseline to Week 216
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Change From Baseline to End of Treatment in Alkaline Phosphatase | 598.8 U/L | Standard Deviation 199.89 |
| Maralixibat Week 48 Values | Change From Baseline to End of Treatment in Alkaline Phosphatase | 528.3 U/L | Standard Deviation 221.93 |
p-value: 0.13495% CI: [-341.6, 58.4]Student's t-test
Secondary
Change From Baseline to Week 216 in Alanine Aminotransferase
This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALT levels.
Time frame: Baseline to week 216
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Change From Baseline to Week 216 in Alanine Aminotransferase | 152.9 U/L | Standard Deviation 82.26 |
| Maralixibat Week 48 Values | Change From Baseline to Week 216 in Alanine Aminotransferase | 222.4 U/L | Standard Deviation 126.53 |
p-value: 0.260795% CI: [-54.4, 166.4]Student's t-test
Secondary
Change From Baseline to Week 216/LOFC Clinician Scratch Scale (CSS) Score
This secondary efficacy endpoint is the mean change from MRX baseline over time to week 216/LOCF in pruritus as measured by the Clinician Scratch Scale (CSS). The Clinician Scratch Scale uses a 5-point scale, where 0 = none; 1 = rubbing or mild scratching when undistracted; 2 = active scratching without evident skin abrasions; 3 = abrasion evident; 4 = cutaneous mutilation, haemorrhage and scarring evident.
Time frame: Baseline to Week 216
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Change From Baseline to Week 216/LOFC Clinician Scratch Scale (CSS) Score | 2.9 Points | Standard Deviation 1.08 |
| Maralixibat Week 48 Values | Change From Baseline to Week 216/LOFC Clinician Scratch Scale (CSS) Score | 1.1 Points | Standard Deviation 1.07 |
p-value: 0.016795% CI: [-3, -0.4]Student's t-test
Secondary
Change From Baseline to Week 218 in Pruritus
This secondary efficacy endpoint is the mean change from MRX baseline over time to week 218 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). Results reported here are the long-term results.
Time frame: Baseline to Week 218
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Change From Baseline to Week 218 in Pruritus | 2.533 score on a scale | Standard Deviation 0.8423 |
| Maralixibat Week 48 Values | Change From Baseline to Week 218 in Pruritus | 0.429 score on a scale | Standard Deviation 0.8571 |
p-value: 0.00595% CI: [-3.101, -1.606]Student's t-test
Secondary
Change From MRX Baseline to Week 216 in Aspartate Aminotransferase
This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in AST levels.
Time frame: Baseline to week 216
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Change From MRX Baseline to Week 216 in Aspartate Aminotransferase | 149.7 U/L | Standard Deviation 88.27 |
| Maralixibat Week 48 Values | Change From MRX Baseline to Week 216 in Aspartate Aminotransferase | 231.4 U/L | Standard Deviation 122.26 |
p-value: 0.147495% CI: [-22.4, 117.6]Student's t-test
Secondary
Change From MRX Baseline to Week 216 in Clinician Xanthoma Severity Score
This secondary efficacy endpoint is the mean change from MRX baseline to week 216 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.
Time frame: Baseline to week 216
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Change From MRX Baseline to Week 216 in Clinician Xanthoma Severity Score | 0.9 Points | Standard Deviation 1.33 |
| Maralixibat Week 48 Values | Change From MRX Baseline to Week 216 in Clinician Xanthoma Severity Score | 1.1 Points | Standard Deviation 1.68 |
p-value: 195% CI: [-0.5, 0.5]Student's t-test
Secondary
Change From MRX Baseline to Week 216 in Fasting Serum Bile Acid (sBA)
The secondary endpoint of this study was the mean change from MRX baseline to week 216 fasting in sBA levels.
Time frame: Baseline to week 216
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Change From MRX Baseline to Week 216 in Fasting Serum Bile Acid (sBA) | 223.62 μmol/L | Standard Deviation 205.041 |
| Maralixibat Week 48 Values | Change From MRX Baseline to Week 216 in Fasting Serum Bile Acid (sBA) | 118.81 μmol/L | Standard Deviation 126.878 |
p-value: 0.146995% CI: [-109.48, 19.19]Student's t-test
Secondary
Change From MRX Baseline to Week 216 in Gamma Glutamyltransferase
This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in GGT.
Time frame: Baseline to Week 216
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Change From MRX Baseline to Week 216 in Gamma Glutamyltransferase | 493.5 U/L | Standard Deviation 380.29 |
| Maralixibat Week 48 Values | Change From MRX Baseline to Week 216 in Gamma Glutamyltransferase | 431 U/L | Standard Deviation 235.35 |
p-value: 0.910895% CI: [-216.6, 238.3]Student's t-test
Secondary
Mean Change From MRX Baseline to Week 216 in Direct Bilirubin
This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in direct bilirubin.
Time frame: Baseline to week 216
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Mean Change From MRX Baseline to Week 216 in Direct Bilirubin | 3.541 mg/dL | Standard Deviation 3.6433 |
| Maralixibat Week 48 Values | Mean Change From MRX Baseline to Week 216 in Direct Bilirubin | 3.714 mg/dL | Standard Deviation 3.8369 |
p-value: 0.092795% CI: [-2.098, 0.212]Student's t-test
Secondary
Mean Change From MRX Baseline to Week 216 in Total Bilirubin
This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in total bilirubin.
Time frame: Baseline to week 216
Population: Since most participants escalated to MRX 280 ug/kg/day, the summary is presented as a single arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MRX Baseline Value | Mean Change From MRX Baseline to Week 216 in Total Bilirubin | 5.62 mg/dL | Standard Deviation 6.42 |
| Maralixibat Week 48 Values | Mean Change From MRX Baseline to Week 216 in Total Bilirubin | 5.39 mg/dL | Standard Deviation 5.181 |
p-value: 0.120795% CI: [-3.03, 0.45]Student's t-test