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Safety and Efficacy Study of LUM001 With a Drug Withdrawal Period in Participants With Alagille Syndrome (ALGS) (ICONIC)

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ClinicalTrials.gov Identifier: NCT02160782
Recruitment Status : Completed
First Posted : June 11, 2014
Last Update Posted : June 19, 2020
Sponsor:
Information provided by (Responsible Party):
Mirum Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE June 9, 2014
First Posted Date  ICMJE June 11, 2014
Last Update Posted Date June 19, 2020
Actual Study Start Date  ICMJE October 28, 2014
Actual Primary Completion Date May 28, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 19, 2018)
  • Mean Change From Week 18 to Week 22 of Fasting Serum Bile Acid Levels [ Time Frame: Week 18, Week 22 ]
    Mean change from Week 18 to Week 22 of fasting serum bile acid levels in participants who previously responded to LUM001 treatment will be assessed.
  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From start of study drug administration up to 98 weeks ]
    An adverse event (AE) is 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 is considered related to the investigational drug product.
Original Primary Outcome Measures  ICMJE
 (submitted: June 9, 2014)
Efficacy [ Time Frame: 4 weeks ]
Mean change in serum bile acid levels from week 18 to week 22
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2018)
  • Change From Week 18 to Week 22 in Liver Enzymes [ Time Frame: Week 18, Week 22 ]
    Change from Week 18 to Week 22 in liver enzymes (alkaline phosphatase [ALP], alanine aminotransferase [ALT], and bilirubin [total and direct]) will be assessed.
  • Mean Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO [ Time Frame: Week 18, Week 22 ]
    Pruritus will be assessed using the Itch caregiver (for participants between the ages of 5 and 8 years) and patient (participants of greater than or equal to [>=] 9 years of age) reported outcome measures (ItchRO) administered as a twice daily electronic diary. Both the morning and evening ItchRO reports have a minimum score of 0 and a maximum score of 4, with 4 representing more severe itching. The highest score between the morning and evening reports will represent the daily score.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 9, 2014)
Efficacy [ Time Frame: 4 weeks ]
Change in liver enzymes and pruritus from week 18 to week 22
Current Other Pre-specified Outcome Measures
 (submitted: September 19, 2018)
  • Change From Baseline in Fasting Serum Bile Acid Levels [ Time Frame: Week 18, 22, 48 and thereafter every 12 weeks until Week 96 ]
    Change from baseline in fasting serum bile acid levels will be assessed.
  • Change From Baseline in Liver Enzymes [ Time Frame: Week 18, 22, 48 and thereafter every 12 weeks until Week 96 ]
    Change from baseline in liver enzymes (ALT, ALP) and bilirubin (total and direct) will be assessed.
  • Change From Baseline in Pruritus as Measured by ItchRO [ Time Frame: Week 18, 22, 48 and thereafter every 12 weeks until Week 96 ]
    Pruritus will be assessed using the Itch caregiver (for participants between the ages of 5 and 8 years) and patient (participants of greater than or equal to [>=] 9 years of age) reported outcome measures (ItchRO) administered as a twice daily electronic diary. Both the morning and evening ItchRO reports have a minimum score of 0 and a maximum score of 4, with 4 representing more severe itching. The highest score between the morning and evening reports will represent the daily score.
  • Change From Baseline in Biochemical Markers of Cholestasis [ Time Frame: Week 18, 22, 48 and thereafter every 12 weeks until Week 96 ]
    Change from baseline in biochemical markers of cholestasis (total cholesterol, low-density lipoprotein cholesterol [LDL-C]) will be assessed.
  • Change From Baseline in Bile Acid Synthesis [ Time Frame: Week 18, 22, 48 and thereafter every 12 weeks until Week 96 ]
    Change from baseline in bile acid synthesis (serum 7 alpha-hydroxy-4-cholesten-3-one [7alphaC4]) will be assessed.
  • Pruritus Respose Rate as Measured by Observer ItchRO/Patient ItchRO [ Time Frame: Weeks 18, 48, 60, 72, 84, 96 and 100 ]
    Pruritus will be assessed using the Itch caregiver (for participants between the ages of 5 and 8 years) and patient (participants of greater than or equal to [>=] 9 years of age) reported outcome measures (ItchRO) administered as a twice daily electronic diary. Both the morning and evening ItchRO reports have a minimum score of 0 and a maximum score of 4, with 4 representing more severe itching. The highest score between the morning and evening reports will represent the daily score.
  • Pruritus Response Rate as Measured by Clinician Scratch Scale [ Time Frame: Weeks 18, 48, 60, 72, 84, 96 and 100 ]
    The clinician's assessment of the participant's pruritus is focused on scratching and visible damage to the skin as a result of scratching as observed by the physician. The clinician scratch scale uses a 5-point scale, in which 0 designates no evidence of scratching and 4 designates cutaneous mutilation with bleeding, hemorrhage and scarring.
  • Change From Baseline in Quality of Life as Measured by Pediatric Quality of Life Scale (PedsQL) [ Time Frame: Baseline, Weeks 18, 22, 48, 60, 72, 84, 96, and 100 ]
    PedsQL Generic Cores Scale is composed of 23 items to assess pediatric health related quality of life (HRQoL) measurements across 4 domains: Physical functioning (8 items), emotional functioning (5 item s). Each item consists of a 5-level Likert item survey: 0= if it is never a problem - 4=if it is almost always a problem.
  • Change From Week 18 to Week 22 in Quality of Life as Measured by Pediatric Quality of Life Scale (PedsQL) [ Time Frame: Week 18, Week 22 ]
    PedsQL Generic Cores Scale is composed of 23 items to assess pediatric health related quality of life (HRQoL) measurements across 4 domains: Physical functioning (8 items), emotional functioning (5 item s). Each item consists of a 5-level Likert item survey: 0= if it is never a problem - 4=if it is almost always a problem.
  • Change From Baseline in Patient Impression of Change (PIC) Scale [ Time Frame: Baseline, Weeks 18, 22, 48, 84, 96, and 100 ]
    PIC is designed to assess the participant's perception of his/her itching at the end of study drug treatment compared to his/her itching prior to the start of treatment with study drug. The questionnaire is designed for self-administration and uses a 7-point scale in which 1 designates the best outcome and 7 designate the worst outcome.
  • Change From Week 18 to Week 22 in Patient Impression of Change (PIC) Scale [ Time Frame: Week 18, Week 22 ]
    PIC is designed to assess the participant's perception of his/her itching at the end of study drug treatment compared to his/her itching prior to the start of treatment with study drug. The questionnaire is designed for self-administration and uses a 7-point scale in which 1 designates the best outcome and 7 designate the worst outcome.
  • Change From Baseline in Caregiver Impression of Change (CIC) Scale [ Time Frame: Baseline, Weeks 18, 22, 48, 84, 96, and 100 ]
    CIC is designed to assess the caregiver's perception of the participant's itch related symptoms and xanthoma severity after various points of study drug treatment compared to his/her itch related symptoms and xanthoma severity prior to the start of treatment with study drug. The questionnaire is designed for self-administration and uses a 7-point scale in which 1 designates the best outcome and 7 designates the worst outcome.
  • Change From Week 18, Week 22 in Caregiver Impression of Change (CIC) Scale [ Time Frame: Week 18, Week 22 ]
    CIC is designed to assess the caregiver's perception of the participant's itch related symptoms and xanthoma severity after various points of study drug treatment compared to his/her itch related symptoms and xanthoma severity prior to the start of treatment with study drug. The questionnaire is designed for self-administration and uses a 7-point scale in which 1 designates the best outcome and 7 designates the worst outcome.
  • Caregiver Global Therapeutic Benefit (CGTB) Assessment [ Time Frame: Weeks 18, 22, 48, 84, 96, and 100 ]
    CGTB questionnaire is designed to assess the caregiver's perception of the treatment benefits on the participant's itching compared to the side effects experienced with study drug. The questionnaire is designed for self-administration and uses a 5-point scale in which 1 designates the best outcome and 5 designates the worst outcome.
  • Change From Week 18, Week 22 in Caregiver Global Therapeutic Benefit (CGTB) Assessment [ Time Frame: Week 18, Week 22 ]
    CGTB questionnaire is designed to assess the caregiver's perception of the treatment benefits on the participant's itching compared to the side effects experienced with study drug. The questionnaire is designed for self-administration and uses a 5-point scale in which 1 designates the best outcome and 5 designates the worst outcome.
  • Change from Baseline in Xanthomas as Measured by Clinician Xanthoma Scale [ Time Frame: Baseline, Week 48 ]
    Clinician Xanthoma Scale is developed to assess xanthomas before and after surgical intervention in children with ALGS. The clinician xanthoma scale uses a 5-point scale that ranges from 0=None to 4=Disabling.
  • Assessment of Palatability [ Time Frame: From Week 12 up to approximately 100 weeks ]
    Palatability will be assessed using an age-dependent palatability questionnaire. Overall palatability will be scored on a scale of 1 through 5, with 1 being least palatable and 5 being most palatable and participants will be asked to describe the taste from a list of predefined descriptors.
Original Other Pre-specified Outcome Measures
 (submitted: June 9, 2014)
Safety and Tolerability [ Time Frame: 48 weeks ]
Evaluation of adverse events, changes in vital signs, laboratory and other safety parameters from baseline to week 48
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy Study of LUM001 With a Drug Withdrawal Period in Participants With Alagille Syndrome (ALGS)
Official Title  ICMJE Long-Term, Open-Label Study With a Double-Blind, Placebo-Controlled, Randomized Drug Withdrawal Period of LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in Patients With Alagille Syndrome
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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Open-label single arm study with a randomized placebo-controlled parallel group period
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Alagille Syndrome
Intervention  ICMJE
  • Drug: LUM001
    LUM001 will be administered orally Once Daily (OD). To be administered Twice Daily (BID) for patients who are eligible.
  • Drug: Placebo
    Placebo will be administered orally once daily during randomized withdrawal period
Study Arms  ICMJE
  • Experimental: LUM001
    LUM001 will be administered orally once a day (QD) up to 400 microgram per kilogram per day (mcg/kg/day) up to Week 52, followed by an increase in dose orally twice a day (BID) during long-term follow-up based on efficacy (serum bile acid [sBA] level and ItchRO[Obs] score) and safety assessment.
    Intervention: Drug: LUM001
  • Placebo Comparator: Placebo
    Placebo will be administered orally once a day during randomized withdrawal period (Week 19 to Week 22)
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 18, 2020)
31
Original Estimated Enrollment  ICMJE
 (submitted: June 9, 2014)
30
Actual Study Completion Date  ICMJE May 28, 2020
Actual Primary Completion Date May 28, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Exclusion Criteria for participants with LUM001 dosing interruption >=7 days:

- All exclusion criteria mentioned above apply upon entry into the long-term optional follow-up period, with the exception of participants weighing over 50 kg at screening.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Months to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   France,   Poland,   Spain,   United Kingdom
Removed Location Countries Canada,   Germany
 
Administrative Information
NCT Number  ICMJE NCT02160782
Other Study ID Numbers  ICMJE LUM001-304
2013-005373-43 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Mirum Pharmaceuticals, Inc.
Study Sponsor  ICMJE Mirum Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director Mirum
PRS Account Mirum Pharmaceuticals, Inc.
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP