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Trial record 2 of 13 for:    Alagille Syndrome

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 : Active, not recruiting
First Posted : June 11, 2014
Last Update Posted : September 21, 2018
Sponsor:
Information provided by (Responsible Party):
Shire

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.

Condition or disease Intervention/treatment Phase
Alagille Syndrome Drug: LUM001 Drug: Placebo Phase 2

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
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
Official Title: 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
Actual Study Start Date : October 28, 2014
Estimated Primary Completion Date : June 28, 2019
Estimated Study Completion Date : June 28, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Drug: LUM001
LUM001 will be administered orally Once Daily (OD). To be administered Twice Daily (BID) for patients who are eligible.

Placebo Comparator: Placebo
Placebo will be administered orally once a day during randomized withdrawal period (Week 19 to Week 22)
Drug: Placebo
Placebo will be administered orally once daily during randomized withdrawal period




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.


Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   12 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02160782


Locations
Australia, New South Wales
Children's Hospital Westmead
Westmead, New South Wales, Australia, 2145
Australia, Victoria
The Royal Children's Hospital Melbourne
Parkville, Victoria, Australia, 3052
Belgium
Cliniques Universitaires Saint-Luc
Brussels, Belgium
France
Hopital Femme Mere Enfant De Lyon
Bron, France, 69677
Hopital Necker-Enfants Malades
Paris, France, 75015
Hopital Kremlin Bicetre
Paris, France, 94275
Poland
The Children's Memorial Health Institute
Warsaw, Poland, 04-730
Spain
Hospital Universitario La Paz- Hospital Materno Infantil
Madrid, Spain, 261
United Kingdom
Paediatric Liver Center, Kings College Hospital
London, United Kingdom, SE5 9RS
Sponsors and Collaborators
Shire
Investigators
Study Director: Study Director Shire

Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT02160782     History of Changes
Other Study ID Numbers: LUM001-304
2013-005373-43 ( EudraCT Number )
First Posted: June 11, 2014    Key Record Dates
Last Update Posted: September 21, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Syndrome
Alagille Syndrome
Substance Withdrawal Syndrome
Disease
Pathologic Processes
Cholestasis, Intrahepatic
Cholestasis
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Liver Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders