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    Summary
    EudraCT Number:2014-005558-21
    Sponsor's Protocol Code Number:LUM001-401
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-01-06
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2014-005558-21
    A.3Full title of the trial
    A Pilot, Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of LUM001, an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTi), in Patients with Primary Sclerosing Cholangitis (PSC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase 2a trial to evaluate the safety and tolerability of LUM001 in subjects with Primary Sclerosing Cholangitis (PSC) during 14 weeks of treatment.
    A.3.2Name or abbreviated title of the trial where available
    CAMEO STUDY
    A.4.1Sponsor's protocol code numberLUM001-401
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02061540
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLumena Pharmaceuticals LLC
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLumena Pharmaceuticals LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLumena Pharmaceuticals LLC
    B.5.2Functional name of contact pointVP, Head Cholestatic Liver Disease
    B.5.3 Address:
    B.5.3.1Street Address12531 High Bluff Drive, Suite 110
    B.5.3.2Town/ citySan Diego, CA
    B.5.3.3Post code92130
    B.5.3.4CountryUnited States
    B.5.4Telephone number001858337 7922
    B.5.6E-mailcikennedy@shire.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1217
    D.3 Description of the IMP
    D.3.1Product nameLUM001
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLUM001
    D.3.9.2Current sponsor codeLUM001
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.5 to 10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology.

    PSC is characterized by inflammation and fibrosis of the intra- and extrahepatic biliary tree resulting in diffuse multifocal stricture formation leading to biliary cirrhosis, portal hypertension and liver failure. PSC is a life-threatening and debilitating disease. The median survival from diagnosis in symptomatic patients with PSC has been estimated to be 12 years.
    E.1.1.1Medical condition in easily understood language
    Primary sclerosing cholangitis (PSC) is an uncommon condition affecting the bile ducts and liver. Inflammation and scarring of the bile ducts can lead to liver damage and cirrhosis.
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10036732
    E.1.2Term Primary sclerosing cholangitis
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study in subjects with primary sclerosing cholangitis (PSC) undergoing daily dosing over a 14-week period is:

    • To evaluate the safety and tolerability of LUM001 in subjects with PSC during 14 weeks of treatment.
    E.2.2Secondary objectives of the trial
    To evaluate the change from baseline on the following measures after 14 weeks of treatment with LUM001:

    • Serum bile acids.
    • Serum alkaline phosphatase and other biochemical markers associated with cholestasis and liver function.
    • Pruritus.
    • Other biochemical markers associated with PSC.
    • Fecal microbiome population.
    • Fecal bile acids.
    • Quality of Life.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To participate in this study subjects must meet all of the following criteria:

    1. Male or female subjects between the ages of 18-80 years, inclusive.

    2. Diagnosis of PSC consistent with American Association for the Study of Liver Disease (AASLD) (Chapman, et al., 2010), which includes the documented history of the following diagnostic factors:

    a. Alkaline phosphatase >1.5 x ULN.
    b. Magnetic resonance cholangiography (MRC), or endoscopic retrograde cholangiography (ERC), or percutaneous transhepatic cholangiography (PTC) demonstrating intrahepatic and/or extrahepatic biliary obstruction, beading, or narrowing consistent with PSC.
    c. If liver biopsied previously, histological findings with features consistent with or diagnostic of PSC.

    3. If inflammatory bowel disease (IBD) is present, disease activity ≤ 2 (normal to moderate), using the physician assessment on the Mayo ulcerative colitis (UC) disease activity score.

    4. Patients receiving azathioprine for intestinal bowel disease are eligible to participate in the study provided that they have had no IBD exacerbations for at least 6 months.

    5. Females of childbearing potential must have a negative serum pregnancy test [β human chorionic gonadotropin (β-hCG)] during screening and negative urine pregnancy test at the baseline/Day 0 visit.

    6. Sexually active females must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use an effective method (≤ 1% failure rate) of contraception during the trial. Effective methods of contraception are considered to be:

    a. Hormonal (e.g., contraceptive pill, patch, intramuscular implant or injection) provided subject has been on stable therapy for at least 3 months; or
    b. Barrier method, i.e., (a) condom (male or female) or (b) diaphragm, with spermicide; or
    c. Intrauterine device (IUD); or
    d. Vasectomy (partner).

    7. Ability to read and understand English in order to use the study-related questionnaires and the text on the eDiary screen.

    8. Must be willing and able to use an eDiary daily for a minimum of 20 weeks.

    9. Must digitally accept the licensing agreement in the eDiary software at the outset of the study.

    10. Must complete at least 10 eDiary Adult ItchRO reports (AM or PM) during each of two consecutive weeks of the screening period prior to allocation to treatment (maximum possible reports = 14 per week).

    11. Access to phone for scheduled calls from study site.

    12. Must agree to comply with the study protocol procedures and provide written informed consent.
    E.4Principal exclusion criteria
    Subjects will be excluded from the study if they meet any of the following criteria:

    1. Small duct PSC (clinical biochemical and histological features compatible with PSC, but having a normal cholangiogram).

    2. Presence of a dominant stricture unless brushings and/or biopsies of the stricture are negative for dysplasia or malignancy within 6 months of screening.

    3. Surgical or endoscopic biliary tree interventions for treatment of clinically significant strictures within 6 months of screening.

    4. IBD flare (Mayo UC disease activity score > 5 including endoscopic evaluation) within 3 months prior to screening.

    5. Secondary cause of sclerosing cholangitis (e.g., choledocholithiasis, post-surgical biliary stricture, intra-arterial chemotherapy, recurrent pancreatitis, IgG4-associated cholangiopathy, AIDS cholangiopathy).

    6. AST or ALT ≥ 5 x ULN at screening.

    7. History or presence of any other concomitant significant liver disease as assessed by the Investigator, including:

    a. Hepatitis B infection (HBsAg positive).
    b. Hepatitis C infection (antibody positive); patients with a positive antibody test will be eligible if there is documented history of negative HCV RNA and not previously treated for HCV.
    c. Any other cholestatic liver disease [e.g., primary biliary cirrhosis (PBC)].
    d. Alcoholic liver disease.
    e. Proven overlap autoimmune hepatitis.
    f. Proven non-alcoholic steatohepatitis (NASH).

    8. Presence of advanced clinical complications of PSC or clinically significant hepatic decompensation, including:

    a. History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15.
    b . Hepatic encephalopathy.
    c . Hepatorenal syndrome (type I or II) or screening serum creatinine >2.00 mg/dL (177 μmol/L).
    d. Recurrent variceal bleeding.
    e. Refractory ascites.

    9. 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 [e.g., untreated celiac disease, terminal ileum resection, or gastric bypass procedures (gastric lap band is acceptable) cystic fibrosis, Wilson’s disease.

    10. Medical conditions that may cause nonhepatic increases in ALP (e.g., Paget’s disease).

    11. Known history of human immunodeficiency virus (HIV) infection.

    12. The anticipated need for a surgical procedure within 20 weeks from randomization.

    13. Any female who is pregnant or lactating or who is planning to become pregnant within 20 weeks of randomization.

    14. History of cancer, except for basal or squamous cell carcinoma of the skin, or with any laboratory or physical exam or diagnostic procedure finding suggestive of current malignancy.

    15. Family history of any documented hereditary cancer syndrome.

    16. History of alcohol or other substance abuse within 1 year prior to screening.

    17. Administration of the following medications:

    a. Within 12 months prior to treatment: rituximab.
    b . Within 6 months prior to treatment: hydroxychloroquine, methotrexate, oral vancomycin, colchicine, bezafibrate/fenofibrate, anti-TNF therapies, leflunomide, tocilizumab, or ≥ 10 mg prednisone (or equivalent); (topical, inhaled, or short course therapy for intercurrent illness are permitted).
    c. Within 28 days prior to treatment: UDCA, bile acid resins.

    18. Receipt of an investigational drug, biologic, or medical device within 30 days prior to Screening, or 5 half-lives of the study agent, whichever is longer.

    19. History of noncompliance with medical regimens, unreliability, mental instability or incompetence that could compromise the validity of informed consent or lead to noncompliance with the study protocol.

    20. Any other conditions or abnormalities which, in the opinion of the Investigator or Medical Monitor, may compromise the safety of the subject, or interfere with the subject participating in or completing the study.
    E.5 End points
    E.5.1Primary end point(s)
    In subjects with PSC who have received at least one dose of LUM001, the following evaluations will be analysed:

    Primary Efficacy Endpoint:
    • Change from baseline in fasting serum bile acid level at Week 14.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The change from baseline in total serum bile acid levels will be displayed for each treatment group by study visit, using summary statistics including the number of observations, the mean, median, standard deviation, minimum and maximum. Differences from baseline will be calculated and summarized as above, with a 95% confidence interval for the mean.

    The change from baseline to Week 14 will be evaluated using the paired t-test or nonparametric methods as appropriate.
    E.5.2Secondary end point(s)
    The following secondary evaluations will be change from baseline to Week 14 in:

    • Liver enzymes [alanine aminotransferase (ALT), alkaline phosphate (ALP), and bilirubin (total and direct)].
    • Pruritus as measured by ItchRO. The weekly sum score will be calculated using the 7 days pre-treatment for baseline, and the last 7 days of treatment for Week 14.

    The following exploratory evaluations will be assessed:

    • Change from baseline in fasting serum bile acid level at Weeks 3 and 6.
    • Change from baseline in fecal bile acid levels at Week 14.
    • Change from baseline in fecal microbiome population at Week 14.
    • Change from baseline for liver enzymes (ALT, ALP, bilirubin (total and direct)) at Weeks 3 and 6.
    • Change from baseline in pruritus as measured by Adult ItchRO weekly sum scores at Weeks 3 and 6.
    • Change from baseline in pruritus as measured by the Adult ItchRO average daily scores at Weeks 3, 6, and 14. The average daily score for a 7-day period will be the sum of the daily scores for the 7-day period divided by the number of days the dairy is completed in that 7-day period.
    • Change from baseline for other biochemical markers of cholestasis [total and conjugated bilirubin, total cholesterol, low-density lipoprotein cholesterol (LDL-C)] at Weeks 3 and 6.
    • Change from baseline in bile acid synthesis [serum 7α-hydroxy-4-cholesten-3-one (7αC4)] at Weeks 3, 6 and 14.
    • Change from baseline in quality of life as measure by the PBC-40 at Week 14.
    • Change from baseline for MOS-Sleep at Week 14.
    • Patient Impression of Change (PIC) at Week 14.
    • Patient Global Therapeutic Benefit (PGTB) assessment at Week 14.

    In addition, the following exploratory evaluations will be conducted if the results of the primary and secondary analyses illustrate sufficient change from baseline in any the primary and secondary parameters related to bile acid metabolism.

    • Change from baseline for measures of bile acid synthesis (FGF-19 and FGF-21) at Weeks 6 and 14.

    Any missing data on the Adult ItchRO daily score will be imputed using the average daily score from the study week where missing data is located. Missing data imputation will not be done for other efficacy endpoints.

    A number of sensitivity analyses will be performed to assess the robustness of the results. Details of these analyses will be outlined in the SAP for the study.
    E.5.2.1Timepoint(s) of evaluation of this end point
    See E.5.2
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    A safety follow-up phone call will be made at Week 18, or 4 weeks after the last LUM001 dose for any subject who terminates prior to the Week 14 visit. Concomitant medications and any adverse events will be recorded.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 5
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 4
    F.4.2.2In the whole clinical trial 20
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Following the completion of the study, subjects will return to standard care.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-02-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-02-12
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