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    EudraCT Number:2014-004070-42
    Sponsor's Protocol Code Number:A4250PBCpruritus
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-10-15
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2014-004070-42
    A.3Full title of the trial
    An Exploratory, Phase IIa Cross-Over Study to Demonstrate the Efficacy
    and Safety of A4250 in Patients with Primary Biliary Cirrhosis and
    Cholestatic Pruritus
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Demonstrate the Efficacy and Safety of A4250 in Patients with
    Primary Biliary Cirrhosis and Cholestatic Pruritus
    A.4.1Sponsor's protocol code numberA4250PBCpruritus
    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 SponsorSahlgrenska Academy
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSwedish Research Council
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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.2.1.2Country which granted the Marketing AuthorisationSweden
    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/3/12/1041
    D.3 Description of the IMP
    D.3.2Product code A4250
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 biliary cirrhosis complicated by cholestatic pruritus.
    E.1.1.1Medical condition in easily understood language
    Primary biliary cirrhosis complicated by cholestatic pruritus.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary efficacy objective of this Phase IIa study is to demonstrate
    the efficacy of once daily dosing of A4250, 1.5 - 3 mg orally during a
    four-week treatment period to relieve patients with Primary Biliary
    Cirrhosis (PBC) from cholestatic pruritus as determined by evaluation of
    effects on pruritus using a visual analogue scale (VAS).

    The primary safety objective of this study is to assess the safety and
    tolerability of A4250, 1.5 - 3 mg orally during a four-week treatment
    period, in patients with PBC and cholestatic pruritus, as determined by
    the occurrence of treatment-emergent SAEs.
    E.2.2Secondary objectives of the trial
    Secondary efficacy objectives of this study are to demonstrate the
    efficacy of A4250 orally on other pruritus variables and on QoL and
    lysophosphatidic acid formation.

    Secondary safety objectives of this study include assessment of the
    safety and tolerability of A4250 during a four-week treatment period, as
    determined by the occurrence of treatment-emergent AEs and changes
    in other safety parameters including liver and kidney function tests and
    vital signs.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Diagnosis of PBC or PBC-Autoimmune hepatitis overlap as established
    according to
    AASLD/EASL definitions. Definite or probable PBC diagnosis, as
    demonstrated by the presence of ≥ 2 of the following 3 diagnostic
    • History of elevated ALP levels (>1.67 ULN) for at least 6 months prior
    to Day 1
    • Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in low titer (<1:80) PBC specific antibodies (anti-GP210 and/or anti-
    SP100 and/or antibodies against the major M2 components (PDC-E2, 2-
    oxo-glutaric acid dehydrogenase complex)
    • Liver biopsy consistent with PBC

    • UDCA non-responders defined as >6 months of UDCA and at the time
    of enrolment a serum ALP >1.67 ULN.
    • Laboratory markers of cholestasis identified within 3 months of Visit
    • Treatment with cholestyramine at a dose >4g BID or colestipol > 5mg
    for at least 3 months
    • The patient has a VAS-Itch of at least 30 mm during the day before
    baseline (Visit 2)
    • The patient reports having understood and has signed both the ICF
    and is willing to comply with all study visits and assessments;
    • The patient is a male or non-pregnant female ≥18 years of age and ≤
    80 years of age with body mass index (BMI) ≥18.5 but <35 kg/m2
    • Women of childbearing capacity (WOCBC) must have a negative
    serum pregnancy test upon inclusion in the trial. WOBC must agree to
    maintain highly effective birth control or practice abstinence (i.e.
    abstaining from penile-vaginal intercourse) if this is the subject's
    preferred and usual lifestyle. The following methods for birth control,
    when used consistently and correctly, offer protection from pregnancy
    with a Pearl index of <1 (i.e. <1% per year) and can be accepted as
    highly effective;
    • Oral hormone contraceptives, with the exception of low-dose
    gestagens (e.g. lynestrenol norestisteron)
    • Injectable or implanted hormonal contraceptives
    • Intrauterine devices
    • Intrauterine systems (e.g. progestin-releasing coil)
    The following conditions are also acceptable;
    • Vasectomised male partner with appropriate post-vasectomy
    documentation of the absence
    E.4Principal exclusion criteria
    English • Any condition that, in the opinion of the Investigator constitutes a risk for the patient or a contraindication for participation and completion
    of the study, or could interfere with study objectives, conduct, or
    • Jaundice of extrahepatic origin
    • The patient has a structural abnormality of the GI tract.
    • The patient has a known, active, clinically significant acute or chronic
    infection, or any major episode of infection requiring hospitalization or
    treatment with parenteral anti infectives within 4 weeks of treatment
    start (study day 1) or completion of oral anti-infective treatment within
    2 weeks prior to start of screening period;
    • The patient has unexplained and clinically significant GI alarm signals
    (e.g., lower GI bleeding or heme-positive stool, iron-deficiency anemia,
    unexplained weight loss) or systemic signs of infection or colitis;
    • The patient has rectal bleeding and/or is heme-positive in the
    absence of known internal or external hemorrhoids;
    • The patient has a history of cancer with last date of proven disease
    activity/presence of malignancy within 5 years, except for adequately
    treated basal cell carcinoma of the skin, cervical dysplasia, or carcinoma
    in situ of the skin or the cervix
    • Other reason for itching such as atopic dermatitis, other primary skin
    diseases etc.
    • Chronic kidney disease
    • Active substance abuse in the year before screening
    • The patient has a history of a psychiatric disorder requiring
    hospitalization or suicide attempt in the 2 years prior to Screening;
    • The patient has participated in any investigational clinical study
    within 30 days prior to Screening or within 5 half-lives of the
    investigated compound (whichever is longer) prior to Screening (unless
    the patient was never randomized to study treatment), or plans to
    participate in another clinical study during this study;
    • The patient is a pregnant, breast-feeding or lactating female.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is change in VAS-Itch (most severe itch
    during last 24 hrs) during the fourth treatment week of A4250 compared
    to the fourth week of treatment period 1.

    The primary safety endpoint will be the occurrence of treatmentemergent
    SAEs during the four weeks of treatment with A4250.
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the fourth treatment week of A4250 compared to the fourth week
    of treatment period 1.
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints are:
    • Change in VAS-Itch (most severe itch during last 24 hrs) during the
    fourth treatment week of A4250 compared to the fourth week of
    treatment period 3 and compared to baseline
    • Change in 5-D Pruritus scale and PBC40 from baseline and from week
    4 of treatment period 1 to fourth week of A4250 treatment and from
    week 4 of A4250 treatment to week 4 of the third treatment period
    • Change in individual and total serum and fecal BAs, FGF19, C4 and
    serum lysophosphatidic acid from baseline and from last day in week 4
    of treatment period 1 to last day in week 4 of A4250 treatment and from
    last day of week 4 of A4250 treatment to last day of week 4 of the third
    treatment period
    • Change in ALP, AST and ALT from baseline and from last day of week
    4 of treatment period 1 to last day in week 4 of A4250 treatment and
    from last day of week 4 of A4250 treatment to last day of week 4 of the
    third treatment period
    • Change in Composite endpoint of ALP and serum bilirubin from
    baseline and from last day of week 4 of treatment period 1 to last day of
    week 4 week of A4250 treatment and from last day of week 4 of A4250
    treatment to last day of week 4 of the third treatment period
    • Change from week 4 of first treatment period to week 4 of A4250 in
    weekly stool consistency of BMs (BSFS) and from week 4 of A4250
    treatment to week 4 of the third treatment period
    • Change in gut microbiota composition

    Secondary safety endpoints will include:
    • Occurrence of TEAEs during the four A4250 treatment weeks.
    Description and severity of any AE will also be reported;
    • Changes in safety laboratory test results (including hematology,
    clinical chemistry and urinalysis) from baseline to Day 28 of A4250
    • Discontinuations from treatment with reasons given.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of the four weeks' treatment period with A4250
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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. 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 No
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    The End-of-Study Visit (Visit 8) will take place 14 days after end of
    Period 3, (Day 126) OR 14 days after the last dose of study medication,
    whether the patient completes the study or discontinues prematurely.
    In this visit the possible occurrence of adverse events will be
    monitored and recorded in the appropriate section of the Case Report
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned 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: 7
    F.1.3Elderly (>=65 years) Yes
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state12
    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)
    Continuous treatment of cholestatic pruritus with resins such as cholestyramine or colestipol.
    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 Decision2014-12-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-04
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-02-21
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