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    Summary
    EudraCT Number:2018-001930-17
    Sponsor's Protocol Code Number:CR845-CLIN3103
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-11-19
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2018-001930-17
    A.3Full title of the trial
    A MULTICENTER, DOUBLE-BLIND, RANDOMIZED,
    PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND
    EFFICACY OF INTRAVENOUS CR845 IN HEMODIALYSIS PATIENTS
    WITH MODERATE-TO-SEVERE PRURITUS, WITH A 52-WEEK
    OPEN-LABEL EXTENSION
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A MULTICENTER, DOUBLE-BLIND, RANDOMIZED,
    PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND
    EFFICACY OF INTRAVENOUS CR845 IN HEMODIALYSIS PATIENTS
    WITH MODERATE-TO-SEVERE PRURITUS, WITH A 52-WEEK
    OPEN-LABEL EXTENSION
    A.3.2Name or abbreviated title of the trial where available
    CR845-CLIN3103
    A.4.1Sponsor's protocol code numberCR845-CLIN3103
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03636269
    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 SponsorCara Therapeutics INC
    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 supportCara Therapeutics Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationICON Clinical Research Limited
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address100 Milton Park
    B.5.3.2Town/ cityAbingdon
    B.5.3.3Post codeOx14 4RY
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number4407831653684
    B.5.6E-mailmarkas.marriott@iconplc.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDifelikefalin
    D.3.2Product code CR845
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDIFELIKEFALIN
    D.3.9.1CAS number 1024828-77-0
    D.3.9.4EV Substance CodeSUB195302
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.05
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    MODERATE-TO-SEVERE PRURITUS IN HEMODIALYSIS PATIENTS
    E.1.1.1Medical condition in easily understood language
    REDUCTION OF MODERATE-TO-SEVERE PRURITUS,IN HEMODIALYSIS PATIENTS
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10064848
    E.1.2Term Chronic kidney disease
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10060884
    E.1.2Term Uremic pruritus
    E.1.2System Organ Class 100000004858
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of IV CR845 at a dose of 0.5 mcg/kg
    compared to placebo in reducing the intensity of itch in
    hemodialysis patients with moderate-to-severe pruritus.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of IV CR845 at a dose of 0.5 mcg/kg
    compared to placebo in improving itch-related quality-of-life
    measures in hemodialysis patients with moderate-to-severe
    pruritus.
    To evaluate the safety of IV CR845 at a dose of 0.5 mcg/kg in
    hemodialysis patients with moderate-to-severe pruritus.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria:
    To be eligible for inclusion into the Double-blind Phase of the study, a
    patient must meet the following criteria:
    1. Willing and able to provide written informed consent prior to participating in this study;
    2. Able to communicate clearly with the Investigator and staff, able to understand the study procedures, and able and willing to comply with the study requirements, including providing written responses to questionnaires;
    3. Male or female between 18 and 85 years of age inclusive; Note:Subjects in Korea, must be male or female between 19 and 85 years of age, inclusive.
    4. Has end-stage renal disease (ESRD) and has been on hemodialysis 3 times per week for at least 3 months prior to the start of screening;
    Note 1: Patients who require an occasional additional dialysis treatment to manage fluid overload or electrolyte excesses may be enrolled as long as it is anticipated that no more than 1 such treatment will be required in any given week and no more than 4 occasions during the 12-week double-blind
    period. Patients routinely on 4 dialyses a week will not be eligible.
    Note 2: Patients receiving in-home hemodialysis may participate as long as they have switched to in-center hemodialysis at least 2 weeks prior to screening and plan to remain on in-center hemodialysis for the duration of the study.
    Note 3: Patients receiving alternate dialysis modalities such as nocturnal dialysis will not be eligible.
    5. If female, is not pregnant or nursing during any period of the study;
    6. If female:
    a. Is surgically sterile; or
    b. Has been amenorrhoeic for at least 1 year and is over the age of 55 years; or
    c. Has a negative serum pregnancy test at screening and agrees to use acceptable contraceptive measures
    (eg, hormonal contraceptives, barrier with spermicide, intrauterine device, vasectomized partner, or abstinence)
    from the time of informed consent until 7 days after the last dose of study drug;
    7. If male, agrees not to donate sperm after the first dose of study drug until 7 days after the last dose of study drug, and agrees to
    use a condom with spermicide or abstain from heterosexual intercourse during the study until 7 days after the last dose of
    study drug. (Note: No restrictions are required for a vasectomized male provided his vasectomy was performed ≥4 months prior to screening);
    8. Has a prescription dry body weight between 40.0 and 135.0 kg, inclusive;
    9. Has at least 2 single-pool Kt/V measurements ≥1.2, or at least 2 urea reduction ratio measurements ≥65%, or 1 single-pool Kt/V measurement ≥1.2 and 1 urea reduction ratio measurement ≥65% on different dialysis days during the 3 months period prior to screening;
    10. Prior to randomization:
    a. Has completed at least four out of eight Worst Itching Intensity Numerical Rating Scale (NRS) worksheets fromhe start of the 7-day Run-in Period up to and including the pre-randomization assessment on Day 1;
    b. Has a mean baseline Worst Itching Intensity NRS score ≥5, defined as the average of all non-missing scores reported from the start of the 7-day Run-in Period up to and including the pre-randomization assessment on Day 1.
    E.4Principal exclusion criteria
    Exclusion Criteria:
    A patient will be excluded from the Double-blind Phase of the study if
    any of the following criteria are met:
    1. Known noncompliance with dialysis treatment that in the opinion of the Investigator would impede completion or validity of the study;
    2. Scheduled to receive a kidney transplant during the study;
    3. Known history of allergic reaction to opiates, such as hives
    (Note: side effects related to the use of opioids, such as constipation or nausea, would not exclude patients from the
    study).
    4. Has a concomitant disease or a history of any medical condition that, in the opinion of the Investigator, could pose undue risk to the patient, impede completion of the study procedures, or would compromise the validity of the study measurements, including, but not limited to:
    a. Known or suspected history of alcohol, narcotic, or other drug abuse, or substance dependence within 12 months prior to screening;
    b. Significant systolic or diastolic heart failure (eg, New York Heart Association Class IV congestive heart failure [Appendix 1, Section 14.1]);
    c. Severe mental illness or cognitive impairment (eg, dementia);
    d. Any other relevant acute or chronic medical or neuropsychiatric condition within 3 months prior to screening (eg, diagnosis of encephalopathy, coma, delirium);
    5. New or change of treatment received for itch including antihistamines and corticosteroids (oral, IV, or topical) within 14 days prior to screening;
    6. New or change of prescription for opioids, gabapentin, or pregabalin within 14 days prior to screening;
    7. Received another investigational drug within 30 days prior to the start of screening or is planning to participate in another clinical study while enrolled in this study;
    8. In the opinion of the Investigator, has pruritus attributed to a cause other than ESRD or its complications (eg, patients with concomitant pruritic dermatological disease or cholestatic liver disease). Patients whose pruritus is attributed to ESRD complications, such as hyperparathyroidism,
    hyperphosphatemia, anemia, or the dialysis procedure or prescription may be enrolled);
    9. Has localized itch restricted to the palms of the hands;
    10. Has pruritus only during the dialysis session (by patient report);
    11. Is receiving ongoing ultraviolet B treatment and anticipates receiving such treatment during the study;
    12. Participated in a previous clinical study with CR845.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint
    • Proportion of patients achieving at least a 3-point improvement
    from baseline with respect to the weekly mean of the daily 24-
    hour Worst Itching Intensity NRS score at Week 12 of the
    Double-blind Treatment Period
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 12
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints
    • Proportion of patients achieving ≥4-point improvement from baseline with respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS at Week 12 of the Double-blind Treatment Period.
    • Proportion of patients achieving ≥3-point improvement from baseline with respect to the weekly mean of the daily 24-hour Worst ItchingIntensity NRS at Week 8 of the Double-blind Treatment Period.
    • Proportion of patients achieving ≥3-point improvement from baseline with respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS at Week 4 of the Double-blind Treatment Period.
    • Proportion of patients achieving ≥4-point improvement from baseline with respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS at Week 8 of the Double-blind Treatment Period.
    • Proportion of patients achieving ≥4-point improvement from baseline with respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS at Week 4 of the Double-blind Treatment Period.
    • Change from baseline in itch-related quality of life at the end of Week 12 of the Double-blind Treatment Period, as assessed by the Skindex-10 Scale total score
    • Change from baseline in itch-related quality of life at the end
    of Week 12 of the Double-blind Treatment Period, as assessed by the 5-D Itch Scale total score

    Additional efficacy endpoints are described in Section 8.7.4. of the protocol
    Safety Endpoints
    The safety endpoints used to evaluate the overall safety and tolerability of CR845 will be adverse events, ECG, vital signs, and clinical safety
    laboratory evaluations.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 4, week 8, week 12

    Please also refer to section 6.5.1 and 6.5.2 Schedule of Events within the Protocol.
    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 No
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned18
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    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
    Australia
    Canada
    Czech Republic
    Germany
    Hungary
    Korea, Republic of
    New Zealand
    Poland
    Romania
    Taiwan
    United Kingdom
    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
    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 months3
    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 months9
    E.8.9.2In all countries concerned by the trial days5
    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: 252
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 98
    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 state80
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 350
    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)
    extension phase- open label 52 weeks
    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 Decision2019-01-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-03-31
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