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    Summary
    EudraCT Number:2019-001899-11
    Sponsor's Protocol Code Number:C1701-202
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-08-29
    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 number2019-001899-11
    A.3Full title of the trial
    A Randomized, Placebo-controlled, Phase 2 Study to Evaluate the Safety and Pharmacodynamics of Once-daily Oral IW-1701 in Patients with Stable Sickle Cell Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of the Effect of IW-1701, a Stimulator of Soluble Guanylate Cyclase (sGC), on Patients With Sickle Cell Disease (SCD)
    A.3.2Name or abbreviated title of the trial where available
    Strong SCD
    A.4.1Sponsor's protocol code numberC1701-202
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03285178
    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 SponsorCyclerion 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 supportCyclerion Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCyclerion Therapeutics
    B.5.2Functional name of contact pointCheryl Gault
    B.5.3 Address:
    B.5.3.1Street Address301 Binney Street
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02142
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18573383273
    B.5.6E-mailcgault@cyclerion.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 nameOlinciguat
    D.3.2Product code IW-1701
    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 INNOlinciguat
    D.3.9.1CAS number 1628732-62-6
    D.3.9.2Current sponsor codeIW-1701
    D.3.9.3Other descriptive nameMM-464110 (alternate Cyclerion code); PCI-103303 (PCI Synthesis product code)
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Stable Sickle Cell Disease (SCD)
    E.1.1.1Medical condition in easily understood language
    Sickle Cell Disease, a disorder that changes the normal round shape of the red blood cells.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10040644
    E.1.2Term Sickle cell disease
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary:
    • To assess the safety and tolerability of oral, once-daily (QD) IW-1701 when administered for approximately 12 weeks to patients aged 16 to 70 years with SCD.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient has provided written consent before any study-specific procedures are performed; for patients <18 years of age, parental permission and child assent will be obtained.
    2. Patient is ambulatory male or female 16 to 70 years of age at the Screening Visit.
    3. Patient has sickle cell disease (SCD), including HbSS, HbSC, HbSβ0-thalassemia, or HbSβ+-thalassemia, documented in their medical history by hemoglobin electrophoresis or genotyping.
    4. If receiving hydroxyurea (HU), erythropoietin, L-glutamine, or prophylactic oral antibiotics, patient has had no change in regimen(s) (ie, drug and dose) for at least 8 weeks before the Randomization Visit and has no plans to change regimen(s) during the study. If receiving HU, patient must have been prescribed HU for at least 6 months prior to the Randomization Visit. (Note: Patient is not required to be taking medication[s] for SCD.)
    Should the patient begin any new chronic treatment/therapy for SCD during the study or alter any current treatment/therapy for SCD during the study, the Sponsor Medical Monitor must be informed.
    5. If receiving chronic medication(s) for hypertension, patient has had no change in regimen(s) (ie, drug and dose) for at least 8 weeks before the Randomization Visit and has no plans to change regimen(s) during the study.
    6. Per medical history and/or patient recall, patient has had at least 1 and no more than 10 sickle cell-related pain crises in the 12 months before the Screening Visit and none occurring in the 4 weeks before the Randomization Visit.
    For assessing study eligibility, an SCD-related pain crisis is defined as an acute episode of new-onset pain that lasts ≥2 hours with no medically determined cause other than a vaso-occlusive event and requires presentation to a medical facility (eg, acute care setting,
    Emergency Department, urgent care clinic) and treatment with oral or parenteral opioids, parenteral nonsteroidal anti-inflammatory drugs, or other analgesics, prescribed by a healthcare provider.
    7. Patient has clinically acceptable (per Investigator discretion) electrocardiogram (ECG) with QT interval corrected using Fridericia’s formula (QTcF interval) <500 ms at the Screening Visit.
    8. Patient has seated systolic blood pressure (BP) from 90 to 160 mmHg at the Screening Visit. (Note: BP for eligibility will be the average of 3 measurements obtained with an appropriately sized cuff at 2-minute intervals after the patient has been sitting quietly for ≥5 minutes.)
    9. Female patient must be postmenopausal (no menses for ≥12 consecutive months) or surgically sterile (ie, bilateral oophorectomy, hysterectomy, or tubal sterilization [tie, clip, band, or burn]); must agree to completely abstain from heterosexual intercourse; or, if heterosexually active, must agree to use 1 of the following methods of birth control from the date she signs the informed consent form (ICF) until 90 days after the final dose of study drug:
    - Progesterone implant and/or an intrauterine device (IUD)
    - Combination of 2 highly effective birth control methods (eg, diaphragm with spermicide plus a condom, condom with spermicide plus a diaphragm or cervical cap, hormonal contraceptive [eg, oral and transdermal patch] plus a barrier method, or partner with vasectomy [conducted ≥60 days before the Screening Visit or confirmed via sperm analysis] plus a hormone or barrier method).
    10. Male patient must be surgically sterile by vasectomy (conducted ≥60 days before the Screening Visit or confirmed via sperm analysis), must agree to completely abstain from heterosexual intercourse, or, if heterosexually active, must agree to use a combination of 2 highly effective birth control methods (eg, partner use of progesterone implant and/or IUD, condom with spermicide plus a partner diaphragm or cervical cap, partner hormonal
    contraceptive [including progesterone implant] plus a barrier method, or postmenopausal partner [for ≥1 year] plus barrier method) from the Screening Visit through 90 days after the final dose of study drug.
    11. Patient is fluent in the language of the local ICF (eg, English, Spanish, Arabic, French).
    12. Patient completes daily eDiary entries for at least 10 days during the last 14 days of the Run-in Period as assessed at the Randomization Visit. (Note: To enter the Run-in Period, patient must meet all eligibility criteria applicable to the Screening Visit.)
    E.4Principal exclusion criteria
    1. Patient requires a program of prescheduled, regularly administered chronic blood transfusion therapy, has received a transfusion in the 8 weeks before the Randomization Visit, and/or is scheduled to receive a transfusion during the study.
    2. Patient has been hospitalized for an SCD-related complication in the 4 weeks before the Randomization Visit.
    3. Patient is planning to undergo major surgery during the trial or has undergone surgery within 4 weeks of the Screening Visit, other than minor dermatologic procedures.
    4. Patient has used oral or parenteral corticosteroids in the 8 weeks before the Randomization visit. Note: Transient use for ≤2 days may be acceptable; consult the Medical Monitor for confirmation.
    5. Patient has taken opioid(s) >200 morphine mg equivalent/day within the 4 weeks before the Randomization Visit.
    6. Patient is taking aspirin ≥325 mg daily, any P2Y12 inhibitor, any anticoagulant medication, specific inhibitors of phosphodiesterase 5 (PDE5), nonspecific inhibitors of PDE5 (including dipyridamole and theophylline), any supplements for the treatment of erectile dysfunction, riociguat, or nitrates or nitric oxide donors in any form.
    Patient is taking moderate or strong cytochrome P450 3A (CYP3A) inhibitors or inducers.
    These medications are prohibited from the Run-in Visit (which may occur from Day -14 to Day -17) through the duration of the study.
    See Appendix 1 of the study protocol for a list of prohibited medications, supplements, and foods.
    7. Patient uses or requires the use of fentanyl.
    8. Patient has any of the following clinical laboratory values at the Screening Visit:
    a. Hemoglobin ≤6 g/dL
    b. Platelets ≤100×109/L
    c. Absolute neutrophils ≤1.5×109/L
    d. Alanine aminotransferase >1.5×the upper limit of normal (ULN) as defined by laboratory
    e. Direct bilirubin >3×ULN as defined by laboratory
    f. Creatinine clearance <30 mL/minute/1.73 m2 by the Modification of Diet in Renal Disease equation
    g. Prothrombin time and/or aPTT >1.5×ULN and considered clinically significant by the Investigator, and/or INR>1.5
    9. Patient has oxygen saturation ≤90% by pulse oximetry on room air at the Screening Visit and/or at the Randomization Visit.
    10. Patient has had inpatient hospitalization for alcoholism or drug addiction in the 12 months before the Screening Visit or is positive for any the following at the Screening Visit unless legally prescribed: Amphetamines, Benzodiazepines, Opiates, Propoxyphene, Barbiturates, Cocaine, Phencyclidine
    11. Patient has major concurrent illness or medical condition that in the opinion of the Investigator would preclude participation in a clinical study, including but not limited to:
    a. Uncontrolled significant cardiovascular disease or clinically significant cardiac arrhythmia as assessed by the Investigator
    b. Serious event such as stroke or transient ischemic attack ≤12 months before Randomization, or deep venous thrombosis or pulmonary embolism ≤6 months before Randomization
    c. History of platelet dysfunction, hemophilia, von Willebrand disease, coagulation disorder, other bleeding diathesis condition(s), or significant, nontraumatic bleeding episodes, such as from a gastrointestinal source, even if patient has normal complete blood count, prothrombin time, and activated partial thromboplastin time at the screening Visit
    d. Known severe central nervous system vasculopathy (eg, Moyamoya disease, arteriovenous malformations)
    e. Interstitial lung disease requiring continuous oxygen
    f. Known severe pulmonary hypertension (tricuspid regurgitant jet velocity ≥3.0 m/sec on 2D echocardiogram or an estimated pulmonary artery systolic pressure ≥40 mmHg) or any pulmonary hypertension associated with idiopathic interstitial pneumonia(s)
    g. Known cirrhosis of the liver with Child-Pugh score of A, B, or C
    12. Patient has a history of cancer, other than basal cell carcinoma, in the last 5 years.
    13. Patient has a history of clinically significant hypersensitivity or allergy to any of the ingredients contained in the active or placebo drug products.
    14. Female patient who is pregnant or breastfeeding (from screening until 90 days after the final dose of study drug).
    15. Female patient who may wish to become pregnant and/or plans to undergo egg donation or egg harvesting for current or future in vitro fertilization during the study and/or within 90 days after the last dose of study drug.
    16. Male patient unwilling to refrain from sperm donation during the study and for at least 90 days after the last dose of study drug.
    Note: Screening Visit assessments may take place over more than 1 day. Patients may be rescreened per Investigator judgement after consultation with the Medical Monitor. Laboratory assessments may be repeated if an error is suspected. In certain circumstances local laboratory values may be acceptable.
    Please refer to the study protocol for the full list of exclusion criteria.
    E.5 End points
    E.5.1Primary end point(s)
    Safety:
    Incidence, frequency, and severity of treatment-emergent adverse events (TEAEs) and study drug-related TEAEs in IW-1701-treated patients compared with placebo-treated patients over the study
    E.5.1.1Timepoint(s) of evaluation of this end point
    Over the study
    E.5.2Secondary end point(s)
    Not applicable
    E.5.2.1Timepoint(s) of evaluation of this end point
    Not applicable
    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 No
    E.6.6Pharmacokinetic Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    Tolerability of oral, once-daily (QD) IW-1701
    Effect of oral, once-daily IW-1701 on symptoms of SCD, health-related quality of life and biomarkers.
    Pain crisis parameters
    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 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 Yes
    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 concerned6
    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
    Lebanon
    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
    Overall study completion is defined by the last subject last visit (LSLV) date and when the clinical event adjudication committee (CEAC) reaches final determination of the vaso-occlusive crisis events (please refer to the section 5.13 of the study protocol)
    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 months9
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years2
    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 Yes
    F.1.1Number of subjects for this age range: 5
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 83
    F.1.3Elderly (>=65 years) No
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 28
    F.4.2.2In the whole clinical trial 88
    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)
    None
    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 Decision2019-10-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-07
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-08-06
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