E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stable Sickle Cell Disease (SCD) |
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E.1.1.1 | Medical condition in easily understood language |
Sickle Cell Disease, a disorder that changes the normal round shape of the red blood cells. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040644 |
E.1.2 | Term | Sickle cell disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.) |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary 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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other 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 |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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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) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |