| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Sickle cell disease (SCD) is a rare inherited red blood cell (RBC) disorder characterized by chronic hemolysis, debilitating pain, progressive multiorgan damage, and premature death. SCD is caused by a specific point mutation in the gene encoding hemoglobin subunit beta that results in the substitution of a hydrophobic valine residue for glutamic acid in the 6th position from the N-terminus of the beta-chain leading to the production of HbS. |
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| E.1.1.1 | Medical condition in easily understood language |
| Sickle cell disease is a rare genetically inherited disease, which affects hemoglobin, the protein in red blood cells that carries oxygen throughout the body. |
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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 |
| To assess the safety and tolerability of IMR-687 in adult patients with sickle cell anaemia (SCA), defined as homozygous sickle haemoglobin (HbSS) or sickle-β0 thalassemia, who are not receiving hydroxyurea (HU) and in adult SCA patients who are receiving a stable dose of HU |
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| E.2.2 | Secondary objectives of the trial |
To characterise the pharmacokinetic (PK) profile of IMR-687 in adult patients with SCA who are/are not receiving a stable dose of HU
To characterise the PK profile of HU in adult patients with SCA before and after receiving IMR 687 to determine if there is a clinically relevant PK interaction.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following criteria to be enrolled in the study:
1. Male or female ≥18 or ≤50 years of age.
2. Confirmed diagnosis of SCA (HbSS or sickle-B0 thalassemia). Note, if not already documented in the patient’s record, the diagnosis of SCA must be confirmed via electrophoresis, HPLC, and/or genotyping.
3. Use of HU:
• For patients in the Population A: Have not received HU within 90 days prior to Screening and are not planning to take HU within the next 6 months
• For patients in Population B: Have received HU for at least 6 months, have been on a stable dose for at least 60 days prior to Screening, and are not planning to change the dose level, dose regimen, or discontinue HU within the next 6 months.
4. Female patients must not be pregnant and be highly unlikely to become pregnant. Male patients must be unlikely to impregnate a partner. Male or female patients must meet at least one of the following criteria:
• A female patient who is not of reproductive potential is eligible without requiring the use of contraception. A female patient who is not of reproductive potential is defined as one who: (1) has reached natural menopause (defined as 12 months of spontaneous amenorrhea without an alternative medical cause, and can be confirmed with serum follicle-stimulating hormone levels in the postmenopausal range as determined by the local laboratory; (2) is 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy; or (3) has undergone bilateral tubal ligation. Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (i.e., anorexia nervosa).
• A male patient who is not of reproductive potential is eligible without requiring the use of contraception. A male patient who is not of reproductive potential is defined as one who has undergone a successful vasectomy. A successful vasectomy is defined as (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post vasectomy.
• A male or female patient who is of reproductive potential agrees to remain truly abstinent or use (or have their partner use) acceptable methods of highly effective contraception starting from the time of consent through 3 months after the completion of study therapy. True abstinence is defined as abstinence that is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of the trial and withdrawal are not acceptable methods of contraception. Acceptable methods of highly effective birth control are combined or progestogen-only hormonal contraception that is associated with inhibition of ovulation, intrauterine device, and intrauterine hormone-releasing system.
5. Be capable of giving informed consent and reading and signing the informed consent form after the nature of the study has been fully explained by the investigator or investigator designee.
6. Be willing and able to complete all study assessments and procedures and to communicate effectively with the investigator and site staff.
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| E.4 | Principal exclusion criteria |
1. Total Hb at Screening >12.5 g/dL or < 6 g/dL.
2.Reticulocyte count <100 x 109/L for Population A; reticulocyte count <80 x 109/L for Population
B.
3. >7 hospitalizations (for at least 24 hours) for vaso-occlusive crises (VOC), including acute chest syndrome (ACS) and priapism, within the prior year.
4. Blood transfusion or donation of blood or any blood product within 60 days of Day 1 or on chronic transfusion therapy regimen.
5. Positive for human immunodeficiency virus (HIV), hepatitis C (HCV) antibodies (unless the patient has successfully completed drug therapy that results in cure/clearance of HCV), and hepatitis B surface antigen.
6. For female patients of childbearing potential, a positive serum human chorionic gonadotropin (hCG) test (Screening) or a positive urine hCG test on Day 1.
7. Estimated glomerular filtration rate (eGFR) <50 mL/min as calculated by the equation from the Modification of Diet in Renal Disease (MDRD) Study using creatinine, age, sex, and ethnicity.
8. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal (ULN)
9. Body Mass Index (BMI) < 17.5 or > 35 kg/m2; a total body weight < 50 kg
10. Use of PDE type 5 inhibitors (including but not limited to sildenafil, tadalafil, vardenafil) within 7 days prior to the first dose of study drug, or planning to use any time during study
11. A history of drug or alcohol abuse as judged by the investigator within the past 1year, or a positive alcohol (breathalyser) test (Screening or Day -1).
12. A cancer that has not been in complete remission for at least 5 years. Patients with squamous cell or basal cell carcinoma of the skin, localised cervical cancer, or localised prostate cancer are eligible if, in the opinion of the investigator, the condition has been adequately diagnosed, and is determined to be clinically in remission, and the patient’s participation in the study would not represent a safety concern.
13. A history of a clinically significant allergic reaction or hypersensitivity, as judged by the investigator, to any drug or any component of the study drug formulations used in the study.
14. On ECG, a corrected QT interval, Fridericia’s formula (QTcF) >450 ms in men and >470 ms in women or the presence of clinically significant abnormalities as determined by the investigator.
15. A history of major surgery within 4 weeks or minor surgery within 2 weeks of Day 1.
16. Any flu-like syndrome or other respiratory infection within 2 weeks of Day 1 or vaccination with attenuated live virus within 4 weeks of Day 1.
17. Participation in an investigational drug or device study within 30 days prior to Day 1.
18. Use within 30 days prior to Day 1, or planning to use during the study, of any drugs or substances that are known to strongly inhibit or induce cytochrome P450 (CYP) enzymes, including but not limited to cimetidine, cyclosporine, erythromycin, omeprazole, rifampin, ritonavir, and St. John’s wort. If there is any question as to whether a substance is permitted, please review the product labelling (if applicable) and consult the Sponsor.
19. Consumption of grapefruit, grapefruit juice, or grapefruit products within 24 hours prior to Day 1 or planning to consume grapefruit products during the study.
20. Use within 30 days prior to Day 1, or planning to use during the study, of any CYP3A sensitive substrates, (excluding opioids), including but not limited to alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib, dronedarone, ebastine, eletriptan, eplerenone, everolimus, felodipine, ibrutinib, indinavir, lomitapide, lurasidone, maraviroc, midazolam, naloxegol, nisoldipine, quetiapine, saquinavir, sirolimus, tacrolimus, ticagrelor, tipranavir, tolvaptan, triazolam. If there is any question as to whether a substance is permitted, please review the product labelling (if applicable) and consult the Sponsor.
21. Use within 30 days prior to Day 1, or planning to use during the study, of any drugs or substances known to be significant substrates or inhibitors of P-glycoprotein (P-gp), including but not limited to cyclosporine, lovastatin, propranolol, quinidine, and simvastatin. If there is any question as to whether a substance is permitted, please review the product labelling (if applicable) and consult the Sponsor.
22. Other prior or ongoing medical condition, physical findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the patient, make it unlikely that the course of treatment or follow-up would be completed, or impair the assessment of study results.
23. In the opinion of the investigator, the patient is unable to meet the requirements of the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
IMR-687 safety and tolerability as measured by:
- Incidence and severity of adverse events (AEs) and serious adverse events (SAEs);
- Change from baseline in 12-lead electrocardiogram (ECG) parameters, clinical
laboratory tests (chemistry, haematology, coagulation, urine), and vital signs
- Physical examination findings |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. AEs/SAEs: continuous;
2. Change frm baseline in 12-lead ECG at weeks 1,13,14,17,21,25 (Pop A), 1,5,17 (Pop B); 1,5,13,14,17,21,25 (Pop A1) and 1,5,25 (Pop B1)
3. Change frm baseline in clin labs at weeks 1,2,5,9,13,17,21,25, 29 (Pop A), 1, 2,5,9,13,17, 21 (Pop B), 1,2,4,5,9,13,17,21, 25,29 (Pop A1) and 1,2,5,9,13,17,21,25,29 (Pop B1)
4. Change from baseline in vitals at weeks 1,2,3,4,5,9,13,14,15,16,17,21,25, 29 (Pop A), 1,2,3,4,5,6,7,8,9,13,17, 21 (Pop B), 1,2,3,4,5,9,13,14,15,16,17,21,25,29 (Pop A1) and 1,2,3,4,5,6,7,8,9,13,17,21,25,29 (Pop B1)
5. Physical exam at weeks 1,2,3,4,5,9,13,14,15,16,17,21,25, 29 (Pop A), 1,2,3,4,5,6,7,8,9,13, 17,21 (Pop B), 1,2,3,4,5,9,13,14, 15,16,17,21,25,29 (Pop A1) and 1,2,3,4,5,6,7,8,9,13,17,21,25,29 (Pop B1) |
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| E.5.2 | Secondary end point(s) |
- The plasma PK profile of IMR-687 after oral administration to adult patients with SCA
(Populations A and B)
- The plasma PK profile of HU before and after oral administration of IMR-687 to adult patients
with SCA (Population B only)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. The plasma PK profile of IMR-687 after oral administration to adult subjects with SCA (Populations A and B)
at week 1, 13 and 25 (Population A), at week 1, 5 and 17 (Population B), at weeks 1, 5, 25 (Population A1) and weeks 1, 5, 25 (Population B1)
2. The plasma PK profile of HU after oral administration of IMR-687 to adult subjects with SCA (Population B only)
at lead-in (for 2 complete HU PK profiles, at least 48 hours apart), week 5, week 17, and one complete HU PK profile at lead-in, plus weeks 5 and 25 (Population B1) |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | 5 |
| 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 | 10 |
| 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 |
| Ghana |
| Kenya |
| United States |
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| E.8.7 | Trial 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
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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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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