E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Thrombotic microangiopathies following haematopoietic stem cell transplant
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E.1.1.1 | Medical condition in easily understood language |
Thrombotic microangiopathies following haematopoietic stem cell transplant |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10064477 |
E.1.2 | Term | Coagulopathies and bleeding diatheses (excl thrombocytopenic) |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10043645 |
E.1.2 | Term | Thrombotic microangiopathy |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10053567 |
E.1.2 | Term | Coagulopathies |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system 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 |
Describe the 100-day survival rate following high risk HSCT-TMA diagnosis. |
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E.2.2 | Secondary objectives of the trial |
- Evaluate the safety and tolerability of intravenous (IV) administration of narsoplimab. - Describe the efficacy of narsoplimab by responder rate; survival at 52 weeks; and mean, median, and overall survival rates. - Evaluate peak and trough PK of IV narsoplimab. - Immunogenicity will be evaluated. - Anti-drug antibody (ADA) responses will be summarized by treatment group and will be evaluated. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age at least 28 days and less than 18 years prior to informed consent (Visit 0). 2. Have informed consent from at least one parent or legal guardian as required by local law and regulation. Patient informed consent will be required if the patient has reached the local legal age of majority. 3. Assent from patients as required by local law and regulation. 4. Have received an allogeneic haematopoietic stem cell transplant for the treatment of non-malignant or malignant disease. All donor cell sources are allowed (i.e., matched, mismatched, and haploidentical; related and unrelated; bone marrow, peripheral blood stem cells, and umbilical cord blood). 5. Have a diagnosis of HSCT-TMA defined as having both of the following: -Platelet count < 50,000/µL or a decrease in platelet count > 50% from the highest value obtained following transplant. -Evidence of microangiopathic hemolysis (presence of schistocytes, serum lactate dehydrogenase [LDH] > upper limit of normal ([ULN], or haptoglobin < lower limit of normal [LLN]) 6. Have at least one of the following HSCT-TMA high-risk criteria: - HSCT-TMA persistence > 2 weeks following modification of calcineurin inhibitors or sirolimus OR - Have evidence of high-risk HSCT-TMA defined as at least one of the following: - Spot protein/creatinine ratio > 2 mg/mg - Serum creatinine > 1.5 x the creatinine level prior to TMA development - Biopsy-proven gastrointestinal TMA - TMA-related neurological abnormality (e.g., confusion, stroke, transient ischemic attack [TIA] or seizures) - Pericardial or pleural effusion without alternative explanation - Pulmonary hypertension without alternative explanation - Have Grade III or Grade IV graft-versus-host disease (GVHD) or, in the opinion of the Investigator, risk for development of Grade III or Grade IV GVHD if immunosuppression were to be modified - Have elevated serum C5b-9 (> 244 ng/mL) 7. If sexually active and of childbearing potential (for female paediatric patients, defined as starting at onset of menses), must agree to practice a highly effective method of birth control throughout the study drug treatment and for at least 12 weeks after the last dose of study drug, such method of birth control defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence (abstinence is acceptable when it is in line with the patient’s preferred and usual lifestyle and is defined as complete abstinence of sexual intercourse, not periodic abstinence or withdrawal), or vasectomized partner. 8. Male patients must be willing to avoid fathering children for at least 12 weeks following the last dose of study medication.
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E.4 | Principal exclusion criteria |
1. All treatments for HSCT-TMA are allowed except eculizumab, ravulizumab, and defibrotide within 3 months prior to informed consent, unless failure of therapy can be documented. a. Patients may not be on eculizumab, ravulizumab, or defibrotide for any indication at screening. 2. Have Shiga toxin-producing Escherichia coli haemolytic uraemic syndrome (STEC-HUS). Test results obtained within 28 days prior to informed consent may be used. 3. Have ADAMTS13 activity < 10%. Test results obtained within 28 days prior to informed consent may be used. 4. Have a severe, uncontrolled systemic bacterial or fungal infection requiring antimicrobial therapy or a severe uncontrolled viral infection (as determined by the investigator); prophylactic antimicrobial therapy administered as standard of care is allowed. 5. Have malignant hypertension (blood pressure [BP] > 99th percentile plus 5 mmHg with bilateral hemorrhages or “cotton-wool” exudates on fundoscopic examination). 6. Due to conditions other than HSCT-TMA, have a poor prognosis with a life expectancy of less than 3 months in the opinion of the Investigator. 7. If pregnant or lactating 8. Have received treatment with an investigational drug or device within 4 weeks of entering study. 9. Have abnormal liver function tests defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times ULN within 28 days prior to informed consent through prior to the first dose. 10. Have a positive test by antigen, antibody, or polymerase chain reaction (PCR) for human immunodeficiency virus (HIV); if negative within 28 days prior to informed consent, the test does not need to be repeated. 11. Patients or their parents or legal guardians are an employee of Omeros, Clinical Research Organization (CRO), an Investigator, a study staff member, or an immediate family member. 12. Have a known hypersensitivity to any constituent of the product. 13. Presence of any condition that the Investigator believes would put the patient at risk.
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E.5 End points |
E.5.1 | Primary end point(s) |
100-day survival rate from date of HSCT-TMA diagnosis |
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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) |
- Survival at 52 weeks and median, mean, and overall survival from date of TMA diagnosis - Narsoplimab peak and trough PK and concomitant lectin pathway activation measured by ex vivo assay - Safety will be evaluated by adverse events (AEs) and laboratory measures - Anti-drug antibody response - Responder rate based on clinical response criteria |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
Israel |
United States |
Germany |
Hungary |
Netherlands |
Spain |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 11 |