E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paroxysmal nocturnal hemoglobinuria (PNH) |
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E.1.1.1 | Medical condition in easily understood language |
Paroxysmal nocturnal hemoglobinuria (PNH) |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055629 |
E.1.2 | Term | Paroxysmal nocturnal hemoglobinuria |
E.1.2 | System Organ Class | 10038359 - Renal and urinary 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 |
The primary objective of the study is to describe the long-term safety, tolerability, and efficacy of pozelimab + cemdisiran combination therapy in patients with paroxysmal nocturnal hemoglobinuria (PNH) |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to describe the long-term effect of the combination of pozelimab and cemdisiran on: • Measures of intravascular hemolysis • Transfusion parameters • Hemoglobin levels • Fatigue as assessed by a Patient Reported Outcome (PRO) • Physical Function as assessed by a PRO • Change in Global Health Status (GHS) as assessed by a PRO • Complement activation • Concentrations of total pozelimab in serum and cemdisiran and total complement component 5 (C5) protein in plasma • Immunogenicity of pozelimab and cemdisiran |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Future Biomedical Research Patients who agree to participate in the future biomedical research (FBR) sub-study will be required to consent to this optional sub-study before samples are banked for FBR. The samples may be utilized for FBR that may or may not be directly related to the study, including being used as reference samples and assay development or validation. The results of these future biomedical research analyses will not be presented in the CSR.
Pharmacogenomic Analysis Patients who agree to participate in the genomics sub-study will be required to consent to this optional sub-study before collection of the samples. The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or biomarker response to pozelimab and cemdisiran, other PNH clinical outcome measures and possible AEs. In addition, associations between genomic variants and prognosis or progression of PNH as well as related complement-mediated diseases may also be studied. These data may be used or combined with data collected from other studies to identify and validate genomic markers related to the study drug, target pathway, or PNH and related diseases. |
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E.3 | Principal inclusion criteria |
Patients Entering from the Parent Study 1. Patients with PNH who have completed, without permanent discontinuation, study treatment in the parent study (R3918-PNH-2021[EudraCT: 2020-004486-40]), including the post-Open-label treatment period (OLTP) transition period, if applicable. 2. Willing and able to comply with clinic visits and study-related procedures, including meningococcal vaccinations required per protocol.
Patients Entering with C5 polymorphism 1. Patients with PNH who have a documented C5 polymorphism rendering them refractory to eculizumab or ravulizumab (eg, p.Arg885His, p.Arg885Cys), as described in the protocol 2. Diagnosis of PNH confirmed by high-sensitivity flow cytometry testing with PNH granulocytes or monocytes 3. Active disease, as defined by the presence of 1 or more PNH-related sign or symptom as described in the protocol 4. LDH level ≥2 × upper limit of normal (ULN) at the screening visit 5. Willing and able to comply with clinic visits and study-related procedures, including meningococcal vaccinations required per protocol
Other protocol-defined Inclusion Criteria apply |
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E.4 | Principal exclusion criteria |
Patients Entering from the Parent Study 1. Significant protocol deviation(s) in the parent study based on the investigator's judgment and to the extent that these would (if continued) impact the study objectives and/or safety of the patient 2. Any new condition or worsening of an existing condition which, in the opinion of the investigator, would make the patient unsuitable for enrollment or could interfere with the patient participating in or completing the study
Patients Entering with C5 polymorphism 1. Prior treatment with complement inhibitors within 5 half-lives of the respective agent prior to screening, except for prior eculizumab or ravulizumab which are not exclusionary 2. Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant 3. Not meeting meningococcal vaccination requirements and, at a minimum, documentation of quadrivalent meningococcal vaccination within 5 years prior to enrollment and serotype B vaccine (when available) within 3 years prior to enrollment as described in the protocol 4. Positive hepatitis B surface antigen or hepatitis C virus Ribonucleic acid (RNA) during screening 5. Patients with known HIV with history of opportunistic infections in the last 1 year as described in the protocol 6. Known hereditary complement deficiency 7. Documented history of active, uncontrolled, ongoing systemicautoimmune diseases 8. Documented history of liver cirrhosis or patients with liver disease with evidence of current impaired liver function or patients with elevations in Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) (unrelated to PNH or its complications) as described in the protocol
Other protocol-defined Exclusion Criteria apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Incidence and severity of treatment-emergent serious adverse events (SAEs) 2. Incidence and severity of treatment-emergent adverse events of special interest (AESIs) 3. Incidence and severity of adverse events (AEs) leading to permanent treatment discontinuation 4. Percent change in lactate dehydrogenase (LDH) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-3: Up to week 108 4: Baseline to week 36 |
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E.5.2 | Secondary end point(s) |
1. Maintenance of adequate control of hemolysis 2. Adequate control of hemolysis 3. Transfusion avoidance 4. Breakthrough hemolysis 5. Hemoglobin stabilization 6. Percent change in lactate dehydrogenase (LDH) 7. Change in fatigue as measured by the FACIT-Fatigue scale 8. Change in physical function (PF) scores on the EORTC QLQ-C30 9. Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30 10. Normalization of LDH 11. Rate of red blood cell (RBC) transfusion 12. Number of units of RBC transfusion 13. Percentage of days with LDH ≤1.5x upper limit of normal (ULN) 14. Change in hemoglobin levels 15. Change in total complement hemolytic activity assay (CH50) 16. Percent change in CH50 17. Concentrations of total pozelimab in serum 18. Concentrations of cemdisiran in plasma 19. Incidence of treatment-emergent anti-drug antibodies to pozelimab 20. Incidence of treatment-emergent anti-drug antibodies to cemdisiran 21. Concentration of total complement component 5 (C5) in plasma 22. Percent change of concentration of total C5 in plasma |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: Post-baseline through week 36, 48, 76, 108 2, 10: Post-baseline through week 108 3-5, 11-13: Post-baseline through week 36, 48, 76, 108 6: From baseline to weeks 48,76 and 108 7-9, 14: From baseline to week 36, 48, 76, 108 15-17, 19-22: Through week 108 18: Through week 24 |
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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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
Colombia |
Malaysia |
Peru |
Philippines |
Singapore |
Korea, Democratic People's Republic of |
Taiwan |
Brazil |
Canada |
China |
India |
Japan |
Jordan |
Mexico |
South Africa |
Thailand |
United Kingdom |
United States |
France |
Germany |
Greece |
Hungary |
Italy |
Poland |
Romania |
Spain |
Türkiye |
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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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The global end of study is defined as the date the last patient completes the last study visit, withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be contacted by the investigator) |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 2 |