| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Paroxysmal nocturnal hemoglobinuria (PNH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| A rare disease causing the breakdown of red blood cells |
|
| 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 | 100000004857 |
|
| 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 |
Cohort A: To describe the effect of pozelimab + cemdisiran combination treatment compared to ravulizumab treatment on hemolysis, as assessed by lactate dehydrogenase (LDH), over a 26-week treatment period in patients with active PNH who are complement inhibitor treatment-naive or have not recently received complement inhibitor therapy.
Cohort B: To evaluate the effect of pozelimab + cemdisiran combination treatment compared to eculizumab treatment on hemolysis, as assessed by sustained suppression of LDH, and transfusion avoidance over a 26-week treatment period in patients with active PNH who are complement inhibitor treatment-naive or have not recently received complement inhibitor therapy. |
|
| E.2.2 | Secondary objectives of the trial |
Cohort A:
•Describe the effect of pozelimab + cemdisiran vs ravulizumab on the following:
-Measures of hemolysis
-Transfusion parameters
-Hemoglobin levels
-Fatigue as assessed by clinical outcome assessments (COAs)
-Health-related quality of life (HRQoL) as assessed by COAs
-Safety and tolerability
-Complement activation
•To assess the concentrations of total pozelimab and total ravulizumab in serum and cemdisiran and total C5 protein in plasma
•To assess the immunogenicity of pozelimab and cemdisiran
Cohort B:
•Evaluate the effect of pozelimab + cemdisiran vs eculizumab on the following:
-Measures of hemolysis
-Transfusion parameters
-Hemoglobin levels
-Fatigue as assessed by COAs
-HRQoL as assessed by COAs
-Safety and tolerability
-Complement activation
•To assess the concentrations of total pozelimab and total eculizumab in serum and cemdisiran and total C5 protein in plasma
•To assess the immunogenicity of pozelimab and cemdisiran |
|
| 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 |
1. Future Biomedical Research (FBR) (Optional):
Residual biomarker samples for study-related research, as well as unused PK and ADA samples, will be stored for up to 15 years after the final date of the database lock (or for a shorter time period if
required per regional laws and regulations). 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.
2. Pharmacogenomic Analysis (Optional):
Whole blood samples for DNA extraction should be collected on day 1/baseline (predose), but can be collected at a later study visit. Whole blood samples for RNA extraction will be collected at time points according to Table 1 of protocol. DNA and RNA samples will be collected for pharmacogenomics analyses to understand the genetic
determinants of efficacy and safety associated with the treatments in this study and the molecular basis of PNH and related diseases. 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 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. Analyses may include sequence determination or single nucleotide polymorphism studies of candidate genes and surrounding genomic regions. Other methods, including whole-exome sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome sequencing (or other methods for quantitating RNA expression) may also be performed. The list of methods may be expanded to include novel methodology that may be developed during the course of this study or sample storage period. |
|
| E.3 | Principal inclusion criteria |
1. Diagnosis of PNH confirmed by high-sensitivity flow cytometry testing with PNH granulocytes described in the protocol
2. Active disease, as defined by the presence of 1 or more PNH-related signs or symptoms described in the protocol
3. LDH level ≥2 × upper limit of normal (ULN) at the screening visit
Note: Other protocol-defined Inclusion Criteria apply |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with eculizumab within 3 months prior to screening, ravulizumab within 6 months prior to screening, or other complement inhibitors within 5 half-lives of the respective agent prior to screening
2. Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant
3. Body weight <40 kilograms at screening visit
4. Planned use of any complement inhibitor therapy other than study drugs during the treatment period
5. Not meeting meningococcal vaccination requirements for ravulizumab (Cohort A) or eculizumab (Cohort B) according to the current local prescribing information (where available) and at a minimum documentation of meningococcal vaccination within 5 years prior to screening visit
6. Any contraindication for receiving Neisseria meningitidis vaccination
7. Unable to take antibiotics for meningococcal prophylaxis (if required by local ravulizumab [Cohort A] or eculizumab [Cohort B] prescribing information, where available, or national guidelines/local practice or if necessary when vaccination is less than 2 weeks from study treatment initiation)
8. Any active, ongoing infection or a recent infection requiring ongoing systemic treatment with antibiotics, antivirals, or antifungals within 2 weeks of screening or during the screening period
9. Documented history of active, uncontrolled, ongoing systemic autoimmune diseases
Note: Other protocol-defined Exclusion Criteria apply |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Cohort A: Percent change in lactate dehydrogenase (LDH)
2. Cohort B: Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN
3. Cohort B: Transfusion avoidance ((not requiring a red blood cell (RBC) transfusion per the protocol) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline to week 26
2. Week 8 through week 26
3. Day 1 through week 26 |
|
| E.5.2 | Secondary end point(s) |
Cohort A and B (unless otherwise indicated)
1. Maintenance of adequate control of hemolysis (defined as LDH ≤1.5 × ULN) (Cohort A)
2. Breakthrough hemolysis (defined as LDH ≥2 × ULN)
3. Adequate control of hemolysis (defined as LDH ≤1.5 × ULN)
4. Hemoglobin stabilization (defined as patients who do not receive an RBC transfusion and have no decrease in hemoglobin level from baseline of ≥2 g/dL)
5. Normalization of LDH
6. Transfusion Avoidance (Cohort A)
7. Change in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT)-Fatigue Scale
8. Change in physical function (PF) scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30)
9. Change in global health status (GHS)/QoL scale score on the EORTC-QLC-C30
10. Percent change in LDH (Cohort B)
11. Rate of RBC transfused per protocol algorithm
12. Number of units of RBC transfused per protocol algorithm
13. Time to first LDH ≤1.5 × ULN
14. Time to first LDH ≤1.0 × ULN
15. Percentage of days with LDH ≤1.5 × ULN
16. Change in hemoglobin levels
17. Incidence and severity of treatment emergent serious adverse events (SAEs)
18. Incidence and severity of treatment-emergent adverse events (TEAEs) of special interest
19. Incidence and severity of TEAE leading to treatment discontinuation
20. Change in total CH50
21. Percent change in total CH50
22. Concentration of total C5 in plasma
23. Concentrations of total pozelimab in serum
24. Concentrations of cemdisiran in plasma
25. Concentrations of total ravulizumab (Cohort A) and total eculizumab (Cohort B) in serum
26. Incidence of treatment emergent anti-drug antibodies (ADAs) to pozelimab
27. Incidence of treatment emergent ADAs to cemdisiran |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: Week 8 through week 26, inclusive
2: Day 1 (post-baseline) through week 26
3: Week 8 through week 26, inclusive
4: Day 1 (post-baseline) through week 26
5: Week 8 through week 26, inclusive
6: Day 1 through week 26
7-10: From baseline to week 26
11-12: Day 1 (post-baseline) through week 26
13-14: Up to Week 26
15. Between week 8 and week 26, inclusive
16: From baseline to week 26
17-19: Up to Week 26
20-21: From baseline to week 26
22-27: Throughout the study, up to 52 weeks (OLTP and SFU) |
|
| 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) | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| Canada |
| China |
| Colombia |
| India |
| Japan |
| Jordan |
| Malaysia |
| Mexico |
| Peru |
| Philippines |
| Singapore |
| South Africa |
| Thailand |
| United States |
| Turkey |
| France |
| Greece |
| Hungary |
| Italy |
| Poland |
| Spain |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
| Romania |
|
| 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
|
|
| 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 | 5 |
| 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 | 5 |
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