| 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 |
| • To evaluate the effect of pozelimab and cemdisiran combination therapy on hemolysis, as assessed by LDH, after 36 weeks of treatment, in patients with PNH who switch from eculizumab or ravulizumab therapy to the combination treatment versus patients who continue their eculizumab or ravulizumab therapy. |
|
| E.2.2 | Secondary objectives of the trial |
• Evaluate the effect of pozelimab and cemdisiran combination treatment versus anti-C5 standard-of-care treatment (eculizumab or ravulizumab) on the following:
− Transfusion requirements and transfusion parameters
− Measures of hemolysis: LDH control, breakthrough hemolysis, and inhibition of CH50
− Hemoglobin levels
− Fatigue as assessed by Clinical Outcome Assessments (COAs)
− Health Related Quality of Life (HRQoL) as assessed by COAs
− Safety and tolerability
• To assess the concentrations of total pozelimab and either total eculizumab or total ravulizumab in serum and emdisiran 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 |
Future Biomedical Research (Optional):
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. 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.
Pharmacogenomic Analysis (Optional):
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. 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. 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. These samples will be single-coded as defined by the International Council on Harmonisation (ICH) guideline E15. 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). If there are specific site or country requirements involving the
pharmacogenomic analyses which the sponsor is unable to comply with, samples will not be collected at those sites.
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 a history of high-sensitivity flow cytometry from prior testing
2. Ongoing treatment with eculizumab or ravulizumab prior to screening visit as described in the protocol Note: Biosimilars are not permitted, unless approved by the Sponsor
Note: Other protocol-defined Inclusion Criteria apply |
|
| E.4 | Principal exclusion criteria |
1. Patients with a screening LDH >1.5 × upper limit of normal (ULN) who have not taken their C5 inhibitor within the labeled dose interval at the dose prior to the screening LDH assessment
2. Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant
3. Body weight < 40 kilograms at screening visit
4. Any use of complement inhibitor therapy other than eculizumab or ravulizumab in the 26 weeks prior to the screening visit or planned use during the study with the exception of study treatments
5. Not meeting meningococcal vaccination requirements for eculizumab or ravulizumab 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. Positive for hepatitis B, and/ or hepatitis C as described in the protocol
8. History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
9. Participation in another interventional clinical study (except R3918-PNH-2021) or use of any experimental therapy within 30 days before screening visit or within 5 half-lives of that investigational product, whichever is greater, with the exception of eculizumab or ravulizumab.
10. Patients with functional or anatomic asplenia
Note: Other protocol-defined Exclusion Criteria apply |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change in lactate dehydrogenase (LDH) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Transfusion avoidance (not requiring a red blood cell (RBC) transfusion per the protocol)
2. Breakthrough hemolysis in patients with a baseline LDH ≤ 1.5× ULN
3. Hemoglobin stabilization (patients who do not receive an RBC transfusion and have no decrease in hemoglobin level from baseline of ≥ 2 g/dL)
4. Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN)
5. Adequate control of hemolysis (LDH ≤1.5 × ULN)
6. Normalization of LDH (LDH ≤1.0 × ULN)
7. Change in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale
8. Change in Physical Function (PF) score on the European organization for research and treatment of cancer quality-of-Life questionnaire Core 30 Items (EORTC-QLQ-C30)
9. Change in global health status (GHS)/QoL scale score on the EORTC-QLQ-C30
10. Transfusion avoidance (not requiring an RBC transfusion as per protocol algorithm based on hemoglobin values after day 1)
11. Breakthrough hemolysis, in patients with a baseline LDH ≤1.5× ULN
12. Hemoglobin stabilization (patients who do not receive an RBC transfusion and have no decrease in hemoglobin level from baseline of ≥ 2 g/dL)
13. Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN)
14. Adequate control of hemolysis (LDH ≤1.5 × ULN)
15. Normalization of LDH (LDH ≤1.0 × ULN)
16. Rate of RBCs transfused per protocol algorithm
17. Number of units of RBCs transfused per protocol algorithm
18. Change in hemoglobin levels
19. Incidence and severity of treatment emergent serious adverse events (SAEs)
20. Incidence and severity of treatment-emergent adverse events (TEAEs) of special interest
21. Incidence and severity TEAEs leading to treatment discontinuation
22. Change in total CH50
23. Percent change in total CH50
24. Concentration of total C5 in plasma
25. Concentrations of total pozelimab in serum
26. Concentrations of cemdisiran in plasma
27. Concentrations of total eculizumab
28. Concentrations of total ravulizumab in serum
29. Incidence of treatment emergent anti-drug antibodies (ADAs) to pozelimab
30. Incidence of treatment emergent ADAs to cemdisiran |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. After day 1 through week 36
4-6. Week 8 through week 36
7-9. Baseline to week 36
10-12. Week 4 through week 36
13-15. After day 1 through week 36
16-17. After day 1 through week 36 and Week 4 through week 36
18. Baseline to week 36
19-21. 36 weeks
22-23. Baseline to week 36
24-29. Throughout the study, up to 62 weeks (OLTP and SFU)
30. 36 weeks |
|
| 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 | 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Brazil |
| Colombia |
| Japan |
| Korea, Republic of |
| Mexico |
| Philippines |
| Singapore |
| Taiwan |
| Thailand |
| United States |
| France |
| Poland |
| Netherlands |
| Romania |
| Spain |
| Germany |
| Greece |
| Italy |
| Hungary |
| Portugal |
| Turkey |
| United Kingdom |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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