Efficacy and Safety of the Combination of Pozelimab and Cemdisiran Versus Continued Eculizumab or Ravulizumab Treatment in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria

Phase 3TerminatedNCT05131204

Regeneron Pharmaceuticals3 enrolled

Overview

The primary objective of the study is: To evaluate the effect of pozelimab and cemdisiran combination therapy on hemolysis, as assessed by lactate dehydrogenase (LDH), after 36 weeks of treatment, in patients with PNH who switch from eculizumab or ravulizumab therapy versus patients who continue their eculizumab or ravulizumab therapy The secondary objectives of the study are to: * 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 total cemdisiran and total C5 protein in plasma * To assess the immunogenicity of pozelimab and cemdisiran

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Paroxysmal Nocturnal Hemoglobinuria

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: 1. Diagnosis of PNH confirmed by a history of high-sensitivity flow cytometry from prior testing 2. Treated with eculizumab or ravulizumab prior to screening visit as described in the protocol Note: Biosimilars are not permitted, unless approved by the Sponsor Key Exclusion Criteria: 1. Patients with a screening LDH \>1.5 × 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 Inclusion/ Exclusion Criteria apply

Outcomes

Primary Outcomes

Percent Change in Lactate Dehydrogenase (LDH) From Baseline to Week 36

Time frame: From baseline to week 36

Secondary Outcomes

Percentage of Participants With Transfusion Avoidance After Day 1 Through Week 36

Participants who do not receive a red blood cell (RBC) transfusion as per protocol algorithm based on post baseline hemoglobin values

Time frame: Day 1 through week 36

Percentage of Participants With Transfusion Avoidance From Week 4 Through Week 36

Participants who do not receive an RBC transfusion as per protocol algorithm based on post baseline hemoglobin values

Time frame: Week 4 through week 36

Percentage of Participants With Breakthrough Hemolysis After Day 1 Through Week 36

Participants with an increase in LDH with concomitant signs or symptoms associated with hemolysis as described in the protocol

Time frame: Day 1 through week 36

Percentage of Participants With Breakthrough Hemolysis From Week 4 Through Week 36

Participants with an increase in LDH with concomitant signs or symptoms associated with hemolysis as described in the protocol

Time frame: Week 4 (day 29) through week 36

Percentage of Participants With Hemoglobin Stabilization After Day 1 Through Week 36

Participants who do not receive an RBC transfusion and have no decrease in hemoglobin level as defined in the protocol

Time frame: Day 1 through week 36

Percentage of Participants With Hemoglobin Stabilization From Week 4 Through Week 36

Participants who do not receive an RBC transfusion and have no decrease in hemoglobin level as defined in the protocol

Time frame: Week 4 (day 29) through week 36

Percentage of Participants With Adequate Control of LDH From Week 8 Through Week 36

Percentage of participants with adequate control of LDH as defined in the protocol

Time frame: Week 8 (day 57) through week 36

Percentage of Participants With Adequate Control of LDH After Day 1 Though Week 36

Percentage of participants with adequate control of LDH as defined in the protocol

Time frame: Day 1 through week 36

Percentage of Participants Who Maintained Adequate Control of Hemolysis From Week 8 Through Week 36

Percentage of participants with adequate control of LDH as defined in the protocol

Time frame: Week 8 through week 36

Percentage of Participants Who Maintained Adequate Control of Hemolysis After Day 1 Through Week 36

Percentage of participants with adequate control of LDH as defined in the protocol

Time frame: Day 1 through week 36

Percentage of Participants With Normalization of LDH From Week 8 Through Week 36

Percentage of participants with normalization of LDH as defined in the protocol

Time frame: Week 8 (day 57) through week 36

Percentage of Participants With Normalization of LDH After Day 1 Through Week 36

Percentage of participants with normalization of LDH as defined in the protocol

Time frame: Day 1 through week 36

Change in Fatigue as Measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale From Baseline to Week 36

The FACIT-Fatigue is a 13 item, self-administered clinical outcome assessment (COA) assessing an individual's level of fatigue during their usual daily activities over the past week. This questionnaire is part of the FACIT measurement system, a compilation of questions measuring health related quality of life (QoL) in patients with cancer and other chronic illnesses. The FACIT-Fatigue assesses the level of fatigue using a Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue.

Time frame: From baseline to week 36

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) From Baseline to Week 36

EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including global health status/quality of life, functional Scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Participants rate items on a 4-point scale, with 1 as "not at all" and 4 as "very much."

Time frame: From baseline to week 36

Change in Global Health Status (GHS)/QoL Scale Score on the EORTC-QLQ-C30 From Baseline to Week 36

EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including global health status/quality of life, functional Scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea and vomiting, and pain), and 7 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, sleep and financial difficulties). Participants rate items on a 4-point scale, with 1 as "not at all" and 4 as "very much."

Time frame: From baseline to week 36

Rate of RBCs Transfused Per Protocol Algorithm After Day 1 Through Week 36

Per protocol algorithm

Time frame: Day 1 through week 36

Rate of RBCs Transfused Per Protocol Algorithm From Week 4 Through Week 36

Per protocol algorithm

Time frame: Week 4 through week 36

Number of Units of RBCs Transfused Per Protocol Algorithm After Day 1 Through Week 36

Per protocol algorithm

Time frame: Day 1 through week 36

Number of Units of RBCs Transfused Per Protocol Algorithm From Week 4 Through Week 36

Per protocol algorithm

Time frame: Week 4 through week 36

Change in Hemoglobin Levels From Baseline to Week 36

Per protocol algorithm

Time frame: From baseline to week 36

Incidence of Treatment Emergent Serious Adverse Events (SAEs)

Treatment period and safety follow up period

Time frame: Up to week 29

Incidence of Treatment-emergent Adverse Events (TEAEs) of Special Interest

Treatment period and safety follow up period

Time frame: Up to week 29

Incidence of TEAEs Leading to Treatment Discontinuation

Treatment period and safety follow up period

Time frame: Up to week 29

Change in Total CH50 From Baseline to Week 36

Time frame: From baseline to week 36

Percent Change in Total CH50 From Baseline to Week 36

Time frame: From baseline to week 36

Concentration of Total C5 in Plasma Through Week 62

Treatment period and safety follow up period

Time frame: Through week 62

Concentrations of Total Pozelimab in Serum Through Week 62

Treatment period and safety follow up period

Time frame: Through week 62

Concentrations of Total Cemdisiran in Plasma Through Week 32

Treatment period

Time frame: Through week 32

Concentrations of Total Eculizumab in Serum Through Week 40

Treatment period

Time frame: Through week 40

Concentrations of Total Ravulizumab in Plasma Through Week 44

Treatment period

Time frame: Through week 44

Incidence of Treatment Emergent Anti-drug Antibodies (ADAs) to Pozelimab Through Week 62

Efficacy and Safety of the Combination of Pozelimab and Cemdisiran Versus Continued Eculizumab or Ravulizumab Treatment in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes