Pozelimab and Cemdisiran Combination Treatment in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Who Have Received Pozelimab Monotherapy
- Conditions
- Paroxysmal Nocturnal Hemoglobinuria
- Interventions
- Registration Number
- NCT04811716
- Lead Sponsor
- Regeneron Pharmaceuticals
- Brief Summary
The primary objective of the study is to evaluate the safety and tolerability of 2 dosing regimens of pozelimab and cemdisiran combination therapy during the open-label treatment period (OLTP)
The secondary objectives of the study are:
* To evaluate the effect of the combination treatment on the following parameters of intravascular hemolysis: lactate dehydrogenase (LDH) control, breakthrough hemolysis, and inhibition of total complement hemolysis activity (CH50)
* To evaluate the effect of the combination treatment on hemoglobin levels
* To evaluate the effect of the combination treatment on red blood cell (RBC) transfusion requirements
* To evaluate the effect of the combination treatment on clinical outcome assessments (COAs) measuring fatigue and health related quality of life
* To assess the concentrations of total pozelimab in serum and total complement component (C) 5 and cemdisiran in plasma
* To assess immunogenicity to pozelimab and cemdisiran
* To evaluate the long-term safety and efficacy of pozelimab and cemdisiran in an optional open-label extension period (OLEP)
* To assess safety after treatment intensification with pozelimab and cemdisiran
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 24
- Participants with PNH who are receiving treatment with pozelimab monotherapy in the R3918- PNH-1868 study (NCT04162470)
Key
- Documented, positive polymerase chain reaction (PCR) or equivalent test based on regional recommendations for COVID-19 or suspected SARS-CoV-2 infection as defined in the protocol
- Participants with documented history of liver cirrhosis or participants with liver disease with evidence of currently impaired liver function; or participants with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) as described in the protocol
- Significant protocol deviation(s) in the parent study based on the investigator's judgment as described in the protocol
- Any new condition or worsening of an existing condition which, in the opinion of the investigator, would make the participant unsuitable for enrollment or would jeopardize the safety of the participant
- Known hypersensitivity to cemdisiran or any component of cemdisiran formulation
NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Pozelimab Q4W + Cemdisiran Cemdisiran - Pozelimab Q2W + Cemdisiran Pozelimab - Pozelimab Q2W + Cemdisiran Cemdisiran - Pozelimab Q4W + Cemdisiran Pozelimab -
- Primary Outcome Measures
Name Time Method Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) Through Week 28 Open Label Treatment Period (OLTP)
- Secondary Outcome Measures
Name Time Method Concentrations of Cemdisiran in Plasma on Week 28 On Week 28 OLTP
Concentrations of Total C5 on Week 28 On Week 28 OLTP
Concentrations of Total Pozelimab in Serum on Week 52 On Week 52 OLEP
Average LDH (U/L) Based on Area Under the Curve (AUC) From OLTP Week 4 Through Week 28 Week 4 through Week 28 OLTP
Percentage of Participants With Normalization of LDH at Each Visit From Baseline (Day 1e) Through Week 52e Baseline (Day 1e) through week 52e OLEP
Percent Change of Lactate Dehydrogenase (LDH) From Pre-treatment to End-of-treatment Period End of treatment period, approximately 28 Weeks OLTP Pre-treatment (mean of LDH values prior to combination dosing); End-of-treatment (mean of LDH value at week 24- through week 28); percentage of change in Upper Limit of Normal (xULN).
Percentage of Participants Maintaining Adequate Control of Hemolysis From Baseline (Day 1) Through Week 28 Baseline (Day 1) through Week 28 OLTP Adequate control of hemolysis is defined as LDH values ≤1.5 × Upper limit of normal (ULN) from baseline (day 1) to week 28
Percentage of Participants Maintaining Adequate Control of Hemolysis From Week 4 Through Week 28 Week 4 through Week 28 OLTP
Percentage of Participants With Adequate Control of Hemolysis at Each Visit Day 1 Through Week 28 Day 1 through Week 28 OLTP; Adequate control at a visit is defined as having LDH \<=1.5 x ULN at that visit
Percentage of Participants With Normalization of LDH at Each Visit From Baseline (Day 1) Through Week 28 Baseline (Day 1) through Week 28 OLTP; Normalization of LDH was defined as LDH ≤1.0 × ULN at each visit
Average LDH (U/L) Based on Area Under the Curve (AUC) From OLTP Baseline (Day 1) Through Week 28 Baseline (Day 1) through Week 28 OLTP
Percentage of Participants With Breakthrough Hemolysis From Baseline (Day 1) Through Week 28 Baseline (Day 1) through Week 28 OLTP
Breakthrough hemolysis is defined as an increase in LDH with concomitant signs or symptoms associated with hemolysis:
• An increase in LDH occurs when:
* LDH ≥2 × ULN if pre-treatment LDH is ≤1.5 × ULN or
* LDH ≥2 × ULN after initial achievement of LDH ≤1.5 × ULN if pre-treatment LDH is \>1.5 × ULN Signs or symptoms should correspond to those known to be associated with intravascular hemolysis due to Paroxysmal nocturnal hemoglobinuria (PNH) limited to the following: new onset or worsening fatigue, headache, dyspnea, hemoglobinuria, abdominal pain, scleral icterus, erectile dysfunction, chest pain, confusion, dysphagia, anemia including hemoglobin value significantly lower (ie, ≥2g/dL decrease) compared to patient's known baseline hemoglobin values, and thrombotic event.Percentage of Participants With Hemoglobin Stabilization From Baseline (Day 1) Through Week 28 Baseline (Day 1) through Week 28 OLTP Hemoglobin stabilization was defined as participants who did not receive an RBC transfusion and had no decrease in hemoglobin level of ≥2 grams per deciLiter (g/dL).
Change in Hemoglobin Levels From Baseline (Day 1) Through Week 28 Baseline (Day 1) to Week 28 OLTP
Percentage of Participants With Transfusion Avoidance From Baseline (Day 1) Through Week 28 Baseline (Day 1) to Week 28 OLTP Not requiring a red blood cell (RBC) transfusion as per protocol algorithm
Rate of Red Blood Cells (RBCs) Transfused From Baseline (Day 1) to Week 28 Baseline (Day 1) to Week 28 OLTP Rate of RBCs transfused is defined as number of events per person-years of treatment. For each participant, the participant-years are the time from first dose date to week 28 (or early terminations visit if subject discontinued the study early) in the OLTP.
Number of Per-Protocol RBC Units Transfused From Baseline (Day 1) Through Week 28 Baseline (Day 1) to Week 28 OLTP
Change in Total Complement Hemolysis Activity Assay (CH50) From Baseline (Day 1) Through Week 28 Baseline (Day 1) to Week 28 OLTP
Change in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale From Baseline (Day 1) Through Week 28 Baseline (Day 1) to Week 28 OLTP FACIT fatigue is a 13-item scale and for each item 4 is not at all fatigued to 0 very much fatigued. Higher FACIT-Fatigue scores indicate less fatigue (scores range from 0-52). A 5-point change is considered clinically meaningful.
Change in Global Health Status/Quality of Life Scale (GHS/QoL) on the European Organization for Research and Treatment of Cancer: Quality-of-Life Questionnaire Core 30 Items (EORTC QLQ-C30) From Baseline (Day 1) Through Week 28 Baseline (Day 1) to Week 28 OLTP EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. Items contributing to the GHS/QoL, were scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that transformed score lies between 0 to 100. A higher score indicates better global health status/functioning and a negative change from baseline indicated less improvement.
Change in Physical Function (PF) Scores on the EORTC QLQ-C30 From Baseline (Day 1) Through Week 28 Baseline (Day 1) to Week 28 OLTP; EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. Items contributing to the GHS/QoL, were scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that transformed score lies between 0 to 100. A higher score indicates better global health status/functioning and a negative change from baseline indicated less improvement.
Concentrations of Total Pozelimab in Serum on Week 28 On Week 28 OLTP
Number of Participants With Pozelimab Anti-Drug Antibody (ADA) Responses Over Time Up to Week 52 (OLTP [ Week 0 - Week 28] + OLEP [Week 28 - Week 52]) OLTP and OLEP
Number of Participants With Cemdisiran Anti-Drug Antibody (ADA) Responses Over Time Up to Week 52 (OLTP [ Week 0 - Week 28] + OLEP [Week 28 - Week 52]) OLTP and OLEP
Percentage of Participants With TEAEs for Participants Who Received Treatment Intensification Through Week 28 OLTP No participants received dose intensification during the study; Therefore, assessment of the safety of pozelimab + cemdisiran combination therapy in participants requiring dose intensification was not conducted.
Change of LDH From Baseline (Day 1e) to Week 24e Baseline (Day 1e) to Week 24e Optional Open-Label Extension Period (OLEP)
Percent Change of LDH From OLEP Baseline (Day 1e) to Week 24e Baseline (Day 1e) to Week 24e OLEP; Percentage of change for units per liter (U/L)
Change of LDH From Baseline (Day 1e) to Week 52e Baseline (Day 1e) to Week 52e OLEP
Percent Change of LDH From Baseline (Day 1e) to Week 52e Baseline (Day 1e) to Week 52e OLEP
Percentage of Participants Maintaining Adequate Control of Hemolysis From Baseline (Day 1e) Through Week 24e Baseline (Day 1e) through Week 24e OLEP
Percentage of Participants Maintaining Adequate Control of Hemolysis From Baseline (Day 1e) Through Week 52e Baseline (Day 1e) through Week 52e OLEP
Percentage of Participants With Adequate Control of Hemolysis at Each Visit From Baseline (Day 1e) Through Week 52e Baseline (Day 1e) through Week 52e OLEP Adequate control at a visit is defined as having LDH \<=1.5 x ULN at that visit
Average LDH (U/L) Based on Area Under the Curve (AUC) From OLEP Baseline (Day 1e) Through Week 52e Baseline (Day 1e) through Week 52e OLEP
Percentage of Participants With Breakthrough Hemolysis From Baseline (Day 1e) Through Week 24e Baseline (Day 1e) through Week 24e OLEP
Percentage of Participants With Breakthrough Hemolysis From Baseline (Day 1e) Through Week 52e Baseline (Day 1e) through Week 52e OLEP
Percentage of Participants With Hemoglobin Stabilization From Baseline (Day 1e) Through Week 24e Baseline (Day 1e) through Week 24e OLEP Participants who did not receive RBC transfusion and had no decrease in hemoglobin levels
Percentage of Participants With Hemoglobin Stabilization From Baseline (Day 1e) Through Week 52e Baseline (Day 1e) through Week 52e OLEP Participants who did not receive RBC transfusion and had no decrease in hemoglobin levels
Change in Hemoglobin Levels From Baseline (Day 1e) to Week 24e Baseline (Day 1e) to Week 24e OLEP
Change in Hemoglobin Levels From Baseline (Day 1e) to Week 52e Baseline (Day 1e) to Week 52e OLEP
Percentage of Participants With Per-Protocol Transfusion Avoidance From Baseline (Day 1e) Through Week 24e Baseline (Day 1e) through Week 24e OLEP Not requiring a RBC transfusion as per protocol algorithm
Percentage of Participants With Per-Protocol Transfusion Avoidance From Baseline (Day 1e) Through Week 52e Baseline (Day 1e) to Week 52e OLEP Not requiring a RBC transfusion as per protocol algorithm
Rate of RBCs Transfused From Baseline (Day 1e) to Week 24e Baseline (Day 1e) to Week 24e OLEP
Rate of RBCs Transfused From Baseline (Day 1e) to Week 52e Baseline (Day 1e) to Week 52e OLEP
Number of Units of RBCs Transfused From Baseline (Day 1e) to Week 24e Baseline (Day 1e) to Week 24e OLEP
Number of Units of RBCs Transfused From Baseline (Day 1e) to Week 52e Baseline (Day 1e) to Week 52e OLEP
Change in CH50 From Baseline (Day 1e) to Week 16e Baseline (Day 1e) to Week 16e OLEP
Change in CH50 From Baseline (Day 1e) to Week 24e Baseline (Day 1e) to Week 24e OLEP
Change in CH50 From Baseline (Day 1e) to Week 52e Baseline (Day 1e) to Week 52e OLEP
Percent Change in CH50 From Baseline (Day 1e) to Week 16e Baseline (Day 1e) to Week 16e OLEP
Percent Change in CH50 From Baseline (Day 1e) to Week 24e Baseline (Day 1e) to Week 24e OLEP
Percent Change in CH50 From Baseline (Day 1e) to Week 52e Baseline (Day 1e) to Week 52e OLEP
Change in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale From Baseline (Day 1e) to Week 52e Baseline (Day 1e) to Week 52e OLEP; The FACIT-Fatigue is a 13-item, self-administered assessment of 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 QoL in participants with cancer and other chronic illnesses. The FACIT-Fatigue items are measured with a 5-point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating less fatigue. A 5-point change is considered clinically meaningful.
Change in GHS/QoL on the EORTC QLQ-C30 From Baseline (Day 1e) to Week 52e Baseline (Day 1e) to Week 52e OLEP; EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. Items contributing to the GHS/QoL, were scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that transformed score lies between 0 to 100. A higher score indicates better global health status/functioning and a negative change from baseline indicated less improvement.
Change in PF Scores on the EORTC QLQ-C30 From Baseline (Day 1e) to Week 52e Baseline (Day 1e) to Week 52e OLEP; EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. Items contributing to the GHS/QoL, were scored 1 ("very poor") to 7 ("excellent"). A linear transformation was applied to the raw scores so that transformed score lies between 0 to 100. A higher score indicates better global health status/functioning and a negative change from baseline indicated less improvement.
Percentage of Participants With TEAEs Up to Week 52 Up to Week 52 OLEP
Concentrations of Total C5 on Week 52 On Week 52 OLEP
Concentrations of Cemdisiran in Plasma on Week 52 On Week 52 OLEP
Trial Locations
- Locations (13)
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Hospital Sibu
🇲🇾Sibu, Sarawak, Malaysia
Yonsei University College of Medicine, Severance Hospital
🇰🇷Seoul, Korea, Republic of
Pusan National University Hospital
🇰🇷Busan, Korea, Republic of
Prince of Wales Hospital
🇭🇰Hong Kong, New Territories, Hong Kong
Hospital Sultanah Nur Zahirah
🇲🇾Kuala Terengganu, Terengganu, Malaysia
Ewha Womans University Medical Centre
🇰🇷Seoul, Korea, Republic of
Hospital Miri
🇲🇾Miri, Sarawak, Malaysia
Chang Gung Memorial Hospital
🇨🇳Taoyuan City, Taiwan
D l Pesti Centrumk rh z Orsz gos Hematol giai s Infektol giai Int zet
🇭🇺Budapest, Nagyvárad Tér 1, Hungary
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
St. James's University Hospital
🇬🇧Leeds, West Yorkshire, United Kingdom
Samsung Medical Center
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of