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
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Administered Sub-cutaneous (SC) per protocol
Administered SC per protocol
Prince of Wales Hospital
Hong Kong, New Territories, Hong Kong
D l Pesti Centrumk rh z Orsz gos Hematol giai s Infektol giai Int zet
Budapest, Nagyvárad Tér 1, Hungary
Hospital Miri
Miri, Sarawak, Malaysia
Hospital Sibu
Sibu, Sarawak, Malaysia
Hospital Sultanah Nur Zahirah
Kuala Terengganu, Terengganu, Malaysia
Samsung Medical Center
Seoul, Seoul Teugbyeolsi, South Korea
Pusan National University Hospital
Busan, South Korea
Seoul National University Hospital
Seoul, South Korea
Yonsei University College of Medicine, Severance Hospital
Seoul, South Korea
Ewha Womans University Medical Centre
Seoul, South Korea
...and 3 more locations
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)
Open Label Treatment Period (OLTP)
Time frame: Through Week 28
Percent Change of Lactate Dehydrogenase (LDH) From Pre-treatment to End-of-treatment Period
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).
Time frame: End of treatment period, approximately 28 Weeks
Percentage of Participants Maintaining Adequate Control of Hemolysis From 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
Time frame: Baseline (Day 1) through Week 28
Percentage of Participants Maintaining Adequate Control of Hemolysis From Week 4 Through Week 28
OLTP
Time frame: Week 4 through Week 28
Percentage of Participants With Adequate Control of Hemolysis at Each Visit Day 1 Through Week 28
OLTP; Adequate control at a visit is defined as having LDH \<=1.5 x ULN at that visit
Time frame: Day 1 through Week 28
Percentage of Participants With Normalization of LDH at Each Visit From Baseline (Day 1) Through Week 28
OLTP; Normalization of LDH was defined as LDH ≤1.0 × ULN at each visit
Time frame: Baseline (Day 1) through Week 28
Average LDH (U/L) Based on Area Under the Curve (AUC) From OLTP Baseline (Day 1) Through Week 28
OLTP
Time frame: Baseline (Day 1) through Week 28
Average LDH (U/L) Based on Area Under the Curve (AUC) From OLTP Week 4 Through Week 28
OLTP
Time frame: Week 4 through Week 28
Percentage of Participants With Breakthrough Hemolysis From 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.
Time frame: Baseline (Day 1) through Week 28
Percentage of Participants With Hemoglobin Stabilization From 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).
Time frame: Baseline (Day 1) through Week 28
Change in Hemoglobin Levels From Baseline (Day 1) Through Week 28
OLTP
Time frame: Baseline (Day 1) to Week 28
Percentage of Participants With Transfusion Avoidance From Baseline (Day 1) Through Week 28
OLTP Not requiring a red blood cell (RBC) transfusion as per protocol algorithm
Time frame: Baseline (Day 1) to Week 28
Rate of Red Blood Cells (RBCs) Transfused From 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.
Time frame: Baseline (Day 1) to Week 28
Number of Per-Protocol RBC Units Transfused From Baseline (Day 1) Through Week 28
OLTP
Time frame: Baseline (Day 1) to Week 28
Change in Total Complement Hemolysis Activity Assay (CH50) From Baseline (Day 1) Through Week 28
OLTP
Time frame: Baseline (Day 1) to Week 28
Change in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale From Baseline (Day 1) Through 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.
Time frame: Baseline (Day 1) to Week 28
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
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.
Time frame: Baseline (Day 1) to Week 28
Change in Physical Function (PF) Scores on the EORTC QLQ-C30 From Baseline (Day 1) Through 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.
Time frame: Baseline (Day 1) to Week 28
Concentrations of Total Pozelimab in Serum on Week 28
OLTP
Time frame: On Week 28
Concentrations of Cemdisiran in Plasma on Week 28
OLTP
Time frame: On Week 28
Concentrations of Total C5 on Week 28
OLTP
Time frame: On Week 28
Number of Participants With Pozelimab Anti-Drug Antibody (ADA) Responses Over Time
OLTP and OLEP
Time frame: Up to Week 52 (OLTP [ Week 0 - Week 28] + OLEP [Week 28 - Week 52])
Number of Participants With Cemdisiran Anti-Drug Antibody (ADA) Responses Over Time
OLTP and OLEP
Time frame: Up to Week 52 (OLTP [ Week 0 - Week 28] + OLEP [Week 28 - Week 52])
Percentage of Participants With TEAEs for Participants Who Received Treatment Intensification
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.
Time frame: Through Week 28
Change of LDH From Baseline (Day 1e) to Week 24e
Optional Open-Label Extension Period (OLEP)
Time frame: Baseline (Day 1e) to Week 24e
Percent Change of LDH From OLEP Baseline (Day 1e) to Week 24e
OLEP; Percentage of change for units per liter (U/L)
Time frame: Baseline (Day 1e) to Week 24e
Change of LDH From Baseline (Day 1e) to Week 52e
OLEP
Time frame: Baseline (Day 1e) to Week 52e
Percent Change of LDH From Baseline (Day 1e) to Week 52e
OLEP
Time frame: Baseline (Day 1e) to Week 52e
Percentage of Participants Maintaining Adequate Control of Hemolysis From Baseline (Day 1e) Through Week 24e
OLEP
Time frame: Baseline (Day 1e) through Week 24e
Percentage of Participants Maintaining Adequate Control of Hemolysis From Baseline (Day 1e) Through Week 52e
OLEP
Time frame: Baseline (Day 1e) through Week 52e
Percentage of Participants With Adequate Control of Hemolysis at Each Visit From Baseline (Day 1e) Through Week 52e
OLEP Adequate control at a visit is defined as having LDH \<=1.5 x ULN at that visit
Time frame: Baseline (Day 1e) through Week 52e
Percentage of Participants With Normalization of LDH at Each Visit From Baseline (Day 1e) Through Week 52e
OLEP
Time frame: Baseline (Day 1e) through week 52e
Average LDH (U/L) Based on Area Under the Curve (AUC) From OLEP Baseline (Day 1e) Through Week 52e
OLEP
Time frame: Baseline (Day 1e) through Week 52e
Percentage of Participants With Breakthrough Hemolysis From Baseline (Day 1e) Through Week 24e
OLEP
Time frame: Baseline (Day 1e) through Week 24e
Percentage of Participants With Breakthrough Hemolysis From Baseline (Day 1e) Through Week 52e
OLEP
Time frame: Baseline (Day 1e) through Week 52e
Percentage of Participants With Hemoglobin Stabilization From Baseline (Day 1e) Through Week 24e
OLEP Participants who did not receive RBC transfusion and had no decrease in hemoglobin levels
Time frame: Baseline (Day 1e) through Week 24e
Percentage of Participants With Hemoglobin Stabilization From Baseline (Day 1e) Through Week 52e
OLEP Participants who did not receive RBC transfusion and had no decrease in hemoglobin levels
Time frame: Baseline (Day 1e) through Week 52e
Change in Hemoglobin Levels From Baseline (Day 1e) to Week 24e
OLEP
Time frame: Baseline (Day 1e) to Week 24e
Change in Hemoglobin Levels From Baseline (Day 1e) to Week 52e
OLEP
Time frame: Baseline (Day 1e) to Week 52e
Percentage of Participants With Per-Protocol Transfusion Avoidance From Baseline (Day 1e) Through Week 24e
OLEP Not requiring a RBC transfusion as per protocol algorithm
Time frame: Baseline (Day 1e) through Week 24e
Percentage of Participants With Per-Protocol Transfusion Avoidance From Baseline (Day 1e) Through Week 52e
OLEP Not requiring a RBC transfusion as per protocol algorithm
Time frame: Baseline (Day 1e) to Week 52e
Rate of RBCs Transfused From Baseline (Day 1e) to Week 24e
OLEP
Time frame: Baseline (Day 1e) to Week 24e
Rate of RBCs Transfused From Baseline (Day 1e) to Week 52e
OLEP
Time frame: Baseline (Day 1e) to Week 52e
Number of Units of RBCs Transfused From Baseline (Day 1e) to Week 24e
OLEP
Time frame: Baseline (Day 1e) to Week 24e
Number of Units of RBCs Transfused From Baseline (Day 1e) to Week 52e
OLEP
Time frame: Baseline (Day 1e) to Week 52e
Change in CH50 From Baseline (Day 1e) to Week 16e
OLEP
Time frame: Baseline (Day 1e) to Week 16e
Change in CH50 From Baseline (Day 1e) to Week 24e
OLEP
Time frame: Baseline (Day 1e) to Week 24e
Change in CH50 From Baseline (Day 1e) to Week 52e
OLEP
Time frame: Baseline (Day 1e) to Week 52e
Percent Change in CH50 From Baseline (Day 1e) to Week 16e
OLEP
Time frame: Baseline (Day 1e) to Week 16e
Percent Change in CH50 From Baseline (Day 1e) to Week 24e
OLEP
Time frame: Baseline (Day 1e) to Week 24e
Percent Change in CH50 From Baseline (Day 1e) to Week 52e
OLEP
Time frame: Baseline (Day 1e) to Week 52e
Change in Fatigue as Measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale From 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.
Time frame: Baseline (Day 1e) to Week 52e
Change in GHS/QoL on the EORTC QLQ-C30 From 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.
Time frame: Baseline (Day 1e) to Week 52e
Change in PF Scores on the EORTC QLQ-C30 From 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.
Time frame: Baseline (Day 1e) to Week 52e
Percentage of Participants With TEAEs Up to Week 52
OLEP
Time frame: Up to Week 52
Concentrations of Total Pozelimab in Serum on Week 52
OLEP
Time frame: On Week 52
Concentrations of Total C5 on Week 52
OLEP
Time frame: On Week 52
Concentrations of Cemdisiran in Plasma on Week 52
OLEP
Time frame: On Week 52
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