ACCESS-EXT: A Study to Examine the Long-term Safety, Tolerability, and Effectiveness of Pozelimab and Cemdisiran Combination Therapy in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria
Study Details
Study Description
Brief Summary
The primary objective of the study is to describe the long-term safety, tolerability, and efficacy of pozelimab and cemdisiran combination therapy in patients with PNH
The secondary objectives of the study are to describe the long-term effect of the combination of pozelimab and cemdisiran on:
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Measures of intravascular hemolysis
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Transfusion parameters
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Hemoglobin levels
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Fatigue as assessed by a Patient Reported Outcome (PRO)
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Physical Function (PF) as assessed by a PRO
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Change in Global Health Status (GHS) as assessed by a PRO
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Complement activation
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Concentrations of total pozelimab in serum and cemdisiran and total complement component 5 (C5) protein in plasma
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Immunogenicity of pozelimab & cemdisiran
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: PNH Transition Patients Patients with PNH who completed treatment/ protocol requirements (as applicable) in the parent studies (R3918-PNH-2021 [NCT05133531] or R3918-PNH-2022 [NCT05131204]) |
Drug: Pozelimab
Administered subcutaneously (SC) every 4 weeks (Q4W)
Other Names:
Drug: Cemdisiran
Administered SC Q4W
Other Names:
|
| Experimental: C5 Polymorphism Patients Patients who have not been treated in either parent study but who have a documented complement component 5 (C5) polymorphism (eg, C5 variants p.Arg885His, p.Arg885R885Cys) rendering them refractory to eculizumab/ravulizumab. |
Drug: Pozelimab
Administered subcutaneously (SC) every 4 weeks (Q4W)
Other Names:
Drug: Cemdisiran
Administered SC Q4W
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence of treatment-emergent serious adverse events (SAEs) [Up to week 108]
An SAE is any untoward medical occurrence that at any dose: Results in death Is life-threatening Requires in-patient hospitalization or prolongation of existing hospitalization. Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect. Is an important medical event
- Severity of treatment-emergent SAEs [Up to week 108]
- Incidence of treatment emergent adverse events of special interest (AESIs) [Up to week 108]
An AESI (serious or non-serious) is one of scientific and medical concern specific to the sponsor's product or program, for which ongoing monitoring and rapid communication by the Investigator to the sponsor can be appropriate. Such an event might warrant further investigation in order to characterize and understand it
- Severity of treatment emergent AESIs [Up to week 108]
- Treatment emergent adverse events (AEs) leading to permanent treatment discontinuation [Up to week 108]
Any untoward medical occurrence in a patient administered a study drug which may or may not have a causal relationship with the study drug.
- Percent change from baseline in lactate dehydrogenase (LDH) [Baseline to week 36]
Secondary Outcome Measures
- Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN) [Post-baseline through week 36]
- Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN) [Post-baseline through week 48]
- Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN) [Post-baseline through week 76]
- Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN) [Post-baseline through week 108]
- Adequate control of hemolysis (LDH ≤1.5 × ULN) [Post-baseline through week 108]
- Transfusion avoidance [Post-baseline through week 36]
Not requiring red blood cell (RBC) transfusion as per protocol algorithm based on hemoglobin values
- Transfusion avoidance [Post-baseline through week 48]
Not requiring red blood cell (RBC) transfusion as per protocol algorithm based on hemoglobin values
- Transfusion avoidance [Post-baseline through week 76]
Not requiring red blood cell (RBC) transfusion as per protocol algorithm based on hemoglobin values
- Transfusion avoidance [Post-baseline through week 108]
Not requiring red blood cell (RBC) transfusion as per protocol algorithm based on hemoglobin values
- Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis) [Post-baseline through week 36]
- Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis) [Post-baseline through week 48]
- Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis) [Post-baseline through week 76]
- Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis) [Post-baseline through week 108]
- Hemoglobin stabilization [Post-baseline through week 36]
Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL
- Hemoglobin stabilization [Post-baseline through week 48]
Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL
- Hemoglobin stabilization [Post-baseline through week 76]
Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL
- Hemoglobin stabilization [Post-baseline through week 108]
Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level of ≥2 g/dL
- Percent change in LDH [From baseline to week 48]
- Percent change in LDH [From baseline to week 76]
- Percent change in LDH [From baseline to week 108]
- Change in fatigue [From baseline to week 36]
Measured by the FACIT-Fatigue scale The FACIT-F is a 13-item, self-reported PRO measure 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 QoL in patients with cancer and other chronic illnesses. The FACIT-fatigue assesses the level of fatigue using 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 greater fatigue.
- Change in fatigue [From baseline to week 48]
Measured by the FACIT-Fatigue scale The FACIT-F is a 13-item, self-reported PRO measure 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 QoL in patients with cancer and other chronic illnesses. The FACIT-fatigue assesses the level of fatigue using a 4-point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue.
- Change in fatigue [From baseline to week 76]
Measured by the FACIT-Fatigue scale The FACIT-F is a 13-item, self-reported PRO measure 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 QoL in patients with cancer and other chronic illnesses. The FACIT-fatigue assesses the level of fatigue using a 4-point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue.
- Change in fatigue [From baseline to weeks 108]
Measured by the FACIT-Fatigue scale The FACIT-F is a 13-item, self-reported PRO measure 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 QoL in patients with cancer and other chronic illnesses. The FACIT-fatigue assesses the level of fatigue using a 4-point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue.
- Change in physical function (PF) scores on the EORTC QLQ-C30 [From baseline to week 36]
EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire) EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.
- Change in PF scores on the EORTC QLQ-C30 [From baseline to week 48]
EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire) EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.
- Change in PF scores on the EORTC QLQ-C30 [From baseline to week 76]
EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire) EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.
- Change in PF scores on the EORTC QLQ-C30 [From baseline to week 108]
EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire) EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.
- Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30 [From baseline to week 36]
GHS/QoL (Global Health Status/ Quality of Life) Global Health Status/Quality of Life (GHS/Qol) Score (Items 29 and 30) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.
- Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30 [From baseline to week 48]
GHS/QoL (Global Health Status/ Quality of Life) Global Health Status/Quality of Life (GHS/Qol) Score (Items 29 and 30) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.
- Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30 [From baseline to week 76]
GHS/QoL (Global Health Status/ Quality of Life) Global Health Status/Quality of Life (GHS/Qol) Score (Items 29 and 30) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.
- Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30 [From baseline to week 108]
GHS/QoL (Global Health Status/ Quality of Life) Global Health Status/Quality of Life (GHS/Qol) Score (Items 29 and 30) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.
- Normalization of LDH [From post-baseline through week 108]
- Rate of red blood cell (RBC) transfusion [Post-baseline through week 36]
Per protocol algorithm
- Rate of RBC transfusion [Post-baseline through week 48]
Per protocol algorithm
- Rate of RBC transfusion [Post-baseline through week 76]
Per protocol algorithm
- Rate of RBC transfusion [Post-baseline through week 108]
Per protocol algorithm
- Number of units of RBC transfusion [Post-baseline through week 36]
Per protocol algorithm
- Number of units of RBC transfusion [Post-baseline through week 48]
Per protocol algorithm
- Number of units of RBC transfusion [Post-baseline through week 76]
Per protocol algorithm
- Number of units of RBC transfusion [Post-baseline through week 108]
Per protocol algorithm
- Percentage of days with LDH ≤1.5x upper limit of normal (ULN) [Post-baseline through week 36]
- Percentage of days with LDH ≤1.5x ULN [Post-baseline through week 48]
- Percentage of days with LDH ≤1.5x ULN [Post-baseline through week 76]
- Percentage of days with LDH ≤1.5x ULN [Post-baseline through week 108]
- Change in hemoglobin levels [From baseline to week 36]
- Change in hemoglobin levels [From baseline to week 48]
- Change in hemoglobin levels [From baseline to week 76]
- Change in hemoglobin levels [From baseline to week 108]
- Change in total complement hemolytic activity assay (CH50) [Through week 108]
- Percent change in CH50 [Through week 108]
- Concentrations of total pozelimab in serum [Through week 108]
- Concentrations of cemdisiran in plasma [Through week 24]
- Incidence of treatment-emergent anti-drug antibodies to pozelimab [Through week 108]
- Incidence of treatment-emergent anti-drug antibodies to cemdisiran [Through week 108]
- Concentration of total complement component 5 (C5) in plasma [Through week 108]
- Percent change of concentration of total C5 in plasma [Through week 108]
Eligibility Criteria
Criteria
Key Inclusion Criteria:
Patients Entering from the Parent Studies
- Patients with PNH who have completed, without permanent discontinuation, study treatment in at least 1 of the parent studies (R3918-PNH-2021[NCT05133531] and/or R3918-PNH-2022 [NCT05131204]), if applicable.
Patients Entering with C5 polymorphism
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Patients with PNH who have a documented C5 polymorphism rendering them refractory to eculizumab or ravulizumab (eg, p.Arg885His, p.Arg885Cys), as described in the protocol
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Diagnosis of PNH confirmed by high-sensitivity flow cytometry testing
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Active disease, as defined by the presence of 1 or more PNH-related sign or symptom as described in the protocol
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LDH level ≥2 × upper limit of normal (ULN) at the screening visit
Key Exclusion Criteria:
Patients Entering from the Parent Studies
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Significant protocol deviation(s) in the parent study based on the investigator's judgment and to the extent that these would (if continued) impact the study objectives and/or safety of the patient
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Any new condition or worsening of an existing condition which, in the opinion of the investigator, would make the patient unsuitable for enrollment or could interfere with the patient participating in or completing the study
Patients Entering with C5 polymorphism
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Prior treatment with complement inhibitors within 5 half-lives of the respective agent prior to screening, except for prior eculizumab or ravulizumab which are not exclusionary
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Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant
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No documentation of meningococcal vaccination within 5 years prior to enrollment
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Positive hepatitis B surface antigen or hepatitis C virus RNA during screening
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Patients with known HIV with history of opportunistic infections in the last 1 year as described in the protocol
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Known hereditary complement deficiency
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Documented history of active, uncontrolled, ongoing systemic autoimmune diseases
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Documented history of liver cirrhosis or patients with liver disease with evidence of current impaired liver function or patients with ALT or AST (unrelated to PNH or its complications) as described in the protocol
Note: Other protocol-defined Inclusion/ Exclusion Criteria apply
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Regeneron Pharmaceuticals
Investigators
- Study Director: Clinical Trial Management, Regeneron Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- R3918-PNH-2050
- 2021-004931-10