ACCESS-1: Ravulizumab-Controlled Study to Evaluate the Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Who Are Complement Inhibitor Treatment-Naive or Have Not Recently Received Complement Inhibitor Therapy
Study Details
Study Description
Brief Summary
The primary objective of the study is:
To evaluate the effect on hemolysis and red blood cells (RBC) transfusions over a 24-week treatment period of pozelimab and cemdisiran combination treatment versus ravulizumab treatment in patients with active Paroxysmal Nocturnal Hemoglobinuria (PNH) who are complement inhibitor treatment-naive or have not recently received complement inhibitor therapy
The secondary objectives of the study are to:
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Evaluate the effect of pozelimab and cemdisiran combination treatment versus ravulizumab treatment on the following:
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Measures of hemolysis
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Transfusion parameters
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Hemoglobin levels
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Fatigue as assessed by Clinical Outcome Assessments (COAs)
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Health-related quality of life (HRQoL) as assessed by COAs
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Safety and tolerability
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Complement activation
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To assess the concentrations of total pozelimab and total ravulizumab in serum and total cemdisiran and total complement factor 5 (C5) protein in plasma
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To assess the immunogenicity of pozelimab and cemdisiran
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Ravulizumab Randomized 1:1 |
Drug: Ravulizumab
Administered Intravenous (IV) per the protocol
Other Names:
|
| Experimental: Pozelimab and Cemdisiran Randomized 1:1 |
Drug: Pozelimab
Administered IV and subcutaneous (SC) per the protocol
Other Names:
Drug: Cemdisiran
Administered SC per the protocol
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Proportion of patients with adequate control of hemolysis [Between week 4 and week 24, inclusive]
Lactate dehydrogenase (LDH) ≤1.5 × upper limit of normal (ULN)
- Proportion of patients with transfusion avoidance [Day 1 through week 24]
No red blood cell (RBC) transfusion per the protocol
Secondary Outcome Measures
- Proportion of patients with breakthrough hemolysis [Post-baseline day 1 through week 24]
LDH ≥2 × ULN per the protocol
- Proportion of patients with hemoglobin stabilization [Day 1 (post-baseline) through week 24]
Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level per the protocol
- Proportion of patients with normalization of LDH [Between week 4 through week 24, inclusive]
LDH ≤1.0 × ULN per the protocol
- Percent change in LDH [From baseline to week 24]
LDH value at day 1 to the LDH value at week 24
- Change in fatigue as measured by the FACIT-Fatigue Scale [From baseline to week 24]
FACIT-Fatigue Scale 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 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 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) [Change from baseline to week 24]
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."
- Change in global health status (GHS)/QoL scale score on the EORTC-QLC-C30 [From baseline to week 24]
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."
- Rate of RBC transfusion per protocol algorithm from day 1 through week 24 [Day 1 through week 24]
Per protocol algorithm
- Number of units of RBC transfusion per protocol algorithm from day 1 through week 24 [Day 1 through week 24]
Per protocol algorithm
- Time to first LDH ≤1.5 × ULN [Up to Week 24]
- Time to first LDH ≤1.0 × ULN [Up to Week 24]
- Percentage of days with LDH ≤1.5 × ULN [Between week 4 and week 24, inclusive]
- Change in hemoglobin levels [From baseline to week 24]
- Incidence and severity of treatment emergent serious adverse events (SAEs) [Up to 24 weeks]
- Incidence and severity of treatment-emergent adverse events (TEAEs) of special interest [Up to 24 weeks]
- Incidence and severity of TEAE leading to treatment discontinuation [Up to 24 weeks]
- Change in total CH50 [From baseline to week 24]
- Percent change in total CH50 [From baseline to week 24]
- Concentration of total C5 in plasma [Up to 50 weeks]
- Concentrations of total pozelimab in serum [Up to 50 weeks]
- Concentrations of total cemdisiran in plasma [Up to 20 weeks]
- Concentrations of total ravulizumab in serum [Up to 34 weeks]
- Incidence of treatment emergent anti-drug antibodies (ADAs) to pozelimab [Up to 50 weeks]
- Incidence of treatment emergent ADAs to cemdisiran [Up to 50 weeks]
Eligibility Criteria
Criteria
Key Inclusion Criteria:
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Diagnosis of PNH confirmed by high-sensitivity flow cytometry testing with PNH granulocytes described in the protocol
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Active disease, as defined by the presence of 1 or more PNH-related signs or symptoms described in the protocol
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LDH level ≥2 × ULN at the screening visit
Key Exclusion Criteria:
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Prior treatment with a complement inhibitor within 6 months prior to screening visit, unless patient was treated with eculizumab or ravulizumab and has documented C5 variant R885H/C in which case there is no exclusion of such patients
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Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant
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Body weight <40 kilograms at screening visit
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Planned use of any complement inhibitor therapy other than study drugs during the treatment period
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Not meeting meningococcal vaccination requirements for 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
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Any contraindication for receiving Neisseria meningitidis vaccination
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Unable to take antibiotics for meningococcal prophylaxis (if required by local ravulizumab prescribing information, where available, or national guidelines/local practice or if necessary when vaccination is less than 2 weeks from study treatment initiation)
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Any active, ongoing infection or a recent infection requiring ongoing systemic treatment with antibiotics, antivirals, or antifungals within 2 weeks of screening or during the screening period
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Documented history of active, uncontrolled, ongoing systemic autoimmune diseases
Note: Other protocol-defined Inclusion/ Exclusion Criteria apply
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | The Oncology Institute of Hope and Innovation | Whittier | California | United States | 90603 |
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-2021
- 2020-004486-40