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

Paroxysmal Nocturnal Hemoglobinuria Clinical Trial

— ACCESS 2  

Official title:

A Randomized, Open-Label, Eculizumab and Ravulizumab Controlled Study to Evaluate the Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Are Currently Treated With Eculizumab or Ravulizumab

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05131204
• Other study ID #: R3918-PNH-2022
• Secondary ID: 2020-002761-33
• Status: Terminated
• Phase: Phase 3
• Start date: October 6, 2022
• Est. completion date: July 12, 2023

Study information

• Verified date: August 2023
• Source: Regeneron Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: July 12, 2023
• Est. primary completion date: July 12, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hemoglobinuria
• Hemoglobinuria, Paroxysmal
• Paroxysmal Nocturnal Hemoglobinuria

Intervention

Drug:
• Cemdisiran
Administered per protocol
• Eculizumab
Administered per protocol
• Pozelimab
Administered per protocol
• Ravulizumab
Administered per protocol

Locations

Country	Name	City	State
United States	Regeneron Research Facility	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
Regeneron Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent change in lactate dehydrogenase (LDH)		From baseline to week 36
Secondary	Proportion of patients with transfusion avoidance	Patients who do not receive an RBC transfusion as per protocol algorithm based on post baseline hemoglobin values	Day 1 through week 36
Secondary	Proportion of patients with transfusion avoidance	Patients who do not receive an RBC transfusion as per protocol algorithm based on post baseline hemoglobin values	Week 4 through week 36
Secondary	Proportion of patients with breakthrough hemolysis	Patients with an increase in LDH with concomitant signs or symptoms associated with hemolysis as described in the protocol	Day 1 through week 36
Secondary	Proportion of patients with breakthrough hemolysis	Patients with an increase in LDH with concomitant signs or symptoms associated with hemolysis as described in the protocol	Week 4 (day 29) through week 36
Secondary	Proportion of patients with hemoglobin stabilization	Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level as defined in the protocol	Day 1 through week 36
Secondary	Proportion of patients with hemoglobin stabilization	Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level as defined in the protocol	Week 4 (day 29) through week 36
Secondary	Proportion of patients with adequate control of LDH	Proportion of patients with adequate control of LDH as defined in the protocol	Day 1 through week 36
Secondary	Proportion of patients with adequate control of LDH	Proportion of patients with adequate control of LDH as defined in the protocol	Week 8 (day 57) through week 36
Secondary	Proportion of patients with normalization of LDH	Proportion of patients with normalization of LDH as defined in the protocol	Day 1 through week 36
Secondary	Proportion of patients with normalization of LDH	Proportion of patients with normalization of LDH as defined in the protocol	Week 8 (day 57) through week 36
Secondary	Change in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale	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.	From baseline to week 36
Secondary	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)	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."	From baseline to week 36
Secondary	Change in global health status (GHS)/QoL scale score on the EORTC-QLQ-C30	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."	From baseline to week 36
Secondary	Rate of RBCs transfused per protocol algorithm	Per protocol algorithm	Day 1 through week 36
Secondary	Rate of RBCs transfused per protocol algorithm	Per protocol algorithm	Week 4 through week 36
Secondary	Number of units of RBCs transfused per protocol algorithm	Per protocol algorithm	Day 1 through week 36
Secondary	Number of units of RBCs transfused per protocol algorithm	Per protocol algorithm	Week 4 through week 36
Secondary	Change in hemoglobin levels	Per protocol algorithm	From baseline to week 36
Secondary	Incidence and severity of treatment emergent serious adverse events (SAEs)	Treatment period and safety follow up period	Up to 88 weeks
Secondary	Incidence and severity of treatment-emergent adverse events (TEAEs) of special interest	Treatment period and safety follow up period	Up to 88 weeks
Secondary	Incidence and severity TEAEs leading to treatment discontinuation	Treatment period and safety follow up period	Up to 88 weeks
Secondary	Change in total CH50		From baseline to week 36
Secondary	Percent change in total CH50		From baseline to week 36
Secondary	Concentration of total C5 in plasma	Treatment period and safety follow up period	Through week 62
Secondary	Concentrations of total pozelimab in serum	Treatment period and safety follow up period	Through week 62
Secondary	Concentrations of total cemdisiran in plasma	Treatment period	Through week 32
Secondary	Concentrations of total eculizumab in serum	Treatment period	Through week 40
Secondary	Concentrations of total ravulizumab in plasma	Treatment period	Through week 44
Secondary	Incidence of treatment emergent anti-drug antibodies (ADAs) to pozelimab	Treatment period and safety follow up period	Through week 62
Secondary	Incidence of treatment emergent ADAs to cemdisiran	Treatment period and safety follow up period	Through week 62