Paroxysmal Nocturnal Hemoglobinuria
Conditions
Keywords
PNH
Brief 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
Interventions
DRUGCemdisiran
Administered per protocol
DRUGEculizumab
Administered per protocol
DRUGPozelimab
Administered per protocol
DRUGRavulizumab
Administered per protocol
Sponsors
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change in Lactate Dehydrogenase (LDH) From Baseline to Week 36 | From baseline to week 36 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Transfusion Avoidance From Week 4 Through Week 36 | Week 4 through week 36 | Participants who do not receive an RBC transfusion as per protocol algorithm based on post baseline hemoglobin values |
| Percentage of Participants With Breakthrough Hemolysis After Day 1 Through Week 36 | Day 1 through week 36 | Participants with an increase in LDH with concomitant signs or symptoms associated with hemolysis as described in the protocol |
| Percentage of Participants With Breakthrough Hemolysis From Week 4 Through Week 36 | Week 4 (day 29) through week 36 | Participants with an increase in LDH with concomitant signs or symptoms associated with hemolysis as described in the protocol |
| Percentage of Participants With Hemoglobin Stabilization After Day 1 Through Week 36 | Day 1 through week 36 | Participants who do not receive an RBC transfusion and have no decrease in hemoglobin level as defined in the protocol |
| Percentage of Participants With Hemoglobin Stabilization From Week 4 Through Week 36 | Week 4 (day 29) through week 36 | Participants who do not receive an RBC transfusion and have no decrease in hemoglobin level as defined in the protocol |
| Percentage of Participants With Adequate Control of LDH From Week 8 Through Week 36 | Week 8 (day 57) through week 36 | Percentage of participants with adequate control of LDH as defined in the protocol |
| Percentage of Participants With Adequate Control of LDH After Day 1 Though Week 36 | Day 1 through week 36 | Percentage of participants with adequate control of LDH as defined in the protocol |
| Percentage of Participants Who Maintained Adequate Control of Hemolysis From Week 8 Through Week 36 | Week 8 through week 36 | Percentage of participants with adequate control of LDH as defined in the protocol |
| Percentage of Participants Who Maintained Adequate Control of Hemolysis After Day 1 Through Week 36 | Day 1 through week 36 | Percentage of participants with adequate control of LDH as defined in the protocol |
| Percentage of Participants With Normalization of LDH From Week 8 Through Week 36 | Week 8 (day 57) through week 36 | Percentage of participants with normalization of LDH as defined in the protocol |
| Percentage of Participants With Normalization of LDH After Day 1 Through Week 36 | Day 1 through week 36 | Percentage of participants with normalization of LDH as defined in the protocol |
| Change in Fatigue as Measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale From Baseline to Week 36 | From baseline to week 36 | 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. |
| 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) From Baseline to Week 36 | From baseline to week 36 | 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. |
| Change in Global Health Status (GHS)/QoL Scale Score on the EORTC-QLQ-C30 From Baseline to Week 36 | From baseline to week 36 | 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 RBCs Transfused Per Protocol Algorithm After Day 1 Through Week 36 | Day 1 through week 36 | Per protocol algorithm |
| Percentage of Participants With Transfusion Avoidance After Day 1 Through Week 36 | Day 1 through week 36 | Participants who do not receive a red blood cell (RBC) transfusion as per protocol algorithm based on post baseline hemoglobin values |
| Number of Units of RBCs Transfused Per Protocol Algorithm After Day 1 Through Week 36 | Day 1 through week 36 | Per protocol algorithm |
| Number of Units of RBCs Transfused Per Protocol Algorithm From Week 4 Through Week 36 | Week 4 through week 36 | Per protocol algorithm |
| Change in Hemoglobin Levels From Baseline to Week 36 | From baseline to week 36 | Per protocol algorithm |
| Incidence of Treatment Emergent Serious Adverse Events (SAEs) | Up to week 29 | Treatment period and safety follow up period |
| Incidence of Treatment-emergent Adverse Events (TEAEs) of Special Interest | Up to week 29 | Treatment period and safety follow up period |
| Incidence of TEAEs Leading to Treatment Discontinuation | Up to week 29 | Treatment period and safety follow up period |
| Change in Total CH50 From Baseline to Week 36 | From baseline to week 36 | — |
| Percent Change in Total CH50 From Baseline to Week 36 | From baseline to week 36 | — |
| Concentration of Total C5 in Plasma Through Week 62 | Through week 62 | Treatment period and safety follow up period |
| Concentrations of Total Pozelimab in Serum Through Week 62 | Through week 62 | Treatment period and safety follow up period |
| Concentrations of Total Cemdisiran in Plasma Through Week 32 | Through week 32 | Treatment period |
| Concentrations of Total Eculizumab in Serum Through Week 40 | Through week 40 | Treatment period |
| Concentrations of Total Ravulizumab in Plasma Through Week 44 | Through week 44 | Treatment period |
| Incidence of Treatment Emergent Anti-drug Antibodies (ADAs) to Pozelimab Through Week 62 | Through week 62 | Treatment period and safety follow up period |
| Incidence of Treatment Emergent ADAs to Cemdisiran Through Week 62 | Through week 62 | Treatment period and safety follow up period |
| Rate of RBCs Transfused Per Protocol Algorithm From Week 4 Through Week 36 | Week 4 through week 36 | Per protocol algorithm |
Countries
United States
Participant flow
Pre-assignment details
A total of 140 participants were expected to be enrolled, however, due to feasibility: five participants were screened and 3 were randomized and treated. There were 2 screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Pozelimab and Cemdisiran Randomized 1:1 | 2 |
| Anti-C5 Standard-of-care Randomized 1:1 | 1 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Sponsor request | 2 | 1 |
Baseline characteristics
| Characteristic | Pozelimab and Cemdisiran | Anti-C5 Standard-of-care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 0 / 2 | 0 / 1 |
Outcome results
Primary
Percent Change in Lactate Dehydrogenase (LDH) From Baseline to Week 36
Time frame: From baseline to week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Change in Fatigue as Measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale From Baseline to Week 36
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.
Time frame: From baseline to week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Change in Global Health Status (GHS)/QoL Scale Score on the EORTC-QLQ-C30 From Baseline to Week 36
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.
Time frame: From baseline to week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Change in Hemoglobin Levels From Baseline to Week 36
Per protocol algorithm
Time frame: From baseline to week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
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) From Baseline to Week 36
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.
Time frame: From baseline to week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Change in Total CH50 From Baseline to Week 36
Time frame: From baseline to week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Concentration of Total C5 in Plasma Through Week 62
Treatment period and safety follow up period
Time frame: Through week 62
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Concentrations of Total Cemdisiran in Plasma Through Week 32
Treatment period
Time frame: Through week 32
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Concentrations of Total Eculizumab in Serum Through Week 40
Treatment period
Time frame: Through week 40
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Concentrations of Total Pozelimab in Serum Through Week 62
Treatment period and safety follow up period
Time frame: Through week 62
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Concentrations of Total Ravulizumab in Plasma Through Week 44
Treatment period
Time frame: Through week 44
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Incidence of TEAEs Leading to Treatment Discontinuation
Treatment period and safety follow up period
Time frame: Up to week 29
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pozelimab and Cemdisiran | Incidence of TEAEs Leading to Treatment Discontinuation | 0 Events |
| Anti-C5 Standard-of-care | Incidence of TEAEs Leading to Treatment Discontinuation | 0 Events |
Secondary
Incidence of Treatment Emergent ADAs to Cemdisiran Through Week 62
Treatment period and safety follow up period
Time frame: Through week 62
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Incidence of Treatment-emergent Adverse Events (TEAEs) of Special Interest
Treatment period and safety follow up period
Time frame: Up to week 29
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pozelimab and Cemdisiran | Incidence of Treatment-emergent Adverse Events (TEAEs) of Special Interest | 1 Events |
| Anti-C5 Standard-of-care | Incidence of Treatment-emergent Adverse Events (TEAEs) of Special Interest | 0 Events |
Secondary
Incidence of Treatment Emergent Anti-drug Antibodies (ADAs) to Pozelimab Through Week 62
Treatment period and safety follow up period
Time frame: Through week 62
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Incidence of Treatment Emergent Serious Adverse Events (SAEs)
Treatment period and safety follow up period
Time frame: Up to week 29
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pozelimab and Cemdisiran | Incidence of Treatment Emergent Serious Adverse Events (SAEs) | 0 Events |
| Anti-C5 Standard-of-care | Incidence of Treatment Emergent Serious Adverse Events (SAEs) | 0 Events |
Secondary
Number of Units of RBCs Transfused Per Protocol Algorithm After Day 1 Through Week 36
Per protocol algorithm
Time frame: Day 1 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Number of Units of RBCs Transfused Per Protocol Algorithm From Week 4 Through Week 36
Per protocol algorithm
Time frame: Week 4 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Percentage of Participants Who Maintained Adequate Control of Hemolysis After Day 1 Through Week 36
Percentage of participants with adequate control of LDH as defined in the protocol
Time frame: Day 1 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Percentage of Participants Who Maintained Adequate Control of Hemolysis From Week 8 Through Week 36
Percentage of participants with adequate control of LDH as defined in the protocol
Time frame: Week 8 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Percentage of Participants With Adequate Control of LDH After Day 1 Though Week 36
Percentage of participants with adequate control of LDH as defined in the protocol
Time frame: Day 1 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Percentage of Participants With Adequate Control of LDH From Week 8 Through Week 36
Percentage of participants with adequate control of LDH as defined in the protocol
Time frame: Week 8 (day 57) through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Percentage of Participants With Breakthrough Hemolysis After Day 1 Through Week 36
Participants with an increase in LDH with concomitant signs or symptoms associated with hemolysis as described in the protocol
Time frame: Day 1 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Percentage of Participants With Breakthrough Hemolysis From Week 4 Through Week 36
Participants with an increase in LDH with concomitant signs or symptoms associated with hemolysis as described in the protocol
Time frame: Week 4 (day 29) through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Percentage of Participants With Hemoglobin Stabilization After Day 1 Through Week 36
Participants who do not receive an RBC transfusion and have no decrease in hemoglobin level as defined in the protocol
Time frame: Day 1 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Percentage of Participants With Hemoglobin Stabilization From Week 4 Through Week 36
Participants who do not receive an RBC transfusion and have no decrease in hemoglobin level as defined in the protocol
Time frame: Week 4 (day 29) through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Percentage of Participants With Normalization of LDH After Day 1 Through Week 36
Percentage of participants with normalization of LDH as defined in the protocol
Time frame: Day 1 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Percentage of Participants With Normalization of LDH From Week 8 Through Week 36
Percentage of participants with normalization of LDH as defined in the protocol
Time frame: Week 8 (day 57) through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Percentage of Participants With Transfusion Avoidance After Day 1 Through Week 36
Participants who do not receive a red blood cell (RBC) transfusion as per protocol algorithm based on post baseline hemoglobin values
Time frame: Day 1 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Percentage of Participants With Transfusion Avoidance From Week 4 Through Week 36
Participants who do not receive an RBC transfusion as per protocol algorithm based on post baseline hemoglobin values
Time frame: Week 4 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints..
Secondary
Percent Change in Total CH50 From Baseline to Week 36
Time frame: From baseline to week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Rate of RBCs Transfused Per Protocol Algorithm After Day 1 Through Week 36
Per protocol algorithm
Time frame: Day 1 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.
Secondary
Rate of RBCs Transfused Per Protocol Algorithm From Week 4 Through Week 36
Per protocol algorithm
Time frame: Week 4 through week 36
Population: Due to Early Termination, this endpoint was removed from the Statistical Analysis Plan and data was not collected for primary and secondary endpoints.