A C5 inhibitor-controlled Study to Evaluate the Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) who are Complement Inhibitor Treatment-Naive or Have Not Recently Received Complement Inhibitor Therapy

JRCT ID: jRCT2031220440

Registered date:05/11/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Paroxysmal Nocturnal Hemoglobinuria
• Date of first enrollment: 02/06/2023
• Target sample size: 12
• Countries of recruitment: Canada,Japan,China,Japan,Colombia,Japan,France,Japan,Greece,Japan,Hungary,Japan,India,Japan,Italy,Japan,Jordan,Japan,Malaysia,Japan,Mexico,Japan,Peru,Japan,Philippines,Japan,Poland,Japan,Romania,Japan,Singapore,Japan,South Africa,Japan,South Korea,Japan,Spain,Japan,Taiwan,Japan,Thailand,Japan,Turkey,Japan,United Kingdom,Japan,United States,Japan
• Study type: Interventional

Intervention(s)

Cohort A:
Ravulizumab Arm:
-Drug: Ravulizumab
Administered Intravenous (IV) per the protocol
Other Names: ALXN1210, Ultomiris

Pozelimab + Cemdisiran Arm:
-Drug: Pozelimab
Administered IV and subcutaneous (SC) per the protocol
Other Name: REGN3918
-Drug: Cemdisiran
Administered SC per the protocol
Other Name: ALN-CC5

Randomized 1:1

Cohort B:
Eculizumab Arm:
-Drug: Eculizumab
Administered Intravenous (IV) per the protocol
Other Names: Soliris

Pozelimab + Cemdisiran Arm:
-Drug: Pozelimab
Administered IV and subcutaneous (SC) per the protocol
Other Name: REGN3918
-Drug: Cemdisiran
Administered SC per the protocol
Other Name: ALN-CC5

Randomized 1:1

Outcome(s)

Primary Outcome

Cohort A:
Percent change in lactate dehydrogenase (LDH) [Time Frame: From baseline to week 26]

Cohort B:
1. Maintenance of adequate control of hemolysis [Time Frame: week 8 through week 26, inclusive]
2. Transfusion avoidance [Time Frame: Day 1 through week 26]

Secondary Outcome

Cohort A:
1. Maintenance of adequate control of hemolysis [Time Frame: From week 8 through week 26, inclusive]
LDH <=1.5xULN per the protocol
2. Breakthrough hemolysis [Time Frame: From post-baseline day 1 through week 26]
LDH >=2xULN per the protocol
3. Adequate control of hemolysis [Time Frame: From week 8 through week 26, inclusive]
LDH <=1.5xULN per the protocol
4. Hemoglobin stabilization [Time Frame: From day 1 (postbaseline) through week 26]
Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level per the protocol
5. Normalization of LDH [Time Frame: From week 8 through week 26, inclusive]
LDH <=1.0xULN per the protocol
6. Transfusion avoidance [Time Frame: From Day 1 through week 26]
Not requiring an RBC transfusion as per protocol algorithm based on post-baseline hemoglobin values
7. Change in fatigue as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale [Time Frame: From baseline to week 26]
8. Change in physical function (PF) scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) [Time Frame: From baseline to week 26]
9. Change in global health status (GHS)/QoL scale score on the EORTC-QLC-C30 [Time Frame: From baseline to week 26]

Cohort B:
1. Percent change in LDH [Time Frame: From baseline to week 26]
2. Breakthrough hemolysis [Time Frame: From post-baseline day 1 through week 26]
3. Adequate control of hemolysis [Time Frame: From week 8 through week 26, inclusive]
LDH <=1.5xULN
4. Hemoglobin stabilization [Time Frame: From day 1(post-baseline) through week 26]
Patients who do not receive an RBC transfusion and have no decrease in hemoglobin level per the protocol
5. Normalization of LDH [Time Frame: From week 8 through week 26, inclusive]
LDH <=1.0xULN per the protocol
6. Change in fatigue as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale from [Time Frame: From baseline to week 26]
7. Change in physical function (PF) scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [Time Frame: From baseline to week 26]
8. Change in global health status (GHS) /QoL scale score on the EORTC-QLC-C30 [Time Frame: From baseline to week 26]

Cohorts A and B:
1. Rate and number of units of RBC transfused [Time Frame: From Post-baseline Day 1 through week 26]
Per protocol algorithm
2. Time to first LDH <=1.5xULN and <=1.0xULN [Time Frame: Up to week 26]
3. Percentage of days with LDH <=1.5xULN [Time Frame: Between week 8 and week 26, inclusive]
4. Change in hemoglobin levels [Time Frame: From baseline to week 26]
5. Incidence and severity of treatment emergent serious adverse events (SAEs), treatment-emergent adverse events (TEAEs) of special interest and TEAEs leading to treatment discontinuation [Time Frame: Up to 26 weeks]
6. Change and percent change in total CH50 [Time Frame: From baseline to week 26]
7. Concentration of total C5 in plasma [Time Frame: Up to 60 weeks]
8. Concentrations of total pozelimab in serum [Time Frame: Up to 60 weeks]
9. Concentrations of cemdisiran in plasma [Time Frame: Up to 60 weeks]
10. Concentrations of total ravulizumab (Cohort A) and total eculizumab (Cohort B) in serum [Time Frame: Up to 34 weeks(Cohort A), 30 weeks (Cohort B)]
11. Incidence of treatment emergent anti-drug antibodies (ADAs) to pozelimab [Time Frame: Up to 52 weeks]
12. Incidence of treatment emergent ADAs to cemdisiran [Time Frame: Up to 52 weeks]

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Diagnosis of PNH confirmed by high-sensitivity flow cytometry testing with PNH granulocytes described in the protocol
2. Active disease, as defined by the presence of 1 or more PNH-related sign or symptom as described in the protocol
3. LDH level >=2xULN at the screening visit
4. Other Inclusion Criteria Apply.

Exclude criteria

1. Prior treatment with eculizumab within 3 months prior to screening, ravulizumab within 6 months prior to screening, or other complement inhibitors within 5 half-lives of the respective agent prior to screening.
2. Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant.
3. Body weight <40 kilograms at screening visit.
4. Planned use of any complement inhibitor therapy other than study drugs during the treatment period.
5. Not meeting meningococcal vaccination requirements for ravulizumab (Cohort A) or eculizumab (Cohort B) 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. Unable to take antibiotics for meningococcal prophylaxis (if required by local ravulizumab [Cohort A] or eculizumab [Cohort B] prescribing information, where available, or national guidelines/local practice or if necessary when vaccination is less than 2 weeks from study treatment initiation).
8. 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.
9. Documented history of active, uncontrolled, ongoing systemic autoimmune diseases.
10. Other Exclusion Criteria Apply.

Related Information

• Primary Sponsor: Aurand Lisa
• Secondary ID(s): NCT05133531, R3918-PNH-2021,2020-004486-40