A Study in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) to Evaluate How Safe Long-term Treatment With Pozelimab + Cemdisiran Combination Therapy is and How Well it Works.

Phase 3

Recruiting

• Conditions: Paroxysmal Nocturnal Hemoglobinuria
• Interventions: Drug: Pozelimab; Drug: Cemdisiran

• Registration Number: NCT05744921
• Lead Sponsor: Regeneron Pharmaceuticals

Brief Summary

This study is researching an experimental treatment combination with two experimental drugs called pozelimab and cemdisiran. The study is focused on patients with paroxysmal nocturnal hemoglobinuria (PNH). The aim of this study is to see how safe and effective the pozelimab + cemdisiran combination is for patients with PNH in the long term. The pozelimab + cemdisiran combination may be referred to as "study drugs" in this section.

This study is looking at several other research questions, including:

* How effective is the pozelimab + cemdisiran combination?

* What side effects may happen from taking the study drugs?

* How much of each study drug is in the blood at different times?

* Whether the body makes antibodies against the study drugs (which could make the drugs less effective or could lead to side effects)

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study First Submitted: 2023-02-06
• Study First Submitted QC: 2023-02-22
• Study First Posted: 2023-02-27
• Study Start: 2023-03-07
• Status Verified: 2024-05
• Last Update Submitted: 2024-12-17
• Last Update Posted: 2024-12-18
• Primary Completion: 2029-02-05
• Study Completion: 2029-02-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 202

Inclusion Criteria

Patients Entering from the Parent Study

1. Patients with PNH who have completed, without permanent discontinuation, study treatment in the parent study (R3918-PNH-2021[NCT05133531]), including the post-Open-label treatment period (OLTP) transition period, if applicable.
2. Willing and able to comply with clinic visits and study-related procedures, including meningococcal vaccinations required per protocol.

Patients Entering with C5 polymorphism

1. 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
2. Diagnosis of PNH confirmed by high-sensitivity flow cytometry testing with PNH granulocytes or monocytes
3. Active disease, as defined by the presence of 1 or more PNH-related sign or symptom as described in the protocol
4. LDH level ≥2 × upper limit of normal (ULN) at the screening visit
5. Willing and able to comply with clinic visits and study-related procedures, including meningococcal vaccinations required per protocol

Key

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Exclusion Criteria

Patients Entering from the Parent Study

1. 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
2. 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

1. 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
2. Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant
3. Not meeting meningococcal vaccination requirements and, at a minimum, documentation of quadrivalent meningococcal vaccination within 5 years prior to enrollment and serotype B vaccine within 3 years prior to enrollment as described in the protocol
4. Positive hepatitis B surface antigen or hepatitis C virus Ribonucleic acid (RNA) during screening
5. Patients with known HIV with history of opportunistic infections in the last 1 year as described in the protocol
6. Known hereditary complement deficiency
7. Documented history of active, uncontrolled, ongoing systemic autoimmune diseases
8. Documented history of liver cirrhosis or patients with liver disease with evidence of current impaired liver function or patients with elevations in Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) (unrelated to PNH or its complications) as described in the protocol

Note: Other protocol-defined Inclusion/ Exclusion Criteria apply

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
C5 Polymorphism Patients	Cemdisiran	Patients who have not been treated in either parent study but who have a documented complement component 5 (C5) variation rendering them refractory to eculizumab/ravulizumab. Note: Loading dose of pozelimab administered IV on Day 1.
PNH Transition Patients	Pozelimab	Patients with PNH who completed treatment/ protocol requirements (as applicable) in the parent study (R3918-PNH-2021 \[NCT05133531\])
C5 Polymorphism Patients	Pozelimab	Patients who have not been treated in either parent study but who have a documented complement component 5 (C5) variation rendering them refractory to eculizumab/ravulizumab. Note: Loading dose of pozelimab administered IV on Day 1.
PNH Transition Patients	Cemdisiran	Patients with PNH who completed treatment/ protocol requirements (as applicable) in the parent study (R3918-PNH-2021 \[NCT05133531\])

Primary Outcome Measures

Name	Time	Method
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
Percent change from baseline in lactate dehydrogenase (LDH)	Baseline to week 36
Severity of 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.
Severity of treatment emergent AESIs	Up to week 108
Incidence of 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.
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

Secondary Outcome Measures

Name	Time	Method
Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN)	Post-baseline through week 108
Transfusion avoidance	Post-baseline through week 108	Not requiring red blood cell (RBC) transfusion as per protocol algorithm based on hemoglobin values
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.
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
Percent change in LDH	From baseline to week 108
Number of units of RBC transfusion	Post-baseline through week 108	Per protocol algorithm
Change in hemoglobin levels	From baseline to week 108
Adequate control of hemolysis (LDH ≤1.5 × ULN)	Post-baseline through week 108
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
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.
Percentage of days with LDH ≤1.5x upper limit of normal (ULN)	Post-baseline through week 36
Rate of red blood cell (RBC) transfusion	Post-baseline through week 36	Per protocol algorithm
Change in total complement hemolytic activity assay (CH50)	Through week 108
Concentrations of total pozelimab in serum	Through week 108
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.
Rate of RBC transfusion	Post-baseline through week 108	Per protocol algorithm
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.
Normalization of LDH	From post-baseline through week 108
Percentage of days with LDH ≤1.5x ULN	Post-baseline through week 108
Percent change in CH50	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

Trial Locations

Locations (32)

Chang Gung Memorial Hospital- Linkou Branch; 🇨🇳 Taoyuan, Taiwan

Toronto General Hospital; 🇨🇦 Toronto, Ontario, Canada

Semmelweis University/Semmelweis Egyetem; 🇭🇺 Budapest, Hungary

Bhagwan Mahaveer Cancer Hospital and Research Centre (BMCHRC); 🇮🇳 Jaipur, India

Aou Careggi; 🇮🇹 Firenze, Forence, Italy

SC Hematology, AOU Città della Salute e della Scienza di Torino; 🇮🇹 Torino, Italy

University of Tsukuba Hospital; 🇯🇵 Tsukuba, Ibaraki, Japan

St. Vincent Hospital; 🇰🇷 Suwon-si, Gyeonggi-do, Korea, Republic of

Ajou University Medical Center; 🇰🇷 Suwon-si, Gyeonggi-do, Korea, Republic of

Gachon University Gil Medical Center; 🇰🇷 Incheon, Namdong-Gu, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Seoul Teugbyeolsi, Korea, Republic of

Pusan National University Hospital; 🇰🇷 Busan, Korea, Republic of

Severance Hospital Yonsei University Health System; 🇰🇷 Seoul, Korea, Republic of

Ewha Womans University Mokdong Hospital; 🇰🇷 Seoul, Korea, Republic of

Hospital Ampang; 🇲🇾 Ampang, Pahang, Malaysia

Hospital Tg Ampuan Afzan; 🇲🇾 Kuantan, Pahang, Malaysia

Hospital Queen Elizabeth; 🇲🇾 Kota Kinabalu, Sabah, Malaysia

St Lukes Medical Center; 🇵🇭 Quezon City, National Capital Region, Philippines

Szpital Uniwersytecki Nr2 Bydgoszcz; 🇵🇱 Bydgoszcz, Poland

Prof Dr Ion Chiricuta Cancer Institute; 🇷🇴 Cluj Napoca, Cluj, Romania

National University Hospital; 🇸🇬 Singapore, Singapore

Hospital Universitario Basurto; 🇪🇸 Bilbao, Bizkaia, Spain

Hospital Clinic de Barcelona; 🇪🇸 Barcelona, Spain

Hualien Tzu Chi Hospital; 🇨🇳 Hualien City, Taiwan

China Medical University Hospital; 🇨🇳 Taichung, Taiwan

Tri-Service General Hospital; 🇨🇳 Taipei City, Taiwan

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan

Prince Of Songkla Hospital, Prince Of Songkhla University; 🇹🇭 Hat-Yai, Songkhla, Thailand

King Chulalongkorn Memorial Hospital; 🇹🇭 Bangkok, Thailand

Chiang Mai University; 🇹🇭 Chiang Mai, Thailand

Srinagarind Hospital; 🇹🇭 Khon Kaen, Thailand

Ege University Faculty of Medicine; 🇹🇷 Bornova, Izmir, Turkey