Clinical trial NCT05744921: 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.
Official title: An Open-Label Extension Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of Pozelimab and Cemdisiran Combination Therapy in Patients With Paroxysmal Nocturnal Hemoglobinuria
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: PNH
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2023-02-27
Enrollment: 202
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)


Eligibility criteria: Key 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 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

Primary outcomes:
measure: Incidence of treatment-emergent serious adverse events (SAEs)
timeFrame: Up to week 108
measure: Severity of treatment-emergent SAEs
timeFrame: Up to week 108
measure: Incidence of treatment emergent adverse events of special interest (AESIs)
timeFrame: Up to week 108
measure: Severity of treatment emergent AESIs
timeFrame: Up to week 108
measure: Incidence of adverse events (AEs) leading to permanent treatment discontinuation
timeFrame: Up to week 108
measure: Severity of adverse events (AEs) leading to permanent treatment discontinuation
timeFrame: Up to week 108
measure: Percent change from baseline in lactate dehydrogenase (LDH)
timeFrame: Baseline to week 36
Secondary outcomes:
measure: Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN)
timeFrame: Post-baseline through week 36
measure: Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN)
timeFrame: Post-baseline through week 48
measure: Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN)
timeFrame: Post-baseline through week 76
measure: Maintenance of adequate control of hemolysis (LDH ≤1.5 × ULN)
timeFrame: Post-baseline through week 108
measure: Adequate control of hemolysis (LDH ≤1.5 × ULN)
timeFrame: Post-baseline through week 108
measure: Transfusion avoidance
timeFrame: Post-baseline through week 36
measure: Transfusion avoidance
timeFrame: Post-baseline through week 48
measure: Transfusion avoidance
timeFrame: Post-baseline through week 76
measure: Transfusion avoidance
timeFrame: Post-baseline through week 108
measure: Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis)
timeFrame: Post-baseline through week 36
measure: Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis)
timeFrame: Post-baseline through week 48
measure: Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis)
timeFrame: Post-baseline through week 76
measure: Breakthrough hemolysis (defined as LDH ≥2 × ULN [subsequent to initial achievement of LDH ≤1.5 × ULN] concomitant with signs or symptoms associated with hemolysis)
timeFrame: Post-baseline through week 108
measure: Hemoglobin stabilization
timeFrame: Post-baseline through week 36
measure: Hemoglobin stabilization
timeFrame: Post-baseline through week 48
measure: Hemoglobin stabilization
timeFrame: Post-baseline through week 76
measure: Hemoglobin stabilization
timeFrame: Post-baseline through week 108
measure: Percent change in LDH
timeFrame: From baseline to week 48
measure: Percent change in LDH
timeFrame: From baseline to week 76
measure: Percent change in LDH
timeFrame: From baseline to week 108
measure: Change in fatigue
timeFrame: From baseline to week 36
measure: Change in fatigue
timeFrame: From baseline to week 48
measure: Change in fatigue
timeFrame: From baseline to week 76
measure: Change in fatigue
timeFrame: From baseline to weeks 108
measure: Change in physical function (PF) scores on the EORTC QLQ-C30
timeFrame: From baseline to week 36
measure: Change in PF scores on the EORTC QLQ-C30
timeFrame: From baseline to week 48
measure: Change in PF scores on the EORTC QLQ-C30
timeFrame: From baseline to week 76
measure: Change in PF scores on the EORTC QLQ-C30
timeFrame: From baseline to week 108
measure: Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30
timeFrame: From baseline to week 36
measure: Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30
timeFrame: From baseline to week 48
measure: Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30
timeFrame: From baseline to week 76
measure: Change in GHS/quality of life (QOL) scale on the EORTC QLQ-C30
timeFrame: From baseline to week 108
measure: Normalization of LDH
timeFrame: From post-baseline through week 108
measure: Rate of red blood cell (RBC) transfusion
timeFrame: Post-baseline through week 36
measure: Rate of RBC transfusion
timeFrame: Post-baseline through week 48
measure: Rate of RBC transfusion
timeFrame: Post-baseline through week 76
measure: Rate of RBC transfusion
timeFrame: Post-baseline through week 108
measure: Number of units of RBC transfusion
timeFrame: Post-baseline through week 36
measure: Number of units of RBC transfusion
timeFrame: Post-baseline through week 48
measure: Number of units of RBC transfusion
timeFrame: Post-baseline through week 76
measure: Number of units of RBC transfusion
timeFrame: Post-baseline through week 108
measure: Percentage of days with LDH ≤1.5x upper limit of normal (ULN)
timeFrame: Post-baseline through week 36
measure: Percentage of days with LDH ≤1.5x ULN
timeFrame: Post-baseline through week 48
measure: Percentage of days with LDH ≤1.5x ULN
timeFrame: Post-baseline through week 76
measure: Percentage of days with LDH ≤1.5x ULN
timeFrame: Post-baseline through week 108
measure: Change in hemoglobin levels
timeFrame: From baseline to week 36
measure: Change in hemoglobin levels
timeFrame: From baseline to week 48
measure: Change in hemoglobin levels
timeFrame: From baseline to week 76
measure: Change in hemoglobin levels
timeFrame: From baseline to week 108
measure: Change in total complement hemolytic activity assay (CH50)
timeFrame: Through week 108
measure: Percent change in CH50
timeFrame: Through week 108
measure: Concentrations of total pozelimab in serum
timeFrame: Through week 108
measure: Concentrations of cemdisiran in plasma
timeFrame: Through week 24
measure: Incidence of treatment-emergent anti-drug antibodies to pozelimab
timeFrame: Through week 108
measure: Incidence of treatment-emergent anti-drug antibodies to cemdisiran
timeFrame: Through week 108
measure: Concentration of total complement component 5 (C5) in plasma
timeFrame: Through week 108
measure: Percent change of concentration of total C5 in plasma
timeFrame: Through week 108
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Budapest
country: Hungary
facility: Semmelweis University/Semmelweis Egyetem
city: New Delhi
country: India
facility: Rajiv Gandhi Cancer Institute & Research Center (RGCIRC) - Rohini Campus
state: Delhi
city: Jaipur
country: India
facility: Bhagwan Mahaveer Cancer Hospital and Research Centre (BMCHRC)
city: Firenze
country: Italy
facility: Aou Careggi
state: Forence
city: Torino
country: Italy
facility: SC Hematology, AOU Città della Salute e della Scienza di Torino
city: Tsukuba
country: Japan
facility: University of Tsukuba Hospital
state: Ibaraki
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Medical Center
state: Gyeonggi-do
city: Suwon
country: Korea, Republic of
facility: St. Vincent Hospital
state: Gyeonggi
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
state: Namdong-Gu
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Mokdong Hospital
city: Kuantan
country: Malaysia
facility: Hospital Tg Ampuan Afzan
state: Pahang
city: Kota Kinabalu
country: Malaysia
facility: Hospital Queen Elizabeth
state: Sabah
city: Ampang
country: Malaysia
facility: Hospital Ampang
state: Selangor
city: Quezon City
country: Philippines
facility: St Lukes Medical Center
state: National Capital Region
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki Nr2 Bydgoszcz
city: Cluj Napoca
country: Romania
facility: Prof Dr Ion Chiricuta Cancer Institute
state: Cluj
city: Singapore
country: Singapore
facility: National University Hospital
city: Bilbao
country: Spain
facility: Hospital Universitario Basurto
state: Bizkaia
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital - Linkou Branch
state: Hunan Province
city: Hualien City
country: Taiwan
facility: Hualien Tzu Chi Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taipei City
country: Taiwan
facility: Tri-Service General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Hat-Yai
country: Thailand
facility: Prince Of Songkla Hospital, Prince Of Songkhla University
state: Songkhla
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Chiang Mai
country: Thailand
facility: Chiang Mai University
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital
city: Bornova
country: Turkey
facility: Ege University Faculty of Medicine
state: Izmir
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust - St. James Institute of Oncology
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References: