Pozelimab and Cemdisiran Combination Treatment in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Who Have Received Pozelimab Monotherapy

Study Overview
=================
Brief Summary
-----------------
The primary objective of the study is to evaluate the safety and tolerability of 2 dosing regimens of pozelimab and cemdisiran combination therapy during the open-label treatment period (OLTP) The secondary objectives of the study are: To evaluate the effect of the combination treatment on the following parameters of intravascular hemolysis: lactate dehydrogenase (LDH) control, breakthrough hemolysis, and inhibition of total complement hemolysis activity (CH50) To evaluate the effect of the combination treatment on hemoglobin levels To evaluate the effect of the combination treatment on red blood cell (RBC) transfusion requirements To evaluate the effect of the combination treatment on clinical outcome assessments (COAs) measuring fatigue and health related quality of life To assess the concentrations of total pozelimab in serum and total complement component (C) 5 and cemdisiran in plasma To assess immunogenicity to pozelimab and cemdisiran To evaluate the long-term safety and efficacy of pozelimab and cemdisiran in an optional open-label extension period (OLEP) To assess safety after treatment intensification with pozelimab and cemdisiran

Official Title
-----------------
A Randomized, Open-label, Two-arm Study to Evaluate the Safety, Efficacy, and Pharmacodynamic Effects of Pozelimab and Cemdisiran Combination Treatment in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Have Received Pozelimab Monotherapy

Conditions
-----------------
Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
-----------------
* Drug: Pozelimab
* Drug: Cemdisiran


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: 1. Participants with PNH who are receiving treatment with pozelimab monotherapy in the R3918- PNH-1868 study (NCT04162470) Key Exclusion Criteria: Documented, positive polymerase chain reaction (PCR) or equivalent test based on regional recommendations for COVID-19 or suspected SARS-CoV-2 infection as defined in the protocol Participants with documented history of liver cirrhosis or participants with liver disease with evidence of currently impaired liver function; or participants with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) as described in the protocol Significant protocol deviation(s) in the parent study based on the investigator's judgment as described in the protocol Any new condition or worsening of an existing condition which, in the opinion of the investigator, would make the participant unsuitable for enrollment or would jeopardize the safety of the participant Known hypersensitivity to cemdisiran or any component of cemdisiran formulation NOTE: Other protocol-defined Inclusion/ Exclusion Criteria apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pozelimab Q4W + Cemdisiran<br> | Drug: Pozelimab<br>* Administered Sub-cutaneous (SC) per protocol<br>* Other names: REGN3918;Drug: Cemdisiran<br>* Administered SC per protocol<br>* Other names: ALN-CC5;|
| Experimental: Pozelimab Q2W + Cemdisiran<br> | Drug: Pozelimab<br>* Administered Sub-cutaneous (SC) per protocol<br>* Other names: REGN3918;Drug: Cemdisiran<br>* Administered SC per protocol<br>* Other names: ALN-CC5;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment emergent adverse events (TEAEs) | Open Label Treatment Period (OLTP) | Through Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change of LDH from pre-treatment to end-of-treatment period | OLTP Pre-treatment (mean of LDH values prior to combination dosing); End-of-treatment (mean of LDH value at week 24- through week 28) | End of treatment period, approximately 28 Weeks | 
| Maintenance of adequate control of hemolysis | OLTP | Day 1 through Week 28 | 
| Maintenance of adequate control of hemolysis | OLTP | Week 4 through Week 28 | 
| Adequate control of hemolysis | OLTP | Day 1 through Week 28 | 
| Normalization of LDH | OLTP | Day 1 through Week 28 | 
| Area under the curve (AUC) of LDH over time | OLTP | Day 1 through Week 28 | 
| AUC of LDH over time | OLTP | Week 4 through Week 28 | 
| Breakthrough hemolysis | OLTP | Baseline through Week 28 | 
| Hemoglobin stabilization | OLTP Participants who do not receive RBC transfusion and have no decrease in hemoglobin levels | Baseline through Week 28 | 
| Change in hemoglobin levels | OLTP | Baseline to Week 28 | 
| Transfusion avoidance | OLTP Not requiring a RBC transfusion as per protocol algorithm | Baseline to Week 28 | 
| Rate of RBCs transfused | OLTP | Baseline to Week 28 | 
| Number of units of RBCs transfused | OLTP | Baseline to Week 28 | 
| Change in CH50 | OLTP | Baseline to Week 28 | 
| Change in fatigue as measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale | OLTP FACIT fatigue is a 13 item scale and for each item 4 is not at all fatigued to 0 very much fatigued | Baseline to Week 28 | 
| Change in global health status/quality of life scale (GHS/QoL) on the European Organization for Research and Treatment of Cancer: Quality-of-Life Questionnaire core 30 items (EORTC QLQ-C30) | OLTP EORTC QLQ-C30 comprises 30 items (i.e. single questions), 24 of which are aggregated into nine multi-item scales, that is, five functioning scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting) and one global health status scale. The remaining six single-item (dyspnoea, appetite loss, sleep disturbance, constipation, diarrhoea and the financial impact) scales assess symptoms. All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient). | Baseline to Week 28 | 
| Change in physical function (PF) scores on the EORTC QLQ-C30 | OLTP | Baseline to Week 28 | 
| Concentrations of total pozelimab in serum | OLTP | Up to Week 28 | 
| Concentrations of cemdisiran in plasma | OLTP | Up to Week 28 | 
| Change from baseline in concentration of total C5 | OLTP | Baseline through Week 28 | 
| Incidence of pozelimab anti-drug antibody (ADA) responses over time | OLTP | Up to Week 28 | 
| Incidence of cemdisiran anti-drug antibody (ADA) responses over time | OLTP | Up to Week 28 | 
| Incidence and severity of TEAEs for participants who received treatment intensification | OLTP | Through Week 28 | 
| Change of LDH | Optional Open-Label Extension Period (OLEP) | Day 1 to Week 24 | 
| Percent change of LDH | OLEP | Day 1 to Week 24 | 
| Change of LDH | OLEP | Day 1 to Week 52 | 
| Percent change of LDH | OLEP | Day 1 to Week 52 | 
| Maintenance of adequate control of hemolysis | OLEP | Day 1 through Week 24 | 
| Maintenance of adequate control of hemolysis | OLEP | Day 1 through Week 52 | 
| Adequate control of hemolysis | OLEP | Day 1 through Week 52 | 
| Normalization of LDH |  | Day 1 through week 52 | 
| AUC of LDH over time | OLEP | Day 1 through Week 52 | 
| Breakthrough hemolysis | OLEP | Day 1 through Week 24 | 
| Breakthrough hemolysis | OLEP | Day 1 through Week 52 | 
| Hemoglobin stabilization | OLEP Participants who do not receive RBC transfusion and have no decrease in hemoglobin levels | Day 1 through Week 24 | 
| Hemoglobin stabilization | OLEP Participants who do not receive RBC transfusion and have no decrease in hemoglobin levels | Day 1 through Week 52 | 
| Change in hemoglobin levels | OLEP | Day 1 to Week 24 | 
| Change in hemoglobin levels | OLEP | Day 1 to Week 52 | 
| Transfusion avoidance | OLEP Not requiring a RBC transfusion as per protocol algorithm | Day 1 through Week 24 | 
| Transfusion avoidance | OLEP Not requiring a RBC transfusion as per protocol algorithm | Day 1 through Week 52 | 
| Rate of RBCs transfused | OLEP | Day 1 to Week 24 | 
| Rate of RBCs transfused | OLEP | Day 1 to Week 52 | 
| Number of units of RBCs transfused | OLEP | Day 1 to Week 24 | 
| Number of units of RBCs transfused | OLEP | Day 1 to Week 52 | 
| Change in CH50 | OLEP | Day 1 to Week 16 | 
| Change in CH50 | OLEP | Day 1 to Week 24 | 
| Change in CH50 | OLEP | Day 1 to Week 52 | 
| Percent change in CH50 | OLEP | Day 1 to Week 16 | 
| Percent change in CH50 | OLEP | Day 1 to Week 24 | 
| Percent change in CH50 | OLEP | Day 1 to Week 52 | 
| Change in fatigue as measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale | OLEP | Day 1 to Week 52 | 
| Change in GHS/QoL on the EORTC QLQ-C30 | OLEP | Day 1 to Week 52 | 
| Change in PF scores on the EORTC QLQ-C30 | OLEP | Day 1 to Week 52 | 
| Incidence and severity of TEAEs | OLEP | Up to Week 52 | 
| Concentrations of total pozelimab in serum | OLEP | Up to Week 52 | 
| Concentrations of total C5 | OLEP | Up to Week 52 | 
| Concentrations of cemdisiran in plasma | OLEP | Up to Week 52 | 
| Incidence of pozelimab anti-drug antibody (ADA) responses over time | OLEP | Up to Week 52 | 
| Incidence of cemdisiran anti-drug antibody (ADA) responses over time | OLEP | Up to Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PNH