A Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Participants With PNH

Study Overview
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Brief Summary
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This is a randomized, double-blind, active-controlled phase 3 study of ABP 959 in participants with paroxysmal nocturnal hemoglobinuria.

Official Title
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A Randomized, Double-Blind, Active-Controlled Phase 3 Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Subjects With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Drug: ABP 959
* Drug: Eculizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥ 18 years of age. Historical diagnosis of PNH. Administration of eculizumab for ≥ 6 months and currently receiving 900 mg of eculizumab. Hemoglobin ≥ 9.0 g/dL for at least 6 weeks before randomization. Lactate dehydrogenase < 1.5 × the upper limit of normal at screening. Platelet count ≥ 50 × 10^9/L. Absolute neutrophil count (ANC) ≥ 0.5 x 10^9/L (500/μL). Participants must be vaccinated against Neisseria meningitidis. Participants must sign an IRB/IEC-approved ICF before participation in any procedures. Exclusion Criteria: Known or suspected hereditary complement deficiency. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure [New York Heart Association ≥ Class III], serious uncontrolled cardiac arrhythmia), peripheral vascular disease, cerebrovascular accident, or transient ischemic attack in the previous 6 months. Evidence of acute thrombosis (liver Doppler ultrasound of hepatic and portal veins). Known to be positive for human immunodeficiency virus. Woman who is pregnant or breastfeeding. Participant is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or participant is receiving other investigational agent(s). Participant has known sensitivity to any of the products to be administered during the study, including mammalian cell-derived drug products. History of meningococcal infection. Presence or suspicion of active bacterial infection, or recurrent bacterial infection. History of bone marrow transplantation. Red blood cell transfusion required within 12 weeks before randomization. Participant experienced ≥ 2 breakthrough events, (ie, signs and symptoms of intravascular hemolysis, that require dose and/or schedule adjustments of eculizumab) in the previous 12 months before screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: T (ABP 959) / R (eculizumab)<br>ABP 959 for 52 weeks in Period 1 followed by eculizumab for 26 weeks in Period 2 | Drug: ABP 959<br>* intravenous infusion<br>* Other names: Treatment T;Drug: Eculizumab<br>* intravenous infusion<br>* Other names: Treatment R;|
| Other: R (eculizumab) / T (ABP 959)<br>Eculizumab for 52 weeks in Period 1 followed by ABP 959 for 26 weeks in Period 2 | Drug: ABP 959<br>* intravenous infusion<br>* Other names: Treatment T;Drug: Eculizumab<br>* intravenous infusion<br>* Other names: Treatment R;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LDH Level at Week 27 (Parallel Comparison) | The primary analysis for the parallel comparison was hemolysis as measured by LDH at Week 27 by initial treatment received (Period 1). | Week 27 | 
| Time-adjusted Area Under the Effect Curve (AUEC) of LDH (Crossover Comparison Per Assigned Treatment) | The primary analysis for the crossover comparison was hemolysis, as measured by the time-adjusted AUEC of LDH, according to treatment assigned during each of the 14-week assessments during Periods 1 and 2. | From Week 13 to Week 27, from Week 39 to Week 53, and from Week 65 to Week 79 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Total Complement (50% Total Hemolytic Complement Activity [CH50]) | Total complement (%) was measured in serum using an assay method and compared the total hemolytic complement activity to the lower limit of the normal human reference (LLN) of 58 U/mL for all CH50 values. The percent of LLN of CH50 at each time point was calculated as mean CH50 results/LLN x 100%. Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79 | 
| Mean Total Hemoglobin Levels | Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79 | 
| Mean Serum-free Hemoglobin Levels | Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79 | 
| Mean Haptoglobin Levels | Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79 | 
| Mean Bilirubin Levels | Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79 | 
| Degree of Hemoglobinuria | The degree of hemoglobinuria was categorized as negative, trace, small, moderate, and large based on the analysis of urine samples collected from each participant at the specified time points. Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79 | 
| Mean Percentage of Type III Erythrocytes | As a measure of hemolysis the mean percentage of Type III erythrocytes was measured at the specified timepoints. Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | Baseline, Week 27, Week 39, Week 53, Week 65 and Week 79 | 
| LDH Levels at Week 53 and Week 79 | The analysis of the crossover comparison of hemolysis, as measured by LDH at Week 53 and Week 79. | Week 53 (first week of Period 2) and Week 79 (last week of Period 2) | 
| Mean LDH Levels by Visit up to Week 79 | Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | Baseline, Week 3, Week 7, Week 13, Week 15, Week 19, Week 25, Week 27, Week 29, Week 33, Week 39, Week 41, Week 43, Week 45, Week 47, Week 49, Week 51, Week 53, Week 55, Week 59, Week 65, Week 67, Week 69, Week 71, Week 73, Week 75, Week 77, and Week 79 | 
| Mean Number of Packed RBC Units Transfused Per Month | Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | Baseline to End of Study (up to Week 79) | 
| Total and Unbound Pharmacokinetics (PK) Area Under the Curve (AUC) of ABP 959 and Eculizumab From Week 13 to Week 15 (Period 1) | The total and unbound PK concentration AUC values from Week 13 to Week 15 in Period 1 are presented by actual treatment received. | PK samples were collected predose and immediately postdose Week 13, 7 days post the Week 13 dose (Week 14), and predose at Week 15 | 
| Total and Unbound Trough Serum Concentrations of ABP 959 and Eculizumab | The total and unbound serum trough concentrations are presented by treatment sequence received for the prespecified time points. Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | PK samples were collected predose at the prespecified timepoints: baseline, Week 3, Week 7, Week 13, Week 15, Week 19, Week 27, Week 33, Week 39, Week 45, Week 51, Week 53, Week 55, Week 59, Week 65, Week 71, Week 77, and Week 79 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs are defined as any adverse event (AE) that began or increased in severity or frequency at or after the time of first treatment up to end of study (up to Week 79). A treatment-emergent serious adverse event (SAE) was a TEAE that met at least 1 of the following criteria: was fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was another medically important serious event. The treatment-emergent events of interest (EOI) prespecified for this study included serious infections (meningococcus aspergillus, and other serious infections/sepsis), and infusion reactions. | Day 1 to End of Study (up to Week 79) | 
| Number of Participants With Antidrug Antibodies (ADAs) | Any samples that tested positive for binding antibodies were also tested for neutralizing antibodies. Treatment boosted ADAs were defined as a positive immunoassay result at baseline and at least 1 postbaseline immunoassay result that was ≥ 4 times the magnitude of the baseline result. Baseline was defined as the last non-missing assessment taken prior to the first dose of IP. | Blood samples for ADA assessments were taken predose at baseline, Week 3, Week 7, Week 13, Week 19, Week 25, Week 27, Week 33, Week 39, Week 45, Week 51, Week 53, Week 55, Week 59, Week 65, Week 71, Week 77 and Week 79. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Marchiafava-Micheli Syndrome, Paroxysmal Cold Hemoglobinuria