A Study of Ravulizumab (ALXN1210) in Children and Adolescents With Paroxysmal Nocturnal Hemoglobinuria

Study Overview
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Brief Summary
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The purpose of this study was to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of ravulizumab in pediatric participants with paroxysmal nocturnal hemoglobinuria (PNH).

Detailed Description
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The study consists of a 4-week Screening Period, a 26-week Primary Evaluation Period, and an Extension Period of up to 4 years (with the exception of any country-specific mandates), whichever occurs first. Efficacy and safety data are reported for the 26-week Primary Evaluation Period only. Analyses were conducted separately for complement inhibitor treatment-naïve participants and eculizumab-experienced participants.

Official Title
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A Phase 3, Open-Label Study of ALXN1210 in Children and Adolescents With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Biological: Ravulizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants from birth up to <18 years of age and weighing ≥ 5 kilograms at the time of consent. PNH diagnosis confirmed by documented high-sensitivity flow cytometry. Presence of 1 or more of the following PNH-related signs or symptoms within 3 months of Screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia, history of a major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cell transfusion due to PNH. Lactate dehydrogenase (LDH) level ≥ 1.5 × upper limit of normal (ULN) for participants not being treated with eculizumab at screening and LDH level ≤ 1.5 × ULN for participants taking eculizumab. Documented meningococcal vaccination not more than 3 years prior to dosing, and vaccination against Streptococcus pneumoniae and Haemophilus influenzae. Female participants of childbearing potential must use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab. Exclusion Criteria: History of bone marrow transplantation. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease that, in the opinion of the investigator or sponsor, would preclude participation. Unstable medical conditions (for example, myocardial ischemia, active gastrointestinal bleed, severe congestive heart failure, anticipated need for major surgery within 6 months of randomization, coexisting chronic anemia unrelated to PNH). Females who are pregnant or breastfeeding or who have a positive pregnancy test at screening or Day 1. Participation in another interventional clinical study or use of any experimental therapy within 30 days before initiation of study drug on Day 1 in this study or within 5 half-lives of that investigational product, whichever is greater.

Ages Eligible for Study
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Maximum Age: 17 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ravulizumab<br>Complement inhibitor treatment-naïve and eculizumab-experienced participants received ravulizumab. | Biological: Ravulizumab<br>* Single intravenous (IV) loading dose on Day 1, followed by regular IV maintenance dosing beginning on Day 15, based on weight.<br>* Other names: Ultomiris;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) Of Ravulizumab | Blood samples for determination of ravulizumab Cmax were collected before and after administration of study drug at designated time points. Results are reported in micrograms/milliliter (μg/mL). | Week 1 (Day 1), Week 2 (Day 15), Week 10 (Day 71), and Week 18 (Day 127) | 
| Trough Serum Concentration (Ctrough) Of Ravulizumab | Blood samples for determination of ravulizumab Ctrough were collected before and after administration of study drug at designated time points. Trough serum concentration was measured at end of dosing interval at steady state. Results are reported in μg/mL. | Week 2 (Day 15), Week 10 (Day 71), Week 18 (Day 127), Week 26 (Day 183) | 
| Mean Accumulation Ratio For Cmax Of Ravulizumab Following The Last Maintenance Dose Relative To The First Maintenance Dose | Blood samples for determination of ravulizumab accumulation ratio for Cmax were collected before and after administration of study drug at designated time points. The accumulation ratio was calculated as Cmax from the last maintenance dose (Week 18) divided by Cmax from the first maintenance dose (Week 2). | Week 18 | 
| Mean Accumulation Ratio For Ctrough Of Ravulizumab Following The Last Maintenance Dose Relative To The First Maintenance Dose | Blood samples for determination of ravulizumab accumulation ratio for Ctrough were collected before and after administration of study drug at designated time points. The accumulation ratio was calculated as Ctrough from the last maintenance dose (Week 18) divided by Ctrough from the first maintenance dose (Week 2). | Week 18 | 
| Change In Free Complement Component C5 (C5) Concentrations Over Time | Blood samples for determination of free C5 were collected before and after administration of study drug at designated time points. | Baseline, Weeks 2, 10, 18, and 26 (end of infusion) | 
| Change In Chicken Red Blood Cell (cRBC) Hemolytic Activity Over Time | Blood samples for determination of cRBC hemolytic activity were collected before and after administration of study drug at designated time points. | Baseline, Weeks 2, 10, 18, and 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline At Week 26 In Lactate Dehydrogenase (LDH) Levels | Blood and urine samples for determination of LDH levels were collected at designated time points. Baseline was defined as the average of all assessments analyzed by the central laboratory prior to first study drug administration. | Baseline, Week 26 | 
| Percentage Of Participants Who Achieved Transfusion Avoidance (TA) | Transfusion avoidance was defined as the proportion of participants who remained transfusion-free and did not require a transfusion according to protocol-specified guidelines. Point estimates and 2-sided 95% exact confidence intervals (CIs) were computed. Participants who withdrew from the study due to lack of efficacy during the Primary Evaluation Period were considered as non-responders and were counted in the group needing transfusion. For participants who withdrew from the study for any other reason during the Primary Evaluation Period, their data up to the time of withdrawal was used to assess TA. | Week 26 | 
| Change In Quality Of Life (QoL) From Baseline To Week 26 | Quality of life was measured by Pediatric Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Questionnaire (participants ≥ 5 years of age), a 13-item questionnaire that assesses fatigue and its impact upon daily activities and function over the preceding 7 days. Each item is scored on a 5-point scale, and total scores range from 0 to 52, with a higher score indicating better QoL. The scoring guideline for the Pediatric FACIT-Fatigue instrument was used to calculate a FACIT-Fatigue score. Changes from baseline in FACIT-Fatigue scores were summarized at baseline and at the study visits where this assessment was collected up to Day 183 (Week 26). At each study visit, the proportion of participants who showed an improvement of at least 3 points for the Pediatric FACIT-Fatigue scores were summarized by point estimates and 2-sided 95% exact CIs. | Baseline, Week 26 | 
| Percentage Of Participants With Stabilized Hemoglobin At Week 26 | Stabilized hemoglobin was defined as avoidance of a ≥ 2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion through Week 26. Point estimates and 2-sided 95% exact CIs were computed. Participants who withdrew from the study due to lack of efficacy during the Primary Evaluation Period were considered as non-responders and were counted in the group who did not meet the stabilized hemoglobin definition. For participants who withdrew from the study for any other reason during the Primary Evaluation Period, their data up to the time of withdrawal were used to assess stabilized hemoglobin. | Week 26 | 
| Percentage Change In Free Hemoglobin From Baseline To Week 26 | Percentage change from baseline in free hemoglobin was summarized at all study visits up to Day 183 (Week 26). Baseline was defined as the last non-missing assessment value prior to the first study drug infusion. | Baseline, Week 26 | 
| Percentage Of Participants With Breakthrough Hemolysis (BTH) At Week 26 | Breakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia, major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH as follows: for participants who entered the study naïve to complement inhibitor treatment, elevated LDH ≥ 2 × the upper limit of normal (ULN) after prior LDH reduction to < 1.5 × ULN on therapy; for participants who entered the study stabilized on eculizumab treatment, elevated LDH ≥ 2 × ULN. Participants who withdrew from the study due to lack of efficacy during the Primary Evaluation Period were considered as non-responders and were counted in the group with BTH. For participants who withdrew from the study for any other reason during the Primary Evaluation Period, their data up to the time of withdrawal were used to assess BTH. No participants experienced BTH. | Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ravulizumab, ALXN1210, Ultomiris, Pharmacokinetics, Pharmacodynamics