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

Blood samples for determination of cRBC hemolytic activity were collected before and after administration of study drug at designated time points.

Time frame: Baseline, Weeks 2, 10, 18, and 26

Population: Pharmacodynamic: all participants who received at least 1 dose of ravulizumab and who had evaluable pharmacodynamic data.

Blood samples for determination of free C5 were collected before and after administration of study drug at designated time points.

Time frame: Baseline, Weeks 2, 10, 18, and 26 (end of infusion)

Population: Pharmacodynamic: all participants who received at least 1 dose of ravulizumab and who had evaluable pharmacodynamic data.

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).

Time frame: Week 1 (Day 1), Week 2 (Day 15), Week 10 (Day 71), and Week 18 (Day 127)

Population: Pharmacokinetic (PK): Participants enrolled into the study who received at least 1 dose of ravulizumab and who had evaluable interim PK data. The PK set was used for all PK analyses.

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).

Time frame: Week 18

Population: Pharmacokinetic (PK): participants enrolled into the study who received at least 1 dose of ravulizumab and who had evaluable interim PK data. The PK set was used for all PK analyses.

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).

Time frame: Week 18

Population: Pharmacokinetic (PK): participants enrolled into the study who received at least 1 dose of ravulizumab and who had evaluable interim PK data. The PK set was used for all PK analyses.

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.

Time frame: Week 2 (Day 15), Week 10 (Day 71), Week 18 (Day 127), Week 26 (Day 183)

Population: Pharmacokinetic (PK): participants enrolled into the study who received at least 1 dose of ravulizumab and who had evaluable interim PK data. The PK set was used for all PK analyses.

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.

Time frame: Baseline, Week 26

Population: Full Analysis: all participants who received at least 1 dose of ravulizumab and had at least 1 efficacy assessment after the first infusion of ravulizumab.

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.

Time frame: Baseline, Week 26

Population: Full Analysis: all participants who received at least 1 dose of ravulizumab and had at least 1 efficacy assessment after the first infusion of ravulizumab.

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.

Time frame: Baseline, Week 26

Population: Full Analysis: all participants who received at least 1 dose of ravulizumab and had at least 1 efficacy assessment after the first infusion of ravulizumab.

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.

Time frame: Week 26

Population: Full Analysis: all participants who received at least 1 dose of ravulizumab and had at least 1 efficacy assessment after the first infusion of ravulizumab.

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.

Time frame: Week 26

Population: Full Analysis: all participants who received at least 1 dose of ravulizumab and had at least 1 efficacy assessment after the first infusion of ravulizumab.

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.

Time frame: Week 26

Population: Full Analysis: all participants who received at least 1 dose of ravulizumab and had at least 1 efficacy assessment after the first infusion of ravulizumab.