Eculizumab Pharmacokinetics/Pharmacodynamics Study in Pediatric/Adolescent Paroxysmal Nocturnal Hemoglobinuria (PNH)

Study Overview
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Brief Summary
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The primary objective of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameter estimates of eculizumab to confirm the dose regimens for pediatric and adolescent participants with PNH.

Detailed Description
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This was an open-label, multi-center study of eculizumab administered to approximately 6 to 8 pediatric and adolescent participants aged 2 to 17 years with PNH. There were 3 periods in this study (screening, treatment, and post-treatment) with the treatment period having 2 dosing phases (induction and maintenance). If all screening criteria were met, the participant was eligible to enter the treatment period of the study after receiving Neisseria meningitidis (N. men), Streptococcus pneumoniae (S. pneumo), and Haemophilus influenzae (H. influ) vaccinations at least 14 days prior to first dose of study drug, or was vaccinated and received treatment with appropriate antibiotics until 14 days after the vaccinations. Participants received eculizumab intravenously (IV) based on their weight. Eculizumab was administered via an IV infusion at a rate of 5 to 10 milliliters (mL) per kilogram (kg) per hour (hr) (mL/kg/hr) for at least 25 minutes. The planned duration of treatment was 12 weeks with a 4-week induction phase and an 8-week maintenance phase. At the Investigator's and parents/legal guardian's discretion, participants who completed this study with eculizumab could continue treatment with commercially available eculizumab (Soliris®) and were followed in the Soliris® PNH Registry. Participants who stopped study participation before study completion or who did not continue with Soliris® treatment at the completion of the study were followed for 8 weeks and monitored for signs and symptoms of serious hemolysis.

Official Title
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An Open-Label Multi-Center Study of Eculizumab in Children and Adolescents With a Diagnosis of Paroxysmal Nocturnal Hemoglobinuria

Conditions
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Hemoglobinuria, Paroxysmal

Intervention / Treatment
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* Drug: Eculizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants between 2 and 17 years of age; Diagnosed with PNH; Participants with ≥ 5% glycosylphosphatidylinositol-deficient red blood cells or granulocytes as confirmed by flow cytometry; Participants must have shown evidence of hemolytic anemia as documented by lactate dehydrogenase greater than the upper limit of normal or at least 1 transfusion in the past 2 years for anemia or anemia related symptoms; Written informed consent from a parent/guardian; Negative pregnancy test for females of child bearing potential at screening; Sexually active females must have documented a reliable and medically approved method of contraception; Participant must have been vaccinated against N. men, S. pneumo, and H. influ at least 14 days prior to study drug initiation or received antibiotics for 14 days after the vaccinations. Exclusion Criteria: Prior eculizumab treatment; Presence or suspicion of active bacterial infection at baseline; Participation in another concurrent clinical study within at least 30 days prior to screening; History of meningococcal/pneumococcal/gonococcal disease; Pregnant, breast feeding, or intending to conceive during the study including the safety follow-up visits; Any other condition that could increase the participant's risk or confound the outcome of the study.

Ages Eligible for Study
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Minimum Age: 2 Years
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: Eculizumab<br>Eculizumab was administered as an IV infusion for 12 weeks. All participants weighed more than 45 kg and received the following weight-based dosing regimen: induction/loading = 600 milligram (mg) weekly x 4; maintenance = 900 mg at Week 5; 900 mg every 2 weeks. | Drug: Eculizumab<br>* 5 mg/mL solution in 5% Dextrose<br>* Other names: Soliris®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak And Trough Concentrations Of Eculizumab In Serum At Week 12 | Serum concentrations of eculizumab were measured by using a validated enzyme-linked immunosorbent assay (ELISA) method developed at Alexion Pharmaceuticals Bioanalytical Laboratory. The range of the analytical assay was 10 to 600 microgram per milliliter (μg/mL). Peak concentrations were not measured at the early termination (ET) visit. | Pre-infusion and 1 hour post-infusion at End of Treatment (EOT) (Day 84 [Week 12]) or ET | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Of Participants With Treatment-emergent Adverse Events (TEAEs) | A TEAE was defined as any adverse event (AE) not present prior to exposure to eculizumab or any event already present that worsened in either intensity or frequency following exposure to eculizumab. A serious TEAE was defined as any event that resulted in death, was immediately life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect. Related TEAEs were considered by investigators to be definitely, probably, or possibly related to administration of the study drug. Relationship is ordered as follows: unrelated, possibly related, probably related, or definitely related. TEAEs and TEAE severity were classified in accordance with the Medical Dictionary for Regulatory Activities (MedDRA) 13.0 dictionary. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module. | First dose of study drug (Day 0) to End of Follow-up (Week 20 [8 weeks after EOT]) | 
| Area Under The Curve (AUC) Of The Change From Baseline To Week 12 In Levels Of Lactate Dehydrogenase (LDH) | The AUC of LDH was calculated by using the change of LDH from baseline values for each participant up to Week 12. For those participants with missing LDH values, the last observation carried forward method (LOCF) was used to impute missing values. Individual AUC values of LDH were summarized and tabulated. | Baseline, EOT (Day 84 [Week 12]) or ET | 
| Concentration Of Plasma-free Hemoglobin At Baseline And Week 12 | Plasma-free hemoglobin was determined for each participant by using standard laboratory assays. The values of plasma-free hemoglobin were summarized by visit. | Baseline, EOT (Day 84 [Week 12]) or ET | 
| Change From Baseline In LDH Levels | Levels of LDH were determined by using standard laboratory assays. LDH values and the change of LDH from baseline were summarized by visit. | Baseline, Weeks 1 to 12 or ET | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alexion, Eculizumab, Paroxysmal Nocturnal Hemoglobinuria, PNH, Soliris