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

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00867932

Enrollment

Registered

2009-03-24

Start date

2009-10-02

Completion date

2011-05-12

Last updated

2018-10-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hemoglobinuria, Paroxysmal

Keywords

Alexion, Eculizumab, Paroxysmal Nocturnal Hemoglobinuria, PNH, Soliris

Brief summary

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

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.

Interventions

DRUGEculizumab

5 mg/mL solution in 5% Dextrose

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

2 Years to 17 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Peak And Trough Concentrations Of Eculizumab In Serum At Week 12	Pre-infusion and 1 hour post-infusion at End of Treatment (EOT) (Day 84 [Week 12]) or ET	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.

Secondary

Measure	Time frame	Description
Number Of Participants With Treatment-emergent Adverse Events (TEAEs)	First dose of study drug (Day 0) to End of Follow-up (Week 20 [8 weeks after EOT])	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.
Area Under The Curve (AUC) Of The Change From Baseline To Week 12 In Levels Of Lactate Dehydrogenase (LDH)	Baseline, EOT (Day 84 [Week 12]) or ET	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.
Concentration Of Plasma-free Hemoglobin At Baseline And Week 12	Baseline, EOT (Day 84 [Week 12]) or ET	Plasma-free hemoglobin was determined for each participant by using standard laboratory assays. The values of plasma-free hemoglobin were summarized by visit.
Change From Baseline In LDH Levels	Baseline, Weeks 1 to 12 or ET	Levels of LDH were determined by using standard laboratory assays. LDH values and the change of LDH from baseline were summarized by visit.

Countries

United States

Participant flow

Recruitment details

The recruitment period lasted from October 2009 to January 2011. Three sites in the United States of America enrolled a total of 7 participants with paroxysmal nocturnal hemoglobinuria (PNH).

Pre-assignment details

Participants who completed this study could have continued treatment with commercially available eculizumab (Soliris®) and been followed in the Soliris® PNH Registry. Those who didn't complete the study or who didn't continue with Soliris® treatment after the study were followed for 8 weeks and monitored for signs and symptoms of serious hemolysis.

Participants by arm

Arm	Count
Eculizumab 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 mg weekly x 4; maintenance = 900 mg at Wk 5; 900 mg Q2W.	7
Total	7

Baseline characteristics

Characteristic	Eculizumab
Age, Continuous	15.01 years STANDARD_DEVIATION 2.28
Age, Customized Adolescents (12 to 17 years)	6 Participants
Age, Customized Children (2 to 11 years)	1 Participants
Sex: Female, Male Female	4 Participants
Sex: Female, Male Male	3 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	7 / 7
serious Total, serious adverse events	2 / 7

Outcome results

Primary

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.

Time frame: Pre-infusion and 1 hour post-infusion at End of Treatment (EOT) (Day 84 [Week 12]) or ET