Back to resultsA Study of Ravulizumab (ALXN1210) in Children and Adolescents With Paroxysmal Nocturnal Hemoglobinuria
Primary Purpose
Paroxysmal Nocturnal Hemoglobinuria
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Ravulizumab
Sponsored by
About this trial
This is an interventional treatment trial for Paroxysmal Nocturnal Hemoglobinuria focused on measuring Ravulizumab, ALXN1210, Ultomiris, Pharmacokinetics, Pharmacodynamics
Eligibility Criteria
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.
Sites / Locations
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Ravulizumab
Arm Description
Complement inhibitor treatment-naïve and eculizumab-experienced participants received ravulizumab.
Outcomes
Primary Outcome Measures
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).
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.
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).
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).
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.
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03406507
Brief Title
A Study of Ravulizumab (ALXN1210) in Children and Adolescents With Paroxysmal Nocturnal Hemoglobinuria
Official Title
A Phase 3, Open-Label Study of ALXN1210 in Children and Adolescents With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Completed
Study Start Date
February 22, 2018 (Actual)
Primary Completion Date
March 25, 2020 (Actual)
Study Completion Date
August 25, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alexion
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Paroxysmal Nocturnal Hemoglobinuria
Keywords
Ravulizumab, ALXN1210, Ultomiris, Pharmacokinetics, Pharmacodynamics
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
13 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ravulizumab
Arm Type
Experimental
Arm Description
Complement inhibitor treatment-naïve and eculizumab-experienced participants received ravulizumab.
Intervention Type
Biological
Intervention Name(s)
Ravulizumab
Other Intervention Name(s)
ALXN1210, Ultomiris
Intervention Description
Single intravenous (IV) loading dose on Day 1, followed by regular IV maintenance dosing beginning on Day 15, based on weight.
Primary Outcome Measure Information:
Title
Maximum Observed Serum Concentration (Cmax) Of Ravulizumab
Description
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)
Title
Trough Serum Concentration (Ctrough) Of Ravulizumab
Description
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)
Title
Mean Accumulation Ratio For Cmax Of Ravulizumab Following The Last Maintenance Dose Relative To The First Maintenance Dose
Description
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
Title
Mean Accumulation Ratio For Ctrough Of Ravulizumab Following The Last Maintenance Dose Relative To The First Maintenance Dose
Description
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
Title
Change In Free Complement Component C5 (C5) Concentrations Over Time
Description
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)
Title
Change In Chicken Red Blood Cell (cRBC) Hemolytic Activity Over Time
Description
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
Secondary Outcome Measure Information:
Title
Percentage Change From Baseline At Week 26 In Lactate Dehydrogenase (LDH) Levels
Description
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
Title
Percentage Of Participants Who Achieved Transfusion Avoidance (TA)
Description
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
Title
Change In Quality Of Life (QoL) From Baseline To Week 26
Description
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
Title
Percentage Of Participants With Stabilized Hemoglobin At Week 26
Description
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
Title
Percentage Change In Free Hemoglobin From Baseline To Week 26
Description
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
Title
Percentage Of Participants With Breakthrough Hemolysis (BTH) At Week 26
Description
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
10. Eligibility
Sex
All
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
Clinical Trial Site
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30329
Country
United States
Facility Name
Clinical Trial Site
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Facility Name
Clinical Trial Site
City
Paris
Country
France
Facility Name
Clinical Trial Site
City
Utrecht
Country
Netherlands
Facility Name
Clinical Trial Site
City
Oslo
Country
Norway
Facility Name
Clinical Trial Site
City
Moscow
Country
Russian Federation
Facility Name
Clinical Trial Site
City
Saint Petersburg
Country
Russian Federation
Facility Name
Clinical Trial Site
City
Leeds
Country
United Kingdom
Facility Name
Clinical Trial Site
City
London
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
Citations:
Citation
Kulagin A, Chonat S, Maschan A, Bartels M, Buechner J, Punzalan R, Richards M, Ogawa M, Hicks E, Yu J, Baruchel A, Kulasekararaj AG. Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria: interim analysis of a phase 3, open-label study. Presented at the European Hematology Association 2021 Virtual Congress, June 9-17, 2021.
Results Reference
result
Learn more about this trial
A Study of Ravulizumab (ALXN1210) in Children and Adolescents With Paroxysmal Nocturnal Hemoglobinuria
We'll reach out to this number within 24 hrs