Study of Ravulizumab in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS)

Study Overview
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Brief Summary
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The purpose of the study is to assess the efficacy of ravulizumab to control disease activity in children and adolescents with aHUS who have not previously used a complement inhibitor (complement inhibitor treatment-naïve), as well as in complement inhibitor-experienced (eculizumab-experienced) adolescent participants.

Official Title
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A Phase 3, Open-Label, Multicenter Study of ALXN1210 in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS)

Conditions
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Atypical Hemolytic Uremic Syndrome (aHUS)

Intervention / Treatment
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* Biological: Ravulizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Complement Inhibitor Treatment Naïve: Participants from birth up to <18 years of age and weighing ≥5 kilograms (kg) at the time of consent. Participants had not been previously treated with complement inhibitors. Evidence of thrombotic microangiopathy (TMA), including low platelet count, hemolysis (breaking of red blood cells inside of blood vessels), and decreased kidney function. Documented meningococcal vaccination not more than 3 years prior to dosing, and vaccination against Streptococcus pneumoniae and Haemophilus influenzae type b. Female participants of childbearing potential and male participants with female partners of childbearing potential must have used highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab. Eculizumab Experienced: Participants between 12 and <18 years of age (non-Japanese sites) or <18 years of age (Japanese sites) who had been treated with eculizumab according to the labelled dosing recommendation for aHUS for at least 90 days prior to screening. Participants with documented diagnosis of aHUS. Participants with clinical evidence of response to eculizumab indicated by stable TMA parameters at screening. Documented meningococcal vaccination not more than 3 years prior to dosing, and vaccination against Streptococcus pneumoniae and Haemophilus influenzae type b. Females of childbearing potential and male participants with female partners of childbearing potential must have used highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab. Exclusion Criteria: Known familial or acquired ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency (activity <5%). Known Shiga toxin-related hemolytic uremic syndrome. Positive direct Coombs test. Females who planned to become pregnant during the study or were currently pregnancy or breastfeeding. Identified drug exposure-related hemolytic uremic syndrome. Bone marrow transplant/hematopoietic stem cell transplant within the last 6 months prior to the start of screening. Hemolytic uremic syndrome related to known genetic defects of cobalamin C metabolism. Known systemic sclerosis (scleroderma), systemic lupus erythematosus, or antiphospholipid antibody positivity or syndrome. Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy for end-stage kidney disease. For eculizumab-experienced participants, prior use of complement inhibitors other than eculizumab. For eculizumab-experienced participants, any known abnormal TMA parameters within 90 days prior to screening.

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>Participants were administered weight-based doses of ravulizumab every 8 weeks thereafter for participants weighing ≥ 20 kg, or once every 4 weeks for participant weighing < 20 kg, for a total of 26 weeks of study treatment in the initial Evaluation Period. After the Initial Evaluation Period, participants rolled over into an Extension Period in which all participant continued their weight-based maintenance dose until the product was registered or approved (in accordance with country specific regulation) or for up to 4.5 years, whichever occurred first. | Biological: Ravulizumab<br>* Participant received weight-based dosages for 26 weeks during the Initial Evaluation Period. Participants received a loading dose on Day 1, followed by maintenance dosing on Day 15 and once every 8 weeks thereafter for participants weighing ≥ 20 kg, or once every 4 weeks for participant weighing < 20 kg.<br>* Other names: Ultomiris;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Of Complement Inhibitor Treatment-naïve Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26 | Complete TMA response during the 26-week Initial Evaluation Period is a composite outcome measure that required normalization of hematological parameters (platelet count and lactate dehydrogenase [LDH]) and improvement in kidney function (≥25% reduction in serum creatinine from baseline); for participants on dialysis, baseline was established at least 6 days after the end of dialysis. Participants had to meet these criteria for 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between. To be considered a responder during the 26-week Initial Evaluation Period, the latest time point a participant could first meet the response criteria was 28 days before the Week 26 (Day 183) assessment. Formal statistical comparison analyses were not planned for this study. Percentage based on the responders among treated participants. Confidence interval (CI) based on exact confidence limits using the Clopper Pearson method. | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To Complete TMA Response In Complement Inhibitor Treatment-naïve Participants | Participants that did not have a response were censored at the date of last visit or study discontinuation at the time when the analysis was performed. The time to complete TMA Response is reported in days. The time of the event of a confirmed complete TMA response was considered the first time point at which all the criteria for complete TMA response were met. Participants had to meet all complete TMA response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between. | Baseline through at least Week 52 and up to Week 111 | 
| Participants Who Do Not Require Dialysis at Weeks 26 and 52 | For participants requiring dialysis within 5 days prior to ALXN1210 treatment initiation, the number of participants no longer requiring dialysis is reported. | Week 26 and Week 52 | 
| Proportion Of Complement Inhibitor Treatment-naïve Participants With Complete TMA Response At Week 52 | The proportion of participants considered responders, along with a 2-sided 95% CI based on exact confidence limits using the Clopper Pearson method is reported. | Week 52 | 
| Change From Baseline In eGFR At Weeks 26 and 52 | Kidney function evaluated by eGFR was summarized at baseline and the Week 26 and Week 52 time points using descriptive statistics for continuous variables for the observed value, as well as the change from baseline. The baseline value was defined as the average of the values from the assessments performed prior to the first study drug infusion (these could include results from Screening and the Day 1 visit). A value of 10 mL/min/1.73 m^2 for eGFR was imputed for participants requiring dialysis for acute kidney injury. The observed value and change from baseline are reported in mL/min/1.73 m^2. An increase indicated improvement in kidney function. | Baseline, Week 26 and Week 52 | 
| Participants With Change From Baseline In CKD Stage At Weeks 26 and 52 | The CKD stage is presented as the change from baseline in the participants that Improved (excluding those with Stage 1 [normal renal function] at baseline as they cannot improve), Worsened (excluding those with Stage 5 at baseline as they cannot worsen), and Stayed the Same, compared to the CKD stage at baseline. Baseline was derived based on the last available eGFR before starting treatment. Stage 5 was considered the worst category, while Stage 1 was considered the best category. A 2-sided 95% CI for the proportion, based on exact confidence limits using the Clopper-Pearson method, was provided for each category. The CKD stage was classified based on the National Kidney Foundation Chronic Kidney Disease Stage. | Baseline, Week 26, and Week 52 | 
| Change From Baseline In Platelet Count At Weeks 26 and 52 | The hematologic TMA parameter of platelet count was summarized at baseline and at Week 26 and Week 52 using descriptive statistics for continuous variables for the change from baseline. Results are reported in platelets*10^9/liter (L) blood. | Baseline, Week 26 and Week 52 | 
| Change From Baseline In LDH At Weeks 26 and 52 | The hematologic TMA parameter of serum LDH was summarized at baseline and at Week 26 and Week 52 using descriptive statistics for continuous variables for the change from baseline. Results are reported in units (U)/L serum. | Baseline, Week 26 and Week 52 | 
| Change From Baseline In Hemoglobin At Weeks 26 and 52 | The hematologic TMA parameter of hemoglobin level was summarized at baseline and at Week 26 and Week 52 using descriptive statistics for continuous variables for the change from baseline. Results are reported in grams (g)/L blood. | Baseline, Week 26 and Week 52 | 
| Percentage Of Complement Inhibitor Treatment-naïve Participants With An Increase From Baseline In Hemoglobin ≥20 g/L Through Week 26 and Week 52 | The percentage of participants with an increase from baseline in hemoglobin ≥20 g/L, observed at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between, was assessed through Week 26 and Week 52 and is presented as the percentage of responders, along with a 2-sided 95% CI. The 95% CIs are based on exact confidence limits using the Clopper-Pearson method. To be considered a responder during the 26-week and 52-week Extension Periods, the latest time point a participant could first meet the response criteria was 28 days before the respective Week 26 and Week 52 assessments (components of the response maintained for at least 28 days). | Baseline through Week 26 and through Week 52 | 
| Change From Baseline In Quality Of Life As Measured By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Version 4 Questionnaire (Participants ≥5 Years Of Age) At Weeks 26 and 52 | Quality of life was assessed in participants >5 years of age by the Pediatric FACIT-Fatigue Questionnaire (reported by participants who were ≥8 years of age at the time of enrollment; caregiver reported or caregiver assistance for participants who were 5 to <8 years of age at the time of enrollment). The FACIT Fatigue data were summarized at baseline and each post baseline time point using descriptive statistics for continuous variables for the observed value as well as the change from baseline. The FACIT Fatigue Version 4 questionnaire at baseline and each post-infusion time point was scored using standard scoring algorithms. The score ranges from 0 to 52, with a higher score indicating less fatigue. An increase in score indicated an improvement in quality of life. | Baseline, Week 26 and Week 52 |