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

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ClinicalTrials.gov Identifier: NCT03131219
Recruitment Status : Active, not recruiting
First Posted : April 27, 2017
Results First Posted : September 16, 2020
Last Update Posted : September 16, 2020
Sponsor:
Information provided by (Responsible Party):
Alexion Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE April 24, 2017
First Posted Date  ICMJE April 27, 2017
Results First Submitted Date  ICMJE July 27, 2020
Results First Posted Date  ICMJE September 16, 2020
Last Update Posted Date September 16, 2020
Actual Study Start Date  ICMJE August 31, 2017
Actual Primary Completion Date December 3, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 28, 2020)
Proportion Of Complement Inhibitor Treatment-naïve Participants With Complete Thrombotic Microangiopathy (TMA) Response [ Time Frame: 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. Proportion based on the responders among treated participants. Confidence interval (CI) based on exact confidence limits using the Clopper Pearson method.
Original Primary Outcome Measures  ICMJE
 (submitted: April 24, 2017)
Complete TMA response [ Time Frame: 26 weeks ]
The proportion of patients who achieved complete thrombotic microangiopathy (TMA) response as assessed by normalization of hematological parameters between Baseline and Day 183
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 28, 2020)
  • Time To Complete TMA Response In Complement Inhibitor Treatment-naïve Participants [ Time Frame: Baseline through at least Week 52 and up to Week 111 ]
    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.
  • Participants Who Do Not Require Dialysis [ Time Frame: Week 26 ]
    For participants requiring dialysis within 5 days prior to ALXN1210 treatment initiation, the number of participants no longer requiring dialysis is reported.
  • Proportion Of Complement Inhibitor Treatment-naïve Participants With Complete TMA Response Through All Available Follow-Up [ Time Frame: At least 52 weeks and up to a maximum of 111 weeks of treatment ]
    The proportion of participants considered responders, along with a 2-sided 95% CI based on exact confidence limits using the Clopper Pearson method through all available follow-up (up to Week 111), is reported.
  • Observed Value And Change From Baseline In eGFR At Week 26 [ Time Frame: Baseline, Week 26 ]
    Kidney function evaluated by eGFR was summarized at baseline and the Week 26 time point 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.
  • Participants With Change From Baseline In CKD Stage At Week 26 [ Time Frame: Baseline, Week 26 ]
    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.
  • Change From Baseline In Platelet Count At Week 26 [ Time Frame: Baseline, Week 26 ]
    The hematologic TMA parameter of platelet count was summarized at baseline and at Week 26 using descriptive statistics for continuous variables for the change from baseline. Results are reported in platelets*10^9/liter (L) blood.
  • Change From Baseline In LDH At Week 26 [ Time Frame: Baseline, Week 26 ]
    The hematologic TMA parameter of serum LDH was summarized at baseline and at Week 26 using descriptive statistics for continuous variables for the change from baseline. Results are reported in units (U)/L serum.
  • Change From Baseline In Hemoglobin At Week 26 [ Time Frame: Baseline, Week 26 ]
    The hematologic TMA parameter of hemoglobin level was summarized at baseline and at Week 26 using descriptive statistics for continuous variables for the change from baseline. Results are reported in grams (g)/L blood.
  • Proportion Of Complement Inhibitor Treatment-naïve Participants With An Increase From Baseline In Hemoglobin ≥20 g/L Through Week 26 [ Time Frame: Baseline through Week 26 ]
    The proportion 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 is presented as the proportion 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 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 (components of the response maintained for at least 28 days).
  • 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 Week 26 [ Time Frame: Baseline, Week 26 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 24, 2017)
  • Dialysis requirement status [ Time Frame: 26 weeks ]
    The proportion of patients who do not require dialysis, among those who had received dialysis within 56 days prior to study drug treatment initiation
  • Time to Complete TMA response [ Time Frame: 26 weeks ]
    Time from start of treatment to achievement of complete TMA response, defined as normalization of hematological parameters and ≥ 25% improvement in serum creatinine from Baseline
  • Complete TMA Response status over time [ Time Frame: 26 weeks ]
    Proportion of patients achieving complete TMA response at each time point.
  • Observed value and change from baseline in estimated glomerular filtration rate (eGFR) [ Time Frame: 26 weeks ]
    Observed value and change from baseline in eGFR
  • Change from baseline in chronic kidney disease (CKD) stage [ Time Frame: 26 weeks ]
    The number and proportion of patients with improvement, worsening, and no change in CKD stage compared to baseline.
  • Change from baseline in hematologic parameters (platelets, lactate dehydrogenase (LDH), hemoglobin) [ Time Frame: 26 weeks ]
    Observed value and change from baseline in platelets, LDH, and hemoglobin.
  • Increase in hemoglobin of ≥ 20 g/L from baseline [ Time Frame: 26 weeks ]
    A proportion of patients with an increase in hemoglobin ≥ 20 g/L from baseline to Day 183
  • Change from baseline in quality of life, as measured by Pediatric Functional Assessment of Chronic Therapy (FACIT) Fatigue questionnaire (patients ≥ 5 years of age) [ Time Frame: 26 weeks ]
    Change in pediatric FACIT-Fatigue scores from baseline to Day 183
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Ravulizumab in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS)
Official Title  ICMJE A Phase 3, Open-Label, Multicenter Study of ALXN1210 in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS)
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Atypical Hemolytic Uremic Syndrome (aHUS)
Intervention  ICMJE Biological: Ravulizumab
Single loading dose on Day 1, followed by regular maintenance dosing beginning on Day 15, based on weight.
Other Names:
  • ALXN1210
  • Ultomiris
Study Arms  ICMJE Experimental: Ravulizumab
Intervention: Biological: Ravulizumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 27, 2020)
31
Original Estimated Enrollment  ICMJE
 (submitted: April 24, 2017)
16
Estimated Study Completion Date  ICMJE January 2024
Actual Primary Completion Date December 3, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Complement Inhibitor Treatment Naïve:

  1. Participants from birth up to <18 years of age and weighing ≥5 kilograms (kg) at the time of consent.
  2. Participants had not been previously treated with complement inhibitors.
  3. Evidence of thrombotic microangiopathy (TMA), including low platelet count, hemolysis (breaking of red blood cells inside of blood vessels), and decreased kidney function.
  4. Documented meningococcal vaccination not more than 3 years prior to dosing, and vaccination against Streptococcus pneumoniae and Haemophilus influenzae type b.
  5. 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:

  1. 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.
  2. Participants with documented diagnosis of aHUS.
  3. Participants with clinical evidence of response to eculizumab indicated by stable TMA parameters at screening.
  4. Documented meningococcal vaccination not more than 3 years prior to dosing, and vaccination against Streptococcus pneumoniae and Haemophilus influenzae type b.
  5. 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:

  1. Known familial or acquired ADAMTS13 ("a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13") deficiency (activity <5%).
  2. Known Shiga toxin-related hemolytic uremic syndrome.
  3. Positive direct Coombs test.
  4. Females who planned to become pregnant during the study or were currently pregnancy or breastfeeding.
  5. Identified drug exposure-related hemolytic uremic syndrome.
  6. Bone marrow transplant/hematopoietic stem cell transplant within the last 6 months prior to the start of screening.
  7. Hemolytic uremic syndrome related to known genetic defects of cobalamin C metabolism.
  8. Known systemic sclerosis (scleroderma), systemic lupus erythematosus, or antiphospholipid antibody positivity or syndrome.
  9. Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy for end-stage kidney disease.
  10. For eculizumab-experienced participants, prior use of complement inhibitors other than eculizumab.
  11. For eculizumab-experienced participants, any known abnormal TMA parameters within 90 days prior to screening.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Germany,   Italy,   Japan,   Korea, Republic of,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03131219
Other Study ID Numbers  ICMJE ALXN1210-aHUS-312
2016-002499-29 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alexion Pharmaceuticals
Study Sponsor  ICMJE Alexion Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Alexion Pharmaceuticals
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP