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

• 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: Alexion Pharmaceuticals
• Information provided by (Responsible Party): Alexion Pharmaceuticals

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Atypical Hemolytic Uremic Syndrome (aHUS)	Biological: Ravulizumab	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Open-Label, Multicenter Study of ALXN1210 in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS)
• Actual Study Start Date: August 31, 2017
• Actual Primary Completion Date: December 3, 2019
• Estimated Study Completion Date: January 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ravulizumab	Biological: Ravulizumab; Single loading dose on Day 1, followed by regular maintenance dosing beginning on Day 15, based on weight.; Other Names: ALXN1210; Ultomiris

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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).
10. 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.

Eligibility Criteria

• Ages Eligible for Study: up to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Colorado

Clinical Trial Site

Aurora, Colorado, United States, 80045

United States, Florida

Clinical Trial Site

Hollywood, Florida, United States, 33021

United States, Georgia

Clinical Trial Site

Atlanta, Georgia, United States, 30322

United States, Michigan

Clinical Trial Site

Detroit, Michigan, United States, 48201

United States, Nebraska

Clinical Trial Site

Omaha, Nebraska, United States, 68114-4113

United States, North Carolina

Clinical Trial Site

Charlotte, North Carolina, United States, 28203

Belgium

Clinical Trial Site

Bruxelles, Belgium

Germany

Clinical Trial Site

Heidelberg, Germany

Italy

Clinical Trial Site

Milan, Italy

Japan

Clinical Trial Site

Fuchū, Japan

Clinical Trial Site

Ōbu, Japan

Korea, Republic of

Clinical Trial Site

Jeju, Korea, Republic of

Clinical Trial Site

Seoul, Korea, Republic of

Clinical Trial Site

Yangsan, Korea, Republic of

Spain

Clinical Trial Site

Barcelona, Spain

Clinical Trial Site

Coruña, Spain

Clinical Trial Site

Esplugues De Llobregat, Spain

Clinical Trial Site

Valencia, Spain

United Kingdom

Clinical Trial Site

Glasgow, United Kingdom, G51 4TF

Clinical Trial Site

London, United Kingdom

Sponsors and Collaborators

Alexion Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Alexion Pharmaceuticals:

Study Protocol  [PDF] July 16, 2019

Statistical Analysis Plan  [PDF] November 7, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tanaka K, Adams B, Aris AM, Fujita N, Ogawa M, Ortiz S, Vallee M, Greenbaum LA. The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab. Pediatr Nephrol. 2020 Oct 13. doi: 10.1007/s00467-020-04774-2. [Epub ahead of print] Erratum in: Pediatr Nephrol. 2020 Dec 9;:.

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03131219
• Other Study ID Numbers: ALXN1210-aHUS-312; 2016-002499-29 ( EudraCT Number )
• First Posted: April 27, 2017
• Results First Posted: September 16, 2020
• Last Update Posted: September 16, 2020
• Last Verified: August 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Azotemia; Hemolytic-Uremic Syndrome; Atypical Hemolytic Uremic Syndrome; Syndrome; Hemolysis; Disease; Pathologic Processes; Uremia; Kidney Diseases; Urologic Diseases; Anemia, Hemolytic; Anemia; Hematologic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Ravulizumab; Complement Inactivating Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs