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Study of ALXN1210 in Complement Inhibitor Treatment-Naïve Adult and Adolescent Participants With Atypical Hemolytic Uremic Syndrome (aHUS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02949128
Recruitment Status : Active, not recruiting
First Posted : October 31, 2016
Results First Posted : February 10, 2020
Last Update Posted : May 5, 2020
Sponsor:
Information provided by (Responsible Party):
Alexion Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE October 25, 2016
First Posted Date  ICMJE October 31, 2016
Results First Submitted Date  ICMJE December 11, 2019
Results First Posted Date  ICMJE February 10, 2020
Last Update Posted Date May 5, 2020
Actual Study Start Date  ICMJE March 18, 2017
Actual Primary Completion Date November 16, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 7, 2020)
Proportion Of 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. The proportion was based on the responders among treated participants. The 95% confidence interval (CI) was based on the asymptotic Gaussian approximation method with a continuity correction.
Original Primary Outcome Measures  ICMJE
 (submitted: October 27, 2016)
Complete TMA response [ Time Frame: 26 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 7, 2020)
  • Time To Complete TMA Response [ Time Frame: Baseline through Week 26 ]
    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.
  • Proportion Of Participants With Complete TMA Response At Week 26 [ Time Frame: Week 26 ]
    The proportion of participants considered responders, along with a 2-sided 95% CI for the Week 26 time point, is reported. 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).
  • Observed Value And Change From Baseline In Estimated Glomerular Filtration Rate (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 milliliters (mL)/minute (min)/1.73 meters squared (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.
  • Proportion Of Participants With Change From Baseline In Chronic Kidney Disease (CKD) Stage At Week 26 [ Time Frame: Baseline, Week 26 ]
    The CKD stage is presented as the change from baseline in the proportion of 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.
  • 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.
  • Proportion Of Participants With An Increase From Baseline In Hemoglobin ≥ 20 g/L Through Week 26 [ Time Frame: Up to 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 the asymptotic Gaussian approximation method with a continuity correction. 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 EuroQol 5-Dimension 3-Level (EQ-5D-3L) At Week 26 [ Time Frame: Baseline, Week 26 ]
    The EQ-5D-3L is a participant-answered questionnaire that scores 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (scored as a 1, 2, or 3, with 3 being the worst health state), as well as health state on a visual analogue scale (0 to 100, with 100 representing the best health state). From these scores, a summary index score is derived using the time trade-off valuation set for the United States and ranges from -1 to 1, where a score above 0.94 indicates full health. An increase in score from baseline indicates improvement in quality of life.
  • Change From Baseline In Quality Of Life As Measured By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Version 4 Questionnaire At Week 26 [ Time Frame: Baseline, Week 26 ]
    Quality of life was evaluated in part using FACIT Fatigue Version 4. The data were summarized at baseline and at the Week 26 time point using descriptive statistics for continuous variables. The FACIT Fatigue Version 4 questionnaire at baseline and the Week 26 timepoint was scored using standard scoring algorithms. The score ranges from 0-52, with a higher score indicating less Fatigue. An increase in score indicated an improvement in quality of life.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 27, 2016)
  • Dialysis requirement status [ Time Frame: 26 weeks ]
  • Time To Complete TMA Response [ Time Frame: 26 weeks ]
  • Complete TMA Response status over time [ Time Frame: 26 weeks ]
  • Observed value and change from baseline in estimated glomerular filtration rate (eGFR) [ Time Frame: 26 weeks ]
  • Change from baseline in chronic kidney disease (CKD) stage [ Time Frame: 26 weeks ]
  • Change from baseline in hematologic parameters (platelets, LDH, hemoglobin) [ Time Frame: 26 weeks ]
  • Increase in hemoglobin ≥ 20g/L from baseline [ Time Frame: 26 weeks ]
  • Change from baseline in quality of life, as measured by the EQ-5D-3L (all patients) [ Time Frame: 26 weeks ]
  • Change from baseline in quality of life, as measured by the FACIT Fatigue Version 4 questionnaire (patients ≥ 18 years of age) [ Time Frame: 26 weeks ]
  • Change from baseline in quality of life, as measured by the Pediatric FACIT Fatigue questionnaire (patients 12 to < 18 years of age) [ Time Frame: 26 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of ALXN1210 in Complement Inhibitor Treatment-Naïve Adult and Adolescent Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
Official Title  ICMJE Single Arm Study of ALXN1210 in Complement Inhibitor Treatment-naïve Adult and Adolescent Patients With Atypical Hemolytic Uremic Syndrome (aHUS)
Brief Summary The purpose of the study is to assess the safety and efficacy of ravulizumab to control disease activity in adolescent and adult participants with aHUS who had not previously used a complement inhibitor.
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: ≥ 40 to < 60 kilograms (kg), 2400 milligrams (mg) loading, then 3000 mg every 8 weeks; ≥ 60 to < 100 kg, 2700 mg loading, then 3300 mg every 8 weeks; ≥ 100 kg, 3000 mg loading, then 3600 mg every 8 weeks.
Other Names:
  • ALXN1210
  • Ultomiris
Study Arms  ICMJE Experimental: Ravulizumab

Participants were administered weight-based doses of ravulizumab every 8 weeks for 26 weeks in the Initial Evaluation Period.

After the Initial Evaluation Period, participants could enter an Extension Period and receive ravulizumab until the product registration or approval (in accordance with country-specific regulations) or for up to 4.5 years, whichever occurs first.

Intervention: Biological: Ravulizumab
Publications * Not Provided

*   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: August 15, 2019)
58
Original Estimated Enrollment  ICMJE
 (submitted: October 27, 2016)
55
Estimated Study Completion Date  ICMJE July 2023
Actual Primary Completion Date November 16, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female ≥ 12 years of age and weighing ≥ 40 kg at the time of consent.
  2. Evidence of thrombotic microangiopathy, including low platelet count, hemolysis (breaking of red blood cells inside of blood vessels), and decreased kidney function.
  3. Documented meningococcal vaccination not more than 3 years prior to, or at the time of, initiating study drug. Participants who received a meningococcal vaccine less than 2 weeks before initiating ravulizumab treatment must have received treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Participants who had not been vaccinated prior to initiating ravulizumab treatment should have received prophylactic antibiotics prior to and for at least 2 weeks after meningococcal vaccination. Participants < 18 years of age must have been vaccinated against haemophilus influenzae type b and streptococcus pneumoniae according to national and local vaccination schedule guidelines.
  4. Female participants of childbearing potential and male participants with female partners of childbearing potential had to use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab.

Exclusion Criteria:

  1. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 deficiency (activity < 5%).
  2. Shiga toxin-related hemolytic uremic syndrome.
  3. Positive direct Coombs test.
  4. Pregnancy or breastfeeding.
  5. Identified drug exposure-related hemolytic uremic syndrome (HUS).
  6. Bone marrow transplant/hematopoietic stem cell transplant within last 6 months prior to start of Screening.
  7. HUS related to known genetic defects of cobalamin C metabolism.
  8. 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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Canada,   France,   Germany,   Italy,   Japan,   Korea, Republic of,   Russian Federation,   Spain,   Taiwan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02949128
Other Study ID Numbers  ICMJE ALXN1210-aHUS-311
2016‐002027‐29 ( 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 February 2020

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