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

• ClinicalTrials.gov Identifier: NCT02949128
• Recruitment Status: Completed
• First Posted: October 31, 2016
• Results First Posted: February 10, 2020
• Last Update Posted: April 18, 2023
• Sponsor: Alexion
• Information provided by (Responsible Party): Alexion

Study Description

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.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 58 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Single Arm Study of ALXN1210 in Complement Inhibitor Treatment-naïve Adult and Adolescent Patients With Atypical Hemolytic Uremic Syndrome (aHUS)
• Actual Study Start Date: March 18, 2017
• Actual Primary Completion Date: November 16, 2018
• Actual Study Completion Date: January 24, 2023

Arms and Interventions

Arm	Intervention/treatment
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.	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

Outcome Measures

Primary Outcome Measures :

1. Percentage Of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26 [ 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 percentage 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.

Secondary Outcome Measures :

1. Time To Complete TMA Response [ Time Frame: Baseline through Week 114 ]
   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.
2. Participants Who Do Not Require Dialysis at Weeks 26 and 52 [ Time Frame: Week 26 and Week 52 ]
   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 Participants With Complete TMA Response At Week 52 [ Time Frame: Week 52 ]
   The proportion of participants considered responders, along with a 2-sided 95% CI for the Week 52 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).
4. Change From Baseline In Estimated Glomerular Filtration Rate (eGFR) At Weeks 26 and 52 [ Time Frame: Baseline, Week 26 and Week 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 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.
5. Participants With Change From Baseline In CKD Stage At Weeks 26 and 52 [ Time Frame: Baseline, Week 26, and Week 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.
6. Change From Baseline In Platelet Count At Weeks 26 and 52 [ Time Frame: Baseline, Week 26 and Week 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.
7. Change From Baseline In LDH At Weeks 26 and 52 [ Time Frame: Baseline, Week 26 and Week 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.
8. Change From Baseline In Hemoglobin At Weeks 26 and 52 [ Time Frame: Baseline, Week 26 and Week 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.
9. Percentage Of Complement Inhibitor Treatment-naïve Participants With An Increase From Baseline In Hemoglobin ≥20 g/L Through Week 26 and Week 52 [ Time Frame: Baseline through Week 26 and through 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).
10. Change From Baseline In Quality Of Life As Measured By The EuroQol 5-Dimension 3-Level (EQ-5D-3L) At Weeks 26 and 52 [ Time Frame: Baseline, Week 26 and Week 52 ]
    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.
11. Change From Baseline In Quality Of Life As Measured By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Version 4 Questionnaire At Weeks 26 and 52 [ Time Frame: Baseline, Week 26 and Week 52 ]
    Quality of life was evaluated in part using FACIT Fatigue Version 4. The data were summarized at baseline and at the Week 26 and Week 52 time point using descriptive statistics for continuous variables. The FACIT Fatigue Version 4 questionnaire at baseline and the Week 52 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.

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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).

Contacts and Locations

Locations

United States, Indiana

Clinical Trial Site

Fort Wayne, Indiana, United States, 46804

Clinical Trial Site

Fort Wayne, Indiana, United States, 46845

United States, North Carolina

Clinical Trial Site

Durham, North Carolina, United States, 27705

Clinical Trial Site

Winston-Salem, North Carolina, United States, 27103

United States, Ohio

Clinical Trial Site

Columbus, Ohio, United States, 43210

Australia

Clinical Trial Site

Clayton, Australia

Clinical Trial Site

Geelong, Australia

Clinical Trial Site

Parkville, Australia

Austria

Clinical Trial Site

Vienna, Austria

Belgium

Clinical Trial Site

Brussels, Belgium

Canada

Clinical Trial Site

London, Canada

France

Clinical Trial Site

Bordeaux, France

Clinical Trial Site

Clermont-Ferrand, France

Clinical Trial Site

Lille, France

Clinical Trial Site

Montpellier, France

Clinical Trial Site

Nice, France

Clinical Trial Site

Paris, France

Germany

Clinical Trial Site

Aachen, Germany

Clinical Trial Site

Essen, Germany

Clinical Trial Site

Hanover, Germany

Clinical Trial Site

Muenchen, Germany

Clinical Trial Site

Tuebingen, Germany

Italy

Clinical Trial Site

Bologna, Italy

Clinical Trial Site

Firenze, Italy

Japan

Clinical Trial Site

Saitama, Japan

Clinical Trial Site

Tokyo, Japan

Korea, Republic of

Clinical Trial Site

Gyeonggi-do, Korea, Republic of

Clinical Trial Site

Seoul, Korea, Republic of

Russian Federation

Clinical Trial Site

Moscow, Russian Federation

Clinical Trial Site

Saint Petersburg, Russian Federation

Spain

Clinical Trial Site

Barcelona, Spain

Clinical Trial Site

Madrid, Spain

Clinical Trial Site

Valencia, Spain

Taiwan

Clinical Trial Site

Taichung, Taiwan

Clinical Trial Site

Taipei City, Taiwan

Clinical Trial Site

Taipei, Taiwan

United Kingdom

Clinical Trial Site

Cardiff, United Kingdom

Clinical Trial Site

London, United Kingdom

Sponsors and Collaborators

Alexion

  Study Documents (Full-Text)

Documents provided by Alexion:

Study Protocol  [PDF] May 7, 2019

Statistical Analysis Plan  [PDF] May 23, 2018

More Information

Publications of Results:

Barbour T, Scully M, Ariceta G, Cataland S, Garlo K, Heyne N, Luque Y, Menne J, Miyakawa Y, Yoon SS, Kavanagh D; 311 Study Group Members. Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome in Adults. Kidney Int Rep. 2021 Mar 24;6(6):1603-1613. doi: 10.1016/j.ekir.2021.03.884. eCollection 2021 Jun.

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

Cammett TJ, Garlo K, Millman EE, Rice K, Toste CM, Faas SJ. Exploratory Prognostic Biomarkers of Complement-Mediated Thrombotic Microangiopathy (CM-TMA) in Adults with Atypical Hemolytic Uremic Syndrome (aHUS): Analysis of a Phase III Study of Ravulizumab. Mol Diagn Ther. 2023 Jan;27(1):61-74. doi: 10.1007/s40291-022-00620-3. Epub 2022 Nov 4. Erratum In: Mol Diagn Ther. 2023 Mar;27(2):281.

Pugh D, O'Sullivan ED, Duthie FA, Masson P, Kavanagh D. Interventions for atypical haemolytic uraemic syndrome. Cochrane Database Syst Rev. 2021 Mar 23;3(3):CD012862. doi: 10.1002/14651858.CD012862.pub2.

Gackler A, Schonermarck U, Dobronravov V, La Manna G, Denker A, Liu P, Vinogradova M, Yoon SS, Praga M. Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis. BMC Nephrol. 2021 Jan 6;22(1):5. doi: 10.1186/s12882-020-02190-0. Erratum In: BMC Nephrol. 2021 Feb 2;22(1):49.

• Responsible Party: Alexion
• ClinicalTrials.gov Identifier: NCT02949128
• Other Study ID Numbers: ALXN1210-aHUS-311; 2016-002027-29 ( EudraCT Number )
• First Posted: October 31, 2016
• Results First Posted: February 10, 2020
• Last Update Posted: April 18, 2023
• Last Verified: April 2023

• 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; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Anemia, Hemolytic; Anemia; Hematologic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Ravulizumab; Complement Inactivating Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs