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

Conditions

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.

David Kavanagh, Yoshitaka Miyakawa, Katherine Garlo, Masayo Ogawa, Larry A. Greenbaum

Nephrology Dialysis Transplantation2025-10-01

10.1093/ndt/gfaf116.0952

PLASMIC score to aid diagnosis of aHUS: an analysis of C5 inhibitor clinical trials and the PINC AI™ healthcare database.

Uriol-Rivera MG, Ernst FR, Booth JN, Comas À, Gasteyger C, Tomazos I, Lum C, Wang Y, Ávila AI.

2025-05-151 citations

10.1186/s12882-025-04156-6

Correlation between a 2-week change in platelet count and clinical outcomes after the initiation of ravulizumab treatment in adult patients with atypical hemolytic uremic syndrome: post-hoc analysis of the phase III trial.

Matsumoto M, Shimono A, Yokosawa J, Hirose K, Wang E, Maruyama S.

2024-10-283 citations

10.1186/s12959-024-00652-1

Ravulizumab in Atypical Hemolytic Uremic Syndrome: An Analysis of 2-Year Efficacy and Safety Outcomes in 2 Phase 3 Trials.

Dixon BP, Kavanagh D, Aris ADM, Adams B, Kang HG, Wang E, Garlo K, Ogawa M, Amancha P, Chakravarty S, Heyne N, Kim SH, Cataland S, Yoon SS, Miyakawa Y, Luque Y, Muff-Luett M, Tanaka K, Greenbaum LA.

2024-06-1415 citations

10.1016/j.xkme.2024.100855

Population Pharmacokinetic Analyses of Ravulizumab on-Body Delivery System for Subcutaneous Administration in Patients with Paroxysmal Nocturnal Hemoglobinuria

Stephan Ortiz, Jonathan Monteleone

Blood2022-11-15

10.1182/blood-2022-155927

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.

Cammett TJ, Garlo K, Millman EE, Rice K, Toste CM, Faas SJ.

2022-11-045 citations

10.1007/s40291-022-00620-3

Two-Year Efficacy and Safety of Ravulizumab in Adults and Children with Atypical Hemolytic Uremic Syndrome (aHUS): Analysis of Two Phase 3 Studies

Bradley P. Dixon, Alvaro Domingo Madris-Aris, Brigitte Adams, David Kavanagh, Hee Gyung Kang et al. (17 authors)

Blood2021-11-053 citations

10.1182/blood-2021-145040

Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome in Adults.

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.

2021-03-2451 citations

10.1016/j.ekir.2021.03.884

Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis

Anja Gäckler, Ulf Schönermarck, Vladimir Dobronravov, Gaetano La Manna, Andrew Denker et al. (9 authors)

BMC Nephrology2021-01-0635 citations

10.1186/s12882-020-02190-0

The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab.

Tanaka K, Adams B, Aris AM, Fujita N, Ogawa M, Ortiz S, Vallee M, Greenbaum LA.

2020-10-1352 citations

10.1007/s00467-020-04774-2

MO020EFFICACY AND SAFETY OF THE LONG-ACTING C5 INHIBITOR RAVULIZUMAB IN PATIENTS WITH POSTPARTUM ATYPICAL HAEMOLYTIC URAEMIC SYNDROME

Anja Gäckler, Vladimir Dobronravov, Gaetano La Manna, Andrew Denker, Peng Liu et al. (9 authors)

Nephrology Dialysis Transplantation2020-06-016 citations

10.1093/ndt/gfaa140.mo020

SO054ONE-YEAR EFFICACY AND SAFETY OF THE LONG ACTING C5 INHIBITOR RAVULIZUMAB FOR THE TREATMENT OF ATYPICAL HAEMOLYTIC URAEMIC SYNDROME (AHUS) IN ADULTS

Thomas Barbour, Marie Scully, Gema Ariceta, Spero Cataland, Katherine Garlo et al. (12 authors)

Nephrology Dialysis Transplantation2020-06-012 citations

10.1093/ndt/gfaa139.so054

Discordance between Free C5 and CH50 Complement Assays in Measuring Complement C5 Inhibition in Patients with aHUS Treated with Ravulizumab

Spero Cataland, Gema Ariceta, Peter Chen, Bradley P. Dixon, Katherine Garlo et al. (9 authors)

Blood2019-11-1323 citations

10.1182/blood-2019-122421

Interventions

BIOLOGICALRavulizumab

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.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Healthy volunteers

No

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).

Design outcomes

Primary

Measure	Time frame	Description
Percentage Of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26	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

Measure	Time frame	Description
Participants Who Do Not Require Dialysis at Weeks 26 and 52	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
Proportion Of Participants With Complete TMA Response At Week 52	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).
Change From Baseline In Estimated Glomerular Filtration Rate (eGFR) At Weeks 26 and 52	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.
Participants With Change From Baseline In CKD Stage At Weeks 26 and 52	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.
Change From Baseline In Platelet Count At Weeks 26 and 52	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.
Time To Complete TMA Response	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.
Change From Baseline In Hemoglobin At Weeks 26 and 52	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.
Percentage Of Complement Inhibitor Treatment-naïve Participants With An Increase From Baseline In Hemoglobin ≥20 g/L Through Week 26 and Week 52	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).
Change From Baseline In Quality Of Life As Measured By The EuroQol 5-Dimension 3-Level (EQ-5D-3L) At Weeks 26 and 52	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.
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	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.
Change From Baseline In LDH At Weeks 26 and 52	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.

Countries

Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Russia, South Korea, Spain, Taiwan, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Ravulizumab Participants received weight-based dosages of ravulizumab for 26 weeks during the Initial Evaluation Period. Participants received a loading dose of ravulizumab intravenously on Day 1, followed by maintenance dosing on Day 15 and once every 8 weeks thereafter. After the Initial Evaluation Period, participants entered an Extension Period and received ravulizumab until the product registration or approval (in accordance with country-specific regulations) or for up to 4.5 years, whichever occurs first.	56
Total	56

Arm

Count

Ravulizumab

Participants received weight-based dosages of ravulizumab for 26 weeks during the Initial Evaluation Period. Participants received a loading dose of ravulizumab intravenously on Day 1, followed by maintenance dosing on Day 15 and once every 8 weeks thereafter. After the Initial Evaluation Period, participants entered an Extension Period and received ravulizumab until the product registration or approval (in accordance with country-specific regulations) or for up to 4.5 years, whichever occurs first.

56

Total

56

Withdrawals & dropouts

Period	Reason	FG000
Extension Period (Up to 4.5 Years)	Death	1
Extension Period (Up to 4.5 Years)	Other than specified	5
Extension Period (Up to 4.5 Years)	Physician Decision	5
Extension Period (Up to 4.5 Years)	Protocol Violation	1
Extension Period (Up to 4.5 Years)	Withdrawal by Subject	9
Initial Evaluation Period (26 Weeks)	Adverse Event	3
Initial Evaluation Period (26 Weeks)	Death	2
Initial Evaluation Period (26 Weeks)	Failed to Meet Eligibility Criteria	2
Initial Evaluation Period (26 Weeks)	Physician Decision	1
Initial Evaluation Period (26 Weeks)	Protocol Violation	1

Baseline characteristics

Characteristic	Ravulizumab
Age, Continuous	42.2 years STANDARD_DEVIATION 14.98
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	41 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	12 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants
Race (NIH/OMB) Asian	15 Participants
Race (NIH/OMB) Black or African American	2 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	9 Participants
Race (NIH/OMB) White	29 Participants
Sex: Female, Male Female	37 Participants
Sex: Female, Male Male	19 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	4 / 58
other Total, other adverse events	56 / 58
serious Total, serious adverse events	38 / 58

Outcome results

Primary

Percentage Of 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. 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.

Time frame: Week 26

Population: Full Analysis Set (FAS): all participants who received at least 1 dose of ravulizumab, had at least 1 post-baseline efficacy assessment, and met pre-specified eligibility criteria.

Arm	Measure	Group	Value (NUMBER)
Ravulizumab	Percentage Of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26	Complete TMA Response	53.6 percentage of participants
Ravulizumab	Percentage Of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26	Platelet count normalization	83.9 percentage of participants
Ravulizumab	Percentage Of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26	LDH normalization	76.8 percentage of participants
Ravulizumab	Percentage Of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26	≥ 25% improvement in serum creatinine from baseline	58.9 percentage of participants

Secondary

Change From Baseline In Estimated Glomerular Filtration Rate (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 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.