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

A Phase 3, Open-Label, Multicenter Study of ALXN1210 in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03131219

Enrollment

Registered

2017-04-27

Start date

2017-08-31

Completion date

2022-12-20

Last updated

2024-03-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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.

Interventions

BIOLOGICALRavulizumab

Participant received weight-based dosages for 26 weeks during the Initial Evaluation Period. Participants received a loading dose on Day 1, followed by maintenance dosing on Day 15 and once every 8 weeks thereafter for participants weighing ≥ 20 kg, or once every 4 weeks for participant weighing \< 20 kg.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Percentage Of Complement Inhibitor Treatment-naïve 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. Percentage based on the responders among treated participants. Confidence interval (CI) based on exact confidence limits using the Clopper Pearson method.

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.
Time To Complete TMA Response In Complement Inhibitor Treatment-naïve Participants	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.
Change From Baseline In 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 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.
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 serum.
Proportion Of Complement Inhibitor Treatment-naïve Participants With Complete TMA Response At Week 52	Week 52	The proportion of participants considered responders, along with a 2-sided 95% CI based on exact confidence limits using the Clopper Pearson method is reported.
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.
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 blood.
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 Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Version 4 Questionnaire (Participants ≥5 Years Of Age) At Weeks 26 and 52	Baseline, Week 26 and Week 52	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.
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.

Countries

Belgium, Germany, Italy, South Korea, Spain, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Complement Inhibitor Treatment Naïve Complement inhibitor treatment-naïve participants received weight-based doses of ravulizumab during the 26-week Initial Evaluation Period. After the Initial Evaluation Period, participants rolled over into an Extension Period in which all participants continued their weight-based maintenance dose of ravulizumab.	24
Eculizumab Experienced Eculizumab-experienced participants received weight-based doses of ravulizumab during the 26-week Initial Evaluation Period. After the Initial Evaluation Period, participants rolled over into an Extension Period in which all participants continued their weight-based maintenance dose of ravulizumab.	10
Total	34

Withdrawals & dropouts

Period	Reason	FG000
Extension Period	Physician Decision	1
Initial Evaluation Period	Adverse Event	2
Initial Evaluation Period	Deemed Ineligible Post Treatment	3
Initial Evaluation Period	Physician Decision	1
Initial Evaluation Period	Protocol Violation	1

Baseline characteristics

Characteristic	Complement Inhibitor Treatment Naïve	Eculizumab Experienced	Total
Age, Continuous	6.0 years STANDARD_DEVIATION 4.79	11.0 years STANDARD_DEVIATION 4.97	8.1 years STANDARD_DEVIATION 5.17
Baseline Estimated Glomerular Filtration Rate (eGFR)	26.4 mL/min/1.73 m^2 STANDARD_DEVIATION 21.17	104.90 mL/min/1.73 m^2 STANDARD_DEVIATION 29.545	NA mL/min/1.73 m^2
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	1 Participants	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	22 Participants	9 Participants	31 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Sex: Female, Male Female	14 Participants	1 Participants	15 Participants
Sex: Female, Male Male	10 Participants	9 Participants	19 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 24	0 / 10
other Total, other adverse events	21 / 24	10 / 10
serious Total, serious adverse events	16 / 24	1 / 10

Outcome results

Primary

Percentage Of Complement Inhibitor Treatment-naïve 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. Percentage based on the responders among treated participants. Confidence interval (CI) based on exact confidence limits using the Clopper Pearson method.

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. Here, Overall 'Number of Participants Analyzed' signifies those who were evaluable for this outcome measure.

Arm	Measure	Group	Value (NUMBER)
Complement Inhibitor Treatment Naïve	Percentage Of Complement Inhibitor Treatment-naïve Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26	Complete TMA response	77.8 percentage of participants
Complement Inhibitor Treatment Naïve	Percentage Of Complement Inhibitor Treatment-naïve Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26	Platelet count normalization	94.4 percentage of participants
Complement Inhibitor Treatment Naïve	Percentage Of Complement Inhibitor Treatment-naïve Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26	LDH normalization	88.9 percentage of participants
Complement Inhibitor Treatment Naïve	Percentage Of Complement Inhibitor Treatment-naïve Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26	≥ 25% improvement in serum creatinine from baseline	83.3 percentage of participants

Secondary

Change From Baseline In 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 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.