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

• Sponsor: Alexion Pharmaceuticals (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03131219
• Collaborator: (none)
• Enrollment: 31
• Locations: 20
• Arm: 1
• Anticipated Duration (Months): 77
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0

Study Details

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
• 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: Aug 31, 2017
• Actual Primary Completion Date: Dec 3, 2019
• Anticipated Study Completion Date: Jan 31, 2024

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Ravulizumab Participants were administered weight-based doses of ravulizumab every 8 weeks thereafter for participants weighing ≥ 20 kg, or once every 4 weeks for participant weighing < 20 kg, for a total of 26 weeks of study treatment in the initial Evaluation Period. After the Initial Evaluation Period, participants rolled over into an Extension Period in which all participant continued their weight-based maintenance dose until the product was registered or approved (in accordance with country specific regulation) or for up to 4.5 years, whichever occurred first.

Biological: Ravulizumab; 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.; Other Names: ALXN1210 Ultomiris

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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).

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 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	Clinical Trial Site	Aurora	Colorado	United States	80045
2	Clinical Trial Site	Hollywood	Florida	United States	33021
3	Clinical Trial Site	Atlanta	Georgia	United States	30322
4	Clinical Trial Site	Detroit	Michigan	United States	48201
5	Clinical Trial Site	Omaha	Nebraska	United States	68114-4113
6	Clinical Trial Site	Charlotte	North Carolina	United States	28203
7	Clinical Trial Site	Bruxelles		Belgium
8	Clinical Trial Site	Heidelberg		Germany
9	Clinical Trial Site	Milan		Italy
10	Clinical Trial Site	Fuchū		Japan
11	Clinical Trial Site	Ōbu		Japan
12	Clinical Trial Site	Jeju		Korea, Republic of
13	Clinical Trial Site	Seoul		Korea, Republic of
14	Clinical Trial Site	Yangsan		Korea, Republic of
15	Clinical Trial Site	Barcelona		Spain
16	Clinical Trial Site	Coruña		Spain
17	Clinical Trial Site	Esplugues De Llobregat		Spain
18	Clinical Trial Site	Valencia		Spain
19	Clinical Trial Site	Glasgow		United Kingdom	G51 4TF
20	Clinical Trial Site	London		United Kingdom

Sponsors and Collaborators

• Alexion Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 16, 2019
• Statistical Analysis Plan - Nov 7, 2018

More Information

Publications

None provided.

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03131219
• Other Study ID Numbers: ALXN1210-aHUS-312; 2016-002499-29
• First Posted: Apr 27, 2017
• Last Update Posted: Aug 1, 2022
• Last Verified: Jul 1, 2022

• 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; Ravulizumab

Study Results

Participant Flow

Arm/Group Title	Complement Inhibitor Treatment Naïve	Eculizumab Experienced
Arm/Group Description	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.	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.
Period Title: Initial Evaluation Period
STARTED	21	10
Received At Least 1 Dose of Study Drug	21	10
COMPLETED	17	10
NOT COMPLETED	4	0
Period Title: Initial Evaluation Period
STARTED	17	10
Received At Least 1 Dose of Study Drug	17	10
Ongoing	16	10
COMPLETED	0	0
NOT COMPLETED	17	10

Baseline Characteristics

Arm/Group Title	Complement Inhibitor Treatment Naïve	Eculizumab Experienced	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	21	10	31
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	6.7 (4.78)	11.0 (4.97)	8.1 (5.17)
Sex: Female, Male (Count of Participants)
Female	11 52.4%	1 10%	12 38.7%
Male	10 47.6%	9 90%	19 61.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 9.5%	1 10%	3 9.7%
Not Hispanic or Latino	19 90.5%	9 90%	28 90.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	7 33.3%	4 40%	11 35.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 14.3%	1 10%	4 12.9%
White	9 42.9%	5 50%	14 45.2%
More than one race	1 4.8%	0 0%	1 3.2%
Unknown or Not Reported	1 4.8%	0 0%	1 3.2%
Weight at Time of First Infusion (Count of Participants)
≥5 to <10 kilograms	3 14.3%	1 10%	4 12.9%
≥10 to <20 kilograms	9 42.9%	1 10%	10 32.3%
≥20 to <30 kilograms	3 14.3%	1 10%	4 12.9%
≥30 to <40 kilograms	3 14.3%	1 10%	4 12.9%
≥40 to <60 kilograms	2 9.5%	5 50%	7 22.6%
≥60 to <100 kilograms	1 4.8%	1 10%	2 6.5%
Dialysis at Baseline (Count of Participants)
Count of Participants [Participants]	6 28.6%	0 0%	6 19.4%
Baseline Estimated Glomerular Filtration Rate (eGFR) (mL/min/1.73 m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/1.73 m^2]	26.4 (21.17)	104.90 (29.545)	NA (NA)
Baseline Chronic Kidney Disease (CKD) Stage (Count of Participants)
Stage 1	0 0%	8 80%	8 25.8%
Stage 2	2 9.5%	1 10%	3 9.7%
Stage 3a	1 4.8%	1 10%	2 6.5%
Stage 3b	1 4.8%	0 0%	1 3.2%
Stage 4	8 38.1%	0 0%	8 25.8%
Stage 5	6 28.6%	0 0%	6 19.4%

Outcome Measures

1. Primary Outcome

Title	Percentage Of Complement Inhibitor Treatment-naïve Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Complement Inhibitor Treatment Naïve
Arm/Group Description	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.
Measure Participants	17
Complete TMA response	77.8 370.5%
Platelet count normalization	94.4 449.5%
LDH normalization	88.9 423.3%
≥ 25% improvement in serum creatinine from baseline	83.3 396.7%

2. Secondary Outcome

Title	Time To Complete TMA Response In Complement Inhibitor Treatment-naïve Participants
Description	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.
Time Frame	Baseline through at least Week 52 and up to Week 111

Outcome Measure Data

Analysis Population Description

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/Group Title	Complement Inhibitor Treatment Naïve
Arm/Group Description	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.
Measure Participants	18
Median (Inter-Quartile Range) [days]	30.0

3. Secondary Outcome

Title	Participants Who Do Not Require Dialysis at Weeks 26 and 52
Description	For participants requiring dialysis within 5 days prior to ALXN1210 treatment initiation, the number of participants no longer requiring dialysis is reported.
Time Frame	Week 26 and Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who received at least 1 dose of ravulizumab, had at least 1 post-baseline efficacy assessment, met pre-specified eligibility criteria, and had evaluable data at specified timepoint. Here, Overall 'Number of Participants Analyzed' signifies those who were evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable for specified categories.

Arm/Group Title	Complement Inhibitor Treatment Naïve	Eculizumab Experienced
Arm/Group Description	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.	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.
Measure Participants	6	0
Week 26	5 23.8%	0 0%
Week 52	6 28.6%	0 0%

4. Secondary Outcome

Title	Proportion Of Complement Inhibitor Treatment-naïve Participants With Complete TMA Response At Week 52
Description	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.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Complement Inhibitor Treatment Naïve
Arm/Group Description	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.
Measure Participants	18
Number (95% Confidence Interval) [proportion of participants]	0.944 4.5%

5. Secondary Outcome

Title	Change From Baseline In eGFR At Weeks 26 and 52
Description	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.
Time Frame	Baseline, Week 26 and Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who received at least 1 dose of ravulizumab, had at least 1 post-baseline efficacy assessment, met pre-specified eligibility criteria, and had evaluable data at the specified timepoint (Week 26 or Week 52). Here, Overall 'Number of Participants Analyzed' signifies those who were evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable for specified categories.

Arm/Group Title	Complement Inhibitor Treatment Naïve	Eculizumab Experienced
Arm/Group Description	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.	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.
Measure Participants	17	10
Baseline	22.0	99.75
Change From Baseline at Week 26	80.0	-2.00
Change From Baseline at Week 52	94.0	-3.00

6. Secondary Outcome

Title	Participants With Change From Baseline In CKD Stage At Weeks 26 and 52
Description	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.
Time Frame	Baseline, Week 26, and Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who received at least 1 dose of ravulizumab, had at least 1 post-baseline efficacy assessment, met pre-specified eligibility criteria, and had evaluable data at the specified timepoint (Week 26 or Week 52). Here, Overall 'Number of Participants Analyzed' signifies those who were evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable for specified categories.

Arm/Group Title	Complement Inhibitor Treatment Naïve	Eculizumab Experienced
Arm/Group Description	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.	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.
Measure Participants	17	10
Week 26, Improved	15 71.4%	0 0%
Week 26, Worsened	0 0%	3 30%
Week 26, Stayed the Same	2 9.5%	7 70%
Week 52, Improved	16 76.2%	0 0%
Week 52, Worsened	0 0%	0 0%
Week 52, Stayed the Same	0 0%	10 100%

7. Secondary Outcome

Title	Change From Baseline In Platelet Count At Weeks 26 and 52
Description	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 Frame	Baseline, Week 26 and Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who received at least 1 dose of ravulizumab, had at least 1 post-baseline efficacy assessment, met pre-specified eligibility criteria, and had evaluable data at the specified time point (Week 26 or Week 52). Here, 'Number Analyzed' signifies participants evaluable for specified categories.

Arm/Group Title	Complement Inhibitor Treatment Naïve	Eculizumab Experienced
Arm/Group Description	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.	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.
Measure Participants	18	10
Baseline	51.25	281.75
Change from Baseline at Week 26	247.00	-2.25
Change from Baseline at Week 52	213.00	-34.75

8. Secondary Outcome

Title	Change From Baseline In LDH At Weeks 26 and 52
Description	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.
Time Frame	Baseline, Week 26 and Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who received at least 1 dose of ravulizumab, had at least 1 post-baseline efficacy assessment, met pre-specified eligibility criteria, and had evaluable data at the specified timepoint (Week 26 or Week 52). Here, Overall 'Number of Participants Analyzed' signifies those who were evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable for specified categories.

Arm/Group Title	Complement Inhibitor Treatment Naïve	Eculizumab Experienced
Arm/Group Description	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.	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.
Measure Participants	17	10
Baseline	1963.00	206.50
Change From Baseline at Week 26	-1851.50	-8.50
Change From Baseline at Week 52	-1825.50	-17.50

9. Secondary Outcome

Title	Change From Baseline In Hemoglobin At Weeks 26 and 52
Description	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.
Time Frame	Baseline, Week 26 and Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who received at least 1 dose of ravulizumab, had at least 1 post-baseline efficacy assessment, met pre-specified eligibility criteria, and had evaluable data at the specified timepoint (Week 26 or Week 52). Here, 'Number Analyzed' signifies participants evaluable for specified categories.

Arm/Group Title	Complement Inhibitor Treatment Naïve	Eculizumab Experienced
Arm/Group Description	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.	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.
Measure Participants	18	10
Baseline	74.25	132.00
Change From Baseline at Week 26	46.50	-3.50
Change From Baseline at Week 52	51.50	5.50

10. Secondary Outcome

Title	Percentage Of Complement Inhibitor Treatment-naïve Participants With An Increase From Baseline In Hemoglobin ≥20 g/L Through Week 26 and Week 52
Description	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).
Time Frame	Baseline through Week 26 and through Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who received at least 1 dose of ravulizumab, had at least 1 post-baseline efficacy assessment, met pre-specified eligibility criteria, and had evaluable data at the specified timepoints (Week 26 or Week 52). Here, Overall 'Number of Participants Analyzed' signifies those who were evaluable for this outcome measure.

Arm/Group Title	Complement Inhibitor Treatment Naïve
Arm/Group Description	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.
Measure Participants	17
Week 26	100 476.2%
Week 52	94.1 448.1%

11. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, Week 26 and Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who received at least 1 dose of ravulizumab, had at least 1 post-baseline efficacy assessment, met pre-specified eligibility criteria, and had evaluable data at the specified timepoint (Week 26 or Week 52). Here, Overall 'Number of Participants Analyzed' signifies those who were evaluable for this outcome measure.

Arm/Group Title	Complement Inhibitor Treatment Naïve	Eculizumab Experienced
Arm/Group Description	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.	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.
Measure Participants	9	8
Baseline	35.00	50.00
Change From Baseline at Week 26	10.00	0.00
Change From Baseline at Week 52	9.00	-1.00

Adverse Events

Time Frame	From the beginning of the initial evaluation period (Day 1) through data cutoff (at least 52 weeks and up to a maximum of 111 weeks of treatment, representing 36.2 patient-years of exposure).
Arm/Group Title	Complement Inhibitor Treatment Naïve		Eculizumab Experienced
Arm/Group Description	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.		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.
All Cause Mortality
	Complement Inhibitor Treatment Naïve		Eculizumab Experienced
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/10 (0%)
Serious Adverse Events
	Complement Inhibitor Treatment Naïve		Eculizumab Experienced
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/21 (66.7%)		1/10 (10%)
Blood and lymphatic system disorders
Anaemia	1/21 (4.8%)		0/10 (0%)
Congenital, familial and genetic disorders
Atrial septal defect	1/21 (4.8%)		0/10 (0%)
Gastrointestinal disorders
Abdominal pain	2/21 (9.5%)		0/10 (0%)
Diarrhoea	1/21 (4.8%)		0/10 (0%)
Pancreatitis	1/21 (4.8%)		0/10 (0%)
Vomiting	1/21 (4.8%)		0/10 (0%)
General disorders
Pyrexia	1/21 (4.8%)		0/10 (0%)
Infections and infestations
Gastroenteritis viral	2/21 (9.5%)		0/10 (0%)
Bronchitis	1/21 (4.8%)		1/10 (10%)
Cytomegalovirus enteritis	1/21 (4.8%)		0/10 (0%)
Escherichia bacteraemia	1/21 (4.8%)		0/10 (0%)
Escherichia pyelonephritis	1/21 (4.8%)		0/10 (0%)
Gastroenteritis	1/21 (4.8%)		0/10 (0%)
Gastroenteritis rotavirus	1/21 (4.8%)		0/10 (0%)
Human bocavirus infection	1/21 (4.8%)		0/10 (0%)
Pharyngitis	1/21 (4.8%)		0/10 (0%)
Pneumonia	1/21 (4.8%)		1/10 (10%)
Viral infection	1/21 (4.8%)		0/10 (0%)
Viral pharyngitis	1/21 (4.8%)		0/10 (0%)
Upper respiratory tract infection	0/21 (0%)		1/10 (10%)
Injury, poisoning and procedural complications
Subdural haematoma	1/21 (4.8%)		0/10 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/21 (4.8%)		0/10 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	1/21 (4.8%)		0/10 (0%)
Nervous system disorders
Headache	1/21 (4.8%)		0/10 (0%)
Posterior reversible encephalopathy syndrome	1/21 (4.8%)		0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary haemorrhage	1/21 (4.8%)		0/10 (0%)
Vascular disorders
Hypertension	1/21 (4.8%)		0/10 (0%)
Hypertensive crisis	1/21 (4.8%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Complement Inhibitor Treatment Naïve		Eculizumab Experienced
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/21 (100%)		10/10 (100%)
Blood and lymphatic system disorders
Lymphadenopathy	2/21 (9.5%)		1/10 (10%)
Anaemia	2/21 (9.5%)		0/10 (0%)
Eye disorders
Lacrimation increased	0/21 (0%)		1/10 (10%)
Photophobia	0/21 (0%)		1/10 (10%)
Gastrointestinal disorders
Abdominal pain	5/21 (23.8%)		1/10 (10%)
Diarrhoea	6/21 (28.6%)		1/10 (10%)
Dyspepsia	0/21 (0%)		1/10 (10%)
Lip dry	0/21 (0%)		1/10 (10%)
Vomiting	7/21 (33.3%)		1/10 (10%)
Constipation	4/21 (19%)		0/10 (0%)
Nausea	4/21 (19%)		0/10 (0%)
Abdominal distension	2/21 (9.5%)		0/10 (0%)
General disorders
Fatigue	2/21 (9.5%)		1/10 (10%)
Pyrexia	10/21 (47.6%)		0/10 (0%)
Infections and infestations
Upper respiratory tract infection	3/21 (14.3%)		4/10 (40%)
Nasopharyngitis	7/21 (33.3%)		2/10 (20%)
Otitis media	0/21 (0%)		2/10 (20%)
Pharyngitis	2/21 (9.5%)		2/10 (20%)
Viral upper respiratory tract infection	2/21 (9.5%)		2/10 (20%)
Bronchitis	0/21 (0%)		1/10 (10%)
Hand-foot-and-mouth disease	0/21 (0%)		1/10 (10%)
Impetigo	0/21 (0%)		1/10 (10%)
Influenza	0/21 (0%)		1/10 (10%)
Pneumonia	2/21 (9.5%)		1/10 (10%)
Viral infection	0/21 (0%)		1/10 (10%)
Tonsilitis	3/21 (14.3%)		0/10 (0%)
Conjunctivitis	2/21 (9.5%)		0/10 (0%)
Sinusitis	2/21 (9.5%)		0/10 (0%)
Injury, poisoning and procedural complications
Contusion	4/21 (19%)		0/10 (0%)
Head injury	2/21 (9.5%)		0/10 (0%)
Skin abrasion	2/21 (9.5%)		0/10 (0%)
Investigations
Influenza A virus test positive	0/21 (0%)		1/10 (10%)
Vitamin D decreased	3/21 (14.3%)		0/10 (0%)
Metabolism and nutrition disorders
Dehydration	0/21 (0%)		1/10 (10%)
Iron deficiency	3/21 (14.3%)		0/10 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/21 (9.5%)		1/10 (10%)
Osteochondrosis	0/21 (0%)		1/10 (10%)
Pain in extremity	2/21 (9.5%)		1/10 (10%)
Tenosynovitis	0/21 (0%)		1/10 (10%)
Myalgia	3/21 (14.3%)		0/10 (0%)
Nervous system disorders
Headache	7/21 (33.3%)		1/10 (10%)
Dizziness	2/21 (9.5%)		0/10 (0%)
Product Issues
Device occlusion	2/21 (9.5%)		0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/21 (0%)		3/10 (30%)
Epistaxis	0/21 (0%)		1/10 (10%)
Rhinitis allergic	0/21 (0%)		1/10 (10%)
Sinus disorder	0/21 (0%)		1/10 (10%)
Cough	5/21 (23.8%)		1/10 (10%)
Rhinorrhoea	4/21 (19%)		0/10 (0%)
Nasal congestion	3/21 (14.3%)		0/10 (0%)
Dyspnoea	2/21 (9.5%)		0/10 (0%)
Productive cough	2/21 (9.5%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Asteatosis	0/21 (0%)		1/10 (10%)
Erythema	0/21 (0%)		1/10 (10%)
Rash	4/21 (19%)		0/10 (0%)
Dermatitis diaper	2/21 (9.5%)		0/10 (0%)
Vascular disorders
Hypertension	6/21 (28.6%)		1/10 (10%)
Hypotension	2/21 (9.5%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.