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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02949128
Registration number
NCT02949128
Ethics application status
Date submitted
25/10/2016
Date registered
31/10/2016
Date last updated
20/02/2024
Titles & IDs
Public title
Study of ALXN1210 in Complement Inhibitor Treatment-Naïve Adult and Adolescent Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
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Scientific title
Single Arm Study of ALXN1210 in Complement Inhibitor Treatment-naïve Adult and Adolescent Patients With Atypical Hemolytic Uremic Syndrome (aHUS)
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Secondary ID [1]
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2016-002027-29
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Secondary ID [2]
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ALXN1210-aHUS-311
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Atypical Hemolytic Uremic Syndrome (aHUS)
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Condition category
Condition code
Blood
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Other blood disorders
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Renal and Urogenital
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Kidney disease
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Renal and Urogenital
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Other renal and urogenital disorders
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Blood
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Anaemia
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Other - Ravulizumab
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.
Treatment: Other: 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.
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Intervention code [1]
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Treatment: Other
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage Of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26
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Assessment method [1]
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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.
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Timepoint [1]
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Week 26
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Secondary outcome [1]
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Time To Complete TMA Response
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline through Week 114
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Secondary outcome [2]
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Participants Who Do Not Require Dialysis at Weeks 26 and 52
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Assessment method [2]
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For participants requiring dialysis within 5 days prior to ALXN1210 treatment initiation, the number of participants no longer requiring dialysis is reported
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Timepoint [2]
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Week 26 and Week 52
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Secondary outcome [3]
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Proportion Of Participants With Complete TMA Response At Week 52
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Assessment method [3]
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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).
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Timepoint [3]
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Week 52
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Secondary outcome [4]
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Change From Baseline In Estimated Glomerular Filtration Rate (eGFR) At Weeks 26 and 52
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Assessment method [4]
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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.
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Timepoint [4]
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Baseline, Week 26 and Week 52
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Secondary outcome [5]
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Participants With Change From Baseline In CKD Stage At Weeks 26 and 52
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Assessment method [5]
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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.
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Timepoint [5]
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Baseline, Week 26, and Week 52
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Secondary outcome [6]
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Change From Baseline In Platelet Count At Weeks 26 and 52
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Assessment method [6]
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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.
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Timepoint [6]
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Baseline, Week 26 and Week 52
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Secondary outcome [7]
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Change From Baseline In LDH At Weeks 26 and 52
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Assessment method [7]
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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.
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Timepoint [7]
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Baseline, Week 26 and Week 52
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Secondary outcome [8]
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Change From Baseline In Hemoglobin At Weeks 26 and 52
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Assessment method [8]
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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.
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Timepoint [8]
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Baseline, Week 26 and Week 52
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Secondary outcome [9]
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Percentage Of Complement Inhibitor Treatment-naïve Participants With An Increase From Baseline In Hemoglobin =20 g/L Through Week 26 and Week 52
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Assessment method [9]
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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).
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Timepoint [9]
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Baseline through Week 26 and through Week 52
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Secondary outcome [10]
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Change From Baseline In Quality Of Life As Measured By The EuroQol 5-Dimension 3-Level (EQ-5D-3L) At Weeks 26 and 52
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Assessment method [10]
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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.
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Timepoint [10]
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Baseline, Week 26 and Week 52
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Secondary outcome [11]
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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
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Assessment method [11]
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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.
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Timepoint [11]
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Baseline, Week 26 and Week 52
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Eligibility
Key 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.
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Minimum age
No limit
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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).
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
11/01/2017
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
24/01/2023
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Sample size
Target
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Accrual to date
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Final
58
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Recruitment in Australia
Recruitment state(s)
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Recruitment hospital [1]
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Clinical Trial Site - Clayton
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Recruitment hospital [2]
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Clinical Trial Site - Geelong
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Recruitment hospital [3]
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Clinical Trial Site - Parkville
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Recruitment postcode(s) [1]
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- Clayton
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Recruitment postcode(s) [2]
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- Geelong
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Recruitment postcode(s) [3]
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- Parkville
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Recruitment outside Australia
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United States of America
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Indiana
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United States of America
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North Carolina
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United States of America
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Ohio
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Austria
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Vienna
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Belgium
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Brussels
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Canada
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London
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France
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Bordeaux
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France
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Clermont-Ferrand
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France
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Lille
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France
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Montpellier
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France
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Nice
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France
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Paris
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Germany
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Aachen
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Germany
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Essen
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Germany
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Hanover
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Germany
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Muenchen
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Germany
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Tuebingen
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Italy
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Bologna
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Italy
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Firenze
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Saitama
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Japan
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Tokyo
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Korea, Republic of
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Gyeonggi-do
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Korea, Republic of
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Seoul
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Russian Federation
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Moscow
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Russian Federation
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Saint Petersburg
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Spain
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Barcelona
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Spain
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Madrid
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Spain
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Valencia
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Taiwan
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Taichung
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Taiwan
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Taipei City
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Taiwan
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Taipei
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United Kingdom
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Cardiff
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United Kingdom
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Alexion Pharmaceuticals, Inc.
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Address
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/study/NCT02949128
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Trial related presentations / publications
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. 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. doi: 10.1007/s40291-023-00643-4. 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. doi: 10.1186/s12882-021-02242-z.
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Public notes
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Contacts
Principal investigator
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Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/28/NCT02949128/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/28/NCT02949128/SAP_002.pdf
Results publications and other study-related documents
Type
Citations or Other Details
Journal
Barbour T, Scully M, Ariceta G, Cataland S, Garlo ...
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More Details
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Results are available at
https://clinicaltrials.gov/study/NCT02949128
Download to PDF