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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03056040
Registration number
NCT03056040
Ethics application status
Date submitted
14/02/2017
Date registered
16/02/2017
Date last updated
27/03/2023
Titles & IDs
Public title
ALXN1210 Versus Eculizumab in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab
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Scientific title
A Phase 3, Randomized, Open-Label, Active-Controlled Study of ALXN1210 Versus Eculizumab in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab
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Secondary ID [1]
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2016-002026-36
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Secondary ID [2]
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ALXN1210-PNH-302
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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:
Paroxysmal Nocturnal Hemoglobinuria (PNH)
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Condition category
Condition code
Blood
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Haematological diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - Ravulizumab
Other interventions - Eculizumab
Experimental: Ravulizumab - On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg). Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.
After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 years.
Active Comparator: Eculizumab - Participants received 900 mg of eculizumab every 2 weeks (q2w) for 26 weeks.
After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 years.
Other interventions: Ravulizumab
All treatments were given as intravenous (IV) infusions. For participants weighing =40 to <60 kilograms (kg): 2400 mg was given as a single loading dose, followed by 3000 mg as maintenance dose. For participants weighing =60 to <100 kg: 2700 mg was given as a loading dose, followed by 3300 mg as maintenance dose. For participants weighing =100 kg: 3000 mg was given as a loading dose, followed by 3600 mg as maintenance dose.
Other interventions: Eculizumab
All treatments were given as IV infusions. Participants received 900 mg of eculizumab q2w.
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Intervention code [1]
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Other interventions
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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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Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 183
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Assessment method [1]
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Lactate dehydrogenase (LDH) is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria. A decrease in LDH indicates reduction (improvement) in hemolysis. Baseline was defined as the average of all available on-study assessments prior to the first study drug infusion. The percent change in LDH was analyzed using a mixed-effect model for repeated measures (MMRM) with the fixed, categorical effects of treatment, study visit, and study visit by treatment group interaction, as well as the continuous, fixed covariate of baseline LDH and the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1).
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Timepoint [1]
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Baseline, Day 183
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Secondary outcome [1]
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Number Of Participants With Breakthrough Hemolysis Through Day 183
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Assessment method [1]
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Breakthrough hemolysis (BTH) was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 grams (g)/deciliter (dL)], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH =2 times the upper limit of normal (ULN).
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Timepoint [1]
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Baseline through Day 183
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Secondary outcome [2]
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Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores
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Assessment method [2]
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FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline was defined as the last non-missing assessment value prior to first study drug dose. Change in FACIT-Fatigue score from Baseline to Day 183 was analyzed using an MMRM with the fixed, categorical effects of treatment, the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1), study visit, and study visit by treatment group interaction, as well as the continuous fixed covariate of Baseline FACIT-Fatigue score.
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Timepoint [2]
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Baseline, Day 183
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Secondary outcome [3]
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Percentage Of Participants Who Achieved Transfusion Avoidance Through Day 183
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Assessment method [3]
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Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines (hemoglobin value of =9 g/dL with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of =7 g/dL regardless of presence of clinical signs or symptoms) through Day 183.
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Timepoint [3]
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Baseline through Day 183
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Secondary outcome [4]
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Percentage Of Participants With Stabilized Hemoglobin Levels Through Day 183
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Assessment method [4]
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Stabilized hemoglobin was defined as avoidance of a =2 g/dL decrease in hemoglobin level from Baseline in the absence of transfusion through Day 183.
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Timepoint [4]
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Baseline through Day 183
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Secondary outcome [5]
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Number Of Participants With Breakthrough Hemolysis Through End of Study
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Assessment method [5]
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BTH was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 g/dL], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH =2 times the ULN.
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Timepoint [5]
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Baseline through end of study (up to 5 years)
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Secondary outcome [6]
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Change From Baseline To End of Study In FACIT-Fatigue Scores Through End of Study
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Assessment method [6]
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FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline was defined as the last non-missing assessment value prior to first study drug dose. Change in FACIT-Fatigue score from Baseline to Day 183 was analyzed using an MMRM with the fixed, categorical effects of treatment, the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1), study visit, and study visit by treatment group interaction, as well as the continuous fixed covariate of Baseline FACIT-Fatigue score.
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Timepoint [6]
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Baseline, End of Study (up to 5 years)
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Secondary outcome [7]
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Percentage Of Participants Who Achieved Transfusion Avoidance Through End of Study
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Assessment method [7]
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Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines (hemoglobin value of =9 g/dL with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of =7 g/dL regardless of presence of clinical signs or symptoms) through the end of study.
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Timepoint [7]
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Baseline through end of study (up to 5 years)
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Secondary outcome [8]
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Percentage Of Participants With Stabilized Hemoglobin Levels Through End of Study
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Assessment method [8]
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Stabilized hemoglobin was defined as avoidance of a =2 g/dL decrease in hemoglobin level from Baseline in the absence of transfusion through end of study.
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Timepoint [8]
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Baseline through end of study (up to 5 years)
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Eligibility
Key inclusion criteria
1. Male or female =18 years of age.
2. Treated with eculizumab for PNH for at least 6 months prior to Day 1.
3. Lactate dehydrogenase level =1.5 times the upper limit of normal (ULN) at screening.
4. PNH diagnosis confirmed by documented by high-sensitivity flow cytometry.
5. Documented meningococcal vaccination not more than 3 years prior to, or at the time
of, initiating study treatment.
6. Female participants of childbearing potential must use highly effective contraception
starting at screening and continuing until at least 8 months after the last dose of
ravulizumab.
7. Willing and able to give written informed consent and comply with study visit
schedule.
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Minimum age
18
Years
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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. History of bone marrow transplantation.
2. Body weight <40 kilograms at screening.
3. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease
that, in the opinion of the investigator or sponsor, would preclude participation.
4. Unstable medical conditions (for example, myocardial ischemia, active gastrointestinal
bleeding, severe congestive heart failure, anticipated need for major surgery within 6
months of randomization, or coexisting chronic anemia unrelated to PNH).
5. Female participants who are pregnant, breastfeeding, or who have a positive pregnancy
test at screening or Day 1.
6. Participation in another interventional clinical study or use of any experimental
therapy within 30 days before initiation of study treatment on Day 1 in this study or
within 5 half-lives of that investigational product, whichever is greater.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled 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
Parallel
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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
5/06/2017
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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
8/04/2022
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Sample size
Target
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Accrual to date
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Final
195
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Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,VIC
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Recruitment hospital [1]
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Clinical Trial Site - Canberra
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Recruitment hospital [2]
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Clinical Trial Site - Kogarah
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Recruitment hospital [3]
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Clinical Trial Site - Liverpool
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Recruitment hospital [4]
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Clinical Trial Site - Woolloongabba
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Recruitment hospital [5]
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Clinical Trial Site - Parkville
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Recruitment postcode(s) [1]
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2605 - Canberra
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Recruitment postcode(s) [2]
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2217 - Kogarah
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Recruitment postcode(s) [3]
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2170 - Liverpool
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Recruitment postcode(s) [4]
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4102 - Woolloongabba
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Recruitment postcode(s) [5]
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3050 - Parkville
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Recruitment outside Australia
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United States of America
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California
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United States of America
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Maryland
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United States of America
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Michigan
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United States of America
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New York
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Canada
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Ontario
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Canada
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Quebec
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France
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Amiens
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France
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Marseille
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France
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Paris
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France
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Pierre-Bénite
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France
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Saint-Priest-en-Jarez
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France
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Strasbourg
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Germany
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Baden Wuerttemberg
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Germany
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Nordrhein Westfalen
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Italy
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Firenze
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Italy
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Milano
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Italy
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Napoli
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Italy
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Torino
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Italy
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Vicenza
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Japan
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Ishikawa
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Japan
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Nagano
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Japan
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Osaka
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Japan
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Tokyo
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Japan
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Fukushima
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Korea, Republic of
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Daegu
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Daejeon
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Gyeonggi-do
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Incheon
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Seoul
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Maastricht
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Nijmegen
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Barcelona
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Spain
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Madrid
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Spain
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Majadahonda
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United Kingdom
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Airdrie
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United Kingdom
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Leeds
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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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Ethics approval
Ethics application status
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Summary
Brief summary
The primary purpose of this study was to assess the noninferiority of ravulizumab compared to
eculizumab in adult participants with PNH who were clinically stable after having been
treated with eculizumab for at least 6 months.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03056040
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Trial related presentations / publications
Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Roth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. doi: 10.1182/blood-2018-09-876805. Epub 2018 Dec 3.
Brodsky RA, Peffault de Latour R, Rottinghaus ST, Roth A, Risitano AM, Weitz IC, Hillmen P, Maciejewski JP, Szer J, Lee JW, Kulasekararaj AG, Volles L, Damokosh AI, Ortiz S, Shafner L, Liu P, Hill A, Schrezenmeier H. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. Haematologica. 2021 Jan 1;106(1):230-237. doi: 10.3324/haematol.2019.236877.
Ishiyama K, Nakao S, Usuki K, Yonemura Y, Ikezoe T, Uchiyama M, Mori Y, Fukuda T, Okada M, Fujiwara SI, Noji H, Rottinghaus S, Aguzzi R, Yokosawa J, Nishimura JI, Kanakura Y, Okamoto S. Results from multinational phase 3 studies of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria: subgroup analysis of Japanese patients. Int J Hematol. 2020 Oct;112(4):466-476. doi: 10.1007/s12185-020-02934-6. Epub 2020 Aug 31.
Kulasekararaj AG, Griffin M, Langemeijer S, Usuki K, Kulagin A, Ogawa M, Yu J, Mujeebuddin A, Nishimura JI, Lee JW, Peffault de Latour R; 301/302 Study Group. Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies. Eur J Haematol. 2022 Sep;109(3):205-214. doi: 10.1111/ejh.13783. Epub 2022 Jun 16.
Kulasekararaj AG, Hill A, Langemeijer S, Wells R, Gonzalez Fernandez FA, Gaya A, Ojeda Gutierrez E, Piatek CI, Mitchell L, Usuki K, Bosi A, Brodsky RA, Ogawa M, Yu J, Ortiz S, Roth A, Lee JW, Peffault de Latour R. One-year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab. Eur J Haematol. 2021 Mar;106(3):389-397. doi: 10.1111/ejh.13564. Epub 2021 Jan 3.
Peffault de Latour R, Brodsky RA, Ortiz S, Risitano AM, Jang JH, Hillmen P, Kulagin AD, Kulasekararaj AG, Rottinghaus ST, Aguzzi R, Gao X, Wells RA, Szer J. Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies. Br J Haematol. 2020 Nov;191(3):476-485. doi: 10.1111/bjh.16711. Epub 2020 May 24.
Schrezenmeier H, Kulasekararaj A, Mitchell L, Sicre de Fontbrune F, Devos T, Okamoto S, Wells R, Rottinghaus ST, Liu P, Ortiz S, Lee JW, Socie G. One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naive to complement inhibitor therapy: open-label extension of a randomized study. Ther Adv Hematol. 2020 Oct 24;11:2040620720966137. doi: 10.1177/2040620720966137. eCollection 2020.
Wietz IC, Kulagin A, Nakao S, Piatek CI, Szer J, Rottinghaus ST, Volles L, Damokosh AI, Aguzzi R, Larratt L, Risitano AM. A Phase 3 study of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria naive to complement inhibitors: results of a subgroup analysis with patients stratified by baseline hemolysis level, transfusion history, and demographics. Blood. 2018;132 (Supplement 1):627. doi: 10.1182/blood-2018-99-110623
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Public notes
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Contacts
Principal investigator
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Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03056040
Download to PDF