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ALXN1210 (Ravulizumab) Versus Eculizumab in Complement Inhibitor Treatment-Naïve Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

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ClinicalTrials.gov Identifier: NCT02946463
Recruitment Status : Active, not recruiting
First Posted : October 27, 2016
Results First Posted : February 12, 2019
Last Update Posted : May 15, 2020
Sponsor:
Information provided by (Responsible Party):
Alexion Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE October 25, 2016
First Posted Date  ICMJE October 27, 2016
Results First Submitted Date  ICMJE January 24, 2019
Results First Posted Date  ICMJE February 12, 2019
Last Update Posted Date May 15, 2020
Actual Study Start Date  ICMJE December 20, 2016
Actual Primary Completion Date January 25, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 19, 2019)
  • Proportion Of Participants With Normalization Of Lactate Dehydrogenase (LDH) Levels [ Time Frame: Day 29 through Day 183 ]
    LDH is an indicator of intravascular hemolysis that occurs in patients with paroxysmal nocturnal hemoglobinuria (PNH). A decrease in LDH from above the upper limit of normal (ULN) to below the ULN indicates reduction (improvement) in hemolysis. Normalization of LDH levels (LDH-N) was LDH levels less than or equal to 1 x ULN, from Day 29 through Day 183. The ULN for LDH is 246 U/L.
  • Percentage Of Participants Who Achieved Transfusion Avoidance (TA) [ Time Frame: Baseline through Day 183 ]
    Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines through Day 183.
Original Primary Outcome Measures  ICMJE
 (submitted: October 25, 2016)
  • Normalization Of Lactate Dehydrogenase (LDH) Levels [ Time Frame: 26 weeks ]
  • Percentage of patients who achieve transfusion avoidance (TA) [ Time Frame: 26 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2019)
  • Percentage Of Participants With Breakthrough Hemolysis (BTH) [ Time Frame: Baseline through Day 183 ]
    Breakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 gram/deciliter (g/dL)], major adverse vascular event [MAVE, including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 × ULN, after prior LDH reduction to <1.5 × ULN on therapy.
  • Percent Change From Baseline In Lactate Dehydrogenase (LDH) Levels [ Time Frame: Baseline, Day 183 ]
    Baseline is defined as the average of all available assessments of LDH levels prior to first study drug dose. Estimates are based on Mixed Model for Repeated Measures (MMRM) that includes treatment group, history of transfusion (as a categorical variable based on the stratification factor levels) and baseline LDH level (as a continuous variable), study visit and study visit by treatment group interaction. An unstructured covariance structure was used.
  • Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue [ Time Frame: Baseline, Day 183 ]
    FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline is defined as the last non-missing value prior to first dose of study drug. Estimates are based on MMRM that includes treatment group, the observed stratification randomization indicators (history of transfusion and LDH) and baseline FACIT-Fatigue level, study visit, and study visit by treatment group interaction. An unstructured covariance structure was used.
  • Percentage Of Participants With Stabilized Hemoglobin Levels [ Time Frame: Baseline through Day 183 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 25, 2016)
  • Percentage change from baseline in lactate dehydrogenase ( LDH) levels [ Time Frame: 26 weeks ]
  • Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue [ Time Frame: 26 weeks ]
  • Percentage of patients with stabilized hemoglobin [ Time Frame: 26 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ALXN1210 (Ravulizumab) Versus Eculizumab in Complement Inhibitor Treatment-Naïve Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Official Title  ICMJE A Phase 3, Randomized, Open-Label, Active-Controlled Study of ALXN1210 Versus Eculizumab in Complement Inhibitor-Naïve Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Brief Summary The primary purpose of this study was to assess the noninferiority of ravulizumab compared to eculizumab in adult participants with PNH who had never been treated with a complement inhibitor (treatment-naïve).
Detailed Description

The study consisted of a 4-week screening period and a 26-week randomized treatment period (Primary Evaluation Period). After completion of the 26-week Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive ravulizumab for up to 5 years.

This study is ongoing. The data presented is for the Primary Evaluation Period. The results for the Extension Period will be reported after study completion.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Paroxysmal Nocturnal Hemoglobinuria (PNH)
Intervention  ICMJE
  • Biological: Ravulizumab
    All treatments were given as intravenous (IV) infusions. For participants weighing ≥40 to <60 kilogram (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 Names:
    • ALXN1210
    • ULTOMIRIS
  • Biological: Eculizumab
    All treatments were given as IV infusions. Participants were administered induction doses of 600 mg followed by maintenance doses of 900 mg.
Study Arms  ICMJE
  • Experimental: Ravulizumab

    Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligram (mg) on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

    After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 5 years.

    Intervention: Biological: Ravulizumab
  • Active Comparator: Eculizumab

    Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

    After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 5 years.

    Interventions:
    • Biological: Ravulizumab
    • Biological: Eculizumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 28, 2017)
246
Original Estimated Enrollment  ICMJE
 (submitted: October 25, 2016)
214
Estimated Study Completion Date  ICMJE January 2023
Actual Primary Completion Date January 25, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female ≥18 years of age.
  2. PNH diagnosis confirmed by documented by high-sensitivity flow cytometry.
  3. Presence of 1 or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin <10 gram/deciliter), history of a major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cells (pRBC) transfusion due to PNH.
  4. Lactate dehydrogenase (LDH) level ≥1.5 times the upper limit of normal at screening.
  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.

Exclusion Criteria:

  1. Treatment with a complement inhibitor at any time.
  2. History of bone marrow transplantation.
  3. Body weight <40 kg.
  4. Females who are pregnant, breastfeeding, or who have a positive pregnancy test at screening or Day 1.
  5. Participation in another interventional clinical study or use of any experimental therapy within 30 days before initiation of study drug on Day 1 in this study or within 5 half-lives of that investigational product, whichever is greater.
  6. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease that, in the opinion of the investigator or sponsor, would preclude participation.
  7. Unstable medical conditions (for example, myocardial ischemia, active gastrointestinal bleed, severe congestive heart failure, anticipated need for major surgery within 6 months of randomization, coexisting chronic anemia unrelated to PNH).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Canada,   Czechia,   Estonia,   France,   Germany,   Italy,   Japan,   Korea, Republic of,   Malaysia,   Mexico,   Poland,   Russian Federation,   Singapore,   Spain,   Sweden,   Taiwan,   Thailand,   Turkey,   United Kingdom,   United States
Removed Location Countries Colombia
 
Administrative Information
NCT Number  ICMJE NCT02946463
Other Study ID Numbers  ICMJE ALXN1210-PNH-301
2016-002025-11 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alexion Pharmaceuticals
Study Sponsor  ICMJE Alexion Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Alexion Pharmaceuticals
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP