Open-label, Multiple Ascending Dose Study of Ravulizumab (ALXN1210) in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

A Phase 2, Open-label, Multiple Ascending Dose Study to Evaluate the Efficacy, Safety, Tolerability, Immunogenicity, Pharmacokinetics, and Pharmacodynamics of ALXN1210 Administered Intravenously to Patients With Paroxysmal Nocturnal Hemoglobinuria

The primary purpose of this study is to evaluate the safety, tolerability, and efficacy of multiple intravenous (IV) doses of ravulizumab administered to complement inhibitor treatment-naïve participants with PNH.

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria; PNH
• Intervention / Treatment: Biological: Ravulizumab

Detailed Description

The study consisted of a screening period of up to 30 days and a Treatment Period of up to 253 days for Cohorts 1-3 and 281 days for Cohort 4. After completion of the Treatment Period, all participants had the opportunity to enter the Extension Period, wherein participants continue to receive ravulizumab for up to 5 years. The first dose in the Extension Period occurred on Day 253 for Cohorts 1-3 and on Day 281 for Cohort 4.

The data presented includes the Primary Completion date of the study for the Treatment Period. The results for the Extension Period will be reported after study completion.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Clinical Trial Site
• France
  • Lille, France, 59037
    • Clinical Trial Site
  • Paris, France, 75475
    • Clinical Trial Site
  • Pierre-Bénite
    • Lyon, Pierre-Bénite, France, 69495
      • Clinical Trial Site
• Germany
  • Baden Wuerttemberg
    • Ulm, Baden Wuerttemberg, Germany, 89081
      • Clinical Trial Site
  • Nordrhein Westfalen
    • Aachen, Nordrhein Westfalen, Germany, 52074
      • Clinical Trial Site
    • Essen, Nordrhein Westfalen, Germany, 45147
      • Clinical Trial Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Clinical Trial Site
  • Seoul, Korea, Republic of, 03722
    • Clinical Trial Site
• Spain
  • Barcelona, Spain, 08036
    • Clinical Trial Site
  • Madrid, Spain, 28040
    • Clinical Trial Site
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Clinical Trial Site
  • Madrid
    • Majadahonda, Madrid, Spain, 28220
      • Clinical Trial Site
• Taiwan
  • Taipei City, Taiwan, 10048
    • Clinical Trial Site
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • Clinical Trial Site
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS9 7TF
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female ≥18 years of age
2. PNH diagnosis confirmed by documented high-sensitivity flow cytometry
3. Documented meningococcal vaccination not more than 3 years prior to dosing
4. Female participants of childbearing potential were to use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab.
5. Willing and able to give written informed consent and comply with the study visit schedule

Exclusion Criteria:

1. Treatment with a complement inhibitor at any time
2. Female participants who are planning to become pregnant, or are pregnant, breastfeeding or who had a positive pregnancy test at screening or Day 1
3. Participation in an interventional clinical study within 30 days before initiation of dosing on Day 1, or use of any experimental therapy within 30 days prior to dosing on Day 1, or within 5 half-lives of the investigational product, whichever was greater
4. History of allergy to any drug, allergen, excipients of ravulizumab or known allergy to Chinese hamster ovary cell proteins
5. Inability to comply with study requirements
6. History of any clinically significant cardiac, hepatic, immunologic, pulmonary, or rheumatoid disease that, in the Investigator's judgment, would preclude participation
7. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the participant unsuitable for enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; During the Treatment Period, participants were administered ravulizumab 1400 milligram (mg) on Day 1, ravulizumab 1000 mg on Day 15 and Day 29, and then ravulizumab 1000 mg every 4 weeks for 7 doses. In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kilograms (kg), 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more.	Biological: Ravulizumab; All treatments were given as IV infusions.; Other Names: Ultomiris; ALXN1210
Experimental: Cohort 2; During the Treatment Period, participants were administered ravulizumab 2000 mg on Day 1, ravulizumab 1600 mg on Day 22 and Day 43, and then ravulizumab 1600 mg every 6 weeks for 4 doses. In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more.	Biological: Ravulizumab; All treatments were given as IV infusions.; Other Names: Ultomiris; ALXN1210
Experimental: Cohort 3; During the Treatment Period, participants were administered ravulizumab 1600 mg on Day 1 and Day 15, ravulizumab 2400 mg on Day 29, and then ravulizumab 2400 mg every 8 weeks for 3 doses. In the Extension Period, participants initially continued to receive their dose. During the second year of the study, participants were administered weight-based doses of ravulizumab every 8 weeks for up to 5 years: 3000 mg for participants weighing 40 to less than 60 kg, 3300 mg for participants weighing 60 to less than 100 kg, and 3600 mg for participants weighing 100 kg or more.	Biological: Ravulizumab; All treatments were given as IV infusions.; Other Names: Ultomiris; ALXN1210
Experimental: Cohort 4; During the Treatment Period, participants were administered ravulizumab 3000 mg on Day 1, ravulizumab 5400 mg on Day 29, and then ravulizumab 5400 mg every 12 weeks for 2 doses. During the Extension Period, participants were administered ravulizumab 5400 mg every 12 weeks for up to 5 years.	Biological: Ravulizumab; All treatments were given as IV infusions.; Other Names: Ultomiris; ALXN1210

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change In LDH Levels From Baseline To Day 253 And Day 281	The percent change in LDH levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.	Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change In Free Hemoglobin Levels From Baseline To Day 253 And Day 281	The percent change in free hemoglobin levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.	Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
Percent Change In Haptoglobin Levels From Baseline To Day 253 And Day 281	The percent change in haptoglobin levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.	Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 253 And Day 281	The percent change in reticulocyte/erythrocyte count levels was assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.	Baseline, Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
Percent Change In PNH RBC Types II And III Clone Size From Baseline To Day 253	The percent change in paroxysmal nocturnal hemoglobinuria (PNH) red blood cell (RBC), summed types II and III, clone size levels were assessed from Baseline to Day 253 for Cohorts 1 to 4.	Baseline, Day 253 (Cohorts 1 to 4)
Percent Change In D-dimer From Baseline To Day 253 And Day 281	The percent change in D-dimer levels were assessed from Baseline to Day 253 for Cohorts 1 to 4 and from Baseline to Day 281 for Cohort 4 only.	Baseline to Day 253 (Cohorts 1 to 4) and Day 281 (Cohort 4)
Change In Clinical Manifestations Of PNH From Baseline To Day 253 And Day 281	Clinical manifestations were assessed from Baseline to Day 253 for Cohorts 1 to 3 and from Baseline to Day 281 for Cohort 4 only. Clinical manifestations were defined as fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction (male participants only). Improvement was defined as present at Baseline and absent at Day endpoint. Worsening was defined as absent at Baseline and present at Day endpoint. No Change was defined as no change from Baseline and time point of endpoint.	Baseline, Day 253 (Cohorts 1 to 3) and Day 281 (Cohort 4)

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals

Publications and helpful links

General Publications

• Roth A, Rottinghaus ST, Hill A, Bachman ES, Kim JS, Schrezenmeier H, Terriou L, Urbano-Ispizua A, Wells RA, Jang JH, Kulasekararaj AG, Szer J, Aguzzi R, Damokosh AI, Shafner L, Lee JW. Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv. 2018 Sep 11;2(17):2176-2185. doi: 10.1182/bloodadvances.2018020644.

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2016
• Primary Completion (Actual): February 23, 2017
• Study Completion (Actual): January 12, 2022

Study Registration Dates

• First Submitted: November 11, 2015
• First Submitted That Met QC Criteria: November 13, 2015
• First Posted (Estimate): November 17, 2015

Study Record Updates

• Last Update Posted (Estimate): January 4, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: complement inhibitor
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Ravulizumab
• Other Study ID Numbers: ALXN1210-PNH-201; 2015-002674-20 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No