Dose-Escalation Study of ALXN1210 IV in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

An Open-Label, Intrapatient, Dose-Escalation Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of ALXN1210 Administered Intravenously to Patients With Paroxysmal Nocturnal Hemoglobinuria

This study evaluated the safety, tolerability, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of multiple intravenous (IV) doses of ALXN1210 administered to participants with PNH who have not previously been treated with complement inhibitor.

Study Overview

• Status: Completed
• Conditions: PNH
• Intervention / Treatment: Biological: ALXN1210

Detailed Description

The data presented is up to the Primary Completion date of the study and is for the 24-week Primary Evaluation period. The study also includes an Extension Period of up to 5 years.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Clinical Trial Site
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Clinical Trial Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Clinical Trial Site
  • Seoul, Korea, Republic of, 03722
    • Clinical Trial Site
  • Seoul, Korea, Republic of, 05505
    • Clinical Trial Site
  • Seoul, Korea, Republic of, 06351
    • Clinical Trial Site
  • Seoul, Korea, Republic of, 06951
    • Clinical Trial Site
  • Ulsan, Korea, Republic of, 44033
    • 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 used highly effective contraception starting at screening and continuing until at least 24-weeks after the last dose of ALXN1210
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. Females who were 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 product, whichever is greater
4. History of allergy to excipients of ALXN1210 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, made the participant unsuitable for enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1; Participants were administered ALXN1210 900 mg. In the Extension period participants continued at the same dose and frequency as the Primary Evaluation Period.	Biological: ALXN1210; Participants were administered ravulizumab as an IV infusion every 4 weeks.
EXPERIMENTAL: Cohort 2; Participants were administered ALXN1210 1800 mg. In the Extension period participants continued at the same dose and frequency as the Primary Evaluation Period.	Biological: ALXN1210; Participants were administered ravulizumab as an IV infusion every 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change In Lactate Dehydrogenase (LDH) Levels From Baseline To Day 169	Baseline was defined as the average of all available assessments prior to first ALXN1210 infusion.	Baseline, Day 169

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change In Free Hemoglobin Levels From Baseline To Day 169 And Day 1821	Baseline was defined as the last non-missing assessment value prior to the first ALXN1210 infusion.	Baseline, Day 169, Day 1821
Percent Change In Haptoglobin Levels From Baseline To Day 169 And Day 1821	Baseline was defined as the last non-missing assessment value prior to the first ALXN1210 infusion.	Baseline, Day 169, Day 1821
Percent Change In Reticulocyte/Erythrocyte Count From Baseline To Day 169 And Day 1821	Baseline was defined as the last non-missing assessment value prior to the first ALXN1210 infusion.	Baseline, Day 169, Day 1821
Percent Change In Paroxysmal Nocturnal Hemoglobinuria (PNH) Red Blood Cell (RBC) Clones From Baseline To Day 169 And Day 1933	Baseline was defined as the last non-missing assessment value prior to the first ALXN1210 infusion.	Baseline, Day 169, Day 1933
Percent Change In D-dimer Levels From Baseline To Day 169 And Day 1821	Baseline was defined as the last non-missing assessment value prior to the first ALXN1210 infusion.	Baseline, Day 169, Day 1821
Change In Clinical Manifestations Of PNH From Baseline To Day 169 And Day 1821	Clinical manifestations are defined as fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction (ED) by cohort. Improvement is defined as present at baseline and absent at Day 169 endpoint. Worsening is defined as absent at Baseline and present at Day 169 endpoint.	Baseline, Day 169, Day 1821
Area Under The Serum Concentration-versus-time-curve From Time 0 (Dosing) To The Last Quantifiable Concentration (AUCt) At Day 1	AUCt reported in hours*microgram/milliliter (h*ug/mL).	Day 1
AUCt/ Dose-normalized (D) At Day 1		Day 1
Area Under The Serum Concentration-versus-time-curve From Time 0 (Dosing) To The End Of The Dosing Interval (AUCtau) At Day 141		Day 141
AUCtau/D At Day 141		Day 141
Maximum Observed Serum Concentration (Cmax) At Day 1 And Day 141		Day 1 and Day 141
Cmax/D At Day 1 And Day 141		Day 1 and Day 141
Concentration At The End Of The Dosage Interval (Ctrough) At Day 1 And At Day 141		Day 1 and Day 141
Time To Maximum Observed Serum Concentration (Tmax) At Day 1 And Day 141		Day 1 and Day 141
Percent Change In Chicken Red Blood Cell (cRBC) Hemolysis From Baseline To Day 1709		Baseline, Day 1709
Percent Change In Free Complement Component 5 (C5) Concentration From Baseline To Day 1709		Baseline, Day 1709
Percent Change In Total C5 Concentration From Baseline To Day 1709		Baseline, Day 1709
Participants Experiencing Antidrug Antibodies (ADAs)		Day 1821

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals
• Investigators: Study Director: Alexion Pharmaceuticals, Inc., 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.

Helpful Links

• Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 12, 2015
• Primary Completion (ACTUAL): July 14, 2016
• Study Completion (ACTUAL): March 11, 2021

Study Registration Dates

• First Submitted: November 2, 2015
• First Submitted That Met QC Criteria: November 4, 2015
• First Posted (ESTIMATE): November 6, 2015

Study Record Updates

• Last Update Posted (ACTUAL): May 16, 2022
• Last Update Submitted That Met QC Criteria: April 22, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: PNH; Paroxysmal Nocturnal Hemoglobinuria; 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-103

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Alexion has a public commitment to allow requests for access to study data and will be supplying a protocol, CSR, and plain language summaries.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR