A Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Participants With PNH (DAHLIA)

A Randomized, Double-Blind, Active-Controlled Phase 3 Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Subjects With Paroxysmal Nocturnal Hemoglobinuria (PNH)

This is a randomized, double-blind, active-controlled phase 3 study of ABP 959 in participants with paroxysmal nocturnal hemoglobinuria.

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria
• Intervention / Treatment: Drug: ABP 959; Drug: Eculizumab

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czechia
  • Olomouc, Czechia, 772 00
    • Fakultni nemocnice Olomouc
  • Ostrava-Poruba, Czechia, 708 52
    • Fakultni Nemocnice Ostrava
  • Jihormoravsky KRAJ
    • Brno, Jihormoravsky KRAJ, Czechia, 625 00
      • Fakultni nemocnice Brno
• Finland
  • Jyväskylä, Finland, FI-40620
    • Keski-Suomen keskussairaala Jyväskylä
  • Lahti, Finland, FI-15850
    • Päijät-Häme Central Hospital
• France
  • Bretagne
    • Cesson-Sevigne, Bretagne, France, 35576
      • Hôpital privé Sévigné
• Ireland
  • Dublin, Ireland, 8
    • Saint James's Hospital
• Italy
  • Cuneo, Italy, 12100
    • Azienda Ospedaliera S. Croce e Carle Cuneo
  • Ravenna, Italy, 48121
    • Azienda USL della Romagna
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli
  • Forli-cesena
    • Meldola, Forli-cesena, Italy, 47014
      • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
  • Monza Brianza
    • Monza, Monza Brianza, Italy, 20052
      • Azienda Ospedaliera San Gerardo di Monza
• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboud Universitair Medisch Centrum
• Norway
  • Oslo, Norway, 0372
    • Oslo University Hospital - Rikshospitalet
• Portugal
  • Porto, Portugal, 4200-072
    • Instituto Portugues de Oncologia do Porto Francisco Gentil
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Univerzitetni klinicni center Ljubljana
• Spain
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanca
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe
• Sweden
  • Stockholm, Sweden, 141 86
    • Karolinska universitetssjukhuset - Huddinge
• Turkey
  • Mersin, Turkey, 33110
    • Mersin Universitesi Tip Fakultesi
  • Izmir
    • Bornova, Izmir, Turkey, 35100
      • Ege Universitesi Hastanesi - Sağlık Uygulama ve Araştırma Merkezi
• United Kingdom
  • England
    • Leeds, England, United Kingdom, LS9 7TF
      • The Leeds Teaching Hospitals Nhs Trust
    • London, England, United Kingdom, SE5 9RS
      • King's College Hospital NHS Foundation Trust
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta at Egleston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women ≥ 18 years of age.
• Historical diagnosis of PNH.
• Administration of eculizumab for ≥ 6 months and currently receiving 900 mg of eculizumab.
• Hemoglobin ≥ 9.0 g/dL for at least 6 weeks before randomization.
• Lactate dehydrogenase < 1.5 × the upper limit of normal at screening.
• Platelet count ≥ 50 × 10^9/L.
• Absolute neutrophil count (ANC) ≥ 0.5 x 10^9/L (500/μL).
• Participants must be vaccinated against Neisseria meningitidis.
• Participants must sign an IRB/IEC-approved ICF before participation in any procedures.

Exclusion Criteria:

• Known or suspected hereditary complement deficiency.
• Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure [New York Heart Association ≥ Class III], serious uncontrolled cardiac arrhythmia), peripheral vascular disease, cerebrovascular accident, or transient ischemic attack in the previous 6 months.
• Evidence of acute thrombosis (liver Doppler ultrasound of hepatic and portal veins).
• Known to be positive for human immunodeficiency virus.
• Woman who is pregnant or breastfeeding.
• Participant is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or participant is receiving other investigational agent(s).
• Participant has known sensitivity to any of the products to be administered during the study, including mammalian cell-derived drug products.
• History of meningococcal infection.
• Presence or suspicion of active bacterial infection, or recurrent bacterial infection.
• History of bone marrow transplantation.
• Red blood cell transfusion required within 12 weeks before randomization.
• Participant experienced ≥ 2 breakthrough events, (ie, signs and symptoms of intravascular hemolysis, that require dose and/or schedule adjustments of eculizumab) in the previous 12 months before screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: T (ABP 959) / R (eculizumab); ABP 959 for 52 weeks in Period 1 followed by eculizumab for 26 weeks in Period 2	Drug: ABP 959; intravenous infusion; Other Names: Treatment T; Drug: Eculizumab; intravenous infusion; Other Names: Soliris; Treatment R
Other: R (eculizumab) / T (ABP 959); Eculizumab for 52 weeks in Period 1 followed by ABP 959 for 26 weeks in Period 2	Drug: ABP 959; intravenous infusion; Other Names: Treatment T; Drug: Eculizumab; intravenous infusion; Other Names: Soliris; Treatment R

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LDH Level at Week 27 (Parallel Comparison)	The primary analysis for the parallel comparison was hemolysis as measured by LDH at Week 27 by initial treatment received (Period 1).	Week 27
Time-adjusted Area Under the Effect Curve (AUEC) of LDH (Crossover Comparison Per Assigned Treatment)	The primary analysis for the crossover comparison was hemolysis, as measured by the time-adjusted AUEC of LDH, according to treatment assigned during each of the 14-week assessments during Periods 1 and 2.	From Week 13 to Week 27, from Week 39 to Week 53, and from Week 65 to Week 79

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Total Complement (50% Total Hemolytic Complement Activity [CH50])	Total complement (%) was measured in serum using an assay method and compared the total hemolytic complement activity to the lower limit of the normal human reference (LLN) of 58 U/mL for all CH50 values. The percent of LLN of CH50 at each time point was calculated as mean CH50 results/LLN x 100%. Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Mean Total Hemoglobin Levels	Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Mean Serum-free Hemoglobin Levels	Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Mean Haptoglobin Levels	Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Mean Bilirubin Levels	Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Degree of Hemoglobinuria	The degree of hemoglobinuria was categorized as negative, trace, small, moderate, and large based on the analysis of urine samples collected from each participant at the specified time points. Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Mean Percentage of Type III Erythrocytes	As a measure of hemolysis the mean percentage of Type III erythrocytes was measured at the specified timepoints. Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	Baseline, Week 27, Week 39, Week 53, Week 65 and Week 79
LDH Levels at Week 53 and Week 79	The analysis of the crossover comparison of hemolysis, as measured by LDH at Week 53 and Week 79.	Week 53 (first week of Period 2) and Week 79 (last week of Period 2)
Mean LDH Levels by Visit up to Week 79	Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	Baseline, Week 3, Week 7, Week 13, Week 15, Week 19, Week 25, Week 27, Week 29, Week 33, Week 39, Week 41, Week 43, Week 45, Week 47, Week 49, Week 51, Week 53, Week 55, Week 59, Week 65, Week 67, Week 69, Week 71, Week 73, Week 75, Week 77, and Week 79
Mean Number of Packed RBC Units Transfused Per Month	Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	Baseline to End of Study (up to Week 79)
Total and Unbound Pharmacokinetics (PK) Area Under the Curve (AUC) of ABP 959 and Eculizumab From Week 13 to Week 15 (Period 1)	The total and unbound PK concentration AUC values from Week 13 to Week 15 in Period 1 are presented by actual treatment received.	PK samples were collected predose and immediately postdose Week 13, 7 days post the Week 13 dose (Week 14), and predose at Week 15
Total and Unbound Trough Serum Concentrations of ABP 959 and Eculizumab	The total and unbound serum trough concentrations are presented by treatment sequence received for the prespecified time points. Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	PK samples were collected predose at the prespecified timepoints: baseline, Week 3, Week 7, Week 13, Week 15, Week 19, Week 27, Week 33, Week 39, Week 45, Week 51, Week 53, Week 55, Week 59, Week 65, Week 71, Week 77, and Week 79
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	TEAEs are defined as any adverse event (AE) that began or increased in severity or frequency at or after the time of first treatment up to end of study (up to Week 79). A treatment-emergent serious adverse event (SAE) was a TEAE that met at least 1 of the following criteria: was fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was another medically important serious event. The treatment-emergent events of interest (EOI) prespecified for this study included serious infections (meningococcus aspergillus, and other serious infections/sepsis), and infusion reactions.	Day 1 to End of Study (up to Week 79)
Number of Participants With Antidrug Antibodies (ADAs)	Any samples that tested positive for binding antibodies were also tested for neutralizing antibodies. Treatment boosted ADAs were defined as a positive immunoassay result at baseline and at least 1 postbaseline immunoassay result that was ≥ 4 times the magnitude of the baseline result. Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.	Blood samples for ADA assessments were taken predose at baseline, Week 3, Week 7, Week 13, Week 19, Week 25, Week 27, Week 33, Week 39, Week 45, Week 51, Week 53, Week 55, Week 59, Week 65, Week 71, Week 77 and Week 79.

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2019
• Primary Completion (Actual): July 12, 2022
• Study Completion (Actual): July 12, 2022

Study Registration Dates

• First Submitted: January 17, 2019
• First Submitted That Met QC Criteria: January 24, 2019
• First Posted (Actual): January 28, 2019

Study Record Updates

• Last Update Posted (Actual): May 23, 2023
• Last Update Submitted That Met QC Criteria: April 27, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Paroxysmal Cold Hemoglobinuria; Marchiafava-Micheli Syndrome
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: 20150168

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

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