Back to resultsA Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Participants With PNH (DAHLIA)
Primary Purpose
Paroxysmal Nocturnal Hemoglobinuria
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
ABP 959
Eculizumab
Sponsored by
About this trial
This is an interventional treatment trial for Paroxysmal Nocturnal Hemoglobinuria focused on measuring Marchiafava-Micheli Syndrome, Paroxysmal Cold Hemoglobinuria
Eligibility Criteria
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.
Sites / Locations
- Children's Healthcare of Atlanta at Egleston
- Fakultní Nemocnice Brno
- Fakultní Nemocnice Olomouc
- Fakultní Nemocnice Ostrava
- Keski-Suomen keskussairaala Jyväskylä
- Päijät-Häme Central Hospital
- Hôpital Privé Sévigné
- Saint James's Hospital
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
- Azienda Ospedaliera San Gerardo di Monza
- Azienda Ospedaliera S. Croce e Carle Cuneo
- Azienda USL della Romagna
- Fondazione Policlinico Universitario Agostino Gemelli
- Radboud Universitair Medisch Centrum
- Oslo University Hospital - Rikshospitalet
- Instituto Português de Oncologia do Porto Francisco Gentil
- Univerzitetni klinični center Ljubljana
- Hospital Universitario de Salamanca
- Hospital Universitario La Fe
- Karolinska Universitetssjukhuset - Huddinge
- Ege Universitesi Hastanesi - Sağlık Uygulama ve Araştırma Merkezi
- Mersin Universitesi Tip Fakultesi
- The Leeds Teaching Hospitals NHS Trust
- King's College Hospital NHS Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm Type
Other
Other
Arm Label
T (ABP 959) / R (eculizumab)
R (eculizumab) / T (ABP 959)
Arm Description
ABP 959 for 52 weeks in Period 1 followed by eculizumab for 26 weeks in Period 2
Eculizumab for 52 weeks in Period 1 followed by ABP 959 for 26 weeks in Period 2
Outcomes
Primary Outcome Measures
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).
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.
Secondary Outcome Measures
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.
Mean Total Hemoglobin Levels
Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.
Mean Serum-free Hemoglobin Levels
Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.
Mean Haptoglobin Levels
Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.
Mean Bilirubin Levels
Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03818607
Brief Title
A Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Participants With PNH
Acronym
DAHLIA
Official Title
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)
Study Type
Interventional
2. Study Status
Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
January 22, 2019 (Actual)
Primary Completion Date
July 12, 2022 (Actual)
Study Completion Date
July 12, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amgen
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This is a randomized, double-blind, active-controlled phase 3 study of ABP 959 in participants with paroxysmal nocturnal hemoglobinuria.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Paroxysmal Nocturnal Hemoglobinuria
Keywords
Marchiafava-Micheli Syndrome, Paroxysmal Cold Hemoglobinuria
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
double-blind
Allocation
Randomized
Enrollment
42 (Actual)
8. Arms, Groups, and Interventions
Arm Title
T (ABP 959) / R (eculizumab)
Arm Type
Other
Arm Description
ABP 959 for 52 weeks in Period 1 followed by eculizumab for 26 weeks in Period 2
Arm Title
R (eculizumab) / T (ABP 959)
Arm Type
Other
Arm Description
Eculizumab for 52 weeks in Period 1 followed by ABP 959 for 26 weeks in Period 2
Intervention Type
Drug
Intervention Name(s)
ABP 959
Other Intervention Name(s)
Treatment T
Intervention Description
intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Eculizumab
Other Intervention Name(s)
Soliris, Treatment R
Intervention Description
intravenous infusion
Primary Outcome Measure Information:
Title
LDH Level at Week 27 (Parallel Comparison)
Description
The primary analysis for the parallel comparison was hemolysis as measured by LDH at Week 27 by initial treatment received (Period 1).
Time Frame
Week 27
Title
Time-adjusted Area Under the Effect Curve (AUEC) of LDH (Crossover Comparison Per Assigned Treatment)
Description
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.
Time Frame
From Week 13 to Week 27, from Week 39 to Week 53, and from Week 65 to Week 79
Secondary Outcome Measure Information:
Title
Mean Total Complement (50% Total Hemolytic Complement Activity [CH50])
Description
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.
Time Frame
Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Title
Mean Total Hemoglobin Levels
Description
Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.
Time Frame
Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Title
Mean Serum-free Hemoglobin Levels
Description
Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.
Time Frame
Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Title
Mean Haptoglobin Levels
Description
Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.
Time Frame
Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Title
Mean Bilirubin Levels
Description
Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.
Time Frame
Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Title
Degree of Hemoglobinuria
Description
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.
Time Frame
Baseline, Week 27, Week 39, Week 53, Week 65, and Week 79
Title
Mean Percentage of Type III Erythrocytes
Description
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.
Time Frame
Baseline, Week 27, Week 39, Week 53, Week 65 and Week 79
Title
LDH Levels at Week 53 and Week 79
Description
The analysis of the crossover comparison of hemolysis, as measured by LDH at Week 53 and Week 79.
Time Frame
Week 53 (first week of Period 2) and Week 79 (last week of Period 2)
Title
Mean LDH Levels by Visit up to Week 79
Description
Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.
Time Frame
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
Title
Mean Number of Packed RBC Units Transfused Per Month
Description
Baseline was defined as the last non-missing assessment taken prior to the first dose of IP.
Time Frame
Baseline to End of Study (up to Week 79)
Title
Total and Unbound Pharmacokinetics (PK) Area Under the Curve (AUC) of ABP 959 and Eculizumab From Week 13 to Week 15 (Period 1)
Description
The total and unbound PK concentration AUC values from Week 13 to Week 15 in Period 1 are presented by actual treatment received.
Time Frame
PK samples were collected predose and immediately postdose Week 13, 7 days post the Week 13 dose (Week 14), and predose at Week 15
Title
Total and Unbound Trough Serum Concentrations of ABP 959 and Eculizumab
Description
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.
Time Frame
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
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description
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.
Time Frame
Day 1 to End of Study (up to Week 79)
Title
Number of Participants With Antidrug Antibodies (ADAs)
Description
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.
Time Frame
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.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
MD
Organizational Affiliation
Amgen
Official's Role
Study Director
Facility Information:
Facility Name
Children's Healthcare of Atlanta at Egleston
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Fakultní Nemocnice Brno
City
Brno
State/Province
Jihormoravsky KRAJ
ZIP/Postal Code
625 00
Country
Czechia
Facility Name
Fakultní Nemocnice Olomouc
City
Olomouc
ZIP/Postal Code
772 00
Country
Czechia
Facility Name
Fakultní Nemocnice Ostrava
City
Ostrava-Poruba
ZIP/Postal Code
708 52
Country
Czechia
Facility Name
Keski-Suomen keskussairaala Jyväskylä
City
Jyväskylä
ZIP/Postal Code
FI-40620
Country
Finland
Facility Name
Päijät-Häme Central Hospital
City
Lahti
ZIP/Postal Code
FI-15850
Country
Finland
Facility Name
Hôpital Privé Sévigné
City
Cesson-Sevigne
State/Province
Bretagne
ZIP/Postal Code
35576
Country
France
Facility Name
Saint James's Hospital
City
Dublin
ZIP/Postal Code
8
Country
Ireland
Facility Name
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
City
Meldola
State/Province
Forli-cesena
ZIP/Postal Code
47014
Country
Italy
Facility Name
Azienda Ospedaliera San Gerardo di Monza
City
Monza
State/Province
Monza Brianza
ZIP/Postal Code
20052
Country
Italy
Facility Name
Azienda Ospedaliera S. Croce e Carle Cuneo
City
Cuneo
ZIP/Postal Code
12100
Country
Italy
Facility Name
Azienda USL della Romagna
City
Ravenna
ZIP/Postal Code
48121
Country
Italy
Facility Name
Fondazione Policlinico Universitario Agostino Gemelli
City
Roma
ZIP/Postal Code
00168
Country
Italy
Facility Name
Radboud Universitair Medisch Centrum
City
Nijmegen
State/Province
Gelderland
ZIP/Postal Code
6525 GA
Country
Netherlands
Facility Name
Oslo University Hospital - Rikshospitalet
City
Oslo
ZIP/Postal Code
0372
Country
Norway
Facility Name
Instituto Português de Oncologia do Porto Francisco Gentil
City
Porto
ZIP/Postal Code
4200-072
Country
Portugal
Facility Name
Univerzitetni klinični center Ljubljana
City
Ljubljana
ZIP/Postal Code
1000
Country
Slovenia
Facility Name
Hospital Universitario de Salamanca
City
Salamanca
ZIP/Postal Code
37007
Country
Spain
Facility Name
Hospital Universitario La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Facility Name
Karolinska Universitetssjukhuset - Huddinge
City
Stockholm
ZIP/Postal Code
141 86
Country
Sweden
Facility Name
Ege Universitesi Hastanesi - Sağlık Uygulama ve Araştırma Merkezi
City
Bornova
State/Province
Izmir
ZIP/Postal Code
35100
Country
Turkey
Facility Name
Mersin Universitesi Tip Fakultesi
City
Mersin
ZIP/Postal Code
33110
Country
Turkey
Facility Name
The Leeds Teaching Hospitals NHS Trust
City
Leeds
State/Province
England
ZIP/Postal Code
LS9 7TF
Country
United Kingdom
Facility Name
King's College Hospital NHS Foundation Trust
City
London
State/Province
England
ZIP/Postal Code
SE5 9RS
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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 URL
https://www.amgen.com/datasharing
Links:
URL
http://www.amgentrials.com
Description
AmgenTrials clinical trials website
Learn more about this trial
A Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Participants With PNH
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