Paroxysmal Nocturnal Hemoglobinuria (PNH)
Conditions
Keywords
PNH, Paroxysmal Nocturnal Hemoglobinuria, ACH-0144471, Danicopan, Eculizumab, ALXN2040
Brief summary
To determine the effectiveness of ACH-0144471 (also known as danicopan and ALXN2040) in improving anemia when given with eculizumab for 24 weeks in participants with PNH. Danicopan dose may be increased within each participant, to a maximum of 200 milligrams (mg) three times daily (TID) based on safety and efficacy at protocol-specified time points.
Detailed description
The purpose of this study is to determine the effectiveness of danicopan in improving anemia, as measured by increased blood hemoglobin, when given with eculizumab (a drug commonly used for treatment of PNH) for 24 weeks in participants with PNH. The 24-week treatment period was followed by a long-term extension phase. In the extension phase, participants received the same danicopan dose plus eculizumab as they were receiving at the end of 24-week treatment phase. Results are reported for the 24-week treatment period.
Interventions
DRUGDanicopan
Participants received a daily oral dose of danicopan TID during the treatment period.
DRUGEculizumab
Participants received intravenous eculizumab administered at the participant's usual dose and schedule.
Sponsors
Achillion, a wholly owned subsidiary of Alexion
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Four groups will be studied and enrolled sequentially.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosed with PNH * Have received at least one red blood cell transfusion within last 12 weeks * Anemia with adequate reticulocytosis * Must be on a stable regimen of eculizumab * Platelet count ≥ 40,000/microliter without the need for platelet transfusions * Documentation of vaccination for Neisseria meningitidis, Haemophilus influenza, and Streptococcus pneumoniae or willingness to receive vaccinations based on local guidelines * Willingness to receive antibiotic prophylaxis * Female participants must use highly effective birth control to prevent pregnancy during the clinical trial and for 30 days after their last dose of study drug * Male participants must use a highly effective birth control with a female partner to prevent pregnancy during the clinical trial and for 90 days after the last dose of study drug Key
Exclusion criteria
* Current evidence of bone marrow failure or aplastic anemia requiring treatment * History of a major organ transplant or hematopoietic stem cell/marrow transplant * Received another investigational agent within 30 days or 5 half-lives of the investigational agent prior to study entry, whichever is greater * Documented C5 complement protein mutations * Known or suspected complement deficiency * Contraindication to any of the required vaccinations * Active bacterial infection or clinically significant active viral infection, a body temperature \>38°C, or other evidence of infection * History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection * History of hypersensitivity reactions to commonly used antibacterial agents Note: Additional inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline In Hemoglobin At Week 24 | Baseline, Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number Of Units Of Red Blood Cells (RBCs) Transfused During 24 Weeks Of Treatment | Within 24 weeks prior to first dose and during 24-week treatment period | — |
| Number Of Participants Without RBC Transfusions During 24 Weeks Of Treatment | Within 24 weeks prior to first dose and during 24-week treatment period | — |
| Change From Baseline In Lactate Dehydrogenase At Week 24 | Baseline, Week 24 | — |
| Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug | Day 1 (after dosing) through end of study (maximum exposure: 1631 days) | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The intensity of an AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Adverse Event Severity Grading Table. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module. |
Countries
Italy, United Kingdom, United States
Participant flow
Pre-assignment details
The study included a 24-Week Treatment Period and Long-term Extension (LTE) Period.
Participants by arm
| Arm | Count |
|---|---|
| Danicopan + Eculizumab Participants were administered 100, 150, or 200 mg danicopan TID in combination with eculizumab for 24 weeks. Danicopan dose may have been increased within each participant, to a maximum of 200 mg TID based on safety and efficacy. After completing the 24-Week Treatment Period, participants who received clinical benefit (as assessed by the Investigator based on improvement in hemoglobin) continued into the LTE and received the same dose of danicopan plus eculizumab treatment as that received at the end of the 24-Week Treatment Period. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 24-Week Treatment Period | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Danicopan + Eculizumab |
|---|---|
| Age, Continuous | 45.59 years STANDARD_DEVIATION 16.385 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 7 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 11 |
| other Total, other adverse events | 10 / 12 | 11 / 11 |
| serious Total, serious adverse events | 2 / 12 | 7 / 11 |
Outcome results
Primary
Change From Baseline In Hemoglobin At Week 24
Time frame: Baseline, Week 24
Population: Efficacy Population: All treated participants who received at least 4 weeks of danicopan.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan + Eculizumab | Change From Baseline In Hemoglobin At Week 24 | Baseline | 7.94 g/dL | Standard Deviation 1.425 |
| Danicopan + Eculizumab | Change From Baseline In Hemoglobin At Week 24 | Week 24 | 10.33 g/dL | Standard Deviation 1.661 |
| Danicopan + Eculizumab | Change From Baseline In Hemoglobin At Week 24 | Change from Baseline | 2.39 g/dL | Standard Deviation 1.333 |
Secondary
Change From Baseline In Lactate Dehydrogenase At Week 24
Time frame: Baseline, Week 24
Population: Efficacy Population: All treated participants who received at least 4 weeks of danicopan.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan + Eculizumab | Change From Baseline In Lactate Dehydrogenase At Week 24 | Baseline | 244.5 IU/L | Standard Deviation 74.4 |
| Danicopan + Eculizumab | Change From Baseline In Lactate Dehydrogenase At Week 24 | Week 24 | 239.5 IU/L | Standard Deviation 48.48 |
| Danicopan + Eculizumab | Change From Baseline In Lactate Dehydrogenase At Week 24 | Change from Baseline | -5.0 IU/L | Standard Deviation 48.6 |
Secondary
Number Of Participants Without RBC Transfusions During 24 Weeks Of Treatment
Time frame: Within 24 weeks prior to first dose and during 24-week treatment period
Population: Efficacy Population: All treated participants who received at least 4 weeks of danicopan.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Danicopan + Eculizumab | Number Of Participants Without RBC Transfusions During 24 Weeks Of Treatment | Within 24 Weeks Prior to First Dose | 1 Participants |
| Danicopan + Eculizumab | Number Of Participants Without RBC Transfusions During 24 Weeks Of Treatment | During 24-Week Treatment Period | 10 Participants |
Secondary
Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The intensity of an AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Adverse Event Severity Grading Table. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time frame: Day 1 (after dosing) through end of study (maximum exposure: 1631 days)
Population: Participants who received at least 1 dose of danicopan were included in the safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Danicopan + Eculizumab | Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug | Grade 3 AEs | 4 Participants |
| Danicopan + Eculizumab | Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug | Grade 4 AEs | 1 Participants |
| Danicopan + Eculizumab | Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug | AEs Leading to Discontinuation of Study Drug | 1 Participants |
| Danicopan + Eculizumab | Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug | SAEs | 2 Participants |
| LTE Period: Danicopan + Eculizumab | Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug | SAEs | 7 Participants |
| LTE Period: Danicopan + Eculizumab | Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug | Grade 3 AEs | 6 Participants |
| LTE Period: Danicopan + Eculizumab | Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug | AEs Leading to Discontinuation of Study Drug | 0 Participants |
| LTE Period: Danicopan + Eculizumab | Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug | Grade 4 AEs | 1 Participants |
Secondary
Number Of Units Of Red Blood Cells (RBCs) Transfused During 24 Weeks Of Treatment
Time frame: Within 24 weeks prior to first dose and during 24-week treatment period
Population: Efficacy Population: All treated participants who received at least 4 weeks of danicopan.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan + Eculizumab | Number Of Units Of Red Blood Cells (RBCs) Transfused During 24 Weeks Of Treatment | Within 24 Weeks Prior to First Dose | 4.5 RBC units | Standard Deviation 3.96 |
| Danicopan + Eculizumab | Number Of Units Of Red Blood Cells (RBCs) Transfused During 24 Weeks Of Treatment | During 24-Week Treatment Period | 0.2 RBC units | Standard Deviation 0.6 |