Danicopan as Add-on Therapy to a C5 Inhibitor in Paroxysmal Nocturnal Hemoglobinuria (PNH) Participants Who Have Clinically Evident Extravascular Hemolysis (EVH)(ALPHA)
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| ClinicalTrials.gov Identifier: NCT04469465 |
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Recruitment Status :
Completed
First Posted : July 14, 2020
Results First Posted : July 24, 2023
Last Update Posted : February 6, 2024
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Sponsor:
Alexion Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Alexion Pharmaceuticals, Inc.
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Brief Summary:
The main objective of this study is to evaluate the efficacy of danicopan as add-on therapy to a complement component 5 (C5) inhibitor (eculizumab or ravulizumab) in participants with PNH who have clinically evident EVH.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Paroxysmal Nocturnal Hemoglobinuria | Drug: Danicopan Drug: Placebo Drug: C5 Inhibitor | Phase 3 |
This is a multiple-region, randomized, double-blind, placebo controlled, multiple-dose, study in participants with PNH who have clinically evident EVH on a C5 inhibitor (eculizumab or ravulizumab).
Participants will be randomized to receive danicopan or placebo, in a 2:1 ratio for 12 weeks (Treatment Period 1) in addition to their C5 inhibitor (eculizumab or ravulizumab) therapy. At Week 12, participants randomized to receive placebo will be switched to danicopan in addition to their C5 inhibitor for an additional 12 weeks (Treatment Period 2) and participants randomized to danicopan will continue on danicopan for an additional 12 weeks, while remaining on their ongoing C5 inhibitor therapy.
At the end of the 2 treatment periods (Week 24), participants may enter a Long-Term Extension (LTE) Period and continue to receive danicopan in addition to their C5 inhibitor therapy. The Long-Term Extension period will consist of a first year of LTE(Year1) and a second year of optional LTE(Year2).All patients will complete 72 weeks of LTE(Year 1) assessments. After Week 72 (at the end of the first year of LTE), patients have the choice to complete participation in this study or continue to the optional second year (Year2) of LTE.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 86 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 3 Study of Danicopan (ALXN2040) as Add-on Therapy to a C5 Inhibitor (Eculizumab or Ravulizumab) in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Have Clinically Evident Extravascular Hemolysis (EVH) |
| Actual Study Start Date : | December 16, 2020 |
| Actual Primary Completion Date : | June 29, 2022 |
| Actual Study Completion Date : | January 16, 2024 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Paroxysmal nocturnal hemoglobinuria
| Arm | Intervention/treatment |
|---|---|
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Experimental: Danicopan + C5 Inhibitor
Participants will receive danicopan, in addition to their C5 inhibitor therapy, for 24 weeks (12 weeks in Treatment Period 1, followed by 12 weeks in Treatment Period 2).
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Drug: Danicopan
Oral tablet
Other Name: ALXN2040 Drug: C5 Inhibitor Participants will continue to receive their ongoing C5 inhibitor (eculizumab or ravulizumab) therapy according to their usual dose and schedule. |
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Placebo Comparator: Placebo + C5 Inhibitor
Participants will receive placebo, in addition to their C5 inhibitor therapy, for 12 weeks during Treatment Period 1. At Week 12, participants randomized to receive placebo will be switched to danicopan for an additional 12 weeks (Treatment Period 2).
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Drug: Placebo
Oral tablet Drug: C5 Inhibitor Participants will continue to receive their ongoing C5 inhibitor (eculizumab or ravulizumab) therapy according to their usual dose and schedule. |
Primary Outcome Measures :
- Change From Baseline in Hgb at Week 12 [ Time Frame: Baseline, Week 12 ]Baseline was defined as the lowest Hgb value observed between and including Screening and Day 1. The least square (LS) mean and standard error (SE) were produced using mixed-effect model for repeated measures (MMRM). Hgb values collected within 4 weeks after transfusion were not included in the MMRM.
Secondary Outcome Measures :
- Percentage of Participants With Hgb Increase of ≥2 g/dL (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12 [ Time Frame: Week 12 ]The criterion was defined as ≥20 g/L increase in Hgb from Baseline to Week 12 and remaining transfusion free during the 12-Week TP1. Participants who withdrew from the study early during the 12-Week TP1 or had missing Hgb value at Week 12 were considered as not achieving the criterion.
- Percentage of Participants With Transfusion Avoidance Through Week 12 [ Time Frame: Week 12 ]Participants achieved transfusion avoidance if they remained transfusion free and did not require a transfusion as per protocol-specified guidelines from Week 1 through Week 12. Participants who discontinued study treatment early before Week 12 were considered as not achieving transfusion avoidance.
- Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12 [ Time Frame: Baseline, Week 12 ]The FACIT-Fatigue was 13-item questionnaire scored on a 5-point Likert scale (0 = not at all, 4 = very much) that assesses self-reported fatigue and its impact on daily activities and function. Total scores range from 0 to 52 with higher score indicating less fatigue better health-related quality of life. LS mean and SE were produced using MMRM.
- Change From Baseline in Absolute Reticulocyte Count at Week 12 [ Time Frame: Baseline, Week 12 ]LS mean and SE were produced using MMRM.
- Change in the Number of Red Blood Cell (RBC) Units Transfused From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment [ Time Frame: 24 weeks prior to initiation of treatment to post 24 weeks of treatment ]
- Change in Number of Transfusion Instances From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment [ Time Frame: 24 weeks prior to initiation of treatment to post 24 weeks of treatment ]
- Percentage of Participants With Transfusion Avoidance Through Week 24 [ Time Frame: Week 24 ]
- Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment [ Time Frame: 12 weeks prior to initiation of treatment to post 12 weeks of treatment ]LS mean and SE were produced using analysis of covariance (ANCOVA).
- Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment [ Time Frame: 12 weeks prior to initiation of treatment to post 12 weeks of treatment ]LS mean and SE were produced using ANCOVA.
- Change From Baseline FACIT Fatigue Scores at Week 24 [ Time Frame: Baseline, Week 24 ]
- Percentage of Participants With Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan [ Time Frame: Week 12 to Week 24 ]
- Percentage of Participants With Hgb Increase of ≥2 g/dL (≥ 20 g/L) From Baseline in the Absence of Transfusion at Week 24 [ Time Frame: Week 24 ]
- Change From Baseline in Total and Direct Bilirubin at Week 12 [ Time Frame: Baseline, Week 12 ]Baseline was defined as the last nonmissing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.
- Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at Week 12 [ Time Frame: Baseline, Week 12 ]The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. Baseline was defined as the last nonmissing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.
- Change From Baseline in C3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12 [ Time Frame: Baseline, Week 12 ]Baseline was defined as the last nonmissing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.
- Change From Baseline in Lactate Dehydrogenase at Week 12 [ Time Frame: Baseline, Week 12 ]Baseline was defined as the average of all available assessments prior to the first dose of study intervention. LS mean and SE were produced using MMRM.
- Percentage of Participants With Hgb Normalization at Week 12 [ Time Frame: Week 12 ]Hgb normalization was defined as Hgb value above lower limit of normal (LLN) reference range. For male, the LLN was 125 grams (g)/liter (L), for female, the LLN was 110 g/L. Participants with transfusions within 4 weeks prior to Week 12 were considered as not meeting Hgb normalization regardless of actual value observed at Week 12.
- Percentage of Participants With Hgb Normalization at Week 24 [ Time Frame: Week 24 ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Diagnosis of PNH
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Clinically Evident EVH defined by:
- Anemia (Hgb ≤9.5 gram/deciliter) with absolute reticulocyte count ≥120 x 10^9/liter
- Receiving an approved C5 inhibitor for at least 6 months prior to Day 1
- Platelet count ≥30,000/microliters (µL)
- Absolute neutrophil counts ≥500/μL
- Documentation of/or willingness to receive vaccinations for N. meningiditis and prophylactic antibiotics as required
Exclusion Criteria:
- History of a major organ transplant or hematopoietic stem cell transplantation (HSCT)
- Participants with known aplastic anemia or other bone marrow failure that requires HSCT or other therapies including anti-thymocyte globulin and/or immunosuppressants
- Known or suspected complement deficiency
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Laboratory abnormalities at screening, including:
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Alanine aminotransferase >2 x ULN (>3 x ULN in case of patients with documented liver iron overload defined by serum ferratin values
- 500 ng/ML)
- Direct bilirubin >2 x ULN (unless due to EVH or documented Gilbert's Syndrome)
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- Current evidence of biliary cholestasis
- Estimated glomerular filtration rate of <30 milliliters/minute/1.73 meter squared and/or are on dialysis
- Evidence of human immunodeficiency virus, hepatitis B, or active hepatitis C infection at screening
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04469465
Locations
Show 62 study locations
Sponsors and Collaborators
Alexion Pharmaceuticals, Inc.
Study Documents (Full-Text)
Documents provided by Alexion Pharmaceuticals, Inc.:
Documents provided by Alexion Pharmaceuticals, Inc.:
Study Protocol [PDF] August 8, 2022
Statistical Analysis Plan [PDF] August 10, 2022
Additional Information:
| Responsible Party: | Alexion Pharmaceuticals, Inc. |
| ClinicalTrials.gov Identifier: | NCT04469465 |
| Other Study ID Numbers: |
ALXN2040-PNH-301 |
| First Posted: | July 14, 2020 Key Record Dates |
| Results First Posted: | July 24, 2023 |
| Last Update Posted: | February 6, 2024 |
| Last Verified: | February 2024 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Alexion Pharmaceuticals, Inc.:
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Paroxysmal Nocturnal Hemoglobinuria (PNH) Extravascular Hemolysis (EVH) Factor D inhibitor |
Complement Danicopan C5 inhibitor |
Additional relevant MeSH terms:
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Hemoglobinuria Hemoglobinuria, Paroxysmal Hemolysis Proteinuria Urination Disorders Urologic Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Urogenital Diseases |
Male Urogenital Diseases Urological Manifestations Anemia, Hemolytic Anemia Hematologic Diseases Myelodysplastic Syndromes Bone Marrow Diseases Pathologic Processes |