Danicopan as Add-on Therapy to a C5 Inhibitor in Paroxysmal Nocturnal Hemoglobinuria (PNH) Participants Who Have Clinically Evident Extravascular Hemolysis (EVH)(ALPHA)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Drug: Danicopan
* Drug: Placebo
* Drug: C5 Inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of PNH 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 Laboratory abnormalities at screening, including: 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) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Danicopan + C5 Inhibitor<br>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). | Drug: Danicopan<br>* Oral tablet<br>* Other names: ALXN2040;Drug: C5 Inhibitor<br>* Participants will continue to receive their ongoing C5 inhibitor (eculizumab or ravulizumab) therapy according to their usual dose and schedule.<br>|
| Placebo Comparator: Placebo + C5 Inhibitor<br>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). | Drug: Placebo<br>* Oral tablet<br>Drug: C5 Inhibitor<br>* Participants will continue to receive their ongoing C5 inhibitor (eculizumab or ravulizumab) therapy according to their usual dose and schedule.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hgb at 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. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Hgb Increase of ≥2 g/dL (≥20 g/L) From Baseline in the Absence of Transfusion at 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. | Week 12 | 
| Percentage of Participants With Transfusion Avoidance Through 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. | Week 12 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at 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. | Baseline, Week 12 | 
| Change From Baseline in Absolute Reticulocyte Count at Week 12 | LS mean and SE were produced using MMRM. | Baseline, Week 12 | 
| 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 |  | 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 |  | 24 weeks prior to initiation of treatment to post 24 weeks of treatment | 
| Percentage of Participants With Transfusion Avoidance Through Week 24 |  | Week 24 | 
| Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | LS mean and SE were produced using analysis of covariance (ANCOVA). | 12 weeks prior to initiation of treatment to post 12 weeks of treatment | 
| Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment | LS mean and SE were produced using ANCOVA. | 12 weeks prior to initiation of treatment to post 12 weeks of treatment | 
| Change From Baseline FACIT Fatigue Scores at Week 24 |  | Baseline, Week 24 | 
| Percentage of Participants With Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan |  | 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 |  | Week 24 | 
| Change From Baseline in Total and Direct Bilirubin at 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. | Baseline, Week 12 | 
| Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at 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. | Baseline, Week 12 | 
| Change From Baseline in C3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at 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. | Baseline, Week 12 | 
| Change From Baseline in Lactate Dehydrogenase at 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. | Baseline, Week 12 | 
| Percentage of Participants With Hgb Normalization at 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. | Week 12 | 
| Percentage of Participants With Hgb Normalization at Week 24 |  | Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paroxysmal Nocturnal Hemoglobinuria (PNH), Extravascular Hemolysis (EVH), Factor D inhibitor, Complement, Danicopan, C5 inhibitor