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

Alexion Pharmaceuticals, Inc.86 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Paroxysmal Nocturnal Hemoglobinuria

Interventions

DanicopanDRUG

Oral tablet

PlaceboDRUG

Oral tablet

C5 InhibitorDRUG

Participants will continue to receive their ongoing C5 inhibitor (eculizumab or ravulizumab) therapy according to their usual dose and schedule.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (62)

Outcomes

Primary Outcomes

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.

Time frame: Baseline, Week 12

Secondary Outcomes

Percentage of Participants With Hgb Increase of ≥2 Grams/Deciliter (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.

Time frame: 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.

Time frame: 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 and better health-related quality of life. LS mean and SE were produced using MMRM.

Time frame: Baseline, Week 12

Change From Baseline in Absolute Reticulocyte Count at Week 12

LS mean and SE were produced using MMRM.

Data from ClinicalTrials.gov

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Research Site

Los Angeles, California, United States

Research Site

Weston, Florida, United States

Research Site

Chicago, Illinois, United States

Research Site

Kalamazoo, Michigan, United States

Research Site

New York, New York, United States

Research Site

Dallas, Texas, United States

Research Site

Milwaukee, Wisconsin, United States

Research Site

Belém, Brazil

Research Site

Curitiba, Brazil

Research Site

Goiânia, Brazil

...and 52 more locations

Time frame: 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

Time frame: 24 weeks prior to initiation of treatment to 24 weeks post initiation 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 24 weeks post initiation of treatment

Percentage of Participants With Transfusion Avoidance Through Week 24

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 24. Participants who discontinued study treatment early before Week 24 were considered as not achieving transfusion avoidance.

Time frame: 24 weeks

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).

Time frame: 12 weeks prior to initiation of treatment to 12 weeks post initiation 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.

Time frame: 12 weeks prior to initiation of treatment to post 12 weeks of treatment (24 weeks)

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

The criterion was defined as Hgb stabilization avoidance of a \>1 g/dL (\>10 g/L) decrease in Hgb level at Week 24 from Week 12. Participants with transfusions within 4 weeks prior to Week 24 were considered as not meeting Hgb stabilization regardless of the actual value observed at Week 24.

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

The criterion was defined as ≥20 g/L increase in Hgb from Baseline to Week 24 and remaining transfusion free during the 12-Week TP2. Participants who withdrew from the study early during the 12-Week TP2 or had missing Hgb value at Week 24 were considered as not achieving the criterion.

Time frame: Week 24

Change From Baseline in Total and Direct Bilirubin at Week 12

Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.

Time frame: 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 non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.

Time frame: Baseline, Week 12

Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12

Baseline was defined as the last non-missing value prior to first dose of study intervention. LS mean and SE were produced using MMRM.

Time frame: 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.

Time frame: 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 g/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.

Time frame: Week 12

Percentage of Participants With Hgb Normalization at Week 24

Hgb normalization was defined as Hgb value above LLN reference range. For male, the LLN was 125 g/L, for female, the LLN was 110 g/L. Participants with transfusions within 4 weeks prior to Week 24 were considered as not meeting Hgb normalization regardless of actual value observed at Week 24.

Time frame: Week 24