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

Paroxysmal Nocturnal Hemoglobinuria Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04469465
• Other study ID #: ALXN2040-PNH-301
• Status: Completed
• Phase: Phase 3
• Start date: December 16, 2020
• Est. completion date: January 16, 2024

Study information

• Verified date: February 2024
• Source: Alexion Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 86
• Est. completion date: January 16, 2024
• Est. primary completion date: June 29, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hemoglobinuria
• Hemoglobinuria, Paroxysmal
• Hemolysis
• Paroxysmal Nocturnal Hemoglobinuria

Intervention

Drug:
• Danicopan
Oral tablet
• Placebo
Oral tablet
• C5 Inhibitor
Participants will continue to receive their ongoing C5 inhibitor (eculizumab or ravulizumab) therapy according to their usual dose and schedule.

Locations

Country	Name	City	State
Brazil	Research Site	Belem
Brazil	Research Site	Curitiba
Brazil	Research Site	Goiania
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Rio De De Janeiro
Canada	Research Site	Toronto	Ontario
Czechia	Research Site	Brno
France	Research Site	Lille
France	Research Site	Paris
France	Research Site	Pessac
France	Research Site	Pierre Benite Cedex
Germany	Research Site	Ulm
Greece	Research Site	Athens
Greece	Research Site	Thessaloniki
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Italy	Research Site	Avellino
Italy	Research Site	Bassano del Grappa
Italy	Research Site	Firenze
Italy	Research Site	Milano
Italy	Research Site	Reggio Calabria
Italy	Research Site	Roma
Japan	Research Site	Bunkyo-Ku
Japan	Research Site	Fukuoka
Japan	Research Site	Kashiwa-shi
Japan	Research Site	Kyoto-shi
Japan	Research Site	Nagakute-shi
Japan	Research Site	Ogaki-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Osakasayama
Japan	Research Site	Shibuya-ku
Japan	Research Site	Tanabe-shi
Japan	Research Site	Toyoake-shi
Japan	Research Site	Tsukuba-shi
Korea, Republic of	Research Site	Daejeon
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Suwon
Malaysia	Research Site	Kota Kinabalu
Malaysia	Research Site	Kuching
Malaysia	Research Site	Miri
Netherlands	Research Site	Maastricht
Poland	Research Site	Gdansk
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Las Palmas de Gran Canaria
Spain	Research Site	Madrid
Spain	Research Site	Majadahonda
Spain	Research Site	Sevilla
Taiwan	Research Site	Taipei
Thailand	Research Site	Bangkok
United Kingdom	Research Site	Airdrie
United Kingdom	Research Site	Leeds
United Kingdom	Research Site	London
United States	Research Site	Chicago	Illinois
United States	Research Site	Dallas	Texas
United States	Research Site	Kalamazoo	Michigan
United States	Research Site	Los Angeles	California
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	New York	New York
United States	Research Site	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Alexion Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Czechia,  France,  Germany,  Greece,  Israel,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Netherlands,  Poland,  Spain,  Taiwan,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Change From Baseline in Absolute Reticulocyte Count at Week 12	LS mean and SE were produced using MMRM.	Baseline, Week 12
Secondary	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
Secondary	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
Secondary	Percentage of Participants With Transfusion Avoidance Through Week 24		Week 24
Secondary	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
Secondary	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
Secondary	Change From Baseline FACIT Fatigue Scores at Week 24		Baseline, Week 24
Secondary	Percentage of Participants With Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan		Week 12 to Week 24
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Percentage of Participants With Hgb Normalization at Week 24		Week 24

External Links

•   A Phase 2 Open-Label Study of Danicopan (ACH-0144471) in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to Eculizumab Monotherapy
•   Danicopan (ACH-4471) in Untreated Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Phase 2, Open-label, Proof of Concept Study of the Oral, Small Molecule Factor D Inhibitor
•   Mechanistic Evaluation of Efficacy Using Biomarkers of the Oral, Small Molecule Factor D Inhibitor, Danicopan (ACH-4471), in Untreated Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)