Clinical trial NCT04469465: Danicopan as Add-on Therapy to a C5 Inhibitor in Paroxysmal Nocturnal Hemoglobinuria (PNH) Participants Who Have Clinically Evident Extravascular Hemolysis (EVH)(ALPHA)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Extravascular Hemolysis (EVH)
Factor D inhibitor
Complement
Danicopan
C5 inhibitor
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2020-07-14
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Hgb at Week 12
timeFrame: Baseline, Week 12
Secondary outcomes:
measure: 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
timeFrame: Week 12
measure: Percentage of Participants With Transfusion Avoidance Through Week 12
timeFrame: Week 12
measure: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Absolute Reticulocyte Count at Week 12
timeFrame: Baseline, Week 12
measure: 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
timeFrame: 24 weeks prior to initiation of treatment to 24 weeks post initiation of treatment
measure: Change in Number of Transfusion Instances From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment
timeFrame: 24 weeks prior to initiation of treatment to 24 weeks post initiation of treatment
measure: Percentage of Participants With Transfusion Avoidance Through Week 24
timeFrame: 24 weeks
measure: Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment
timeFrame: 12 weeks prior to initiation of treatment to 12 weeks post initiation of treatment
measure: Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment
timeFrame: 12 weeks prior to initiation of treatment to post 12 weeks of treatment (24 weeks)
measure: Change From Baseline FACIT Fatigue Scores at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Participants With Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan
timeFrame: Week 12 to Week 24
measure: Percentage of Participants With Hgb Increase of ≥2 g/dL (≥ 20 g/L) From Baseline in the Absence of Transfusion at Week 24
timeFrame: Week 24
measure: Change From Baseline in Total and Direct Bilirubin at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Lactate Dehydrogenase at Week 12
timeFrame: Baseline, Week 12
measure: Percentage of Participants With Hgb Normalization at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Hgb Normalization at Week 24
timeFrame: Week 24
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Weston
country: United States
facility: Research Site
state: Florida
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Kalamazoo
country: United States
facility: Research Site
state: Michigan
city: New York
country: United States
facility: Research Site
state: New York
city: Dallas
country: United States
facility: Research Site
state: Texas
city: Milwaukee
country: United States
facility: Research Site
state: Wisconsin
city: Belem
country: Brazil
facility: Research Site
city: Curitiba
country: Brazil
facility: Research Site
city: Goiania
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Rio De De Janeiro
country: Brazil
facility: Research Site
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Brno
country: Czechia
facility: Research Site
city: Lille
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Pessac
country: France
facility: Research Site
city: Pierre-Benite
country: France
facility: Research Site
city: Ulm
country: Germany
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Thessaloniki
country: Greece
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Avellino
country: Italy
facility: Research Site
city: Bassano del Grappa
country: Italy
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Reggio Calabria
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Bunkyo-Ku
country: Japan
facility: Research Site
city: Fukuoka
country: Japan
facility: Research Site
city: Kashiwa-shi
country: Japan
facility: Research Site
city: Kyoto-shi
country: Japan
facility: Research Site
city: Nagakute-shi
country: Japan
facility: Research Site
city: Ogaki-shi
country: Japan
facility: Research Site
city: Osaka-shi
country: Japan
facility: Research Site
city: Osakasayama
country: Japan
facility: Research Site
city: Shibuya-ku
country: Japan
facility: Research Site
city: Tanabe-shi
country: Japan
facility: Research Site
city: Toyoake-shi
country: Japan
facility: Research Site
city: Tsukuba-shi
country: Japan
facility: Research Site
city: Daejeon
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Suwon
country: Korea, Republic of
facility: Research Site
city: Kota Kinabalu
country: Malaysia
facility: Research Site
city: Kuching
country: Malaysia
facility: Research Site
city: Miri
country: Malaysia
facility: Research Site
city: Maastricht
country: Netherlands
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Las Palmas de Gran Canaria
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Majadahonda
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Airdrie
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
Study officials:
References:
citation: Lee JW, Griffin M, Kim JS, Lee Lee LW, Piatek C, Nishimura JI, Carrillo Infante C, Jain D, Liu P, Filippov G, Sicre de Fontbrune F, Risitano A, Kulasekararaj AG; ALXN2040-PNH-301 Investigators. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023 Dec;10(12):e955-e965. doi: 10.1016/S2352-3026(23)00315-0.