Study of Danicopan in Participants With Paroxysmal Nocturnal Hemoglobinuria With Inadequate Response to Eculizumab (PNH)

• ClinicalTrials.gov Identifier: NCT03472885
• Recruitment Status: Active, not recruiting
• First Posted: March 21, 2018
• Results First Posted: June 25, 2021
• Last Update Posted: August 17, 2022
• Sponsor: Alexion Pharmaceuticals
• Collaborator: Achillion, a wholly owned subsidiary of Alexion
• Information provided by (Responsible Party): Alexion Pharmaceuticals

Study Description

Brief Summary:

To determine the effectiveness of ACH-0144471 (also known as danicopan and ALXN2040) in improving anemia when given with eculizumab for 24 weeks in participants with PNH. Danicopan dose may be increased within each participant, to a maximum of 200 milligrams (mg) three times daily (TID) based on safety and efficacy at protocol-specified time points.

Condition or disease	Intervention/treatment	Phase
Paroxysmal Nocturnal Hemoglobinuria (PNH)	Drug: Danicopan; Drug: Eculizumab	Phase 2

Detailed Description:

The purpose of this study is to determine the effectiveness of danicopan in improving anemia, as measured by increased blood hemoglobin, when given with eculizumab (a drug commonly used for treatment of PNH) for 24 weeks in participants with PNH.

The 24-week treatment period was followed by a long-term extension phase (ongoing). In the extension phase, participants receive the same danicopan dose plus eculizumab as they were receiving at the end of 24-week treatment phase.

Results are reported for the 24-week treatment period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Four groups will be studied and enrolled sequentially.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Open-label Study of ACH-0144471 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to Eculizumab Monotherapy
• Actual Study Start Date: May 8, 2018
• Actual Primary Completion Date: September 20, 2019
• Estimated Study Completion Date: July 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group 1: 100 mg Danicopan TID + Eculizumab; Starting dose of 100 mg danicopan TID in combination with eculizumab.	Drug: Danicopan; Participants received a daily oral dose of danicopan TID during the treatment period.; Drug: Eculizumab; Participants received intravenous eculizumab administered at the participant's usual dose and schedule.; Other Name: Soliris
Experimental: Group 2: Initial dose 100 or 150 mg Danicopan TID + Eculizumab; Starting dose of 100 or 150 mg danicopan TID in combination with eculizumab.	Drug: Danicopan; Participants received a daily oral dose of danicopan TID during the treatment period.; Drug: Eculizumab; Participants received intravenous eculizumab administered at the participant's usual dose and schedule.; Other Name: Soliris
Experimental: Group 3: Initial dose of 100, 150, or 200 mg Danicopan TID + Eculizumab; Starting dose of 100, 150, or 200 mg danicopan TID in combination with eculizumab.	Drug: Danicopan; Participants received a daily oral dose of danicopan TID during the treatment period.; Drug: Eculizumab; Participants received intravenous eculizumab administered at the participant's usual dose and schedule.; Other Name: Soliris
Experimental: Group 4: Optimal Dose of Danicopan TID + Eculizumab; Optimal dose (starting dose of either 100, 150, or 200 mg, as determined from Groups 1-3) of danicopan TID in combination with eculizumab.	Drug: Danicopan; Participants received a daily oral dose of danicopan TID during the treatment period.; Drug: Eculizumab; Participants received intravenous eculizumab administered at the participant's usual dose and schedule.; Other Name: Soliris

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline In Hemoglobin At Week 24 [ Time Frame: Baseline, Week 24 ]

Secondary Outcome Measures :

1. Number Of Units Of Red Blood Cells (RBCs) Transfused During 24 Weeks Of Treatment [ Time Frame: From 24 weeks prior to first dose through 24 weeks of treatment ]
2. Number Of Participants Without RBC Transfusions [ Time Frame: From 24 weeks prior to first dose through 24 weeks of treatment ]
3. Change From Baseline In Lactate Dehydrogenase At Week 24 [ Time Frame: Baseline, Week 24 ]
4. Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug [ Time Frame: Day 1 (after dosing) through 24 weeks ]
   An AE was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The intensity of an AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Adverse Event Severity Grading Table. Laboratory abnormalities were determined from laboratory measurements analyzed at the central or local laboratories, and were graded using CTCAE. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• Diagnosed with PNH
• Have received at least one red blood cell transfusion within last 12 weeks
• Anemia with adequate reticulocytosis
• Must be on a stable regimen of eculizumab
• Platelet count ≥ 40,000/microliter without the need for platelet transfusions
• Documentation of vaccination for Neisseria meningitidis, Haemophilus influenza, and Streptococcus pneumoniae or willingness to receive vaccinations based on local guidelines
• Willingness to receive antibiotic prophylaxis
• Female participants must use highly effective birth control to prevent pregnancy during the clinical trial and for 30 days after their last dose of study drug
• Male participants must use a highly effective birth control with a female partner to prevent pregnancy during the clinical trial and for 90 days after the last dose of study drug

Key Exclusion Criteria:

• Current evidence of bone marrow failure or aplastic anemia requiring treatment
• History of a major organ transplant or hematopoietic stem cell/marrow transplant
• Received another investigational agent within 30 days or 5 half-lives of the investigational agent prior to study entry, whichever is greater
• Documented C5 complement protein mutations
• Known or suspected complement deficiency
• Contraindication to any of the required vaccinations
• Active bacterial infection or clinically significant active viral infection, a body temperature >38°C, or other evidence of infection
• History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection
• History of hypersensitivity reactions to commonly used antibacterial agents

Note: Additional inclusion/exclusion criteria may apply, per protocol.

Contacts and Locations

Locations

United States, Maryland

Clinical Study Site

Baltimore, Maryland, United States, 21287

United States, Ohio

Clinical Study Site

Cleveland, Ohio, United States, 44195

Italy

Clinical Study Site

Florence, Italy

Clinical Study Site

Naples, Italy

United Kingdom

Clinical Study Site

London, United Kingdom

Sponsors and Collaborators

Alexion Pharmaceuticals

Achillion, a wholly owned subsidiary of Alexion

  Study Documents (Full-Text)

Documents provided by Alexion Pharmaceuticals:

Study Protocol  [PDF] February 19, 2019

Statistical Analysis Plan  [PDF] March 9, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kulasekararaj AG, Risitano AM, Maciejewski JP, Notaro R, Browett P, Lee JW, Huang M, Geffner M, Brodsky RA. Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab. Blood. 2021 Nov 18;138(20):1928-1938. doi: 10.1182/blood.2021011388.

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03472885
• Other Study ID Numbers: ACH471-101; 2016-003526-16 ( EudraCT Number ); U1111-1209-4655 ( Other Identifier: UTN )
• First Posted: March 21, 2018
• Results First Posted: June 25, 2021
• Last Update Posted: August 17, 2022
• Last Verified: August 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Alexion Pharmaceuticals:

PNH; Paroxysmal Nocturnal Hemoglobinuria; ACH-0144471; Danicopan; Eculizumab; ALXN2040

Additional relevant MeSH terms:

Hemoglobinuria; Hemoglobinuria, Paroxysmal; Proteinuria; Urination Disorders; Urologic Diseases; Urological Manifestations; Anemia, Hemolytic; Anemia; Hematologic Diseases; Myelodysplastic Syndromes; Bone Marrow Diseases; Eculizumab; Complement Inactivating Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs