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

• Sponsor: Alexion Pharmaceuticals (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03472885
• Collaborator: Achillion, a wholly owned subsidiary of Alexion (Industry)
• Enrollment: 12
• Locations: 5
• Arms: 4
• Anticipated Duration (Months): 62.8
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0

Study Details

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
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Four groups will be studied and enrolled sequentially.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: Sep 20, 2019
• Anticipated Study Completion Date: Jul 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 Names: 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 Names: 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 Names: 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 Names: Soliris

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

1. Number Of Units Of Red Blood Cells (RBCs) Transfused During 24 Weeks Of Treatment [From 24 weeks prior to first dose through 24 weeks of treatment]

2. Number Of Participants Without RBC Transfusions [From 24 weeks prior to first dose through 24 weeks of treatment]

3. Change From Baseline In Lactate Dehydrogenase At Week 24 [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 [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

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	Clinical Study Site	Baltimore	Maryland	United States	21287
2	Clinical Study Site	Cleveland	Ohio	United States	44195
3	Clinical Study Site	Florence		Italy
4	Clinical Study Site	Naples		Italy
5	Clinical Study Site	London		United Kingdom

Sponsors and Collaborators

• Alexion Pharmaceuticals
• Achillion, a wholly owned subsidiary of Alexion

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 19, 2019
• Statistical Analysis Plan - Mar 9, 2020

More Information

Publications

None provided.

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03472885
• Other Study ID Numbers: ACH471-101; 2016-003526-16; U1111-1209-4655
• First Posted: Mar 21, 2018
• Last Update Posted: Aug 17, 2022
• Last Verified: Aug 1, 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; Eculizumab

Study Results

Participant Flow

Arm/Group Title	Danicopan + Eculizumab
Arm/Group Description	Participants were administered 100, 150, or 200 milligrams (mg) danicopan three times daily (TID) in combination with eculizumab. Danicopan dose may have been increased within each participant, to a maximum of 200 mg TID based on safety and efficacy. The study was based on a flexible dosing design. Data from all participants were pooled for analysis.
Period Title: Overall Study
STARTED	12
Safety Population: Received at Least 1 Dose of Study Drug	12
Efficacy Population: Received Study Drug for at Least 4 Weeks	11
COMPLETED	11
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Danicopan + Eculizumab
Arm/Group Description	Participants were administered 100, 150, or 200 mg danicopan TID in combination with eculizumab. Danicopan dose may have been increased within each participant, to a maximum of 200 mg TID based on safety and efficacy. The study was based on a flexible dosing design. Data from all participants were pooled for analysis.
Overall Participants	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.60 (16.375)
Sex: Female, Male (Count of Participants)
Female	10 83.3%
Male	2 16.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	12 100%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	7 58.3%
Asian	1 8.3%
Black or African American	3 25%
Other	1 8.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline In Hemoglobin At Week 24
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Efficacy Population: All treated participants who receive at least 4 weeks of danicopan.

Arm/Group Title	Danicopan + Eculizumab
Arm/Group Description	Participants were administered 100, 150, or 200 mg danicopan TID in combination with eculizumab. Danicopan dose may have been increased within each participant, to a maximum of 200 mg TID based on safety and efficacy. The study was based on a flexible dosing design. Data from all participants were pooled for analysis.
Measure Participants	11
Baseline	7.94 (1.425)
Week 24	10.33 (1.661)
Change from Baseline	2.39 (1.333)

2. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

Efficacy Population: All treated participants who receive at least 4 weeks of danicopan.

Arm/Group Title	Danicopan + Eculizumab
Arm/Group Description	Participants were administered 100, 150, or 200 mg danicopan TID in combination with eculizumab. Danicopan dose may have been increased within each participant, to a maximum of 200 mg TID based on safety and efficacy. The study was based on a flexible dosing design. Data from all participants were pooled for analysis.
Measure Participants	11
Within 24 Weeks Prior to First Dose	4.5 (3.96)
During 24-Week Treatment Period	0.2 (0.60)

3. Secondary Outcome

Title	Number Of Participants Without RBC Transfusions
Time Frame	From 24 weeks prior to first dose through 24 weeks of treatment

Outcome Measure Data

Analysis Population Description

Efficacy Population: All treated participants who receive at least 4 weeks of danicopan.

Arm/Group Title	Danicopan + Eculizumab
Arm/Group Description	Participants were administered 100, 150, or 200 mg danicopan TID in combination with eculizumab. Danicopan dose may have been increased within each participant, to a maximum of 200 mg TID based on safety and efficacy. The study was based on a flexible dosing design. Data from all participants were pooled for analysis.
Measure Participants	11
Within 24 Weeks Prior to First Dose	1 8.3%
During 24-Week Treatment Period	10 83.3%

4. Secondary Outcome

Title	Change From Baseline In Lactate Dehydrogenase At Week 24
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Efficacy Population: All treated participants who receive at least 4 weeks of danicopan.

Arm/Group Title	Danicopan + Eculizumab
Arm/Group Description	Participants were administered 100, 150, or 200 mg danicopan TID in combination with eculizumab. Danicopan dose may have been increased within each participant, to a maximum of 200 mg TID based on safety and efficacy. The study was based on a flexible dosing design. Data from all participants were pooled for analysis.
Measure Participants	11
Baseline	244.5 (74.40)
Week 24	239.5 (48.48)
Change from Baseline	-5.0 (48.60)

5. Secondary Outcome

Title	Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Adverse Events (AEs), And Events Leading To Discontinuation Of Study Drug
Description	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.
Time Frame	Day 1 (after dosing) through 24 weeks

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of danicopan were included in the safety assessment.

Arm/Group Title	Danicopan + Eculizumab
Arm/Group Description	Participants were administered 100, 150, or 200 mg danicopan TID in combination with eculizumab. Danicopan dose may have been increased within each participant, to a maximum of 200 mg TID based on safety and efficacy. The study was based on a flexible dosing design. Data from all participants were pooled for analysis.
Measure Participants	12
SAEs	2 16.7%
Grade 3 AEs	3 25%
Grade 4 AEs	1 8.3%
AEs Leading to Discontinuation of Study Drug	1 8.3%

Adverse Events

Time Frame	Day 1 (after dosing) through 24 weeks
Arm/Group Title	Danicopan + Eculizumab
Arm/Group Description	Participants were administered 100, 150, or 200 mg danicopan TID in combination with eculizumab. Danicopan dose may have been increased within each participant, to a maximum of 200 mg TID based on safety and efficacy. The study was based on a flexible dosing design. Data from all participants were pooled for analysis.
All Cause Mortality
	Danicopan + Eculizumab
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Serious Adverse Events
	Danicopan + Eculizumab
	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)
Infections and infestations
Pneumonia	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Pulmonary oedema	1/12 (8.3%)
Other (Not Including Serious) Adverse Events
	Danicopan + Eculizumab
	Affected / at Risk (%)	# Events
Total	10/12 (83.3%)
Blood and lymphatic system disorders
Anaemia	1/12 (8.3%)
Neutropenia	1/12 (8.3%)
Cardiac disorders
Palpitations	1/12 (8.3%)
Sinus tachycardia	1/12 (8.3%)
Eye disorders
Periorbital swelling	1/12 (8.3%)
Gastrointestinal disorders
Abdominal pain	2/12 (16.7%)
Diarrhoea	1/12 (8.3%)
Gastrointestinal disorder	1/12 (8.3%)
Gastrooesophageal reflux disease	1/12 (8.3%)
Lip swelling	1/12 (8.3%)
Nausea	2/12 (16.7%)
Tongue ulceration	1/12 (8.3%)
General disorders
Chest pain	1/12 (8.3%)
Fatigue	2/12 (16.7%)
Feeling abnormal	1/12 (8.3%)
Pyrexia	1/12 (8.3%)
Thirst	1/12 (8.3%)
Vaccination site pain	2/12 (16.7%)
Immune system disorders
Seasonal allergy	1/12 (8.3%)
Infections and infestations
Nasopharyngitis	3/12 (25%)
Upper respiratory tract infection	1/12 (8.3%)
Injury, poisoning and procedural complications
Contusion	2/12 (16.7%)
Investigations
Alanine aminotransferase increased	2/12 (16.7%)
Bilirubin conjugated increased	1/12 (8.3%)
Blood bilirubin increased	1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/12 (16.7%)
Musculoskeletal pain	1/12 (8.3%)
Neck pain	1/12 (8.3%)
Pain in extremity	2/12 (16.7%)
Nervous system disorders
Dizziness	1/12 (8.3%)
Headache	3/12 (25%)
Psychiatric disorders
Anxiety	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Cough	3/12 (25%)
Dysphonia	1/12 (8.3%)
Nasal congestion	1/12 (8.3%)
Oropharyngeal pain	2/12 (16.7%)
Sinus congestion	1/12 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.