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Study of Danicopan in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Primary Purpose

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Danicopan

About this trial

This is an interventional treatment trial for Paroxysmal Nocturnal Hemoglobinuria (PNH) focused on measuring PNH, Paroxysmal, Hemoglobinuria

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Currently untreated PNH participants with PNH Type III erythrocyte and/or granulocyte clone size ≥10% and anemia (hemoglobin <12 grams/deciliter) with adequate reticulocytosis (as determined by the Investigator).
LDH ≥1.5 x the upper limit of normal.
Platelets ≥50,000/microliter without the need for platelet transfusions.
Documentation of vaccination for Neisseria meningitidis, Haemophilus influenza, and Streptococcus pneumoniae, or willingness to receive vaccinations during the screening period.
Negative pregnancy test for females prior to dosing and throughout the study.

Exclusion Criteria:

History of a major organ transplant (for example, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
Participants who had received another investigational agent within 30 days or 5 half-lives of the investigational agent prior to study entry, whichever is greater.
Participants who had received eculizumab at any dose or interval within the past 75 days before study entry.
Participants with known or suspected complement deficiency.
Participants with active bacterial infection or clinically significant active viral infection, a body temperature >38°Celsius, or other evidence of infection on Day 1, or with a history of febrile illness within 14 days prior to first study drug administration.
History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection.
Females who were pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration or participants with a female partner who was pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration.

Sites / Locations

Clinical Trial Site
Clinical Trial Site
Clinical Trial Site
Clinical Trial Site
Clinical Trial Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Danicopan

Arm Description

Starting doses of danicopan ranged from 100 to 150 milligrams (mg) three times daily (TID), with subsequent dose escalation up to 200 mg TID based on response (clinical and biochemical) for 28 days (Part 1). Participants with reductions in lactate dehydrogenase (LDH) meeting specified criteria were offered continued dosing beyond Day 28, for up to 8 additional weeks (Part 2).

Outcomes

Primary Outcome Measures

Change From Baseline In Serum LDH Levels At Day 28

Change from Baseline = Serum LDH levels on Day 28 - Baseline Serum LDH levels.

Secondary Outcome Measures

Change From Baseline In Hemoglobin (Hgb) At Days 28 And 84

Change from Baseline = Hgb levels on Days 28 or 84 - Baseline Hgb levels.

Change From Baseline In Serum LDH Levels At Day 84

Change from Baseline = Serum LDH levels on Day 84 - Baseline Serum LDH levels.

Paroxysmal Nocturnal Hemoglobinuria (PNH) Type III Red Blood Cell (RBC) Clone Size

PNH RBC, summed type III, clone size levels were assessed from Baseline to Day 28 and Day 84. The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population.

Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation

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. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

Grade 3 And Grade 4 Laboratory Abnormalities

Laboratory abnormalities were determined from laboratory measurements analyzed at the central or local laboratories, and were graded using CTCAE.

Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Post-dose (AUC0-8)

Serial blood samples were collected predose and up to 8 hours postdose.

PK: Maximum Plasma Concentration (Cmax)

Serial blood samples were collected predose and up to 12 hours postdose.

PK: Time To Maximum Concentration (Tmax)

Serial blood samples were collected predose and up to 12 hours postdose.

Complement Alternative Pathway (AP) Functional Activity

Serum AP functional activity was measured by the Wieslab functional immunoassay method.

Complement Bb

Plasma Bb was measured by enzyme-linked immunosorbent assay (ELISA).

Full Information

NCT ID

NCT03053102

First Posted

February 1, 2017

Last Updated

May 31, 2022

Sponsor

Alexion

Collaborators

Achillion, a wholly owned subsidiary of Alexion

1. Study Identification

Unique Protocol Identification Number

NCT03053102

Brief Title

Study of Danicopan in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Official Title

A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, and Pharmacokinetics of ACH-0144471 in Untreated Patients With Paroxysmal Nocturnal Hemoglobinuria

Study Type

Interventional

2. Study Status

Record Verification Date

May 2022

Overall Recruitment Status

Completed

Study Start Date

March 31, 2017 (Actual)

Primary Completion Date

November 14, 2018 (Actual)

Study Completion Date

November 14, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Alexion

Collaborators

Achillion, a wholly owned subsidiary of Alexion

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this study was to determine the safety and efficacy of ACH-0144471 (also known as danicopan and ALXN2040) in currently untreated participants with PNH.

Detailed Description

After 12 weeks of treatment, participants deriving clinical benefit were offered enrollment in a separate long-term extension study (ACH471-103, NCT03181633).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Keywords

PNH, Paroxysmal, Hemoglobinuria

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Danicopan

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Danicopan

Other Intervention Name(s)

ACH-0144471, ACH-4471, ACH4471, 4471, ALXN2040

Intervention Description

Danicopan was administered as multiple oral doses over a period of at least 28 days.

Primary Outcome Measure Information:

Title

Change From Baseline In Serum LDH Levels At Day 28

Description

Change from Baseline = Serum LDH levels on Day 28 - Baseline Serum LDH levels.

Time Frame

Baseline, Day 28

Secondary Outcome Measure Information:

Title

Change From Baseline In Hemoglobin (Hgb) At Days 28 And 84

Description

Change from Baseline = Hgb levels on Days 28 or 84 - Baseline Hgb levels.

Time Frame

Baseline, Days 28 and 84

Title

Change From Baseline In Serum LDH Levels At Day 84

Description

Change from Baseline = Serum LDH levels on Day 84 - Baseline Serum LDH levels.

Time Frame

Baseline, Day 84

Title

Paroxysmal Nocturnal Hemoglobinuria (PNH) Type III Red Blood Cell (RBC) Clone Size

Description

Time Frame

Baseline, Day 28, and Day 84

Title

Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation

Description

Time Frame

After the first dose of study medication (Day 1) through 14 days after the last dose of study drug (up to Day 104)

Title

Grade 3 And Grade 4 Laboratory Abnormalities

Description

Laboratory abnormalities were determined from laboratory measurements analyzed at the central or local laboratories, and were graded using CTCAE.

Time Frame

After the first dose of study medication (Day 1) through 14 days after the last dose of study drug (up to Day 104).

Title

Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Post-dose (AUC0-8)

Description

Serial blood samples were collected predose and up to 8 hours postdose.

Time Frame

Days 6 and 20

Title

PK: Maximum Plasma Concentration (Cmax)

Description

Serial blood samples were collected predose and up to 12 hours postdose.

Time Frame

Days 6 and 20

Title

PK: Time To Maximum Concentration (Tmax)

Description

Serial blood samples were collected predose and up to 12 hours postdose.

Time Frame

Days 6 and 20

Title

Complement Alternative Pathway (AP) Functional Activity

Description

Serum AP functional activity was measured by the Wieslab functional immunoassay method.

Time Frame

Baseline and Day 28

Title

Complement Bb

Description

Plasma Bb was measured by enzyme-linked immunosorbent assay (ELISA).

Time Frame

Baseline and Day 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Currently untreated PNH participants with PNH Type III erythrocyte and/or granulocyte clone size ≥10% and anemia (hemoglobin <12 grams/deciliter) with adequate reticulocytosis (as determined by the Investigator). LDH ≥1.5 x the upper limit of normal. Platelets ≥50,000/microliter without the need for platelet transfusions. Documentation of vaccination for Neisseria meningitidis, Haemophilus influenza, and Streptococcus pneumoniae, or willingness to receive vaccinations during the screening period. Negative pregnancy test for females prior to dosing and throughout the study. Exclusion Criteria: History of a major organ transplant (for example, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant. Participants who had received another investigational agent within 30 days or 5 half-lives of the investigational agent prior to study entry, whichever is greater. Participants who had received eculizumab at any dose or interval within the past 75 days before study entry. Participants with known or suspected complement deficiency. Participants with active bacterial infection or clinically significant active viral infection, a body temperature >38°Celsius, or other evidence of infection on Day 1, or with a history of febrile illness within 14 days prior to first study drug administration. History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection. Females who were pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration or participants with a female partner who was pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration.

Facility Information:

Facility Name

Clinical Trial Site

City

Florence

Country

Italy

Facility Name

Clinical Trial Site

City

Naples

Country

Italy

Facility Name

Clinical Trial Site

City

Seoul

Country

Korea, Republic of

Facility Name

Clinical Trial Site

City

Auckland

Country

New Zealand

Facility Name

Clinical Trial Site

City

London

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

33121236

Citation

Risitano AM, Kulasekararaj AG, Lee JW, Maciejewski JP, Notaro R, Brodsky R, Huang M, Geffner M, Browett P. Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. Haematologica. 2021 Dec 1;106(12):3188-3197. doi: 10.3324/haematol.2020.261826.

Results Reference

result

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Study of Danicopan in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

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