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A Proof-of-Mechanism Study to Determine the Effect of Danicopan on C3 Levels in Participants With C3G or IC-MPGN

Primary Purpose

C3 Glomerulonephritis, Dense Deposit Disease, C3 Glomerulopathy

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Danicopan

About this trial

This is an interventional basic science trial for C3 Glomerulonephritis focused on measuring factor D, FD, alternative pathway, complement mediated disease, idiopathic MPGN, MPGN Type I, MPGN Type II, MPGN Type III, Primary MPGN, MCGN, Mesangiocapillary Glomerulonephritis, C3 Glomerulopathy, C3G, Membranoproliferative Glomerulonephritis, C3GN, Dense Deposit Disease, DDD

Eligibility Criteria

16 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

Must have had clinical diagnosis of C3G (C3 glomerulonephritis or dense deposit disease, the 2 types of C3G) or idiopathic IC-MPGN by renal biopsy for at least 3 months prior to dosing, with the pathologic diagnosis verified by a review of the renal biopsy by the study central pathologist
C3 must have been <50% of the lower limit of normal
C4 complement protein (C4) must have been >90% of the lower limit of normal
Must have been willing to comply with study-specific vaccination requirements for Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis strains A, C, W, and Y
Negative pregnancy test for females prior to dosing and throughout the study

Key Exclusion Criteria:

History of a major organ transplant (for example, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant. Individuals receiving renal replacement therapy were also excluded
Evidence of monoclonal gammopathy of unclear significance, infections, malignancy, autoimmune diseases, or other conditions to which C3G or IC-MPGN may have been secondary
Estimated glomerular filtration rate (using Modification of Diet in Renal Disease equation) <45 milliliters/minute/1.73 square meters at the time of Screening or at any time over the preceding 4 weeks
Receipt of eculizumab at any dose or interval within the past 75 days prior to dosing
Use of tacrolimus or cyclosporine within 2 weeks of the first dose of danicopan
History of febrile illness, a body temperature >38°Celsius, or other evidence of a clinically significant active infection, within 14 days prior to 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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Group 1: Danicopan 100 mg TID (Sentinel)

Group 2: Danicopan up to 200 mg TID

Arm Description

All participants received 100 milligrams (mg) of danicopan three times per day (TID) during the Treatment Period.

All participants received not more than 200 mg of danicopan TID depending on the available safety, pharmacokinetic, and pharmacodynamic data from Group 1 (Sentinel) during the Treatment Period.

Outcomes

Primary Outcome Measures

Change From Baseline In Serum C3 Complement Protein (C3) Levels On Day 15

Serum C3 levels were measured by conventional Roche immunoturbidimetric assay method. Change from Baseline = Serum C3 levels on Day 15 - Baseline Serum C3 levels

Change From Baseline In Plasma Intact C3 Level On Day 15

Plasma Intact C3 level were measured by a novel multiplex assay method. Change from Baseline = Plasma Intact C3 levels on Day 15 - Baseline Plasma Intact C3 levels

Secondary Outcome Measures

Change From Baseline In Total Complement Classical Pathway (CP) Activity On Day 14

CP activity was measured in serum by the DiaSorin Complement Activation Enzyme (CAE) functional immunoassay method, which measures terminal complement complex formation following activation. Results are expressed in CAE units which are calculated relative to previously established CAE activity of a positive control serum. Change from Baseline = Total Complement CP Activity on Day 14 - Baseline Total Complement CP Activity

Change From Baseline In Total Complement Alternative Pathway (AP) Functional Activity (AP Wieslab) On Day 15

AP functional activity was measured in serum by the Wieslab functional immunoassay method, which measures terminal complement complex (TCC) formation following AP-specific activation. Results are expressed as percent TCC production relative to a positive control serum. Change from Baseline = Total Complement AP Functional Activity on Day 15 - Baseline Total Complement AP Functional Activity

Time To Achieving Peak Serum C3 Levels

Serial serum samples were collected on Days 1, 7, and 14.

Number Of Participants With 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.

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

Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.

PK: Maximum Plasma Concentration (Cmax)

Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.

PK: Time To Maximum Concentration (Tmax)

Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.

Change From Baseline In Bb Fragment Of Complement Factor B (Bb) At Day 15

Plasma Bb was measured by enzyme-linked immunosorbent assay (ELISA). Change from Baseline = Complement Bb on Day 15 - Baseline

Change From Baseline In Soluble Terminal Complement Complex (sC5b-9) At Day 15

Plasma sC5b-9 was measured by ELISA. Change from Baseline = sC5b-9 on Day 15 - Baseline sC5b-9

Full Information

NCT ID

NCT03124368

First Posted

April 12, 2017

Last Updated

October 7, 2021

Sponsor

Alexion

Collaborators

Achillion, a wholly owned subsidiary of Alexion

1. Study Identification

Unique Protocol Identification Number

NCT03124368

Brief Title

A Proof-of-Mechanism Study to Determine the Effect of Danicopan on C3 Levels in Participants With C3G or IC-MPGN

Official Title

A Phase 2a Proof-of-Mechanism, Open-Label Study to Determine the Effect of ACH-0144471 on C3 Levels in Participants With Low C3 Levels Due to Either C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN)

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Completed

Study Start Date

August 9, 2017 (Actual)

Primary Completion Date

December 21, 2018 (Actual)

Study Completion Date

January 9, 2019 (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

5. Study Description

Brief Summary

The primary objective of this study was to determine whether ACH-0144471 (also known as danicopan and ALXN2040) increases blood C3 complement protein (C3) levels in participants with low C3 levels due to either C3G or IC-MPGN.

6. Conditions and Keywords

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

C3 Glomerulonephritis, Dense Deposit Disease, C3 Glomerulopathy, Immune Complex Mediated Membranoproliferative Glomerulonephritis, Membranoproliferative Glomerulonephritis Types I, II, and III

Keywords

factor D, FD, alternative pathway, complement mediated disease, idiopathic MPGN, MPGN Type I, MPGN Type II, MPGN Type III, Primary MPGN, MCGN, Mesangiocapillary Glomerulonephritis, C3 Glomerulopathy, C3G, Membranoproliferative Glomerulonephritis, C3GN, Dense Deposit Disease, DDD

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group 1: Danicopan 100 mg TID (Sentinel)

Arm Type

Experimental

Arm Description

All participants received 100 milligrams (mg) of danicopan three times per day (TID) during the Treatment Period.

Arm Title

Group 2: Danicopan up to 200 mg TID

Arm Type

Experimental

Arm Description

All participants received not more than 200 mg of danicopan TID depending on the available safety, pharmacokinetic, and pharmacodynamic data from Group 1 (Sentinel) during the Treatment Period.

Intervention Type

Drug

Intervention Name(s)

Danicopan

Other Intervention Name(s)

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

Intervention Description

Participants received study drug for 14 days (Treatment Period), followed by a taper over the next 7 days (Taper Period).

Primary Outcome Measure Information:

Title

Change From Baseline In Serum C3 Complement Protein (C3) Levels On Day 15

Description

Serum C3 levels were measured by conventional Roche immunoturbidimetric assay method. Change from Baseline = Serum C3 levels on Day 15 - Baseline Serum C3 levels

Time Frame

Baseline, Day 15

Title

Change From Baseline In Plasma Intact C3 Level On Day 15

Description

Plasma Intact C3 level were measured by a novel multiplex assay method. Change from Baseline = Plasma Intact C3 levels on Day 15 - Baseline Plasma Intact C3 levels

Time Frame

Baseline, Day 15

Secondary Outcome Measure Information:

Title

Change From Baseline In Total Complement Classical Pathway (CP) Activity On Day 14

Description

Time Frame

Baseline, Day 14

Title

Change From Baseline In Total Complement Alternative Pathway (AP) Functional Activity (AP Wieslab) On Day 15

Description

Time Frame

Baseline, Day 15

Title

Time To Achieving Peak Serum C3 Levels

Description

Serial serum samples were collected on Days 1, 7, and 14.

Time Frame

From The First Day Of Dosing through Day 14

Title

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

Description

Time Frame

Up to Day 49

Title

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

Description

Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.

Time Frame

Days 1 and 7

Title

PK: Maximum Plasma Concentration (Cmax)

Description

Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.

Time Frame

Days 1 and 7

Title

PK: Time To Maximum Concentration (Tmax)

Description

Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.

Time Frame

Days 1 and 7

Title

Change From Baseline In Bb Fragment Of Complement Factor B (Bb) At Day 15

Description

Plasma Bb was measured by enzyme-linked immunosorbent assay (ELISA). Change from Baseline = Complement Bb on Day 15 - Baseline

Time Frame

Baseline, Day 15

Title

Change From Baseline In Soluble Terminal Complement Complex (sC5b-9) At Day 15

Description

Plasma sC5b-9 was measured by ELISA. Change from Baseline = sC5b-9 on Day 15 - Baseline sC5b-9

Time Frame

Baseline, Day 15

10. Eligibility

Sex

All

Minimum Age & Unit of Time

16 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Key Inclusion Criteria: Must have had clinical diagnosis of C3G (C3 glomerulonephritis or dense deposit disease, the 2 types of C3G) or idiopathic IC-MPGN by renal biopsy for at least 3 months prior to dosing, with the pathologic diagnosis verified by a review of the renal biopsy by the study central pathologist C3 must have been <50% of the lower limit of normal C4 complement protein (C4) must have been >90% of the lower limit of normal Must have been willing to comply with study-specific vaccination requirements for Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis strains A, C, W, and Y Negative pregnancy test for females prior to dosing and throughout the study Key Exclusion Criteria: History of a major organ transplant (for example, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant. Individuals receiving renal replacement therapy were also excluded Evidence of monoclonal gammopathy of unclear significance, infections, malignancy, autoimmune diseases, or other conditions to which C3G or IC-MPGN may have been secondary Estimated glomerular filtration rate (using Modification of Diet in Renal Disease equation) <45 milliliters/minute/1.73 square meters at the time of Screening or at any time over the preceding 4 weeks Receipt of eculizumab at any dose or interval within the past 75 days prior to dosing Use of tacrolimus or cyclosporine within 2 weeks of the first dose of danicopan History of febrile illness, a body temperature >38°Celsius, or other evidence of a clinically significant active infection, within 14 days prior to 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

Melbourne

Country

Australia

Facility Name

Clinical Trial Site

City

Antwerpen

Country

Belgium

Facility Name

Clinical Trial Site

City

Leiden

Country

Netherlands

12. IPD Sharing Statement

Learn more about this trial

A Proof-of-Mechanism Study to Determine the Effect of Danicopan on C3 Levels in Participants With C3G or IC-MPGN

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