A Proof of Concept Study for a 12 Month Treatment in Patients With C3G or IC-MPGN Treated With ACH-0144471
Primary Purpose
C3 Glomerulonephritis, C3 Glomerulopathy, Immune Complex Membranoproliferative Glomerulonephritis
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Danicopan
Sponsored by
About this trial
This is an interventional treatment trial for C3 Glomerulonephritis focused on measuring factor D, fD, alternative pathway, complement mediated disease, C3GN, DDD, idiopathic MPGN, MPGN Type I, MPGN Type II, MPGN Type III, Primary MPGN, MCGN, Mesangiocapillary Glomerulonephritis
Eligibility Criteria
Key Inclusion Criteria:
- At least 12 years of age
- Completion of the ACH471-201 clinical study OR diagnosed with biopsy-confirmed primary C3G or IC-MPGN
- If a pre-treatment biopsy is obtained, or if a historical biopsy is available for review, it must have no more than 50% global fibrosis and no more than 50% of glomeruli with cellular crescents
- Clinical evidence of ongoing disease based on significant proteinuria (defined as ≥500 mg/day of protein in a 24-hour urine) attributable to C3G disease or IC-MPGN in the opinion of the principal investigator (PI), and present prior to study entry and confirmed during Screening
- If on corticosteroids, anti-hypertensive medications, anti-proteinuric medications (for example, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), or mycophenolate mofetil, must be on a stable dose for at least 2 weeks prior to screening
- Female participants must use an acceptable method birth control to prevent pregnancy during the clinical study and for 30 days after the last dose of study medication
- Male participants must use highly effective birth control with a female partner to prevent pregnancy during the clinical study and for 90 days after the last dose of study medication
- Must be up-to-date on routine vaccinations, or willing to be brought up-to-date, based on local guidelines
- Must have access to emergency medical care
Key Exclusion Criteria
- Have a history of a major organ transplant (for example, heart, lung, kidney, or liver) or hematopoietic stem cell/marrow transplant
- Have a history or presence of any clinically relevant co-morbidities that would make the participant inappropriate for the study (for example, a comorbidity that is likely to result in deterioration of the participant's condition, affect the participant's safety during the study, or confound the results of the study), in the opinion of the PI
- Have an eGFR <30 milliliter/minute/1.73 m^2 at the time of screening or at any time over the preceding 4 weeks
- Is a renal transplant recipient or receiving renal replacement therapy
- Have other renal diseases that would interfere with the interpretation of the study
- Have evidence of monoclonal gammopathy of unclear significance, infections, malignancy, autoimmune diseases, or other conditions to which C3G or IC-MPGN is secondary
- Have been diagnosed with or show evidence of hepatobiliary cholestasis
- Females who are pregnant, nursing, or planning to become pregnant during the study or within 90 days of ACH-0144471 administration or participants with a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days of ACH-0144471 administration
- Have a history of febrile illness, a body temperature >38°Celsius, or other evidence of a clinically significant active infection, within 14 days prior to danicopan administration
- Have evidence of human immunodeficiency virus, hepatitis B infection, or active hepatitis C infection at Screening
- Have a history of meningococcal infection within the prior year
- Have a history of hypersensitivity reactions to commonly used antibacterial agents, including beta-lactams, penicillin, aminopenicillins, fluoroquinolones, cephalosporins, and carbapenems, which, in the opinion of the investigator and/or an appropriately qualified immunology or infectious disease expert, would make it difficult to properly provide either empiric antibiotic therapy or treat an active infection.
- Have participated in a clinical study in which an investigational drug was given within 30 days, or within 5 half-lives of the investigational drug, whichever is longer, prior to the first dose of ACH-0144471
- Have received eculizumab at any dose or interval within the past 50 days prior to the first dose of ACH-0144471
- Have received tacrolimus or cyclosporine within 2 weeks of the first dose of ACH-0144471
- Have a 12-lead electrocardiogram (ECG) with a QT interval Fridericia correction formula >450 millisecond (msec) for males or >470 msec for females, or have ECG findings which, in the opinion of the PI, could put the participant at undue risk
- Have received any drug known to prolong the corrected QT interval within 2 weeks of the first dose of ACH-0144471 and which, in the opinion of the PI, could put the participant at undue risk
Have any of the following laboratory abnormalities at screening:
- Alanine transaminase > upper limit of normal (ULN)
- Aspartate aminotransferase > ULN
- Absolute neutrophil counts <1,000/microliter
- Total bilirubin >1.5* ULN
- Indirect bilirubin > ULN
- Any laboratory abnormality that, in the opinion of the PI, would make the participant inappropriate for the study
- Unwilling or unable to comply with the study protocol for any reason
Sites / Locations
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
- Clinical Study Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Danicopan
Arm Description
Danicopan was to be administered to participants with C3G or IC-MPGN at a starting dose of 100 milligrams (mg) 3 times daily (TID) for the first 2 weeks, then the dosage was to be increased to 200 mg TID for the remainder of the study.
Outcomes
Primary Outcome Measures
Change From Baseline In Composite Biopsy Score At End Of Initial 12-Month Treatment Period
The composite biopsy score was based on a score incorporating changes in the activity index, glomerular C3c staining, and glomerular macrophage infiltration at the end of the initial 12 months of treatment. The composite renal biopsy index scoring system ranged from 0 to 21, with higher scores indicating worse outcomes.
Participants With Reduction In Proteinuria At End Of Initial 12-Month Treatment Period
Proteinuria reduction was defined as ≥30% decrease from baseline based on 24-hour urine protein (mg/day).
Secondary Outcome Measures
Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period
Proteinuria was assessed based on 24-hour urine collections at baseline and end of the initial 12-month Treatment Period.
Percent Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period
Proteinuria was assessed based on 24-hour urine collections at baseline and end of initial 12-month Treatment Period.
Slope Of Estimated Glomerular Filtration Rate (eGFR) From Baseline To End Of Initial 12-Month Treatment Period
Slope of eGFR was estimated using a simple linear regression for each participant, including all data values from baseline until the end of the Initial 12-Month Treatment Period, with eGFR as the dependent variable and time as the independent variable.
Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period
Change from baseline in eGFR at end of initial 12-Month Treatment Period is presented.
Participants With Significant Improvement In eGFR Relative To Baseline At End Of Initial 12-Month Treatment Period
Significant improvement relative to baseline was defined as a ≥ 25% increase from baseline in eGFR.
Change From Baseline in eGFR Over 12 Months of Treatment For Participants Meeting eGFR Inclusion Criteria
Participants were eligible for enrollment if inclusion criteria were met including having an eGFR >=30 milliliters (mL)/minute (min)/1.73 square meter (m^2) at the time of screening or at any time over the preceding 4 weeks. This Outcome Measure was registered in case there were participants who were enrolled and ended up not meeting the Eligibility Criteria and was intended to report data for change from baseline in eGFR for only the participants who met the eligibility criteria (that is, participants who did not meet the eligibility criteria would have been excluded from analysis for this Outcome Measure). Since all enrolled participants met the Eligibility Criteria, none of the participants were excluded from this analysis. Therefore, this data is the same data that is presented in Outcome Measure #6 "Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period". Change from baseline in eGFR at end of initial 12-Month Treatment Period is presented.
Change From Baseline In Measured GFR At The End Of The Initial 12-Month Treatment Period
Data for this Outcome Measure was to be collected where available. None of the sites collected data for this Outcome Measure.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03459443
Brief Title
A Proof of Concept Study for a 12 Month Treatment in Patients With C3G or IC-MPGN Treated With ACH-0144471
Official Title
An Open-Label Phase 2 Proof-of-Concept Study in Patients With C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) Treated With ACH-0144471
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Terminated
Why Stopped
The reason for terminating study early was inconclusive efficacy results. No safety findings were identified.
Study Start Date
June 20, 2018 (Actual)
Primary Completion Date
March 29, 2021 (Actual)
Study Completion Date
March 29, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alexion
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The primary purpose of this study was to evaluate the efficacy of 12 months of oral ACH-0144471 (also known as danicopan and ALXN2040) in participants with C3G or IC-MPGN based on histologic scoring and proteinuria.
Detailed Description
This was an open-label study to evaluate the efficacy of treatment with danicopan in participants 12 years of age or older with biopsy-confirmed C3G or IC-MPGN who had not undergone renal transplantation. All participants were to receive active treatment with danicopan for approximately 40 months. The starting dosage was to be 100 mg TID, and after 2 weeks, the dosage was to be increased to 200 mg TID for participants with body weight ≥ 60 kg or 150 mg TID for participants with body weight < 60 kg. Planned enrollment was approximately 20 participants.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
C3 Glomerulonephritis, C3 Glomerulopathy, Immune Complex Membranoproliferative Glomerulonephritis, IC-MPGN, Dense Deposit Disease
Keywords
factor D, fD, alternative pathway, complement mediated disease, C3GN, DDD, idiopathic MPGN, MPGN Type I, MPGN Type II, MPGN Type III, Primary MPGN, MCGN, Mesangiocapillary Glomerulonephritis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
22 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Danicopan
Arm Type
Experimental
Arm Description
Danicopan was to be administered to participants with C3G or IC-MPGN at a starting dose of 100 milligrams (mg) 3 times daily (TID) for the first 2 weeks, then the dosage was to be increased to 200 mg TID for the remainder of the study.
Intervention Type
Drug
Intervention Name(s)
Danicopan
Other Intervention Name(s)
ACH-4471, ACH4471, 4471, ALXN2040
Intervention Description
Danicopan was to be administered as an oral tablet.
Primary Outcome Measure Information:
Title
Change From Baseline In Composite Biopsy Score At End Of Initial 12-Month Treatment Period
Description
The composite biopsy score was based on a score incorporating changes in the activity index, glomerular C3c staining, and glomerular macrophage infiltration at the end of the initial 12 months of treatment. The composite renal biopsy index scoring system ranged from 0 to 21, with higher scores indicating worse outcomes.
Time Frame
Baseline, end of initial 12-Month Treatment Period
Title
Participants With Reduction In Proteinuria At End Of Initial 12-Month Treatment Period
Description
Proteinuria reduction was defined as ≥30% decrease from baseline based on 24-hour urine protein (mg/day).
Time Frame
Baseline, end of initial 12-Month Treatment Period
Secondary Outcome Measure Information:
Title
Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period
Description
Proteinuria was assessed based on 24-hour urine collections at baseline and end of the initial 12-month Treatment Period.
Time Frame
Baseline, end of initial 12-Month Treatment Period
Title
Percent Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period
Description
Proteinuria was assessed based on 24-hour urine collections at baseline and end of initial 12-month Treatment Period.
Time Frame
Baseline, end of initial 12-Month Treatment Period
Title
Slope Of Estimated Glomerular Filtration Rate (eGFR) From Baseline To End Of Initial 12-Month Treatment Period
Description
Slope of eGFR was estimated using a simple linear regression for each participant, including all data values from baseline until the end of the Initial 12-Month Treatment Period, with eGFR as the dependent variable and time as the independent variable.
Time Frame
End of initial 12-Month Treatment Period
Title
Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period
Description
Change from baseline in eGFR at end of initial 12-Month Treatment Period is presented.
Time Frame
Baseline, end of initial 12-Month Treatment Period
Title
Participants With Significant Improvement In eGFR Relative To Baseline At End Of Initial 12-Month Treatment Period
Description
Significant improvement relative to baseline was defined as a ≥ 25% increase from baseline in eGFR.
Time Frame
Baseline, end of initial 12-Month Treatment Period
Title
Change From Baseline in eGFR Over 12 Months of Treatment For Participants Meeting eGFR Inclusion Criteria
Description
Participants were eligible for enrollment if inclusion criteria were met including having an eGFR >=30 milliliters (mL)/minute (min)/1.73 square meter (m^2) at the time of screening or at any time over the preceding 4 weeks. This Outcome Measure was registered in case there were participants who were enrolled and ended up not meeting the Eligibility Criteria and was intended to report data for change from baseline in eGFR for only the participants who met the eligibility criteria (that is, participants who did not meet the eligibility criteria would have been excluded from analysis for this Outcome Measure). Since all enrolled participants met the Eligibility Criteria, none of the participants were excluded from this analysis. Therefore, this data is the same data that is presented in Outcome Measure #6 "Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period". Change from baseline in eGFR at end of initial 12-Month Treatment Period is presented.
Time Frame
End of initial 12-Month Treatment Period
Title
Change From Baseline In Measured GFR At The End Of The Initial 12-Month Treatment Period
Description
Data for this Outcome Measure was to be collected where available. None of the sites collected data for this Outcome Measure.
Time Frame
End of initial 12-Month Treatment Period
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
At least 12 years of age
Completion of the ACH471-201 clinical study OR diagnosed with biopsy-confirmed primary C3G or IC-MPGN
If a pre-treatment biopsy is obtained, or if a historical biopsy is available for review, it must have no more than 50% global fibrosis and no more than 50% of glomeruli with cellular crescents
Clinical evidence of ongoing disease based on significant proteinuria (defined as ≥500 mg/day of protein in a 24-hour urine) attributable to C3G disease or IC-MPGN in the opinion of the principal investigator (PI), and present prior to study entry and confirmed during Screening
If on corticosteroids, anti-hypertensive medications, anti-proteinuric medications (for example, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), or mycophenolate mofetil, must be on a stable dose for at least 2 weeks prior to screening
Female participants must use an acceptable method birth control to prevent pregnancy during the clinical study and for 30 days after the last dose of study medication
Male participants must use highly effective birth control with a female partner to prevent pregnancy during the clinical study and for 90 days after the last dose of study medication
Must be up-to-date on routine vaccinations, or willing to be brought up-to-date, based on local guidelines
Must have access to emergency medical care
Key Exclusion Criteria
Have a history of a major organ transplant (for example, heart, lung, kidney, or liver) or hematopoietic stem cell/marrow transplant
Have a history or presence of any clinically relevant co-morbidities that would make the participant inappropriate for the study (for example, a comorbidity that is likely to result in deterioration of the participant's condition, affect the participant's safety during the study, or confound the results of the study), in the opinion of the PI
Have an eGFR <30 milliliter/minute/1.73 m^2 at the time of screening or at any time over the preceding 4 weeks
Is a renal transplant recipient or receiving renal replacement therapy
Have other renal diseases that would interfere with the interpretation of the study
Have evidence of monoclonal gammopathy of unclear significance, infections, malignancy, autoimmune diseases, or other conditions to which C3G or IC-MPGN is secondary
Have been diagnosed with or show evidence of hepatobiliary cholestasis
Females who are pregnant, nursing, or planning to become pregnant during the study or within 90 days of ACH-0144471 administration or participants with a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days of ACH-0144471 administration
Have a history of febrile illness, a body temperature >38°Celsius, or other evidence of a clinically significant active infection, within 14 days prior to danicopan administration
Have evidence of human immunodeficiency virus, hepatitis B infection, or active hepatitis C infection at Screening
Have a history of meningococcal infection within the prior year
Have a history of hypersensitivity reactions to commonly used antibacterial agents, including beta-lactams, penicillin, aminopenicillins, fluoroquinolones, cephalosporins, and carbapenems, which, in the opinion of the investigator and/or an appropriately qualified immunology or infectious disease expert, would make it difficult to properly provide either empiric antibiotic therapy or treat an active infection.
Have participated in a clinical study in which an investigational drug was given within 30 days, or within 5 half-lives of the investigational drug, whichever is longer, prior to the first dose of ACH-0144471
Have received eculizumab at any dose or interval within the past 50 days prior to the first dose of ACH-0144471
Have received tacrolimus or cyclosporine within 2 weeks of the first dose of ACH-0144471
Have a 12-lead electrocardiogram (ECG) with a QT interval Fridericia correction formula >450 millisecond (msec) for males or >470 msec for females, or have ECG findings which, in the opinion of the PI, could put the participant at undue risk
Have received any drug known to prolong the corrected QT interval within 2 weeks of the first dose of ACH-0144471 and which, in the opinion of the PI, could put the participant at undue risk
Have any of the following laboratory abnormalities at screening:
Alanine transaminase > upper limit of normal (ULN)
Aspartate aminotransferase > ULN
Absolute neutrophil counts <1,000/microliter
Total bilirubin >1.5* ULN
Indirect bilirubin > ULN
Any laboratory abnormality that, in the opinion of the PI, would make the participant inappropriate for the study
Unwilling or unable to comply with the study protocol for any reason
Facility Information:
Facility Name
Clinical Study Site
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Clinical Study Site
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Clinical Study Site
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06511
Country
United States
Facility Name
Clinical Study Site
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45221
Country
United States
Facility Name
Clinical Study Site
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Clinical Study Site
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Clinical Study Site
City
Sydney
State/Province
New South Wales
Country
Australia
Facility Name
Clinical Study Site
City
Brisbane
State/Province
Queensland
Country
Australia
Facility Name
Clinical Study Site
City
Melbourne
State/Province
Victoria
Country
Australia
Facility Name
Clinical Study Site
City
Antwerpen
Country
Belgium
Facility Name
Clinical Study Site
City
Ranica
Country
Italy
Facility Name
Clinical Study Site
City
Leiden
Country
Netherlands
Facility Name
Clinical Study Site
City
Nijmegen
Country
Netherlands
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Alexion has a public commitment to allow requests for access to study data and will be supplying a protocol, CSR, and plain language summaries.
Learn more about this trial
A Proof of Concept Study for a 12 Month Treatment in Patients With C3G or IC-MPGN Treated With ACH-0144471
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