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TerminatedNCT03459443Updated Aug 21, 2023Results posted

A Proof of Concept Study for a 12 Month Treatment in Patients With C3G or IC-MPGN Treated With ACH-0144471

A Phase 2 interventional study of Danicopan in C3 Glomerulonephritis, C3 Glomerulopathy and Immune Complex Membranoproliferative Glomerulonephritis, sponsored by Alexion Pharmaceuticals, Inc.. Terminated at 13 sites in 5 countries. Open to participants aged 12 Years and older. Per ClinicalTrials.gov, last updated 2023-08-21.

Sponsored by Alexion Pharmaceuticals, Inc. · Phase 2, Interventional, and Treatment

Why this study was terminated
The reason for terminating study early was inconclusive efficacy results. No safety findings were identified.
Phase
Phase 2
Study type
Interventional
Enrollment
22
Allocation
Not applicable
Ages
12 Years and older
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • 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
03

Who can participate

Ages eligible
12 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

Key Inclusion Criteria:

  1. At least 12 years of age
  2. Completion of the ACH471-201 clinical study OR diagnosed with biopsy-confirmed primary C3G or IC-MPGN
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Must be up-to-date on routine vaccinations, or willing to be brought up-to-date, based on local guidelines
  9. Must have access to emergency medical care

Key Exclusion Criteria

  1. Have a history of a major organ transplant (for example, heart, lung, kidney, or liver) or hematopoietic stem cell/marrow transplant
  2. 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
  3. Have an eGFR \<30 milliliter/minute/1.73 m\^2 at the time of screening or at any time over the preceding 4 weeks
  4. Is a renal transplant recipient or receiving renal replacement therapy
  5. Have other renal diseases that would interfere with the interpretation of the study
  6. Have evidence of monoclonal gammopathy of unclear significance, infections, malignancy, autoimmune diseases, or other conditions to which C3G or IC-MPGN is secondary
  7. Have been diagnosed with or show evidence of hepatobiliary cholestasis
  8. 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
  9. 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
  10. Have evidence of human immunodeficiency virus, hepatitis B infection, or active hepatitis C infection at Screening
  11. Have a history of meningococcal infection within the prior year
  12. 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.
  13. 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
  14. Have received eculizumab at any dose or interval within the past 50 days prior to the first dose of ACH-0144471
  15. Have received tacrolimus or cyclosporine within 2 weeks of the first dose of ACH-0144471
  16. 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
  17. 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
  18. 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
  19. Unwilling or unable to comply with the study protocol for any reason
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
22 participants (actual)

Study arms

  • Experimental
    Danicopan

    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.

    Drug: Danicopan

Interventions

  • DrugDanicopan

    Danicopan was to be administered as an oral tablet.

    Also known as: ACH-4471, ACH4471, 4471, ALXN2040

05

What researchers measure

Primary outcomes

  1. 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.

    Time frame: Baseline, end of initial 12-Month Treatment Period

  2. 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).

    Time frame: Baseline, end of initial 12-Month Treatment Period

Secondary outcomes

  1. 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.

    Time frame: Baseline, end of initial 12-Month Treatment Period

  2. 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.

    Time frame: Baseline, end of initial 12-Month Treatment Period

  3. 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.

    Time frame: End of initial 12-Month Treatment Period

  4. 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: Baseline, end of initial 12-Month Treatment Period

  5. 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.

    Time frame: Baseline, end of initial 12-Month Treatment Period

  6. 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.

    Time frame: End of initial 12-Month Treatment Period

  7. 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.

    Time frame: End of initial 12-Month Treatment Period

06

Results

Posted Aug 11, 2022

Participant flow

Participant flow — Overall Study
MilestoneDanicopan
Started22
Received at least 1 dose of study drug22
Completed0
Not completed22
Withdrew: Lack of efficacy3
Withdrew: Adverse event1
Withdrew: Sponsor's decision to close the study18

Outcome measures

PrimaryChange 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.

Time frame:
Baseline, end of initial 12-Month Treatment Period
Reported as:
Mean · score on a scale
Change From Baseline In Composite Biopsy Score At End Of Initial 12-Month Treatment Period
score on a scaleDanicopan
Baseline10.6 ± 3.59
End of 12-Month Initial Treatment Period8.0 ± 4.53
Change from Baseline-0.9 ± 1.89
PrimaryParticipants 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).

Time frame:
Baseline, end of initial 12-Month Treatment Period
Reported as:
Number · participants
Participants With Reduction In Proteinuria At End Of Initial 12-Month Treatment Period
participantsDanicopan
Participants With Reduction In Proteinuria At End Of Initial 12-Month Treatment Period8
SecondaryChange 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.

Time frame:
Baseline, end of initial 12-Month Treatment Period
Reported as:
Mean · mg/day
Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period
mg/dayDanicopan
Baseline4252.28 ± 2684.959
End of Initial 12-Month Treatment Period3512.63 ± 3335.765
Mean Change from Baseline-671.11 ± 2695.592
SecondaryPercent 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.

Time frame:
Baseline, end of initial 12-Month Treatment Period
Reported as:
Mean · percent change
Percent Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period
percent changeDanicopan
Percent Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period-17.1 ± 53.17
SecondarySlope 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.

Time frame:
End of initial 12-Month Treatment Period
Reported as:
Mean · mL/min/1.73 m^2 per month
Slope Of Estimated Glomerular Filtration Rate (eGFR) From Baseline To End Of Initial 12-Month Treatment Period
mL/min/1.73 m^2 per monthDanicopan
Slope Of Estimated Glomerular Filtration Rate (eGFR) From Baseline To End Of Initial 12-Month Treatment Period-1.24917 ± 1.811457
SecondaryChange 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:
Baseline, end of initial 12-Month Treatment Period
Reported as:
Mean · mL/min/1.73 m^2
Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period
mL/min/1.73 m^2Danicopan
Baseline90.692 ± 35.4939
End of Initial 12-Month Treatment Period81.412 ± 38.3320
Change from Baseline-9.795 ± 14.3806
SecondaryParticipants 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.

Time frame:
Baseline, end of initial 12-Month Treatment Period
Reported as:
Number · participants
Participants With Significant Improvement In eGFR Relative To Baseline At End Of Initial 12-Month Treatment Period
participantsDanicopan
Participants With Significant Improvement In eGFR Relative To Baseline At End Of Initial 12-Month Treatment Period0
SecondaryChange 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.

Time frame:
End of initial 12-Month Treatment Period
Reported as:
Mean · mL/min/1.73 m^2
Change From Baseline in eGFR Over 12 Months of Treatment For Participants Meeting eGFR Inclusion Criteria
mL/min/1.73 m^2Danicopan
Baseline90.692 ± 35.4939
End of Initial 12-Month Treatment Period81.412 ± 38.3320
Change from Baseline-9.795 ± 14.3806
SecondaryChange 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.

Time frame:
End of initial 12-Month Treatment Period

No measurements were reported for this outcome.

Adverse events

Collected over Day 1 (after dosing) up to 4 weeks after last dose of study drug (up to Week 108). Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Danicopan0/22 (0%)3/22 (13.6%)22/22 (100%)
Most frequent serious events
Most frequent serious events
EventDanicopan
Atrial fibrillationCardiac disorders1/22
PyrexiaGeneral disorders1/22
Rhinovirus infectionInfections and infestations1/22
Renal impairmentRenal and urinary disorders1/22
Most frequent other events
Showing 10 of 150
Most frequent other events
EventDanicopan
PyrexiaGeneral disorders11/22
Oedema peripheralGeneral disorders8/22
VomitingGastrointestinal disorders6/22
GastroenteritisInfections and infestations6/22
PharyngitisInfections and infestations6/22
HeadacheNervous system disorders6/22
AnaemiaBlood and lymphatic system disorders5/22
DiarrhoeaGastrointestinal disorders5/22
FatigueGeneral disorders5/22
Blood creatine phosphokinase increasedInvestigations5/22

Baseline characteristics

All participants who received at least 1 dose of study drug during treatment period.

Age, Continuous
Age, Continuous(years)Danicopan
Mean24.3 ± 9.90
Sex: Female, Male
Sex: Female, Male(Participants)Danicopan
Female10
Male12
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Danicopan
Hispanic or Latino0
Not Hispanic or Latino22
Unknown or Not Reported0
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Danicopan
American Indian or Alaska Native0
Asian2
Native Hawaiian or Other Pacific Islander1
Black or African American0
White19
More than one race0
Unknown or Not Reported0
07

Study locations

13 sites
  • Clinical Study Site
    Birmingham, Alabama 35294, United States
  • Clinical Study Site
    Stanford, California 94305, United States
  • Clinical Study Site
    New Haven, Connecticut 06511, United States
  • Clinical Study Site
    Cincinnati, Ohio 45221, United States
  • Clinical Study Site
    Columbus, Ohio 43210, United States
  • Clinical Study Site
    Philadelphia, Pennsylvania 19104, United States
  • Clinical Study Site
    Sydney, New South Wales, Australia
  • Clinical Study Site
    Brisbane, Queensland, Australia
  • Clinical Study Site
    Melbourne, Victoria, Australia
  • Clinical Study Site
    Antwerpen, Belgium
  • Clinical Study Site
    Ranica, Italy
  • Clinical Study Site
    Leiden, Netherlands
  • Clinical Study Site
    Nijmegen, Netherlands
08

References and documents

Study documents

  • Study protocol · May 15, 2020
  • Statistical analysis plan · Oct 30, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Alexion has a public commitment to allow requests for access to study data and will be supplying a protocol, CSR, and plain language summaries.

Supporting information: Sap, Csr

09

Registry details

Key details

Study ID
NCT03459443
Lead sponsor
Alexion Pharmaceuticals, Inc.
Responsible party
Sponsor
First posted
Mar 9, 2018
Start date
Jun 20, 2018
Primary completion
Mar 29, 2021
Completion
Mar 29, 2021
Results posted
Aug 11, 2022
Last update
Aug 21, 2023

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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