| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| biopsy-confirmed C3 Glomerulopathy (C3G) or idiopathic Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) and eGFR >30 mL/min/1.73 m^2 |
|
| E.1.1.1 | Medical condition in easily understood language |
| low C3 blood levels due to either C3G or IC-MPGN |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10077827 |
| E.1.2 | Term | C3 glomerulopathy |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy of 12 months of oral ACH-0144471 in patients with C3G or IC-MPGN based on:
• Histologic scoring and proteinuria |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the clinical effect of 12 months of oral ACH-0144471 in participants with C3G or IC-MPGN based on significant improvement in slope of estimated glomerular filtration rate (eGFR) relative to baseline over time
• To evaluate for improvement in eGFR following treatment with ACH-0144471
• Where available evaluate the change in measured (m) eGFR relative to baseline at the end of 12 months of treatment with ACH-0144471
• To evaluate the safety and tolerability of ACH-0144471 in partiecipants with C3G or IC-MPGN by assessing serious adverse events (SAEs) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A sub-study is being conducted to evaluate the effects of ACH-0144471 on renal pathology.
For participants in the renal biopsy sub-study, biopsies will be obtained after approximately 6 and/or 24 months of treatment, as described in the Schedule of Assessments, to allow evaluation of changes in renal pathology. The biopsy at the end of the treatment period should be performed during the last 2 weeks of study drug treatment |
|
| E.3 | Principal inclusion criteria |
1. Must have completed the C3G Proof of Mechanism (POM) study (ACH471-201) (participation in the long-term follow-up portion of ACH471-201 is not required), OR must meet all the following criteria:
a. Must have biopsy-confirmed primary C3G or IC-MPGN
b. Must have 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 PI, and present prior to study entry and confirmed during Screening.
c. 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
d. Must be 12 years or age or older and capable of swallowing tablets
2. If on corticosteroids, anti-hypertensive medications, anti-proteinuric medications (e.g., ACE inhibitors or angiotensin receptor blockers [ARBs]), or mycophenolate mofetil (MMF), must be on a stable dose for at least 2 weeks prior to the first screening visit
3. Female participants of childbearing potential must agree to use an acceptable method of contraception (as defined in Section 5.5.5) from the date of signing the informed consent to the first day of dosing (Day 1), and must agree to use a highly effective form of contraception (as defined in Section 5.5.5) from the first day of dosing to 30 days after their last dose of study drug. Female participants of childbearing potential must also have a negative serum pregnancy test during Screening and negative urine pregnancy test on Day 1. Female participants of non-childbearing potential need not employ a method of contraception.
4. Non-sterile male participants must agree to use a highly effective form of contraception (as defined in Section 5.5.5) with their partner(s) of childbearing potential from the first day of dosing to 90 days after their last dose of study drug. Male participants who are surgically sterile need not employ additional contraception. Male participants must agree not to donate sperm while enrolled in this study and for up to 90 days after their last dose of study drug.
5. Adult participants must be capable of providing written informed consent, and adolescent participants must be capable of providing
written assent. All participants must be willing and able to comply with the requirements and restrictions listed in the consent form and with all procedures in the protocol, including, the visit schedule, the treatment plan, the schedule for laboratory testing, and other study procedures
6. Must be up-to-date on routine vaccinations, or willing to be brought up-to-date, based on local guidelines
7. Must have access to emergency medical care |
|
| E.4 | Principal exclusion criteria |
1. Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant
2. Have a history or presence of any clinically relevant co-morbidities that would make the patient inappropriate for the study (for example, a comorbidity which is likely to result in deterioration of the patient’s condition, affect the patient’s safety during the study, or confound the results of the study), in the opinion of the PI
3. Have an estimated GFR <30 mL/min/1.73 m2 at the time of screening or at any time over the preceding four weeks
4. Is a renal transplant recipient or receiving renal replacement therapy
5. Have other renal diseases that would interfere with interpretation of the study
6. Have evidence of monoclonal gammopathy of unclear significance(MGUS), 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°C, or other evidence of a clinically significant active infection, within 14 days prior to ACH-0144471 administration
10. Have evidence of human immunodeficiency virus (HIV), 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 ECG with a QTcF >450 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 QTc 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 (ALT) > upper limit of normal (ULN)
• Aspartate aminotransferase (AST) > ULN
• Absolute neutrophil counts (ANC) <1,000/μL
• Total bilirubin >1.5× ULN
• Indirect bilirubin > ULN
• Any laboratory abnormality that, in the opinion of the PI, would
make the particpant inappropriate for the study
19. Are unwilling or unable to comply with the study protocol for any
reason |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoints:
• Change from baseline in biopsy, based on a score incorporating changes in both the activity index and C3 staining at the end of 12 months of treatment.
• Number and percent of participants with reduction in proteinuria relative to baseline at the end of 12 months of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please be referred to section 3.2.1.2 of the protocol |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
• Number and proportion of participants with significant (≥25%) increase in eGFR relative to baseline at the end of 12 months of treatment
• Change and percent change from baseline in proteinuria and eGFR over 12 months of treatment period for all participantson 3.2.1.2 of the protocol
• Change and percent change from baseline in eGFR over 12 months of treatment for participants meeting eGFR inclusion criterion at study entry
• Descriptive analysis of slope of GFR over the treatment period of - 4471 therapy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please be referred to section 3.2.1.2 of the protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| United States |
| Belgium |
| Italy |
| Netherlands |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS Day 833 (Screening approx. 75 days + treatment 24 months + 28 days follow-up) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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