| 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 a low serum C3 level |
|
| 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] - Blood and lymphatic diseases [C15] |
| 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 determine whether the administration of ACH-0144471 can increase C3 levels in patients with low C3 levels due to either C3G or IC-MPGN |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of ACH-0144471 in patients with C3G or IC-MPGN
• To evaluate the pharmacokinetic (PK) profile of ACH-0144471 in patients with C3G or IC-MPGN
• To evaluate the effect of ACH-0144471 on biomarkers of alternative pathway activity (AP) in patients with C3G or IC-MPGN
• To explore the relationship between study drug exposure and changes in C3 levels and other biomarkers of alternative pathway activity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must be between the ages of 16 and 65 years, inclusive
2. Must have a clinical diagnosis of C3G (C3 glomerulonephritis [C3GN] or dense deposit disease [DDD], the 2 types of C3G) or idiopathic immune-complex membranoproliferative glomerulonephritis (IC-MPGN) by renal biopsy for at least 3 months prior to dosing, with the pathologic diagnosis verified by review of the renal biopsy by the study central pathologist
3. C3 must be <50% of the lower limit of normal (LLN)
4. C4 must be >90% of the LLN
5. Female patients of childbearing potential must either agree to abstinence or to use two effective methods of contraception as defined in Section 5.5.5 from screening through 3 months after the last dose of ACH-0144471. Females who are of non-childbearing potential as defined in Section 5.5.5 need not employ a method of contraception.
6. Male patients must either agree to abstinence or to use two effective methods of contraception as defined in Section 5.5.5 throughout the dosing period and for at least 3 months after the last dose of ACH-0144471. Males who are surgically sterile need not employ additional contraception. Males must agree to not donate sperm throughout the dosing period and for at least 3 months following the last dose of ACH-0144471.
7. Must be capable of providing written informed consent, must be willing and able to comply with the requirements and restrictions listed in the consent form and with the visit schedule, treatment plan, laboratory tests, pharmacokinetic sampling schedule, and other study procedures, and must be willing and able to return for all study visits
8. Must be up-to-date on routine vaccinations, or be willing to be brought up-to-date, based on local guidelines
9. Must be willing to comply with study-specific vaccination requirements for Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis strains A, C, W, and Y
10. Must be willing, at all times for the duration of study participation, to have transportation and telephone access, and to be within one hour of an emergency medical center |
|
| E.4 | Principal exclusion criteria |
1. History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant. Individuals receiving renal replacement therapy are also excluded
2. History or presence of any clinically relevant co-morbidities that would make the patient inappropriate for the study (for example, 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 Principal Investigator
3. Evidence of monoclonal gammopathy of unclear significance (MGUS), infections,malignancy, autoimmune diseases, or other conditions to which C3 glomerulopathy or IC-MPGN may be secondary
4. Patients with other renal diseases that would interfere with interpretation of the study
5. Presence or evidence of hepatobiliary cholestasis
6. Known Gilbert’s syndrome and/or patients with a history suggestive of Gilbert’s syndrome
7. Females who are pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration, or patients with a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration
8. Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 at the time of screening or at any time over the preceding four-weeks
9. History of febrile illness, a body temperature >38°C, or other evidence of a clinically significant active infection, within 14 days prior to study drug administration
10. Patients with evidence of human immunodeficiency virus, hepatitis B or hepatitis C infection (positive serology for HIV-1 antibody, positive hepatitis B surface antigen, or positive anti-HCV antibody at Screening or historically)
11. History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection
12. Contraindication to one or more of the required vaccinations
13. 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
14. Participation 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 study drug administration
15. Receipt of eculizumab at any dose or interval within the past 75 days prior to dosing
16. Use of tacrolimus or cyclosporine within 2 weeks of the first dose of ACH-0144471
17. 12-lead electrocardiogram with a QTcF >500 msec or findings which, in the opinion of the PI, could put the patient at undue risk
18. Any of the following laboratory abnormalities at screening:
• Alanine transaminase > ULN
• Aspartate aminotransferase > ULN
• Alkaline phosphatase > ULN
• Absolute neutrophil counts <1,000/μL
• Total bilirubin >1.5× ULN
• Indirect bilirubin > ULN
• Any laboratory abnormality that, in the opinion of the PI, would make the patient inappropriate for the study, or put the patient at undue risk
19. Donation of blood or blood products in excess of 500 mL within a 60 day period prior to the first dose of the current study
20. Receipt of blood or blood products within 30 days of screening
21. Clinically significant history of drug allergy as determined by the Investigator
22. Unwilling or unable to comply with the study protocol for any reason |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Increase in C3 levels relative to baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
2. Serious Adverse Events (SAEs), Grade 3 or higher Adverse Events (AEs), and AEs leading to discontinuation [Day 49]
3. Time (in days) to achieving peak C3 levels from the first day of dosing
4. Profile of Pharmacokinetics: Area under the curve (AUC)
5. Profile of Pharmacokinetics: Maximum plasma concentration (Cmax)
6. Profile of Pharmacokinetics: Time to maximum concentration (Tmax)
7. Change in biomarkers of alternative pathway activity (AP) relative to baseline (AP Wieslab, factor D, and Bb)
8. Relationship between ACH-0144471 exposure and changes in C3 levels and other biomarkers of alternative pathway activity (AP Wieslab, factor D, and Bb) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
2. Serious Adverse Events (SAEs), Grade 3 or higher Adverse Events (AEs), and AEs leading to discontinuation [Day 49]
3. Time (in days) to achieving peak C3 levels from the first day of dosing [Day 14]
4. Profile of Pharmacokinetics: Area under the curve (AUC) [Days 1 & 7]
5. Profile of Pharmacokinetics: Maximum plasma concentration (Cmax) [Days 1 & 7]
6. Profile of Pharmacokinetics: Time to maximum concentration (Tmax) [Days 1 & 7]
7. Change in biomarkers of alternative pathway activity (AP) relative to baseline (AP Wieslab, factor D, and Bb) [Day 14]
8. Relationship between ACH-0144471 exposure and changes in C3 levels and other biomarkers of alternative pathway activity (AP Wieslab, factor D, and Bb) [Day 14] |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| 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 | No |
| 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 | 4 |
| 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 |
| Belgium |
| 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 49 - + long term follow up |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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