E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Alport syndrome is an inherited form of kidney disease caused by mutations in genes coding for the capillary basement membrane collagen IV |
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E.1.1.1 | Medical condition in easily understood language |
Alport syndrome is a condition which causes damage to your kidneys over time |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
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 |
Primary Objective: • To assess the safety and tolerability of RG-012 when administered weekly for 24 weeks
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives: • To assess the effect of RG-012 on endogenous renal microRNA-21 (miR-21) • To assess the effect of RG-012 on other selected blood, urine, and renal biomarkers • To assess pharmacokinetic (PK) parameters of the parent compound (RG456070) and its active major metabolite (RG0005) following administration of RG-012 • To assess potential formation of anti-drug antibodies (ADAs) following administration of RG 012 • To assess the preliminary efficacy of RG 012 to reduce the decline in renal function over time
Exploratory Objective: • To assess changes in quality of life (QoL) following administration of RG 012
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Capable of providing written informed consent 2. Male or female subjects aged 18 to 65 years (inclusive) Capable of providing written informed consent 3. Confirmed diagnosis of Alport syndrome (clinical, histopathologic, and/or genetic diagnosis) 4. As estimated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine or creatinine–cystatin C equation, all 3 of the following eGFR criteria must be met: • eGFR at the initial screening measurement between 45 and 90 ml/min/1.73 m2 • Declining eGFR at a rate ≥5ml/min/1.73m2 per year • Final screening/baseline eGFR >30ml/min/1.73m2 5.Proteinuria ≥500 mg protein/g creatinine at initial screening and baseline visits 6. On a stable dosing regimen of an ACE inhibitor and/or ARB for ≥30 days prior to screening 7. Female subjects of childbearing potential must agree to use an acceptable methods of contraception from screening through 30 days after the last dose of study drug 8. Male subjects with female partners of childbearing potential must agree to use one an acceptable contraception methods from the time of the first dose of study drug through 30 days after the last dose of study drug 9. Negative drug screen for opiates, cocaine, heroin, phencyclidine, amphetamines (including ecstasy), barbiturates, and benzodiazepines 10. Negative screening results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, and human immunodeficiency virus (HIV) antibody 11. Screening hematology, clinical chemistries, coagulation, and urinalysis are not clinically significant as assessed by the Investigator, and the following criteria are met: • Platelets >100x109/L • Total white blood cells >3.0x109/L and absolute neutrophil count >1.5x109/L • Hemoglobin >10 g/dL for females and >11 g/dL for males • Total and direct bilirubin <1.5x upper limit of normal (ULN), unless elevated bilirubin is associated with a known benign condition (e.g., Gilbert's syndrome) • Alanine aminotransferase (ALT) <3x ULN • Aspartate aminotransferase (AST) <3x ULN • Alkaline phosphatase (ALP) <3x ULN 12. Agree not to start any new prescription medication and to maintain stable regimens of existing medications, except as prescribed or approved by the Investigator, or if required in an emergency 13. Agree not to take any over-the-counter medication or herbal supplements during the study, except as instructed or approved by the Investigator 14. Able to understand all study procedures in the informed consent form (ICF) and willing to comply with all aspects of the protocol |
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E.4 | Principal exclusion criteria |
1. Causes of chronic kidney disease aside from Alport syndrome (including, but not limited to, diabetic nephropathy, hypertensive nephropathy, lupus, IgA nephropathy) 2. ESRD as evidenced by ongoing dialysis therapy or history of renal transplantation 3. Female subjects who are pregnant or lactating 4. Concurrent clinically significant medical diagnosis (other than Alport syndrome) that would potentially interfere with the subject's study compliance or confound the study results, including but not limited to: significant or unstable cardiac disease (unstable angina, myocardial infarction within the last 6 months, coronary heart disease, congestive heart failure, prolonged QT syndrome [torsade de pointes], significant arrhythmia, and/or any other clinically significant ECG abnormalities); cancer; uncontrolled seizure disorder; chronic infection (e.g., tuberculosis); diabetes; and/or significant thyroid disease 5. Any history of malignancy within the last 1 year (history of localized basal cell or squamous cell carcinoma that has been excised/appropriately treated is not considered exclusionary) 6. Concurrent social conditions (e.g., drug or alcohol abuse) that would potentially interfere with the subject's study compliance 7. Use of over-the-counter medications or herbal supplements that may interact with the bioavailability of the investigational product or use of alternative medicines that may have influence on the disease outcome. 8. Mental disability or history of or current significant psychiatric disease that may impair ability to provide informed consent or impact compliance with study procedures 9. Clinically significant illness within 30 days prior to screening that in the judgment of the Investigator could interfere with interpretation of study results, impair compliance with study procedures, or impact the safety of the subject 10. Participation in a recent investigational study and receipt of an investigational drug or investigational use of a licensed drug within 30 days or 5 half lives, whichever is longer, prior to screening 11. History or presence of hypersensitivity, idiosyncratic reaction, or allergic reaction to the study drug, inactive ingredients, or related compounds 12. History of any clinically significant reaction (in the judgment of the Investigator) to previous injection of an oligonucleotide product 13. History or presence of alcoholism or drug abuse within the past 2 years prior to screening 14. Any other condition or circumstance that, in the opinion of the Investigator, may make the subject unlikely to complete the study or comply with study procedures and requirements, or may pose a risk to the subject's safety and well-being |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety Endpoints: • Incidence of adverse events (AEs), serious AEs (SAEs), severe AEs, drug-related AEs, and AEs leading to withdrawal • Observed values and changes from baseline in clinical laboratory parameters (e.g., hematology, chemistry, complement, and urinalysis) • Observed values and changes from baseline in vital signs • 12-Lead electrocardiogram (ECG) • Physical examinations Pharmacodynamic Endpoints: • Change over time in renal biomarkers (including miR-21 in renal biopsy tissue, blood urea nitrogen [BUN], serum creatinine, urine protein/albumin, kidney injury molecule-1 [KIM 1], β-2 microglobulin, clusterin, cystatin C) and exploratory biomarkers (including, but not necessarily limited to, additional microRNAs, asymmetric dimethylarginine [ADMA], transforming growth factor-β [TGFβ], connective tissue growth factor [CTGF], neutrophil gelatinase-associated lipocalin [NGAL]) Pharmacokinetic Endpoints: • Plasma concentrations and calculated PK parameters of the parent compound (RG456070) and its active metabolite (RG0005) • Incidence and titer of ADAs Efficacy Endpoint: • Change in eGFR from baseline to Week 24 Exploratory Endpoint: • Change over time in QoL as measured using the Short Form 36 Health Survey® (SF-36) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 24 weeks of treatment |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 2 |
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 |
Canada |
France |
Germany |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |