E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital, hereditary and neonatal diseases |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
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 | 10001843 |
E.1.2 | Term | Alport's syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 assess the efficacy of lademirsen (SAR339375) in reducing the decline in renal function -To assess the safety and tolerability of lademirsen (SAR339375) in subjects with Alport syndrome
|
|
E.2.2 | Secondary objectives of the trial |
-To assess plasma pharmacokinetic (PK) parameters of the parent compound and its metabolites -To assess the potential formation of anti-drug antibodies (ADAs) following administration of lademirsen (SAR339375) -To assess the pharmacodynamic effect of lademirsen (SAR339375) on miR-21 and on changes in renal injury and function biomarkers.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female - Confirmed diagnosis of Alport syndrome 1.Clinical diagnosis (hematuria, family history, hearing loss, ocular change), AND 2.Genetic confirmation of Alport Syndrome in the subject or the family member, OR 3.Kidney biopsy showing glomerular basement membrane abnormalities (eg, significant thinning, thickening, irregularity or lucencies) consistent with Alport Syndrome. - Age 18-55 years old - eGFR > 35 ml/min/1.73m^2 and <90 mL/min/1.73m^2 (based on CKD-EPI) at screening - Renal Function Criteria (patients must meet at least one of the following CRITERIA A, B or C): - A)Decline in eGFR of ≥4 mL/min/1.73 m^2/year (eGFR slope <= -4) based on a linear regression slope analysis of ≥4 eGFR measurements within 3 years prior to the study and with a minimum of 2-year time span (the last, of the screening measurement, and first eGFR measurements should be separated by at least 2 years). eGFR should be calculated by using either the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation. - B) proteinuria (UPCR) >2000 mg/g (UACR>1000 mg/g) - C) Age and sex adjusted eGFR (based on CKD-Epi; male 18-23 eGFR<90 mL/min/1.73m^2 - ACE inhibitor and/or ARB, the dosing regimen should be stable for at least 30 days prior to screening - Sexually active female subjects of childbearing potential and sexually mature male subjects must agree to practice true abstinence in line with their preferred and usual lifestyle or to use two acceptable effective methods of contraception for the entire duration of the study and for at least 6 weeks after last dose. - Negative drug screen for opiates, cocaine, heroin, phencyclidine, amphetamines (including ecstasy), barbiturates, benzodiazepines, and cannabinoids. At the Investigator’s discretion, subjects prescribed benzodiazepines, cannabinoids, or opiates with positive results on a drug screen may be allowed. - Negative screening results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, and human immunodeficiency virus (HIV) antibody - Normal biological tests - Able to understand all study procedures in the informed consent form (ICF) and willing to comply with all aspects of the protocol
|
|
E.4 | Principal exclusion criteria |
- Causes of chronic kidney disease aside from Alport syndrome (including but not limited to other heritable disorders leading to chronic kidney disease, diabetic nephropathy, hypertensive nephropathy, lupus nephritis, IgA nephropathy) - ESRD as evidenced by ongoing dialysis therapy or history of renal transplantation - Any clinically significant illness within 30 days before screening or surgical or medical condition (other than Alport syndrome) that could interfere with the subject’s study compliance; confound the study results; impact subject safety; or significantly alter the absorption, distribution, metabolism, or excretion of drugs. - Weight > 110 kg - Any history of active malignancy within the last 1 year (history of localized basal cell or squamous cell carcinoma and cervical carcinoma in situ that has been excised/appropriately treated or a fully excised malignant lesion with a low probability of recurrence will not be considered exclusionary) - Prior treatment with Bardoxolone within 90 days prior to screening - History or presence of alcoholism or drug abuse within 2 years before screening or other concurrent social conditions that would potentially interfere with the subject’s study compliance, at the discretion of the Investigator - 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 - History or presence of hypersensitivity or idiosyncratic, allergic, or other clinically significant reaction to the study drug (including placebo), inactive ingredients, or related compounds (eg, other oligonucleotide products) - 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
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
1-Number of participants with treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) 2-Annualized change in estimated glomerular filtration rate eGFR from baseline to 48 weeks |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-Baseline to maximum 106 weeks 2-Baseline to 48 weeks |
|
E.5.2 | Secondary end point(s) |
1-Pharmacokinetics (PK) : Maximum concentration in plasma (Cmax):Plasma concentrations (Cmax) - Plasma concentrations (Cmax) of lademirsen (SAR339375), RG0005, and sum of lademirsen (SAR339375) and RG0005 (SUM) 2-Pharmacokinetics (PK) : Trough plasma concentration (Ctrough):Plasma concentrations (Ctrough) - Plasma concentrations (Ctrough) of sum of lademirsen (SAR339375) and RG0005 (SUM) 3-Number of participants with anti-drug antibodies (ADAs) incidents and titer 4-Number of participant with adverse events associated to ADA:Association of ADAs with adverse events per participants will be collected 5-Percent change in eGFR values from baseline to 24 weeks and 48 weeks 6-Proportion of subjects who reach end staged renal disease (ESRD):Proportion of participants who reach ESRD as defined by an eGFR ≤15 mL/min/1.73 m^2 or initiation of hemodialysis or renal transplantation from baseline to 48 weeks 7-Change in circulating miR-21 - Change of circulating miR-21 from baseline to 24 weeks, 48 weeks and 96 weeks 8-Change in renal injury and function biomarkers from baseline - Change of biomarkers from baseline to 24 weeks, 48 weeks and 96 weeks
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2: 24 weeks and 48 weeks 3-4: Baseline to maximum 106 weeks 5: Baseline to 24 weeks and 48 weeks 6: Baseline to 48 weeks 7: Weeks 24, 48, and 96 8: Baseline to Weeks 24, 48, and 96 |
|
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 | 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 | Yes |
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 | 2 |
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 | 11 |
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 |
China |
United States |
France |
Germany |
Spain |
United Kingdom |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 6 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 7 |