Study of Lademirsen (SAR339375) in Patients With Alport Syndrome
Condition: Alport Syndrome
MeSH terms: Nephritis, Hereditary; Syndrome
Intervention: lademirsen (SAR339375); Placebo
Intervention description: Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 43.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: Kidney disease; Nephritis; Hereditary nephritis; Hereditary kidney disease

Summary:

      Primary Objectives:

        -  To assess the efficacy of lademirsen (SAR339375) in reducing the decline in renal
           function.

        -  To assess the safety and tolerability of lademirsen (SAR339375) in participants with
           Alport syndrome.

      Secondary Objectives:

        -  To assess plasma pharmacokinetic (PK) parameters of the parent compound and its active
           major metabolite.

        -  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.
    

Eligibility criteria:

        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 participant or the family member,
                  OR

               3. Kidney biopsy showing glomerular basement membrane abnormalities (e.g.,
                  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 (participants must have met 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 was 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 participants of childbearing potential and sexually mature male
             participants must have agreed 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, participants prescribed benzodiazepines, cannabinoids, or
             opiates with positive results on a drug screen were 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 to
             comply with all aspects of the protocol.

        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).

          -  End stage renal disease (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
             participant's study compliance; confound the study results; impact participant 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
             participant'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
             was 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 (e.g., other oligonucleotide products).

          -  Any other condition or circumstance that, in the opinion of the Investigator, may make
             the participant unlikely to complete the study or comply with study procedures and
             requirements, or may pose a risk to the participant's safety and well-being.

        The above information was not intended to contain all considerations relevant to a
        participant's potential participation in a clinical trial.