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Study of Lademirsen (SAR339375) in Patients With Alport Syndrome (HERA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02855268
Recruitment Status : Recruiting
First Posted : August 4, 2016
Last Update Posted : July 22, 2021
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )

Tracking Information
First Submitted Date  ICMJE July 28, 2016
First Posted Date  ICMJE August 4, 2016
Last Update Posted Date July 22, 2021
Actual Study Start Date  ICMJE November 2, 2019
Estimated Primary Completion Date June 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 5, 2021)
  • Number of participants with adverse events [ Time Frame: Baseline to maximum 106 weeks ]
    Number of participants with treatment emergent adverse events (TEAEs) and serious adverse events (SAEs)
  • Annualized change in estimated glomerular filtration rate eGFR from baseline [ Time Frame: Baseline to 48 weeks ]
    Annualized change in estimated glomerular filtration rate eGFR from baseline to 48 weeks
Original Primary Outcome Measures  ICMJE
 (submitted: August 1, 2016)
Safety and tolerability assessed by the number of subjects with Adverse Events [ Time Frame: 24 Weeks ]
Assessed by variables such as AEs, laboratory parameters, vital signs, ECGs, and injection site reactions
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 5, 2021)
  • Pharmacokinetics (PK) : Maximum concentration in plasma (Cmax) [ Time Frame: 24 weeks and 48 weeks ]
    Plasma concentrations (Cmax) of lademirsen (SAR339375), RG0005, and sum of lademirsen (SAR339375) and RG0005 (SUM)
  • Pharmacokinetics (PK) : Trough plasma concentration (Ctrough) [ Time Frame: 24 weeks, 48 weeks and 96 weeks ]
    Plasma concentrations (Ctrough) of sum of lademirsen (SAR339375) and RG0005 (SUM)
  • Number of participants with anti-drug antibodies (ADAs) [ Time Frame: Baseline to maximum 106 weeks ]
    Number of participants with ADAs incidents and titer
  • Number of participant with adverse events associated to ADAs [ Time Frame: Baseline to maximum 106 weeks ]
    Association of ADAs with adverse events per participants will be collected.
  • Percent change in eGFR values [ Time Frame: Baseline to 24 weeks, 48 weeks and 96 weeks ]
    Percent change in eGFR values from baseline to 24 weeks and 48 weeks
  • Proportion of subjects who reach end staged renal disease (ESRD) [ Time Frame: Baseline to 48 weeks ]
    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
  • Proportion of subjects with a reduction from baseline in eGFR [ Time Frame: Baseline to Weeks 24, 48, and 96 ]
    Proportion of subjects with a reduction from baseline in eGFR of <10%, <20%, <30%, or <40% reduction at Week 24, 48 and 96
  • Change in circulating miR-21 [ Time Frame: Weeks 24, 48, and 96 ]
    Change of circulating miR-21 from baseline to 24 weeks, 48 weeks and 96 weeks
  • Change in blood urea nitrogen [ Time Frame: Baseline to Weeks 24, 48, and 96 ]
    Change in blood urea nitrogen from baseline to 24 weeks, 48 weeks and 96 weeks
  • Change in protein/creatinine ratio and albumin/creatinine ratio in urine only [ Time Frame: Baseline to Weeks 24, 48, and 96 ]
    Change in protein/creatinine ratio and albumin/creatinine ratio in urine only from baseline to 24 weeks, 48 weeks and 96 weeks
  • Change in epidermal growth factor (EGF) in urine only [ Time Frame: Baseline to Weeks 24, 48, and 96 ]
    Change in EFG from baseline to 24 weeks, 48 weeks and 96 weeks
  • Change in creatinine in both blood and urine [ Time Frame: Baseline to Weeks 24, 48, and 96 ]
    Change in ceatinine from baseline to 24 weeks, 48 weeks and 96 weeks
  • Change in Cystatin C in both blood and urine [ Time Frame: Baseline to Weeks 24, 48, and 96 ]
    Change in Cystatin C from baseline to 24 weeks, 48 weeks and 96 weeks
  • Change in transforming growth factor-β (TGF-β) in both blood and urine [ Time Frame: Baseline to Weeks 24, 48, and 96 ]
    Change in TGF-β from baseline to 24 weeks, 48 weeks and 96 weeks
  • Change in neutrophil gelatinase-associated lipocalin (NGAL) in both blood and urine [ Time Frame: Baseline to Weeks 24, 48, and 96 ]
    Change in NGAL from baseline to 24 weeks, 48 weeks and 96 weeks
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Lademirsen (SAR339375) in Patients With Alport Syndrome
Official Title  ICMJE A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Efficacy, Pharmacodynamics, and Pharmacokinetics of Lademirsen (SAR339375) for Subcutaneous Injection Administered Every Week in Patients With Alport Syndrome
Brief 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 subjects with Alport syndrome

Secondary Objectives:

  • 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.
Detailed Description

The planned length of participation in the study for each subject is up to approximately 110 weeks (from screening through completion of follow-up). This includes:

  • Screening/baseline period of up to 4 weeks
  • Double-blind, placebo-controlled treatment period of 48 weeks
  • Open-label extension treatment period of 48 weeks ( all subject to enter a 48-week open label extension period and receive active treatment with lademirsen (SAR339375))
  • Post-treatment follow-up period of 10 weeks
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Alport's Syndrome
Intervention  ICMJE
  • Drug: lademirsen (SAR339375)
    Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection
  • Drug: Placebo
    Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection
Study Arms  ICMJE
  • Experimental: lademirsen (SAR339375)
    Eligible participants will receive subcutaneous injection every week for 48 weeks
    Intervention: Drug: lademirsen (SAR339375)
  • Placebo Comparator: Placebo
    Eligible participants will receive subcutaneous injection every week for 48 weeks
    Intervention: Drug: Placebo
Publications * Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021 Mar;36(3):711-719. doi: 10.1007/s00467-020-04819-6. Epub 2020 Nov 6. Review. Erratum in: Pediatr Nephrol. 2021 Jan 12;:.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 3, 2019)
45
Original Estimated Enrollment  ICMJE
 (submitted: August 1, 2016)
30
Estimated Study Completion Date  ICMJE June 2023
Estimated Primary Completion Date June 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Trial Transparency email recommended (Toll free number for US & Canada) 800-633-1610 ext option 6 Contact-US@sanofi.com
Listed Location Countries  ICMJE Australia,   China,   France,   Germany,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02855268
Other Study ID Numbers  ICMJE ACT16248
2019-004394-10 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/
Responsible Party Sanofi ( Genzyme, a Sanofi Company )
Study Sponsor  ICMJE Genzyme, a Sanofi Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP