Study of Lademirsen (SAR339375) in Patients With Alport Syndrome

NCT02855268 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: ACT162482019-004394-10
• Study Type: interventional
• Target: 43
• Locations: 7 countries
• Sites: 23

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 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.

Conditions

Alport Syndrome

Keywords

Kidney disease; Nephritis; Hereditary nephritis; Hereditary kidney disease

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

  Adverse event (AE): any untoward medical occurrence in a participant who received study drug and did not necessarily had to have a causal relationship with the treatment. Serious adverse event (SAE) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs: AEs with onset after the first dose of investigational medicinal product (IMP) or existing AEs that worsened during TEAE Period (for DB Period: from first IMP administration up to first administration in OLE period for participant who entered OLE period; and up to 7 days post last IMP administration for participant not continuing OLE period; for open-label: time from 1st IMP administration in open-label to last IMP administration+ 10 weeks).

  DB: from 1st dose of IMP upto 1st dose of IMP in OLE for participant who entered OLE (Week 48); up to 7 days post last dose for participant not continuing to OLE (Week 49); OLE:1st dose of IMP (at Week 48) in OLE upto 10 weeks post last dose (Week 106)

• DB Period: Annualized Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 48

  Annualized change in eGFR was calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation (for participants with age greater than 16 years) as: eGFR=142\*min(Scr/K, 1)α\*max(Scr/K, 1)\^-1.200\*0.9938\^Age\*1.012 \[if female\], where Scr = serum creatinine in milligrams per deciliter (mg/dL), K = 0.7 for females (F) and 0.9 for males (M), α = -0.241(F) and -0.302(M); age=years, calculated at time of creatinine measurement. eGFR measurements collected from baseline to Week 48 were the response variable and included fixed effects of treatment (lademirsen or placebo), screening eGFR stratification factor (less than \[\<\]60 versus greater than or equal to \[\>=\]60 milliliters per minute per 1.73 meters squared \[mL/min/1.73 m\^2\]), time, and treatment-by-time interaction. Least square (LS) mean and standard error (SE) estimated by linear mixed effect model.

  Baseline, Week 48

Secondary Outcomes (26)

• DB Period: Absolute Change From Baseline in eGFR Values at Week 24 and 48

  Baseline, Weeks 24 and 48

• DB Period: Percent Change From Baseline in eGFR Values at Week 24 and 48

  Baseline, Weeks 24 and 48

• DB Period: Number of Participants With a Reduction From Baseline in eGFR of <10%, <20%, <30%, or <40% at Weeks 24 and 48

  At Weeks 24 and 48

• DB Period: Number of Participants Who Developed End Stage Renal Disease (ESRD)

  From Baseline up to Week 48

• DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities (PCSA): Hematological Parameters

  From Baseline up to Week 48

Study Arms (2)

Placebo/Lademirsen

EXPERIMENTAL

Participants received subcutaneous (SC) doses of placebo (matched to lademirsen) every week (QW) during the 48 weeks of double blind (DB) treatment period. Participants who received placebo and completed DB treatment period entered in open-label extension (OLE) treatment period and received lademirsen at a dose of 110 milligrams (mg) QW for an additional 48 weeks (i.e., up to Week 96).

Drug: lademirsen (SAR339375)

Lademirsen/Lademirsen

EXPERIMENTAL

Participants received SC doses of lademirsen 110 mg QW during the 48 weeks of DB treatment period. Participants who completed DB treatment period entered in OLE treatment period and continued the same lademirsen treatment in OLE period for an additional 48 weeks (i.e., up to Week 96).

Drug: Placebo

Interventions

lademirsen (SAR339375) DRUG

Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection

Placebo/Lademirsen

Placebo DRUG

Pharmaceutical form: Solution for injection Route of administration: Subcutaneous injection

Lademirsen/Lademirsen

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female.
• Confirmed diagnosis of Alport syndrome
• Clinical diagnosis (hematuria, family history, hearing loss, ocular change), AND
• Genetic confirmation of Alport Syndrome in the participant or the family member, OR
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (23)

Investigational Site Number :8400002

Los Angeles, California, 90024, United States

Location

University of Minnesota Childrens' Hospital_Investigational Site Number :8400003

Minneapolis, Minnesota, 55454, United States

Location

Columbia University Medical Center_Investigational Site Number :8400004

New York, New York, 10032, United States

Location

The Cleveland Clinic Foundation_Investigational Site Number :8400001

Cleveland, Ohio, 44195, United States

Location

University of Utah_Investigational Site Number :8400005

Salt Lake City, Utah, 84132, United States

Location

Investigational Site Number :0360003

Herston, Queensland, 4029, Australia

Location

Investigational Site Number :0360001

Parkville, Victoria, 3050, Australia

Location

Investigational Site Number :0360002

Nedlands, Western Australia, 6009, Australia

Location

Investigational Site Number :1560001

Beijing, 100034, China

Location

Investigational Site Number :1560002

Beijing, 100730, China

Location

Investigational Site Number :1560004

Guangzhou, 510080, China

Location

Investigational Site Number :2500001

Paris, 75015, France

Location

Investigational Site Number :2500002

Toulouse, 31403, France

Location

Uniklinik Köln, Innere Medizin II - Nephrologie, Rheumatologie, Diabetologie und Allgemeine Innere Medizin_Investigational Site Number :2760001

Cologne, 50937, Germany

Location

Universitätsmedizin Göttingen, Klinik für Nephrologie und Rheumatologie_Investigational Site Number :2760002

Göttingen, 37075, Germany

Location

Investigational Site Number :7240005

Córdoba, Andalusia, 14004, Spain

Location

Investigational Site Number :7240001

Barcelona, Barcelona [Barcelona], 08025, Spain

Location

Investigational Site Number :7240004

Barcelona, Barcelona [Barcelona], 08035, Spain

Location

Investigational Site Number :7240002

Madrid / Madrid, Madrid, Comunidad de, 28040, Spain

Location

Investigational Site Number :7240003

Granada, 18014, Spain

Location

Investigational Site Number :8260001

London, London, City of, NW3 2QG, United Kingdom

Location

Investigational Site Number :8260002

Nottingham, Nottinghamshire, NG5 1PB, United Kingdom

Location

Investigational Site Number :8260003

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (2)

• Gale DP, Gross O, Wang F, Esteban de la Rosa RJ, Hall M, Sayer JA, Appel G, Hariri A, Liu S, Maski M, Shen Y, Zhang Q, Iqbal S, Kowthalam MU, Lin J, Ding J; HERA Clinical Trial Group. A Randomized Controlled Clinical Trial Testing Effects of Lademirsen on Kidney Function Decline in Adults with Alport Syndrome. Clin J Am Soc Nephrol. 2024 Aug 1;19(8):995-1004. doi: 10.2215/CJN.0000000000000458. Epub 2024 Jun 3.

  PMID: 38829703 DERIVED

• 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.

  PMID: 33159213 DERIVED

Related Links

• ACT16248 Plain Language Results Summary

MeSH Terms

Conditions

Nephritis, Hereditary; Kidney Diseases; Nephritis

Condition Hierarchy (Ancestors)

Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urologic Diseases; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Collagen Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Limitations and Caveats

Due to early study termination, Stage 2/Cohort 2 was not conducted. In Stage 1 analysis of DB period was performed until 48 weeks. In Stage 1 OL period, only safety data was collected and assessed.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi-Aventis Recherche & Développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 28, 2016
• First Posted: August 4, 2016
• Study Start: November 2, 2019
• Primary Completion: September 22, 2022
• Study Completion: September 22, 2022
• Last Updated: September 11, 2025
• Results First Posted: October 23, 2023

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

DE (2); ES (5); AU (3); FR (2); US (5); GB (3); CN (3)