Clinical trial NCT02855268: Study of Lademirsen (SAR339375) in Patients With Alport Syndrome
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alport Syndrome
Keywords: Kidney disease
Nephritis
Hereditary nephritis
Hereditary kidney disease
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2016-08-04
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: The planned length of participation in the study for each participant was up to approximately 110 weeks (from screening through completion of follow-up). This included:

* 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 participant to enter a 48-week open label extension period and receive active treatment with lademirsen \[SAR339375\]).
* Post-treatment follow-up period of 10 weeks.

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.

Primary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: 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)
measure: DB Period: Annualized Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 48
timeFrame: Baseline, Week 48
Secondary outcomes:
measure: DB Period: Absolute Change From Baseline in eGFR Values at Week 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Percent Change From Baseline in eGFR Values at Week 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Number of Participants With a Reduction From Baseline in eGFR of <10%, <20%, <30%, or <40% at Weeks 24 and 48
timeFrame: At Weeks 24 and 48
measure: DB Period: Number of Participants Who Developed End Stage Renal Disease (ESRD)
timeFrame: From Baseline up to Week 48
measure: DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities (PCSA): Hematological Parameters
timeFrame: From Baseline up to Week 48
measure: DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Renal Function Parameters
timeFrame: From Baseline up to Week 48
measure: DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Liver Function Parameters
timeFrame: From Baseline up to Week 48
measure: DB Period: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs
timeFrame: From Baseline up to Week 48
measure: DB Period: Number of Participants With Potentially Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings
timeFrame: From Baseline up to Week 48
measure: DB Period: Pharmacokinetics (PK): Plasma Concentration of Lademirsen, Its Metabolite (RG0005) and SUM (Lademirsen+RG0005)
timeFrame: Post-dose (4 hours) on Day 1, Weeks 24 and 48
measure: DB Period: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of SUM (Lademirsen+RG0005)
timeFrame: Pre-dose (up to 4 hours before study drug administration) on Weeks 4, 12, 24, 36 and 48
measure: DB Period: Number of Participants With Treatment-emergent Anti-drug Antibodies (ADAs) Response
timeFrame: From first IMP administration (Day 1) up to first administration in OLE period for participant who entered OLE period (i.e., up to W48) & up to 7 days post last IMP administration for participant not continuing OLE period (i.e., up to W49)
measure: DB Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Anti-drug Antibody (ADA) Responses
timeFrame: From first IMP administration (Day 1) up to first administration in OLE period for participant who entered OLE period (i.e., up to W48) & up to 7 days post last IMP administration for participant not continuing OLE period (i.e., up to W49)
measure: DB Period: Change From Baseline in Circulating MicroRNA-21 at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Blood Urea Nitrogen (BUN) Values at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Urine Protein/Creatinine Ratio at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Urine Albumin/Creatinine Ratio at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Urine Epidermal Growth Factor (EGF)/Creatinine Ratio at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Blood Creatinine Values at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Urine Creatinine Values at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Blood Cystatine C Values at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Urine Cystatin C/Creatinine Ratio at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Blood Transforming Growth Factor Beta 1 Values at Week 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Urine Transforming Growth Factor Beta 1/Creatinine Ratio at Week 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Blood Lipocalin-2 Values at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: DB Period: Change From Baseline in Urine Lipocalin-2/Creatinine Ratio at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Investigational Site Number :8400002
state: California
city: Minneapolis
country: United States
facility: University of Minnesota Childrens' Hospital_Investigational Site Number :8400003
state: Minnesota
city: New York
country: United States
facility: Columbia University Medical Center_Investigational Site Number :8400004
state: New York
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation_Investigational Site Number :8400001
state: Ohio
city: Salt Lake City
country: United States
facility: University of Utah_Investigational Site Number :8400005
state: Utah
city: Herston
country: Australia
facility: Investigational Site Number :0360003
state: Queensland
city: Parkville
country: Australia
facility: Investigational Site Number :0360001
state: Victoria
city: Nedlands
country: Australia
facility: Investigational Site Number :0360002
state: Western Australia
city: Beijing
country: China
facility: Investigational Site Number :1560001
city: Beijing
country: China
facility: Investigational Site Number :1560002
city: Guangzhou
country: China
facility: Investigational Site Number :1560004
city: Paris
country: France
facility: Investigational Site Number :2500001
city: Toulouse
country: France
facility: Investigational Site Number :2500002
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen, Klinik für Nephrologie und Rheumatologie_Investigational Site Number :2760002
city: Köln
country: Germany
facility: Uniklinik Köln, Innere Medizin II - Nephrologie, Rheumatologie, Diabetologie und Allgemeine Innere Medizin_Investigational Site Number :2760001
city: Cordoba
country: Spain
facility: Investigational Site Number :7240005
state: Andalucia
city: Barcelona
country: Spain
facility: Investigational Site Number :7240001
state: Barcelona [Barcelona]
city: Barcelona
country: Spain
facility: Investigational Site Number :7240004
state: Barcelona [Barcelona]
city: Madrid / Madrid
country: Spain
facility: Investigational Site Number :7240002
state: Madrid, Comunidad De
city: Granada
country: Spain
facility: Investigational Site Number :7240003
city: London
country: United Kingdom
facility: Investigational Site Number :8260001
state: London, City Of
city: Nottingham
country: United Kingdom
facility: Investigational Site Number :8260002
state: Nottinghamshire
city: Newcastle Upon Tyne
country: United Kingdom
facility: Investigational Site Number :8260003
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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.