Study of Lademirsen (SAR339375) in Patients With Alport Syndrome

• Register: ClinicalTrials.gov
• Last refreshed on: 30 October 2023
• Main ID: NCT02855268
• Date of registration: 28/07/2016
• Prospective Registration: Yes
• Primary sponsor: Genzyme, a Sanofi Company
• Public title: Study of Lademirsen (SAR339375) in Patients With Alport Syndrome HERA
• Scientific 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
• Date of first enrolment: November 2, 2019
• Target sample size: 43
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/ct2/show/NCT02855268
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator).
• Phase: Phase 2

Countries of recruitment

Australia, Canada, China, France, Germany, Spain, United Kingdom, United States

Contacts

• Name: Clinical Sciences & Operations
• Affiliation: Sanofi

Key inclusion & exclusion 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.



Age minimum: 18 Years
Age maximum: 55 Years
Gender: All

Health Condition(s) or Problem(s) studied

Alport Syndrome

Intervention(s)

Drug: Placebo

Drug: lademirsen (SAR339375)

Primary Outcome(s)

DB Period: Annualized Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 48 [Time Frame: Baseline, Week 48]

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [Time Frame: 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)]

Secondary Outcome(s)

DB Period: Change From Baseline in Blood Transforming Growth Factor Beta 1 Values at Week 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Change From Baseline in Urine Lipocalin-2/Creatinine Ratio at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Change From Baseline in Urine Creatinine Values at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Change From Baseline in Urine Transforming Growth Factor Beta 1/Creatinine Ratio at Week 24 and 48 [Time Frame: 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 [Time Frame: At Weeks 24 and 48]

DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities (PCSA): Hematological Parameters [Time Frame: From Baseline up to Week 48]

DB Period: Change From Baseline in Blood Urea Nitrogen (BUN) Values at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Absolute Change From Baseline in eGFR Values at Week 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Change From Baseline in Blood Creatinine Values at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Number of Participants Who Developed End Stage Renal Disease (ESRD) [Time Frame: From Baseline up to Week 48]

DB Period: Change From Baseline in Blood Cystatine C Values at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Number of Participants With Potentially Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings [Time Frame: From Baseline up to Week 48]

DB Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Anti-drug Antibody (ADA) Responses [Time Frame: 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)]

DB Period: Pharmacokinetics (PK): Plasma Concentration of Lademirsen, Its Metabolite (RG0005) and SUM (Lademirsen+RG0005) [Time Frame: Post-dose (4 hours) on Day 1, Weeks 24 and 48]

DB Period: Change From Baseline in Urine Cystatin C/Creatinine Ratio at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Change From Baseline in Blood Lipocalin-2 Values at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Change From Baseline in Urine Protein/Creatinine Ratio at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of SUM (Lademirsen+RG0005) [Time Frame: Pre-dose (up to 4 hours before study drug administration) on Weeks 4, 12, 24, 36 and 48]

DB Period: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs [Time Frame: From Baseline up to Week 48]

DB Period: Change From Baseline in Circulating MicroRNA-21 at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Change From Baseline in Urine Albumin/Creatinine Ratio at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Renal Function Parameters [Time Frame: From Baseline up to Week 48]

DB Period: Number of Participants With Treatment-emergent Anti-drug Antibodies (ADAs) Response [Time Frame: 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)]

DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Liver Function Parameters [Time Frame: From Baseline up to Week 48]

DB Period: Percent Change From Baseline in eGFR Values at Week 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

DB Period: Change From Baseline in Urine Epidermal Growth Factor (EGF)/Creatinine Ratio at Weeks 24 and 48 [Time Frame: Baseline, Weeks 24 and 48]

Secondary ID(s)

2019-004394-10

ACT16248

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 23/10/2023
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02855268