Study of Lademirsen (SAR339375) in Patients With Alport Syndrome

Phase 2TerminatedNCT02855268

Genzyme, a Sanofi Company43 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Alport Syndrome

Interventions

lademirsen (SAR339375)DRUG

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

PlaceboDRUG

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

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 Years

Medical Language ↔ Plain English

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.

Locations (23)

Outcomes

Primary Outcomes

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).

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)

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.

Time frame: Baseline, Week 48

Secondary Outcomes

Data from ClinicalTrials.gov

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

eGFR was used to measure level of kidney function and determine the stage of kidney disease. eGFR was calculated using CKD-EPI Creatinine Equation as: eGFR =142\*min (Scr/K, 1) α\*max (Scr/K, 1)\^-1.200\*0.9938\^Age\*1.012 \[if female\], where Scr was serum creatinine in mg/dL, K is 0.7 for females and 0.9 for males, α was -0.241 for females and -0.302 for males. Unit of age was years, calculated to reflect the age at the time when creatinine was measured.

Time frame: Baseline, Weeks 24 and 48

DB Period: Percent Change From Baseline in eGFR Values 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

Estimated glomerular filtration rate was used to measure level of kidney function and determine the stage of kidney disease. eGFR was calculated using CKD-EPI Creatinine Equation as: eGFR = 142\*min(Scr/K,1)α\*max(Scr/K,1)\^-1.200\*0.9938\^Age\*1.012 \[if female\], where Scr was serum creatinine in mg/dL, K is 0.7 for females and 0.9 for males, α was -0.241 for females and -0.302 for males. Number of participants with a reduction from baseline in eGFR value of \<10%, \<20%, \<30%, or \<40% at Weeks 24 and 48 were reported in this outcome measure.

Time frame: At Weeks 24 and 48

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

ESRD was defined as: eGFR \<=15 mL/min/1.73 m\^2; or initiation of hemodialysis; or receiving a renal transplantation during the double-blind treatment period.

Time frame: From Baseline up to Week 48

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

Criteria for PCSA included: Hemoglobin (Hb): \<= 115 grams per liter (g/L) (Male), \<= 95 g/L (Female); greater than or equal to (\>=) 185 g/L (18.5 g/dL) (Male), \>= 165 g/L (16.5g/dL) (Female); decrease from Baseline (DFB) = 20 g/L (2g/dL); Hematocrit: \<= 0.37 volume/volume (v/v) (Male); \<= 0.32 v/v (Female); \>= 0.55 v/v (Male); \>= 0.5 v/v (Female); Red Blood Cells (RBCs):\>=6 Tera/ liter (L) and Platelets: \<100 Giga/L; \>= 700 Giga/L.

Time frame: From Baseline up to Week 48

DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Renal Function Parameters

Criteria for potentially clinically significant abnormalities: Creatinine: \>=150 micromol/L (adults); \>=30% change from baseline, \>=100% change from baseline; Blood urea nitrogen: \>=17 millimoles per liter (mmol/L); Uric acid: \<120 micromol/L; \>408 micromol/L; Creatinine clearance: \<15 mL/min; \>=15 to \<30 mL/min; \>=30 to \<60 mL/min; \>=60 to \<90 mL/min; \>=90 mL/min; eGFR: \< 15 mL/min/1.73m\^2; \>=15 to \<30 mL/min/1.73m\^2; \>=30 to \<60 mL/min/1.73m\^2; \>=60 to \<90 mL/min/1.73m\^2; \>=90 mL/min. Participants might be counted more than once for specified categories.

Time frame: From Baseline up to Week 48

DB Period: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Liver Function Parameters

Criteria for PCSA: Total bilirubin (TBILI): \>1.5 upper limit of normal (ULN); \>2 ULN; Alanine Aminotransferase (ALT): \>3 ULN; \>5 ULN; \>10 ULN; \>20 ULN; Aspartate aminotransferase (AST): \>3ULN; \>5 ULN; \>10 ULN; \>20 ULN; Alkaline phosphatase: \>1.5 ULN; ALT\>3 ULN and TBILI\>2 ULN and Direct Bilirubin\> 35% TBILI and TBILI\> 1.5 ULN.

Time frame: From Baseline up to Week 48

DB Period: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs

Criteria for potentially clinically significant vital sign abnormalities: Systolic blood pressure (SBP):\<=95 mmHg and DFB \>=20 mmHg; \>=160 mmHg and increase from baseline (IFB) \>=20 mmHg; SBP (Orthostatic): \<=-20mmHg; Diastolic blood pressure (DBP): \<=45 mmHg and DFB \>=10 mmHg; \>=110 mmHg and IFB \>=10 mmHg; DBP (Orthostatic): \<=10 mmHg; heart rate (HR): \<=50 beats per minute (bpm) and DFB \>=20 bpm; \>=120 bpm and IFB\>=20 bpm and Weight: \>=5% DFB; \>=5% IFB.

Time frame: From Baseline up to Week 48

DB Period: Number of Participants With Potentially Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings

Criteria for potentially clinically significant ECG abnormalities: HR: \<50 bpm; \<50 bpm and DFB \>=20 bpm; \<40 bpm; \<40 bpm and DFB \>=20 bpm; \<30 bpm; \<30 bpm and DFB \>=20 bpm; \>90 bpm; \>=90 bpm and IFB \>=20 bpm; \>100 bpm; \>=100bpm and IFB \>=20 bpm; \>120 bpm; \>=120 bpm and IFB \>=20 bpm; PR Interval: \>200 millisecond(ms); \>200 ms and IFB \>=25%; \>220 ms; \>220 ms and IFB \>=25%; \>240 ms; \>240 ms and IFB\>=25%; QRS Interval: \>110 ms; \>110 ms and IFB \>=25%; \>120 ms; \>120 ms and IFB \>=25%; QT Interval: \>500 ms and QTc Fridericia (QTc F): \>450 ms; \>480 ms; \>500 ms; IFB \>30 and \<=60 ms; IFB \>60 ms.

Time frame: From Baseline up to Week 48

DB Period: Pharmacokinetics (PK): Plasma Concentration of Lademirsen, Its Metabolite (RG0005) and SUM (Lademirsen+RG0005)

Post-dose (4 hours) plasma concentration of lademirsen, its active major metabolite (RG0005), and SUM (lademirsen+RG0005) on Day 1, and at Weeks 24 and 48 are reported in the outcome measure. 4-hour SUM concentrations are calculated values (sum of measured lademirsen+RG0005).

Time frame: Post-dose (4 hours) on Day 1, Weeks 24 and 48

DB Period: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of SUM (Lademirsen+RG0005)

Ctrough was measured from the pre-dose (up to 4 hours before study drug administration) plasma samples collected at Weeks 4, 12, 24, 36 and 48. SUM concentrations (lademirsen+RG0005) are measured values (assay measures 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 Treatment-emergent Anti-drug Antibodies (ADAs) Response

ADA responses were categorized as: treatment-induced, and treatment-boosted response. Participant whose ADA status was negative at baseline but positive (ADA titer value \>=50) anytime post-baseline or missing at baseline was considered to have treatment-induced ADA. Participant whose ADA status was positive at baseline (pre-existing ADA) and the ADA titer level anytime post-baseline was significantly higher (\>= twice the minimum required dilution) than that at baseline was considered to have treatment-boosted ADA.

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 Treatment-emergent Adverse Events (TEAEs) Associated With Anti-drug Antibody (ADA) Responses

TEAEs: AE developed/worsened/became serious during TEAE period (from first IMP administration in DB period to first administration in OLE period for those who entered OLE (i.e., up to W48), up to 7 days post last dose for those not continuing to OLE period (i.e., up to W49). TESAEs: any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization/prolongation of hospitalization, resulted in persistent/significant disability, was a congenital anomaly/birth defect, or a medically important event. ADA response was categorized as treatment-induced (participant whose ADA status was positive \[ADA titer value \>=50\] anytime post-baseline and was negative/missing at baseline), treatment-boosted (participant whose ADA status was positive at baseline \& ADA titer level anytime post-baseline was significantly higher). In this outcome measure, number of participants with TEAEs as per ADA responses (positive or negative) were reported.

DB Period: Change From Baseline in Circulating MicroRNA-21 at Weeks 24 and 48

Circulating microRNA-21 were the supportive biomarkers assessed in study.

Time frame: Baseline, Weeks 24 and 48

DB Period: Change From Baseline in Blood Urea Nitrogen (BUN) Values at Weeks 24 and 48

BUN was the supportive biomarker assessed during the study. Change from Baseline in BUN at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

DB Period: Change From Baseline in Urine Protein/Creatinine Ratio at Weeks 24 and 48

Urine protein and creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine protein to creatinine ratio at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

DB Period: Change From Baseline in Urine Albumin/Creatinine Ratio at Weeks 24 and 48

Urine albumin and creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine albumin to creatinine ratio at Weeks 24 and 48 was reported in this outcome measure.

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

EGF and creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine EGF to creatinine ratio at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

DB Period: Change From Baseline in Blood Creatinine Values at Weeks 24 and 48

Creatinine was the supportive biomarker assessed during the study. Change from Baseline in blood creatinine values at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

DB Period: Change From Baseline in Urine Creatinine Values at Weeks 24 and 48

Creatinine was the supportive biomarker assessed during the study. Change from Baseline in urine creatinine values at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

DB Period: Change From Baseline in Blood Cystatine C Values at Weeks 24 and 48

Cystatine C was the supportive biomarker assessed during the study. Change from Baseline in blood cystatine C values at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

DB Period: Change From Baseline in Urine Cystatin C/Creatinine Ratio at Weeks 24 and 48

Cystatin C and Creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine cystatin C to creatinine ratio at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

DB Period: Change From Baseline in Blood Transforming Growth Factor Beta 1 Values at Week 24 and 48

Transforming growth factor beta 1 was the supportive biomarker assessed during the study. Change from Baseline in blood transforming growth factor beta 1 values at Week 24 and 48 was reported in this outcome measure.

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

Transforming growth factor beta 1 and creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine transforming growth factor beta 1 to creatinine ratio at Week 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

DB Period: Change From Baseline in Blood Lipocalin-2 Values at Weeks 24 and 48

Blood Lipocalin-2 was the supportive biomarker assessed during the study. Change from Baseline in blood lipocalin-2 at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

DB Period: Change From Baseline in Urine Lipocalin-2/Creatinine Ratio at Weeks 24 and 48

Lipocalin-2 and Creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine lipocalin-2 to creatinine ratio at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48