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

Primary Purpose

Alport Syndrome

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

lademirsen (SAR339375)

Placebo

About this trial

This is an interventional treatment trial for Alport Syndrome focused on measuring Kidney disease, Nephritis, Hereditary nephritis, Hereditary kidney disease

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Investigational Site Number :8400002
University of Minnesota Childrens' Hospital_Investigational Site Number :8400003
Columbia University Medical Center_Investigational Site Number :8400004
The Cleveland Clinic Foundation_Investigational Site Number :8400001
University of Utah_Investigational Site Number :8400005
Investigational Site Number :0360003
Investigational Site Number :0360001
Investigational Site Number :0360002
Investigational Site Number :1560001
Investigational Site Number :1560002
Investigational Site Number :1560004
Investigational Site Number :2500001
Investigational Site Number :2500002
Universitätsmedizin Göttingen, Klinik für Nephrologie und Rheumatologie_Investigational Site Number :2760002
Uniklinik Köln, Innere Medizin II - Nephrologie, Rheumatologie, Diabetologie und Allgemeine Innere Medizin_Investigational Site Number :2760001
Investigational Site Number :7240005
Investigational Site Number :7240001
Investigational Site Number :7240004
Investigational Site Number :7240002
Investigational Site Number :7240003
Investigational Site Number :8260001
Investigational Site Number :8260002
Investigational Site Number :8260003

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Placebo/Lademirsen

Lademirsen/Lademirsen

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

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 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.

Secondary Outcome Measures

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.

DB Period: Percent Change From Baseline in eGFR Values at Week 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.

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.

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.

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT02855268

First Posted

July 28, 2016

Last Updated

October 19, 2023

Sponsor

Genzyme, a Sanofi Company

1. Study Identification

Unique Protocol Identification Number

NCT02855268

Brief Title

Study of Lademirsen (SAR339375) in Patients With Alport Syndrome

Acronym

HERA

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

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Terminated

Why Stopped

The results of the futility analysis led to the study termination. No unexpected safety findings were identified.

Study Start Date

November 2, 2019 (Actual)

Primary Completion Date

September 22, 2022 (Actual)

Study Completion Date

September 22, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Genzyme, a Sanofi Company

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alport Syndrome

Keywords

Kidney disease, Nephritis, Hereditary nephritis, Hereditary kidney disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

43 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo/Lademirsen

Arm Type

Experimental

Arm Description

Arm Title

Lademirsen/Lademirsen

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

lademirsen (SAR339375)

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Description

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)

Title

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

Description

Time Frame

Baseline, Week 48

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

Baseline, Weeks 24 and 48

Title

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

Description

Time Frame

Baseline, Weeks 24 and 48

Title

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

Description

Time Frame

At Weeks 24 and 48

Title

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

Description

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

Title

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

Description

Time Frame

From Baseline up to Week 48

Title

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

Description

Time Frame

From Baseline up to Week 48

Title

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

Description

Time Frame

From Baseline up to Week 48

Title

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

Description

Time Frame

From Baseline up to Week 48

Title

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

Description

Time Frame

From Baseline up to Week 48

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

Pre-dose (up to 4 hours before study drug administration) on Weeks 4, 12, 24, 36 and 48

Title

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

Description

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)

Title

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

Description

Time Frame

Title

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

Description

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

Time Frame

Baseline, Weeks 24 and 48

Title

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

Description

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

Title

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

Description

Time Frame

Baseline, Weeks 24 and 48

Title

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

Description

Time Frame

Baseline, Weeks 24 and 48

Title

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

Description

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

Title

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

Description

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

Title

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

Description

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

Title

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

Description

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

Title

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

Description

Time Frame

Baseline, Weeks 24 and 48

Title

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

Description

Time Frame

Baseline, Weeks 24 and 48

Title

DB Period: Change From Baseline in Urine Transforming Growth Factor Beta 1/Creatinine Ratio at Week 24 and 48

Description

Time Frame

Baseline, Weeks 24 and 48

Title

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

Description

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

Title

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

Description

Time Frame

Baseline, Weeks 24 and 48

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: 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. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Sciences & Operations

Organizational Affiliation

Sanofi

Official's Role

Study Director

Facility Information:

Facility Name

Investigational Site Number :8400002

City

Los Angeles

State/Province

California

ZIP/Postal Code

90024

Country

United States

Facility Name

University of Minnesota Childrens' Hospital_Investigational Site Number :8400003

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55454

Country

United States

Facility Name

Columbia University Medical Center_Investigational Site Number :8400004

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

The Cleveland Clinic Foundation_Investigational Site Number :8400001

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

Facility Name

University of Utah_Investigational Site Number :8400005

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84132

Country

United States

Facility Name

Investigational Site Number :0360003

City

Herston

State/Province

Queensland

ZIP/Postal Code

4029

Country

Australia

Facility Name

Investigational Site Number :0360001

City

Parkville

State/Province

Victoria

ZIP/Postal Code

3050

Country

Australia

Facility Name

Investigational Site Number :0360002

City

Nedlands

State/Province

Western Australia

ZIP/Postal Code

6009

Country

Australia

Facility Name

Investigational Site Number :1560001

City

Beijing

ZIP/Postal Code

100034

Country

China

Facility Name

Investigational Site Number :1560002

City

Beijing

ZIP/Postal Code

100730

Country

China

Facility Name

Investigational Site Number :1560004

City

Guangzhou

ZIP/Postal Code

510080

Country

China

Facility Name

Investigational Site Number :2500001

City

Paris

ZIP/Postal Code

75015

Country

France

Facility Name

Investigational Site Number :2500002

City

Toulouse

ZIP/Postal Code

31403

Country

France

Facility Name

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

City

Göttingen

ZIP/Postal Code

37075

Country

Germany

Facility Name

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

City

Köln

ZIP/Postal Code

50937

Country

Germany

Facility Name

Investigational Site Number :7240005

City

Cordoba

State/Province

Andalucia

ZIP/Postal Code

14004

Country

Spain

Facility Name

Investigational Site Number :7240001

City

Barcelona

State/Province

Barcelona [Barcelona]

ZIP/Postal Code

08025

Country

Spain

Facility Name

Investigational Site Number :7240004

City

Barcelona

State/Province

Barcelona [Barcelona]

ZIP/Postal Code

08035

Country

Spain

Facility Name

Investigational Site Number :7240002

City

Madrid / Madrid

State/Province

Madrid, Comunidad De

ZIP/Postal Code

28040

Country

Spain

Facility Name

Investigational Site Number :7240003

City

Granada

ZIP/Postal Code

18014

Country

Spain

Facility Name

Investigational Site Number :8260001

City

London

State/Province

London, City Of

ZIP/Postal Code

NW3 2QG

Country

United Kingdom

Facility Name

Investigational Site Number :8260002

City

Nottingham

State/Province

Nottinghamshire

ZIP/Postal Code

NG5 1PB

Country

United Kingdom

Facility Name

Investigational Site Number :8260003

City

Newcastle Upon Tyne

ZIP/Postal Code

NE7 7DN

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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://vivli.org

Citations:

PubMed Identifier

33159213

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. Erratum In: Pediatr Nephrol. 2021 Jan 12;:

Results Reference

derived

Learn more about this trial

Study of Lademirsen (SAR339375) in Patients With Alport Syndrome

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