Study of Sparsentan Treatment in Pediatrics With Proteinuric Glomerular Diseases

Focal Segmental Glomerulosclerosis Clinical Trial

— EPPIK  

Official title:

A Phase 2, Open-Label, Single-Arm, Cohort Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Sparsentan Treatment in Pediatric Subjects With Selected Proteinuric Glomerular Diseases

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05003986
• Other study ID #: RTRX-RE021-201
• Status: Recruiting
• Phase: Phase 2
• Start date: August 12, 2021
• Est. completion date: June 1, 2025

Study information

• Verified date: May 2024
• Source: Travere Therapeutics, Inc.
• Contact: Travere Call Center
• Phone: 1-877-659-5518
• Email: medinfo[@]travere.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To evaluate the safety, efficacy and tolerability of sparsentan oral suspension and tablets, and assess changes in proteinuria after once-daily dosing over 108 weeks.

Description:

This is a multicenter, open-label, 112-week study of sparsentan in approximately 67 pediatric subjects aged ≥1 year to <18 years with selected proteinuric glomerular diseases, divided into 3 populations, defined as follows:

• Population 1: Subjects with selected proteinuric glomerular diseases associated with Focal Segmental Glomerulosclerosis (FSGS) and Minimal Change Disease (MCD) histological patterns

• Population 2: Subjects with kidney biopsy-confirmed immunoglobulin A nephropathy (IgAN), immunoglobulin A vasculitis (IgAV), or Alport syndrome (AS)

• Population 3: Subjects with kidney biopsy-confirmed IgAN

The study will evaluate long-term safety, tolerability, and efficacy with pharmacokinetic (PK) evaluations at Day 1 (Baseline), Day 2 (Visit 4), and Week 12 (Visit 9) in Population 1 and Population 2. In Population 3, PK values will be evaluated at Day 1 (Baseline) and at Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96. For Population 1 and Population 2, subjects will be enrolled in 3 cohorts based on age ranges. For Population 3, subjects will be enrolled in one cohort.

Study Enrollment:

• Population 1: FSGS and/or MCD (30 subjects total)

1. Cohort 1 (6 subjects): ≥8 years to <18 years

2. Cohort 2 (18 subjects): ≥3 years to <8 years

3. Cohort 3 (6 subjects): ≥1 year to <3 years

• Population 2: IgAN, IgAV, or AS (27 subjects total)

1. Cohort 1 (9 subjects): ≥8 years to <18 years

2. Cohort 2 (12 subjects): ≥5 years to <8 years

3. Cohort 3 (6 subjects): ≥2 years to <5 years

• Population 3: IgAN (10 subjects total)

1. 10 subjects: ≥8 years to <18 years

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 67
• Est. completion date: June 1, 2025
• Est. primary completion date: May 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 17 Years

Eligibility

Inclusion Criteria for All Subjects (All Three Populations):

A subject must meet all of the following criteria to be eligible for participation in this study:

• The subject or parent/legal guardian (as appropriate) is willing and able to provide signed informed consent/assent, and where required, the subject is willing to provide assent before any screening procedures per local requirements.

• The subject has an estimated glomerular filtration rate (eGFR) =30 mL/min/1.73 m2 at screening.

• The subject has a mean seated blood pressure between the 5th and 95th percentile for sex and height.

Inclusion Criteria for Population 1:

• The subject is male or female =1 year at screening and <18 years of age at Day 1 (Baseline).

• The subject has a UP/C =1.5 g/g (170 mg/mmol) at screening AND one of the following:

• Kidney biopsy-proven FSGS or MCD histological patterns and clinical presentation consistent with primary FSGS or MCD and qualifying proteinuria at screening despite history or ongoing treatment with corticosteroids and/or other immunosuppressive disease-modifying agents.

• Documentation of a genetic mutation in a podocyte protein associated with FSGS or MCD. Subjects with a documented podocytic mutation do not require kidney biopsy.

• Kidney biopsy-proven FSGS histological pattern with medical history and clinical presentation consistent with maladaptive cause of the lesion.

Note: The kidney biopsy may have been performed at any time in the past but must include light microscopy and electron microscopy characteristics and/or immunofluorescence findings consistent with FSGS or MCD.

Inclusion Criteria for Population 2:

• The subject is male or female =2 years at screening and <18 years of age at Day 1 (Baseline).

• The subject has UP/C =0.6 g/g (68 mg/mmol) at screening AND one of the following diagnoses:

• Kidney biopsy-confirmed IgAN, IgAV, or AS

• Diagnosis of AS by genetic testing (pathogenic X-linked Collagen, Type IV, Alpha-5 (COL4A5) mutation OR autosomal-recessive mutations in both alleles of Collagen, Type IV, Alpha-3 (COL4A3) and/or Collagen, Type IV, Alpha-4 (COL4A4) OR autosomal-dominant COL4A3 and/or COL4A4 and digenic mutations [ie, simultaneous mutations in 2 of the COL4A3, COL4A4, and COL4A5 genes])

Inclusion Criteria for Population 3:

• The subject is male or female =8 years at screening and <18 years of age at Day 1 (Baseline).

• The subject has UP/C =1.0 g/g (113 mg/mmol) at screening AND has kidney biopsy-confirmed IgAN

• Subject weighs =40 kg

• The subject has been on ACEI and/or ARB therapy for at least 12 weeks prior to screening

Exclusion Criteria for All Subjects (All Three Populations):

A subject who meets any of the following will be excluded from this study:

• The subject weighs <7.3 kg at screening.

• The subject has FSGS or MCD histological pattern secondary to viral infections, drug toxicities, or malignancies.

• The subject has immunoglobulin A (IgA) glomerular deposits not in the context of primary IgAN or IgAV (ie, secondary to another condition; eg, systemic lupus erythematosus and liver cirrhosis).

• The subject has had an acute onset or presentation of glomerular disease or a diagnostic biopsy or a relapse of glomerular disease requiring new or different class of immunosuppressive treatment (including, but not limited to, systemic corticosteroids, calcineurin inhibitors and mycophenolate mofetil, abatacept, cyclophosphamide, rituximab, ofatumumab, and ocrelizumab) within 6 months before screening.

• Subjects taking chronic immunosuppressive medications (including systemic steroids) not on a stable dose for =1 month before screening.

• The subject requires any of the prohibited concomitant medications as defined in the study protocol.

• The subject has undergone any organ transplantation, with the exception of corneal transplants.

• The subject has a documented history of congenital or acquired heart failure (modified Ross heart failure classification for children Class II to Class IV) and/or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema.

• The subject has hemodynamically significant cardiac valvular disease.

• The subject has clinically significant congenital vascular disease.

• The subject has jaundice, hepatitis, or known hepatobiliary disease, or alanine aminotransferase and/or aspartate aminotransferase >2 times the upper limit of the normal range at screening.

• The subject has a history of malignancy within the past 2 years.

• The subject has a screening hematocrit <27% (0.27 L/L) or a hemoglobin value <9 g/dL (90 g/L).

• The subject has a screening potassium value >5.5 milliequivalent (mEq)/L (5.5 mmol/L).

• The subject has any abnormal clinical laboratory screening values that are considered by the Investigator to be clinically significant.

• The subject has a history of allergic response to any angiotensin II antagonist or endothelin receptor antagonist, including sparsentan, or has a hypersensitivity to any of the excipients in the study medication.

• The female subject is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.

• Female subjects of childbearing potential, beginning at menarche, who do not agree to use 1 highly reliable (ie, can achieve a failure rate of <1% per year) method of contraception from 7 days before the first dose of the study medication until 28 days after the last dose of study medication. Examples of highly reliable contraception methods include stable oral, implanted, transdermal, or injected contraceptive hormones associated with the inhibition of ovulation or an intrauterine device. One additional barrier method must also be used during vaginal sexual activity, such as a diaphragm, diaphragm with spermicide (preferred), or male partner's use of male condom or male condom with spermicide (preferred), from Day 1/Randomization until 28 days after the last dose of study medication. Female subjects of childbearing potential are defined as those who are fertile after menarche, unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. All female subjects of childbearing potential must have a negative serum pregnancy test result at screening (Visit 1) and a negative urine pregnancy test result, with positive results confirmed by serum, at every study visit from Day 1 (Visit 3) and after.

Note: Before menarche, pregnancy testing and contraceptive use are not required. However, subjects and their parents/legal guardians must be advised that, immediately upon menarche, subjects will be required to begin pregnancy testing and initiate contraceptive use. This requirement cannot be waived.

• The subject has participated in a study of another study medication within 28 days before screening or plans to participate in such a study during the course of this study.

• The subject has had prior exposure to sparsentan.

• The subject or parent/legal guardian (as appropriate), in the opinion of the Investigator, are unable to adhere to the requirements of the study including but not limited to, a history of noncompliance and/or any other reason that causes the Investigator to believe the subject would not be a good candidate for the study.

• For Population 3 - the subject is unable to swallow the study medication tablets whole.

Related Conditions & MeSH terms

• Alport Syndrome
• Focal Segmental Glomerulosclerosis
• Glomerulonephritis, IGA
• Glomerulosclerosis, Focal Segmental
• IgA Vasculitis
• Immunoglobulin A Nephropathy
• Minimal Change Disease
• Nephritis, Hereditary
• Nephrosis, Lipoid
• Vasculitis

Intervention

Drug:
• Sparsentan
Population 1: 800 mg Sparsentan (oral suspension)
• Sparsentan
Population 2: 400 mg Sparsentan (oral suspension)
• Sparsentan
Population 3: 400 mg Sparsentan (tablets)

Locations

Country	Name	City	State
Germany	Travere Investigational Site	Hamburg
Germany	Travere Investigational Site	Heidelberg
Germany	Travere Investigational Site	Köln
Italy	Travere Investigational Site	Bari
Italy	Travere Investigational Site	Genova
Italy	Travere Investigational Site	Milano
Italy	Travere Investigational Site	Padova
Italy	Travere Investigational Site	Roma
Netherlands	Travere Investigational Site	Amsterdam
Netherlands	Travere Investigational Site	Nijmegen
Poland	Travere Investigational Site	Kraków
Poland	Travere Investigational Site	Lódz
Poland	Travere Investigational Site	Warsaw
Spain	Travere Investigational Site	Barcelona
Spain	Travere Investigational Site	Madrid
Spain	Travere Investigational Site	Madrid
Spain	Travere Investigational Site	Sevilla
Sweden	Travere Investigational Site	Göteborg
Sweden	Travere Investigational Site	Stockholm
United Kingdom	Travere Investigational Site	Bristol
United Kingdom	Travere Investigational Site	Glasgow
United Kingdom	Travere Investigational Site	Liverpool
United Kingdom	Travere Investigational Site	London
United Kingdom	Travere Investigational Site	Manchester
United States	Travere Investigational Site	Ann Arbor	Michigan
United States	Travere Investigational Site	Boston	Massachusetts
United States	Travere Investigational Site	Chapel Hill	North Carolina
United States	Travere Investigational Site	Charlotte	North Carolina
United States	Travere Investigational Site	Columbus	Ohio
United States	Travere Investigational Site	Durham	North Carolina
United States	Travere Investigational Site	Hackensack	New Jersey
United States	Travere Investigational Site	Houston	Texas
United States	Travere Investigational Site	Iowa City	Iowa
United States	Travere Investigational Site	Kansas City	Missouri
United States	Travere Investigational Site	Los Angeles	California
United States	Travere Investigational Site	Miami	Florida
United States	Travere Investigational Site	Miami	Florida
United States	Travere Investigational Site	Minneapolis	Minnesota
United States	Travere Investigational Site	Neptune	New Jersey
United States	Travere Investigational Site	New Hyde Park	New York
United States	Travere Investigational Site	New York	New York
United States	Travere Investigational Site	Oklahoma City	Oklahoma
United States	Travere Investigational Site	Philadelphia	Pennsylvania
United States	Travere Investigational Site	Philadelphia	Pennsylvania
United States	Travere Investigational Site	Seattle	Washington
United States	Travere Investigational Site	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
Travere Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Germany,  Italy,  Netherlands,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), AEs leading to treatment discontinuation, and adverse events of interest (AEOIs)	The incidence of TEAEs, SAEs, AEs leading to treatment discontinuation, and AEOIs	After the last patient has undergone the week 108 visit (Visit 15).
Primary	Urine protein/creatinine ratio (UP/C) at week 108	Change from baseline in UP/C over 108 weeks	After the last patient has undergone the Week 108 visit (Visit 15)
Secondary	Observed plasma Pharmacokinetic (PK) concentrations	Observed plasma PK concentrations at scheduled timepoints and visits	At scheduled Day 1, Day 2 and Week 12 visits for Population 1 and 2. At scheduled Day 1 and Week 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96 visits for Population 3.
Secondary	Steady-state PK parameters area under the plasma concentration-time curve during a dosing interval ([AUCt])	Steady-state PK parameters [AUCt]	Week 108
Secondary	Steady-state PK parameters [Cmax_ss]	Maximum steady-state plasma drug concentration [Cmax_ss]	Week 108
Secondary	Steady-state PK parameters [Cmin_ss]	Minimum steady-state plasma drug concentration [Cmin_ss]	Week 108
Secondary	Urine albumin/creatinine ratio (UA/C) over 108 weeks	Change from baseline in UA/C over 108 weeks	Week 108
Secondary	Estimated glomerular filtration rate (eGFR) over 108 weeks	Change from baseline in eGFR over 108 weeks	Week 108
Secondary	Proportion of subjects achieving complete remission of proteinuria	The proportion of subjects achieving complete remission of proteinuria, defined as UP/C <0.3 g/g over 108 weeks	Week 108
Secondary	Proportion of subjects with FSGS and/or MCD histological patterns achieving partial remission	The proportion of subjects with FSGS and/or MCD histological patterns achieving partial remission defined as UP/C =1.5 g/g and >40% reduction in UP/C over 108 weeks	Week 108
Secondary	Proportion of subjects who discontinue study medication due to inability to tolerate the oral suspension	The proportion of subjects who discontinue study medication due to inability to tolerate the smell, taste, aftertaste, volume of administration, or method of administration of oral suspension in Population 1 and Population 2	Week 108

External Links

•   Sponsor Website
•   Study Website