Clinical trial NCT05003986: Study of Sparsentan Treatment in Pediatrics With Proteinuric Glomerular Diseases
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Focal Segmental Glomerulosclerosis
Minimal Change Disease
Immunoglobulin A Nephropathy
IgA Vasculitis
Alport Syndrome
Keywords: Alport, AS, FSGS, IgAN, IgAV, MCD, pediatrics, peds
Lead sponsor: Travere Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2021-08-13
Enrollment: 67
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), AEs leading to treatment discontinuation, and adverse events of interest (AEOIs)
timeFrame: After the last patient has undergone the week 108 visit (Visit 15).
measure: Urine protein/creatinine ratio (UP/C) at week 108
timeFrame: After the last patient has undergone the Week 108 visit (Visit 15)
Secondary outcomes:
measure: Observed plasma Pharmacokinetic (PK) concentrations
timeFrame: 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.
measure: Steady-state PK parameters area under the plasma concentration-time curve during a dosing interval ([AUCτ])
timeFrame: Week 108
measure: Steady-state PK parameters [Cmax_ss]
timeFrame: Week 108
measure: Steady-state PK parameters [Cmin_ss]
timeFrame: Week 108
measure: Urine albumin/creatinine ratio (UA/C) over 108 weeks
timeFrame: Week 108
measure: Estimated glomerular filtration rate (eGFR) over 108 weeks
timeFrame: Week 108
measure: Proportion of subjects achieving complete remission of proteinuria
timeFrame: Week 108
measure: Proportion of subjects with FSGS and/or MCD histological patterns achieving partial remission
timeFrame: Week 108
measure: Proportion of subjects who discontinue study medication due to inability to tolerate the oral suspension
timeFrame: Week 108
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Travere Investigational Site
state: California
city: Wilmington
country: United States
facility: Travere Investigational Site
state: Delaware
city: Miami
country: United States
facility: Travere Investigational Site
state: Florida
city: Miami
country: United States
facility: Travere Investigational Site
state: Florida
city: Iowa City
country: United States
facility: Travere Investigational Site
state: Iowa
city: Boston
country: United States
facility: Travere Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Travere Investigational Site
state: Michigan
city: Minneapolis
country: United States
facility: Travere Investigational Site
state: Minnesota
city: Kansas City
country: United States
facility: Travere Investigational Site
state: Missouri
city: Hackensack
country: United States
facility: Travere Investigational Site
state: New Jersey
city: Neptune
country: United States
facility: Travere Investigational Site
state: New Jersey
city: New Hyde Park
country: United States
facility: Travere Investigational Site
state: New York
city: New York
country: United States
facility: Travere Investigational Site
state: New York
city: Chapel Hill
country: United States
facility: Travere Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: Travere Investigational Site
state: North Carolina
city: Durham
country: United States
facility: Travere Investigational Site
state: North Carolina
city: Columbus
country: United States
facility: Travere Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: Travere Investigational Site
state: Oklahoma
city: Philadelphia
country: United States
facility: Travere Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Travere Investigational Site
state: Pennsylvania
city: Houston
country: United States
facility: Travere Investigational Site
state: Texas
city: Seattle
country: United States
facility: Travere Investigational Site
state: Washington
city: Hamburg
country: Germany
facility: Travere Investigational Site
city: Heidelberg
country: Germany
facility: Travere Investigational Site
city: Köln
country: Germany
facility: Travere Investigational Site
city: Bari
country: Italy
facility: Travere Investigational Site
city: Genova
country: Italy
facility: Travere Investigational Site
city: Milano
country: Italy
facility: Travere Investigational Site
city: Padova
country: Italy
facility: Travere Investigational Site
city: Roma
country: Italy
facility: Travere Investigational Site
city: Amsterdam
country: Netherlands
facility: Travere Investigational Site
city: Nijmegen
country: Netherlands
facility: Travere Investigational Site
city: Kraków
country: Poland
facility: Travere Investigational Site
city: Warsaw
country: Poland
facility: Travere Investigational Site
city: Łódź
country: Poland
facility: Travere Investigational Site
city: Barcelona
country: Spain
facility: Travere Investigational Site
city: Madrid
country: Spain
facility: Travere Investigational Site
city: Madrid
country: Spain
facility: Travere Investigational Site
city: Sevilla
country: Spain
facility: Travere Investigational Site
city: Göteborg
country: Sweden
facility: Travere Investigational Site
city: Stockholm
country: Sweden
facility: Travere Investigational Site
city: Bristol
country: United Kingdom
facility: Travere Investigational Site
city: Glasgow
country: United Kingdom
facility: Travere Investigational Site
city: Liverpool
country: United Kingdom
facility: Travere Investigational Site
city: London
country: United Kingdom
facility: Travere Investigational Site
city: Manchester
country: United Kingdom
facility: Travere Investigational Site
Study officials:
affiliation: Travere Therapeutics, Inc.
name: Radko Komers, MD, PhD
role: STUDY_DIRECTOR
References: