Clinical trial NCT03762850: A Study of the Effect and Safety of Sparsentan in the Treatment of Patients With IgA Nephropathy
Official title: A Randomized, Multicenter, Double-blind, Parallel-group, Active-control Study of the Efficacy and Safety of Sparsentan for the Treatment of Immunoglobulin A Nephropathy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Immunoglobulin A Nephropathy
Lead sponsor: Travere Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2018-12-04
Enrollment: 406
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To determine the long-term (approximately 2 years) nephroprotective potential of treatment with sparsentan as compared to an angiotensin receptor blocker in patients with immunoglobulin A nephropathy (IgAN).

Detailed description: This is a 114-week,randomized, multicenter, double-blind, parallel-group, active-control study with an open-label extension period of up to 156 weeks, for a total duration of up to 270 weeks in patients with IgAN who have persistent overt proteinuria and remain at high risk of disease progression despite being on a stable dose (or doses) of an angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) that is (are) a maximum tolerated dose that is at least one half of the maximum labeled dose (MLD) (according to approved labeling. Approximately 380 patients aged ≥18 years will be enrolled in the study globally. The investigational drug (sparsentan) is a dual acting angiotensin receptor blocker and endothelin receptor antagonist. The active control is irbesartan.

The purpose of the study is to evaluate the potential benefit of sparsentan on kidney function by analyzing change in proteinuria (protein in urine) and estimated glomerular filtration rate (eGFR) as compared to current standard treatment.

Patients enrolled in the PROTECT study (Protocol 021IGAN17001) will be those at high risk of progressing to renal failure. They will be randomly assigned in a 1:1 ratio to either sparsentan or irbesartan, as the active control (current standard treatment) at the Day 1 (Randomization) visit. Study medication (sparsentan and irbesartan) will be administered as a single oral morning dose.

The primary analysis is change in proteinuria (urine protein/creatinine ratio) from baseline at Week 36 in sparsentan-treated patients as compared to irbesartan-treated patients.

Primary completion date represents the anticipated completion date of the double-blind portion of the study. Study completion date represents the anticipated completion date of the open-label extension portion of the study.

Patients participating in the open-label extension period may be evaluated for eligibility to participate in a randomized, open-label, controlled Sub study evaluating the safety and efficacy of an SGLT2 inhibitor in addition to stable sparsentan treatment (OLE Sub study). The SGLT2 inhibitor, dapagliflozin will be provided as "study medication" for the OLE Sub study. Following completion of the visit 12 weeks after the OLE baseline visit, eligible patients may receive open-label dapagliflozin for at least 12 weeks but up to 24 additional weeks, or through the end of the open-label extension period, whichever is shortest. Approximately 60 patients from the open-label extension period will be enrolled into the OLE Sub study.

Eligibility criteria: Key Inclusion Criteria for the Double-Blind Period:

* Age 18 years or older at screening
* Biopsy-proven primary IgAN
* Proteinuria of ≥1 g/day at screening
* eGFR ≥30 mL/min/1.73 m2 at screening
* Currently on stable dose of ACEI and/or ARB therapy, for at least 12 weeks prior to screening (maximum tolerated dose and at least one-half of the maximum labeled dose)
* Systolic BP ≤150 mmHg and diastolic BP ≤100 mmHg at screening
* Willing to undergo change in ACEI and/or ARB and anti-hypertensive medications
* Agree to contraception

Key Exclusion Criteria for the Double-Blind Period:

* IgAN secondary to another condition
* Presence of cellular glomerular crescents in \>25% of glomeruli on renal biopsy (if biopsy available within 6 months of screening)
* Chronic kidney disease (CKD) in addition to IgAN
* History of organ transplantation, with exception of corneal transplants
* Require any prohibited medications
* Treatment of systemic immunosuppressive medications (including corticosteroids) for \>2 weeks within 3 months of screening
* History of heart failure or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema
* Clinically significant cerebrovascular disease or coronary artery disease within 6 months of screening
* Jaundice, hepatitis, or known hepatobiliary disease or elevations of transaminases (ALT/AST) \>2 times upper limit of normal at screening
* History of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years
* Hematocrit value \<27% (0.27 V/V) or hemoglobin value \<9 g/dL (90 g/L) at Screening
* Potassium \>5.5 mEq/L (5.5 mmol/L) at Screening
* History of alcohol of illicit drug use disorder
* History of serious side effect or allergic response to any angiotensin II antagonist or endothelin receptor antagonist, including sparsentan or irbesartan, or has a hypersensitivity to any of the excipients in the study medications
* For female: Pregnancy, or planning to become pregnant during the course of the study, or breastfeeding
* Participation in a study of another investigational product within 28 days of screening

Key Inclusion Criteria for the Open-Label Extension Period based on assessments at the Week 110 visit:

* Completed participation in the double-blind period, including the Week 114 visit
* Did not permanently discontinue study medication during the double-blind period
* Agree to contraception

Key Exclusion Criteria for the Open-Label Extension Period based on assessments at the Week 110 and Week 114 visits:

* Progression to end-stage renal disease (ESRD) requiring renal replacement therapy (RRT)
* Development of any criteria for discontinuation of study medication or discontinuation from the study, between Week 110 and Week 114
* Patient was unable to initiate, or developed contraindications to, treatment with RAAS inhibitors between Week 110 and Week 114
* eGFR ≤20 mL/min/1.73 m2 at Week 110
* Female patient is pregnant or breastfeeding

Key Inclusion Criteria for the OLE Sparsentan + SGLT2 Inhibitor Sub study:

* Participating in the open-label extension and is willing and able to provide signed informed consent for participation in the open-label extension period Sub study
* A urine protein excretion value of ≥0.3 g/day.
* An eGFR of ≥25 mL/min/1.73m2
* On a stable dose of sparsentan for ≥8 weeks in the open-label extension period that is the maximum tolerated dose.

Key Exclusion Criteria for the OLE Sparsentan + SGLT2 Inhibitor Sub study:

* Progressed to ESRD requiring RRT
* Initiated or changed dose of a systemic immunosuppressive medication (including systemic steroids) within 12 weeks
* Taking an SGLT2 inhibitor within 12 weeks

Primary outcomes:
measure: Percent Change From Baseline in the Urine Protein/Creatinine (UP/C) at Week 36
timeFrame: Baseline (Day 1) and at Week 36
Secondary outcomes:
measure: Total Slope of Estimated Glomerular Filtration Rate (eGFR) Over a 110-week Period
timeFrame: From Day 1 to Week 110
measure: Annualized Slope of eGFR Following the Initial Acute Effect of Randomized Treatment (Chronic Slope)
timeFrame: From Week 6 to Week 110 post randomization
Other outcomes:
Locations:
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facility: Travere Investigational Site
state: Alabama
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facility: Travere Investigational Site
state: Alabama
city: Glendale
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state: California
city: Montebello
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city: San Diego
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city: New Lambton Heights
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city: Randwick
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state: New South Wales
city: St Leonards
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city: Birtinya
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city: Adelaide
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city: Reservoir
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city: Nedlands
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city: Liège
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country: Croatia
facility: Travere Investigational Site
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city: Praha 10
country: Czechia
facility: Travere Investigational Site
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country: Czechia
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city: Tallinn
country: Estonia
facility: Travere Investigational Site
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country: Estonia
facility: Travere Investigational Site
city: Tartu
country: Estonia
facility: Travere Investigational Site
city: Marseille
country: France
facility: Travere Investigational Site
state: Bouches-du-Rhone
city: Montpellier Cedex 5
country: France
facility: Travere Investigational Site
state: Herault
city: Grenoble Cedex 9
country: France
facility: Travere Investigational Site
state: Isere
city: Saint-Priest-en-Jarez
country: France
facility: Travere Investigational Site
state: Loire
city: Paris Cedex 15
country: France
facility: Travere Investigational Site
state: Paris
city: Clermont Ferrand Cedex
country: France
facility: Travere Investigational Site
state: Puy De Dome
city: Créteil
country: France
facility: Travere Investigational Site
city: Paris
country: France
facility: Travere Investigational Site
city: Villingen-Schwenningen
country: Germany
facility: Travere Investigational Site
state: Baden Wuerttemberg
city: Hanover
country: Germany
facility: Travere Investigational Site
state: Lower Saxony
city: Duesseldorf
country: Germany
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state: Nordrhein Westfalen
city: Aachen
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state: North Rhine Westphalia
city: Kaiserslautern
country: Germany
facility: Travere Investigational Site
state: Rheinland Palatinate
city: Trier
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state: Rheinland Palatinate
city: Kiel
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state: Schleswig Holstein
city: Kiel
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state: Schleswig-Holstein
city: Jena
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state: Thueringen
city: Berlin
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city: Kwun Tong
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city: Tsuen Wan
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country: Italy
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state: Bergamo
city: Milan
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city: Bari
country: Italy
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country: Korea, Republic of
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country: Korea, Republic of
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country: Poland
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country: Poland
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country: Poland
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country: Portugal
facility: Travere Investigational Site
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country: Portugal
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country: Portugal
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country: Portugal
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city: Setúbal
country: Portugal
facility: Travere Investigational Site
city: Vila Nova De Gaia
country: Portugal
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city: Palma De Mallorca
country: Spain
facility: Travere Investigational Site
state: Baleares
city: Sagunto
country: Spain
facility: Travere Investigational Site
state: Valencia
city: Barcelona
country: Spain
facility: Travere Investigational Site
city: Barcelona
country: Spain
facility: Travere Investigational Site
city: Barcelona
country: Spain
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city: Barcelona
country: Spain
facility: Travere Investigational Site
city: Madrid
country: Spain
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city: Madrid
country: Spain
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city: Madrid
country: Spain
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city: Sevilla
country: Spain
facility: Travere Investigational Site
city: Valencia
country: Spain
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city: Valencia
country: Spain
facility: Travere Investigational Site
city: Zaragoza
country: Spain
facility: Travere Investigational Site
city: Hualien City
country: Taiwan
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city: Kaohsiung
country: Taiwan
facility: Travere Investigational Site
city: Kaohsiung
country: Taiwan
facility: Travere Investigational Site
city: New Taipei City
country: Taiwan
facility: Travere Investigational Site
city: Taichung
country: Taiwan
facility: Travere Investigational Site
city: Reading
country: United Kingdom
facility: Travere Investigational Site
state: Berkshire
city: Cambridge
country: United Kingdom
facility: Travere Investigational Site
state: Cambridgeshire
city: Middlesbrough
country: United Kingdom
facility: Travere Investigational Site
state: Cleveland
city: Derby
country: United Kingdom
facility: Travere Investigational Site
state: Derbyshire
city: Brighton
country: United Kingdom
facility: Travere Investigational Site
state: East Sussex
city: London
country: United Kingdom
facility: Travere Investigational Site
state: Greater London
city: London
country: United Kingdom
facility: Travere Investigational Site
state: Greater London
city: Manchester
country: United Kingdom
facility: Travere Investigational Site
state: Greater Manchester
city: Salford
country: United Kingdom
facility: Travere Investigational Site
state: Greater Manchester
city: Preston
country: United Kingdom
facility: Travere Investigational Site
state: Lancashire
city: Leicester
country: United Kingdom
facility: Travere Investigational Site
state: Leicestershire
city: Edinburgh
country: United Kingdom
facility: Travere Investigational Site
state: Scotland
city: Stoke-on-Trent
country: United Kingdom
facility: Travere Investigational Site
state: Staffordshire
city: Glasgow
country: United Kingdom
facility: Travere Investigational Site
state: Strathclyde
city: Carshalton
country: United Kingdom
facility: Travere Investigational Site
state: Surrey
city: Cardiff
country: United Kingdom
facility: Travere Investigational Site
state: West Glamorgan
city: Birmingham
country: United Kingdom
facility: Travere Investigational Site
state: West Midlands
city: Liverpool
country: United Kingdom
facility: Travere Investigational Site
city: London
country: United Kingdom
facility: Travere Investigational Site
city: London
country: United Kingdom
facility: Travere Investigational Site
Study officials:
affiliation: Travere Therapeutics, Inc.
name: Radko Komers, MD, PhD
role: STUDY_DIRECTOR
References: