A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PARALLEL, ACTIVECONTROL STUDY OF THE EFFECTS OF SPARSENTAN, A DUAL ENDOTHELIN RECEPTOR AND ANGIOTENSIN RECEPTOR BLOCKER, ON RENAL OUTCOMES IN PATIENTS WITH PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)
Study ID: STU 122017-059
This is a randomized, multicenter, double-blind, parallel, active-control study. approximately 300 patients aged 8 to 75 years, inclusive (uS) and 18-75 years, inclusive (outside of the uS) will be enrolled in the study. Patients who meet inclusion criteria during screening who are taking RaaS inhibitors will undergo a 2-week washout period from these agents prior to Day 1/Randomization. Following screening (and the washout period for patients taking RaaS inhibitors), all patients will undergo comprehensive baseline evaluations and clinical laboratory tests, and will be randomly assigned in a 1:1 ratio to receive either sparsentan (initial dose of 400 mg daily for 2 weeks, titrating up to a target dose of 800 mg daily) or an active control (irbesartan; initial dose of 150 mg daily for 2 weeks, titrating up to a target dose of 300 mg daily) (see Section 8.1). Randomization will include stratification by screening eGFR and uP/C values. The strata will be as follow: * eGFR strata: [?] [GreaterThanorequalTo]30 to [Less Than]60 mL/min/1.73 m2 (all patients) [?] [GreaterThanorequalTo]60 mL/min/1.73 m2 (all patients) * uP/C strata: [?] [LessThanorequalTo]3.5 g/g (patients [GreaterThanorequalTo]18 years of age) or [LessThanorequalTo]2 g/g (patients [Less Than]18 years of age) [?] [Greater Than]3.5 g/g (patients [GreaterThanorequalTo]18 years of age) or [Greater Than]2 g/g (patients [Less Than]18 years of age) Sparsentan and irbesartan concentrations in plasma will be evaluated. at applicable visits (see Section 15.1), one trough sample will be obtained pre-dose in the clinic. unless otherwise specified, endpoints will use pre-treatment values obtained prior to randomization as baseline. The follow-up visits to obtain measurements will be conducted at 3-month intervals unless otherwise specified. additional antihypertensive agents are allowed during the study to maintain blood pressure [LessThanorequalTo]130/80 mmHg (patients [GreaterThanorequalTo]18 years of age) or [LessThanorequalTo] the 75th percentile (patients [Less Than]18 years of age; Banker, 2016), with the exception of those that inhibit the RaaS and eT systems (see Section 15.2.1 for concomitant medication considerations). an unblinded analysis will be performed after 36 weeks following randomization of at least 190 patients (approximately 95 per treatment group) to evaluate the surrogate efficacy endpoint (ie, the proportion of patients achieving a uP/C [LessThanorequalTo]1.5 g/g and a [Greater Than]40% reduction in uP/C at Week 36). Following a 108-week blinded treatment period, treatment with study medication will be discontinued. at this time, the investigator should resume standard-of-care treatment, including treatment with RaaS inhibitors provided there are no contraindications for their use. if the patient was treated with irbesartan at study entry, an alternative aRB at an equivalent dose is required from Week 108 to Week 112. The investigator may make additional adjustments in antihypertensive medications as necessary to adequately control the patient's blood pressure. Patients will return to the site for the final visit 4 weeks after study medication has been discontinued.
1. The patient or parent/legal guardian (as appropriate) is willing and able to provide signed informed consent, and where required, the patient is willing to provide assent, prior to any screening procedures. 2. The patient has biopsy-proven FSGS or documentation of a genetic mutation in a podocyte protein associated with FSGS. The biopsy may have been performed at any time in the past. The patient may be enrolled based on light microscopy diagnosis of FSGS in the absence of EM and/or IF analysis, provided the history and/or the course of the disease are indicative of primary FSGS. 3. Sites within the US: The patient is male or female aged 8 to 75 years, inclusive, weighing >=20 kg, at screening. Sites outside the US: The patient is male or female aged 18 to 75 years, inclusive, weighing >=20 kg, at screening. 4. The patient has a UP/C >=1.5 g/g at screening. 5. The patient has an eGFR >=30 mL/min/1.73 m2 at screening. 6. The patient has a mean seated blood pressure >=100/60 mmHg and <=160/100 mmHg (patients >=18 years of age) or between the 5th and 95th percentile for age, sex, and height (patients <18 years of age; Banker, 2016). 7. Women of childbearing potential (WOCBP), beginning at menarche, must agree to the use of one highly reliable (ie, can achieve a failure rate of <1% per year) method of contraception from 7 days prior to the first dose of study medication until 90 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 inhibition of ovulation, or an intrauterine device (IUD) in place for at least 3 months. One additional barrier method must also be used during sexual activity, such as a diaphragm or diaphragm with spermicide (preferred), or male partner[Single Quote]s use of male condom or male condom with spermicide (preferred), from Day 1/Randomization until 90 days after the last dose of study medication. WOCBP are defined as those who are fertile, following menarche and until becoming postmenopausal unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as amenorrhea for more than 24 consecutive months without an alternative medical cause; women on hormone replacement therapy must have a documented plasma follicle-stimulating hormone level >40 mIU/mL. All WOCBP must have a negative serum pregnancy test at Screening (Visit 1), and a negative urine pregnancy test, with positive results confirmed by serum, at every study visit from Randomization (Visit 3) and after. NOTE: Prior to menarche, pregnancy testing and contraceptive use is not required. However, the patient and their parent/guardian must be advised that, immediately upon menarche, the patient will be required to begin pregnancy testing and initiate contraceptive use. This requirement cannot be avoided.
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- ELIZABETH J BROWN
efficacy objective The efficacy objective of the study is to determine the long-term nephroprotective potential of treatment with sparsentan as compared to an angiotensin receptor blocker in patients with primary and genetic focal segmental glomerulosclerosis (FSGS). Safety objective The safety objective of the study is to assess the safety and tolerability of sparsentan by double-blind monitoring of safety endpoints. Rational of the study The preliminary results from the interim analysis of data from the DueT trial (see Section 4) indicate that sparsentan has a markedly stronger antiproteinuric effect than irbesartan over a period of 8 weeks in patients with primary FSGS. although most nephrologists accept that even a short-term treatment-associated reduction in proteinuria results in better long-term renal outcomes, this hypothesis must be investigated further in a long-term study focusing on the durability of sparsentan's effect over a longer time period, and also on kidney function as measured by eGFR.