Effectiveness and Safety of Sparsentan as treatment for Immunoglobulin A Nephropathy (IgAN)

• Register: EUCTR
• Last refreshed on: 26 November 2018
• Main ID: EUCTR2017-004605-41-ES
• Date of registration: 30/07/2018
• Prospective Registration: Yes
• Primary sponsor: Retrophin, Inc.
• Public title: Effectiveness and Safety of Sparsentan as treatment for Immunoglobulin A Nephropathy (IgAN)
• Scientific 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
• Date of first enrolment: 27/09/2018
• Target sample size: 280
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-004605-41
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Croatia, Czech Republic, Estonia, France, Germany, Hong Kong, Hungary, Italy, Korea, Republic of, Lithuania, Malaysia, New Zealand, Poland, Portugal, Spain, Turkey, United Kingdom, United States

Contacts

• Name: Retrophin Call Center
• Affiliation: Retrophin, Inc.

• Name: Retrophin Call Center
• Affiliation: Retrophin, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. The patient is willing and able to provide signed informed consent.
2. The patient is male or female, aged >=18 years.
3. The patient has biopsy-proven primary IgAN. The biopsy may have been performed at any time in the past.
4. The patient has a urine total protein value >=1.0 g/day at screening.
5. The patient has an eGFR >=30 mL/min/1.73 m2 at screening.
6. The patient has been on a stable dose of ACEI and/or ARB therapy for at least 12 weeks prior to screening that is:
A. the patient’s maximum tolerated dose, AND
B. at least one-half of the maximum labeled dose (according to approved labeling).
7. In the Investigator’s opinion, the patient’s blood pressure has been managed in accordance with standard of care using ACEI and/or ARB therapy as described in Inclusion Criterion #6 and additional antihypertensive agents if needed. At screening, the patient’s systolic blood pressure must be <=150 mmHg and diastolic blood pressure must be <=100 mmHg.
8. The patient is willing to undergo a change in ACEI and/or ARB and antihypertensive medications.
9. Women of childbearing potential (WOCBP) must agree to the simultaneous use of 2 medically accepted methods of contraception from randomization until 90 days after the last dose of study medication. At least one method of contraception must be highly reliable (ie, can achieve a failure rate of <1% per year), such as 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. The other method of contraception must be a barrier method, such as a diaphragm with spermicide or male partner’s use of male condom with spermicide. 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 pregnancy test (urine, with positive results confirmed by serum) at screening and randomization.
10. Males must be surgically sterile (more than 3 months post-vasectomy) or must agree to the use of medically accepted methods of contraception that are considered highly reliable from randomization until 90 days after the last dose of study medication.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 260
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

Exclusion criteria:
1. The patient has IgAN secondary to another condition (eg, systemic lupus erythematosus, liver cirrhosis) or Henoch-Schonlein purpura.
2. The patient has cellular glomerular crescents present in >25% of glomeruli on renal biopsy within 6 months prior to screening.
3. The patient has a history of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8%), or nonfasting blood glucose >180 mg/dL at screening.
4. The patient has undergone any organ transplantation, with the exception of corneal transplants.
5. The patient requires any of the prohibited concomitant medications.
6. The patient has been taking any systemic immunosuppressive medications (including corticosteroids) for >2 weeks within 3 months prior to screening.
7. The patient has a documented history of heart failure (New York Heart Association Class II-IV) and/or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema.
8. The patient has clinically significant cerebrovascular disease (transient ischemic attack or stroke) and/or coronary artery disease (hospitalization for myocardial infarction or unstable angina, new onset of angina with positive functional tests, coronary angiogram revealing stenosis, or a coronary revascularization procedure) within 6 months prior to screening.
9. The patient has jaundice, hepatitis, or known hepatobiliary disease (including asymptomatic cholelithiasis), or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 times the upper limit of the normal range at screening.
10. The patient has a history of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years.
11. The patient has a screening hematocrit value <27% or hemoglobin value <9 g/dL.
12. The patient has a screening potassium value of >5.5 mEq/L.
13. The patient has a history of alcohol or illicit drug use disorder (as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition).
14. The patient has a 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.
15. The female patient is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.
16. The male patient plans to father a child during the course of the study.
17. The patient has participated in a study of another investigational product within 28 days prior to screening, or plans to participate in such a study during the course of this study.
18. The patient, in the opinion of the Investigator, is unable to adhere to the requirements of the study, including the ability to swallow the study medication capsules whole.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Symptoms and general pathology [C23]

Immunoglobulin A Nephropathy (IgAN)
MedDRA version: 20.0 Level: PT Classification code 10021263 Term: IgA nephropathy System Organ Class: 10038359 - Renal and urinary disorders

Intervention(s)

Product Name: Sparsentan
Product Code: RE-021
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Sparsentan
CAS Number: 254740-64-2
Current Sponsor code: RE-021
Other descriptive name: SPARSENTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Trade Name: Irbesartan tablets (Approved in the USA. Reference listed drug Avapro) NDC # 43547-0374-03
Product Name: over-encapsulated 150 mg Irbesartan Tablets
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Irbesartan
CAS Number: 138402-11-6
Other descriptive name: IRBESARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Primary Outcome(s)

Secondary Objective: Not applicable

Timepoint(s) of evaluation of this end point: Primary efficacy endpoints will be evaluated at Week 36. The primary safety endpoint will be evaluated from randomization to Week 114.

Main Objective: The efficacy objective of the study is to determine the effect of sparsentan on proteinuria and renal function, as compared to an angiotensin receptor blocker, in patients with Immunoglobulin A Nephropathy (IgAN).

The safety objective of the study is to assess the safety and tolerability of sparsentan by double-blind monitoring of safety endpoints.

Primary end point(s): Efficacy End points:
The primary efficacy endpoint is the change from baseline in the urine protein/creatinine ratio (UP/C), based on a 24-hour urine sample, at Week 36, assessed on the log scale.

Safety End points:
• Changes from baseline in body weight, vital signs, physical examinations, peripheral edema, and clinical laboratory parameters
• The incidence of TEAEs

Secondary Outcome(s)

Secondary end point(s): Secondary efficacy endpoints:
The secondary efficacy endpoints with Type I error control are:
• The rate of change in eGFR over a 52-week (approximately 1-year) period following the initial acute effect of randomized therapy (the initial acute effect of randomized therapy is defined as the first 6 weeks of randomized treatment with study medication; thus, the analysis is from 6 weeks post randomization to 58 weeks post randomization)
• The rate of change in eGFR over a 104-week (approximately 2-year) period following the initial acute effect of randomized therapy (the initial acute effect of randomized therapy is defined as the first 6 weeks of randomized treatment with study medication; thus, the analysis is from 6 weeks post randomization to 110 weeks post randomization)
• Achievement of urinary protein excretion, based on a 24-hour urine sample, <0.3 g/day at Week 36

Other Efficacy Endpoints:
• The mean change from baseline over time in selected proteinuria variables, based on a 24-hour urine sample (eg, total urine protein, total urine albumin, urine albumin/creatinine ratio [UA/C]), up to Week 110
• The proportion of patients reaching a confirmed 40% change in eGFR, end-stage renal disease (ESRD), or death. (ESRD is defined as initiation of renal replacement therapy [RRT], kidney transplantation, or sustained eGFR <15 mL/min/1.73 m2.)

Exploratory endpoints are:
• The change from baseline in eGFR at 6 weeks post randomization (ie, the acute effect of randomized therapy)
• The change from end-of-treatment (EOT; ie, Week 110) in eGFR 4 weeks following cessation of treatment (ie, at Week 114)
• The proportion of patients with hematuria at each visit
• The proportion of patients requiring immunosuppressive medication during the study
• Mean changes from baseline in quality of life (QOL), measured via patient-reported outcome (PRO) at each visit beginning with Week 36
• Frequency and duration of hospitalizations (for any reason and for reasons related to the kidney)
• Trough plasma PK concentrations

Timepoint(s) of evaluation of this end point: The subsequent key secondary endpoint analysis of 6- to 110-week eGFR rate of change will be assessed at the 4% two-sided alpha level if the 6- to 58-week eGFR rate of change analysis fails to achieve p<0.01; otherwise the 6- to 110-week eGFR rate of change will be assessed at the 5% two-sided alpha level.

Secondary ID(s)

021IGAN17001

2017-004605-41-LT

Source(s) of Monetary Support

Retrophin, Inc.