Please select the eligibility criteria that correspond to the clinical trial below.
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
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).


Options:
A: Inclusion Criteria:

* Male or female patients from 18-70 years with histologically proven primary IgAN with typical mesangioproliferative features. Diagnosis has to be made by a neuropathologist.
* Proteinuria above 0.75 g/day within 12 weeks prior to or at the first visit in the run-in phase (month -6)and presence of at least one further risk factor for the development of end stage renal disease

  1. arterial hypertension, defined as ambulatory blood pressure \>140/90 mm Hg or the use of antihypertensive medication or
  2. impaired renal function, defined as creatinine clearance or estimated GFR \<90 ml/min.

Exclusion Criteria:

* Known allergy or intolerance to study medication (except in case of ACE-inhibitor, in which case a change to an angiotensin receptor blocker is possible).
* Women who are pregnant or breastfeeding and women without sufficient contraception.
* Any prior immunosuppressive therapy.
* Variants of primary IgAN (e.g. rapidly progressive IgAN with crescents in \>50% of glomeruli or minimal change GN with glomerular IgA deposits).
* Significant liver dysfunction (more than three fold increased GPT compared to norm)
* Contraindication for immunosuppressive therapy, like

  * acute or chronic infectious disease incl. hepatitis and HIV positive patients
  * any malignancy
  * leukocytopenia, thrombocytopenia or known allergy against prednisolone, cyclophosphamide or azathioprine
  * active intestinal bleeding, active gastric or duodenal ulcer
  * Need of permanent immunosuppression, (e.g. transplanted patients, steroid-dependent inflammatory diseases)
* Secondary IgAN or diseases associated with glomerular deposits of IgA.
* Additional other chronic renal disease.
* Creatinine clearance below 30 ml/min (mean of 3 measurements).
* Alcohol or drug abuse
* Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study
* Subject unlikely to comply with protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
* Participation in a parallel clinical trial or participation in another clinical trial within the last 3 months.
* Subjects who are in any state of dependency to the sponsor or the investigators.
* Employees of the sponsor or the investigators.
* Subjects who have been committed to an institution by legal or regulatory order.
B: Inclusion Criteria:

Coronary Artery Disease: Previous Myocardial infarction(\> 2 days prior to informed consent), or stable or previous unstable angina (\> 30 days prior to informed consent) with documented multivessel coronary artery disease or a positive stress test, or multivessel Percutaneous Transluminal Coronary Angioplasty (\> 30 days prior to informed consent), or previous multivessel Coronary Artery Bypass Grafting without angina (if surgery performed \> 4 years prior to informed consent) or with recurrent angina after surgery.

Other High Risk:

1. Peripheral Arterial Disease: Previous limb bypass surgery or angioplasty or amputation, intermittent claudication on history with ankle/arm Blood Pressure ratio \< 0.8 on at least one side, or significant stenosis by angiography or non-invasive testing
2. Previous stroke
3. Transient ischemic Attack \> 7 days and \< 1 year prior to informed consent
4. Diabetes Mellitus (types I or II): with evidence of end-organ damage (retinopathy, Left ventricular hypertrophy, micro or macro albuminuria), or any evidence of previous cardiac or vascular disease.

No definite and specific indication or contraindication for any of the study treatments. Written informed consent.

Exclusion Criteria:

A. Medication use:

1. Inability to discontinue Angiotension Converting Enzyme (ACE) inhibitors or Angiotension 2 receptor antagonists (AIIAs).
2. Patients with known hypersensitivity or intolerance to Angiotension 2 receptor antagonists (AIIAs) or Angiotension Converting Enzyme (ACE)inhibitors.

NOTE: Patients with known intolerance to Angiotension Converting Enzyme inhibitor intolerance ( ACE-I) can be enrolled in the TRANSCEND study.

B. Cardiovascular disease:

1. Symptomatic congestive heart failure.
2. Hemodynamically significant primary valvular or outflow tract obstruction (e.g. aortic or mitral valve stenosis, asymmetric septal hypertrophy, malfunctioning prosthetic valve).
3. Constrictive pericarditis.
4. Complex congenital heart disease.
5. Syncopal episodes of unknown etiology \< 3 months before informed consent.
6. Planned cardiac surgery or angioplasty within three months.
7. Uncontrolled hypertension on treatment (i.e.Blood pressure ( BP) \> 160/100).
8. Heart transplant recipient.
9. Strokes due to subarachnoid hemorrhage

C. Other conditions:

1. Significant renal disease defined as:

   1. Renal artery stenosis;
   2. Creatinine clearance \< 0.6 ml/min or serum creatinine \> 265 umol/L (\> 3.0 mg/dL);
   3. Hyperkalemia: potassium \> 5.5 mmol/L.
   4. Proteinuria\* (for TRANSCEND only).
2. Hepatic dysfunction as defined by the following laboratory parameters: Serum Glutamate Pyruvate Transaminase( SGPT) Alaninaminotransferase (ALT) or Serum Glutamic Oxaloacetic Transaminase (SGOT) Aspartate aminotransferase (AST) \> than 4 times upper limit of normal or additional criteria for hepatic impairment the upper limit of normal range, total Bilirubin \> 20 umol/L, biliary obstructive disorders.
3. Uncorrected volume depletion or sodium depletion.
4. Primary aldosteronism.
5. Hereditary fructose intolerance.
6. Any other major non-cardiac illness expected to reduce life expectancy or interfere with study participation.
7. Patient is simultaneously taking another experimental drug.
8. Patient with significant disability that precludes regular attendance at clinic for follow-up.
9. Patient has sufficient disability or other incapacity that precludes regular attendance at clinic for follow-up.
10. Unable or unwilling to provide written informed consent.
C: 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
D: Inclusion Criteria:

* Clinical diagnosed as chronic nephritic syndrome
* IgA nephropathy diagnosed by kidney biopsy
* Aged from 18 to 65 years，male or female
* Blood pressure of ≤140/90mmHg
* Estimated Glomerular Filtration Rate (eGFR)≥45ml/min/1.73 m2
* 24-hour proteinuria ranged between 0.5g-3.0g
* Obtaining the signed informed consent from patients

Exclusion Criteria:

* Secondary IgA nephropathy
* Be allergic to Huangkui Capsule or Losartan potassium tablet
* Taken Huangkui Capsule or ACEI or ARB in last 6 weeks
* Taken the glucocorticoids, immunosuppressants or common threewingnut root and such as drugs with immunosuppressive actions in the last 12 months
* Blood pressure \<90/60mmHg
* Serum potassium level \> 5.5mmol / L
* Serum albumin level \<30g / L
* Lactation, pregnancy or plans pregnancy during the study period
* Unilateral or bilateral renal artery stenosis
* Combined with severe primary diseases of heart, brain, liver and hematopoietic system and so on, or other serious diseases which can affect the patient's life
* Participating in another clinical study in the same period

Answer: C