A Study to Evaluate the Soluble Guanylate Cyclase (sGC) Stimulator IW-1973 in Diabetic Nephropathy / Diabetic Kidney Disease as Measured by Albuminuria

Study Overview
=================
Brief Summary
-----------------
To evaluate the safety and efficacy of IW-1973 in patients with type 2 diabetes mellitus with albuminuria who are on a stable regimen of renin-angiotensin system inhibitors.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the Safety and Efficacy of IW-1973 in Patients With Type 2 Diabetes With Albuminuria Treated With Renin-Angiotensin System Inhibitors

Conditions
-----------------
Type 2 Diabetes Mellitus With Diabetic Nephropathy

Intervention / Treatment
-----------------
* Drug: IW-1973
* Drug: IW-1973
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Patient is an ambulatory male or female from 25 to 75 years old at the Screening Visit. Patient has type 2 diabetes diagnosed by a physician or nurse practitioner ≥6 months before the Screening Visit, has been on ≥1 antihyperglycemic medication for ≥12 weeks preceding the Randomization Visit, and has been on a stable regimen (ie, same drug and same dose) of ≥1 antihyperglycemic medication for ≥28 days preceding the Randomization Visit. (Modification of short-acting insulin throughout the Screening Period will not affect eligibility.) Patient has been on a stable regimen (ie, same drug and dose) of antihypertensive medications, which must include an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), for ≥28 days preceding the Randomization Visit and is expected to remain on their regimen through the Follow-up Visit. Patient has the following: Estimated glomerular filtration rate (eGFR) 30 to 75 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (1) at the Screening and Baseline Visits Urine albumin-to-creatinine ratio (UACR) >200 mg/g at the Screening and Baseline Visits and <5000 mg/g at Screening and Baseline Visits Serum albumin >3.0 g/dL at the Screening and Baseline Visits Hemoglobin A1c (HbA1c) ≤11% at the Screening and Baseline Visits Systolic blood pressure (BP) of 110 to 160 mm Hg at the Screening and Baseline Visits Women of childbearing potential must have a negative pregnancy test prior to randomization and must agree to use protocol-specified contraception from the Screening Visit through 60 days after the final dose of study drug. Male patients must be surgically sterile by vasectomy (conducted ≥60 days before the Screening Visit or confirmed via sperm analysis) or must agree to use protocol-specified contraception from the Screening Visit through 60 days after the final dose of study drug. Other inclusion criteria per protocol. Key Exclusion Criteria: Patient has a history of secondary hypertension (ie, renal artery stenosis, primary aldosteronism, or pheochromocytoma). Patient has a body mass index (BMI) <20 or >45 kg/m2 at the Screening Visit. Patient has a history of platelet dysfunction, hemophilia, von Willebrand disease, coagulation disorder, other bleeding diathesis, or significant, nontraumatic bleeding episode(s), such as from a gastrointestinal source. Patient has hepatic impairment defined as Child-Pugh A, B, C. Patient has significant comorbidities (eg, malignancy, advanced liver disease, pulmonary hypertension, pulmonary fibrosis, lung disease requiring supplemental oxygen) or other significant conditions that, in the Investigator's opinion, would limit the patient's ability to complete or participate in this clinical study; has been hospitalized for cardiovascular, renal, or metabolic cause in the 3 months before the Screening Visit; or has a life expectancy of less than 1 year. Patient has had prior dialysis, renal transplant, or planned renal transplant. Patient has clinically active, symptomatic, or unstable coronary artery or heart disease within the 3 months before the Screening Visit, defined as 1 of the following: Hospitalization for myocardial infarction (MI), unstable angina, or heart failure New-onset angina with positive functional study or coronary angiogram revealing stenosis Coronary revascularization procedure Patient has a history of clinically significant hypersensitivity or allergies to any of the inactive ingredients contained in the active or placebo drug products. Patient has previously received IW-1973 in a study, or received an investigational drug during the 30 days or 5 half-lives of that investigational drug (whichever is longer) before the Screening Visit, or is planning to receive another investigational drug at any time during the study. Patient is taking specific inhibitors of phosphodiesterase 5 (PDE5), nonspecific inhibitors of PDE5 (including dipyridamole and theophylline), any supplements for the treatment of erectile dysfunction, riociguat, or nitrates or nitric oxide (NO) donors in any form. These medications and supplements are prohibited from 7 days before Randomization through the duration of the study. Patient is taking strong cytochrome P450 3A (CYP3A) inhibitors (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, and nefazodone). These medications are prohibited 14 days before Randomization through the duration of the trial. Other exclusion criteria per protocol.

Ages Eligible for Study
-----------------
Minimum Age: 25 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 2, randomized, double-blind, placebo-controlled, parallel-group study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IW-1973 Low Dose<br>Administered daily for 12 weeks | Drug: IW-1973<br>* Oral Tablet<br>|
| Experimental: IW-1973 High Dose<br>Administered daily for 12 weeks | Drug: IW-1973<br>* Oral Tablet<br>|
| Placebo Comparator: Placebo<br>Placebo to match experimental drug administered daily for 12 weeks | Drug: Placebo<br>* Oral Tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Study Drug-Related TEAEs | An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TEAEs are defined as those AEs that started or worsened in severity after the initiation of study drug administration. Causality relationship to study drug was per Investigator assessment. | Day 1 up to Day 115 | 
| Percent Change From Baseline in Urine Albumin Creatinine Ratio (UACR) Over Weeks 8 and 12 | Urine samples were collected for the analysis of UACR. UACR (milligrams per gram [mg/g]) was calculated as urine albumin (mg per deciliter [mg/dL]) / urine creatinine (g/dL). Change from Baseline was calculated as the average of the UCAR values at Weeks 8 and 12 minus the Baseline value. Data were analyzed using a mixed-effects model repeated measures (MMRM) analysis with change from Baseline in log-transformed UACR as the response variable, treatment, visit, treatment-by visit interaction, and Baseline estimated glomerular filtration rate stratum as fixed effects, Baseline log-transformed UACR and Baseline mean arterial pressure as covariates, and unstructured as the variance-covariance structure. | Baseline; Week 8 to Week 12 |