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

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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus With Diabetic Nephropathy
• Intervention / Treatment: Drug: IW-1973; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 156
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Chula Vista, California, United States, 91910
      • California Institute of Renal Research
    • Fullerton, California, United States, 92835
      • St. Joseph Heritage Healthcare (St. Jude Hospital DBA)
    • La Mesa, California, United States, 91942
      • California Institute of Renal Research
    • Lomita, California, United States, 90717
      • Torrance Clinical Research Institute, Inc.
    • Los Angeles, California, United States, 90022
      • Academic Medical Research Institute
    • Los Angeles, California, United States, 90017
      • American Institute of Research
    • Northridge, California, United States, 91324
      • California Medical Research Associates, Inc. (CMRA)
    • Riverside, California, United States, 92503
      • Riverside Nephrology Physicians, Inc.
    • San Dimas, California, United States, 91773
      • California Kidney Specialists
    • San Dimas, California, United States, 91773
      • North American Research Institute
    • Santa Monica, California, United States, 90025
      • UCLA
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
  • Colorado
    • Denver, Colorado, United States, 80209
      • Creekside Endocrine Associates
  • Delaware
    • Newark, Delaware, United States, 19713
      • Christiana Care Health Services
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • The George Washington University Medical Faculty Associates
  • Florida
    • Hialeah, Florida, United States, 33012
      • AGA Clinical Trials
    • Miami, Florida, United States, 33144
      • Elite Clinical Research
    • Miami, Florida, United States, 33015
      • Leon Medical Research Corp.
    • Miami, Florida, United States, 33155
      • DL Research Solutions
    • Miami, Florida, United States, 33165
      • Premier Research Associates, Inc.
    • Miami Lakes, Florida, United States, 33016
      • Sweet Hope Research Speciality, Inc.
    • Palmetto Bay, Florida, United States, 33157
      • IMIC, Inc.
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Atlanta Center for Clinical Research Nephrology
    • Columbus, Georgia, United States, 31904
      • Columbus Regional Research Institute
    • Lawrenceville, Georgia, United States, 30046
      • Gwinnett Biomedical Research
    • Macon, Georgia, United States, 31210
      • East Coast Institute for Clinical Research
    • Macon, Georgia, United States, 31210
      • East Coast Institute for Research
  • Idaho
    • Nampa, Idaho, United States, 83686
      • Saltzer Medical Group
  • Illinois
    • Chicago, Illinois, United States, 60643
      • Research by Design, LLC
  • Indiana
    • Franklin, Indiana, United States, 46131
      • American Health Network of Indiana
  • Kansas
    • Manhattan, Kansas, United States, 66502
      • My Kidney Center
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Kentucky Diabetes Endocrinology Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Michigan
    • Flint, Michigan, United States, 48504
      • Aa Mrc, Llc
  • Missouri
    • Saint Louis, Missouri, United States, 63136
      • St. Louis Heart & Vascular, P.C.
  • New Jersey
    • Linden, New Jersey, United States, 07036
      • NJ Heart, P.A.
  • New York
    • Albany, New York, United States, 12206
      • Albany Medical College, Division of Community Endocrinology
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • Physicians East Endocrinology
  • South Carolina
    • Greer, South Carolina, United States, 29651
      • Mountain View Clinical Research
    • Orangeburg, South Carolina, United States, 29118
      • South Carolina Nephrology & Hypertension Center
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • University of Tennessee Health Science Center at Memphis University Hospital
  • Texas
    • Beaumont, Texas, United States, 77702
      • Pioneer Research Solutions
    • El Paso, Texas, United States, 79935
      • Academy of Diabetes, Thyroid and Endocrine, P.A.
    • Fort Worth, Texas, United States, 76116
      • The Medical Group Of Texas
    • Fort Worth, Texas, United States, 76164
      • Rockwood Medical Center
    • Houston, Texas, United States, 77099
      • Pioneer Research Solutions, Inc.
    • Houston, Texas, United States, 77079
      • Endocrine Ips, Pllc
    • Lampasas, Texas, United States, 76550
      • Fmc Science, Llc
    • San Antonio, Texas, United States, 78215
      • Clinical Advancement Center PLLC
    • San Antonio, Texas, United States, 78224
      • Briggs Clinical Research
  • Virginia
    • Burke, Virginia, United States, 22015
      • Burke Internal Medicine and Research
    • Manassas, Virginia, United States, 20110
      • Manassas Clinical Research Center
  • Washington
    • Spokane, Washington, United States, 99208
      • Northside Endocrinology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. 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
  2. Urine albumin-to-creatinine ratio (UACR) >200 mg/g at the Screening and Baseline Visits and <5000 mg/g at Screening and Baseline Visits
  3. Serum albumin >3.0 g/dL at the Screening and Baseline Visits
  4. Hemoglobin A1c (HbA1c) ≤11% at the Screening and Baseline Visits
  5. 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:

  1. Hospitalization for myocardial infarction (MI), unstable angina, or heart failure
  2. New-onset angina with positive functional study or coronary angiogram revealing stenosis
  3. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Akebia Therapeutics
• Collaborators: Cyclerion Therapeutics
• Investigators: Study Director: John Hanrahan, MD MPH, Cyclerion Therapeutics, Inc.

Publications and helpful links

General Publications

• Hanrahan JP, de Boer IH, Bakris GL, Wilson PJ, Wakefield JD, Seferovic JP, Chickering JG, Chien YT, Carlson K, Cressman MD, Currie MG, Milne GT, Profy AT. Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease: A Randomized Placebo-Controlled Clinical Trial. Clin J Am Soc Nephrol. 2020 Dec 31;16(1):59-69. doi: 10.2215/CJN.08410520. Epub 2020 Dec 16.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2017
• Primary Completion (Actual): August 20, 2019
• Study Completion (Actual): August 20, 2019

Study Registration Dates

• First Submitted: July 12, 2017
• First Submitted That Met QC Criteria: July 12, 2017
• First Posted (Actual): July 14, 2017

Study Record Updates

• Last Update Posted (Actual): September 15, 2022
• Last Update Submitted That Met QC Criteria: August 18, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Urological Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Urination Disorders; Proteinuria; Diabetes Mellitus, Type 2; Kidney Diseases; Diabetic Nephropathies; Albuminuria; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Enzyme Activators; Praliciguat
• Other Study ID Numbers: C1973-203

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No