Type 2 Diabetes Mellitus With Diabetic Nephropathy
Conditions
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.
Interventions
DRUGIW-1973
Oral Tablet
DRUGPlacebo
Oral Tablet
Sponsors
Cyclerion Therapeutics
Akebia Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Phase 2, randomized, double-blind, placebo-controlled, parallel-group study
Eligibility
Sex/Gender
ALL
Age
25 Years to 75 Years
Healthy volunteers
No
Inclusion 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: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Study Drug-Related TEAEs | Day 1 up to Day 115 | 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. |
| Percent Change From Baseline in Urine Albumin Creatinine Ratio (UACR) Over Weeks 8 and 12 | Baseline; Week 8 to Week 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. |
Countries
United States
Participant flow
Recruitment details
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to assess the safety and efficacy of praliciguat (IW-1973) in participants with type 2 diabetes mellitus with albuminuria who were on a stable regimen of renin-angiotensin system inhibitors.
Pre-assignment details
A total of 156 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive matching placebo orally for 12 weeks: 1 week of twice daily (BID) dosing (Days 1 through 7) followed by 11 weeks of once daily (QD) dosing. | 54 |
| Praliciguat 20 mg Participants were randomized to receive praliciguat 20 milligrams (mg) orally for 12 weeks: 1 week of BID dosing (Days 1 through 7) followed by 11 weeks of QD dosing. | 50 |
| Praliciguat 40 mg Participants were randomized to receive praliciguat 40 mg orally for 12 weeks: 1 week of BID dosing (Days 1 through 7) followed by 11 weeks of QD dosing. | 52 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 6 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 3 |
Baseline characteristics
| Characteristic | Placebo | Praliciguat 20 mg | Praliciguat 40 mg | Total |
|---|---|---|---|---|
| Age, Customized 18 - 45 | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Age, Customized >45 - 65 | 26 Participants | 25 Participants | 23 Participants | 74 Participants |
| Age, Customized >65 | 28 Participants | 24 Participants | 27 Participants | 79 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 30 Participants | 30 Participants | 85 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 20 Participants | 22 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 13 Participants | 14 Participants | 37 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 41 Participants | 33 Participants | 37 Participants | 111 Participants |
| Sex: Female, Male Female | 17 Participants | 16 Participants | 20 Participants | 53 Participants |
| Sex: Female, Male Male | 37 Participants | 34 Participants | 32 Participants | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 50 | 0 / 52 |
| other Total, other adverse events | 24 / 54 | 21 / 50 | 21 / 52 |
| serious Total, serious adverse events | 1 / 54 | 1 / 50 | 4 / 52 |
Outcome results
Primary
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.
Time frame: Day 1 up to Day 115
Population: Safety Population consisted of all randomized participants who received at least 1 dose of study drug. Participants in this population were summarized according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Study Drug-Related TEAEs | Any TEAE | 24 Participants |
| Placebo | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Study Drug-Related TEAEs | Study drug-related TEAEs | 6 Participants |
| Praliciguat 20 mg | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Study Drug-Related TEAEs | Any TEAE | 21 Participants |
| Praliciguat 20 mg | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Study Drug-Related TEAEs | Study drug-related TEAEs | 3 Participants |
| Praliciguat 40 mg | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Study Drug-Related TEAEs | Any TEAE | 22 Participants |
| Praliciguat 40 mg | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Study Drug-Related TEAEs | Study drug-related TEAEs | 10 Participants |
Primary
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.
Time frame: Baseline; Week 8 to Week 12
Population: Intent-to-Treat Population consisted of all randomized participants who received at least 1 dose of study drug. Participants in this population were evaluated according to the treatment group they were assigned to at Randomization.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Urine Albumin Creatinine Ratio (UACR) Over Weeks 8 and 12 | -14.8 Percent Change |
| Praliciguat 20 mg | Percent Change From Baseline in Urine Albumin Creatinine Ratio (UACR) Over Weeks 8 and 12 | -28.4 Percent Change |
| Praliciguat 40 mg | Percent Change From Baseline in Urine Albumin Creatinine Ratio (UACR) Over Weeks 8 and 12 | -27.3 Percent Change |
| Praliciguat Overall | Percent Change From Baseline in Urine Albumin Creatinine Ratio (UACR) Over Weeks 8 and 12 | -27.8 Percent Change |
Comparison: Treatment comparison between placebo and praliciguat 20 mg. Geometric mean change (%) and the associated confidence intervals (CIs) were derived as 100×\[exp(Least Squares Mean Change)-1\].p-value: =0.214290% CI: [-33.3, 5.8]Mixed Models Analysis
Comparison: Treatment comparison between placebo and praliciguat 40 mg. Geometric mean change (%) and the associated CIs were derived as 100×\[exp(Least Squares Mean Change)-1\].p-value: =0.271890% CI: [-32.7, 8.3]Mixed Models Analysis
Comparison: Treatment comparison between placebo and praliciguat overall. Geometric mean change (%) and the associated CIs were derived as 100×\[exp(Least Squares Mean Change)-1\].p-value: =0.173690% CI: [-30.7, 3.6]Mixed Models Analysis