Trial of IW-1973, A Stimulator of Soluble Guanylate Cyclase (sGC) in Patients With Stable Type 2 Diabetes and Hypertension

Study Overview
=================
Brief Summary
-----------------
To compare the safety, tolerability, pharmacokinetic (PK) profile, and pharmacodynamic (PD) effects of 2 treatment regimens of IW-1973 tablet (40 mg per day) administered orally for 2 weeks to patients with stable type 2 diabetes mellitus and hypertension.

Official Title
-----------------
A Phase 2 Study to Compare the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 2 Dose Regimens of IW-1973 in Patients With Stable Type 2 Diabetes and Hypertension

Conditions
-----------------
Diabetes Mellitus, Type 2, Hypertension

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient is ambulatory male or female Patient's body mass index score is > 20 and < 40 kg/m^2 at the Screening Visit Women of childbearing potential must have a negative pregnancy test at the time of screening and check-in and must agree to use protocol-specified contraception throughout the duration of the study Patient's health is stable with no clinically significant findings on physical examination Patient has type 2 (ie, adult onset) diabetes mellitus diagnosed by a physician or nurse practitioner > 6 months before the Screening Visit, is on a stable glycemic control medication, and protocol specified hemoglobin (Hb)A1c values at the Screening Visit Patient has hypertension diagnosed by a physician or nurse practitioner > 6 months before the Screening Visit, and blood pressure (BP) within the protocol's acceptable range Patients must be on a stable regimen for hypertension control that includes an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), stable for 28 days Other inclusion criteria per protocol Exclusion Criteria: Patient has a clinically significant active or unstable medical condition that, in the opinion of the Investigator, would preclude trial participation Patient is on medication(s) that, when co-administered with a sGC stimulator, could increase the risk of hypotension Patient has evidence of severe or active end-organ damage Patient is an active smoker or has used any nicotine-containing products (cigarettes, e-cigarettes, vape pens, cigars, chewing tobacco, gum, patches) during the 6 months before Check-in. Use of nicotine is excluded during the study until after the End of Trial Visit. Other exclusion criteria per protocol

Ages Eligible for Study
-----------------
Minimum Age: 30 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IW-1973 QD/QD<br>On Days 1-14: IW-1973 40 mg taken once daily (QD) in morning (AM) and placebo taken QD at night (PM). | Drug: IW-1973<br>* Oral Tablet<br>Drug: Placebo<br>* Oral Tablet<br>|
| Experimental: IW-1973 BID (Twice Daily)/QD<br>On Days 1-7: IW-1973 20 mg taken in AM and IW-1973 20 mg taken in PM. On Days 8-14: IW-1973 40 mg taken QD in AM and placebo taken QD in PM. | Drug: IW-1973<br>* Oral Tablet<br>Drug: Placebo<br>* Oral Tablet<br>|
| Placebo Comparator: Placebo<br>On Days 1-14: Placebo taken in AM and in PM. | Drug: Placebo<br>* Oral Tablet<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Study Baseline Over Time in Supine Systolic Blood Pressure |  | Study Baseline (Day 1 predose AM); Days 2-14: predose AM; Days 1, 2, 7, 8, 13: postdose AM 1 hour and 4 hour; Day 1: postdose AM 8 hour; Days 1, 2, 8, 13: predose PM; Days 1, 2: postdose PM 1 hour; Days 2, 3: postdose PM 4 hour; Days 15, 21, 42 | 
| Change From Study Baseline Over Time in Supine Diastolic Blood Pressure |  | Study Baseline (Day 1 predose AM); Days 2-14: predose AM; Days 1, 2, 7, 8, 13: postdose AM 1 hour and 4 hour; Day 1: postdose AM 8 hour; Days 1, 2, 8, 13: predose PM; Days 1, 2: postdose PM 1 hour; Days 2, 3: postdose PM 4 hour; Days 15, 21, 42 | 
| Change From Study Baseline Over Time in Supine Pulse |  | Study Baseline (Day 1 predose AM); Days 2-14: predose AM; Days 1, 2, 7, 8, 13: postdose AM 1 hour and 4 hour; Day 1: postdose AM 8 hour; Days 1, 2, 8, 13: predose PM; Days 1, 2: postdose PM 1 hour; Days 2, 3: postdose PM 4 hour; Days 15, 21, 42 | 
| Percentage of Participants With Postdose Supine Blood Pressure Less Than 130/80 mmHg Over Time |  | Baseline, Days 1-14, Day 15, 21, 42 | 
| Orthostatic Systolic Blood Pressure Over Time | An orthostatic measurement is obtained by subtracting the supine measurement from the standing measurement. | Days -1, 1, 2, 7, 8, 13: 1 and 4 hour AM; Days -1, 1, 2, 8, 13: 0 hour PM; Days -1, 1, 2: 1 hour PM; Days 1, 2, 7, 8, 13: 0 hour AM; Day 1: 8 hour AM; Days 1, 2: 4 hour PM | 
| Orthostatic Diastolic Blood Pressure Over Time | An orthostatic measurement is obtained by subtracting the supine measurement from the standing measurement. | Days -1, 1, 2, 7, 8, 13: 1 and 4 hour AM; Days -1, 1, 2, 8, 13: 0 hour PM; Days -1, 1, 2: 1 hour PM; Days 1, 2, 7, 8, 13: 0 hour AM; Day 1: 8 hour AM; Days 1, 2: 4 hour PM | 
| Orthostatic Pulse Over Time | An orthostatic measurement is obtained by subtracting the supine measurement from the standing measurement. | Days -1, 1, 2, 7, 8, 13: 1 and 4 hour AM; Days -1, 1, 2, 8, 13: 0 hour PM; Days -1, 1, 2: 1 hour PM; Days 1, 2, 7, 8, 13: 0 hour AM; Day 1: 8 hour AM; Days 1, 2: 4 hour PM | 
| Change From Time-Matched Baseline Over Time in Ambulatory Blood Pressure Monitoring (ABPM) 24-hour Averages of Systolic Blood Pressure | 24-hour average is the average of ABPM assessments over 24 hour intervals from the time of dosing. Time-matched baseline is the 24 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM Daytime (12-Hour) Averages of Systolic Blood Pressure | Daytime 12-hour average is the average of ABPM assessments over daytime 12-hour intervals from the time of dosing. Time-matched baseline is the daytime 12 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM Nighttime (12-Hour) Averages of Systolic Blood Pressure | Nighttime 12-hour average is the average of ABPM assessments over nighttime 12-hour intervals from the time of dosing. Time-matched baseline is the nighttime 12 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM 4-hour Averages of Systolic Blood Pressure | Postdose is the average of assessments over 4-hour intervals from the time of dosing that day. Time-matched baseline is the corresponding 4-hour average on Day -1. | Time-matched baseline (Day -1), Days 1, 7, 14: 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 hours postdose | 
| Change From Time-Matched Baseline Over Time in ABPM 24-hour Averages of Mean Arterial Pressure | 24-hour average is the average of ABPM assessments over 24 hour intervals from the time of dosing. Time-matched baseline is the 24 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM Daytime (12-hour) Averages of Mean Arterial Pressure | Daytime 12-hour average is the average of ABPM assessments over daytime 12-hour intervals from the time of dosing. Time-matched baseline is the daytime 12 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM Nighttime (12-Hour) Averages of Mean Arterial Pressure | Nighttime 12-hour average is the average of ABPM assessments over nighttime 12-hour intervals from the time of dosing. Time-matched baseline is the nighttime 12 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM 4-hour Averages of Mean Arterial Pressure | Postdose is the average of assessments over 4-hour intervals from the time of dosing that day. Time-matched baseline is the corresponding 4-hour average on Day -1. | Time-matched baseline (Day -1), Days 1, 7, 14: 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 hours postdose | 
| Change From Time-Matched Baseline Over Time in ABPM 24-hour Averages of Diastolic Blood Pressure | 24-hour average is the average of ABPM assessments over 24 hour intervals from the time of dosing. Time-matched baseline is the 24 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM Daytime (12-hour) Averages of Diastolic Blood Pressure | Daytime 12-hour average is the average of ABPM assessments over daytime 12-hour intervals from the time of dosing. Time-matched baseline is the daytime 12 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM Nighttime (12-Hour) Averages of Diastolic Blood Pressure | Nighttime 12-hour average is the average of ABPM assessments over nighttime 12-hour intervals from the time of dosing. Time-matched baseline is the nighttime 12 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM 4-hour Averages of Diastolic Blood Pressure | Postdose is the average of assessments over 4-hour intervals from the time of dosing that day. Time-matched baseline is the corresponding 4-hour average on Day -1. | Time-matched baseline (Day -1), Days 1, 7, 14: 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 hours postdose | 
| Change From Time-Matched Baseline Over Time in ABPM 24-hour Averages of Pulse | 24-hour average is the average of ABPM assessments over 24 hour intervals from the time of dosing. Time-matched baseline is the 24 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM Daytime (12-hour) Averages of Pulse | Daytime 12-hour average is the average of ABPM assessments over daytime 12-hour intervals from the time of dosing. Time-matched baseline is the daytime 12 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM Nighttime (12-Hour) Averages of Pulse | Nighttime 12-hour average is the average of ABPM assessments over nighttime 12-hour intervals from the time of dosing. Time-matched baseline is the nighttime 12 hours average during Day -1. | Time Matched Baseline (Day -1), Days 1, 7, and 14 | 
| Change From Time-Matched Baseline Over Time in ABPM 4-hour Averages of Pulse | Postdose is the average of assessments over 4-hour intervals from the time of dosing that day. Time-matched baseline is the corresponding 4-hour average on Day -1. | Time-matched baseline (Day -1), Days 1, 7, 14: 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 hours postdose | 
| Change From Baseline in Reactive Hyperemia Index (RHI) on Day 13 | RHI is a measure of the extent of vessel dilatation and augmentation in vascular blood flow after a prespecified period of flow interruption. RHI is determined as the ratio of the post-to-pre- occlusion peripheral arterial tonometry amplitude of the tested (occluded) arm, divided by the post to-pre-occlusion ratio of the control arm. RHI values >1.67 indicate normal endothelial function, while values ≤1.67 indicate endothelial dysfunction. | Baseline, Day 13 predose AM | 
| Post-Baseline Platelet Reactivity on Days 8 and 14: P2Y12 Reaction Units (PRU) Assay | Platelet reactivity, as measured by VerifyNow PRU assay, and presented as number of participants with < 180 PRU or ≥ 180 PRU post-baseline (Days 8 and 14), by baseline category. The VerifyNow PRU assay measures effects on platelet activation caused by inhibition of the platelet receptor, P2Y12. This receptor is activated by adenosine 5'-diphosphate (ADP) in the cascade leading to platelet aggregation but can be blocked by P2Y12 inhibitor drugs, such as clopidogrel. Blockage of this receptor diminishes platelet activation and the ability of platelets to bind to fibrinogen. VerifyNow PRU assay values < 180 units indicate impairment of platelet aggregation. | Baseline, Day 8, Day 14 | 
| Post-Baseline Platelet Reactivity on Days 8 and 14: Aspirin Reaction Units (ARU) Assay | Platelet reactivity, as measured by VerifyNow ARU assay, and presented as number of participants with ≤ 549 ARU or > 549 ARU post-baseline (Days 8 and 14), by baseline category. Aspirin irreversibly inhibits cyclooxygenase 1, which converts arachidonic acid to thromboxane A2, which in turn is involved in the activation of the glycoprotein (GP)IIb/IIIa receptor necessary to initiate platelet aggregation. Impairment of platelet aggregation of the aspirin type is defined for the VerifyNow aspirin assay as values ≤ 549 ARU. | Baseline, Day 8, Day 14 | 
| Change From Study Baseline Over Time in Platelet Function Assessments: PRU Assay | The VerifyNow PRU assay measures effects on platelet activation caused by inhibition of the platelet receptor, P2Y12. This receptor is activated by adenosine 5'-diphosphate (ADP) in the cascade leading to platelet aggregation but can be blocked by P2Y12 inhibitor drugs, such as clopidogrel. Blockage of this receptor diminishes platelet activation and the ability of platelets to bind to fibrinogen. VerifyNow PRU assay values <180 PRU indicate impairment of platelet aggregation. | Study Baseline (Day 1 predose), Day 8 (predose AM), Day 14 (predose AM) | 
| Change From Study Baseline Over Time in Platelet Function Assessments: ARU Assay | Aspirin irreversibly inhibits cyclooxygenase 1, which converts arachidonic acid to thromboxane A2, which in turn is involved in the activation of the GPIIb IIIa receptor necessary to initiate platelet aggregation. Impairment of platelet aggregation of the aspirin type is defined for the VerifyNow aspirin assay as values ≤ 549 ARU. | Study Baseline (Day 1 predose), Day 8 (pre AM dose), Day 14 (pre AM dose) | 
| Percent Change From Study Baseline Over Time in HOMA-IR in Participants Without Concomitant Use of Insulin | Blood samples were taken for fasting glucose and insulin levels. From these results, insulin resistance was then estimated using the updated homeostasis model assessment method for insulin resistance (HOMA-IR) computer algorithm. A higher HOMA-IR indicates a higher degree of insulin resistance. Typically a cutoff of HOMA-IR for identifying those with insulin resistance is 2.5. | Study baseline (defined as the last non-missing assessment before the first administration of study drug), Day 8, pre-AM dose, Day 15 | 
| IW-1973 Pharmacokinetics: Area Under the Plasma Concentration Time Curve During a Dosing Interval (AUCtau) on Days 1 and 7 | Equivalent to AUC from time 0 to the last measurable concentration (AUClast), with time of last measurable concentration (Tlast)=12 hours for BID dosing and Tlast=24 hours for QD dosing. | Days 1 and 7 (AM): 1, 3, and 6 hours postdose | 
| IW-1973 Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) on Days 1 and 7 |  | Days 1 and 7 (AM): 1, 3, and 6 hours postdose | 
| IW-1973 Pharmacokinetics: Time to Cmax on Days 1 and 7 |  | Days 1 and 7 (AM): 1, 3, and 6 hours postdose | 
| IW-1973 Pharmacokinetics: Trough Plasma Concentrations at the End of the Dosing Interval (Ctrough) on Days 1, 2, 6, 7 |  | Days 1 and 7: predose; Day 2 (BID AM): predose; Day 6 (BID PM/QD): predose | 
| IW-1973 Pharmacokinetics: Area Under the Plasma Concentration Time Curve From Time Zero to the Last Measurable Plasma Concentration (AUClast) on Days 8 and 14 |  | Day 8 and 14: 1, 3, 6h (± 5 min) postdose | 
| IW-1973 Pharmacokinetics: AUCtau on Day 14 |  | Day 14: 1, 3, 6h (± 5 min) postdose | 
| IW-1973 Pharmacokinetics: Tmax on Days 8 and 14 |  | Day 8 and 14: 1, 3, 6h (± 5 min) postdose | 
| IW-1973 Pharmacokinetics: Cmax on Days 8 and 14 |  | Day 8 and 14: 1, 3, 6h (± 5 min) postdose | 
| IW-1973 Pharmacokinetics: Ctrough on Days 13 and 14 |  | Days 13 and 14: predose | 
| IW-1973 Pharmacokinetics: Apparent Total Body Clearance (CL/F) on Day 14 |  | Day 14: 1, 3, 6h (± 5 min) postdose | 
| IW-1973 Pharmacokinetics: Apparent Volume of Distribution During the Terminal Phase (Vz/F) on Day 14 |  | Day 14: 1, 3, 6h (± 5 min) postdose | 
| IW-1973 Pharmacokinetics: Apparent Terminal Elimination Phase Half-Life (t1/2) |  | Day 14 (final dose) time points 12 hours, 24 hours, 7 days after final dose (Day 21), and 28 days after final dose(Day 42) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to TEAEs | An adverse event (AE) is any untoward medical occurrence, which does not necessarily have to have a causal relationship with study treatment. An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical events. TEAEs are defined as those AEs that started or worsened in severity after the initiation of study drug administration. AEs of clinical interest (AECI) included those related to bleeding and to hypotension. Study drug causality as assessed by the Investigator who was blinded to study drug assignment. | From first dose of study drug to End of Trial Visit (42 [± 3] days) | 
| Number of Participants With Clinically Meaningful Postbaseline Laboratory Test Results |  | From first dose of study drug to End of Trial Visit (42 [± 3] days) | 
| Number of Participants With Notable Changes in Postbaseline Blood Pressure and Heart Rate Values | Supine systolic blood pressure (SSBP): ≥ 180 mmHg and increase (↑) from baseline (BL) ≥ 30 mmHg; ≤ 90 mmHg and decrease (↓) from BL ≥ 30 mmHg. Supine diastolic blood pressure (SDBP): ≥ 105 mmHg and ↑ from BL ≥ 20 mmHg; ≤ 50 mmHg and ↓ from BL ≥ 20 mmHg. Supine heart rate (SHR): ≥ 110 bpm and ↑ from BL ≥ 20 bpm; ≤ 50 bpm and ↓ from BL ≥ 20 bpm. Standing systolic blood pressure (StSBP): ≥ 180 mmHg and increase (↑) from baseline (BL) ≥ 30 mmHg; ≤ 90 mmHg and decrease (↓) from BL ≥ 30 mmHg. Standing Diastolic Blood Pressure (StDBP): ≥ 105 mmHg and ↑ from BL ≥ 20 mmHg; ≤ 50 mmHg and ↓ from BL ≥ 20 mmHg. Standing heart rate (StHR): ≥ 110 bpm and ↑ from BL ≥ 20 bpm; ≤ 50 bpm and ↓ from BL ≥ 20 bpm. Orthostatic systolic blood pressure (SBP): ↓ > 20 mmHg from supine to standing. Orthostatic diastolic blood pressure (DBP): ↓ > 15 mmHg from supine to standing. Orthostatic HR: ↓ > 30 bpm from supine to standing. | From first dose of study drug to End of Trial Visit (42 [± 3] days) | 
| Number of Participants With Clinically Significant Post-Randomization Physical Examination Findings | Physical examinations included examination and assessment of the following: general appearance, lymph nodes, skin, cardiovascular system, head, eyes, ears, nose, and throat, central nervous system, respiratory system, neck, peripheral nervous system, abdomen/liver/spleen, musculoskeletal system. | Post-randomization to End of Trial Visit (42 [± 3] days) | 
| Number of Participants With Clinically Significant Postbaseline 12-Lead Electrocardiogram (ECG) Results |  | From first dose of study drug to End of Trial Visit (42 [± 3] days) | 
| Change From Study Baseline Over Time in Estimated Glomerular Filtration Rate (eGFR) |  | Study Baseline, Day 15/Discharge, Day 42/End of Trial |