Study of IW-1701, A Stimulator of Soluble Guanylate Cyclase (sGC), in Patients With Type I or II Achalasia

Study Overview
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Brief Summary
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The objectives of this study are as follows: In participants with primary Type I or II achalasia, following a single 5-mg dose of olinciguat (IW-1701), To assess the safety and tolerability To determine the effects on measures of esophageal function by high-resolution impedance manometry (HRIM) To determine the pharmacokinetic (PK) parameters

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Single-dose, Phase 2a Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IW-1701 in Patients With Achalasia

Conditions
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Achalasia

Intervention / Treatment
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* Drug: Olinciguat
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patient has a diagnosis of primary Type I or II achalasia. Patient has no contraindications to the performance of the baseline and postdose HRIM procedures per Investigator discretion. Key Exclusion Criteria: Patient has had any prior esophageal, periesophageal, or gastric surgery, or treatment with sclerosing agent. More than 1 pneumatic dilation procedure to a diameter of > 2 cm in their lifetime. Pneumatic dilation procedure to a diameter of > 2 cm within 1 year prior to randomization. Prior bougie dilation(s) or pneumatic dilation(s) ≤ 2 cm are allowed. Prior esophageal injection of botulinum toxin (Botox) within 6 months prior to randomization or more than 2 esophageal Botox injection procedures in their lifetime. Patients with malignant or premalignant esophageal lesions. Patient has taken any drug that can affect gastrointestinal (GI) motility in the 72 hours before check-in through discharge from the clinic. Other inclusion and exclusion criteria specified in the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IW-1701<br>Single 5-mg dose of IW-1701 administered orally | Drug: Olinciguat<br>* oral tablet<br>* Other names: IW-1701;|
| Placebo Comparator: Placebo<br>Matching placebo administered orally | Drug: Matching Placebo<br>* oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Deaths, Serious Adverse Events (SAEs), and Adverse Events Resulting in Study Drug Discontinuation (ADOs) | 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 any AE occurring at any dose that results in any of the following outcomes: death; life-threatening: the patient was at immediate risk of death from the reaction as it occurred; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical event. Deaths and SAEs include those that occurred on or after the participant signed the informed consent at the Screening Visit through the End-of-Trial Visit. TEAEs are defined as adverse events that occurred on/after administration of the double-blind study drug and within 72 hours after the double-blind study drug administration. | Deaths, SAEs, and AEs: from enrollment through end-of-trial visit Day 21 (±7 days). TEAEs: from first dose of study drug through 72 hours postdose. | 
| Change From Baseline in Supine Bolus Flow Time (BFT) | Supine BFT defined as the median measurement from the 10 available swallows in supine position as measured by high resolution impedance manometry (HRIM), and determined by the central read (seconds; longer times=more severe achalasia). Change=(postdose supine BFT - predose supine BFT). | Day 1: predose (baseline) and 3 hours (+15 minutes) postdose | 
| Change From Baseline in Upright BFT | Upright BFT defined as the median measurement from the 5 available swallows in the upright position as measured by HRIM, and determined by the central read (seconds; longer times=more severe achalasia). Change = (postdose upright BFT - predose upright BFT). | Day 1: predose (baseline) and 3 hours (+15 minutes) postdose | 
| Change From Baseline in Supine Integrated Relaxation Pressure (IRP) | Supine IRP defined as the median measurement from the 10 available swallows in supine position as determined by the central read (mmHg; higher pressure=more severe achalasia), measured by HRIM. Change = (postdose supine IRP - predose supine IRP). | Day 1: predose (baseline) and 3 hours (+15 minutes) postdose | 
| Change From Baseline in Upright IRP | Upright IRP is defined as the median measurement from the 5 available swallows in the supine position as determined by the central read (mmHg; higher pressure=more severe achalasia), measured by HRIM. Change = (postdose upright IRP - predose upright IRP). | Day 1: predose (baseline) and 3 hours (+15 minutes) postdose | 
| Change From Baseline in 1 Minute Impedance Bolus Height (IBH) | 1 minute IBH defined by the height in esophagus of 200 mL saline bolus 1 minute post-bolus as measured by HRIM and determined by the central read (cm; greater height=more severe achalasia). Change = (postdose height 1 min IBH - predose height 1 min IBH) | Day 1: predose (baseline) and 3 hours (+15 minutes) postdose | 
| Change From Baseline in 2 Minute IBH | 2 minute IBH defined by the height in esophagus of 200 mL saline bolus 2 minutes post-bolus as measured by HRIM and determined by the central read (cm; greater height=more severe achalasia). Change = (postdose height 2 min IBH - predose height 2 min IBH). | Day 1: predose (baseline) and 3 hours (+15 minutes) postdose | 
| Change From Baseline in 5 Minute IBH | 5 minute IBH defined by the height in esophagus of 200 mL saline bolus 5 minutes post-bolus as determined by the central read (cm; greater height=more severe achalasia). Change = (postdose height 5 min IBH - predose height 5 min IBH). | Day 1: predose (baseline) and 3 hours (+15 minutes) postdose | 
| Area Under the Plasma Concentration Time Curve From Time 0 to the Last Observation (AUClast) |  | Day 1 predose: 0 (≤15 minutes); Day 1 postdose: 0.5 hours (±2 minutes), 1, 2, 3, 4, 5, 6, 8 hours (±5 minutes), 12, 17 hours (±15 minutes). Day 2 postdose 24 hours (±30 minutes). End of Treatment Visit: Day 21 (±7 days). | 
| Maximum Observed Plasma Concentration (Cmax) |  | Day 1 predose: 0 (≤15 minutes); Day 1 postdose: 0.5 hours (±2 minutes), 1, 2, 3, 4, 5, 6, 8 hours (±5 minutes), 12, 17 hours (±15 minutes). Day 2 postdose 24 hours (±30 minutes). End of Treatment Visit: Day 21 (±7 days). | 
| Time of Maximum Observed Plasma Concentration (Tmax) |  | Day 1 predose: 0 (≤15 minutes); Day 1 postdose: 0.5 hours (±2 minutes), 1, 2, 3, 4, 5, 6, 8 hours (±5 minutes), 12, 17 hours (±15 minutes). Day 2 postdose 24 hours (±30 minutes). End of Treatment Visit: Day 21 (±7 days). |