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

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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02931565

Enrollment

Registered

2016-10-13

Start date

2017-04-06

Completion date

2018-05-01

Last updated

2021-05-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Achalasia

Brief summary

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

Interventions

DRUGOlinciguat

oral tablet

DRUGMatching Placebo

oral tablet

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

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

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Deaths, Serious Adverse Events (SAEs), and Adverse Events Resulting in Study Drug Discontinuation (ADOs)	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.	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.
Change From Baseline in Supine Bolus Flow Time (BFT)	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose	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).
Change From Baseline in Upright BFT	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose	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).
Change From Baseline in Supine Integrated Relaxation Pressure (IRP)	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose	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).
Change From Baseline in Upright IRP	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose	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).
Change From Baseline in 1 Minute Impedance Bolus Height (IBH)	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose	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)
Change From Baseline in 2 Minute IBH	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose	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).
Change From Baseline in 5 Minute IBH	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose	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).
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).	—

Countries

United States

Participant flow

Pre-assignment details

Up to 20 participants were planned to be randomized in a 3:1 ratio to receive either olinciguat or matching placebo. The study was prematurely terminated due to enrollment challenges after 9 participants had completed the study.

Participants by arm

Arm	Count
Placebo or Olinciguat Matching placebo administered orally or single 5-mg dose of olinciguat administered orally	9
Total	9

Baseline characteristics

Characteristic	Placebo or Olinciguat
Age, Continuous	46.6 years STANDARD_DEVIATION 14.4
Ethnicity (NIH/OMB) Hispanic or Latino	NA Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	NA Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	NA Participants
Race (NIH/OMB) American Indian or Alaska Native	NA Participants
Race (NIH/OMB) Asian	NA Participants
Race (NIH/OMB) Black or African American	NA Participants
Race (NIH/OMB) More than one race	NA Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	NA Participants
Race (NIH/OMB) Unknown or Not Reported	NA Participants
Race (NIH/OMB) White	NA Participants
Sex: Female, Male Female	3 Participants
Sex: Female, Male Male	6 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 2	0 / 7
other Total, other adverse events	1 / 2	2 / 7
serious Total, serious adverse events	0 / 2	0 / 7

Outcome results

Primary

Area Under the Plasma Concentration Time Curve From Time 0 to the Last Observation (AUClast)

Time frame: 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).

Population: Pharmacokinetic (PK) Population: All participants who received olinciguat and had at least 1 evaluable postdose PK parameter assessment.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Placebo	Area Under the Plasma Concentration Time Curve From Time 0 to the Last Observation (AUClast)	700.8 h*ng/mL	Geometric Coefficient of Variation 17.4

Primary

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)