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

• Sponsor: Cyclerion Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02931565
• Collaborator: (none)
• Enrollment: 9
• Locations: 5
• Arms: 2
• Actual Duration (Months): 12.8
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Achalasia	Drug: Olinciguat; Drug: Matching Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Apr 6, 2017
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IW-1701 Single 5-mg dose of IW-1701 administered orally	Drug: Olinciguat; oral tablet; Other Names: IW-1701
Placebo Comparator: Placebo Matching placebo administered orally	Drug: Matching Placebo; oral tablet

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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).

3. 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).

4. 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).

5. 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).

6. 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)

7. 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).

8. 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).

9. 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).]

10. 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).]

11. 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).]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Connecticut Clinical Research Foundation, Gastroenterology Institute	Bristol	Connecticut	United States	06010
2	Mayo Clinic	Rochester	Minnesota	United States	55905
3	Washington University in St. Louis - School of Medicine	Saint Louis	Missouri	United States	63110
4	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
5	University of Utah School of Medicine, Division of Gastroenterology, Hepatology & Nutrition	Salt Lake City	Utah	United States	84132

Sponsors and Collaborators

• Cyclerion Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Oct 3, 2017
• Statistical Analysis Plan - Jul 23, 2018

More Information

Publications

None provided.

• Responsible Party: Cyclerion Therapeutics
• ClinicalTrials.gov Identifier: NCT02931565
• Other Study ID Numbers: C1701-201
• First Posted: Oct 13, 2016
• Last Update Posted: May 4, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Esophageal Achalasia

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Placebo	Olinciguat
Arm/Group Description	Matching placebo administered orally	Single 5-mg dose of olinciguat administered orally
Period Title: Overall Study
STARTED	2	7
COMPLETED	2	7
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo or Olinciguat
Arm/Group Description	Matching placebo administered orally or single 5-mg dose of olinciguat administered orally
Overall Participants	9
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.6 (14.4)
Sex: Female, Male (Count of Participants)
Female	3 33.3%
Male	6 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	NA NaN
Not Hispanic or Latino	NA NaN
Unknown or Not Reported	NA NaN
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	NA NaN
Asian	NA NaN
Native Hawaiian or Other Pacific Islander	NA NaN
Black or African American	NA NaN
White	NA NaN
More than one race	NA NaN
Unknown or Not Reported	NA NaN

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs), Deaths, Serious Adverse Events (SAEs), and Adverse Events Resulting in Study Drug Discontinuation (ADOs)
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

All participants who received study drug were included in the Safety Population and were evaluated for according to the treatment they actually received.

Arm/Group Title	Placebo	Olinciguat
Arm/Group Description	Matching placebo administered orally	Single 5-mg dose of olinciguat administered orally
Measure Participants	2	7
>= 1 TEAE	1 11.1%	2 NaN
Deaths	0 0%	0 NaN
>= 1 SAE	0 0%	0 NaN
>= 1 ADO	0 0%	0 NaN

2. Primary Outcome

Title	Change From Baseline in Supine Bolus Flow Time (BFT)
Description	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).
Time Frame	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) Population: All participants who received study drug had at least 1 postdose PD assessment.

Arm/Group Title	Placebo	Olinciguat
Arm/Group Description	Matching placebo administered orally	Single 5-mg dose of olinciguat administered orally
Measure Participants	1	6
Baseline	1.240 (NA)	0.297 (0.727)
Change From Baseline	-0.570 (NA)	0.270 (0.657)

3. Primary Outcome

Title	Change From Baseline in Upright BFT
Description	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).
Time Frame	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose

Outcome Measure Data

Analysis Population Description

PD Population: All participants who received study drug and had at least 1 postdose PD assessment.

Arm/Group Title	Placebo	Olinciguat
Arm/Group Description	Matching placebo administered orally	Single 5-mg dose of olinciguat administered orally
Measure Participants	1	7
Baseline	1.160 (NA)	0.002 (0.004)
Change From Baseline	0.580 (NA)	0.143 (0.356)

4. Primary Outcome

Title	Change From Baseline in Supine Integrated Relaxation Pressure (IRP)
Description	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).
Time Frame	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose

Outcome Measure Data

Analysis Population Description

PD Population: All participants who received study drug and had at least 1 postdose PD assessment.

Arm/Group Title	Placebo	Olinciguat
Arm/Group Description	Matching placebo administered orally	Single 5-mg dose of olinciguat administered orally
Measure Participants	2	7
Baseline	17.950 (9.263)	45.214 (15.730)
Change From Baseline	3.900 (8.556)	-7.471 (7.456)

5. Primary Outcome

Title	Change From Baseline in Upright IRP
Description	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).
Time Frame	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose

Outcome Measure Data

Analysis Population Description

PD Population: All participants who received study drug and had at least 1 postdose PD assessment.

Arm/Group Title	Placebo	Olinciguat
Arm/Group Description	Matching placebo administered orally	Single 5-mg dose of olinciguat administered orally
Measure Participants	2	7
Baseline	17.650 (7.142)	45.757 (12.164)
Change From Baseline	3.850 (9.122)	-9.350 (5.613)

6. Primary Outcome

Title	Change From Baseline in 1 Minute Impedance Bolus Height (IBH)
Description	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)
Time Frame	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose

Outcome Measure Data

Analysis Population Description

PD Population: All participants who received study drug and had at least 1 postdose PD assessment.

Arm/Group Title	Placebo	Olinciguat
Arm/Group Description	Matching placebo administered orally	Single 5-mg dose of olinciguat administered orally
Measure Participants	1	7
Baseline	4.60 (NA)	15.80 (3.81)
Change From Baseline	10.90 (NA)	-2.76 (4.66)

7. Primary Outcome

Title	Change From Baseline in 2 Minute IBH
Description	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).
Time Frame	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose

Outcome Measure Data

Analysis Population Description

PD Population: All participants who received study drug and had at least 1 postdose PD assessment.

Arm/Group Title	Placebo	Olinciguat
Arm/Group Description	Matching placebo administered orally	Single 5-mg dose of olinciguat administered orally
Measure Participants	1	7
Baseline	2.90 (NA)	14.73 (4.32)
Change From Baseline	8.90 (NA)	-2.37 (3.88)

8. Primary Outcome

Title	Change From Baseline in 5 Minute IBH
Description	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).
Time Frame	Day 1: predose (baseline) and 3 hours (+15 minutes) postdose

Outcome Measure Data

Analysis Population Description

PD Population: All participants who received study drug and had at least 1 postdose PD assessment.

Arm/Group Title	Placebo	Olinciguat
Arm/Group Description	Matching placebo administered orally	Single 5-mg dose of olinciguat administered orally
Measure Participants	1	6
Baseline	2.30 (NA)	13.07 (3.62)
Change from Baseline	5.80 (NA)	-1.52 (4.99)

9. Primary Outcome

Title	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).

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Olinciguat
Arm/Group Description	Single 5-mg dose of olinciguat administered orally
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	700.8 (17.4)

10. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax)
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).

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Olinciguat
Arm/Group Description	Single 5-mg dose of olinciguat administered orally
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	43.4 (17.7)

11. Primary Outcome

Title	Time of Maximum Observed Plasma Concentration (Tmax)
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).

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Olinciguat
Arm/Group Description	Single 5-mg dose of olinciguat administered orally
Measure Participants	7
Median (Full Range) [hours]	5.0

Adverse Events

Time Frame	Deaths and SAEs: from enrollment through end-of trial visit Day 21 (±7 days). AEs: from first dose of study drug through Day 2 (±72 hours).
Arm/Group Title	Placebo		Olinciguat
Arm/Group Description	Matching placebo administered orally		Single 5-mg dose of olinciguat administered orally
All Cause Mortality
	Placebo		Olinciguat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/7 (0%)
Serious Adverse Events
	Placebo		Olinciguat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Olinciguat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		2/7 (28.6%)
Nervous system disorders
Presyncope	0/2 (0%)		1/7 (14.3%)
Dizziness	1/2 (50%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/2 (0%)		1/7 (14.3%)

Limitations/Caveats

The study was prematurely terminated due to enrollment challenges after 9 participants had completed the study. The small number of participants limits the interpretation of study results.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI may publish or disclose the results of the study 24 months after final data lock provided that sponsor can review the publication prior to public release, sponsor can request removal of confidential information of sponsor (not including results of trial), and sponsor can request a publication delay in order to protect potentially patentable information. Furthermore, if a publication committee is developing an initial publication, PI is to delay disclosure until that publication is published.