Efficacy of Endothelin Receptor Antagonism in Coronary Artery Spasm (EDIT-CAS)

Efficacy of Endothelin Receptor Antagonism in Treatment of Coronary Artery Spasm: a Randomized Controlled Clinical Trial

The goal of this randomized clinical trial is to assess if adjunctive bosentan therapy, in comparison to placebo, can reduce the rate of epicardial vasospasm at follow-up spasm provocation CFT (fuCFT) in patients with previously proven epicardial vasospasm on acetylcholine reactivity testing (at index CFT) and ongoing angina(-like) complaints.

Participants will

• Use either endothelin receptor antagonist or placebo for 10 weeks
• Undergo follow-up acetylcholine spasm provocation test after 10 weeks
• Answer online questionnaires on angina and quality of life

Study Overview

• Status: Enrolling by invitation
• Conditions: Coronary Spasm
• Intervention / Treatment: Drug: Endothelin Receptor Antagonist; Other: Placebo control

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6525GA
    • Radboudumc
  • Utrecht, Netherlands, 3584CX
    • UMC Utrecht
  • Noord-Brabant
    • Eindhoven, Noord-Brabant, Netherlands, 5623EJ
      • Catharina Ziekenhuis
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3079DZ
      • Maasstad Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Definitive diagnosis of epicardial vasospasm on maximal acetylcholine dose of 100µg (at iCFT)
2. At least 18 years of age
3. On optimal regular care ( current or previous treatment with at least 2 daily anti-anginal medicines i.e. nitrate and calcium channel blocker
4. Continuing episodes of angina(-like) complaints at least once weekly despite 3.
5. Signed online informed consent for participation in NL-CFT registry (the Netherlands Registry of invasive coronary vasomotor function testing), or willing to co-sign for registry at time of inclusion in EDIT-CAS
6. Written informed consent for EDIT-CAS

Exclusion Criteria:

1. Systolic blood pressure (SBP) <85 mmHg measured at Visit 1
2. Significant hepatic impairment at time of iCFT lab (ASAT/ALAT >3x upper limit of normal (ULN)) or history of liver cirrhosis (Child-Pugh 7-15)
3. Severe anemia (Hb<6.0mmol/L) without identified cause at time of inclusion
4. Patients with limited life expectancy (<1 year)
5. Participation in another randomized clinical study with an use of an Investigational Medicinal Product (IMP) up to one month prior to enrolment.
6. Pregnancy, active desire to become pregnant or unwilling to take adequate* contraceptive measures when of child bearing potential for the duration of 6 months (active medication period + 3 months safety).
7. Known heart failure with reduced ejection fraction<35%
8. Known pulmonary hypertension of any type
9. Potentially dangerous interaction due to the use of another CYP3A4 or CYP2C9 substrate (e.g. ciclosporin A, glibenclamide, fluconazole, rifampicin, tacrolimus/sirolimus, lopinavir/ritonavir)

10. Repeat spasm provocation test deemed unsafe (e.g. allergic reaction at iCFT)

    • Adequate in this case meaning if on hormonal contraceptives, additional measures to be taken (e.g. condom).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bosentan; Bosentan 62.5 mg twice daily Uptitrated to 125mg twice daily if tolerated after 4 weeks Total 10 weeks	Drug: Endothelin Receptor Antagonist; Oral capsules twice daily; Other Names: Bosentan
Placebo Comparator: Placebo; Placebo 62.5 mg twice daily Uptitrated to 125mg twice daily if tolerated after 4 weeks Total 10 weeks	Other: Placebo control; Oral capsules twice daily; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Successful treatment	On repeat invasive spasm provocation according to Coronary Vasomotor Disorders International Study Group (COVADIS) criteria. Successful treatment is defined as absence of epicardial vasospasm according to COVADIS criteria during repeat spasm provocation test at 10 weeks.	10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of anginal complaints	As measured with Seattle Angina Questionnaire (SAQ) summary score and change from baseline to follow-up. Score can range from 0-100, with higher scores indicating better health status.	10 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of quality of life	Measured with EuroQol 5 Dimensions (EQ5D) and separate SAQ domains. Scores can range from 0-100, with higher scores indicating better health status.	10 weeks
Microvascular spasm	The rate of occurence of microvascular spasm according to COVADIS criteria at fuCFT	10 weeks
Endothelin levels at baseline	Circulating endothelin-1 plasma levels in peripheral blood drawn at visit 1.	10 weeks
Change in spasm provocation reactivity	Any deterioration or improvement according to prespecified outcomes measured by repeated spasm provocation test. If a higher dose of acetylcholine is needed to induce epicardial spasm for example, this change will be documented. If microvascular spasm can, but epicardial can not be provoked, this will be documented. The incidence of these changes will be analyzed.	10 weeks
Incidence of liver panel disturbances	Assessed by means of repeat laboratory analysis	10 weeks
Incidence of hypotension	Assessed by means of repeat blood pressure measurements	10 weeks
Incidence of MACE	Assessed by (S)AE reporting, during all follow-up contacts	10 weeks
Rate of study drug discontinuation / study withdrawal.	Assessed and captured at every follow-up contact moment.	10 weeks

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: UMC Utrecht; Catharina Ziekenhuis Eindhoven; Maasstad Hospital
• Investigators: Principal Investigator: Peter Damman, MD, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2024
• Primary Completion (Estimated): June 15, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: May 10, 2024
• First Submitted That Met QC Criteria: May 21, 2024
• First Posted (Actual): May 29, 2024

Study Record Updates

• Last Update Posted (Estimated): November 18, 2024
• Last Update Submitted That Met QC Criteria: November 14, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: angina; epicardial spasm; endothelin receptor antagonism
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Muscular Diseases; Neuromuscular Manifestations; Heart Diseases; Coronary Disease; Myocardial Ischemia; Spasm; Coronary Vasospasm; Muscle Cramp; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists
• Other Study ID Numbers: 114746

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No