## Protocol Section
### Identification Module
**NCT ID:** NCT06432452

**Acronym:** EDIT-CAS

**Brief Title:** Efficacy of Endothelin Receptor Antagonism in Coronary Artery Spasm

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

#### Organization Study ID Info
**ID:** 114746
#### Organization
**Class:** OTHER
**Full Name:** Radboud University Medical Center
### Status Module
#### Completion Date
**Date:** 2026-04-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-29

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-21

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-01-15

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-08-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-29
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-10
**Study First Submit QC Date:** 2024-05-21
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** UMC Utrecht

**Class:** OTHER

**Name:** Catharina Ziekenhuis Eindhoven

**Class:** OTHER

**Name:** Maasstad Hospital

#### Lead Sponsor

**Class:** OTHER

**Name:** Radboud University Medical Center

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Is US Export:** False

### Description Module

**Brief Summary:** 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

### Conditions Module

**Conditions:**

- Coronary Spasm

**Keywords:**

- epicardial spasm

- endothelin receptor antagonism

- angina

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** TRIPLE

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 100

**Type:** ESTIMATED

**Phases:**

- PHASE2

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Bosentan 62.5 mg twice daily Uptitrated to 125mg twice daily if tolerated after 4 weeks Total 10 weeks

**Intervention Names:**

- Drug: Endothelin Receptor Antagonist

**Label:** Bosentan

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Placebo 62.5 mg twice daily Uptitrated to 125mg twice daily if tolerated after 4 weeks Total 10 weeks

**Intervention Names:**

- Other: Placebo control

**Label:** Placebo

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Bosentan

**Description:** Oral capsules twice daily

**Name:** Endothelin Receptor Antagonist

**Other Names:**

- Bosentan

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Placebo

**Description:** Oral capsules twice daily

**Name:** Placebo control

**Other Names:**

- Placebo

**Type:** OTHER

### Outcomes Module

#### Other Outcomes

**Description:** Measured with EuroQol 5 Dimensions (EQ5D) and separate SAQ domains. Scores can range from 0-100, with higher scores indicating better health status.

**Measure:** Improvement of quality of life

**Time Frame:** 10 weeks

**Description:** The rate of occurence of microvascular spasm according to COVADIS criteria at fuCFT

**Measure:** Microvascular spasm

**Time Frame:** 10 weeks

**Description:** Circulating endothelin-1 plasma levels in peripheral blood drawn at visit 1.

**Measure:** Endothelin levels at baseline

**Time Frame:** 10 weeks

**Description:** 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.

**Measure:** Change in spasm provocation reactivity

**Time Frame:** 10 weeks

**Description:** Assessed by means of repeat laboratory analysis

**Measure:** Incidence of liver panel disturbances

**Time Frame:** 10 weeks

**Description:** Assessed by means of repeat blood pressure measurements

**Measure:** Incidence of hypotension

**Time Frame:** 10 weeks

**Description:** Assessed by (S)AE reporting, during all follow-up contacts

**Measure:** Incidence of MACE

**Time Frame:** 10 weeks

**Description:** Assessed and captured at every follow-up contact moment.

**Measure:** Rate of study drug discontinuation / study withdrawal.

**Time Frame:** 10 weeks

#### Primary Outcomes

**Description:** 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.

**Measure:** Successful treatment

**Time Frame:** 10 weeks

#### Secondary Outcomes

**Description:** 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.

**Measure:** Improvement of anginal complaints

**Time Frame:** 10 weeks

### Eligibility Module

**Eligibility Criteria:** 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).

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** peter.damman@radboudumc.nl

**Name:** Peter Damman

**Phone:** 0243616785

**Role:** CONTACT

**Contact 2:**

**Email:** caia.crooijmans@radboudumc.nl

**Name:** Caïa Crooijmans

**Phone:** 0243096546

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Eindhoven

**Contacts:**

***Contact 1:***

- **Name:** Annemiek de Vos, MD

- **Role:** CONTACT

**Country:** Netherlands

**Facility:** Catharina Ziekenhuis

**State:** Noord-Brabant

**Zip:** 5623EJ

**Location 2:**

**City:** Rotterdam

**Contacts:**

***Contact 1:***

- **Name:** Valeria Paradies, MD, PhD

- **Role:** CONTACT

**Country:** Netherlands

**Facility:** Maasstad Hospital

**State:** Zuid-Holland

**Zip:** 3079DZ

**Location 3:**

**City:** Nijmegen

**Contacts:**

***Contact 1:***

- **Name:** Peter Damman, MD, PhD

- **Role:** CONTACT

**Country:** Netherlands

**Facility:** RadboudUMC

**Zip:** 6525GA

**Location 4:**

**City:** Utrecht

**Contacts:**

***Contact 1:***

- **Name:** Tim van de Hoef, MD, PhD

- **Role:** CONTACT

**Country:** Netherlands

**Facility:** UMC Utrecht

**Zip:** 3584CX

#### Overall Officials

**Official 1:**

**Affiliation:** Radboud University Medical Center

**Name:** Peter Damman, MD, PhD

**Role:** PRINCIPAL_INVESTIGATOR

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000020879

- Term: Neuromuscular Manifestations

- ID: D000009461

- Term: Neurologic Manifestations

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000009135

- Term: Muscular Diseases

- ID: D000009140

- Term: Musculoskeletal Diseases

- ID: D000003327

- Term: Coronary Disease

- ID: D000017202

- Term: Myocardial Ischemia

- ID: D000006331

- Term: Heart Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

- ID: D000014652

- Term: Vascular Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC05

- Name: Musculoskeletal Diseases

- Abbrev: BC10

- Name: Nervous System Diseases

### Condition Browse Module - Browse Leaves

- ID: M4117

- Name: Angina Pectoris

- Relevance: LOW

- As Found: Unknown

- ID: M12077

- Name: Muscle Cramp

- Relevance: HIGH

- As Found: Spasm

- ID: M15837

- Name: Spasm

- Relevance: HIGH

- As Found: Spasm

- ID: M6551

- Name: Coronary Vasospasm

- Relevance: HIGH

- As Found: Coronary Artery Spasm

- ID: M22619

- Name: Neuromuscular Manifestations

- Relevance: LOW

- As Found: Unknown

- ID: M12404

- Name: Neurologic Manifestations

- Relevance: LOW

- As Found: Unknown

- ID: M12092

- Name: Muscular Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12097

- Name: Musculoskeletal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M6546

- Name: Coronary Artery Disease

- Relevance: LOW

- As Found: Unknown

- ID: M6549

- Name: Coronary Disease

- Relevance: LOW

- As Found: Unknown

- ID: M19506

- Name: Myocardial Ischemia

- Relevance: LOW

- As Found: Unknown

- ID: M10543

- Name: Ischemia

- Relevance: LOW

- As Found: Unknown

- ID: M9419

- Name: Heart Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M17400

- Name: Vascular Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000009120

- Term: Muscle Cramp

- ID: D000013035

- Term: Spasm

- ID: D000003329

- Term: Coronary Vasospasm

### Intervention Browse Module - Ancestors

- ID: D000000959

- Term: Antihypertensive Agents

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: AnAg

- Name: Antihypertensive Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M1753

- Name: Bosentan

- Relevance: HIGH

- As Found: Urethral

- ID: M30466

- Name: Endothelin Receptor Antagonists

- Relevance: HIGH

- As Found: ASP8062

- ID: M4277

- Name: Antihypertensive Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000077300

- Term: Bosentan

- ID: D000065128

- Term: Endothelin Receptor Antagonists

### Misc Info Module

- Version Holder: 2024-05-31
