Overview
Sponsor-declared trial summary
Phase
Phase II and Phase III (Integrated)
Status
Ongoing, recruiting
Participants planned
100
Countries
1
Sites
5
Coronary vasomotor dysfunction (spasm)
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.
Key facts
- Sponsor
- Stichting Radboud University Medical Center
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Cardiovascular Diseases [C14]
- Trial duration
- 27 Sep 2024 → ongoing
- Decision date (initial)
- 2024-04-16
- Transition trial
- No
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- No
- Funding sources
- Hartstichting · Abbott
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Therapy
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.
Secondary objectives 7
- Secondary: Efficacy of bosentan on anginal complaints (SAQ summary score)
- Explorative: Quality of life at 10 weeks (EQ-5D)
- Explorative: Assessing differences in circulating endothelin levels at baseline.
- Safety objective: assess safety and feasibility of bosentan treatment in this specific patient population
- Explorative: efficacy of adjunctive bosentan treatment in reducing anginal complaints on different SAQ domains
- Explorative: assess if bosentan more frequently changes epicardial to microvascular spasm when compared to placebo and if this corresponds with changes in anginal complaints
- Explorative: assess effect of bosentan on coronary reactivity during repeat spasm provocation test (e.g. at what ACH dose during fuCFT does spasm occur).
Conditions and MedDRA coding
Coronary vasomotor dysfunction (spasm)
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | LLT | 10011110 | Coronary vasospasm | 10007541 |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 6
- Definitive diagnosis of epicardial vasospasm on maximal acetylcholine dose of 100µg (at iCFT)
- At least 18 years of age
- On optimal regular care ( current or previous treatment with at least 2 daily antianginal medicines i.e. nitrate and calcium channel blocker)
- Continuing episodes of angina(-like) complaints at least once weekly despite optimal regular care
- Signed online informed consent for participation in NL-CFT registry, or willing to co-sign for registry at time of inclusion in EDIT-CAS
- Written informed consent for EDIT-CAS
Exclusion criteria 10
- Systolic blood pressure (SBP) <85mmHg measured at Visit 1
- Repeat spasm provocation test deemed unsafe (e.g. allergic reaction at iCFT)
- 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)
- Severe anemia (Hb<6.0mmol/L) without identified cause at time of inclusion
- Patients with limited life expectancy (<1 year)
- Participation in another randomized clinical study with an use of an Investigational Medicinal Product (IMP) up to one month prior to enrolment.
- 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).
- Known heart failure with reduced ejection fraction<35%
- Known pulmonary hypertension of any type
- Potentially dangerous interaction due to the use of another CYP3A4 or CYP2C9 substrate (see appendix A: ciclosporin A, glibenclamide, fluconazole, rifampicine, tacrolimus/sirolimus, lopinavir/ritonavir)
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Successful treatment is defined as absence of epicardial vasospasm according to COVADIS criteria (see Table 1 explanatory text in protocol) during repeat spasm provocation test at 10 weeks.
Secondary endpoints 6
- Angina relief. The mean within subject change in SAQSS from baseline to 10 weeks is assessed and compared between bosentan and placebo group.
- Explorative: Anginal complaints and quality of life
- Explorative: Microvascular spasm
- Explorative: Endothelin levels
- Explorative: Improvement, deterioration or no effect on spasm
- Explorative safety endpoint: by means of repeat laboratory analysis, blood pressure measurements and the occurrence of major adverse cardiovascular events (MACE), other adverse events (hospitalization for hypotension, angina or myocardial infarction) and rate and reason of study drug discontinuation / study withdrawal
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 4
Bosentan Accord 125 mg filmomhulde tabletten
PRD10145531 · Product
- Active substance
- Bosentan
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 250 mg milligram(s)
- Max total dose
- 10500 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- C02KX01 — BOSENTAN
- Marketing authorisation
- RVG 114397
- MA holder
- ACCORD HEALTHCARE B.V.
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Bosentan Abdi 125 mg filmomhulde tabletten
PRD10395224 · Product
- Active substance
- Bosentan Monohydrate
- Substance synonyms
- BOSENTAN HYDRATE
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 250 mg milligram(s)
- Max total dose
- 10500 mg milligram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- C02KX01 — BOSENTAN
- Marketing authorisation
- RVG 117026
- MA holder
- ABDI FARMA GMBH
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Bosentan Abdi 62,5 mg filmomhulde tabletten
PRD10395223 · Product
- Active substance
- Bosentan Monohydrate
- Substance synonyms
- BOSENTAN HYDRATE
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 125 mg milligram(s)
- Max total dose
- 4375 mg milligram(s)
- Max treatment duration
- 4 Week(s)
- Authorisation status
- Authorised
- ATC code
- C02KX01 — BOSENTAN
- Marketing authorisation
- RVG 117025
- MA holder
- ABDI FARMA GMBH
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Bosentan Accord 62,5 mg filmomhulde tabletten
PRD2402460 · Product
- Active substance
- Bosentan
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 125 mg milligram(s)
- Max total dose
- 4375 mg milligram(s)
- Max treatment duration
- 4 Week(s)
- Authorisation status
- Authorised
- ATC code
- C02KX01 — BOSENTAN
- Marketing authorisation
- RVG 114393
- MA holder
- ACCORD HEALTHCARE B.V.
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Placebo 1
SUB12626MIG · Substance
- Active substance
- Microcrystalline Cellulose
- Pharmaceutical form
- ORAL POWDER
- Route of administration
- ORAL
- Max daily dose
- 125 mg milligram(s)
- Max total dose
- 4375 mg milligram(s)
- Max treatment duration
- 4 Week(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Auxiliary 1
PRD318028 · Product
- Active substance
- Acetylcholine Chloride
- Pharmaceutical form
- INTRAOCULAR INSTILLATION SOLUTION
- Route of administration
- INTRACORONARY USE
- Max daily dose
- 220 µg microgram(s)
- Max total dose
- 220 µg microgram(s)
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- S01EB09 — ACETYLCHOLINE
- Marketing authorisation
- RVG 10512
- MA holder
- DR. GERHARD MANN CHEM.-PHARM. FABRIK GMBH
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Stichting Radboud University Medical Center
- Sponsor organisation
- Stichting Radboud University Medical Center
- Address
- Geert Grooteplein Zuid 10
- City
- Nijmegen
- Postcode
- 6525 GA
- Country
- Netherlands
Scientific contact point
- Organisation
- Stichting Radboud University Medical Center
- Contact name
- Peter Damman
Public contact point
- Organisation
- Stichting Radboud University Medical Center
- Contact name
- Peter Damman
Locations
1 EU/EEA country · 5 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Netherlands | Ongoing, recruiting | 100 | 5 |
| Rest of world | — | 0 | — |
Investigational sites
Amsterdam UMC Stichting
Cardiology, Meibergdreef 9, 1105 AZ, Amsterdam
Catharina Ziekenhuis Stichting
Cardiology, Michelangelolaan 2, 5623 EJ, Eindhoven
Radboud universitair medisch centrum / RADBOUDUMC
Cardiology, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen
Universitair Medisch Centrum Utrecht
Cardiology, Heidelberglaan 100, 3584 CX, Utrecht
Maasstad Ziekenhuis Stichting
Cardiology, Maasstadweg 21, 3079 DZ, Rotterdam
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Netherlands | 2024-09-27 | 2024-11-11 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Serious breaches 1 · Art. 52 CTR
Serious breach SB-119893
- Sponsor became aware
- 2026-02-17
- Date of breach
- 2026-02-11
- Submission date
- 2026-02-18
- Member states concerned
- Netherlands
- Categories
- Protocol
- Areas impacted
- Subject safety, Data reliability or robustness
- Benefit-risk balance changed
- Yes
- Description
- 4th randomised participant in Maasstad was randomised to one arm, used medication in the safety uptitration phase (low dose 63,5mg) of the correct arm. But was supplied with the other arm medication after uptitration to 125mg, which participant started using from the 11th of february. Apothecary of Maasstad discovered mistake yesterday and alerted sponsor.
After consulting PI, descision was made to wait with deblinding, sinces patient had already invested 5 weeks of medication use and 2 visits. Local Maasstad study team contacted patient this morning who was feeling a bit better than the past few weeks and is not experiencing any side effects. After explaining what happened participant was asked if they would want to continue the trial if this would be a possibility. Participant wants to continue.
We are now communicating an extra safety lab control (after use of 7 days of 125mg) to ensure apart from clinial status also no biochemical side effects are seen. If this is completely normal, we want to suggest keeping patient in the study without deblinding anyone. All study procedures will take place as was agreed upon in patient information sheet. - Sponsor actions
- Pharmacy of Maasstad and local study team of maasstad are planning a meeting to discuss where the mistake has occured and how to prevent this from happening again.
A report to Radboudumc will be given. We will stay in contact and evaluate the case after deblinding has taken place (preferably at same time as for all other 99 participants).
Of note, if patient was mistakenly switched from bosentan to placebo, there was no safety issue for patient, but a data reliability issue. If the other way around, there was a potential risk for patient, e.g. unwanted side-effects due to blood pressure lowering which would have been more profound with a 'starting dose' of 125mg.
| Organisation | City | Country | Type |
|---|---|---|---|
| Maasstad Ziekenhuis Stichting | Rotterdam | Netherlands | Clinical facility BE/BA |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 7 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol_2023-507782-25-00_redacted | 1.6 |
| Recruitment arrangements (for publication) | K1 _ recruitment procedure | 1.1 |
| Subject information and informed consent form (for publication) | L1_ SIS and ICF adults_redacted | 1.6 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_ SmPC bosentan | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_ SmPC bosentan | 1 |
| Synopsis of the protocol (for publication) | D1_Protocol synopsis Dutch | 1.1 |
| Synopsis of the protocol (for publication) | D1_protocol synopsis English | 1.1 |
Application history
5 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-01-07 | Netherlands | Acceptable with conditions 2024-04-16
|
2024-04-16 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2024-07-25 | Netherlands | Acceptable with conditions 2024-08-29
|
2024-08-29 |
| 3 | SUBSTANTIAL MODIFICATION | SM-2 | 2024-10-02 | Netherlands | Acceptable 2024-11-07
|
2024-11-07 |
| 4 | SUBSTANTIAL MODIFICATION | SM-3 | 2025-07-03 | Netherlands | Acceptable 2025-08-12
|
2025-08-12 |
| 5 | SUBSTANTIAL MODIFICATION | SM-5 | 2026-01-14 | Netherlands | Acceptable 2026-02-25
|
2026-02-25 |