REFORM version 1.0, dated 3 September 2019
Research type
Research Study
Full title
A Prospective, Randomized, Non-Inferiority Trial to Determine the Safety and Efficacy of the Biolimus A9TM Drug Coated Balloon for the Treatment of In-Stent Restenosis: First-in-Man Trial (REFORM)
IRAS ID
270648
Contact name
Hans-Peter Stoll
Contact email
Sponsor organisation
Biosensors Europe SA
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 8 months, 31 days
Research summary
Research Summary
Atherosclerosis (disease, in which the heart arteries are narrowed) is a major cause of premature death worldwide.
Patients with a narrowing in one or more of the blood vessels supplying the heart (coronary arteries) are often treated with a stent (a small mesh-like device which holds the artery open after it is placed in). The coronary arteries can gradually become re-narrowed inside the stent. The standard care for treating this can be either placing another stent inside the artery or inserting a small tube which has a balloon at the end, which is inflated to squeeze open the narrowing. Sometimes these balloons have a special drug coating on the lining which is called a drug-coated balloon (DCB).
In this trial, a drug-coated balloon ”Biolimus A9™ (BA9™)” will be tested for the first time in humans. Eligible patients will have coronary artery disease and an indication for interventional treatment for a re-narrowing inside one or more coronary stents. The DCB only angioplasty (the procedure where the balloon is passed into the artery) allows a rapid release and local drug delivery into the artery and a shorter duration of dual antiplatelet therapy (blood thinning tablets) without the stent-related complications.
This clinical trial seeks to evaluate safety and performance of the Biolimus A9™ (BA9™) DCB (not commercialized) and demonstrate that it is non-inferior to the Sequent Please-DCB (commercialized) with respect to % diameter stenosis (how much the artery is narrowed) as well as to demonstrate that it has similar safety characteristics.
This study will recruit 201 patients in several countries. Enrolled patients will be randomized into one of two treatment arms: either treatment by the BA9™ or by the Sequent® Please DCBs. Patients will be followed for 2 years after the procedure.
Summary of Results
The REFORM study is a prospective, randomized, Non-Inferiority Trial to determine the Safety and Efficacy of the Biolimus A9TMDrug Coated Balloon for the Treatment of In-Stent Restenosis: First-in-Man Trial.
The study was initiated by Biosensors Europe, S.A, the sponsor of the study.Two devices were used in this study, and both are Drug Coated Balloons (DCBs): the Biolimus A9-DCB and the SeQuent® Please-DCB.
The Drug Coated Balloons (DCB) can deliver antiproliferative drugs to local arterial tissue during a single 30-60s balloon inflation, potentially providing a good improvement in luminal diameter without stenting and at the same time reducing restenosis.The objective of the study was to prove that the Biolimus A9-DCB is non-inferior to the approved CE marked SeQuent® Please-DCB with respect to % Diameter Stenosis (DS) and has similar safety characteristics.
To be more precise, the primary endpoint was to assess the % Diameter Stenosis (DS) of the target segment assessed by Quantitative Coronary Angiography (QCA), an imaging analysis technique 6 months after the procedure. This allowed a check to see if the artery had narrowed in this time point.
The Biolimus A9™ Drug Coated Balloon, the experimental device of the study, is comprised of two key components:
- The Biolimus A9™, an active pharmaceutical ingredient which is a highly lipophilic compound with a partition coefficient (log P) of 7.63.
- A semi-compliant rapid exchange balloon catheter.Compared to sirolimus and everolimus, antiproliferative drugs that are commonly used in cardiology, the Biolimus A9™ drug has over 10 times higher lipophilicity. This property is expected to facilitate the penetration and distribution of the drug into the arterial wall during the short (30 sec.) vessel wall exposure during the expansion of the device.
202 patients were included in the study, which were patients with coronary artery disease who have an indication for interventional treatment of in-stent restenosis (ISR) in a Bare-Metal Stent (BMS) or a Drug-Eluting Stent (DES).
Once the patients signed the informed consent form, they had an angiography and were randomised with a 2:1 ratio to one of the following two treatment arms:
• Biolimus A9-DCB
• SeQuent Please-DCBBased on the result of the randomization, the chosen balloon was used for the procedure.
The patients received Dual Antiplatelet Therapy including a P2Y12 inhibitor in combination with aspirin for 3 months.
Follow-up assessments of the patients’ condition were done post-procedure, at 1 month (±7 days), 6 Month (± 30 days), 12 Month (± 30 days) and 24 Month (± 30 days).
At the 6 months follow-up, the participants underwent a planned control angiography to assess the primary endpoint of the study.The study took place at 20 sites in Europe and Asia, from 06 August 2020 (initial enrollment) to 31 July 2024 (the last visit of the last patient).
The number of subjects in each group was of 135 subjects in the Biolimus A9™ Drug Coated Balloon group and 67 in the comparator group, treated with the SeQuent Please-DCB.
Except for a slight imbalance in lesion preparation, demographic, baseline, and procedure and angiographic characteristics between the two groups were similar.
Minimal lumen diameter and diameter stenosis post-procedure showed equal QCA results.A total of 360 serious and non-serious adverse events (AEs) in 138 patients were reported by the sites. More precisely:
- 179 serious AEs
o 48 were determined as possibly Device Related- 181 non-serious AEs.
o 32 were determined as possibly Device Related
No Unanticipated Serious Adverse Device Effects (USADEs) were reported by the site.
These events included:
- 1 arteriosclerosis, stenosis, vascular insufficiency and necrosis
- 8 blood and lymphatic system disorder
- 53 cardiac disorders,
- 2 eye disorders
- 15 gastrointestinal disorders,
- 31 general disorders and administration site conditions,
- 3 hepatobiliary disorders
- 23 infection and infestations,
- 16 injuries, poisoning and procedural complications,
- 4 investigations
- 1 metabolism and nutrition disorders
- 11 musculoskeletal and connective tissue disorders,
- 3 neoplasms benign, malignant and unspecified (including cysts and polyps)
- 7 nervous system disorders,
- 9 renal and urinary disorders,
- 11 respiratory, thoracic and mediastinal disorders
- 21 surgical and medical procedures
- 26 vascular disorders.There are limitations to this study. First, the primary endpoint was angiographic and as such the study was not powered to detect differences in clinical event, this needs to be assessed in larger studies, powered for clinical outcomes. Furthermore, the trial design was single blind and not double blind which could have influenced operator.
The study failed to show non-inferiority for angiographic outcomes compared to the SeQuent Please DCB. SeQuent Please performed extremely well in this study with the lowest late lumen loss value of any prior studies in DES-ISR using this device, which means that the vessel stayed mostly open, with very little narrowing. At six months the data showed a very low late lumen loss of 0.20mm in the SeQuent Please-DCB group compared to 0.50mm in the Biolimus A9-DCB group.
To find more information regarding this study, you can consult the site Clinicaltrials.gov at this link https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fclinicaltrials.gov%252Fstudy%252FNCT04079192.%2FNBTI%2F3fq_AQ%2FAQ%2Face9d888-c6d6-403a-b999-7800a46482ad%2F1%2FFIKdKL-_Q3&data=05%7C02%7Cdulwich.rec%40hra.nhs.uk%7Cb8d66efaf40346344a8a08ddcdd8f61e%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638893053930177141%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=eJEwK7pLVBWgsWODlgxJyRw8easmhyP%2BKp17%2FnGQn08%3D&reserved=0 An overview of the study, the sites that participated and more details can be found there.
REC name
London - Dulwich Research Ethics Committee
REC reference
20/LO/0072
Date of REC Opinion
6 Apr 2020
REC opinion
Further Information Favourable Opinion