Protocol for a randomized controlled trial comparing the efficacy of n-butyl cyanoacrylate glue versus endovenous laser ablation for recurrent varicose veins due to residual/ recurrent incompetent perforators.

Study design

This is an interventional, parallel-group, randomized controlled trial with a superiority framework. The random allocation sequence will be generated by an independent statistician using a computer-generated randomization method (simple randomization) with a 1:1 allocation ratio. The study is single-blind, with blinding of the outcome assessor and data analyst. The present study will be conducted on the patients admitted under the Department of Interventional Radiology Department of Interventional Radiology, JNMC and Acharya Vinoba Bhave Rural Hospital at Datta Meghe Institute of Higher Education and Research, Sawangi, Maharashtra, India, from September 2025 to August 2026. Patients and the public were not directly involved in the design of this study; however, the study outcomes were selected based on clinically relevant endpoints that impact patient quality of life.

Eligibility criteria

All patients (aged more than 18 years old) admitted under the Department of Interventional Radiology and diagnosed with recurrent varicose veins will be included in the study. All the patients should have a clear history of prior treatment. The varicose veins shall be diagnosed and confirmed by ultrasound and patient shall be classified according to the Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification. Patients belonging to CEAP classes C3 to C6 shall be included in the trial. All the cases where they refuse to consent to participate in the study and any patient with deep vein thrombosis, with medical conditions like terminal cancer, immunocompromised status or known coagulopathies, patients on anticoagulants or patients allergic to any of the study drugs will be excluded. Pregnant and lactating women shall also be excluded.

Ethical considerations & consent

Prior to initiation of the study, approval was obtained from the Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research (Approval Reference No.: DMIHER (DU)/IEC/2025/231; dated 05 July 2025). The study will be conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and Good Clinical Practice guidelines. The trial has been prospectively registered with the Clinical Trials Registry of India (CTRI/2025/08/093813) (http://ctri.nic.in) on 28 August 2025.

Protocol amendments and communication

Any important protocol modifications (such as changes to eligibility criteria, interventions, outcomes, or analysis methods) will be submitted to the Institutional Ethics Committee for approval prior to implementation. Approved amendments will be communicated to all relevant stakeholders, including investigators, study personnel, and the Clinical Trials Registry of India (CTRI), where the trial record will be updated accordingly.

Informed consent

Informed consent will be obtained from all participants prior to enrolment in the study. The consent process will be conducted by the Principal Investigator or a trained Co-investigator. Participants will be provided with a detailed patient information sheet explaining the purpose of the study, procedures involved, potential risks and benefits, and their rights as research participants. Adequate time will be given to ask questions and consider participation. Written informed consent will be obtained voluntarily before any study-related procedures are performed. For participants unable to provide consent, consent will be obtained from a legally authorized representative in accordance with ethical guidelines. The consent form will be provided in a language understandable to the participant. No biological specimens will be collected as part of this study, and no ancillary or future use of participant data is planned beyond the objectives of this trial. Therefore, no additional consent provisions are required.

Confidentiality

Personal information of participants will be collected as part of routine clinical evaluation and study documentation and will be recorded in the Case Record Form. Each participant will be assigned a unique study identification number, and all data used for analysis will be de-identified to ensure confidentiality. Access to identifiable data will be restricted to the Principal Investigator and authorized study personnel only. Electronic data will be stored in password-protected systems, and physical records will be maintained in locked cabinets within the research office. Participant data will not be shared outside the study team except in anonymized form for scientific publication or as required by regulatory authorities. Confidentiality of participant information will be maintained throughout the study and after its completion in accordance with institutional policies and applicable regulations. All procedures will comply with applicable data protection and privacy regulations.

Sample size and sampling procedure

The sample size was calculated for comparison of two independent proportions (anatomical closure rates) between cyanoacrylate glue and endovenous laser ablation. Based on existing literature, the expected closure rate for EVLA in recurrent varicose veins is approximately 70–80%, while cyanoacrylate glue demonstrates closure rates of 85–95%. For the purpose of sample size estimation, a conservative assumption of 75% closure for EVLA and 90% for cyanoacrylate glue was considered, corresponding to an absolute difference of 15%. The sample size was calculated using a two-sided test for difference in proportions, with a significance level (alpha) of 0.05 and statistical power of 80%. Using the standard formula for comparison of two independent proportions, the required sample size was estimated to be 97 patients per group. To account for minimal attrition and ensure adequate statistical power, the sample size was rounded to 100 patients per group, resulting in a total sample size of 200 patients.

The final sample size is 100 participants per group. All consecutive patients meeting the inclusion and exclusion criteria will be included in the study till the desired sample size is met. All patients meeting the inclusion and exclusion criteria shall be approached by the Research Team and given detailed information about the trial, its importance and impact. A written Information sheet shall be given and all the questions of the patients shall be answered by the Research Team.

Participants will be recruited from patients presenting with recurrent varicose veins to the Department of Interventional Radiology at Datta Meghe Institute of Higher Education and Research, a tertiary care referral center with a high patient load of chronic venous disease. Potential participants will be identified through outpatient clinics and inpatient referrals. Consecutive eligible patients meeting the inclusion criteria will be screened and approached for participation. To ensure adequate enrolment, collaboration with departments of vascular surgery and general medicine will be established to facilitate referral of eligible cases. Regular screening logs will be maintained to monitor recruitment rates.

Patients will be provided detailed information about the study, including its clinical relevance and potential benefits, to enhance participation. Given the institutional patient volume and referral pattern, recruitment of the required sample size within the defined study period is considered feasible.

Group allocation and blinding

After inclusion in the study, the patients will be randomly divided into Group A (Laser Group) and Group B (Glue Group). The random allocation sequence will be generated by an independent statistician using a computer-generated randomization method (simple randomization) with a 1:1 allocation ratio. No stratification factors will be applied. No blocking or other restriction methods will be used in sequence generation. As simple randomization is employed, no additional restricted randomization details are maintained. Allocation concealment will be ensured using sequentially numbered, opaque, sealed envelopes (SNOSE), prepared by an independent statistician which will be opened only after participant enrolment. Participants will be enrolled by the Principal Investigator, and allocation will be assigned using SNOSE. The allocation will be revealed at the time of intervention by the treating interventional radiologist. This process will ensure that the allocation sequence remains concealed from investigators and participants until assignment, thereby minimizing selection bias. The random allocation sequence will be accessible only to the independent statistician responsible for sequence generation. Personnel involved in participant enrolment and intervention assignment will not have access to the allocation sequence. Allocation will be revealed only after enrolment through sequential opening of sealed envelopes, ensuring that the allocation sequence remains concealed until the point of assignment.

This study will be conducted as a single-blind trial. Due to the nature of the interventions (use of tumescent anaesthesia in EVLA and absence of it in cyanoacrylate glue), blinding of participants and treating interventional radiologists is not feasible. However, outcome assessors (duplex ultrasound evaluators) and data analysts/statisticians will be blinded to the treatment allocation to minimize assessment and analysis bias. Blinding will be maintained during follow-up assessments and data analysis.

As participants and treating interventional radiologists are not blinded, unblinding is only applicable to outcome assessors and data analysts. Unblinding will be permissible only in exceptional circumstances where knowledge of the allocated intervention is essential for patient safety or clinical management. The decision to unblind will be made by the Principal Investigator.

In such cases, the allocation will be revealed through access to the corresponding sealed envelope or study records. All instances of unblinding will be documented, including the reason, timing, and personnel involved. Routine unblinding will not be performed, and blinding will otherwise be maintained throughout outcome assessment and data analysis.

Procedure

All procedures will be performed in the interventional radiology suite under aseptic conditions by experienced interventional radiologists trained in endovenous interventions. The procedures will be performed as single-session interventions following standardized institutional protocols. No separate intervention manual is used; however, all procedural steps have been standardized and described in sufficient detail within this protocol to allow reproducibility. The treatment will be as follows:

Following both the procedures, haemostasis will be achieved by immediate compression and thereafter, sterile dressing shall be applied. Patients will be discharged on the same day with instructions for the use of compression stockings and avoidance of strenuous activities for 6 weeks. Reflux status, thrombosis and anatomical closure will be assessed on follow-up duplex ultrasound. Follow-up visits will be performed at 6 months and 1 year. The schedule of enrolment, interventions, and assessments is summarized in Table 1.

Ancillary and post-trial care and compensation

Participants will receive standard-of-care treatment for their condition throughout the study period. Any complications or adverse events arising during or after the procedure will be managed appropriately as per institutional protocols. No additional ancillary care beyond routine clinical management is specifically planned as part of this trial. Post-trial care will be provided as required based on the clinical condition of the patient, and participants will continue to receive appropriate medical management at the institution. In the event of any trial-related injury, appropriate medical care will be provided, and compensation will be managed in accordance with institutional policies and applicable regulatory guidelines.

Criteria for discontinuing or modifying allocated intervention

The allocated intervention may be discontinued or modified in the following situations:

In such cases, appropriate standard-of-care management will be provided. All instances of discontinuation or modification will be documented, including the reason and timing.

Strategies to improve and monitor adherence to intervention protocols

Trial monitoring

Trial conduct will be monitored internally by the Principal Investigator to ensure adherence to the study protocol, data accuracy, and participant safety. Monitoring will be performed on a periodic basis throughout the study, including review of data entry, protocol compliance, and reporting of adverse events. Given the single-center design and the use of standard-of-care interventions with established safety profiles, no independent external monitoring body has been constituted. The study may be subject to audit by the Institutional Ethics Committee as deemed necessary to ensure compliance with ethical standards and Good Clinical Practice guidelines.

Adherence to the allocated intervention will be ensured and monitored at multiple levels. All procedures will be performed according to predefined standardized protocols by trained interventional radiologists to maintain procedural consistency. A procedural checklist will be used intra-operatively to ensure compliance with key technical steps, including correct device positioning, energy delivery parameters (for EVLA), and volume and technique of NBCA.

Immediate post-procedure documentation will confirm whether the intervention was delivered as per the allocated group. Any protocol deviations will be recorded in the Case Record Form along with justification. Post-procedural adherence will be reinforced through standardized discharge instructions, including use of compression stockings and activity restrictions. Patients will be followed up at predefined intervals (6 months and 1 year), and adherence to follow-up visits will be monitored through scheduled appointments and reminders.

Concomitant care permitted and prohibited during the trial

Concomitant care during the trial will be standardized to minimize confounding effects.

Permitted care:

Prohibited care:

Conditional care:

All concomitant treatments and deviations from protocol will be recorded in the Case Record Form and considered during analysis.

Primary outcomes

1. Anatomical closure of incompetent perforators:

Measurement variable: Presence or absence of flow within the treated perforator on duplex ultrasound (binary outcome).

Analysis metric: Proportion of successfully occluded perforators in each group.

Method of aggregation: Percentage (%) of patients achieving complete closure.

Time points: 6 months and 1 year post-procedure.

2. Clinical improvement:

Measurement variable: Venous Clinical Severity Score (VCSS).

Analysis metric: Change in VCSS from baseline to follow-up.

Method of aggregation: Mean ± standard deviation (or median with interquartile range depending on distribution).

Time points: Baseline, 6 months, and 1 year.

Secondary Outcomes.

1. Procedure-related complications (safety outcomes):

Measurement variable: Incidence of complications (e.g., deep vein thrombosis, thrombophlebitis, skin necrosis, nerve injury, allergic reaction).

Analysis metric: Proportion of patients experiencing at least one complication.

Method of aggregation: Percentage (%) of patients with complications.

Time points: Immediate post-procedure, 6 months, and 1 year.

2. Procedure duration:

Measurement variable: Time taken to complete the procedure (in minutes).

Analysis metric: Mean difference between groups.

Method of aggregation: Mean ± standard deviation (or median with interquartile range).

Time point: Intra-procedural (single measurement).

Data pertaining to demographics and aforementioned parameters shall be collected and recorded in standardized Case Record Form. All ultrasound assessments will be performed by trained personnel using standardized protocols.

There is no run-in period or washout phase in this study. All eligible participants will directly undergo randomization followed by intervention. All follow-up assessments will be performed using standardized clinical evaluation and duplex venous Doppler ultrasound by a blinded outcome assessor. The patients will be explained in detail about the trial interventions and follow-up protocol at the time of enrolment in the trial. The dates of follow-up shall be scheduled at the time of discharge including room for delay or early follow-ups (3 to 4 days).

Participant retention and follow-up

Strategies to promote participant retention will include clear communication regarding the importance of follow-up visits, provision of written and verbal instructions at discharge, and scheduling of follow-up appointments at the time of enrolment. Reminder calls will be made prior to scheduled visits to improve compliance. All participants will be followed up at predefined intervals (6 months and 1 year), and efforts will be made to minimize loss to follow-up. Missed visits will be actively tracked, and participants will be contacted to reschedule assessments wherever possible. In cases where participants discontinue the intervention or deviate from the assigned protocol, outcome data including anatomical closure status (duplex ultrasound), VCSS score, and occurrence of complications will still be collected whenever feasible. All such cases will be documented, and analysis will be performed according to the intention-to-treat principle.

Data handling, analysis and reporting of adverse events

Data management

Data will be collected using standardized Case Record Forms and entered into Microsoft Excel by an independent data entry operator and analysed using SPSS version 25.0. Each participant will be assigned a unique study identification number to ensure anonymization, and no personally identifiable information will be used in the analysis dataset. Data quality will be ensured through regular cross-checking of entries and validation procedures, including range and consistency checks. Periodic internal data audits may be performed to ensure completeness and accuracy. Any discrepancies will be verified against source documents and corrected under supervision of the Principal Investigator. Access to the dataset will be restricted to the Principal Investigator and authorized study personnel. Electronic data will be stored in password-protected systems, and physical documents (CRFs) will be stored in locked cabinets within the research office. All data will be securely stored for the duration of the study and retained as per institutional and regulatory requirements. No external data management system is used, and all procedures are described within this protocol.

Data monitoring committee

No independent Data Monitoring Committee (DMC) has been constituted for this study. This is because both interventions (endovenous laser ablation and cyanoacrylate glue) are established, standard-of-care procedures with well-documented safety profiles, and the study does not involve high-risk experimental interventions. Continuous oversight of trial conduct, participant safety, and data integrity will be provided by the Principal Investigator. Any adverse events or safety concerns will be promptly reported to the Institutional Ethics Committee and the Clinical Trials Registry of India (CTRI) as per regulatory requirements. There is no external audit planned. However, the trial may be subjected to internal audit by the Institutional Ethics Committee as and when deemed necessary to ensure compliance to the approved protocol and to the Good Clinical Practice Guidelines. The trial will be coordinated by the Principal Investigator at the coordinating site. No separate steering committee or endpoint adjudication committee has been constituted due to the single-centre design. Data management will be overseen by the Principal Investigator with support from trained study personnel.

Interim analysis and stopping guidelines

No formal interim analysis is planned for this study due to the relatively short duration of follow-up and the use of established, low-risk interventions. There are no predefined stopping guidelines for efficacy or futility. However, in the event of unexpected serious safety concerns or a significantly higher rate of adverse events in any study group, the trial may be reviewed and, if necessary, terminated. The decision to terminate the study will be made by the Principal Investigator in consultation with the Institutional Ethics Committee. No interim results will be routinely generated or accessed during the study.

Data collection methods and quality assurance

Data will be collected prospectively using a standardized Case Record Form (CRF) for all enrolled participants. Baseline demographic and clinical data, procedural details, and follow-up outcomes will be recorded at predefined time points.

Clinical assessment will include evaluation using the Venous Clinical Severity Score (VCSS), a validated and widely used scoring system for chronic venous disease. Imaging data will be obtained using duplex venous Doppler ultrasound, which is the standard and reliable modality for assessing venous reflux and vessel occlusion. To ensure data quality and consistency, all outcome assessments will be performed by trained personnel using standardized protocols. Duplex ultrasound examinations will be conducted by experienced operators, and efforts will be made to maintain uniform technique across assessments. Data accuracy will be ensured through regular cross-verification of entries, and any discrepancies will be resolved by the Principal Investigator. De-identified individual participant data, data dictionary, and statistical code will be made available upon reasonable request after publication, subject to institutional policies.

Definition and classification of adverse events

Adverse events will be prospectively recorded and classified based on severity and clinical impact. Minor complications will include self-limiting events not requiring significant intervention, such as local pain or discomfort, ecchymosis or localized hematoma, mild superficial thrombophlebitis and transient skin erythema or inflammation.

Major complications will include events requiring medical or interventional management, prolonged hospitalization, or resulting in significant morbidity. These include deep vein thrombosis (DVT), non-target embolization, nerve injury (persistent sensory or motor deficit), severe allergic reaction or anaphylaxis and skin necrosis or ulceration.

All adverse events will be recorded with respect to time of occurrence (intra-procedural, immediate post-procedural, 6 months, and 1 year follow-up) and graded for severity.

Adverse events will be assessed using a systematic and structured approach. Active surveillance will be performed at predefined time points, including immediate post-procedure, 6 months, and 1 year follow-up visits, through clinical evaluation and duplex ultrasound examination. In addition, non-systematic reporting will be allowed, whereby patients will be encouraged to report any symptoms or complications occurring between scheduled visits. All adverse events will be identified through a combination of clinical assessment, imaging findings (duplex ultrasound), and patient-reported symptoms. The outcome assessor and treating physician will document and verify all events. Each adverse event will be categorized by severity (minor or major), timing, and clinical impact. Where applicable, causality in relation to the intervention will be assessed by the treating interventional radiologist.

A standardized Case Record Form will be used to ensure uniform documentation of all adverse events.

Data analysis and statistical plan

Statistical analysis will be performed using Statistical Package for the Social Sciences (SPSS) version 25.0. Descriptive statistics will be presented as mean ± standard deviation or median with interquartile range for continuous variables, depending on data distribution, and as frequency and percentage for categorical variables.

Primary outcomes:

Anatomical closure rates (binary outcome) will be compared between groups using the Chi-square test or Fisher’s exact test, as appropriate. The treatment effect will be expressed as risk difference and relative risk (RR) with 95% confidence intervals.

Change in Venous Clinical Severity Score (VCSS) will be analysed using the independent samples t-test or Mann–Whitney U test, depending on normality of distribution. Mean difference between groups will be reported.

Secondary outcomes:

Procedure-related complications (harms) will be analysed as categorical variables and compared using the Chi-square test or Fisher’s exact test. The incidence of complications will be reported as proportions with 95% confidence intervals.

Procedure duration (continuous variable) will be compared using the independent samples t-test or Mann–Whitney U test, as appropriate.

A p-value <0.05 will be considered statistically significant. Normality of data distribution will be assessed using the Shapiro–Wilk test.

All patient data shall be anonymized with access to the Principal Investigator only.

Efforts will be made to minimize missing data through structured follow-up. In case of missing outcome data, primary analysis will follow the intention-to-treat principle with all randomized patients included in the analysis irrespective of protocol adherence and missing data will be handled using appropriate imputation methods (e.g. multiple imputation where feasible), depending on the nature and extent of missingness.

Pre-specified subgroup analyses may be performed to assess the consistency of treatment effects across different patient groups. Subgroups will include CEAP classification (C3–C6) and number of incompetent perforators (single versus multiple). Treatment effects within subgroups will be analysed and compared descriptively. All subgroup and sensitivity analyses will be considered exploratory in nature, and results will be interpreted with caution.

Sensitivity analyses will be conducted to evaluate the robustness of the primary outcomes, including analysis excluding participants with major protocol deviations and analysis using different methods for handling missing data.

In cases of protocol deviation, withdrawal, or loss to follow-up, available outcome data will be included in the analysis wherever possible. Missing data will be handled using appropriate statistical methods as described. A secondary per-protocol analysis may be performed including only those participants who completed the intervention and follow-up as per the study protocol, to assess the consistency of results.

Handling of missing data

All analyses will be conducted according to the intention-to-treat principle. Efforts will be made to minimize missing data through structured follow-up and participant retention strategies. For the primary analysis, available data will be used. In cases of missing outcome data, appropriate imputation methods will be applied depending on the type and extent of missingness. Sensitivity analyses will be performed to assess the impact of missing data on study outcomes.

Dissemination

The results of the study will be presented in conferences/scientific meetings and will also be published in a peer-reviewed journal. Authorship shall be determined according to the International Committee of Medical Journal Editors (ICMJE) guidelines. The full protocol with anonymized details of patients, after publication, shall be made available upon reasonable request.

Study status

The study is currently recruiting and in follow-up phase, expected to be completed in July 2026 (Protocol version 1.0 dated 05.07.2025).