Treatment of haemorrhoids: rubber band ligation or sclerotherapy (THROS)? Study protocol for a multicentre, non-inferiority, randomised controlled trial

Trial design

The THROS trial is a non-inferiority, multicentre, randomised controlled trial with two parallel groups: RBL vs. SCL. The allocation ratio is 1:1. Crossover is possible for patients who experience no improvement of symptoms after at least two treatments within one treatment arm. It is expected that when two treatments have not reduced symptoms and a third treatment is necessary, both patients and surgeons are inclined to try a new treatment option. So crossover rate is also indicative for treatment success. Also, when patients have a strong preference for one of the two treatment arms and refuse randomisation, then registration in the preference arm is allowed. All patients’ symptoms could not be effectively managed by conservative treatment, which included dietary changes, laxatives, and lifestyle improvements. Conservative management was the first step of therapy in all cases. After eligibility has been established and patients have given their written informed consent, allocation or registration to one of the two treatment arms is possible. Data will be analysed on both ‘intention to treat’ and ‘per protocol’ basis.

The trial was registered at the Dutch Trial Register (NL8377). The protocol was drafted in accordance with the Standard Protocol Items: Recommendations for Interventional Trials statements (SPIRIT) [12].

Eligibility criteriaInclusion criteria Exclusion criteria

Grade 3 and 4 haemorrhoids (Golligher classification)

Patients that have undergone treatment for HD within the last 12 months, regardless of the type of treatment.

Interventions

Eligible patients are randomised via CastorEDC to either the SCL or RBL arm. Patients who deny randomisation are eligible to the preference arm of their choice. Patients who are randomised to receive SCL are treated with 4 cc Aethoxysklerol 3% (polidocanol) in the haemorrhoidal tissue via a small 18 mm proctoscope (Sapimed). Patients who are randomised to receive RBL are treated via the same small proctoscope with 3 rubber bands which are placed at the base of the haemorrhoidal tissue (Barron ligation). When after approximately 6–8 weeks a second treatment is required this should be the same treatment as the first (SCL or RBL), after which, in case of persistence after at least two treatments and again 6–8 weeks in between treatments, a crossover is permitted. There are no restrictions regarding concomitant care during the trial.

OutcomesPrimary outcomes

The primary outcome measures are treatment efficacy measured through PROMs according to the ESCP core outcome set of symptom reduction, subjective recurrences and complications (Table 1). The follow-up period for this outcome set is 6 months, and data will be collected at 4 different time points during this period (baseline, 1 week, 6 weeks and 6 months after the first procedure).

Table 1 Primary and secondary outcome measures Treatment efficacy

This outcome follows the patient-reported outcome measure-haemorrhoidal impact and satisfaction score (PROM-HISS) questionnaire from the international Delphi procedure of the European Coloproctology group, for which recently the first steps in the validation process were taken [10, 11, 13].

This questionnaire consists of three domains: (1) HD symptoms, (2) impact of HD on daily activities, and (3) satisfaction with treatment [13]. The first domain contains five HD symptoms of which each is scored on a Likert scale ranging from 1 (“not at all”) till 5 (“very much”), resulting in a maximum possible score of 25. During follow-up, any reduction in score on this numeric scale is classified as ‘improvement’. This will then be translated into a binary outcome: “yes” or “no” improvement of symptoms. Both the second and third domains only contain one item, the impact of HD on daily activities and patients’ satisfaction with treatment, respectively. Both are scored on a 10-point numeric rating scale. In respect to the impact of symptoms on daily activities, 0 correlates with “no impact at all” and 10 with “highly impacted on daily activities”. On the contrary, for patient satisfaction with treatment, this ranges between 0 “not at all satisfied” and 10 “very satisfied”. Data from the PROM-HISS questionnaire is collected 1 week after the procedure, so the recall period comprises “the past week” [13].

Complications (i.e. incontinence, abscess, fistula, fissure, urine retention, anal stenosis, arterial bleeding or thrombosed haemorrhoid) are scored at the 6–8 week clinical follow-up appointment at the outpatient clinic. Subjective return of initial symptoms (recurrence) is recorded during the 6-month follow-up period.

Secondary outcomes

Secondary outcome measures consist of patient experience outcomes (PREMs), number of treatments, crossover and number of days on work leave.

Patient experience outcomes are recorded on the PREM questionnaire (Appendix). It contains a series of questions regarding the patients’ experience of the treatment, which is partly scored on a Likert scale ranging from 1 (“not at all”) till 5 (“very much”). Two additional binary (yes/no) questions are added regarding whether patients would undergo the same treatment and whether they would recommend the treatment to acquaintances suffering from similar HD symptoms. The administration of this questionnaire takes place 1 week after treatment. The total number of treatments, the crossover of treatment arms and days of work leave are recorded after a total of 6 months of follow-up. All data entries are stored in CastorEDC.

Participant timeline

Treatment is provided according to the following timeline (Table 2):

T = day 0 → outpatient clinic treatment with either SCL or RBL after providing written informed consent to the treating physician.

T = day 7 → telephone appointment with a blinded researcher: the PROM and PREM questionnaires are completed by the researcher.

T = 6 → weeks outpatient clinic appointment with a physician. The PROM and Wexner incontinence scale are completed together with a physical examination. If needed, the same treatment (SCL or RBL) is repeated.

T = 6 → months telephone appointment with a blinded researcher: PROM questionnaire completed and (subjective) symptoms related to recurrence are assessed.

Table 2 Participant timelineSample size calculation

The sample size is based on a success percentage of 70% in both treatment arms, in terms of symptom reduction. Based on the available literature from Cocorullo et al. [6], we will perform a non-inferiority analysis with a two-sided significance (alpha 2.5%), 80% power and a 10% non-inferiority limit. Consequently, a total of 330 randomised patients are required per arm, so 660 randomised patients in total.

Significance level (a) = 2.5%

Power (1-beta) = 80%

Non-inferiority limit = 10%

Proportionality group A = 70%

Proportionality group B = 70%

Sample size required per group = 330

Total sample size required = 660

Recruitment and blinding

In the Netherlands patients with HD are mostly referred to the surgeon by their general practitioner. The outpatient clinic nurses or researchers will screen for eligibility and send the patient written information (study information folder (PIF) and plan their appointment at the outpatient clinic. This allows for a minimum of 48 h to reflect on the information. The patient takes the information to the outpatient clinic appointment to discuss with the treating physician. In the case of participation, oral and written consent are gathered.

The treating physician generates the allocation process or registration to the preference arm, after written informed consent has been provided.

The randomization sequence will be computer generated with the CastorEDC program (version 24.41) without stratification, with 1:1 allocation to either group, generating a unique record number.

Both patient and treating physician are not blinded for the treatment arm.

In concept, the researcher who completes the telephone interviews at 7 days and 6 months is blinded to the given therapy and is instructed not to actively ask patients which treatment they received. However, the data is added in the same database system, so complete blinding is not guaranteed. The physician at T = 0 and T = 6 weeks is not blinded as it is otherwise impossible to complete the treatment. Also, at 6 weeks the treating physician should repeat the initial treatment when necessary, following protocol.

Data collection

Each participating centre’s personnel involved in treating patients with HD are trained in providing eligible patients with both oral and written information about the study. All the medical baseline and procedure data are collected at the individual hospitals. The data is stored in standardized case record forms (CRFs) within Castor.

The surgeons involved in treating patients with HD are responsible in collecting the data from the initial visit/treatment and the 6-week outpatient visit where complications are scored. Research personnel of each participating centre is responsible for their own data collection during the 6-month follow-up period.

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