The objective of this study is to compare, in a prospective randomized way, the anal fistula plug with the mucosal advancement flap in the treatment of high transphincteric perianal fistula in terms of fistula closure rate, continence, morbidity, postoperative pain, and quality of life.
The PLUG trial is a prospective double blinded randomized multicenter trial. Patients with high perianal fistulas of cryptoglandular origin will be randomized to either the fistula plug or the mucosal advancement flap. Randomization will be performed during surgery after finding the internal opening. The computer randomization will be done centrally in the Academic Medical Centre in Amsterdam, the Netherlands. Stratification is performed for the randomizing centers.
Patients will be blinded for the type of intervention i.e. anal fistula plug or mucosal advancement flap. Patients are followed-up at two weeks, four weeks, and 16 weeks. At the final follow-up closure rate is determined by clinical examination. Follow-up is done by a colorectal surgeon, who is blinded for the type of intervention. The fistula will be rated closed if the external and the internal opening are closed and no discharge is experienced. Otherwise it is considered as a persistent fistula.
The study population consists of patients with high perianal fistulas.
Inclusion criteria are; age above 18 years, high anorectal fistula of cryptoglandular origin (transsphincteric, upper 2/3 of the sphinctercomplex which is confined by the puborectal sling and the end of the anal canal), and informed consent.
Exclusion criteria are; no internal opening found during surgery, HIV-positive patients, Crohn's disease, malignant cause, tuberculosis, hydradenitis suppurativa, and pilonidal sinus disease.
Primary and secondary endpoints
The primary endpoints of the PLUG trial are fistula closure rate and continence. Continence will be evaluated pre- and postoperatively using the COREFO, the Wexner and the Vaizey score. The COREFO questionnaire has 27 questions to asses colorectal functional outcome . The Vaizey scale consists of three items about the type (gas, fluid, solid) and frequency of incontinence (all scored from zero to four) and four additional items that address alteration in lifestyle (zero to four), the need to wear a pad or plug (zero or two), the use of constipating medication (zero or two), and the lack of ability to defer defecation for 15 minutes (zero or four). The total score on the Vaizey scale ranges from 0 (complete continence) to 24 (complete incontinence) .
Secondary endpoints are morbidity, postoperative pain, and quality of life. Postoperatively patients will be asked to grade their pain on a visual analogue scale (VAS: 0, no pain; 10, worst imaginable pain) on different moments during the follow-up. Quality of life will be evaluated using the SF-36 questionnaire. The SF-36 measures eight health attributes: physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, pain, vitality and general health perception. The higher the score, the better the health rating with 100 points as the maximum for each concept. In addition the EQ-5D questionnaire is used.
Six Dutch hospitals, including one academic and five non-academic hospitals, will enrol patients.
The study is conducted in accordance with the principles of the Declaration of Helsinki and 'good clinical practice' guidelines. The protocol has been approved by the Medical Ethics Committee of the Academic Medical Centre in Amsterdam and the local Ethical Committees of the participating centers. Prior the randomization informed consent will be obtained from all patients.
Patients presenting in the outpatients department with high perianal fistulas of cryptoglandular origin will be asked for informed consent when the patient fulfils in- and exclusion criteria.
Positioning of the anal fistula plug will be done according to the instructions of Cook SIS technology. The plug is fabricated from Surgisis (Cook Surgical, Inc., Bloomington, IN), a bioabsorbable xenograft, made of lyophilized porcine intestinal submucosa. The material has inherent resistance to infection, produces no foreign body or giant cell reaction, and becomes repopulated with host cell tissue during a period of three months. All procedures will be performed under general or locoregional anaesthesia. Prophylactic broad-spectrum antibiotics will be administered before surgery. During surgery the internal fistula tract opening will be identified, followed by cleaning and debriding the fistula tract with hydrogen peroxide. A suture will be attached to the tail of the plug. A probe is inserted into the external opening exiting through the internal opening and the suture attached to the tail of the plug is grasped. Then the plug is pulled into the fistula tract, tail first. The suture is drawn into the tract until the plug securely blocks the internal opening and fits snugly within the tract. Any remaining portion of the plug that is not implanted in the tract is trimmed and discarded. The internal end of the plug is sutured in place with at least two sutures. The internal sutures should close the anal canal opening. In contrast with former instructions, no external fixation suture is placed. The external opening is left open to allow for drainage of the tract. In case of a wide fistula tract, a second fistula plug can be put in place.
The rectal advancement flap was done according to the following technique. The internal opening was excised followed by mobilization of the mucosa, submucosa, and a small amount of muscular fibers from the internal sphincter complex. A rectal flap with a 2 to 3 cm broad base was mobilized. The rectal flap was mobilized sufficiently to cover the internal opening with overlap. Hemostasis was performed to prevent a hematoma under the flap. The fistula tract was curetted. The internal opening was not closed before advancing the flap over the internal opening. Finally the flap was sutured in the distal anal canal.
Intention to treat
The analysis will be performed in accordance with the intention to treat principle.
Sample size calculation
A success percentage of 87% was reported by Armstrong and colleagues for the anal fistula plug . For the mucosal advancement flap a success percentage of 37% was reported recently by Hagen and colleagues in a series of 41 patients with a follow-up of 72 months .
To detect an increase in success percentage from 40% to 80%, using a significance level of 0.05, at least 46 patients have to be randomized to achieve a power of 80%. In total, 60 patients will be randomized.
Data collection and monitoring
Data are collected via datasheets on paper, which are sent to the Academic Medical Centre by mail. Postoperatively questionnaires on pain are filled in by patients. Sixteen weeks after surgery questionnaires are sent to the patients to assess continence and quality of life.
There will be regular contact between the study coordinators and the participating centers. One research fellow will monitor the included data of every patient.