Comparing Laparoscopic Elective Sigmoid Resection With Conservative Treatment in Improving Quality of Life of Patients With Diverticulitis

Key Points Question Does elective sigmoid resection improve the quality of life in patients with recurrent diverticulitis, complicated diverticulitis, and/or chronic pain after an episode of diverticulitis? Findings In this randomized clinical trial that included 85 adults, the Gastrointestinal Quality of Life Index (GIQLI) score improved 11.8 points in patients randomized to sigmoid resection and 0.2 points in patients randomized to conservative treatment between baseline and 6 months, a statistically and clinically significant difference. Among 41 patients randomized to sigmoid resection, 4 (10%) experienced major complications. Meaning Sigmoid resection improved quality of life in patients with recurrent, complicated, or persistent painful diverticulitis but was associated with a small but significant risk of major complications.

It has previously been recommended that patients with recurrent diverticulitis undergo elective sigmoid resection to avoid further problems with complicated diverticulitis . However, retrospective work has found that the most difficult diverticulitis episode is usually the very first one, and the occurrence of complicated diverticulitis decreases with the recurrence of diverticulitis . Second, elective surgery for complicated diverticulitis (e.g., abscess) has been recommended . However, this recommendation has also recently been questioned . On the other hand, elective sigmoid resection has been shown to improve quality of life in selected patients with either recurrent diverticulitis or complicated diverticulitis .
Current knowledge of who should have elective sigmoid resection is very limited, is based on retrospective comparative series or prospective studies that lack a control group. To date, no randomized, prospective study comparing surgical treatment to conservative treatment in patients with a relative indication (recurrent diverticulitis, complicated diverticulitis, pain after acute diverticulitis) to elective sigmoid resection has been published. An extensive recent treatment recommendation for diverticulitis cannot provide definitive recommendations for the selection of patients for elective sigmoid resection due to the lack of randomized work .
The main objective of the study is to investigate the effect of elective sigmoid resection on gastrointestinal quality of life by comparing surgical treatment to conservative treatment in a randomized prospective multicenter study. The secondary objective is to investigate recurrence, mortality, and surgical complications of diverticulitis.
7. Acute diverticulitis that has not resolved (inflammatory values need to have returned to normal and fever has stopped) 8. Colonoscopy / sigmoidoscopy or colon computed tomography (virtual colonoscopy) has not been performed within 2 years of randomisation 9. Age <18 or> 75 years 10. Pregnancy 11. Inability to answer quality of life surveys (eg dementia, psychiatric illness, etc.)

Randomization
The patient is randomized 1: 1 for either elective sigmoid resection or conservative treatment. Patients are stratified based on inclusion criteria so that there are equal numbers of patients from each inclusion group in both randomization groups. Randomization is done using a computer centrally from the Helsinki University Central Hospital (HUCH). In practice, the person performing the randomisation connects to the HUCH server via the Internet, which provides the researcher with information about the patient's randomisation group. Randomization is performed at an outpatient visit, after the patient has first given written consent to participate in the study. Based on the group, treatment is selected, i.e. the patient is either placed in a surgical queue for elective sigmoid resection or given lifestyle instructions as well as instructions on how to use fiber supplementation. Upon randomization, the patient completes SF-36 and GIQLI quality of life questionnaires. Patients are analyzed according to the intention-to-treat principle according to the original randomization group.

Elective laparoscopic sigmoid resection
The patient is scheduled for elective laparoscopic sigmoid resection. Surgery is performed within a maximum of 3 months of randomisation. CRF # 3 is filled just before surgery (e.g., during a preoperative visit). CRF # 2 is filled as the patient is discharged after elective sigmoid resection. After the operation, the patient is given lifestyle instructions as well as a recommendation for the use of a fiber supplement. Recommendation on the use of fiber supplement.
Action in the event of elective sigmoid resection in a patient randomized to conservative treatment: Conservative treatment should be tried for at least 6 months of randomisation (= until the first quality of life survey) before it can be concluded that it has failed and the patient referred to elective sigmoid resection. Of course, surgical treatment can be performed earlier if the patient has developed absolute indications for elective sigmoid resection (eg fistula, stricture). If a patient randomized to conservative treatment has to be treated with elective sigmoid resection, the patient should complete the GIQLI and SF-36 quality of life questionnaires at the time of surgery. After surgery, the patient is followed according to the original follow-up schedule (i.e., surveys just before surgery (preoperative visit, etc.), 6 months, 12 months, 24 months, 48 months, and 96 months after the initial randomisation). In accordance with normal research ethical principles, the patient may also opt out of the study altogether, at which point his or her follow-up will cease and he or she will be treated according to normal treatment lines and at the discretion of the attending physician.

Primary outcome
Gastrointestinal Quality of Life Index (GIQLI) -difference between 0 months and 6 months from randomisation.

Follow-up
The attached flow chart shows patient randomisation, timing of treatment procedures, and follow-up.
Patients are called by phone 6 months after randomisation to inquire about well-being and a decision can be made on a possible change in treatment (a patient in the conservative treatment group can be referred for elective sigmoid resection).
Patients are also monitored by mailed questionnaires (SF-36, GIQLI, and a questionnaire prepared by researchers, see appendix) just before surgery (preoperative visit, etc.) and 6 months, 12 months, 24 months, 48 months, and 96 months after randomisation. The same questionnaires are also completed just before elective sigmoid resection. If there is any ambiguity in the answers to the questionnaire, the researcher will, if necessary, contact the patient by telephone to clarify the ambiguities.
The researcher at each center collects a questionnaire from his or her own center and also checks the entries in the patient records in his or her own area. Based on these, the researcher fills out a CRF # 3 form, which is therefore completed at each follow-up time point.

Costs
The study is not expected to incur significant additional costs, as elective sigmoid resection is already a normal treatment and inclusion criteria follow general treatment recommendations. The only costs come from the phone call made to the patient (at 6 months) and the postage costs of the questionnaires.
Research may even save hospital costs, as half of patients are randomized to conservative care and no surgical costs are involved.

Parameters to be collected
Case Report Form (see appendix). Case report form # 1 is completed at the time of randomization (outpatient visit). Case report from # 2 is completed electronically when the patient is discharged. Case report form # 3 is completed at each follow-up time point (just before surgery (preoperative visit, etc.), 6 months, 12 months, 24 months, 48 months, 96 months).

The sample size
In previous publications, preoperative GIQLI has been 95-100 (SD 22) and postoperative GIQLI 112-114 (SD [19][20][21][22]  . The sample size calculation was made using these values, and the study aims to show a difference of 12 GIQLI points, the standard deviation being assumed to be 22 points in both groups. Using 0.05 alpha, 0.9 power, and 1: 1 allocation, a sample size per group of 60 patients is obtained. The sample size calculation was performed using G * Power 3.1.5.1 (comparison of means, two-tailed, A priori). Approximately 10% of patients are estimated to disappear at follow-up, bringing the final sample size to a total of 133 patients.

Schedule, interim analysis and completion of the study
The study is planned to start in summer / autumn 2014. An interim analysis will be performed in the middle of the study, ie for 66 patients. If a statistically significant difference is obtained for the primary outcome already at this stage, the study will not be continued. Otherwise, the study will continue until 133 patients have been randomized. It is estimated that it will take about five years to recruit patients. The follow-up phase will continue for another eight years.

Registration
The study is registered with clinicaltrials.gov before randomization begins.

Privacy Policy
Personal data of randomized patients are collected in the study folder, and CRF # 1, # 2, and # 3 are completed for them. Patients who meet the inclusion criteria and thus are evaluated for participation in the study will be accounted for, how many patients will be excluded from the study, and for what reason (fulfillment of the exclusion criterion, refusal, etc.). Personal data of patients who dropped out of the study will not be collected. The material to be collected is stored in a locked state and the electronic data is protected by passwords and encryption on computers.

(English translation of original study protocol in Finnish)
Research plan v.1.7 (11.1.2017

Background
Diverticulosis is an increasingly common ailment in the aging population. An estimated 25% develop acute diverticulitis . The prognosis of acute diverticulitis is related to its severity measured according to the Hinchey classification. The mildest diverticulitis heals on its own, while mortality from diverticulitis that causes fecal peritonitis is high . Peritoneal inflammation caused diverticulitis usually leads to an emergency sigmoid resection and possible intestinal contents diversion through the stoma. In contrast, milder forms of acute diverticulitis are usually treated conservatively with an intravenous antibiotic and abscesses are drained.
It has previously been recommended that patients with recurrent diverticulitis undergo elective sigmoid resection to avoid further problems with complicated diverticulitis . However, retrospective work has found that the most difficult diverticulitis episode is usually the very first one, and the occurrence of complicated diverticulitis decreases with the recurrence of diverticulitis . Second, elective surgery for complicated diverticulitis (e.g., abscess) has been recommended . However, this recommendation has also recently been questioned . On the other hand, elective sigmoid resection has been shown to improve quality of life in selected patients with either recurrent diverticulitis or complicated diverticulitis .
Current knowledge of who should have elective sigmoid resection is very limited, is based on retrospective comparative series or prospective studies that lack a control group. To date, no randomized, prospective study comparing surgical treatment to conservative treatment in patients with a relative indication (recurrent diverticulitis, complicated diverticulitis, pain after acute diverticulitis) to elective sigmoid resection has been published. An extensive recent treatment recommendation for diverticulitis cannot provide definitive recommendations for the selection of patients for elective sigmoid resection due to the lack of randomized work .
The main objective of the study is to investigate the effect of elective sigmoid resection on gastrointestinal quality of life by comparing surgical treatment to conservative treatment in a randomized prospective multicenter study. The secondary objective is to investigate recurrence, mortality, and surgical complications of diverticulitis.

Hypothesis
Elective sigmoid resection improves quality of life and reduces recurrence of diverticulitis in follow-up.

Procedures
The study sites

Randomization
The patient is randomized 1: 1 for either elective sigmoid resection or conservative treatment. Patients are stratified based on inclusion criteria so that there are equal numbers of patients from each inclusion group in both randomization groups. Randomization is done using a computer centrally from the Helsinki University Central Hospital (HUCH). In practice, the person performing the randomisation connects to the HUCH server via the Internet, which provides the researcher with information about the patient's randomisation group. Randomization is performed at an outpatient visit, after the patient has first given written consent to participate in the study. Based on the group, treatment is selected, i.e. the patient is either placed in a surgical queue for elective sigmoid resection or given lifestyle instructions as well as instructions on how to use fiber supplementation. Upon randomization, the patient completes SF-36 and GIQLI quality of life questionnaires. Patients are analyzed according to the intention-to-treat principle according to the original randomization group.

Elective laparoscopic sigmoid resection
The patient is scheduled for elective laparoscopic sigmoid resection. Surgery is performed within a maximum of 3 months of randomisation. CRF # 3 is filled just before surgery (e.g., during a preoperative visit). CRF # 2 is filled as the patient is discharged after elective sigmoid resection. After the operation, the patient is given lifestyle instructions as well as a recommendation for the use of a fiber supplement. Action in the event of elective sigmoid resection in a patient randomized to conservative treatment: Conservative treatment should be tried for at least 6 months of randomisation (= until the first quality of life survey) before it can be concluded that it has failed and the patient referred to elective sigmoid resection. Of course, surgical treatment can be performed earlier if the patient has developed absolute indications for elective sigmoid resection (eg fistula, stricture). If a patient randomized to conservative treatment has to be treated with elective sigmoid resection, the patient should complete the GIQLI and SF-36 quality of life questionnaires at the time of surgery. After surgery, the patient is followed according to the original follow-up schedule (i.e., surveys just before surgery (preoperative visit, etc.), 6 months, 12 months, 24 months, 48 months, and 96 months after the initial randomisation). In accordance with normal research ethical principles, the patient may also opt out of the study altogether, at which point his or her follow-up will cease and he or she will be treated according to normal treatment lines and at the discretion of the attending physician.

Primary outcome
Gastrointestinal Quality of Life Index (GIQLI) -difference between 0 months and 6 months from randomisation.

Follow-up
The attached flow chart shows patient randomisation, timing of treatment procedures, and follow-up.
Patients are called by phone 6 months after randomisation to inquire about well-being and a decision can be made on a possible change in treatment (a patient in the conservative treatment group can be referred for elective sigmoid resection).
Patients are also monitored by mailed questionnaires (SF-36, GIQLI, and a questionnaire prepared by researchers, see appendix) just before surgery (preoperative visit, etc.) and 6 months, 12 months, 24 months, 48 months, and 96 months after randomisation. The same questionnaires are also completed just before elective sigmoid resection. If there is any ambiguity in the answers to the questionnaire, the researcher will, if necessary, contact the patient by telephone to clarify the ambiguities.
The researcher at each center collects a questionnaire from his or her own center and also checks the entries in the patient records in his or her own area. Based on these, the researcher fills out a CRF # 3 form, which is therefore completed at each follow-up time point.

Costs
The study is not expected to incur significant additional costs, as elective sigmoid resection is already a normal treatment and inclusion criteria follow general treatment recommendations. The only costs come from the phone call made to the patient (at 6 months) and the postage costs of the questionnaires.
Research may even save hospital costs, as half of patients are randomized to conservative care and no surgical costs are involved.

Parameters to be collected
Case Report Form (see appendix). Case report form # 1 is completed at the time of randomization (outpatient visit). Case report from # 2 is completed electronically when the patient is discharged. Case report form # 3 is completed at each follow-up time point (just before surgery (preoperative visit, etc.), 6 months, 12 months, 24 months, 48 months, 96 months).

The sample size
In previous publications, preoperative GIQLI has been 95-100 (SD 22) and postoperative GIQLI 112-114 (SD [19][20][21][22]  . The sample size calculation was made using these values, and the study aims to show a difference of 12 GIQLI points, the standard deviation being assumed to be 22 points in both groups. Using 0.05 alpha, 0.9 power, and 1: 1 allocation, a sample size per group of 60 patients is obtained. The sample size calculation was performed using G * Power 3.1.5.1 (comparison of means, two-tailed, A priori). Approximately 10% of patients are estimated to disappear at follow-up, bringing the final sample size to a total of 133 patients.

Schedule, interim analysis and completion of the study
The study is planned to start in summer / autumn 2014. An interim analysis will be performed in the middle of the study, ie for 66 patients. If a statistically significant difference is obtained for the primary outcome already at this stage, the study will not be continued. Otherwise, the study will continue until 133 patients have been randomized. It is estimated that it will take about five years to recruit patients. The follow-up phase will continue for another eight years.

Registration
The study is registered with clinicaltrials.gov before randomization begins.

Privacy Policy
Personal data of randomized patients are collected in the study folder, and CRF # 1, # 2, and # 3 are completed for them. Patients who meet the inclusion criteria and thus are evaluated for participation in the study will be accounted for, how many patients will be excluded from the study, and for what reason (fulfillment of the exclusion criterion, refusal, etc.). Personal data of patients who dropped out of the study will not be collected. The material to be collected is stored in a locked state and the electronic data is protected by passwords and encryption on computers.