Randomised, placebo-controlled, double-blinded trial of fecal microbiota transplantation in severe obesity: a study protocol.

INTRODUCTION: Obesity is one of the main threats to public health in western countries and increases the risk of several diseases, overall morbidity and mortality. Sustained weight loss will reduce risk factors and improve several obesity comorbidities. Options are conservative treatment such as lifestyle changes, bariatric surgery or medications. Conservative treatment has a low success rate, and bariatric surgery is typically not reversible, with the risk of complications and recurrences. Treatment of obesity with medications has in recent years shown great promise, but the side effects are many, and the long-term effect is unknown. There is also a need for an option for patients where surgery has contraindications and conservative follow-up does not succeed.The research on obesity and gut microbiota has yielded promising results regarding weight reduction and metabolic health, but more research is needed to better understand the relationship between gut microbiota and severe obesity. This study could show proof of concept that gut microbiota from a lean donor could, in addition to lifestyle intervention, contribute to weight reduction in people suffering from severe obesity. METHOD AND ANALYSIS: This study aims to investigate if a fecal microbiota transplantation (FMT) from a lean donor leads to weight reduction in participants suffering from severe obesity. The study is a single-centre, double-blinded, placebo-controlled, parallel-group study with 60 participants. Participants will be randomised 1:1 for FMT from a lean donor or placebo. FMT or placebo will be delivered once by enema.We will include participants from the outpatient clinic for severe obesity, at the Medical Department, University Hospital of North Norway, Harstad, by invitation only. The study has a follow-up period of 12 months, with study visits of 3, 6 and 12 months post FMT. The primary endpoint is a weight reduction of ≥10%, 12 months after intervention.The results of the study will be published in open access journals. At the end of the study, the participants will receive information on which treatment group they belong to. ETHICS AND DISSEMINATION: The Regional Ethical Committee in North Norway (REK) approved the study protocol (2017/1655/REK Nord). We plan to present the results from the study at (inter)national conferences and publish in open-access general peer-reviewed journals. The enema method for FMT administration used in this study was developed by our study team. TRIAL REGISTRATION NUMBER: NCT03273855.

Colonic distribution of FMT by different enema procedures compared to colonoscopy - proof of concept study using contrast fluid.

BACKGROUND: Fecal microbiota transplantation (FMT) has become an important treatment method in recurrent Clostridioides difficile infections and is under investigation as a treatment for several other diseases. FMT's mechanism of action is assumed to be through alterations of the colon microbiota. FMT can be delivered by several methods, but few studies have directly compared how FMT is distributed in the colon by different methods. Specifically, the proximal distribution of FMT delivered by enema is unknown. METHODS: In eight participants, we administered contrast fluid (CF) with viscosity similar to an FMT in a crossover study design. First, CF was administered by colonoscopy, followed by an abdominal X-ray to visualize the CF distribution. Next, after four to eight weeks, participants were given CF, but as an enema, followed by a positioning procedure. X-rays were obtained before (enema ÷) and after (enema +) the positioning procedure. CONCLUSION: Proportion of participants with CF in cecum were 100% after colonoscopy, 50% after enema + and 38% after enema ÷. In the transverse colon, proportions were 100% (colonoscopy), 88% (enema +) and 63% (enema ÷). There were no adverse events. INTERPRETATION: This study shows proof of concept for the distribution of FMT to proximal colon when delivered by enema. A positioning procedure after the enema slightly improves the proximal distribution. However, colonoscopy is the only method that ensures delivery to the cecum. Studies are needed to see if FMT colon distribution correlates with treatment effectiveness. TRIAL REGISTRATION: The study was retrospectively registered at ClinicalTrials.gov (NCT05121285) (16/11/2021).

Health-related quality of life in inflammatory bowel disease: a comparison of patients receiving nurse-led versus conventional follow-up care.

BACKGROUND: Inflammatory bowel disease (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder with a considerable negative impact on health-related quality of life (HRQoL). During the past decade, IBD nurse specialists have been increasingly involved in follow-up care of IBD outpatients, in a consultative and coordinating role, closely cooperating with gastroenterologists. Whether patients' HRQoL differs between nurses' follow-up care (NF) and conventional follow-up care (CF) has not been widely researched and the aim of this study was to compare two different follow-up regimes with respect to patients' HRQoL. METHODS: This cross-sectional, multicenter study involved seven centers; five organized as CF, two as NF. RESULTS: A total of 304 patients aged 18-80 years, 174 females and 130 males, were included, of whom 140 received care under the NF model and 164 under the CF model. Participants in the NF group had a statistically significant higher median total score on the Inflammatory Bowel Disease Questionnaire (IBDQ) (p-value < .001). This pattern could also be seen in the sub-scores of the different IBDQ domains. Despite a trend of higher IBDQ score in all domains in the NF model, the overall result in our study did not reach the limit of 16 points, defined as clinically significant. A higher proportion of NF patients had IBDQ scores defined as remission, as well as a statistically significant higher frequency of outpatient check-ups during a two-year follow-up period. CONCLUSIONS: Nurse-led models are not inferior to conventional models with regards to patient reported HRQoL except in the social domain where the model showed to be clinically significant better. Further studies are needed to advance efforts to implement these models and increase access to IBD care.

Integrating the clinical pharmacist into the emergency department interdisciplinary team: a study protocol for a multicentre trial applying a non-randomised stepped-wedge study design.

INTRODUCTION: The 'emergency department (ED) pharmacist' is an integrated part of the ED interdisciplinary team in many countries, which have shown to improve medication safety and reduce costs related to hospitalisations. In Norway, few EDs are equipped with ED pharmacists, and research describing effects on patients has not been conducted. The aim of this study is to investigate the impact of introducing clinical pharmacists to the interdisciplinary ED team. In this multicentre study, the intervention will be pragmatically implemented in the regular operation of three EDs in Northern Norway; Tromsø, Bodø and Harstad. Clinical pharmacists will work as an integrated part of the ED team, providing pharmaceutical care services such as medication reconciliation, review and/or counselling. The primary endpoint is 'time in hospital during 30 days after admission to the ED', combining (1) time in ED, (2) time in hospital (if hospitalised) and (3) time in ED and/or hospital if re-hospitalised during 30 days after admission. Secondary endpoints include time to rehospitalisation, length of stay in ED and hospital and rehospitalisation and mortality rates. METHODS AND ANALYSIS: We will apply a non-randomised stepped-wedge study design, where we in a staggered way implement the ED pharmacists in all three EDs after a 3, 6 and 9 months control period, respectively. We will include all patients going through the three EDs during the 12-month study period. Patient data will be collected retrospectively from national data registries, the hospital system and from patient records. ETHICS AND DISSEMINATION: The Regional Committee for Medical and Health Research Ethics and Local Patient Protection Officers in all hospitals have approved the study. Patients will be informed about the ongoing study on a general basis with ads on posters and flyers. TRIAL REGISTRATION NUMBER: NCT04722588.

Effects of fecal microbiota transplantation in subjects with irritable bowel syndrome are mirrored by changes in gut microbiome.

Irritable bowel syndrome (IBS) is a common disorder of the lower gastrointestinal tract. The pathophysiology is far from settled, but a gut microbial dysbiosis is hypothesized to be a contributing factor. We earlier published a randomized double-blind placebo-controlled clinical trial on fecal microbiota transplantation (FMT) for IBS - the REFIT trial. The present data set describes the engraftment and includes participants from the study who received active FMT; 14 participants with effect of FMT (Effect) and 8 without (No effect). Samples were collected at baseline, after 6 and 12 months. Samples from the transplants (Donor) served as a comparator. In total 66 recipient samples and 17 donor samples were subjected to deep metagenomic sequencing, and taxonomic and functional analyses were performed. Alpha diversity measures showed a significantly increased diversity and evenness in the IBS groups compared to the donors. Taxonomic profiles showed higher relative abundance of phylum Firmicutes, and lower relative abundance of phylum Bacteroidetes, compared to donors at baseline. This profile was shifted toward the donor profile following FMT. Imputed growth rates showed that the resulting growth pattern was a conglomerate of donor and recipient activity. Thirty-four functional subclasses showed distinct differences between baseline samples and donors, most of which were shifted toward a donor-like profile after FMT. All of these changes were less pronounced in the No effect group. We conclude that FMT induces long-term changes in gut microbiota, and these changes mirror the clinical effect of the treatment. The study was registered in ClinicalTrials.gov (NCT02154867).

The effect of fecal microbiota transplantation on IBS related quality of life and fatigue in moderate to severe non-constipated irritable bowel: Secondary endpoints of a double blind, randomized, placebo-controlled trial.

BACKGROUND: Severity in irritable bowel syndrome (IBS) is associated to impaired quality of life and fatigue. Fecal microbiota transplantation (FMT) induces significant relief in gastro-intestinal related complaints. The objective was to evaluate the effect of FMT on the secondary endpoints: IBS-related quality of life and fatigue in patients with non-constipated IBS. METHOD: In this double-blind randomized placebo-controlled, parallel-group, single-center study, we enrolled patients with non-constipated IBS, defined by the ROME 3 criteria. We randomly assigned participants (2:1) in blocks of six to active or placebo FMT. Responder in fatigue and quality of life were defined as a decrease of 20 points in total Fatigue Impact Scale score, and improvement of 14 points in the IBS-quality of life questionnaire, respectively. In a modified-intention-to-treat population, we excluded participants who did not undergo treatment or who were diagnosed with any other disease by pinch biopsies during the treatment procedure. FINDINGS: Between Jan1, and Oct 30, 2015, we recruited 90 participants and randomly assigned them to active treatment (n = 60) or placebo (n = 30). Three participants did not undergo FMT and four were excluded after diagnosis of microscopic colitis, leaving 83 for final modified intention-to-treat analysis (55 in the active treatment group and 28 in the placebo group). Significant improvement in QoL (Odds ratio (OR) 3,801; confidence interval (CI) = 1,309-11,042 p = 0.011) and fatigue (OR = 4,398; CI = 1,175-16,468 and p = 0,020) was found at six months. Absence of other self reported functional disorders and presence of depression at baseline is suggested to predict a lasting effect of FMT in QoL and fatigue, respectively. INTERPRETATION: FMT induced significant relief in quality of life and fatigue. Results suggest a lasting effect of FMT in subgroups that should be further investigated in future studies. Funding Helse Nord, Norway and the Norwegian Centre of Rural Medicine, University of Tromsø, Norway.

Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial.

BACKGROUND: Irritable bowel syndrome (IBS) is a common condition characterised by abdominal pain, bloating, and poor quality of life. IBS might be caused by a gut dysbiosis. We aimed to compare faecal microbiota transplantation (FMT) with placebo in patients with IBS. METHODS: In this double-blind, randomised, placebo-controlled, parallel-group, single-centre study, we enrolled patients with IBS with diarrhoea or with diarrhoea and constipation (excluding dominating constipation) defined by the ROME III criteria, scored as moderate to severe according to the IBS severity scoring system (IBS-SSS; a score of ≥175). Eligible participants were aged 18-75 years and were recruited locally by general practitioners in northern Norway. We randomly assigned participants (2:1) in blocks of six to active or placebo FMT. Personnel not involved in the clinical performance of the trial generated the randomisation sequence using a randomisation website. Non-study personnel performed the final allocation and standardised the active and placebo transplants to make them identical in appearance and temperature. The faeces were freshly processed, and were used the same day (fresh transplant) or were stored in a freezer for later use (frozen transplant); participants' own faeces served as placebo. A dose of 8 mg loperamide was administered orally 2 h before endoscopy to retain the transplant. The transplant (50-80 g of faeces mixed with 200 mL of isotonic saline and 50 mL of 85% glycerol) was administered by a colonoscope to the caecum. The primary endpoint was symptom relief of more than 75 points assessed by IBS-SSS, 3 months after FMT. The primary analysis was done in the modified intention-to-treat population, excluding participants who did not undergo treatment or who were diagnosed with any other disease by pinch biopsies obtained during the treatment procedure. For the safety analysis, only participants who did not undergo treatment were excluded. The study is registered with ClinicalTrials.gov, number NCT02154867. The trial has been extended with an open-labelled study treating the placebo group with frozen FMT for further exploratory studies. FINDINGS: Between Jan 1, and Oct 30, 2015, we recruited 90 participants and randomly assigned them to active treatment (n=60) or placebo (n=30). Three participants did not undergo FMT and four were excluded after diagnosis of microscopic colitis, leaving 83 for final modified intention-to-treat analysis (55 in the active treatment group and 28 in the placebo group). 36 (65%) of 55 participants receiving active treatment versus 12 (43%) of 28 receiving the placebo showed response at 3 months (p=0·049). One participant had transient nausea and vertigo (active group) and was observed at the hospital for a few hours after the procedure. Two participants had soiling of transplant on their way home from treatment (one in each group) and three experienced self-limiting intermittent abdominal pain (one in the active group and two in the placebo group). No serious adverse events could be attributed to FMT. INTERPRETATION: FMT induced significant symptom relief in patients with IBS. However, larger multicentre studies are needed to confirm the results. FUNDING: HelseNord and the Norwegian Centre of Rural Medicine, University of Tromsø.

The effect of referral templates on out-patient quality of care in a hospital setting: a cluster randomized controlled trial.

BACKGROUND: The assessment of quality of care is an integral part of modern medicine. The referral represents the handing over of care from the general practitioner to the specialist. This study aimed to assess whether an improved referral could lead to improved quality of care. METHODS: A cluster randomized trial with the general practitioner surgery as the clustering unit was performed. Fourteen surgeries in the area surrounding the University Hospital of North Norway Harstad were randomized stratified by town versus countryside location. The intervention consisted of implementing referral templates for new referrals in four clinical areas: dyspepsia; suspected colorectal cancer; chest pain; and confirmed or suspected chronic obstructive pulmonary disease. The control group followed standard referral practice. Quality of treatment pathway as assessed by newly developed quality indicators was used as main outcome. Secondary outcomes included subjective quality assessment, positive predictive value of referral and adequacy of prioritization. Assessment of outcomes was done at the individual level. The patients, hospital doctors and outcome assessors were blinded to the intervention status. RESULTS: A total of 500 patients were included, with 281 in the intervention and 219 in the control arm. From the multilevel regression model the effect of the intervention on the quality indicator score was insignificant at 1.80% (95% CI, -1.46 to 5.06, p = 0.280). No significant differences between the intervention and the control groups were seen in the secondary outcomes. Active use of the referral intervention was low, estimated at approximately 50%. There was also wide variation in outcome scoring between the different assessors. CONCLUSIONS: In this study no measurable effect on quality of care or prioritization was revealed after implementation of referral templates at the general practitioner/hospital interface. The results were hindered by a limited uptake of the intervention at GP surgeries and inconsistencies in outcome assessment. TRIAL REGISTRATION: The study was registered under registration number NCT01470963 on September 5th, 2011.

Microscopic colitis: a missed diagnosis among patients with moderate to severe irritable bowel syndrome.

OBJECTIVE: Irritable bowel syndrome (IBS) is a very common condition in general practise, affecting 10-20% of the population in the Western world. The clinical picture of diarrhoea-predominant IBS (IBS-D) resembles other chronic diarrhoeic conditions, such as microscopic colitis (MC). It is impossible to separate these by clinical examinations or lab-tests that can be done in general practise. The aim of this study was to detect any missed diagnoses when only using a symptom-based approach for the diagnosis of IBS. MATERIAL AND METHODOLOGY: We examined 87 participants diagnosed with IBS by the Rome III criteria. All the participants underwent full clinical examination, lab-tests and colonoscopy including mucosa biopsies for histological examination. RESULTS: The histological analysis revealed four cases of MC in participants who for years had been diagnosed with IBS. We found no biochemical or clinical markers that made it possible to differentiate between IBS and MC. MC was only found in the participants diagnosed with IBS-D. CONCLUSION: When long-lasting, unresolved diarrhoeic conditions are present in patients over 45-50 years of age, colonoscopy with biopsy should be performed to rule out MC and other pathologies before diagnosing IBS. In younger patients with pronounced watery diarrhoea, one should consider colonoscopy individually if there is no response to IBS-treatment.

Impact of referral templates on the quality of referrals from primary to secondary care: a cluster randomised trial.

BACKGROUND: The referral letter is an important document facilitating the transfer of care from a general practitioner (GP) to secondary care. Hospital doctors have often criticised the quality and content of referral letters, and the effectiveness of improvement efforts remains uncertain. METHODS: A cluster randomised trial was conducted using referral templates for patients in four diagnostic groups: dyspepsia, suspected colorectal cancer, chest pain and chronic obstructive pulmonary disease. The GP surgery was the unit of randomisation. Of the 14 surgeries served by the University Hospital of North Norway Harstad, seven were randomised to the intervention group. Intervention GPs used referral templates soliciting core clinical information when initiating a new referral in one of the four clinical areas. Intermittent surgery visits by study personnel were also carried out. A total of 500 patients were included, with 281 in the intervention and 219 in the control arm. Referral quality scoring was performed by three blinded raters. Data were analysed using multi-level regression modelling. All analyses were conducted on intention-to-treat basis. RESULTS: In the final multilevel model, referrals in the intervention group scored 18% higher (95% CI (11%, 25%), p < 0.001) on the referral quality score than the control group. The model also showed that board certified GPs and GPs in larger surgeries produced referrals of significantly higher quality. CONCLUSION: In this study, the dissemination of referral templates coupled with intermittent surgery visits produced higher quality referrals. TRIAL REGISTRATION: This trial has been registered at ClinicalTrials.gov. The trial registration number is NCT01470963.

Practical health co-operation - the impact of a referral template on quality of care and health care co-operation: study protocol for a cluster randomized controlled trial.

BACKGROUND: The referral letter plays a key role both in the communication between primary and secondary care, and in the quality of the health care process. Many studies have attempted to evaluate and improve the quality of these referral letters, but few have assessed the impact of their quality on the health care delivered to each patient. METHODS: A cluster randomized trial, with the general practitioner office as the unit of randomization, has been designed to evaluate the effect of a referral intervention on the quality of health care delivered. Referral templates have been developed covering four diagnostic groups: dyspepsia, suspected colonic malignancy, chest pain, and chronic obstructive pulmonary disease. Of the 14 general practitioner offices primarily served by University Hospital of North Norway Harstad, seven were randomized to the intervention group. The primary outcome is a collated quality indicator score developed for each diagnostic group. Secondary outcomes include: quality of the referral, health process outcome such as waiting times, and adequacy of prioritization. In addition, information on patient satisfaction will be collected using self-report questionnaires. Outcome data will be collected on the individual level and analyzed by random effects linear regression. DISCUSSION: Poor communication between primary and secondary care can lead to inappropriate investigations and erroneous prioritization. This study's primary hypothesis is that the use of a referral template in this communication will lead to a measurable increase in the quality of health care delivered. TRIAL REGISTRATION: This trial has been registered at ClinicalTrials.gov. The trial registration number is NCT01470963.