Methods

Randomized, double‐blind, placebo‐controlled. Duration of treatment was 8 weeks, plus an 8 week treatment‐free follow‐up, for a total of 16 weeks

Participants

Patients (n = 28) aged > 18 years with clinically and histologically confirmed active collagenous colitis

Clinical: minimum 3 semi‐loose or loose stools per day for at least 8 weeks, no other significant cause on history/physical, negative stool examination for pathogens, parasites, and C. difficile toxin and no macroscopic inflammation on colonoscopy (and no other endoscopic findings other than diverticulosis or diminutive polyps). Histological: subepithelial collagen band > 10 um thick and typical feathery appearance of the inferior border; increased mixed inflammatory cell infiltrate in lamina propria. Cases with overlapping features with lymphocytic colitis were allowed if the collagen band was a predominant finding

Patients with significant gastrointestinal disease (except controlled gastroesophageal reflux disease and celiac disease on a long‐term gluten‐free diet) were excluded

Interventions

Budesonide (Budenofalk) 9 mg/day (n = 14) versus placebo (n = 14) for 8 weeks

Outcomes

Proportion of patients achieving clinical and/or histological response

Clinical: reduction of stool frequency in last week of treatment by at least 50%.
Histological: statistically significant reduction of the infiltrate in the lamina propria and/or a significant reduction in the mean thickness of the collagen band
Other end‐points were impact on abdominal pain, stool consistency score, patient's general well‐being, amount of time necessary to induce remission, safety of budesonide, and long‐term clinical effects of budesonide including the relapse rates after weaning or discontinuing budesonide

All patients kept a diary throughout the study period. Each patient underwent colonoscopy and standardized biopsy protocol pre‐ and post‐treatment

Notes

Data from first 8 weeks of the study only were included in the analysis, as this was the duration of treatment with active drug or placebo. Five patients that failed to meet the inclusion criteria after being randomized into the trial (upon review of their stool diaries) were excluded from the analysis. Medications that could possibly affect stool frequency or the natural history of the disease were not allowed during the study and were discontinued (with an appropriate wash‐out period) before inclusion. Other chronic medications were allowed to be continued as long as the intake remained stable throughout the study period. 3 patients (2 placebo) dropped out of the study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The method of randomization was not described

Allocation concealment (selection bias)

Low risk

Randomization was done centrally by the company delivering the drugs and placebo

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Quote: "double‐blind"

Quote: "All biopsies were randomly read by 2 blinded expert pathologists"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "All calculations were made on an intention‐to‐treat basis"

Quote: "Three patients dropped out of the study (2 placebo), one for noncompliance and 2 because of treatment failure"

Intention‐to‐treat was followed for clinical response

Intention‐to‐treat was not followed for histologic response (denominators of 13 and 12 for the treatment and placebo group respectively)

Selective reporting (reporting bias)

Low risk

All primary outcomes were reported. Time to clinical remission was not directly reported in text, but it was interpretable from one of their published figures (Figure 1)

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

Randomized, double‐blind, placebo‐controlled. Duration of study was 8 weeks. Stool frequency and stool weight was recorded pre‐ and immediately after stopping treatment. All patients underwent sigmoidoscopy with standardized biopsy protocol pre‐ and post‐treatment. Randomization was performed by the drug company. Medication and placebo were delivered prepackaged with consecutive randomized numbers

Participants

Patients (n = 20, 16 females) aged > 18 years with clinically and histologically confirmed active collagenous colitis

Clinical: > 4 stools/day and/or stool weight > 200 g/day averaged over 3 days pre‐treatment. Negative stool samples for pathogens, parasites, and ova. Histological: collagen layer > 10 um Inflammation was graded on a scale (0 to 3) independently by 2 pathologists

Patients with other chronic gastrointestinal diseases were excluded, as were those with clinically significant renal or hepatic disease, those who had been treated with anti‐inflammatory drugs (aminosalicylates, corticosteroids, azathioprine) in the previous 3 months or were pregnant or breast feeding

Interventions

Budesonide (9 mg/day for 4 weeks, 6 mg for 2 weeks and 3 mg for 2 weeks) versus placebo for 8 weeks

Outcomes

Primary outcome was the proportion of patients that achieved a clinical or histological response

Clinical: reduction of stool frequency and/or stool weight by > 50%
Histological: decrease in inflammation grade or reduction in thickness of the collagen layer

Notes

No antiinflammatory drug treatment was allowed during the study period or for 3 months prior to inclusion. During the study antidiarrheal medications were allowed except during the periods of stool sampling. During these periods no other treatments with effects on the GI tract were allowed. NSAIDS were not permitted, but other chronic medications (e.g. ‐ antihypertensives) were allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described in published study

Allocation concealment (selection bias)

Low risk

Randomization was performed centrally by the drug company

Medication and placebo were delivered prepackaged with consecutive randomized numbers

Blinding (performance bias and detection bias)
All outcomes

Low risk

Quote: "double‐blind"

Quote: "The placebo medication was identical in appearance"

Quote: "Histopathological evaluation was performed blindly by the two pathologists"

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No description of dropouts or withdrawals

Selective reporting (reporting bias)

Low risk

The primary outcome of clinical remission was reported

Histopathological changes were also described

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

Randomized, double‐blind, placebo‐controlled. Randomization was done with a computerized randomization program in blocks of 4 patients

Induction: 6 weeks

Maintenance: 24 weeks

Treatment‐free follow‐up: 24 weeks

Participants

Patients (n = 42) aged > 18 years with clinically (> 3 stools/day over 3 days registration) and histologically (subepithelial collagen layer with a thickness > 10 um, inflammation of the lamina propria, and a lymphocytic infiltrate of the epithelium) confirmed active collagenous colitis plus negative faecal cultures for intestinal pathogens

Induction: n = 42

Maintenance: n = 34, 17 in each arm

Follow‐up: n = 15, 13 in the budesonide arm and 2 in the placebo arm

Patients were excluded if they had been treated with salazopyrine, 5‐aminosalicylic acid, budesonide or a systemic glucocorticoid within 3 months of trial enrolment or treated with ketoconazole during the 7 days before random selection. Other exclusionary criteria were other chronic gastrointestinal diseases (including celiac disease), clinically relevant impairment of kidney or liver function, previous intestinal resection or stoma

Interventions

Induction: 6 weeks, open‐label 9 mg/day budesonide, randomized to maintenance or placebo therapy

Maintenance: 24 weeks, budesonide 6 mg/day versus placebo

Treatment‐free follow‐up: 24 weeks

Patients who relapsed during the maintenance or follow‐up were offered treatment with open‐label budesonide (9 mg/day for 6 weeks, followed by budesonide 6 mg/day for 24 weeks)

Outcomes

Induction: proportion entering clinical/histological remission, randomized to maintenance or placebo therapy after 6 weeks

Maintenance: proportion maintaining clinical/histological remission after 24 weeks

Treatment‐free follow‐up: proportion maintaining clinical/histological remission 24 weeks

Clinical remission was defined as mean stool frequency of < 3 per day

*Each patient underwent colonoscopy or sigmoidoscopy pre‐treatment. All were scheduled to undergo sigmoidoscopy at relapse or at the end of treatment, but this was only performed in 21 patients
Other outcome measures included: fecal weight (g/day), safety data, maintained histological response (collagen layer <10 um and inflammation score <1), the time to relapse and the rate of relapse after stopping treatment

Notes

Data from the 24 weeks of the study only were included as the primary outcome measure, as this was the duration of active treatment with budesonide or placebo

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Computer‐generated block randomisation"

Allocation concealment (selection bias)

Low risk

Allocation sequence appears to be centrally generated

Blinding (performance bias and detection bias)
All outcomes

Low risk

Quote: "double‐blind"

Quote: "budesonide 6 mg once a day (2 x 3 mg capsules) or matching placebo"

Quote: "blinded follow‐up period (the randomisation code was unbroken until completion of follow‐up, such that neither patients nor physicians knew which treatment the patient had received during maintenance therapy)"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "All analyses were completed on an intention‐to‐treat basis; premature discontinuation of treatment was considered as relapse in both treatment arms"

Quote: "Two patients, one in each group, discontinued maintenance treatment because of adverse events"

Selective reporting (reporting bias)

Low risk

All outcomes were reported

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

Randomized, unblinded, open‐label study

Participants

Patients (n = 819) who presented to clinic, underwent a colonoscopy because of chronic watery diarrhoea and were diagnosed with microscopic colitis (aged 19–68 years; n = 64; 23 with collagenous colitis and 41 with lymphocytic colitis)

Clinical components of diagnosis: Chronic or recurrent non‐bloody diarrhea
Histological components of diagnosis: Increased chronic inflammatory infiltrate (plasma cells, lymphocytes, eosinophils) in the lamina propria; increased number of intraepithelial lymphocytes, damage to surface epithelium, with flattening of epithelial cells and/or epithelial loss and detachment and minimal crypt architecture distortion; specific to the diagnosis of collagenous colitis was a subepithelial collagen band >10 um thick, which entraps superficial capillaries, with an irregular lacy appearance at the lower edge of the basement membrane
"Patients with a clear correlation between symptoms and [consumption] of drugs (e.g. NSAIDS, ticlopidine, PPI) were excluded"

Interventions

Mesalazine 800 mg po tid (n = 20 with lymphocytic colitis and 11 with collagenous colitis) vs. mesalazine 800 mg po tid + cholestyramine 4 g po od (n = 21 with lymphocytic colitis and 12 with collagenous colitis) for 6 months

A 24‐month treatment free follow was also performed

A second round of 6 month‐therapy was offered if patients relapsed in follow‐up

Outcomes

Primary outcomes:

Clinical response: "Complete response was complete resolution of diarrhoea. Partial response was improvement but not resolution of diarrhoea
Histological response: Normalization of histologic pattern at the end of 6 months

Secondary outcomes:

24‐month follow‐up with coloscopies and biopsies, annually; adverse events; and days to remission or relapse, as well as various lab data (routine blood biochemistry and hematological counts, C‐reactive protein, antinuclear antibodies blood assay, serum T4 and thyroid stimulating hormone; IgA‐IgG antigliadin, antiendomysium, IgG anti tTG antibody blood assays; and parasitic‐bacterial, fecal‐stool, and hemo‐occult test

Notes

"Relapse was defined as stool frequency greater than three soft or liquid stools per day"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization was performed with a computer generated list

Allocation concealment (selection bias)

Unclear risk

Not described in published study

Blinding (performance bias and detection bias)
All outcomes

High risk

Quote: "open‐label"

Quote: "All biopsies were analyzed by a single experienced pathologist in a blinded fashion"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3 of 23 patients with collagenous colitis were lost to follow‐up over a 24 month period

The treatment groups and reasons for the missing data were not reported

Selective reporting (reporting bias)

Unclear risk

Outcomes were not pre‐specified in the methods section of the manuscript

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

Randomized, double‐blind, placebo‐controlled. Duration of study was 8 weeks. After 8 weeks, placebo group remained blinded and crossed over to active treatment with bismuth salicylate

Participants

Patients (n = 14, split evenly) with microscopic colitis (11F, 3M; aged 35‐78 years; 9 with thickened subepithelial collagen, 5 without)

Clinical: 8 weeks of non bloody watery diarrhea (without steatorrhea) and normal endoscopic appearance of the colonic mucosa.
Histological (including involvement of the distal colon): excess mononuclear inflammatory cells in the lamina propria and surface epithelium without significant neutrophilia or eosinophilic inflammation, numerous crypt abscesses, or granuloma; and no other evidence of Crohn's disease

Interventions

Bismuth subsalicylate (nine 262 mg/day chewable tablets in 3 divided doses) versus placebo (identically coloured and flavoured sucrose tablets) for 8 weeks.

Outcomes

"48 hour fecal weight and consistency, and distal colonic histology (from 16 biopsies obtained by flexible sigmoidoscopy)" were assessed pre and post therapy

Clinical: improvement of diarrhea to passage of 2 or less formed or semi‐formed stools/day
Histological: improvement of histopathology score by at least 50%

Notes

Only patients with a thickened subepithelial collagen band on biopsy were included (scored as normal, focally thickened, or diffusely thickened). 4 patients with normal thickness of the subepithelial collagen band were excluded from the analysis. Patients were not to take antibiotics or anti‐inflammatory agents for minimum 6 weeks, and not to take antidiarrheals for minimum 2 weeks prior to the beginning of the study

Abstract publication

For the histological outcome analysis, a histopathology score from 0 to 10 was based on the following parameters: surface epithelium assessed for micro‐ulceration, cell flattening, and mucin depletion (scored: 0 ‐ normal, 1 ‐ moderate, 2 ‐ severe); crypts (scored: 0 ‐ normal, 1 ‐ distorted architecture and/or cryptitis with neutrophils, 2 ‐ containing crypt abscesses); lamina propria cellularity (scored: 0 ‐ normal, 1 ‐ focally increased with neutrophils, mononuclear inflammatory cells, or both, 2 ‐ diffusely increased with neutrophils, mononuclear inflammatory cells, or both); number of intraepithelial lymphocytes within surface epithelium (scored 0 ‐ normal, 1 ‐ moderately increased, 2 ‐ significantly increased); number of intraepithelial lymphocytes within crypt epithelium (scored 0 ‐ normal, 1 ‐ moderately increased, 2 ‐ significantly increased)

Additional information provided by author

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomization was performed by pulling pieces of paper out of a sealed box"

Allocation concealment (selection bias)

Unclear risk

Not described in abstract publication

Blinding (performance bias and detection bias)
All outcomes

Low risk

Quote: "double‐blind"

Quote: "identically coloured and favoured sucrose‐placebo tablets"

Quote: "Blind histologic analysis"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "All patients taking BSS completed the study; one patient receiving placebo dropped out of the study after 4 weeks"

Selective reporting (reporting bias)

Low risk

All outcomes were reported

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

Randomized, double‐blind, placebo‐controlled trial performed at multiple German centres. Duration of study was 6 weeks. Study had potential crossover for the non‐responders in the placebo group

Participants

Patients (n = 31) aged 18‐80 years with clinically and histologically confirmed collagenous colitis ("at least five liquid or soft stools per day on average per week, and a complete colonoscopy performed within the last 4 weeks before randomization")

Histological diagnosis made with colonoscopy with biopsy: main criteria was collagen band > 10 um thick

Other analyzed criteria included inflammation of lamina propria (semi‐quantitative definition) and degeneration of surface epithelium (qualitative definition)
Patients were excluded if they had other endoscopically or histologically verified causes for diarrhea, infectious diarrhea, pregnancy or lactation, previous colonic surgery, or known intolerance to Boswellia serrata extract. Patients who had received therapy within 4 weeks of randomization were also excluded if therapies included budesonide, salicylates, steroids, prokinetics, antibiotics, ketoconazole, or non‐steroidal anti‐inflammatt ory drugs

Interventions

Boswellia serrata extract (three 400 mg/day capsules) versus placebo for 6 weeks

Cross‐over therapy offered to non‐responders after 6 weeks, open‐labelled BSE 400 mg po t.i.d

Outcomes

Primary endpoint was clinical remission after 6 weeks (stool frequency of < 3 per day)

stool frequency of less than 3 per day
Secondary endpoints were histological changes and quality of life

Histological (via colonoscopy with biopsy): improvement in baseline parameters
Quality of life: assessed with SF‐36 surveys at the beginning and at the end of 6 weeks of therapy

"Stool frequency and consistency, intake of study medication, adverse events, and any intake of allowed concomitant medication were assessed by standardized questionnaire"

"Patients who did not respond to treatment after 6 weeks were individually unblinded. If they were in the active treatment group, they were judged as treatment failure. If they were in the placebo group, crossover therapy with open‐labelled BSE 400 mg, given orally three times daily was offered"

Notes

During the first three weeks of treatment loperamide was allowed as rescue medication. "Patients were allowed to use butylscopolamine in case of abdominal pain"

Steroids, anti‐inflammatory drugs, immunosuppressives, antibiotics, prokinetics and bismuth compounds were not allowed during the study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization was via a central computer generated randomization list in groups of four patients

Allocation concealment (selection bias)

Low risk

Quote: "central computer‐generated randomization list"

Blinding (performance bias and detection bias)
All outcomes

Low risk

Quote: "double‐blind"

Quote: "Physicians, patients, and pathologist were blinded to the treatment group. Study medication was provided in identical‐ looking white boxes labelled with consecutive numbers corresponding to the randomization list. In addition, the placebo containers were prepared from the inside to mimic the typical scent of incense to prevent unblinding by the typical odour of BSE."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

5/31 patients discontinued (4 patients, reasons described) the trial or were lost to follow‐up (1 patient). All 31 patients were included in the intention‐to‐treat analysis, 26 patients were included in the per‐protocol analysis

Selective reporting (reporting bias)

Low risk

All outcomes were reported

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

Randomized, double‐blind, placebo‐controlled performed at 35 centres in Germany (hospitals and private clinics), which used a centrally‐removed pathologist. Duration of study was 6 weeks

Participants

Patients (n = 51) aged 18‐80 years with clinically and histologically confirmed collagenous colitis ("at least five liquid or soft stools per day on average per week, and a complete colonoscopy performed within the last 4 weeks before randomization"). Female patients must also be using appropriate contraception

Histological diagnosis made with colonoscopy with biopsy: main criteria was collagen band > 10 um thick by Van Giesen staining. Other analyzed criteria included inflammation of lamina propria (semi‐quantitative definition) and degeneration of surface epithelium (qualitative definition)

Patients were excluded if they had evidence of infectious diarrhea (from culture or biopsy), any other endoscopic or histologic findings (polyps 2 cm, tumors, Crohn’s disease, ulcerative colitis, ischemic colitis) which may have caused diarrhea, known intolerance to budesonide, pregnancy, lactation, or prior partial colonic resection, or if they had received treatment with budesonide, salicylates, steroids, prokinetics, antibiotics, ketoconazole, or non‐steroidal anti‐inflammatory drugs within 4 weeks before randomization

Interventions

Budesonide 9 mg/day (three 3 mg/day tablets once in the morning) versus identically‐matched placebo for 6 weeks

Cross‐over therapy offered to non‐responders after 6 weeks, open‐label budesonide, 9 mg/day po for another 6 weeks

Outcomes

Proportion of patients achieving clinical remission or histological improvement after 6 weeks

Clinical remission defined as: average of < 3 soft stools per day during the last week of treatment
Histological (via colonoscopy with biopsy): change of 2 of 3 of the following parameters: collagen band thickness no more than 10 um or reduced to 50% compared to baseline; improvement of inflammation of the lamina propria; improvement of degeneration of surface epithelium
Patients also recorded daily stool frequency and consistency, "intake of the study medication, any side effects, and any intake of allowed concomitant medication"

Patients who did not respond to treatment after 6 weeks were unblinded. If they were in the active treatment group, they were judged as treatment failure. If they were in the placebo group, crossover therapy with open‐label budesonide, 9 mg/day po for another 6 weeks

Notes

Other therapies for collagenous colitis were discontinued for at least 3 weeks prior to enrolment in the trial. Loperamide was allowed for the first 4 weeks of the trial (used by 4 patients in the placebo group and 2 in the budesonide group), but no anti‐diarrhoeals allowed in the last two weeks. Patients were allowed to use butylscopolamine for abdominal pain

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Eligible patients were randomized by groups of 4 patients according to a central computer‐generated randomization list"

Allocation concealment (selection bias)

Low risk

Centralized randomization

Blinding (performance bias and detection bias)
All outcomes

Low risk

Quote: "double‐blind"

Quote: "Active and placebo capsules were identical in appearance"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

6/51 patients withdrew (3 from placebo and 3 from budesonide) from the trial (reasons described)

Both per‐protocol and intention‐to‐treat analysis available

For endoscopic investigations per‐protocol analysis used

Selective reporting (reporting bias)

Low risk

All outcomes were reported

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

Randomized, double‐blind, placebo‐controlled performed at 38 centres in Germany

Participants

Patients aged >18 years with symptomatic and histologically proven collagenous colitis

Clinically active defined as ">3 watery/loose stools per day on ≥ 4 of the previous 7 days and had a history of diarrhoea for ≥ 4 weeks"

Histological requirements: Subepithelial collagen band > 10 um; inflammatory infiltrate in the lamina propria

Exclusion criteria: infectious causes for diarrhea; other inflammatory bowel diseases; history of colonic surgery; celiac disease; malignancies; severe concomitant (organ) diseases that would interfere with the study; at time of inclusion, were being treated 5‐aminosalicylates, salicylates (except in doses ≤165 mg for cardiovascular prophylaxis), systemic steroids, antibiotics, or NSAIDs (including selective cyclo‐oxygenase‐2 inhibitors); used of budesonide within the 2 weeks prior to enrolment, known intolerance to budesonide; pregnancy, lactation, drug and/or alcohol abuse

Induction phase: n = 48

Maintenance phase: n = 46, split equally to budesonide and placebo

Interventions

Induction phase: open‐label budesonide 9 mg/day (3 x 3 mg capsules [Entocort CIR capsules]) once/day for 6 weeks (all included patients)

Maintenance phase: budesonide 6 mg/day or placebo for 6 months

Outcomes

Primary endpoint was cumulative rate of relapse at the end of 6 months (maintenance phase); remission had been induced during the 6 week induction phase. Relapse was defined as > 3 stools per day on ≥ 4 consecutive days. Relapse rates were determined from daily patient diaries

Secondary outcomes were time to relapse during maintenance therapy; the proportions of patients with clinical remission after 6 weeks’ induction therapy and after 2 and 4 months of maintenance therapy; HRQOL outcomes; and changes in histologic variables after 6 months’ maintenance therapy ("thickness of the collagen band (>10 or <10 µm); inflammation of the lamina propria (infiltration with lymphocytes and plasma cells; absent, mild, moderate, or severe); and degeneration of the surface epithelium (absent, or present)"). Histologic improvement defined as improvement in ≥ 2 variables versus baseline

Safety and tolerability assessments were also performed

Notes

HRQOL was assessed using the validated Medical Outcome Short Form (SF)‐36 questionnaire26 and the Short Inflammatory Bowel Disease Questionnaire (sIBDQ)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomization not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation not described in published study

Blinding (performance bias and detection bias)
All outcomes

Low risk

Quote: "double‐blind"

Quote: "budesonide and placebo capsules appeared identical and were packaged in identical bottles"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

21/46 patients withdrew during the maintenance phase, 17 due to relapse (14 taking placebo and 3 taking budesonide), 4 due to adverse events (1 taking placebo and 3 taking budesonide)

Quote: "for the purposes of intention‐to‐treat analysis, patients who withdrew because of adverse events during maintenance therapy were counted as relapses"

Selective reporting (reporting bias)

Low risk

All outcomes were reported

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

Randomized, double‐blind, double‐dummy, placebo‐controlled, comparative phase‐3 trial performed at 31 European centres (hospitals and private clinics) ‐ Germany, Denmark, Lithuania, Spain, and the United Kingdom. Duration of study was 8 weeks

Participants

N = 92 (budesonide n = 30; mesalamine n = 25, placebo n = 37)

Inclusion criteria:

Clinical: Patients between 18 and 80 years of age with >4 watery or soft stools on ≥4 days and >3 stools/day in the week prior to baseline. Patients must have also had chronic diarrhoea for ≥3 months prior to baseline and have had a colonoscopy within 4 months of baseline

Histological: confirmed collagenous colitis with subepithelial collagenous band > 10 um and degeneration of the surface epithelium

Exclusion criteria: "other significant colonic diseases (i.e. polyps >2 cm, tumors, Crohn’s disease, ulcerative colitis, ischemic colitis), partial colonic resection, infectious diarrhea, celiac disease (blood tests and/or duodenal histology required), diarrhea caused by other organic diseases of the gastrointestinal tract, treatment with budesonide, Boswellia serrata extract, salicylates, steroids, antibiotics, cholestyramine, nonsteroidal anti‐inflammatory, or other immunosuppressant drugs within the last 4 weeks before baseline, malignant disease, severe comorbidity, abnormal hepatic function or liver cirrhosis, renal insufficiency, active peptic ulcer disease, known intolerance or resistance to study drugs, pregnancy, or breast‐feeding"

Interventions

Budesonide 9 mg/day ["(3x3 mg pH‐modified release capsules, Budenofalk) 30 minutes before breakfast"]

Mesalamine 3 g/day [morning dosage of "sachets each containing 1.5 g mesalamine presented as a granule formulation, Salofalk"]

Placebo

All medications take for 8 weeks if responsive. If unresponsive after 4 weeks, or relapsed in the 16 week treatment‐free follow‐up, patient's removed from study arm and received 9 mg/day of budesonide for the remaining 4 weeks.

Outcomes

Measured at each interim visit: 2, 4, 6, 8 weeks; 8 and 16 weeks

Primary Outcomes:

Clinical: remission defined as ≤3 stools/day in the week before the visit.

Histological: measured collagen band thickness (≤10um or 50% reduction), lamina propria inflammation (by scoring), intraepithelial lymphocytes (by scoring) and whether the surface epithelium was degenerated. Improvement was defined as improvement of two of the parameters. Histological remission was defined as "collagen band thickness 10 mm and no inflammation of the lamina propria with neutrophilic and eosinophilic granulocytes."

Secondary Outcome:

Clinical remission was also evaluated according to Hjortswang‐Criteria of disease activity ("mean <3 stools per day, with <1 watery stool per day)"

Also, "time to remission, number of watery and solid stools per week, abdominal pain, histopathology,
tolerability and safety, symptom relapse during treatment‐free follow‐up, and response to open‐label budesonide"

Notes

Relapse was defined as: ">4 watery/soft stools on at least 4 days in the week before the visit and >3 stools per day within the last 7 days before the visit"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer generated random numbers assigning at a 1:1:1 ratio between the 3 arms of the study

Allocation concealment (selection bias)

Low risk

Computer generated, random numbers list prepared by a contract research organization that had no clinical involvement with the trial

Used medication packed in boxes with consecutive numbers according to the randomization list

Blinding (performance bias and detection bias)
All outcomes

Low risk

"double‐blind, double‐dummy"

Identical placebo capsules and sachets

Single pathologist was blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

21/92 patients withdrew from the trial prematurely (before 8 weeks). Two taking budesonide, 9 taking mesalamine and 10 taking placebo. Reasons described. 64/92 entered follow up, 16 entered open‐label budesonide. Intention‐to‐treat was followed

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

An initial 8‐week open‐label induction phase with budesonide therapy to achieve clinical remission was followed by a double‐blind, randomized, placebo‐controlled, parallel‐group, multicentre, 12‐month phase for maintenance of clinical remission. After this there was 6 months of treatment‐free follow‐up

Participants

A total of 148 patients were screened, all age ≥ 18 years

Inclusion criteria:

1. Histologically established diagnosis of collagenous
colitis, defined as thickened subepithelial collagen layer ≥10 mm on well‐orientated sections, and increased inflammatory cells indicating chronic inflammation in the lamina propria

2. Prescreening history of non‐bloody, watery diarrhea for ≥2 weeks in patients with newly diagnosed collagenous colitis, or a prescreening history of clinical relapse for ≥1 week in patients with previously established collagenous colitis

3. A mean of ≥3 stools/day, including a mean of ≥1 watery stool/day, during the week prior to baseline

Exclusion criteria:

1. Diabetes mellitus, infection, glaucoma, tuberculosis, peptic ulcer disease or hypertension if careful medical monitoring was not ensured

2. Established cataract

3. Known hereditary problems of galactose or fructose intolerance, lactase deficiency, increased levels of anti‐transglutaminase 2 antibodies

4. Established osteoporosis with T‐score <−2.5

As per Figure 2:

110 met eligibility criteria and started the open‐label phase. 92 patients had achieved remission during the open‐label phase and were randomized for treatment in the double‐blind phase (44 budesonide, 48 placebo). 43 completed the 12‐month study visit (32 budesonide, 11 placebo). 36 patients at the end of the double‐blind phase (28 budesonide, 8 placebo) entered the follow‐up phase

Interventions

During the open‐label induction phase, all patients received once‐daily budesonide (Budenofalk 3 mg capsules) at a dose of 9 mg/day for 4 weeks, then 6 mg/day for 2 weeks, followed by alternate daily doses of 6 and 3 mg/day (mean 4.5 mg/day) for the final 2 weeks

During the double‐blind phase, the active treatment group received once‐daily budesonide 6 and 3 mg/day on alternate days (mean 4.5 mg/day). The placebo group received two placebo capsules and one placebo capsule on alternate days, administered once daily

After the final visit of the double‐blind phase (month 12), there was a 2‐week tapering‐off period, during which patients in the active treatment group received 3 mg/day budesonide for 1 week followed by 3 mg/day budesonide every second day for 1 week. Patients in the placebo group received one placebo capsule on the corresponding days

Patients who remained in clinical remission at the end of the double‐blind phase received no further study drug after the 2‐week tapering‐off period

During the treatment‐free follow‐up, no intervention was given

Outcomes

The primary endpoint was the proportion of patients remaining in clinical remission during the 12‐month double‐blind phase, with clinical remission defined as a mean of <3 stools/day, including a mean of <1 watery stool/day over 1 week

The main secondary endpoints during the double‐label phase included health‐related quality of life using the Short Health Scale (SHS) and the Psychological General Well‐Being Index (PGWBI)

Further secondary endpoints during the double‐blind phase were achievement of histological remission or histological improvement

Notes

During the entire study period, loperamide, anti‐inflammatory or immunosuppressant drugs were not permitted
Prophylactic treatment of osteoporosis with calcium and vitamin D3 was strongly recommended and under the responsibility of the investigator

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Method of randomization was described as "a computer‐generated randomisation list using randomly permuted blocks"

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not described

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double‐blinding is mentioned, but not described in more detail. Placebo capsules were used

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Well described patient disposition in Figure 2 and had intention‐to‐treat analysis described. They accounted for attrition/exclusions with reasons given

Selective reporting (reporting bias)

Low risk

All primary outcomes were reported. Most secondary outcomes were reported with exception of histological outcomes

Safety and adverse‐effect data was also presented, but not described as part of methods section

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

Randomized, double‐blind, placebo‐controlled, multi‐centred trial

Participants

Patients (n = 12, 11 with collagenous colitis and 1 with lymphocytic colitis) aged >18 years reporting at least 3 months with diarrhoea without blood or pus and with a stool volume ≥350 g/day or ≥200 g/day and a stool frequency ≥5/day and a histological diagnosis of microscopic colitis. Female patients also needed to use appropriate contraceptive techniques

Patients were diagnosed histologically using a macroscopic normal colonoscopy or sigmoidoscopy plus a normal barium enema and confirmed by an independent pathologist with either lymphocytic colitis or collagenous colitis using the following criteria: “chronic inflammatory infiltrate in the lamina propria and either a lymphocytic infiltration of at least 20% of epithelial crypt cells (lymphocytic colitis) and/or a subepithelial collagen bond >10 µm in a well‐oriented biopsy (collagenous colitis)”

Excluded patients: tested positive for pathogenic bacteria or parasites; failed a normal lactose absorption test and vitamin B12 absorption test, or a normal barium follow through; had celiac disease (confirmed with IgG and IgA antigliadin antibodies and antiendomysium antibodies and/or abnormal histology in duodenal biopsies); had bile acid malabsorption and/or no response to cholestyramine, and/or steatorrhoea; had other gastrointestinal diseases or previous gastrointestinal surgery (exception: cholecystectomy); had other serious diseases, abnormal laboratory tests (haematology, renal function, liver enzymes, urinalysis); had been treated with immunosuppressives within 3 months of randomization; or used medicines with known effects on gastrointestinal functioning including anti‐ulcer medication, antacids, antibiotics and NSAIDs

Interventions

Prednisolone, n = 9 (50 mg/dayfor 2 weeks, tapered to 37.5 mg/day in third week) versus placebo, n = 3, for 2 weeks. All patients also received Ca 500 mg + vitamin D 5 ug/day

Outcomes

Proportion of patients achieving clinical remission after 2 weeks

Clinical remission was defined as stool weight ≤ 200 g/day or frequency ≤ 2/day; effect was defined as >50% reduction of either stool frequency or weight.
Side effects were also recorded

Notes

Inclusion of patients was stopped when planned monitoring indicated that prednisone did not induce remission. Protocol also included a 48‐week azathioprine continuation phase which was closed when it became clear that the calculated number of patients could not be recruited

Medications with immunosuppressive effects, antidiarrhoeals or those with known effects on gastrointestinal function were not allowed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomization not described

Allocation concealment (selection bias)

Unclear risk

Method of allocation not described in published study

Blinding (performance bias and detection bias)
All outcomes

Low risk

Quote: "double‐blind"

Quote: "identical placebo tablets"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing data

Quote: "All patients complied with and completed the treatment protocol"

Selective reporting (reporting bias)

Low risk

All outcomes were reported

Other bias

Low risk

Study appeared to be free of other forms of bias

Methods

Randomized, double‐blind, placebo‐controlled trial at 4 Danish centres. Randomization was in a 2:1 fashion (probiotic:placebo)

Participants

Patients (n = 36*, therefore n = 29, 2 men) aged ≥18 years with confirmed histological diagnosis of collagenous colitis that is active and untreated for at least 4 weeks prior to study inclusion.

Clinically active disease is defined as > 21 liquid or soft stools per week or stool weight of > 200 g/day for at least 4 weeks
Histological diagnosis required "a subepithelial collagen band > 10 um in a well oriented section of the mucosa and inflammation of the lamina propria with infiltration of predominantly lymphocytes and plasma cells"
Exclusion criteria included: pregnancy or breast feeding, chronic liver or kidney disease, severe vascular or cardiopulmonary disease, malignancy, immunosuppressive disease or treatment, known inflammatory bowel disease besides collagenous colitis (including celiac disease), evidence of infectious diarrhea, prior gastrointestinal surgery other than appendectomy, and malabsorption syndromes. Treatment with aminosalicylates, antibiotics, cholestyramine, nonsteroidal anti‐inflammatory drugs, and steroids was not allowed 4 weeks prior to study entrance

Interventions

Probiotic (AB‐Cap‐10; two capsules twice daily) or placebo (2 capsules twice daily) for 12 weeks. Loperamide and opioids were allowed during the study

Outcomes

Primary outcome was the proportion of patients with a at least a 50% reduction in the number of stools per week at 12 weeks
Secondary outcomes: changes in bowel frequency, stool consistency, stool weight, abdominal pain and bloating, histopathology scores from biopsies, Short Inflammatory Bowel Disease Questionnaire (SIBDQ) scores, use of antidiarrhoeal medication, and adverse events

Histological scores from: significant change in three parameters: reduction of thickness of the collagen band; improvement in the degree of inflammation of the lamina propria; improvement of degeneration of surface epithelium

The study period was 17 weeks (12 weeks treatment + 5 weeks follow up) with patients being assessed at weeks ‐1, 0, 4, 6, 12, and 16. All patients kept a diary throughout the study period

Notes

AB‐Cap‐10 is a mixture of L. acidophilus strain LA‐5 and B. animalis subsp. lactis strain BB‐12. Each capsule contained 0.5 x 10^10 colony‐forming units of each bacterium, leading to a total delivery of 1 x 10^10 CFU per capsule

SIBDQ; a 10‐item questionnaire measuring health‐related quality of life [HRQOL] intended for patients with Crohn’s disease and ulcerative colitis

*Seven patients that failed to meet the inclusion criteria after being randomized into the trial (six patients had lymphocytic colitis and one had a subepithelial collagen band < 10 um thick) are excluded from the analysis
Study enrolment was stopped early due to difficulties recruiting patients

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization was completed in blocks of 9 using a table of random numbers

Allocation concealment (selection bias)

Unclear risk

Method of randomization not described in study

Blinding (performance bias and detection bias)
All outcomes

Low risk

Quote: "double‐blind"

Quote: "Placebo medication (Chr. Hansen A/S) was identical in appearance, size, and taste"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3 probiotic treatment patients dropped out because of lack of response

Quote: "When data at week 12 were missing because of withdrawals, the last observation was carried forward"

Selective reporting (reporting bias)

Low risk

All outcome reported. One post hoc analysis noted

Other bias

Low risk

Study appeared to be free of other forms of bias