A randomized placebo controlled trial to compare symptom and quality of life in patients with IBS taking a probiotic or non- probiotic fermented dairy product was conducted in primary care practices.
Setting and participants
13 general practices in the Midlands Research Practices Consortium (MidReC) situated within the West Midlands, UK. Patients were identified through searches of electronic patient records for symptomatic individuals with a diagnosis of IBS > 6 months or having received two or more prescriptions in the previous 24 months for anti-spasmodics, bulking agents or laxatives. A confirmatory screening questionnaire based on ROME III criteria  was sent to all patients. Lower than anticipated yield, led to administration of the screening questionnaire to all patients aged 18–65 in five of the thirteen practices. No other alterations were made to the study protocol during trial conduct. General practitioners applied discretion to prevent contact with patients considered inappropriate for contact or inclusion, for example individuals known to be in a terminal stage of illness or experiencing acute and severe mental illness.
Study eligibility was assessed from the information provided on the screening questionnaire plus telephone follow-up to verify responses. Individuals were considered eligible for inclusion if they were aged 18–65, met ROME III  criteria for a diagnosis of IBS with symptoms being present for > 6 months and reported a constipation element to their symptom profile (either constipation predominant or a mixed symptom profile).
Eligible patients were mailed a symptom diary for completion over the two weeks prior to their randomization appointment. At the baseline recruitment clinic research nurses confirmed eligibility and applied further study exclusions: individuals reporting passing more than 3 soft stools per day in the absence of laxative mediation during the pre-study phase; individuals without problematic symptoms judged by an IBS Symptom Severity Score (IBS-SSS)  of <75; individuals with known organic disease or reporting clinical signs of alarm; individuals who were pregnant, breast-feeding or lactose intolerant; individuals with a BMI >35 or <18, as this was deemed suggestive of abnormal diet or function; and those with a recent change of IBS medication (in the preceding month) to reduce likelihood of co-intervention bias.
Randomization and interventions
Blocked randomization lists (1:1 allocation) were produced by the lead statistician (RH) for each general practice site and held centrally. Because of the short shelf-life of dairy products randomised allocation lists were sent to the sponsors for product production prior to randomisation clinics so that two weeks supply of the relevant allocated product was available at the point of randomization. All volunteers gave written informed consent before inclusion in the study.
The test product was a commercially available fermented product containing Bifidobacterium lactis (strain number I-2494 in French National Collection of Cultures of Micro-organisms (CNCM, Paris, France; Danone collection number DN-173 010) together with the two classical yoghurt starters, S. thermophilus (CNCM strain number I-1630) and L. bulgaricus (CNCM strain numbers I-1632 and I-1519). The test product contains 1.25×1010 colony forming unit (cfu) of Bifidobacterium lactis CNCM I-2494 per cup and 1.2×109 cfu/cup of S. thermophilus and L. bulgaricus.
The control product was a milk-based non-fermented dairy product without probiotics and with similar lactose content to the test product. Both the test and control products were without flavour. Each pot contained 125 g. Both products were specifically prepared for the study and provided by Danone Research (Palaiseau, France). Nurses, GPs, patients and the research team remained blind to product allocation until all analyses had been completed.
In both groups consumption of the product twice daily was instructed and all patients received a two week supply of the allocated product in the first instance and instructions to collect repeat supplies fortnightly for 12 weeks.
Outcomes and follow-up
All patients returned completed daily diaries at follow-up visits after 4, 8 and 12 weeks. The daily diary assessed stool frequency and consistency (evaluated in accordance with the Bristol stool scale) and bowel movement difficulty (using a 5-point Likert scale which ranged from no difficulty to extreme difficulty). Weekly entries assessed subjective global assessment (SGA) [29, 30] of symptom relief (“Do you consider that in the past week you have had adequate relief of your IBS symptoms?”) and individual IBS specific symptom assessment of bloating, pain and flatulence (6 point Likert scale ranging from 0 (none) to 5 (very severe)).
Participants completed the Birmingham IBS Symptom Score , the IBS SSS  and an IBS specific quality of life (QoL) tool  at baseline and at weeks 4, 8 and 12. The Birmingham Symptom Score  uses 11 questions to assess pain, diarrhoea and constipation, scores range from 0–100 for each dimension with higher scores indicating greater well-being. The IBS –SSS  utilises five questions each generating a maximum score of 100 and a total possible score of 500 with higher scores indicating a greater symptom burden. The IBS specific QoL  tool evaluates dimensions; dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual and relationship using 34 five point Likert statements. Items are summed to create a total score with higher scores indicating better QoL.
The primary outcome was pre-specified as SGA of symptom relief at week 4 in line with the recent trial evidence on which the study was powered  and after discussion with the product manufacturer and sponsor. Comparison of all other outcomes at weeks 4, 8 and 12 between groups formed specified secondary outcome measures.
The sample size calculation was based on a previous study  demonstrating a 20% between group difference (62% active vs. 42% control) for SGA. Therefore, 107 patients with IBS-C were required in each group to demonstrate a 20% difference between groups in proportions reporting adequate IBS symptoms relief at week 4, with a significance of 5% and 80% power. This was inflated to 240 patients to be divided in two groups of 120 to allow for drop-outs. No stopping guidelines were in place due to the short trial duration and assumed safety of a commercially available product. Data analyses for all outcomes were performed on an intention to treat basis (ITT) and further analyses were undertaken to compare differences in those not deviating from protocol (per protocol). Analyses were performed on available data for each parameter. ANCOVA with primary care centre as a random effect, baseline as a covariate and product as a fixed effect was used to compare the intervention and control groups with respect to all outcomes. Ordinal logistic regression with centre and product as fixed effects was used to explore change within each arm of the study. Analyses were conducted using MINITAB version 14, S Plus version 8 and ML wiN version 2.1 statistical software.
Role of the funding source
The study was funded by Danone Ltd. Contracts including a right to publication of all findings were approved and signed by both parties prior to commencement of the research. The funders contributed to discussion about study design and selection of outcome measures. All subsequent data review was blinded and the analysis was undertaken independently of the funders. The paper was reviewed by the sponsor and an expert nominated by them with some requested changes included in the final version.