Can real-world evidence help improve treatment of functional gastrointestinal disorders?

Posted On: 
11th February 2019

Using novel methods based on a combination of social media platforms and validated self-assessment instruments, a study has recently been completed on 6,785 users of a milk with modified beta casein protein, of whom 5,535 were adults. The results have been encouraging and form the basis of a low-risk strategy for supporting and advising patients, writes Dr Martin Goldman. 

There are no simple answers for patients who present with functional symptoms such as bloating or the symptoms of irritable bowel syndrome (IBS). The plethora of controlled studies has provided many answers, and, surprisingly, many of them are positive. The methodologies of real-world evidence may add to our knowledge of what is going on by providing data on large numbers of participants in their real-world setting, rather than the contrived situation of a clinical trial.

Using novel methods based on a combination of social media platforms and validated self-assessment instruments, a study has recently been completed on 6,785 users of a milk with modified beta casein protein, of whom 5,535 were adults. The results have been encouraging and form the basis of a low-risk strategy for supporting and advising patients.

Gastrointestinal symptoms are a common presentation in primary care both in adults and in children. Some may not even get as far as primary care, with patients or their carers using non-prescribed healthcare interventions such as over-the-counter remedies or health foods. Functional GI disorders have a relatively new definition. Rome IV defines them as “disorders of gut–brain interaction. It is a group of disorders classified by GI symptoms related to any combination of the following: motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered central nervous system processing”.

It appears that 33–90% of patients do not consult a physician, and that a proportion of patients who meet the IBS criteria are not diagnosed with IBS.

The fact that the Rome criteria encompass these symptoms supports the notion that these are real issues, particularly for the patients. For example, the current Rome IV criteria, which differ from Rome III, for IBS are:

Recurrent abdominal pain, on average, at least one day/week in the last three months, associated with two or more of the following criteria:

• Related to defecation

• Associated with a change in frequency of stool

• Associated with a change in form (appearance) of stool.

The incidence and prevalence of IBS may vary depending on the diagnostic criteria used, but it is estimated that the prevalence in the UK is 17% overall, with a prevalence of 11% among men and 23% among women. It appears that 33–90% of patients do not consult a physician, and that a proportion of patients who meet the IBS criteria are not diagnosed with IBS. The lack of emergence of constant definitions and gold standard treatments suggests that either the final common pathway symptoms may be indicators of multiple pathoaetiologies (as suggested earlier) or that treatments may need to be tailored to each patient.

Healthcare since the 1950s has been driven by the outcomes of conventional clinical trials and, by preference, the double-blind placebo controlled study. However these can be highly artificial situations with selected groups of patients, and thechance of a false positive outcome may be as high as 1 in 20 if the significance levels are set to p</= 0.05, but being right 19 times out of 20 is not a bad average.

Data from clinical trials are confusing, and a systematic review of the literature showed that parents’ views were not taken into account.

More recently, as an adjunct to controlled clinical trials, structured generation and collection of real-world evidence has added to knowledge of what actually happens to real patients (i.e. the ones we see in our surgeries) as a result of a healthcare intervention. A good example of this has been a recent study of the efficacy ofsimeticone in the treatment of the infantile functional gastroenterological condition, infant colic (IC). Data from clinical trials are confusing, and a systematic review of the literature showed that parents’ views were not taken into account. A recently published study of real-world evidence showed that more than two-thirds (69.7%) of 4,004 respondents, who either used simeticone on its own or alongside another treatment, reported improvements in the signs of IC within one day. Almost all (93.2%) considered that its use was associated with either complete resolution of IC or had some effect on symptoms.

Whenever possible, symptoms were evaluated using validated self-administered questionnaires.

Another recently completed study, using similar methodology, has looked at the consequences of changing from conventional milk to a product with no A1 beta casein protein: a2 Milk™. Gastrointestinal proteolytic digestion of A1 variant of β-casein (raw/processed milk) leads to generation of bioactive peptide, beta casomorphin 7 (BCM-7). Excessive exposure to A1 β-casein has been postulated as being associated with several clinical disorders, including abnormal gastrointestinal function, atherosclerosis/ischaemic heart disease, type 1 diabetes, and augmentation of the behavioural symptoms of schizophrenia and autism. BCM-7 is primarily metabolised by dipeptidyl peptidase 4 (DPP4). Individuals with low DPP4 activities, particularly infants, are unable to break down BCM-7 and experience more severe symptoms. Reducing or eliminating the consumption of A1 β-casein, and replacing it with another major protein source, such as A2 β-casein, may avoid some of these disorders or improve their symptoms.

Using the method of social media-derived data collection, open retrospective data was collected from 6,785 users (5,535 adults) who had switched to a2 Milk™. This adult cohort was used to provide answers to a structured set of questions, which collected symptom experience in a consistent manner. Whenever possible, symptoms were evaluated using validated self-administered questionnaires. Of the 5,535 adults, 2,876 either had a professional diagnosis of IBS or considered that they had IBS. Those who reported that alleviating IBS symptoms was their primary reason for buying a2 Milk™ (862/5,335) completed a series of questions specific to this condition. It was remarkable to record that 83% of the cohort had experienced an improvement in their IBS symptoms after changing from conventional to a2 Milk™, with reductions in self-reported (visual analogue scale) pain, distension, improved bowel habit and improvement in quality of life. Forty per cent of the responders indicated that they had been taking medication for their IBS, and half of them reported reducing the amount of medication used after changing to a2 Milk™. Of the 5,535 adult participants, 1,823 indicated that they had other functional gastrointestinal symptoms (which were not IBS) and these included non-specific abdominal pains, wind, bloating and relative constipation/diarrhoea.

Meanwhile, 1,445/1,823 indicated that switching milk had made a positive difference to their symptoms (79.3%). 111/1,823 (6.1%) indicated that switching had not helped/not made a difference or had made symptoms worse.

It is difficult to propose that sensitivity to milk is the single most important factor in the symptomatology of IBS or other functional gastrointestinal symptoms, but in the opinions of the users of a2 Milk™ (and, of course, no information is available on those that did not use a2 Milk™ as only these people entered the study), they had found a simple and safe intervention which had improved their health and quality of life. There does not seem to be a risk for changing from conventional to a2 Milk™, and given the user response, making this suggestion would seem to be a relatively safe first option compared to either eliminating dairy completely or offering pharmacotherapy with agents, none of which have emerged as the gold standard.

Dr Martin Goldman has received financial support and funding from healthcare companies Allergan, Teva and a2 Milk™ for his work on generation of real-world data. The opinions expressed in this article are solely those of the author. First appeared in issue 11 (Winter 2018) of the Digest, the journal of the Primary Care Society for Gastroenterology.