Irritable bowel syndrome (IBS) is a condition that affects the digestive system. IBS can cause a range of symptoms such as cramps, bloating, diarrhoea and constipation. These symptoms come and go and can last from days to months at a time. IBS is very common. In the United Kingdom between one in ten and one in five people are estimated to suffer from IBS, mainly women between the age of 20 and 30. People with IBS have different symptoms, some patients mainly experience diarrhoea, some constipation (IBS-C) and other patients alternate between the two. Traditional treatment of patients with IBS-C include lifestyle and diet improvements, and medications such as laxatives.
Linaclotide is the first medication to be approved in the European Union for the treatment of patients with moderate to severe IBS-C. Although linaclotide is effective in relieving constipation symptoms it may cause diarrhoea. This study, requested by the European Medicines Agency, aims to describe how often patients taking linaclotide develop severe complications of diarrhoea. It also aims to investigate which patients are most likely to suffer from such complications. The results of this study are expected to inform physicians and improve how they treat patients with IBS-C.
Irritable bowel syndrome (IBS) is a chronic, relapsing gastrointestinal condition characterised by abdominal pain, bloating, and changes in bowel habits. Prevalence estimations vary with the diagnostic criteria used, and in the United Kingdom (UK) were estimated between 9.5% and 22% with more recent estimates using Rome IV criteria ranging between 4% (95% CI: 3.1-4.8%) and 4.6% (95% CI: 3.7-5.5%). IBS can be classified according to Rome IV criteria into four subtypes, based on stool form, as IBS predominantly with diarrhea (IBS-D), IBS predominantly with constipation (IBS-C), IBS with mixed bowel habits (IBS-M) and IBS unsubtyped (IBS-U). IBS-U is used only when there is insufficient abnormality of stool consistency to meet the criteria for any of the other above subtypes.
Linaclotide (Constella®), a guanylate cyclase-C receptor agonist with visceral analgesic and secretory activities, was approved as the first medicine authorised for the symptomatic treatment of moderate-to-severe IBS-C in adults in the European Union (EU), and as a condition for approval the EMA requested a post-authorisation safety study to assess the risk of diarrhoeal complications in patients taking linaclotide.
This study plans to investigate the risk of developing severe complications of diarrhoea (SCD) during treatment with linaclotide among patients with IBS-C in the UK and to investigate what the risk factors for experiencing SCD are.
CPRD GOLD, CPRD Aurum, Hospital Episode Statistics, and Office for National Statistics data will be used.
This study is a retrospective case-control study nested in a cohort of patients with IBS-C, with validation of potential cases of SCD. Descriptive statistics and Cox proportional hazards regression will be used.
The results of this study are expected to inform physicians and improve how they treat patients with IBS-C, aiming to prevent potential SCD experienced by these patients.
SCD is the main outcome of interest and will be defined as diarrhoea (as documented by diagnostic codes) and subsequently (between the diarrhoea diagnosis date and 45 days afterwards) any of the following outcomes:
− Dehydration that requires intravenous rehydration
− Dehydration that requires oral rehydration with solutions of electrolytes
− Electrolyte imbalance: potassium (serum potassium levels 3.0–3.5 mEq/L or <3.0 mEq/L) and sodium (serum sodium levels >150 mEq/L)
− Oliguria (urine output < 400 mL in 24 h)
− Anuria (urine output < 50 mL in 24 h)
− New-onset thromboembolism episodes
− New-onset orthostatic hypotension
− New-onset syncope
− New-onset dizziness
− New-onset vertigo
− Acute renal failure
− Hypovolemic shock
− Hospitalisation due to diarrhoea
− Stupor
− Coma
− Death
Read and Systematized Nomenclature of Medicine [SNOMED] codes used to identify these conditions are provided in Appendix II. The definition will be validated through a GP questionnaire to estimate the positive predictive value of this definition.
Javier Cid - Chief Investigator - Evidera Ltd - UK
Javier Cid - Corresponding Applicant - Evidera Ltd - UK
Ahunna Ukah - Collaborator - AbbVie Inc. USA (Headquarters)
Hai Nguyen - Collaborator - Evidera Ltd - UK
Mai Duong - Collaborator - Evidera Ltd - UK
Robert Donaldson - Collaborator - Evidera Ltd - UK
Sonia Halhol - Collaborator - Evidera Ltd - UK
HES Accident and Emergency;HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data;Practice Level Index of Multiple Deprivation;CPRD Aurum Pregnancy Register;CPRD GOLD Pregnancy Register