Linaclotide Safety Study for the Assessment of Diarrhoea - Complications and Associated Risk Factors in the UK population with IBS-C

Date of Approval
Application Number
18_298
Technical Summary

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%. IBS can be classified according to Rome III criteria on the basis of the stool's characteristics: IBS predominantly with diarrhoea (IBS-D); IBS predominantly with constipation (IBS-C); and IBS with mixed bowel habits (IBS-M), with approximately one third of IBS patients having each type.

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.

Health Outcomes to be Measured

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 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.

Collaborators

Javier Cid - Chief Investigator - Evidera, Inc
Nafeesa Dhalwani - Corresponding Applicant - Evidera, Inc
Ahunna Ukah - Collaborator - Allergan, Inc
Anna Schultze - Collaborator - Evidera, Inc
Mireia Raluy Callado - Collaborator - Evidera, Inc
Robert Donaldson - Collaborator - Evidera, Inc

Linkages

HES Accident and Emergency;HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data;Practice Level Index of Multiple Deprivation;Pregnancy Register