Evaluation of indomethacin challenge on intestinal permeability

• Research type

  Research Study

• Full title

  A three-period cross-over study to evaluate the effect of an indomethacin challenge on intestinal permeability using sugar probes in healthy male and female participants aged 18 to 60 years.

• IRAS ID

  316973

• Contact name

  Ugochukwu Stephanie Igwe

• Contact email

  stephanie.x.igwe@gsk.com

• Sponsor organisation

  GlaxoSmithKline

• Duration of Study in the UK

  0 years, 5 months, 28 days

• Research summary

  LAY SUMMARY: Bowel diseases, such as inflammatory bowel disease and irritable bowel
  syndrome, are associated with an increase in gut ‘leakiness’, which is the ability
  of the gut to allow substances to pass through it into the bloodstream and urine.
  Indomethacin, an approved non-steroidal anti-inflammatory medication, has
  been shown in previous studies to also cause a temporary increase in gut
  leakiness.
  The aim of this study was to understand whether administering indomethacin to
  healthy participants could result in a reproducible increase in gut leakiness. If so,
  a similar study could be used to assess medicines that will reduce gut leakiness
  when they are developed for the treatment of bowel diseases. Gut leakiness was
  measured by asking participants to ingest a sugar solution, and then measuring
  the ratio of the sugars lactulose and rhamnose (lactulose:rhamnose (L:R) ratio) in
  the bloodstream and urine.
  Twenty healthy males and females, aged 18 to 60 years, were enrolled. Three
  study periods were planned for each participant. During each period, participants
  took either 2 doses of indomethacin (called an indomethacin challenge) or 2
  doses of placebo (a substance with no therapeutic effect) and urine and blood
  samples were subsequently collected.
  The indomethacin challenge was safe and generally well tolerated. The results of
  the study showed that an indomethacin challenge was associated with a two-fold
  increase in gut leakiness, which reflected results from previous similar studies.
  Changes in gut leakiness were also generally consistent and reproducible and this
  ‘leakiness’ could be accurately measured in both the blood and urine, over 5
  hours and over 2 hours. This study confirms the suitability of this approach for
  future studies of medicines treating bowel diseases by targeting gut leakiness

  Patients with bowel diseases have been found to have a gut (small intestine and colon) that is ‘leaky’ and allows substances to pass through more easily. This study aims to understand whether administering indomethacin to healthy volunteers can cause reproducible changes in the ability of substances to pass through the gut, which could be used to assess medicines that will reduce gut leakiness for future treatment of patients with bowel diseases.
  Changes in gut leakiness will be assessed using a mixture of 4 sugars which volunteers will drink and then measuring them in blood and urine over 24 hours. Volunteers will have their sugar levels assessed after being given indomethacin or placebo (a dummy tablet). As there is natural variability in volunteers’ gut’s ability to allow substances to pass through it, the measurements will be taken more than once, to inform if the measurements can be repeated.
  Approximately 30 healthy male and female adults aged between 18 and 60 years will be included in the study.
  The study will consist of 3 periods, each volunteer will be randomly allocated to a sequence so they receive indomethacin and placebo at least once as well as a repeat of either indomethacin or placebo. The study doctor and the volunteers will be blinded to the treatments given at each period.
  The study will involve the following periods
  • A screening period 28 days before the first dose
  • 3 study periods including 2 nights stay at the clinical unit during each period
  • A washout of 7-21 days between each period
  • A follow-up phone call 5-9 days after the last study drug administration.
  The study will be conducted in an MHRA accredited clinical research unit in the UK with appropriate medical and safety monitoring for all the volunteers taking part in the study.
  

• REC name

  London - Riverside Research Ethics Committee

• REC reference

  22/PR/1043

• Date of REC Opinion

  10 Oct 2022

• REC opinion

  Further Information Favourable Opinion