Clinical trial NCT04344717: Pharmacokinetics of Apixaban in Patients With Short Bowel Syndrome Requiring Long Term Parenteral Nutrition
Official title: Pharmacokinetics of Apixaban in Patients With Short Bowel Syndrome Requiring Long Term Parenteral Nutrition
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Short Bowel Syndrome
Anticoagulation
Keywords: Apixaban
Pharmacokinetics
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
First posted: 2020-04-14
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Interventional, non-randomized, open label, monocentric controlled study
Primary purpose: TREATMENT

Brief summary: Short bowel syndrome (SBS) is defined as a loss of function of the small intestine resulting in a malabsorptive disorder. In SBS, oral drug absorption may be altered due to extensive intestinal resection. It remains unclear to what extent apixaban exposure is impacted in SBS.Therefore this study tries to investigate the pharmacokinetics (PK) of apixaban in adult patients with SBS requiring long-term parenteral nutrition (PN).


Eligibility criteria: Inclusion criteria SBS single dose:

- patients with SBS (small bowel length of \<2m after Treitz ligament) on long term (\>3 months) PN or fluids who are apixaban-, vitamin K antagonist- and teduglutide naive

Inclusion criteria SBS steady-state:

- patients with SBS (small bowel length of \<2m after Treitz ligament) on long term (\>3 months) PN or fluids who are teduglutide naive and who are already taking apixaban 2,5 mg or 5 mg twice daily for ≥ 4 days

Inclusion criteria non-SBS single dose:

- healthy individuals without history of GI resections or other conditions associated with impaired absorption, who are apixaban- and vitamin K antagonist naive

Inclusion criteria non-SBS steady-state:

- patients without history of gastrointestinal resections or other conditions associated with impaired absorption (= controls), who are already taking apixaban 2,5 mg or 5 mg twice daily for ≥ 4 days

Exclusion criteria SBS (single dose+ steady-state):

* \<18 years
* non-Dutch speaking
* recent (\<6 months) major bleeds according with the International Society on Thrombosis and Haemostasis definition of major bleeding in non-surgical patients (20)
* creatinine clearance of \< 15 mL/min or dialysis dependent
* liver failure classified as Child Pugh C
* total bilirubin ≥ 1.77 mg/dL (= 1,5 x upper limit of normal)
* presence of coagulopathy and a clinically relevant bleeding risk
* pregnancy or lactation
* concomitant intake of strong combined inhibitors of CYP3A4 and P-gp
* participation in a recent (\<1 month) trial with an investigational product
* recent (\<6 months) gastrointestinal surgery
* gastrointestinal mucosal disease interfering with absorption (e.g. radio-enteritis, inflammatory bowel disease, celiac disease, ...)
* gastrointestinal fistulae
* SBS with intestinal failure resulting from gastric bypass surgery

Exclusion criteria non-SBS (single dose+ steady-state):

* \<18 years
* non-Dutch speaking
* recent (\<6 months) major bleeds according with the International Society on Thrombosis and Haemostasis definition of major bleeding in non-surgical patients (20)
* creatinine clearance of \< 15 mL/min or dialysis dependent
* liver failure classified as Child Pugh C
* total bilirubin ≥ 1.77 mg/dL (= 1,5 x upper limit of normal)
* presence of coagulopathy and a clinically relevant bleeding risk
* pregnancy or lactation
* concomitant intake of strong combined inhibitors of CYP3A4 and P-gp
* use of prokinetics, antimotility drugs or opioids
* participation in a recent (\<1 month) trial with an investigational product

Primary outcomes:
measure: Difference in Cmax of apixaban between SBS and patients with a normal gastrointestinal tract
timeFrame: Through study completion, an average of 1.5 years
Secondary outcomes:
measure: Difference in estimated trough level (Cmin) of apixaban between SBS and patients with a normal gastrointestinal tract
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in time to reach Cmax (Tmax) of apixaban between SBS patients and patients with a normal gastrointestinal tract
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in exposure (AUC0-12h) of apixaban between SBS patients and patients with a normal gastrointestinal tract
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in absorption rate constant of apixaban between SBS patients and patients with a normal gastrointestinal tract
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in bioavailability of apixaban between SBS patients and patients with a normal gastrointestinal tract
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in volume of distribution of apixaban between SBS patients and patients with a normal gastrointestinal tract
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in clearance of apixaban between SBS patients and patients with a normal gastrointestinal tract
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in half-life of apixaban between SBS patients and patients with a normal gastrointestinal tract
timeFrame: Through study completion, an average of 1.5 years
measure: To set up an optimized dosing scheme of apixaban for SBS patients
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in Cmax between SBS patients with and without teduglutide
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in Cmin between SBS patients with and without teduglutide
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in Tmax between SBS patients with and without teduglutide
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in AUC SBS patients with and without teduglutide
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in AUC between SBS patients with and without teduglutide
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in absorption rate constant between SBS patients with and without teduglutide
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in bioavailability between SBS patients with and without teduglutide
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in volume of distribution between SBS patients with and without teduglutide
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in clearance between SBS patients with and without teduglutide
timeFrame: Through study completion, an average of 1.5 years
measure: Difference in half-life between SBS patients with and without teduglutide
timeFrame: Through study completion, an average of 1.5 years
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: University Hospitals Leuven
Study officials:
References:
citation: Jeppesen PB. Spectrum of short bowel syndrome in adults: intestinal insufficiency to intestinal failure. JPEN J Parenter Enteral Nutr. 2014 May;38(1 Suppl):8S-13S. doi: 10.1177/0148607114520994. Epub 2014 Jan 31.
citation: Santamaria MM, Villafranca JJA, Abiles J, Lopez AF, Rodas LV, Goitia BT, Navarro PU. Systematic review of drug bioavailability following gastrointestinal surgery. Eur J Clin Pharmacol. 2018 Dec;74(12):1531-1545. doi: 10.1007/s00228-018-2539-9. Epub 2018 Aug 22.
citation: Eikelboom JW, Quinlan DJ, Hirsh J, Connolly SJ, Weitz JI. Laboratory Monitoring of Non-Vitamin K Antagonist Oral Anticoagulant Use in Patients With Atrial Fibrillation: A Review. JAMA Cardiol. 2017 May 1;2(5):566-574. doi: 10.1001/jamacardio.2017.0364.