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Impact of Body Weight and Weight Loss on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers (COCKTAIL)

Primary Purpose

Obesity

Status
Active
Phase
Not Applicable
Locations
Norway
Study Type
Interventional
Intervention
Gastric bypass
Very low calorie diet
Sponsored by
The Hospital of Vestfold
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Obesity

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients scheduled for GBP surgery or VLCD intervention for obesity as well as patients scheduled for cholecystectomy.
  2. BMI ≥ 18.5 kg/m2
  3. Able and willing to donate biopsies (as specified in the protocol) and for the GBP and VLCD patients also willing to perform follow-up 24 hour PK-investigations and other assessments as required by the clinical study protocol
  4. Stable body weight (< 5 kg self reported weight change) during the last 3 months before inclusion.
  5. Signed informed consent.

Exclusion Criteria:

  • Concomitant treatment with drugs (according to available literature, appendix 3) and/or other factors that may influence the cocktail drug pharmacokinetics such as grapefruit juice, Seville oranges, Pomelo juice, St. Johns wort, tobacco and coffee/tea in close approximation to the investigations.
  • Bradyarrhythmia, Wolff-Parkinson-White (WPW)-syndrome, atrioventricular block 2-3.
  • Electrolyte disturbances (particularly hypokalemia or hypomagnesemia).
  • Renal impairment: eGFR < 30 mL/min.
  • Blood donations the last 4 months.
  • Previous bariatric or upper gastrointestinal surgery.
  • Diabetic patients treated with glitazones, insulin or sulfonylureas.
  • Pregnancy (checked with HCG in urine at screening) and breast-feeding mothers.
  • Known hypersensitivity (including allergy) to drugs included in the cocktail and/or local anesthesia.
  • Anticoagulants with associated risk in combination with biopsies.
  • Non-compliance with regards to visits and/or diet.

Sites / Locations

  • HVestfold

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

No Intervention

Arm Label

Gastric bypass

Very low calorie diet

Gall bladder operation

Arm Description

40 patients will undergo gastric bypass

40 patients will undergo a very low calorie diet

20 patients will be asked to undergo one pharmacokinetic study only, and then finish the study. They will not undergo any weight loss intervention.

Outcomes

Primary Outcome Measures

Bioavailability of drugs (1)
Changes in absolute bioavailability (Area Under Curve - oral / Area Under Curve -intravenous) of midazolam after Gastric Bypass and Very Low Calorie Diet, respectively.
Bioavailability of drugs (2)
Changes in bioavailability (Area Under Curve - oral) of caffeine, losartan, digoxin, rosuvastatin and omeprazole after Gastric Bypass and Very Low Calorie Diet, respectively.

Secondary Outcome Measures

Full Information

First Posted
February 24, 2015
Last Updated
August 1, 2022
Sponsor
The Hospital of Vestfold
Collaborators
University of Oslo, AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT02386917
Brief Title
Impact of Body Weight and Weight Loss on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers
Acronym
COCKTAIL
Official Title
Impact of Body Weight, Low Calorie Diet and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 18, 2015 (Actual)
Primary Completion Date
June 2019 (Actual)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Hospital of Vestfold
Collaborators
University of Oslo, AstraZeneca

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Drug bioavailability and disposition vary according to body weight and weight loss after bariatric surgery. This study evaluates the impact of body weight and weight loss on the pharmacokinetics of various probe drugs, and compares these effects in three groups of patients receiving either a gall bladder operation, gastric bypass or a very low calorie diet.
Detailed Description
This study aims to to investigate the relationship between body composition and the liver/intestine activity and expression of proteins (drug metabolizing enzymes, transporters and regulatory factors) important for drug bioavailability and disposition in the range from normal to morbid obesity (the combined gastric bypass and cholecystectomy groups) at baseline. to compare the short-term (6-week) and long-term (2 years) effect of gastric bypass (GBP) and a very low calorie diet (VLCD) (matched weight loss) on bioavailability and pharmacokinetics of probe drugs (caffeine, omeprazole, digoxin, midazolam, rosuvastatin, losartan) and biomarkers (and adjoining protein expressions) for cytochrome P450 (CYP)1A2, CYP2C9, CYP2C19, CYP3A, P-glycoprotein (gp) and organic anion-transporting polypeptide (OATP)1B1. to compare the 3 study groups (GBP, VLCD and cholecystectomy) at baseline with respect to body composition, cardiovascular risk factors and metabolic biomarkers. to compare the short-term (6-week) changes in glucose metabolism, blood pressure, blood lipids and body composition of matched weight loss and long-term effects (2 year) on body composition, cardiovascular risk factors and metabolic biomarkers, between the GBP and VLCD groups.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obesity

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
Investigator
Allocation
Non-Randomized
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Gastric bypass
Arm Type
Active Comparator
Arm Description
40 patients will undergo gastric bypass
Arm Title
Very low calorie diet
Arm Type
Active Comparator
Arm Description
40 patients will undergo a very low calorie diet
Arm Title
Gall bladder operation
Arm Type
No Intervention
Arm Description
20 patients will be asked to undergo one pharmacokinetic study only, and then finish the study. They will not undergo any weight loss intervention.
Intervention Type
Procedure
Intervention Name(s)
Gastric bypass
Intervention Description
Weight loss surgery
Intervention Type
Behavioral
Intervention Name(s)
Very low calorie diet
Intervention Description
Non-surgical weight loss procedure
Primary Outcome Measure Information:
Title
Bioavailability of drugs (1)
Description
Changes in absolute bioavailability (Area Under Curve - oral / Area Under Curve -intravenous) of midazolam after Gastric Bypass and Very Low Calorie Diet, respectively.
Time Frame
0 hours and 0.25, 0.5, 1, 1.5, 2, 3, 4, 4.25, 4.5, 5, 5.5, 6, 8, 10*, 12*, 23 and 24 hours following administration
Title
Bioavailability of drugs (2)
Description
Changes in bioavailability (Area Under Curve - oral) of caffeine, losartan, digoxin, rosuvastatin and omeprazole after Gastric Bypass and Very Low Calorie Diet, respectively.
Time Frame
0 hours and 0.25, 0.5, 1, 1.5, 2, 3, 4, 4.25, 4.5, 5, 5.5, 6, 8, 10*, 12*, 23 and 24 hours following administration

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients scheduled for GBP surgery or VLCD intervention for obesity as well as patients scheduled for cholecystectomy. BMI ≥ 18.5 kg/m2 Able and willing to donate biopsies (as specified in the protocol) and for the GBP and VLCD patients also willing to perform follow-up 24 hour PK-investigations and other assessments as required by the clinical study protocol Stable body weight (< 5 kg self reported weight change) during the last 3 months before inclusion. Signed informed consent. Exclusion Criteria: Concomitant treatment with drugs (according to available literature, appendix 3) and/or other factors that may influence the cocktail drug pharmacokinetics such as grapefruit juice, Seville oranges, Pomelo juice, St. Johns wort, tobacco and coffee/tea in close approximation to the investigations. Bradyarrhythmia, Wolff-Parkinson-White (WPW)-syndrome, atrioventricular block 2-3. Electrolyte disturbances (particularly hypokalemia or hypomagnesemia). Renal impairment: eGFR < 30 mL/min. Blood donations the last 4 months. Previous bariatric or upper gastrointestinal surgery. Diabetic patients treated with glitazones, insulin or sulfonylureas. Pregnancy (checked with HCG in urine at screening) and breast-feeding mothers. Known hypersensitivity (including allergy) to drugs included in the cocktail and/or local anesthesia. Anticoagulants with associated risk in combination with biopsies. Non-compliance with regards to visits and/or diet.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jøran Hjelmesæth, Professor
Organizational Affiliation
The Hospital of Vestfold
Official's Role
Principal Investigator
Facility Information:
Facility Name
HVestfold
City
Tønsberg
State/Province
Vestfold
ZIP/Postal Code
3103
Country
Norway

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35648149
Citation
Eide Kvitne K, Hole K, Krogstad V, Wollmann BM, Wegler C, Johnson LK, Hertel JK, Artursson P, Karlsson C, Andersson S, Andersson TB, Sandbu R, Hjelmesaeth J, Skovlund E, Christensen H, Jansson-Lofmark R, Asberg A, Molden E, Robertsen I. Correlations between 4beta-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range. Eur J Clin Pharmacol. 2022 Aug;78(8):1289-1299. doi: 10.1007/s00228-022-03336-9. Epub 2022 Jun 1.
Results Reference
derived
PubMed Identifier
29844102
Citation
Hjelmesaeth J, Asberg A, Andersson S, Sandbu R, Robertsen I, Johnson LK, Angeles PC, Hertel JK, Skovlund E, Heijer M, Ek AL, Krogstad V, Karlsen TI, Christensen H, Andersson TB, Karlsson C. Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL). BMJ Open. 2018 May 29;8(5):e021878. doi: 10.1136/bmjopen-2018-021878.
Results Reference
derived

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Impact of Body Weight and Weight Loss on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers

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