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

• ClinicalTrials.gov Identifier: NCT02386917
• Recruitment Status: Active, not recruiting
• First Posted: March 12, 2015
• Last Update Posted: February 10, 2021
• Sponsor: The Hospital of Vestfold
• Collaborators: University of Oslo; AstraZeneca
• Information provided by (Responsible Party): Jøran Hjelmesæth, The Hospital of Vestfold

Tracking Information

• First Submitted Date: February 24, 2015
• First Posted Date: March 12, 2015
• Last Update Posted Date: February 10, 2021
• Study Start Date: March 2015
• Actual Primary Completion Date: June 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 5, 2017)

• Bioavailability of drugs (1) [ 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 ]
  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) [ 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 ]
  Changes in bioavailability (Area Under Curve - oral) of caffeine, losartan, digoxin, rosuvastatin and omeprazole after Gastric Bypass and Very Low Calorie Diet, respectively.

Original Primary Outcome Measures (submitted: March 8, 2015)

• 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 ]
• 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 ]

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Impact of Body Weight and Weight Loss on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers
• Official Title: Impact of Body Weight, Low Calorie Diet and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers
• 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

1. 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.
2. 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.
3. to compare the 3 study groups (GBP, VLCD and cholecystectomy) at baseline with respect to body composition, cardiovascular risk factors and metabolic biomarkers.
4. 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.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: Single (Investigator); Primary Purpose: Basic Science
• Condition: Obesity

Intervention

• Procedure: Gastric bypass
  Weight loss surgery
• Behavioral: Very low calorie diet
  Non-surgical weight loss procedure

Study Arms

• Active Comparator: Gastric bypass
  40 patients will undergo gastric bypass
  Intervention: Procedure: Gastric bypass
• Active Comparator: Very low calorie diet
  40 patients will undergo a very low calorie diet
  Intervention: Behavioral: Very low calorie diet
• No Intervention: Gall bladder operation
  20 patients will be asked to undergo one pharmacokinetic study only, and then finish the study. They will not undergo any weight loss intervention.

• Publications *: Hjelmesæth J, Åsberg 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: March 8, 2015): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2023
• Actual Primary Completion Date: June 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Norway

Administrative Information

• NCT Number: NCT02386917
• Other Study ID Numbers: 2013-2379
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Jøran Hjelmesæth, The Hospital of Vestfold
• Original Responsible Party: Same as current
• Current Study Sponsor: The Hospital of Vestfold
• Original Study Sponsor: Same as current

Collaborators

• University of Oslo
• AstraZeneca

Investigators

• Principal Investigator: Jøran Hjelmesæth, Professor; The Hospital of Vestfold

• PRS Account: The Hospital of Vestfold
• Verification Date: February 2021