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

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ClinicalTrials.gov Identifier: NCT02386917
Recruitment Status : Active, not recruiting
First Posted : March 12, 2015
Last Update Posted : August 7, 2019
Sponsor:
Collaborators:
University of Oslo
AstraZeneca
Information provided by (Responsible Party):
Jøran Hjelmesæth, The Hospital of Vestfold

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.

Condition or disease Intervention/treatment Phase
Obesity Procedure: Gastric bypass Behavioral: Very low calorie diet Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Basic Science
Official Title: Impact of Body Weight, Low Calorie Diet and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers
Study Start Date : March 2015
Actual Primary Completion Date : June 2019
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Gastric bypass
40 patients will undergo gastric bypass
Procedure: Gastric bypass
Weight loss surgery

Active Comparator: Very low calorie diet
40 patients will undergo a very low calorie diet
Behavioral: Very low calorie diet
Non-surgical weight loss procedure

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.



Primary Outcome Measures :
  1. 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.

  2. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02386917


Locations
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Norway
HVestfold
Tønsberg, Vestfold, Norway, 3103
Sponsors and Collaborators
The Hospital of Vestfold
University of Oslo
AstraZeneca
Investigators
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Principal Investigator: Jøran Hjelmesæth, Professor The Hospital of Vestfold

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Jøran Hjelmesæth, Professor, Head, The Hospital of Vestfold
ClinicalTrials.gov Identifier: NCT02386917     History of Changes
Other Study ID Numbers: 2013-2379
First Posted: March 12, 2015    Key Record Dates
Last Update Posted: August 7, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Body Weight
Signs and Symptoms