Function of Metformin at the Cellular Level and Best Dosing for Children and Adults With DM or Pre-DM

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 by Johns Hopkins University
Sponsor:
Information provided by (Responsible Party):
Dr. Sally Radovick, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01876992
First received: May 2, 2013
Last updated: June 11, 2013
Last verified: June 2013
  Purpose

The investigators know that metformin works at the level of the cells in the body by acting on a protein called CREB binding protein or CBP. What the investigators do not know is how this process is affected when the dose of the metformin is increased or changed.

Currently the same doses of metformin are often used in both children and adults, but it is possible that the dose of metformin should be based on age and weight. Understanding how CBP works could potentially help us to tailor metformin treatment individually for patients based on their age, weight and CBP response.


Condition Intervention
Diabetes
Pre-diabetes
Obesity
Drug: Metformin

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Pilot Study of Metformin-induced CBP Phosphorylation at the Cellular Level and Corresponding Clinical Dose Response in Adults and Children

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • CBP Phosphorylation [ Time Frame: Approximately Week 10 ] [ Designated as safety issue: No ]
    To assess metformin-induced CBP phosphorylation in circulating white blood cells both in vivo and ex vivo and determine its relationship to subsequent changes in body mass index, fasting blood glucose, insulin and glucagon.


Other Outcome Measures:
  • Effect of dose escalation [ Time Frame: Approximately Week 10 ] [ Designated as safety issue: No ]
    Compare the effect of dose escalation of metformin on CBP phosphorylation in white blood cells in both in vivo and ex vivo assays to subsequent physiological changes in vivo for adults and children.


Estimated Enrollment: 23
Study Start Date: January 2012
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Metformin

Doses will be increased incrementally. Decisions to escalate the metformin dose will be made based upon tolerability of side effects as described in the schedule of evaluations to follow. All subjects will be monitored for safety while receiving metformin. Any participant with blood glucose of <60mg/dl at any time while receiving metformin will have therapy stopped and will be withdrawn from the study.

For children <50kg:

Baseline:250mg po qd, Week 2:250mg po bid, Week 4:500mg po AM/250mg po PM, Week 8:500mg po bid.

For children ≥50kg:

Baseline:500mg po qd, Week 2:500mg po bid, Week 4:1000mg po AM/500mg po PM, Week 8:1000mg po bid.

For adults:

Baseline:500mg po qd,Week2:500mg po bid,Week 4:1000mg po AM/500mg po PM,Week 8:1000mg po bid.

Drug: Metformin
Other Name: Glucophage, Fortamet
No Intervention: Obese Controls

Three obese but otherwise healthy adult participants will be recruited into the study as controls. These will be individuals who are not currently (or previously) on any diabetic medication including metformin.

There will be a single study visit and no medication will be administered. They will be administered a meal and pre and post-prandial blood samples will be drawn.


  Eligibility

Ages Eligible for Study:   10 Years to 79 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Pediatric Inclusion Criteria:

  • Children 10-17 years.
  • Both genders (male and female)
  • All children must have a Primary Care Physician and/or an Endocrinologist who must be aware that the child under their care will be part of the study.
  • All children must have a Primary Care Physician and/or an Endocrinologist who is considering initiating metformin therapy now or in the near future as part of standard clinical care.
  • Naïve to metformin.
  • EITHER: Prediabetic children OR diabetic children under good glycemic control

Pediatric Exclusion Criteria:

  • Children ages 10-17 who do not have parental consent and/or do not give assent
  • Children living in foster care
  • Children with allergies to foods in the breakfast menu
  • Children who currently consume ANY alcohol
  • Children on current antidiabetic medication or those who have been on any antidiabetic medication in the 3 months prior to enrolment
  • Children with a history of /or concurrent chronic disease (eg. heart, kidney, liver disease or any type of malignancy or pre-malignant condition) that required hospitalization within the last 6 months
  • Pregnancy
  • Refusal by a female participant who is of child bearing potential and sexually active to use contraceptive methods such as oral contraceptive pills, barrier methods and abstinence
  • Children weighing less than 36 kg
  • Children with any condition that increases the risk of lactic acidosis (e.g. cancer, infection, congestive heart failure, renal disease )
  • Children with history of recent hospitalization for surgery, dehydration, sepsis, hypoxemia (within the past 6 months)
  • Children with history of weight loss, polyuria and polydipsia
  • Children who are currently enrolled in a weight management program
  • Children with known hypersensitivity to metformin
  • Children with a fasting blood glucose of >180mg/dl
  • Children with a HbA1c level of ≥7%
  • Children with glycosuria
  • Children with clinical or laboratory evidence of hepatic disease- transaminase levels three times the upper normal range (AST and ALT) and/or a increased level of GGT, PT, INR from the reference normal range and a serum albumin less than the reference normal range of the Johns Hopkins Clinical Laboratories.
  • If iodinated contrast is used on a participant, due to possible acute alteration of renal function resulting in increased risk of lactic acidosis, the participant will be excluded.
  • Children with renal impairment

    • In children >50kg, renal impairment is defined by a serum creatinine 1.4 mg/dl or higher in females or 1.5mg/dl or higher in males OR estimated Glomerular Filtration Rates (eGFR) ≤60mL/min by the Schwartz formula.
    • In children <50kg, renal impairment is defined by eGFR <100 mL/min by the Schwartz formula.
  • Children with acid-base disturbance as defined by serum bicarbonate levels less than 20mEq/L or greater than 29mEq/L.

Adult Inclusion Criteria:

  • Adults 18-79 years
  • Both genders (male and female)
  • All participants must have a Primary Care Physician and/or an Endocrinologist who must be aware that the adult under their care will be part of the study
  • All participants must have a Primary Care Physician and/or an Endocrinologist who is considering initiating metformin therapy now or in the near future as part of standard clinical care.
  • Naive to metformin
  • EITHER: Prediabetic adults OR diabetic adults, under fair glycemic control:

Adult Exclusion Criteria:

  • Pregnancy
  • Adults who are not able to understand the Informed Consent document and who are unwilling to do the study
  • Adults with allergies to any of the foods in the breakfast menu
  • Adults on current antidiabetic medication or on any antidiabetic medication in the 3 months prior to enrolment.
  • Adults with a history of /or concurrent chronic disease (e.g. heart, kidney, liver disease or any type of malignancy or pre-malignant condition) that required hospitalization within the last 6 months
  • Refusal by a female participant who is of child bearing potential and sexually active to use contraceptive methods such as oral contraceptive pills, barrier methods and abstinence
  • Adults with excessive current intake of alcohol (>2 drinks/day for males and >1 drink/day for females)
  • Adults who have engaged in binge drinking (>5 drinks within a 2 hour period) in the last 3 months
  • Adults with history of recent hospitalization for surgery, dehydration, sepsis, hypoxemia (past 6 months)
  • Hypersensitivity to metformin.
  • Adults with fasting blood glucose of >180mg/dl.
  • Adults with HbA1c level of ≥8%
  • Adults with glycosuria.
  • Adults with any condition that increases the risk of lactic acidosis (e.g. cancer, infection, congestive heart failure, renal disease )
  • Adults with clinical or laboratory evidence of hepatic disease- transaminase levels three times the upper normal range (AST and ALT) and/or a increased level of GGT, PT, INR from the reference normal range and a serum albumin less than the reference normal range of the Johns Hopkins Clinical Laboratories.
  • If iodinated contrast is used on a participant, due to possible acute alteration of renal function resulting in increased risk of lactic acidosis, the adult participant will be excluded.
  • Adults with renal impairment as defined by a serum creatinine 1.4 mg/dl or higher in females or 1.5mg/dl or higher in males OR estimated Glomerular Filtration Rates (eGFR) ≤60mL/min by Modification of Diet in Renal Disease (MDRD) formula.
  • Adults with acid-base disturbance as defined as serum bicarbonate levels less than 20mEq/L or greater than 29mEq/L.

Adult Obese Control Inclusion Criteria:

  • Age 18-79
  • Both genders (male and female)
  • BMI > 30 kg/m2

Adult Obese Control Exclusion Criteria:

  • Subjects previously or currently on any diabetes medication, including metformin, will be excluded.
  • Pregnancy
  • Subjects with history of or concurrent chronic disease (e.g. heart, kidney, liver disease or any type of malignancy or pre-malignant condition) that required hospitalization within the last 6 months will be excluded.
  • Adults with allergies to any of the foods in the breakfast menu
  • Adults with excessive current intake of alcohol (>2 drinks/day for males and >1 drink/day for females)
  • Adults who have engaged in binge drinking (>5 drinks within a 2 hour period) in the last 3 months
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01876992

Contacts
Contact: Sally Radovick, MD 410-502-7580 sradovick@jhmi.edu

Locations
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Principal Investigator: Sally Radovick, MD         
Sponsors and Collaborators
Johns Hopkins University
Investigators
Principal Investigator: Sally Radovick, MD Johns Hopkins University Department of Medicine
  More Information

No publications provided

Responsible Party: Dr. Sally Radovick, Professor, School of Medicine, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01876992     History of Changes
Other Study ID Numbers: NA_00046072, NA_00046072
Study First Received: May 2, 2013
Last Updated: June 11, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Johns Hopkins University:
diabetes
pediatrics
obesity
healthy volunteers
metformin
nutrition
healthy controls
bmi

Additional relevant MeSH terms:
Diabetes Mellitus
Obesity
Glucose Intolerance
Prediabetic State
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Hyperglycemia
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 20, 2014