Metformin at the Cellular Level and Dosing for Diabetes Mellitus (DM)

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01876992
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arms: 2
• Duration (Months): 41
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The investigators know that metformin works at the level of the cells in the body by acting on a protein called Cyclic amine monophosphate- Response Binding Elements (CREB) binding protein or Constitutive Reverter of eIF2α Phosphorylation (CREP) Binding Protein (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 or Disease	Intervention/Treatment	Phase
Diabetes; Pre-diabetes; Obesity	Drug: Metformin	N/A

Detailed Description

Our studies have shown that metformin acts at the cellular level by acting on a target protein, Cyclic amine monophosphate-Response Binding Elements (CREB) binding protein or CREP Binding Protein (CBP). Patients are treated with many different doses of metformin, some patients respond well to low doses while others require much higher doses. The investigators do not understand why this may be and are interested in knowing if the investigators can treat patents effectively with low doses. What the investigators do not know is how this process is affected when the dose of the metformin is increased or changed. Changes in metformin's target protein will provide evidence on the effectiveness of the dose.

Also, 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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.

Outcome Measures

Primary Outcome Measures

1. % Cyclic Amine Mono Phosphate (cAMP) Response Element Binding Protein (CBP) White Blood Cell (WBC) Phosphorylation (Metformin Treated vs no Treatment) [10 weeks]

   To assess metformin-induced Cyclic Amine Mono Phosphate (cAMP) response element binding protein (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.

Secondary Outcome Measures

1. Change in BMI [Baseline and after about 30 days]

   The BMI is an index measure of body weight and is used to define states of obesity. Height ( in meters) and weight (in Kilograms) are used to calculate a BMI (kg/m2).

2. Fasting Blood Glucose. [30 days]

   A fasting blood sugar level less than 100 mg/dL is normal. A fasting blood sugar level from 100 to 125 mg/dL is considered prediabetes. If a subject has a blood sugar of 126 mg/dL or higher on two separate tests, they are diagnosed with diabetes. Metformin decreases fasting blood sugar.

Other Outcome Measures

1. Effect of Dose Escalation [Approximately Week 10]

   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. CBP phosphorylation will be measured by western blot analysis using a probe that is specific for the phosphorylated CBP protein. The outcome will be the % difference between the patient before starting metformin and at each dose increment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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 (Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)) and/or a increased level of Gamma-glutamyltransferase (GGT), Prothrombin Time (PT), International Normalized Ratio (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

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Johns Hopkins University

Investigators

• Principal Investigator: Sally Radovick, MD, Johns Hopkins University Department of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT01876992
• Other Study ID Numbers: NA_00046072; NA_00046072
• First Posted: Jun 13, 2013
• Last Update Posted: Sep 26, 2017
• Last Verified: Aug 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Johns Hopkins University: diabetes; pediatrics; obesity; healthy volunteers; metformin; nutrition; healthy controls; bmi
• Additional relevant MeSH terms: Diabetes Mellitus; Prediabetic State; Metformin

Study Results

Participant Flow

Recruitment Details	Patients recruited through the Clinical Research Center.

Arm/Group Title	Metformin	Obese Controls
Arm/Group Description	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. Metformin	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.
Period Title: Overall Study
STARTED	5	5
COMPLETED	5	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Metformin	Obese Controls	Total
Arm/Group Description	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. Metformin	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.	Total of all reporting groups
Overall Participants	5	5	10
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	5 100%	5 100%	10 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	32	36	34
Sex: Female, Male (Count of Participants)
Female	3 60%	3 60%	6 60%
Male	2 40%	2 40%	4 40%
Region of Enrollment (participants) [Number]
United States	5 100%	5 100%	10 100%

Outcome Measures

1. Primary Outcome

Title	% Cyclic Amine Mono Phosphate (cAMP) Response Element Binding Protein (CBP) White Blood Cell (WBC) Phosphorylation (Metformin Treated vs no Treatment)
Description	To assess metformin-induced Cyclic Amine Mono Phosphate (cAMP) response element binding protein (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.
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Obese Controls
Arm/Group Description	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. Metformin	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.
Measure Participants	5	5
Mean (Full Range) [percent phosphorylation]	15	9

2. Secondary Outcome

Title	Change in BMI
Description	The BMI is an index measure of body weight and is used to define states of obesity. Height ( in meters) and weight (in Kilograms) are used to calculate a BMI (kg/m2).
Time Frame	Baseline and after about 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Obese Controls
Arm/Group Description	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. Metformin	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.
Measure Participants	5	5
Mean (Full Range) [change in BMI (kg/m2)]	-0.5	0

3. Secondary Outcome

Title	Fasting Blood Glucose.
Description	A fasting blood sugar level less than 100 mg/dL is normal. A fasting blood sugar level from 100 to 125 mg/dL is considered prediabetes. If a subject has a blood sugar of 126 mg/dL or higher on two separate tests, they are diagnosed with diabetes. Metformin decreases fasting blood sugar.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Data were not collected for this outcome measure.

Arm/Group Title	Metformin	Obese Controls
Arm/Group Description	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. Metformin	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.
Measure Participants	0	0

4. Other Pre-specified Outcome

Title	Effect of Dose Escalation
Description	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. CBP phosphorylation will be measured by western blot analysis using a probe that is specific for the phosphorylated CBP protein. The outcome will be the % difference between the patient before starting metformin and at each dose increment.
Time Frame	Approximately Week 10

Outcome Measure Data

Analysis Population Description

Escalating CBP phosphorylation was measured.

Arm/Group Title	Metformin	Obese Controls
Arm/Group Description	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. Metformin	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.
Measure Participants	5	5
Mean (Full Range) [percent phosphorylation]	21	8

Adverse Events

Arm/Group Title	Metformin		Obese Controls
Arm/Group Description	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. Metformin		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.
All Cause Mortality
	Metformin		Obese Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Metformin		Obese Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Metformin		Obese Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.