History of Changes for Study: NCT01729156

Effects of Metformin on Hepatic FFA Metabolism

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Study Record Versions

Version	Submitted Date	Changes
1	November 13, 2012	None (earliest Version on record)
2	November 26, 2012	Outcome Measures, Study Description and Study Status
3	May 10, 2016	Recruitment Status, Study Status, Contacts/Locations, Arms and Interventions and Study Design
4	May 4, 2017	Recruitment Status, Study Status and Oversight
5	March 9, 2019	Outcome Measures, Study Status, Eligibility and Study Description
6	September 24, 2019	Study Status, Outcome Measures, Document Section and Results

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Merged
Side-by-Side

Study Identification


Unique Protocol ID:	C11palmitatMetformin
Brief Title:	Effects of Metformin on Hepatic FFA Metabolism
Official Title:	Effects of Metformin on Hepatic Free Fatty Acid Metabolism in Patients Diagnosed With Type 2 Diabetes: A C11 PET Study
Secondary IDs:

Study Status


Record Verification:	September 2019
Overall Status:	Completed
Study Start:	January 2013
Primary Completion:	May 5, 2017 [Actual]
Study Completion:	May 5, 2017 [Actual]

First Submitted:	November 13, 2012
First Submitted that Met QC Criteria:	November 13, 2012
First Posted:	November 20, 2012 [Estimate]

Results First Submitted:	September 24, 2019
Results First Submitted that Met QC Criteria:	September 24, 2019
Results First Posted:	October 15, 2019 [Actual]

Last Update Submitted that Met QC Criteria:	September 24, 2019
Last Update Posted:	October 15, 2019 [Actual]

Sponsor/Collaborators


Sponsor:	Lars Christian Gormsen
Responsible Party:	Sponsor-Investigator Investigator: Lars Christian Gormsen Official Title: Senior Registrar, MD PhD Affiliation: Aarhus University Hospital
Collaborators:

Oversight


U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring:	Yes

Study Description

Brief Summary:

Background: Metformin treatment has beneficial effects on both glucose and lipid metabolism. Whereas there is general agreement that the blood glucose lowering effect of metformin results from inhibition of hepatic gluconeogenesis, it is less clear exactly how the drug lowers blood triglyceride concentration. There are indications that it enhances hepatic free fatty acid (FFA) oxidation thus diminishing substrate for reesterification and resecretion as very-low-density-lipoprotein (VLDL) triglycerides (TG). However, the liver is not easily accessible for sampling in humans and data on the clinical effects of metformin in the liver are therefore lacking. This may change due to the increasing use of the positron emission tomography (PET) technique. Using PET isotopes (11C or 18F) coupled to either palmitate or a fatty acid analogue, it is possible to non-invasively measure hepatic fatty acid handling.

Aim: To determine how 3 months metformin treatment (1000 mg twice daily) affects hepatic lipid and glucose metabolism in patients with newly diagnosed type 2 diabetes.

Design: Randomized, placebo controlled, double-blind parallel study with patients receiving either metformin or placebo. A control group of BMI and age-matched non-diabetic individuals will receive metformin for 3 months.

Hypothesis: Metformin lowers VLDL-TG secretion and circulating triglycerides by increasing hepatic fatty acid oxidation

Detailed Description:

Conditions


Conditions:	Type 2 Diabetes Dyslipidemia
Keywords:	Type 2 diabetes Hepatic fatty acid oxidation Dyslipidemia Metformin

Study Design


Study Type:	Interventional
Primary Purpose:	Basic Science
Study Phase:	Phase 4
Interventional Study Model:	Parallel Assignment
Number of Arms:	3
Masking:	Double (Participant, Investigator)
Allocation:	Randomized
Enrollment:	36 [Actual]

Arms and Interventions

Arms	Assigned Interventions
Healthy controls Healthy controls receiving 1000 mg metformin twice daily for 3 months	Drug: Metformin 1000 mg metformin twice daily in 3 months Other Names: Metformin "Sandoz" 500 mg
Placebo Comparator: Placebo Placebo	Drug: Placebo 2 tablets twice daily in 3 months
Active Comparator: Metformin Metformin "Sandoz", 1000 mg twice daily for 3 months	Drug: Metformin 1000 mg metformin twice daily in 3 months Other Names: Metformin "Sandoz" 500 mg

Outcome Measures

[See Results Section.]


Primary Outcome Measures:
1.	Hepatic Fatty Acid Oxidation [ Time Frame: 90 days ] Hepatic fatty acid oxidation assessed by dynamic C11-palmitate PET
2.	Hepatic Fatty Acid Reesterification [ Time Frame: 90 days ] Hepatic fatty acid reesterification assessed by C11-palmitate PET
3.	Hepatic Fatty Acid Uptake [ Time Frame: 90 days ] Hepatic fatty acid uptake assessed by C11-palmitate PET
4.	VLDL-TG Secretion [ Time Frame: 90 days ] Hepatic VLDL-TG secretion assessed by [1-14C] VLDL tracer
5.	Whole Body Glucose Rd [ Time Frame: 90 days ] Whole body basal glucose metabolism assessed by [3-3H]glucose tracer kinetics
Secondary Outcome Measures:
1.	Fatty Acid Turnover [ Time Frame: 90 days ] Fatty acid turnover assessed as whole body C11-palmitate turnover
2.	VLDL-TG Oxidation [ Time Frame: 90 days ] VLDL-TG oxidation assessed by 14C carbon dioxide (CO2) in exhaled breath

Eligibility


Minimum Age:	50 Years
Maximum Age:	70 Years
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	Yes
Criteria:	Inclusion Criteria: Recently diagnosed type 2 diabetes Age 50-70 years BMI<40 Exclusion Criteria: Insulin treatment NASH (non alcoholic steatohepatitis) Cancer Anemia HbA1C>8.5 % Chronic or acute pancreatitis Alcohol or medicine abuse Allergy towards metformin Claustrophobia Severe obesity (weight >130 kilogram)

Contacts/Locations


Study Officials:	Lars C Gormsen, MD PhD Principal Investigator Aarhus University Hospital
Locations:

IPDSharing


Plan to Share IPD:

References


Links:
Available IPD/Information:

Document Section


	Study Protocol Document Date: February 4, 2013 Uploaded: 09/24/2019 09:06 File Name: Prot_000.pdf
	No Statistical Analysis Plan (SAP) exists for this study.

Participant Flow

Recruitment Details

Pre-assignment Details

Arm/Group Title	Healthy Controls	Placebo	Metformin
Arm/Group Description	Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months	Placebo Placebo: 2 tablets twice daily in 3 months	Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months

Period Title: Overall Study
Started	12	12	12
Completed	11	12	12
Not Completed	1	0	0
Reason Not Completed
Withdrawal by Subject	1	0	0

Baseline Characteristics


Arm/Group Title		Healthy Controls	Placebo	Metformin	Total
Arm/Group Description		Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months	Placebo Placebo: 2 tablets twice daily in 3 months	Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months	Total of all reporting groups
Overall Number of Baseline Participants		12	12	12	36
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: years	Number Analyzed	12 Participants	12 Participants	12 Participants	36 Participants
		62(6)	60(5)	64(5)	62(5)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	12 Participants	12 Participants	12 Participants	36 Participants
	Female	6 50%	3 25%	6 50%	15 41.67%
	Male	6 50%	9 75%	6 50%	21 58.33%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	12 Participants	12 Participants	12 Participants	36 Participants
	American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
	Asian	0 0%	0 0%	0 0%	0 0%
	Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
	Black or African American	0 0%	0 0%	0 0%	0 0%
	White	12 100%	12 100%	12 100%	36 100%
	More than one race	0 0%	0 0%	0 0%	0 0%
	Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
BMI Mean (Standard Deviation) Unit of measure: kg/m2	Number Analyzed	12 Participants	12 Participants	12 Participants	36 Participants
BMI Mean (Standard Deviation) Unit of measure: kg/m2		27.3(4.1)	31.2(4.3)	30.3(5.7)	29.6(4.7)
HbA1C Mean (Standard Deviation) Unit of measure: mmol/mmol	Number Analyzed	12 Participants	12 Participants	12 Participants	36 Participants
HbA1C Mean (Standard Deviation) Unit of measure: mmol/mmol		37(3)	45(6)	51(6)	44(5)

Outcome Measures

1. Primary Outcome:

Title

Hepatic Fatty Acid Oxidation

Description

Hepatic fatty acid oxidation assessed by dynamic C11-palmitate PET

Time Frame

90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Healthy Controls	Placebo	Metformin
Arm/Group Description	Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months	Placebo Placebo: 2 tablets twice daily in 3 months	Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months
Overall Number of Participants Analyzed	10	11	10
Mean (Standard Deviation) Unit of Measure: micromol/ml/min	0.052(0.024)	0.045(0.024)	0.042(0.017)

2. Primary Outcome:

Title

Hepatic Fatty Acid Reesterification

Description

Hepatic fatty acid reesterification assessed by C11-palmitate PET

Time Frame

90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Healthy Controls	Placebo	Metformin
Arm/Group Description	Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months	Placebo Placebo: 2 tablets twice daily in 3 months	Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months
Overall Number of Participants Analyzed	10	11	10
Mean (Standard Deviation) Unit of Measure: micromol/ml/min	0.134(0.056)	0.091(0.035)	0.113(0.025)

3. Primary Outcome:

Title

Hepatic Fatty Acid Uptake

Description

Hepatic fatty acid uptake assessed by C11-palmitate PET

Time Frame

90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Healthy Controls	Placebo	Metformin
Arm/Group Description	Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months	Placebo Placebo: 2 tablets twice daily in 3 months	Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months
Overall Number of Participants Analyzed	10	11	10
Mean (Standard Deviation) Unit of Measure: micromol/ml/min	0.186(0.067)	0.137(0.051)	0.155(0.029)

4. Primary Outcome:

Title

VLDL-TG Secretion

Description

Hepatic VLDL-TG secretion assessed by [1-14C] VLDL tracer

Time Frame

90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Healthy Controls	Placebo	Metformin
Arm/Group Description	Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months	Placebo Placebo: 2 tablets twice daily in 3 months	Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months
Overall Number of Participants Analyzed	11	11	11
Mean (Standard Deviation) Unit of Measure: micromol/min	48(30)	83(49)	71(31)

5. Primary Outcome:

Title

Whole Body Glucose Rd

Description

Whole body basal glucose metabolism assessed by [3-3H]glucose tracer kinetics

Time Frame

90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Healthy Controls	Placebo	Metformin
Arm/Group Description	Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months	Placebo Placebo: 2 tablets twice daily in 3 months	Metformin "Sandoz", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months
Overall Number of Participants Analyzed	11	12	11
Mean (Standard Deviation) Unit of Measure: mg/kg/min	1.74(0.29)	1.30(0.31)	1.78(0.43)

6. Secondary Outcome:

Title

Fatty Acid Turnover

Description

Fatty acid turnover assessed as whole body C11-palmitate turnover

Time Frame

90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Healthy Controls	Placebo	Metformin
Arm/Group Description	Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months	Placebo Placebo: 2 tablets twice daily in 3 months	Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months
Overall Number of Participants Analyzed	10	11	11
Mean (Standard Deviation) Unit of Measure: micromol/min	464(127)	476(149)	559(295)

7. Secondary Outcome:

Title

VLDL-TG Oxidation

Description

VLDL-TG oxidation assessed by 14C carbon dioxide (CO2) in exhaled breath

Time Frame

90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Healthy Controls	Placebo	Metformin
Arm/Group Description	Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months	Placebo Placebo: 2 tablets twice daily in 3 months	Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months
Overall Number of Participants Analyzed	11	12	11
Mean (Standard Deviation) Unit of Measure: percentage of 14C-VLDL	29(5)	30(7)	27(9)

Adverse Events


Time Frame	During the 90 days trial
Adverse Event Reporting Description	[Not specified]

Arm/Group Title	Healthy Controls		Placebo		Metformin
Arm/Group Description	Healthy controls receiving 1000 mg metformin twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months		Placebo Placebo: 2 tablets twice daily in 3 months		Metformin "Teva", 1000 mg twice daily for 3 months Metformin: 1000 mg metformin twice daily in 3 months
All-Cause Mortality
	Healthy Controls		Placebo		Metformin
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	0 / 12 (0%)		0 / 12 (0%)		0 / 12 (0%)
Serious Adverse Events
	Healthy Controls		Placebo		Metformin
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	0 / 12 (0%)		0 / 12 (0%)		0 / 12 (0%)

Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Healthy Controls		Placebo		Metformin
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	1 / 12 (8.33%)		1 / 12 (8.33%)		0 / 12 (0%)
Gastrointestinal disorders
Gastrointestinal uncomfort ^∗	1 / 12 (8.33%)	1	0 / 12 (0%)	0	0 / 12 (0%)	0
Musculoskeletal and connective tissue disorders
Fractured vertebral column ^∗	0 / 12 (0%)		1 / 12 (8.33%)	1	0 / 12 (0%)	0
∗Indicates events were collected by non-systematic methods.

Limitations and Caveats


[Not specified]

More Information


Certain Agreements:
Principal Investigators are NOT employed by the organization sponsoring the study. There is NOT an agreement between the Principal Investigator and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact:
Name/Official Title:	Lars C. Gormsen, Consultant
Organization:	Department of Nuclear Medicine & PET Centre, Aarhus University Hospital
Phone:	004578456260
Email:	lars.christian.gormsen@clin.au.dk