AMTIDD: Adjunctive Metformin Therapy in Double Diabetes

• Sponsor: University of Massachusetts, Worcester (Other)
• Overall Status: Completed
• CT.gov ID: NCT01334125
• Collaborator: (none)
• Enrollment: 28
• Location: 1
• Arms: 2
• Duration (Months): 46
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The significance of this project is to investigate the effects of adjunctive metformin therapy in children and adolescents with double diabetes. Double diabetes describes a clinical state where an individual possesses features of both type 1 and type 2 diabetes. There is a paucity of data on the role of adjunctive metformin therapy in children and adolescents with double diabetes. To help fill this knowledge gap, the investigators propose a randomized, double-blind, placebo-controlled trial of metformin in double diabetes. Specifically, the investigators will evaluate changes in hemoglobin A1c and anthropometry in patients with a diagnosis of type 1 diabetes who also have features of type 2 diabetes or metabolic syndrome as well as patients with type 2 diabetes who possess diabetes-associated autoantibodies. This will help determine the safety profile, and efficacy of adjunctive metformin therapy in these subjects.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: Metformin; Drug: Placebo	Phase 3

Detailed Description

In this 12-month clinical trial, a 3-month run-in period will precede the interventional phase of the study. All patients will be placed on treat-to-target insulin regimen alone during the run-in phase. At the end of the 3-month run-in period, all participants will continue on treat-to-target insulin regimen, and will then be randomized to either of the 2 arms of the study: an experimental arm, consisting of treat-to-target insulin regimen plus metformin, and a control arm consisting of treat-to-target insulin regimen plus placebo. Both the physicians and patients will be blinded to the oral agents being administered to patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Glycemic Control in Children and Adolescents With Double Diabetes: Trial of Optimized Insulin-Metformin Regimen
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin Metformin 1000 mg once daily by mouth for 9 months	Drug: Metformin; Metformin 1000 mg once daily by mouth for 9 months; Other Names: Glucophage
Placebo Comparator: Placebo 2 capsules once daily by mouth for 9 months	Drug: Placebo; 2 capsules once daily by mouth for 9 months

Outcome Measures

Primary Outcome Measures

1. Baseline Adjusted Hemoglobin A1c Over Time [Baseline, 3mo, 6mo, and 9 months]

   Comparison of the baseline-adjusted differences in HbA1c between the metformin and placebo groups during the trial. Hemoglobin A1c is a marker of glycemic control. The reported values represented means adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model).

Secondary Outcome Measures

1. Baseline Adjusted Changes in Lipid Profile Over Time [Baseline, 3mo, 6mo, and 9 months]

   Comparison of the baseline-adjusted differences in total cholesterol/high density cholesterol index over time between the metformin and the placebo groups. The reported values represented means adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model).

2. Baseline Adjusted Changes in Adiponectin/Leptin Ratio Over Time [Baseline, 3mo, 6 mo, and 9 months]

   Comparison of the baseline-adjusted differences in adiponectin/leptin ratio over time between the metformin and the placebo groups. The reported values represented mean adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model).

3. Number of Participants With Minor, Major, and Nocturnal Hypoglycemia [12 months]

   Comparison of the occurrence of hypoglycemic event requiring a third party assistance (major hypoglycemia) per subject during the study, and minor hypoglycemia (plasma glucose of <60 mg/dL or no measurement), as well as nocturnal hypoglycemia (plasma glucose of ≤60 mg/dL between 11PM and 6AM).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 20 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. General inclusion criteria

1. Ten to 20 years of age.

2. Pubertal (Tanner stages 2-5, by examination).

3. Hemoglobin A1c level of > 8.0% in the 6 months prior to enrollment.

4. All subjects must have access to a computer.

1. Specific inclusion criteria: [Subjects could have either #1, or #2].

1. Subjects with clinical and biochemical features of T2DM of > 6mo duration who also have positive T1DM antibodies

• Clinical features: acanthosis nigricans, BMI >85%

• Biochemical: evidence of insulin resistance at diagnosis

• fasting insulin >27 uIU/mL(normal range 6-27) at a fasting blood glucose of ≥ 126 mg/dL, or

• fasting c-peptide level of > 7.1 ng/mL (normal range 0.9 - 7.1), or

• Homeostasis model of insulin resistance of >3.16

1. Patients with T1DM of > one yr duration with BMI >85%

• Presentation with ketoacidosis at diagnosis

• C-peptide <0.9 ng/mL (normal range 0.9 - 7.1),or (insulin < 6 uIU/mL) (NR 6-27) at diagnosis (when blood glucose is ≥ 126 mg/dL)

• Can be antibody positive or negative

• Increased insulin requirement (>2 Units/kg/day)

Exclusion Criteria:

1. Subjects on weight altering medications, such as orlistat.

2. Subjects with eating disorder

3. Subjects on medications other than insulin and or metformin that may affect blood glucose level.

4. Subjects with abnormal hepatic function tests.

5. Subjects with nephropathy, defined in this case as an overnight albumin excretion rate of >200 mcg/min using a first morning urine sample collection.

6. Subjects with recurrent diabetes ketoacidosis (more than 2 episodes in the past 12 months), or recurrent severe hypoglycemia (more than 2 episodes of hypoglycemia with altered level of consciousness, requiring assistance to treat in the past year).

7. Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate contraceptive measures.

8. Known or suspected allergy to metformin.

9. The receipt of any investigational drug within 6 months prior to this trial.

10. Active malignant neoplasms.

11. No access to a computer.

12. Subjects currently taking metformin for clinical purposes are not eligible to be enrolled in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UmassMemorial Medical Center	Worcester	Massachusetts	United States	01655

Sponsors and Collaborators

• University of Massachusetts, Worcester

Investigators

• Principal Investigator: Benjamin U Nwosu, MD, University of Massachusetts, Worcester

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Benjamin U. Nwosu, Study Principle Investigator, University of Massachusetts, Worcester
• ClinicalTrials.gov Identifier: NCT01334125
• Other Study ID Numbers: 13938
• First Posted: Apr 12, 2011
• Last Update Posted: Mar 4, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Benjamin U. Nwosu, Study Principle Investigator, University of Massachusetts, Worcester: Double Diabetes; Type 1 diabetes; Type 2 diabetes; Obesity; Acanthosis nigricans; Diabetes associated autoantibodies
• Additional relevant MeSH terms: Diabetes Mellitus; Metformin

Study Results

Participant Flow

Recruitment Details	This study was conducted at a tertiary institution. The first patient was recruited on March 3rd 2011, and the last study patient was recruited on August 1, 2013. The study was closed on August 8, 2013.
Pre-assignment Detail	Following enrollment, all subjects entered a run-in phase of 3-month duration during which participants were placed on insulin aspart and insulin detemir, and the treat-to-target insulin regimen (TTIR) started.

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 1000 mg once daily by mouth for 9 months Metformin: Metformin 1000 mg once daily by mouth for 9 months	1 capsule once daily by mouth for 9 months Placebo: 1 capsule once daily by mouth for 9 months
Period Title: Overall Study
STARTED	15	13
COMPLETED	12	10
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	Metformin	Placebo	Total
Arm/Group Description	Metformin 1000 mg once daily by mouth for 9 months Metformin: Metformin 1000 mg once daily by mouth for 9 months	1 capsule once daily by mouth for 9 months Placebo: 1 capsules once daily by mouth for 9 months	Total of all reporting groups
Overall Participants	15	13	28
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15 (2.5)	14.5 (3.1)	14.7 (2.7)
Sex: Female, Male (Count of Participants)
Female	7 46.7%	8 61.5%	15 53.6%
Male	8 53.3%	5 38.5%	13 46.4%
Region of Enrollment (participants) [Number]
United States	15 100%	13 100%	28 100%

Outcome Measures

1. Primary Outcome

Title	Baseline Adjusted Hemoglobin A1c Over Time
Description	Comparison of the baseline-adjusted differences in HbA1c between the metformin and placebo groups during the trial. Hemoglobin A1c is a marker of glycemic control. The reported values represented means adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model).
Time Frame	Baseline, 3mo, 6mo, and 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 1000 mg once daily by mouth for 9 months Metformin: Metformin 1000 mg once daily by mouth for 9 months	1 capsule once daily by mouth for 9 months Placebo: 1 capsules once daily by mouth for 9 months
Measure Participants	15	13
Mean (95% Confidence Interval) [percentage of HbA1c]	9.46	9.85

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin, Placebo
	Comments	Analyses were based on the intent-to-treat principle and were performed using SPSS v.22 (IBM Corporation, Armonk, NY).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.903
	Comments	Individual two-way mixed ANOVA models were fitted for each of our outcomes of interest, with treatment type (metformin or placebo) as the fixed effect, and baseline values, age, gender, and BMI as covariates.
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Baseline Adjusted Changes in Lipid Profile Over Time
Description	Comparison of the baseline-adjusted differences in total cholesterol/high density cholesterol index over time between the metformin and the placebo groups. The reported values represented means adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model).
Time Frame	Baseline, 3mo, 6mo, and 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 1000 mg once daily by mouth for 9 months Metformin: Metformin 1000 mg once daily by mouth for 9 months	1 capsule once daily by mouth for 9 months Placebo: 1 capsule once daily by mouth for 9 months
Measure Participants	15	13
Mean (95% Confidence Interval) [ratio]	3.5	4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin, Placebo
	Comments	Analyses were based on the intent-to-treat principle and were performed using SPSS v.22 (IBM Corporation, Armonk, NY).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.578
	Comments	Individual two-way mixed ANOVA models were fitted for each of our outcomes of interest, with treatment type (metformin or placebo) as the fixed effect, and baseline values, age, gender, and BMI as covariates.
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Baseline Adjusted Changes in Adiponectin/Leptin Ratio Over Time
Description	Comparison of the baseline-adjusted differences in adiponectin/leptin ratio over time between the metformin and the placebo groups. The reported values represented mean adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model).
Time Frame	Baseline, 3mo, 6 mo, and 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 1000 mg once daily by mouth for 9 months Metformin: Metformin 1000 mg once daily by mouth for 9 months	1 capsule once daily by mouth for 9 months Placebo: 1 capsule once daily by mouth for 9 months
Measure Participants	15	13
Mean (95% Confidence Interval) [ratio]	2.0	1.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin, Placebo
	Comments	Two way ANOVA comparison of the means of the adiponectin/leptin ratios between the metformin and placebo groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.057
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Number of Participants With Minor, Major, and Nocturnal Hypoglycemia
Description	Comparison of the occurrence of hypoglycemic event requiring a third party assistance (major hypoglycemia) per subject during the study, and minor hypoglycemia (plasma glucose of <60 mg/dL or no measurement), as well as nocturnal hypoglycemia (plasma glucose of ≤60 mg/dL between 11PM and 6AM).
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 1000 mg once daily by mouth for 9 months Metformin: Metformin 1000 mg once daily by mouth for 9 months	1 capsule once daily by mouth for 9 months Placebo: 1 capsule once daily by mouth for 9 months
Measure Participants	15	13
Major hypoglycemia	1 6.7%	0 0%
Minor hypoglycemia	3 20%	2 15.4%
Nocturnal hypoglycemia	2 13.3%	2 15.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin, Placebo
	Comments	p value represents the analysis for minor hypoglycemia
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Metformin, Placebo
	Comments	p value represents the analysis of the nocturnal hypoglycemia
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	12 months
Arm/Group Title	Metformin		Placebo
Arm/Group Description	Metformin 1000 mg once daily by mouth for 9 months Metformin: Metformin 1000 mg once daily by mouth for 9 months		1 capsule once daily by mouth for 9 months Placebo: 1 capsule once daily by mouth for 9 months
All Cause Mortality
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/15 (26.7%)		1/13 (7.7%)
Endocrine disorders
Diabetic ketoacidosis	2/15 (13.3%)	2	0/13 (0%)	0
Severe hypoglycemia	1/15 (6.7%)	1	0/13 (0%)	0
Gastrointestinal disorders
Appendicitis	1/15 (6.7%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/15 (0%)	0	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		3/13 (23.1%)
Ear and labyrinth disorders
Otitis media	0/15 (0%)	0	1/13 (7.7%)	1
Eye disorders
Eye infection	1/15 (6.7%)	1	0/13 (0%)	0
Immune system disorders
Hidradenitis	0/15 (0%)	0	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	0/15 (0%)	0	1/13 (7.7%)	1

Limitations/Caveats

The trial was stopped before reaching enrollment target because most youth were reluctant to commit to this long-term study.

More Information

Certain Agreements

Principal Investigators are NOT 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.