Type 1 DiabetesPhase 3EMERALDNCT01808690

EMERALD: Effects of Metformin on Cardiovascular Function in Adolescents With Type 1 Diabetes

A Phase 3 study testing Metformin in people with Type 1 Diabetes, run by University of Colorado, Denver at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 12 to 21 years
Conditions the study is for: Type 1 Diabetes
What is being tested?: Metformin
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 52 participants
Where: 1 siteUnited States
Study dates: Mar 2013to 2 Dec 2016
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 12 to 21 years
All sexes
No healthy volunteers
Child, Adult

Who may be able to join

Adolescents 12-21 years of age with type 1 diabetes (defined as having positive antibodies as well as insulin requirement)
Willing to consent for participation in study
Body Mass Index (BMI) >5% on growth charts

Who cannot join

Current use of medications known to affect insulin sensitivity: oral glucocorticoids within 10 days, atypical antipsychotics, immunosuppressant agents, metformin or thiazolidinediones.
Currently pregnant or breastfeeding women
Use of a thiazolidinedione within 12 weeks
Severe illness or Diabetic Ketoacidosis within 60 days
Macroalbuminuria
Hemoglobin A1c > 12%

Show all 12Show fewer

Weight > 136.4 kg or < 42 kg, BMI < 5%
Creatinine > 1.2
Hemoglobin < 9
Major psychiatric or developmental disorder limiting informed consent
Implanted metal devices
Inability to tolerate ≥500mg twice a day of metformin

Trial locations and contacts

1 site in 1 country.

United States1 site

Children's Hospital Colorado and University of Colorado Denver Health Sciences Center
Aurora, Colorado, 80045

Other trials in United States

About this study

Official title: Effects of Metformin on Cardiovascular Function in Adolescents With Type 1 Diabetes

Diabetes is increasingly common among youth, forecasting early complications. Type 1 (T1D) cause early heart disease, shortening lifespan despite modern improvements in control of blood sugars and other risk factors for heart disease. Poor insulin action, otherwise known as insulin resistance (IR), is the main factor causing heart disease in type 2 diabetes (T2D), but the cause of increased heart disease in T1D is unclear. IR may contribute to heart disease in T1D as in T2D, as the investigators and others have found the presence of IR in T1D. Much less is known about IR in T1D, but a better understanding of its role in T1D is critical to understanding causes of heart disease in T1D. The investigators long-term goal is to understand the early causes of heart disease in diabetes so that we can prevent it. The investigators unique initial findings suggest that even reasonably well-controlled, normal weight, T1D youth are IR. The IR appears directly related to the heart, blood vessel, and exercise defects, but in a pattern that appears very different from T2D. The goals of this study are to determine the unique heart, blood vessel and insulin sensitivity abnormalities in T1D youth, and determine whether metformin improves these abnormalities. A clear understanding of these factors will help determine the causes, and what treatments could help each abnormality.

Hypothesis 1: Metformin will improve insulin function and mitochondrial function in T1D.

Hypothesis 2: Metformin will improve vascular and cardiac function in T1D.

All measures will be performed twice, before and after a 3-month randomized, placebo-controlled design where subjects are randomized to either metformin or placebo. The independent impact of insulin action as well as glucose levels, BMI, T1D duration, and gender on baseline outcomes and the impact of changes in insulin action, glucose levels and BMI on response to metformin will also be examined to help customize future strategies to prevent heart disease in T1D. This study will advance the field by providing new information about the role of poor insulin action in the heart disease of T1D, and whether improving insulin action in T1D is helpful. If a focus on directly improving insulin action in T1D youth is supported by our studies, the clinical approach to T1D management may significantly change.

Conditions: Type 1 Diabetes
Being tested: Metformin, Placebo
Keywords: Adolescent, Youth, Diabetes, Insulin Resistance, Cardiovascular, Metformin
Medical subject headings: Diabetes Mellitus, Type 1, Diabetes Mellitus, Insulin Resistance

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

MetforminDrug
PlaceboDrug

Study groups in NCT01808690
Study group	Role	What they receive
Metformin	Experimental	Metformin will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to placebo. Receives: Drug: Metformin
Placebo	Placebo comparator	Placebo will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to metformin. Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

Change in Insulin Sensitivity
Hypothesis 1: Metformin will improve insulin function in Type 1 Diabetes. Insulin function will be measured using a euglycemic-hyperinsulinemic clamp procedure at both baseline and after 3 months of treatment. A clamp measures insulin sensitivity. A higher number indicates a better outcome; a lower number indicates a worse outcome.
Measured: Baseline, Month 3

Secondary outcomes (5)

Change in ADP Time Constant
Hypothesis 1b: Metformin will improve mitochondrial function in Type 1 Diabetes. 31Phosphorus magnetic resonance spectroscopy (MRS) was used before, during, and after 90 seconds of near-maximal isometric exercise of the calf muscle for post-exercise muscle mitochondrial function. ADP time constant is the time for conversion of ADP → ATP and is a measure of muscle mitochondrial health (energy metabolism).
A faster recovery is a better outcome; a slower recovery is a worse outcome.
Measured: Baseline, Month 3
Change in Pulse Wave Velocity (PWV)
Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via pulse wave velocity (PWV) by MRI. PWV is a measure of central arterial stiffness.
A lower value indicates a better outcome.
Measured: Baseline, Month 3
Change in Central Arterial Intimal Medial Thickness (cIMT)
Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via central arterial intimal medial (cIMT) thickness by carotid ultrasound. cIMT is a measure used to diagnose the extent of carotid atherosclerotic vascular disease. The test measures the thickness of the inner two layers of the carotid artery-the intima and media.
A lower result is a better outcome.
Measured: Baseline, Month 3
Change in Mitral Valve E/A Ratio by Echocardiogram
Hypothesis 2b: Metformin will improve cardiac function in Type 1 Diabetes by echocardiogram.
Mitral Valve E/A ratio is the ratio of early (E) to late (A) ventricular filling velocities.
Ideal myocardial tissue relaxation is indicated by a ratio of >0.8 and <2.0.
Measured: Baseline, Month 3
Change in Aortic Wall Sheer Stress (WSS)
Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via Aortic Wall Sheer Stress (WSS) by MRI. WSS is a measure of central arterial stiffness.
A lower value indicates a better outcome.
Measured: Baseline, Month 3

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Mar 20132 Dec 2016

First posted11 Mar 2013 (estimated)
Study startMar 2013
Primary completion2 Dec 2016
Study completion2 Dec 2016

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Type 1 DiabetesStudies of the same condition, open and under way.
More trials run by University of Colorado, DenverThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 52 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01808690
Sponsor's protocol ID: 12-1528
Other IDs: R56DK078645
Acronym: EMERALD
Status last verified: Sep 2021
First submitted: 6 Mar 2013
Last updated: 30 Sep 2021
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
Individual data sharing: No

Publications

Tommerdahl KL, Baumgartner K, Schafer M, Bjornstad P, Melena I, Hegemann S, Baumgartner AD, Pyle L, Cree-Green M, Truong U, Browne L, Regensteiner JG, Reusch JEB, Nadeau KJ. Impact of Obesity on Measures of Cardiovascular and Kidney Health in Youth With Type 1 Diabetes as Compared With Youth With Type 2 Diabetes. Diabetes Care. 2021 Mar;44(3):795-803. doi: 10.2337/dc20-1879. Epub 2021 Jan 5.
PubMed 33402367
Bjornstad P, Schafer M, Truong U, Cree-Green M, Pyle L, Baumgartner A, Garcia Reyes Y, Maniatis A, Nayak S, Wadwa RP, Browne LP, Reusch JEB, Nadeau KJ. Metformin Improves Insulin Sensitivity and Vascular Health in Youth With Type 1 Diabetes Mellitus. Circulation. 2018 Dec 18;138(25):2895-2907. doi: 10.1161/CIRCULATIONAHA.118.035525.
PubMed 30566007

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 30 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Effects of Metformin on Cardiovascular Function in Adolescents With Type 1 Diabetes
ClinicalTrials.gov ID: NCT01808690
Acronym / sponsor ID: EMERALD / 12-1528
Conditions: Type 1 Diabetes
Keywords: Adolescent, Youth, Diabetes, Insulin Resistance, Cardiovascular, Metformin
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 52 participants (actual)
Lead sponsor: University of Colorado, DenverUniversity, hospital or other
Collaborators: American Diabetes Association, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study start: Mar 2013
Primary completion: 2 Dec 2016 (actual)
Study completion: 2 Dec 2016 (actual)
First posted: 11 Mar 2013 (estimated)
Results: Posted 5 Feb 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Hypothesis 1: Metformin will improve insulin function and mitochondrial function in T1D.

Hypothesis 2: Metformin will improve vascular and cardiac function in T1D.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Metformin	Experimental	Drug: MetforminMetformin will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to placebo.
Placebo	Placebo comparator	Drug: PlaceboPlacebo will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to metformin.

Who may qualify

Ages: 12 to 21 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult

Key inclusion criteria (3 listed)

Adolescents 12-21 years of age with type 1 diabetes (defined as having positive antibodies as well as insulin requirement)
Willing to consent for participation in study
Body Mass Index (BMI) >5% on growth charts

Key exclusion criteria (12 listed)

Current use of medications known to affect insulin sensitivity: oral glucocorticoids within 10 days, atypical antipsychotics, immunosuppressant agents, metformin or thiazolidinediones.
Currently pregnant or breastfeeding women
Use of a thiazolidinedione within 12 weeks
Severe illness or Diabetic Ketoacidosis within 60 days
Macroalbuminuria

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Metformin	Drug	Metformin
Placebo	Drug	Placebo

Primary outcome

Change in Insulin Sensitivity
Time frame: Baseline, Month 3
Hypothesis 1: Metformin will improve insulin function in Type 1 Diabetes. Insulin function will be measured using a euglycemic-hyperinsulinemic clamp procedure at both baseline and after 3 months of treatment. A clamp measures insulin sensitivity. A higher number indicates a better outcome; a lower number indicates a worse outcome.

5 secondary outcomes

Change in ADP Time Constant
Time frame: Baseline, Month 3
Change in Pulse Wave Velocity (PWV)
Time frame: Baseline, Month 3
Change in Central Arterial Intimal Medial Thickness (cIMT)
Time frame: Baseline, Month 3
Change in Mitral Valve E/A Ratio by Echocardiogram
Time frame: Baseline, Month 3
Change in Aortic Wall Sheer Stress (WSS)
Time frame: Baseline, Month 3

Results and safety

Results posted to the registry on 5 Feb 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Metformin	25	24
Placebo	23	21

Primary outcome: Change in Insulin Sensitivity

Time frame: Baseline, Month 3. Mean (Standard Deviation). Unit: (mg/kg/min)/(insulin)

Measure	Metformin n = 23	Placebo n = 19
Value	12.2 (3.2)	-2.4 (3.6)

Metformin vs Placebo: p = 0.005, Regression, Linear

Population analysed: Metformin group: 1 participant lost to follow-up, 1 IV access problem Placebo group: 2 lost to follow-up, 2 IV access problems

5 secondary outcomes are reported in the full results.

Adverse events

Time frame: 3 months. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Metformin	0 of 25 (0%)	10 of 25 (40%)	0 of 25
Placebo	0 of 23 (0%)	2 of 23 (8.7%)	0 of 23

Limitations and caveats (from the sponsor): Results may not apply to prepubertal youth. Treatment duration limited to 3 months. MRI unavailable during scanner replacement. Lacked measure to monitor BGs during vascular assessments. Not all females studied in traditional follicular phase.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 30 Sep 2021.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 33402367Tommerdahl KL, Baumgartner K, Schafer M, Bjornstad P, Melena I, Hegemann S, Baumgartner AD, Pyle L, Cree-Green M, Truong U, Browne L, Regensteiner JG, Reusch JEB, Nadeau KJ. Impact of Obesity on Measures of Cardiovascular and Kidney Health in Youth With Type 1 Diabetes as Compared With Youth With Type 2 Diabetes. Diabetes Care. 2021 Mar;44(3):795-803. doi: 10.2337/dc20-1879. Epub 2021 Jan 5.
Derived from this study: PubMed 30566007Bjornstad P, Schafer M, Truong U, Cree-Green M, Pyle L, Baumgartner A, Garcia Reyes Y, Maniatis A, Nayak S, Wadwa RP, Browne LP, Reusch JEB, Nadeau KJ. Metformin Improves Insulin Sensitivity and Vascular Health in Youth With Type 1 Diabetes Mellitus. Circulation. 2018 Dec 18;138(25):2895-2907. doi: 10.1161/CIRCULATIONAHA.118.035525.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Kristen Nadeau, MD, MS principal investigator

University of Colorado/Children's Hospital Colorado

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Metformin in people with Type 1 Diabetes, run by University of Colorado, Denver at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 5 Feb 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Insulin Sensitivity (time frame: Baseline, Month 3). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01808690, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Sep 2021.