Genomic Outcomes of Metformin (GOMET)
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|ClinicalTrials.gov Identifier: NCT02986659|
Recruitment Status : Completed
First Posted : December 8, 2016
Last Update Posted : November 6, 2019
|Condition or disease||Intervention/treatment||Phase|
|Coronary Artery Disease Mild Cognitive Impairment Obesity, Abdominal Hypertension||Drug: Metformin Drug: Placebo||Phase 4|
The number of older adults is projected to increase dramatically by 2050. Aging-related diseases and conditions still seriously compromise the quality of life among most older adults. Several pharmaceutical agents, such as metformin, have been tested to extend lifespan and delay aging-related diseases and dysfunctions in mice. Metformin, a biguanide antidiabetic drug, reduces the risk for developing type-2 diabetes in persons at risk by over one-third with few adverse effects (e.g., gastrointestinal irritation). Metformin prevents type-2 diabetes primarily through decreasing hepatic glucose synthesis, as well as enhancing insulin sensitivity and increasing peripheral glucose uptake. The molecular mechanisms remain unclear, although a number of potential mechanism such as activation of AMP-activated protein kinase (AMPK) and inhibition of mitochondrial glycerophosphate dehydrogenase have been proposed. The fact that metformin treatment in persons with type-2 diabetes has been associated with reduced risk of other aging-related diseases and conditions, including cardiovascular disease, cancer and cognitive decline supports the possibility of the beneficial effects of metformin on healthy aging. It is imperative to capitalize on these leads to extend health span among older adults.
To translate animal findings to human intervention trials, appropriate aging biomarkers are needed. Methylomic and transcriptomic profiles in relevant cells may reflect molecular features that mediate effects of both genetic and environmental factors on aging-related functional decline and disease. The roles of monocytes have been implicated in development of many aging-related diseases such as cardiovascular disease, cancer and neurodegenerative disease. In a cross-sectional association study of 1,200 monocyte samples, we identified 1,794 age-associated methylation sites and 2,704 age-associated transcripts, which were over-represented in two networks (autophagy and oxidative phosphorylation) and suggestive of decline in those functions with age. Both autophagy and oxidative phosphorylation are considered as key contributors to the aging process, and their dysfunctions have been linked to aging-related diseases. Changes in these aging-related omic biomarkers may be early indicators of cellular damage or disruption that eventually leads to age-related dysfunctions. Assessment of these aging biomarkers in response to therapeutic intervention may also provide molecular insight for personalizing treatment. The investigators propose a pilot study to examine changes in aging-related omic profiles after 3 months of metformin treatment in 35 monocyte samples from older adults using a randomized, double-blind, placebo-controlled crossover study design.
Our overarching goal of the pilot study is to evaluate the utility of using the aging-related omic biomarkers as an indicator of pharmacologic responses in the anti-aging therapeutic intervention trials through the following specific aims. Although this pilot study does not have sufficient power to definitively test all the aims, it will provide essential preliminary data for developing a full scale research program.
- Aim 1A: To test the effects of the metformin treatment on transcriptomic profiles and related functional changes in human monocytes,
- Aim 1B: To explore the effects of the metformin treatment on methylomic profiles in human monocytes,
- Aim 2: To investigate the longitudinal relationship between transcriptional and functional changes in human monocytes during the metformin treatment and
- Aim 3: To test the effects of the metformin treatment on frailty and other aging-related physical and cognitive measures and investigate the longitudinal relationship between these changes and transcriptional changes.
A randomized, double-blind, placebo-controlled crossover trial in 30 participants using metformin and matching placebo will be used. In the absence of a treatment by sequence interaction effect, this design can increase study power for evaluating treatment effects by allowing each participant to be his/her own control. The period effect may be minimum because the primary outcomes, methylation and transcriptional measures, are relatively stable overtime.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||34 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Primary Purpose:||Health Services Research|
|Official Title:||Genomic Outcomes of Metformin|
|Actual Study Start Date :||August 3, 2016|
|Actual Primary Completion Date :||November 15, 2018|
|Actual Study Completion Date :||November 15, 2018|
Active Comparator: Metformin then Placebo
Metformin dosing at 425, 850 and 1700 mg with GLUCOPHAGE® (metformin hydrochloride) Tablets. Treatment with metformin will be initiated at a dose of 425 mg (half pill) taken orally once a day at night for 7 days. After the week, the participant will be called to assess tolerance and will be asked to increase dose to one pill at night at a dose of 850 mg for one week. At the end of the second week, participants will be called again and if they tolerated the second dose, they will be asked to take two 850 mg pills, one in the morning and one at night, for a total dose of 1700 mg which is within the range of the usual effective dose of 1500 to 2000 mg/day for the remainder of the 3 months. Will then cross over to 3 months on placebo.
Placebo Comparator: Placebo then Metormin
Dietary Supplement: Placebo with Methylcellulose capsules. Treatment with placebo will be initiated at a dose of a half pill taken orally once a day at night for 7 days. After the week, the participant will be called to assess tolerance and will be asked to increase dose to one pill at night for one week. At the end of the second week, participants will be called again and if they tolerated the second dose, they will be asked to take two pills, one in the morning and one at night for the remainder of the 3 months. After 3 months on placebo, participants will then cross over to 3 months of metformin as described in the other arm.
- Change in eigengene scores [ Time Frame: baseline, 12 weeks, 24 weeks ]Individual methylation sites and transcripts, especially the eigengenes of autophage, oxidative phosphorylation and protein synthesis networks Methylomic and transcriptomic profiles in monocytes will be quantified using the Illumina HumanMethylation450 BeadChip and the Illumina HumanHT-12 v4 Expression BeadChips, respectively. All of these measures will be aggregated into one eigengene score.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02986659
|United States, North Carolina|
|Wake Forest Health Sciences|
|Winston-Salem, North Carolina, United States, 27157|
|Principal Investigator:||Jingzhong Ding, PhD||Wake Forest University Health Sciences|