| ID | Type | Description | Link |
|---|---|---|---|
| 1R01HL130296-01A1 | U.S. NIH Grant/Contract | View source |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
Not provided
Not provided
Not provided
Health organizations recommend exercise in an intensity based manner to promote cardiovascular adaptation and prevent disease. Metformin is a common anti-diabetes medication that reduces future type 2 diabetes and cardiovascular disease (CVD) risk. However, the optimal dose of exercise to be combined with metformin for vascular health remains unknown. The purpose of this study is to evaluate whether combining high or low intensity exercise with metformin has the potential to outperform either exercise intensity alone on blood flow across the arterial tree as well as impact insulin action in individuals with metabolic syndrome. Identification of such outcomes will indicate 1) whether and how metformin should be combined with physical activity for CVD prevention, 2) provide the first indication of whether exercise intensity reduces CVD risk via multi-level vasculature function vs. metabolic insulin action, and 3) provide a rational early treatment for people with metabolic syndrome to prevent/treat type 2 diabetes and CVD.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| LoEx with Placebo | Placebo Comparator | Low intensity exercise with placebo. |
|
| HiEx with Placebo | Placebo Comparator | High intensity exercise with placebo. |
|
| LoEx with Metformin | Active Comparator | Low intensity exercise with metformin. |
|
| HiEx with Metformin | Active Comparator | High intensity exercise with metformin. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug | Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Fasting Unscaled Flow Mediated Dilation (FMD) of the Brachial Artery | Endothelial function assessed as a percentage change in brachial artery diameter from baseline to deflation (5 minutes after artery occlusion by blood pressure cuff inflation). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. | 0 and 16 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Metabolic Insulin Sensitivity. Glucose Infusion Rate Normalized to Steady-State Insulin (GIR). | The glucose infusion rate (mg/kg/min) divided by steady-state insulin (uU/mL) during a 120 minute euglycemic-hyperinsulinemic clamp provides an index of metabolic insulin sensitivity. Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. |
Not provided
Inclusion Criteria:
At minimum, subject will have abdominal obesity (increased waist circumference as defined below) and may have any additional National Cholesterol Education Adult Treatment Panel III Metabolic Syndrome criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Steven K Malin, PhD | Rutgers University - New Brunswick | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Rutgers University Loree Gymnasium | New Brunswick | New Jersey | 08901 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12677025 | Background | Laurent S, Katsahian S, Fassot C, Tropeano AI, Gautier I, Laloux B, Boutouyrie P. Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke. 2003 May;34(5):1203-6. doi: 10.1161/01.STR.0000065428.03209.64. Epub 2003 Apr 3. | |
| 18340209 | Background | Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Fernando Costa. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: Executive Summary. Crit Pathw Cardiol. 2005 Dec;4(4):198-203. doi: 10.1097/00132577-200512000-00018. No abstract available. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | LoEx With Placebo | Low intensity exercise with placebo. Placebo: Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets. Low Intensity Exercise: Low intensity exercise will consist of 16 weeks of walking at ~55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
| FG001 | HiEx With Placebo | High intensity exercise with placebo. Placebo: Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets. High Intensity Exercise: High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
| FG002 | LoEx With Metformin | Low intensity exercise with metformin. Metformin: Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d. Low Intensity Exercise: Low intensity exercise will consist of 16 weeks of walking at ~55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
| FG003 | HiEx With Metformin | High intensity exercise with metformin. Metformin: Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d. High Intensity Exercise: High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | LoEx With Placebo | Low intensity exercise with placebo. Placebo: Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets. Low Intensity Exercise: Low intensity exercise will consist of 16 weeks of walking at ~55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Fasting Unscaled Flow Mediated Dilation (FMD) of the Brachial Artery | Endothelial function assessed as a percentage change in brachial artery diameter from baseline to deflation (5 minutes after artery occlusion by blood pressure cuff inflation). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. | Analysis includes only individuals that had both pre and post data. | Posted | Mean | 95% Confidence Interval | Percent change in diameters | 0 and 16 weeks |
|
Adverse events were collected after the first dose of double-blind study medication and within 14 days after the last dose of double-blind study medication, an average of 18 weeks.
Any event reported by the participant or observed by the study staff was was documented and reported to the Institutional Review Board, irrespective of the relation to the research study. Adverse events were collected in a non-systematic method by which participants reported events or in response to to open-ended questions, which occurred once every week for 16 weeks.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | LoEx With Placebo | Low intensity exercise with placebo. Placebo: Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets. Low Intensity Exercise: Low intensity exercise will consist of 16 weeks of walking at ~55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal Distress | Gastrointestinal disorders | Non-systematic Assessment |
Due to unforeseen technical issues with the vascular imaging files, we were regrettably unable to analyze the endothelial function data (FMD) for a majority of participants who had been randomized to HiEx with Metformin group, as well as others in the remaining 3 treatment groups.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Steven Malin | Rutgers University | 848-932-705 | steven.malin@rutgers.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 11, 2022 | Aug 5, 2025 | Prot_SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 6, 2023 | Aug 5, 2025 | ICF_003.pdf |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D024821 | Metabolic Syndrome |
| ID | Term |
|---|---|
| D007333 | Insulin Resistance |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D008687 | Metformin |
| D000072696 | High-Intensity Interval Training |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D064797 |
Not provided
Not provided
Each subject will be randomly assigned to receive low intensity exercise training + placebo, high intensity exercise training + placebo, or these exercise programs with metformin.
Not provided
Not provided
Not provided
| Placebo | Drug | Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets. |
|
| Low Intensity Exercise | Behavioral | Low intensity exercise will consist of 16 weeks of walking at ~55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
|
|
| High Intensity Exercise | Behavioral | High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
|
|
| 0 and 16 weeks |
| Change in Fasting Augmentation Index | Measure of Arterial Stiffness calculated by dividing the augmentation pressure by the pulse pressure, then multiplying by 100 and normalizing to a heart rate of 75 bpm (AIx75). Delta = Week 16 - Week 0. Lower values and negative change scores following the intervention indicate a better outcome. | 0 and 16 weeks |
| Change in Insulin-stimulated Microvascular Blood Flow (MBF) of the Forearm. | Product of microvascular blood volume (VI; video intensity units) and microvascular flow velocity (sec^-1). Insulin-stimulated microvascular blood flow is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. | 0 and 16 weeks |
| Change in Insulin-stimulated Microvascular Flow Velocity (MFV) of the Forearm. | Replenishment curves of the forearm flexor muscle acquired during steady-state infusion of Definity microbubbles. Insulin-stimulated microvascular flow velocity is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. | 0 and 16 weeks |
| Change in Insulin-stimulated Microvascular Blood Volume (MBV) of the Forearm. | Replenishment curves of the forearm flexor muscle acquired during steady-state infusion of Definity microbubbles. Insulin-stimulated microvascular blood volume is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. | 0 and 16 weeks |
| 21802577 | Background | DeFronzo RA, Abdul-Ghani M. Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am J Cardiol. 2011 Aug 2;108(3 Suppl):3B-24B. doi: 10.1016/j.amjcard.2011.03.013. |
| 21741606 | Background | Bateman LA, Slentz CA, Willis LH, Shields AT, Piner LW, Bales CW, Houmard JA, Kraus WE. Comparison of aerobic versus resistance exercise training effects on metabolic syndrome (from the Studies of a Targeted Risk Reduction Intervention Through Defined Exercise - STRRIDE-AT/RT). Am J Cardiol. 2011 Sep 15;108(6):838-44. doi: 10.1016/j.amjcard.2011.04.037. Epub 2011 Jul 7. |
| 23505172 | Background | Malin SK, Nightingale J, Choi SE, Chipkin SR, Braun B. Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose tolerant adults. Obesity (Silver Spring). 2013 Jan;21(1):93-100. doi: 10.1002/oby.20235. |
| 23036993 | Background | Malin SK, Niemi N, Solomon TP, Haus JM, Kelly KR, Filion J, Rocco M, Kashyap SR, Barkoukis H, Kirwan JP. Exercise training with weight loss and either a high- or low-glycemic index diet reduces metabolic syndrome severity in older adults. Ann Nutr Metab. 2012;61(2):135-41. doi: 10.1159/000342084. |
| 21947428 | Background | Potteiger JA, Claytor RP, Hulver MW, Hughes MR, Carper MJ, Richmond S, Thyfault JP. Resistance exercise and aerobic exercise when paired with dietary energy restriction both reduce the clinical components of metabolic syndrome in previously physically inactive males. Eur J Appl Physiol. 2012 Jun;112(6):2035-44. doi: 10.1007/s00421-011-2174-y. Epub 2011 Sep 23. |
| 20057377 | Background | Mestek ML, Westby CM, Van Guilder GP, Greiner JJ, Stauffer BL, DeSouza CA. Regular aerobic exercise, without weight loss, improves endothelium-dependent vasodilation in overweight and obese adults. Obesity (Silver Spring). 2010 Aug;18(8):1667-9. doi: 10.1038/oby.2009.467. Epub 2010 Jan 7. |
| 25529367 | Background | Phillips SA, Mahmoud AM, Brown MD, Haus JM. Exercise interventions and peripheral arterial function: implications for cardio-metabolic disease. Prog Cardiovasc Dis. 2015 Mar-Apr;57(5):521-34. doi: 10.1016/j.pcad.2014.12.005. Epub 2014 Dec 18. |
| 18606913 | Background | Tjonna AE, Lee SJ, Rognmo O, Stolen TO, Bye A, Haram PM, Loennechen JP, Al-Share QY, Skogvoll E, Slordahl SA, Kemi OJ, Najjar SM, Wisloff U. Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot study. Circulation. 2008 Jul 22;118(4):346-54. doi: 10.1161/CIRCULATIONAHA.108.772822. Epub 2008 Jul 7. |
| 22040838 | Background | Malin SK, Gerber R, Chipkin SR, Braun B. Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes. Diabetes Care. 2012 Jan;35(1):131-6. doi: 10.2337/dc11-0925. Epub 2011 Oct 31. |
| 12767663 | Background | Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol. 2003 May 21;41(10):1769-75. doi: 10.1016/s0735-1097(03)00333-4. |
| 20338492 | Background | Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010 Mar 30;55(13):1318-27. doi: 10.1016/j.jacc.2009.10.061. |
| 22961574 | Background | Eggleston EM, Jahn LA, Barrett EJ. Early microvascular recruitment modulates subsequent insulin-mediated skeletal muscle glucose metabolism during lipid infusion. Diabetes Care. 2013 Jan;36(1):104-10. doi: 10.2337/dc11-2399. Epub 2012 Sep 6. |
| 19567533 | Background | Liu Z, Liu J, Jahn LA, Fowler DE, Barrett EJ. Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature. J Clin Endocrinol Metab. 2009 Sep;94(9):3543-9. doi: 10.1210/jc.2009-0027. Epub 2009 Jun 30. |
| 16682488 | Background | Vincent MA, Clerk LH, Lindner JR, Price WJ, Jahn LA, Leong-Poi H, Barrett EJ. Mixed meal and light exercise each recruit muscle capillaries in healthy humans. Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1191-7. doi: 10.1152/ajpendo.00497.2005. |
| 21610226 | Background | Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E252-63. doi: 10.1152/ajpendo.00186.2011. Epub 2011 May 24. |
| 16644702 | Background | Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006 May;55(5):1436-42. doi: 10.2337/db05-1373. |
| 19487636 | Background | Keske MA, Clerk LH, Price WJ, Jahn LA, Barrett EJ. Obesity blunts microvascular recruitment in human forearm muscle after a mixed meal. Diabetes Care. 2009 Sep;32(9):1672-7. doi: 10.2337/dc09-0206. Epub 2009 Jun 1. |
| 21047922 | Background | Liu J, Jahn LA, Fowler DE, Barrett EJ, Cao W, Liu Z. Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans. J Clin Endocrinol Metab. 2011 Feb;96(2):438-46. doi: 10.1210/jc.2010-1174. Epub 2010 Nov 3. |
| 21200002 | Background | Anderson TJ, Charbonneau F, Title LM, Buithieu J, Rose MS, Conradson H, Hildebrand K, Fung M, Verma S, Lonn EM. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation. 2011 Jan 18;123(2):163-9. doi: 10.1161/CIRCULATIONAHA.110.953653. Epub 2011 Jan 3. |
| 12379578 | Background | Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation. 2002 Oct 15;106(16):2085-90. doi: 10.1161/01.cir.0000033824.02722.f7. |
| 24744384 | Background | Donley DA, Fournier SB, Reger BL, DeVallance E, Bonner DE, Olfert IM, Frisbee JC, Chantler PD. Aerobic exercise training reduces arterial stiffness in metabolic syndrome. J Appl Physiol (1985). 2014 Jun 1;116(11):1396-404. doi: 10.1152/japplphysiol.00151.2014. Epub 2014 Apr 17. |
| 24947027 | Background | Green DJ, Eijsvogels T, Bouts YM, Maiorana AJ, Naylor LH, Scholten RR, Spaanderman ME, Pugh CJ, Sprung VS, Schreuder T, Jones H, Cable T, Hopman MT, Thijssen DH. Exercise training and artery function in humans: nonresponse and its relationship to cardiovascular risk factors. J Appl Physiol (1985). 2014 Aug 15;117(4):345-52. doi: 10.1152/japplphysiol.00354.2014. Epub 2014 Jun 19. |
| 24299160 | Background | Swift DL, Weltman JY, Patrie JT, Saliba SA, Gaesser GA, Barrett EJ, Weltman A. Predictors of improvement in endothelial function after exercise training in a diverse sample of postmenopausal women. J Womens Health (Larchmt). 2014 Mar;23(3):260-6. doi: 10.1089/jwh.2013.4420. Epub 2013 Dec 3. |
| 11300445 | Background | Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001 Apr;37(5):1344-50. doi: 10.1016/s0735-1097(01)01129-9. |
| 16115299 | Background | Vitale C, Mercuro G, Cornoldi A, Fini M, Volterrani M, Rosano GM. Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med. 2005 Sep;258(3):250-6. doi: 10.1111/j.1365-2796.2005.01531.x. |
| 17785362 | Background | Patel C, Ghanim H, Ravishankar S, Sia CL, Viswanathan P, Mohanty P, Dandona P. Prolonged reactive oxygen species generation and nuclear factor-kappaB activation after a high-fat, high-carbohydrate meal in the obese. J Clin Endocrinol Metab. 2007 Nov;92(11):4476-9. doi: 10.1210/jc.2007-0778. Epub 2007 Sep 4. |
| 26583801 | Background | Malin SK, Braun B. Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk. Exerc Sport Sci Rev. 2016 Jan;44(1):4-11. doi: 10.1249/JES.0000000000000070. |
| 18955635 | Background | Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, Feldman L, Vassy J, Wilson R, Bass EB, Brancati FL. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008 Oct 27;168(19):2070-80. doi: 10.1001/archinte.168.19.2070. |
| 41796987 | Derived | Malin SK, Heiston EM, Battillo DJ, Ragland TJ, Shah AM, Patrie JT. Metformin Alters Exercise Training Induced Blood Pressure and Aortic Waveform Adaptations in Adults at Risk for Metabolic Syndrome. J Clin Hypertens (Greenwich). 2026 Mar;28(3):e70215. doi: 10.1111/jch.70215. |
| 40018087 | Derived | Malin SK, Remchak ME, Heiston EM, Fabris C, Shah AM. Pancreatic beta-cell Function is Higher in Morning Versus Intermediate Chronotypes With Obesity. Obes Sci Pract. 2025 Feb 26;11(2):e70064. doi: 10.1002/osp4.70064. eCollection 2025 Apr. |
| 36597186 | Derived | Ragland TJ, Heiston EM, Ballantyne A, Stewart NR, La Salvia S, Musante L, Luse MA, Isakson BE, Erdbrugger U, Malin SK. Extracellular vesicles and insulin-mediated vascular function in metabolic syndrome. Physiol Rep. 2023 Jan;11(1):e15530. doi: 10.14814/phy2.15530. |
| 35429387 | Derived | Remchak ME, Heiston EM, Ballantyne A, Dotson BL, Stewart NR, Spaeth AM, Malin SK. Insulin Sensitivity and Metabolic Flexibility Parallel Plasma TCA Levels in Early Chronotype With Metabolic Syndrome. J Clin Endocrinol Metab. 2022 Jul 14;107(8):e3487-e3496. doi: 10.1210/clinem/dgac233. |
| Lost to Follow-up |
|
| Withdrawal by Subject |
|
| BG001 | HiEx With Placebo | High intensity exercise with placebo. Placebo: Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets. High Intensity Exercise: High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
| BG002 | LoEx With Metformin | Low intensity exercise with metformin. Metformin: Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d. Low Intensity Exercise: Low intensity exercise will consist of 16 weeks of walking at ~55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
| BG003 | HiEx With Metformin | High intensity exercise with metformin. Metformin: Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d. High Intensity Exercise: High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Body Mass Index | Median | Inter-Quartile Range | kg/m^2 |
|
| VO2peak | Median | Inter-Quartile Range | ml/kg/min |
|
| OG001 | HiEx With Placebo | High intensity exercise with placebo. Placebo: Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets. High Intensity Exercise: High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
| OG002 | LoEx With Metformin | Low intensity exercise with metformin. Metformin: Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d. Low Intensity Exercise: Low intensity exercise will consist of 16 weeks of walking at ~55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
| OG003 | HiEx With Metformin | High intensity exercise with metformin. Metformin: Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d. High Intensity Exercise: High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. |
|
|
|
| Secondary | Change in Metabolic Insulin Sensitivity. Glucose Infusion Rate Normalized to Steady-State Insulin (GIR). | The glucose infusion rate (mg/kg/min) divided by steady-state insulin (uU/mL) during a 120 minute euglycemic-hyperinsulinemic clamp provides an index of metabolic insulin sensitivity. Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. | Analysis includes only individuals that had both pre and post data. | Posted | Mean | 95% Confidence Interval | (mg/kg/min)/(uU/mL) | 0 and 16 weeks |
|
|
|
|
| Secondary | Change in Fasting Augmentation Index | Measure of Arterial Stiffness calculated by dividing the augmentation pressure by the pulse pressure, then multiplying by 100 and normalizing to a heart rate of 75 bpm (AIx75). Delta = Week 16 - Week 0. Lower values and negative change scores following the intervention indicate a better outcome. | Analysis includes only individuals that had both pre and post data. | Posted | Mean | 95% Confidence Interval | Percent of pulse pressure | 0 and 16 weeks |
|
|
|
|
| Secondary | Change in Insulin-stimulated Microvascular Blood Flow (MBF) of the Forearm. | Product of microvascular blood volume (VI; video intensity units) and microvascular flow velocity (sec^-1). Insulin-stimulated microvascular blood flow is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. | Analysis includes only individuals that had both pre and post data. | Posted | Mean | 95% Confidence Interval | VI * sec^-1 | 0 and 16 weeks |
|
|
|
|
| Secondary | Change in Insulin-stimulated Microvascular Flow Velocity (MFV) of the Forearm. | Replenishment curves of the forearm flexor muscle acquired during steady-state infusion of Definity microbubbles. Insulin-stimulated microvascular flow velocity is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. | Analysis includes only individuals that had both pre and post data. | Posted | Mean | 95% Confidence Interval | sec^-1 | 0 and 16 weeks |
|
|
|
|
| Secondary | Change in Insulin-stimulated Microvascular Blood Volume (MBV) of the Forearm. | Replenishment curves of the forearm flexor muscle acquired during steady-state infusion of Definity microbubbles. Insulin-stimulated microvascular blood volume is the change during a 120 minute euglycemic-hyperinsulinemic clamp (120-0 minutes). Delta = Week 16 - Week 0. Higher values and positive change scores following the intervention indicate a better outcome. | Analysis includes only individuals that had both pre and post data. | Posted | Mean | 95% Confidence Interval | Video Intensity Units (VI) | 0 and 16 weeks |
|
|
|
|
| 0 |
| 22 |
| 0 |
| 22 |
| 0 |
| 22 |
| EG001 | HiEx With Placebo | High intensity exercise with placebo. Placebo: Oral placebo for 16 weeks. Placebo tablets will follow a four-stage progression: Week 1 = 1 tablet; Week 2 = 2 tablets; Week 3 = 3 tablets; Week 4-16 = 4 tablets. High Intensity Exercise: High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. | 0 | 21 | 0 | 21 | 0 | 21 |
| EG002 | LoEx With Metformin | Low intensity exercise with metformin. Metformin: Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d. Low Intensity Exercise: Low intensity exercise will consist of 16 weeks of walking at ~55% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. | 0 | 24 | 0 | 24 | 0 | 24 |
| EG003 | HiEx With Metformin | High intensity exercise with metformin. Metformin: Oral metformin 2000 mg/d for 16 weeks. Metformin dosage will follow 500 mg/d ramp up progression: Week 1 = 500 mg/d; Week 2 = 1,000 mg/d; Week 3 = 1500 mg/d; Week 4-16 = 2000 mg/d. High Intensity Exercise: High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate. Supervised exercised will occur on a treadmill 3d/wk and the duration will be determined based on individual fitness levels to expand 400 kcals. Supervised exercise training will follow a three-phase progression: Weeks 1-2 = 3 supervised sessions at 75% duration; Week 3-4 = 3 supervised sessions at 87% duration; Weeks 5-16 = 3 supervised sessions at 100% duration. Unsupervised exercised will be 2d/wk and the duration will half the time of the supervised training sessions. | 0 | 24 | 0 | 24 | 1 | 24 |
Not provided
Not provided
| D009750 |
| Nutritional and Metabolic Diseases |
| Physical Conditioning, Human |
| D015444 | Exercise |
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention GIR. | 0.198 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.008. | Mean Difference (Final Values) | 0.0097 | 2-Sided | 95 | -0.0055 | 0.0250 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention GIR. | 0.622 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.033. | Mean Difference (Final Values) | 0.0041 | 2-Sided | 95 | -0.0129 | 0.0211 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention GIR. | 0.666 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.050. | Mean Difference (Final Values) | -0.0024 | 2-Sided | 95 | -0.0136 | 0.0088 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention GIR. | 0.634 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.042. | Mean Difference (Final Values) | -0.0032 | 2-Sided | 95 | -0.0169 | 0.0104 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention GIR, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention GIR. | 0.336 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.017. | Mean Difference (Final Values) | -0.0056 | 2-Sided | 95 | -0.0174 | 0.0062 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention AIx75. | 0.170 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.025. | Mean Difference (Final Values) | -4.82 | 2-Sided | 95 | -11.84 | 2.19 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention AIx75. | 0.839 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.050. | Mean Difference (Final Values) | -0.66 | 2-Sided | 95 | -7.29 | 5.97 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention AIx75. | 0.024 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.008. | Mean Difference (Final Values) | 6.33 | 2-Sided | 95 | 0.86 | 11.80 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention AIx75. | 0.385 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.033. | Mean Difference (Final Values) | -2.16 | 2-Sided | 95 | -7.16 | 2.83 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention AIx75 change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention AIx75. | 0.080 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.017. | Mean Difference (Final Values) | 4.17 | 2-Sided | 95 | -0.53 | 8.86 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MBF. | 0.960 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.050. | Mean Difference (Final Values) | 0.001 | 2-Sided | 95 | -0.059 | 0.062 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MBF. | 0.075 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.008. | Mean Difference (Final Values) | -0.052 | 2-Sided | 95 | -0.109 | 0.006 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MBF. | 0.258 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.033. | Mean Difference (Final Values) | -0.033 | 2-Sided | 95 | -0.094 | 0.028 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MBF. | 0.443 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.042. | Mean Difference (Final Values) | -0.020 | 2-Sided | 95 | -0.075 | 0.035 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBF change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MBF. | 0.144 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.025. | Mean Difference (Final Values) | -0.053 | 2-Sided | 95 | -0.126 | 0.020 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MFV. | 0.943 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.050. | Mean Difference (Final Values) | 0.001 | 2-Sided | 95 | -0.016 | 0.017 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MFV. | 0.108 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.008. | Mean Difference (Final Values) | -0.012 | 2-Sided | 95 | -0.027 | 0.003 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MFV. | 0.319 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.033. | Mean Difference (Final Values) | -0.008 | 2-Sided | 95 | -0.024 | 0.009 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MFV. | 0.496 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.042. | Mean Difference (Final Values) | -0.005 | 2-Sided | 95 | -0.019 | 0.010 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MFV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MFV. | 0.187 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.025. | Mean Difference (Final Values) | -0.012 | 2-Sided | 95 | -0.031 | 0.007 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MBV. | 0.608 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.050. | Mean Difference (Final Values) | 0.110 | 2-Sided | 95 | -0.354 | 0.574 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MBV. | 0.110 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.017. | Mean Difference (Final Values) | -0.344 | 2-Sided | 95 | -0.779 | 0.090 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MBV. | 0.145 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.033. | Mean Difference (Final Values) | -0.340 | 2-Sided | 95 | -0.818 | 0.137 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MBV. | 0.565 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.042. | Mean Difference (Final Values) | -0.114 | 2-Sided | 95 | -0.538 | 0.309 | Superiority |
| Intention to treat Full Maximum Likelihood based comparisons of baseline covariate adjusted pre- to post-intervention MBV change, where the difference is between treatment combination #2 and treatment combination #1 (i.e. treatment combination # 2 - treatment combination #1). | ANCOVA | ANCOVA linear model adjusted for pre-intervention MBV. | 0.110 | Benjamini and Hochberg method was used to decrease the false discovery rate with an overall error rate of 0.05. The B&H P-value threshold for this comparison was 0.025. | Mean Difference (Final Values) | -0.454 | 2-Sided | 95 | -1.025 | 0.116 | Superiority |