Clinical trial NCT00427193: CALERIE: Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy
Official title: Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Aging
Keywords: dietary restriction
disease /disorder prevention /control
nutrition of aging
bioenergetics
cardiovascular function
disease /disorder proneness /risk
insulin sensitivity / resistance
Lead sponsor: Duke University
Sponsor class: OTHER
First posted: 2007-01-26
Enrollment: 238
Sex: ALL
Minimum age (years): 21
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to test the hypothesis that two years of sustained 25% caloric restriction (CR) in men age 21-50 (inclusive) and women age 21-47 (inclusive) will slow aging and protect against age-related disease processes.

Detailed description: The overall aim of CALERIE Phase 2 is to test the hypothesis that two years of sustained caloric restriction (CR), involving a reduction in energy intake to 75% of baseline (25% CR), in healthy, non-obese men aged 21-50 (inclusive) and women aged 21-47 (inclusive), will result in the same adaptive changes that were observed in a wide variety of animal studies. Particular emphasis is on the adaptive responses thought to be involved in slowing the aging process and protecting against age-related disease processes. Primary outcomes include core body temperature and resting metabolic rate. Secondary outcomes include risk factors for cardiovascular disease, inflammatory markers, immune function, psychological and physical function; oxidative changes in lipids, proteins, and DNA; and, risk factors for age-related conditions such as diabetes and body composition. An important secondary aim is to identify potential adverse effects of CR in humans.

The study will be conducted as a multi-center, parallel-group, randomized, controlled trial (RCT). A sample of 200 participants will be enrolled, and assigned to either the CR intervention or a control group. Control participants will be advised to simply continue their current diets. Participants in both treatment arms will be followed over a period of 24 months. A comprehensive set of evaluations will be performed prior to initiating the intervention, with follow-up evaluations at 1, 3, 6, 9, 12, 18 and 24 months afterwards.

Eligibility criteria: Inclusion Criteria:

* Age must be between 21-50 (inclusive) for men and 21-47 (inclusive) for women
* Body mass index (BMI) must be greater than or equal to 22 and less than 28
* Female participants must use acceptable forms of contraception (barrier method, oral contraceptive, intra-uterine device, or similar) and be willing to continue using such a method while enrolled in the study

Exclusion Criteria:

* History or clinical manifestation of cardiovascular disease or an elevated blood pressure (greater than 140/90 mm Hg)
* Abnormal resting ECG
* History or clinical manifestation of diabetes
* History or clinical manifestation of cholelithiasis (the presence or formation of gallstones in the gallbladder or bile ducts)
* History of anaphylaxis, severe allergies, or asthma
* History or clinical manifestation of any other significant metabolic, hematologic, pulmonary, cardiovascular, gastrointestinal, neurologic, immune, hepatic, renal, urologic disorders, or cancer that, in opinion of the investigator, would make the candidate ineligible for the study
* History of stomach or intestinal surgery (except appendectomy) or major abdominal, thoracic or non-peripheral vascular surgery within one year prior to the randomization date
* Any disease or condition that seriously affects body weight and/or body composition
* Potassium level above the upper limit of normal at the screening visit confirmed by a test repeated within two weeks
* Hemoglobin, hematocrit, RBC, or iron level below the lower limit of normal at the screening visit confirmed by a test repeated within two weeks
* Evidence of active liver disease or ALT levels above 1.5 times the upper limit of normal
* Practice a vegan dietary lifestyle
* History or clinical manifestation of any eating disorder
* Any history of pharmacologic treatment for a psychiatric disorder within one year prior to the randomization date or a history of more than one episode of a pharmacologic treatment for a psychiatric disorder within lifetime
* History of drug or alcohol abuse (up to 14 drinks a week are allowed) within the past two years
* BDI (Beck Depression Inventory) score of 20 or higher at screening or baseline
* Treatment with steroids for more than a month within five years prior to the randomization date, or short-term (less than a month) treatment with steroids within six months prior to the randomization date
* Regular use of other medications, except contraceptives
* Participated in the CALERIE Phase 1 studies
* Lost or gained 3 kg or more over the past six months
* A volunteer must be either a never-smoker of tobacco products or an ex-smoker who quit completely at least 12 months prior to the screening visit
* Donated blood within 30 days prior to the randomization date
* Concurrent participation in any other interventional study
* Breast-feeding or pregnant women or women intending to become pregnant before the scheduled end of the intervention
* Engaged in a regular program of physical fitness involving some kind of heavy physical activity (e.g., jogging, running or riding fast on a bicycle for 30 minutes or more) five or more times per week over the past year
* Unwilling to be assigned at random to the CR or control intervention
* Unwilling or unable to adhere to the rigors of the CR intervention over the entire two-year intervention period
* Unable or unwilling to discontinue dietary supplements or adhere to the alcohol consumption restrictions during the study
* Unwilling or unable to adhere to the rigors of the data collection and clinical evaluation schedule over the entire two-year period follow-up period

Primary outcomes:
measure: Change in Core Body Temperature, Baseline to 12 Months
timeFrame: Baseline to 12 months
measure: Change in Core Temperature, Baseline to 24 Months
timeFrame: Baseline to 24 months
measure: Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition, Baseline to 12 Months
timeFrame: Baseline, 12 months
measure: Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition
timeFrame: Baseline, 24 months
Secondary outcomes:
measure: Change in Tumor Necrosis Factor-α (TNF-α), Baseline to 12 Months
timeFrame: change baseline to 12 months
Other outcomes:
measure: Change in Fat Mass
timeFrame: change 0 to 24 months
measure: Change in Fat Mass
timeFrame: baseline, 12 months
Locations:
city: Baton Rouge
country: United States
facility: Pennington Biomedical Research Center
state: Louisiana
city: Boston
country: United States
facility: Jean Mayer Human Nutrition Research Center on Aging at Tufts University
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Duke Clinical Research Institute
name: William Kraus, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, Roberts SB; CALERIE Study Group. A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. J Gerontol A Biol Sci Med Sci. 2015 Sep;70(9):1097-104. doi: 10.1093/gerona/glv057. Epub 2015 Jul 17.
citation: Rochon J, Bales CW, Ravussin E, Redman LM, Holloszy JO, Racette SB, Roberts SB, Das SK, Romashkan S, Galan KM, Hadley EC, Kraus WE; CALERIE Study Group. Design and conduct of the CALERIE study: comprehensive assessment of the long-term effects of reducing intake of energy. J Gerontol A Biol Sci Med Sci. 2011 Jan;66(1):97-108. doi: 10.1093/gerona/glq168. Epub 2010 Oct 5.
citation: Racette SB, Rochon J, Uhrich ML, Villareal DT, DAS SK, Fontana L, Bhapkar M, Martin CK, Redman LM, Fuss PJ, Roberts SB, Kraus WE. Effects of Two Years of Calorie Restriction on Aerobic Capacity and Muscle Strength. Med Sci Sports Exerc. 2017 Nov;49(11):2240-2249. doi: 10.1249/MSS.0000000000001353.
citation: Belsky DW, Huffman KM, Pieper CF, Shalev I, Kraus WE. Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis. J Gerontol A Biol Sci Med Sci. 2017 Dec 12;73(1):4-10. doi: 10.1093/gerona/glx096.
citation: Martin CK, Bhapkar M, Pittas AG, Pieper CF, Das SK, Williamson DA, Scott T, Redman LM, Stein R, Gilhooly CH, Stewart T, Robinson L, Roberts SB; Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) Phase 2 Study Group. Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults: The CALERIE 2 Randomized Clinical Trial. JAMA Intern Med. 2016 Jun 1;176(6):743-52. doi: 10.1001/jamainternmed.2016.1189.
citation: Dorling JL, Ravussin E, Redman LM, Bhapkar M, Huffman KM, Racette SB, Das SK, Apolzan JW, Kraus WE, Hochsmann C, Martin CK; CALERIE Phase 2 Study Group. Effect of 2 years of calorie restriction on liver biomarkers: results from the CALERIE phase 2 randomized controlled trial. Eur J Nutr. 2021 Apr;60(3):1633-1643. doi: 10.1007/s00394-020-02361-7. Epub 2020 Aug 14.
citation: Thomas DM, Clark N, Turner D, Siu C, Halliday TM, Hannon BA, Kahathuduwa CN, Kroeger CM, Zoh R, Allison DB. Best (but oft-forgotten) practices: identifying and accounting for regression to the mean in nutrition and obesity research. Am J Clin Nutr. 2020 Feb 1;111(2):256-265. doi: 10.1093/ajcn/nqz196.
citation: Dorling JL, Bhapkar M, Das SK, Racette SB, Apolzan JW, Fearnbach SN, Redman LM, Myers CA, Stewart TM, Martin CK; CALERIE Study Group. Change in self-efficacy, eating behaviors and food cravings during two years of calorie restriction in humans without obesity. Appetite. 2019 Dec 1;143:104397. doi: 10.1016/j.appet.2019.104397. Epub 2019 Aug 6.
citation: Kraus WE, Bhapkar M, Huffman KM, Pieper CF, Krupa Das S, Redman LM, Villareal DT, Rochon J, Roberts SB, Ravussin E, Holloszy JO, Fontana L; CALERIE Investigators. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 2019 Sep;7(9):673-683. doi: 10.1016/S2213-8587(19)30151-2. Epub 2019 Jul 11.
citation: Broskey NT, Marlatt KL, Most J, Erickson ML, Irving BA, Redman LM. The Panacea of Human Aging: Calorie Restriction Versus Exercise. Exerc Sport Sci Rev. 2019 Jul;47(3):169-175. doi: 10.1249/JES.0000000000000193.
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citation: Redman LM, Smith SR, Burton JH, Martin CK, Il'yasova D, Ravussin E. Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging. Cell Metab. 2018 Apr 3;27(4):805-815.e4. doi: 10.1016/j.cmet.2018.02.019. Epub 2018 Mar 22.
citation: Das SK, Roberts SB, Bhapkar MV, Villareal DT, Fontana L, Martin CK, Racette SB, Fuss PJ, Kraus WE, Wong WW, Saltzman E, Pieper CF, Fielding RA, Schwartz AV, Ravussin E, Redman LM; CALERIE-2 Study Group. Body-composition changes in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2 study: a 2-y randomized controlled trial of calorie restriction in nonobese humans. Am J Clin Nutr. 2017 Apr;105(4):913-927. doi: 10.3945/ajcn.116.137232. Epub 2017 Feb 22.
citation: Rochon J, Bhapkar M, Pieper CF, Kraus WE. Application of the Marginal Structural Model to Account for Suboptimal Adherence in a Randomized Controlled Trial. Contemp Clin Trials Commun. 2016 Dec 15;4:222-228. doi: 10.1016/j.conctc.2016.10.005. Epub 2016 Nov 3.
citation: Sparks LM, Redman LM, Conley KE, Harper ME, Yi F, Hodges A, Eroshkin A, Costford SR, Gabriel ME, Shook C, Cornnell HH, Ravussin E, Smith SR. Effects of 12 Months of Caloric Restriction on Muscle Mitochondrial Function in Healthy Individuals. J Clin Endocrinol Metab. 2017 Jan 1;102(1):111-121. doi: 10.1210/jc.2016-3211.
citation: Meydani SN, Das SK, Pieper CF, Lewis MR, Klein S, Dixit VD, Gupta AK, Villareal DT, Bhapkar M, Huang M, Fuss PJ, Roberts SB, Holloszy JO, Fontana L. Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. Aging (Albany NY). 2016 Jul;8(7):1416-31. doi: 10.18632/aging.100994.
citation: Sanghvi A, Redman LM, Martin CK, Ravussin E, Hall KD. Validation of an inexpensive and accurate mathematical method to measure long-term changes in free-living energy intake. Am J Clin Nutr. 2015 Aug;102(2):353-8. doi: 10.3945/ajcn.115.111070. Epub 2015 Jun 3.
citation: Wong WW, Roberts SB, Racette SB, Das SK, Redman LM, Rochon J, Bhapkar MV, Clarke LL, Kraus WE. The doubly labeled water method produces highly reproducible longitudinal results in nutrition studies. J Nutr. 2014 May;144(5):777-83. doi: 10.3945/jn.113.187823. Epub 2014 Feb 12.
citation: Redman LM, Kraus WE, Bhapkar M, Das SK, Racette SB, Martin CK, Fontana L, Wong WW, Roberts SB, Ravussin E; CALERIE Study Group. Energy requirements in nonobese men and women: results from CALERIE. Am J Clin Nutr. 2014 Jan;99(1):71-8. doi: 10.3945/ajcn.113.065631. Epub 2013 Nov 20.
citation: Huffman KM, Redman LM, Landerman LR, Pieper CF, Stevens RD, Muehlbauer MJ, Wenner BR, Bain JR, Kraus VB, Newgard CB, Ravussin E, Kraus WE. Caloric restriction alters the metabolic response to a mixed-meal: results from a randomized, controlled trial. PLoS One. 2012;7(4):e28190. doi: 10.1371/journal.pone.0028190. Epub 2012 Apr 16.