CALERIE: Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00427193
• Collaborator: (none)
• Enrollment: 238
• Locations: 3
• Arms: 2
• Duration (Months): 66.1
• Patients Per Site: 79.3
• Patients Per Site Per Month: 1.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Aging	Behavioral: Caloric Restriction (CR); Behavioral: Control	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 238 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Masking Description: all lab based assays were masked due to de-identified person and time interval measured. All physical measures were masked to intervention group status.
• Primary Purpose: Prevention
• Official Title: Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE)
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Caloric Restriction (CR) 25% caloric restriction	Behavioral: Caloric Restriction (CR); Participants follow a diet with 25% fewer calories than calculated at baseline over a period of 24 months
Active Comparator: Control, Ad libitum (AL) Ad libitum energy intake	Behavioral: Control; Participants continue their current diet for 24 months

Outcome Measures

Primary Outcome Measures

1. Change in Core Body Temperature, Baseline to 12 Months [Baseline to 12 months]

2. Change in Core Temperature, Baseline to 24 Months [Baseline to 24 months]

3. Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition, Baseline to 12 Months [Baseline, 12 months]

4. Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition [Baseline, 24 months]

Secondary Outcome Measures

1. Change in Tumor Necrosis Factor-α (TNF-α), Baseline to 12 Months [change baseline to 12 months]

Other Outcome Measures

1. Change in Fat Mass [change 0 to 24 months]

   Difference in change in Fat Mass between prescribed 25% Caloric Restriction (CR) and Ad Libitum (AL) at 12 and 24 months as measured by dual X-ray absorptiometry (DXA) using the Hologic 4500A, Delphi W or Discovery A, by a standardized protocol according to a standardized protocol. Fat Mass (FM) was determined for the whole body.

2. Change in Fat Mass [baseline, 12 months]

   Difference in change in Fat Mass between prescribed 25% Caloric Restriction (CR) and Ad Libitum (AL) at 12 and 24 months as measured by dual X-ray absorptiometry (DXA) using the Hologic 4500A, Delphi W or Discovery A, by a standardized protocol according to a standardized protocol. Fat Mass (FM) was determined for the whole body.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pennington Biomedical Research Center	Baton Rouge	Louisiana	United States	70808
2	Jean Mayer Human Nutrition Research Center on Aging at Tufts University	Boston	Massachusetts	United States	02111
3	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Duke University

Investigators

• Principal Investigator: William Kraus, MD, Duke Clinical Research Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• CALERIE website

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00427193
• Other Study ID Numbers: Pro00016876; PBRC U01-AG0204878; Tufts U01-AG020480; WashU U01-AG020487; DCRI/Duke U01-AG022132; AG0078
• First Posted: Jan 26, 2007
• Last Update Posted: Mar 16, 2022
• Last Verified: Mar 1, 2022

• Keywords provided by Duke University: dietary restriction; disease /disorder prevention /control; nutrition of aging; bioenergetics; cardiovascular function; disease /disorder proneness /risk; insulin sensitivity / resistance

Study Results

Participant Flow

Pre-assignment Detail	238 Participants were eligible, 18 participants withdrew prior to randomization, 220 participants were randomized to the study, and 2 participants withdrew prior to initiating the intervention.

Arm/Group Title	Caloric Restriction (CR)	Ad Libitum
Arm/Group Description	25% caloric restriction Caloric Restriction (CR): Participants follow a diet with 25% fewer calories than calculated at baseline over a period of 24 months	Ad libitum energy intake Control: Participants continue their current diet for 24 months
Period Title: Overall Study
STARTED	143	75
COMPLETED	117	71
NOT COMPLETED	26	4

Baseline Characteristics

Arm/Group Title	Caloric Restriction (CR)	Ad Libitum	Total
Arm/Group Description	25% caloric restriction Caloric Restriction (CR): Participants follow a diet with 25% fewer calories than calculated at baseline over a period of 24 months	Ad libitum energy intake Control: Participants continue their current diet for 24 months	Total of all reporting groups
Overall Participants	143	75	218
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.2 (7.3)	38.1 (6.9)	38.1 (7.2)
Sex: Female, Male (Count of Participants)
Female	99 69.2%	53 70.7%	152 69.7%
Male	44 30.8%	22 29.3%	66 30.3%
Race/Ethnicity, Customized (Count of Participants)
White	111 77.6%	57 76%	168 77.1%
African-American	15 10.5%	11 14.7%	26 11.9%
Other	17 11.9%	7 9.3%	24 11%

Outcome Measures

1. Primary Outcome

Title	Change in Core Body Temperature, Baseline to 12 Months
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Caloric Restriction (CR)	Ad Libitum
Arm/Group Description	25% caloric restriction Caloric Restriction (CR): Participants follow a diet with 25% fewer calories than calculated at baseline over a period of 24 months	Ad libitum energy intake Control: Participants continue their current diet for 24 months
Measure Participants	143	75
Mean (Standard Deviation) [degrees Celsius]	-0.05 (0.02)	-0.03 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caloric Restriction (CR), Ad Libitum
	Comments	All analysis under intention-to-treat. All observations were included The primary analytic was a repeated measures analysis. The dependent variable was the change from baseline 12 & 14mos., with treatment, time, and the treatment × time interaction as independent variables. Site, sex, BMI stratum, and the baseline value of the outcome were included as covariates. The predicted mean changes ± standard errors are the adjusted values from the contrasts of the multiple timepoints.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments	Type I error was controlled using a hierarchical gatekeeping strategy.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	difference in mean change
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.019 to 0.059
	Parameter Dispersion	Type: Standard Deviation; Value: 0.02
	Estimation Comments

2. Primary Outcome

Title	Change in Core Temperature, Baseline to 24 Months
Time Frame	Baseline to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prescribed 25% Caloric Restriction	Ad Libitum
Arm/Group Description	2 years of prescribed 25% Caloric Restriction	Usual caloric intake
Measure Participants	143	75
Mean (Standard Deviation) [degrees Celsius]	-0.05 (0.02)	-0.02 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caloric Restriction (CR), Ad Libitum
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.0092 to 0.069
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.02
	Estimation Comments

3. Primary Outcome

Title	Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition, Baseline to 12 Months
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Caloric Restriction (CR)	Ad Libitum
Arm/Group Description	25% caloric restriction Caloric Restriction (CR): Participants follow a diet with 25% fewer calories than calculated at baseline over a period of 24 months	Ad libitum energy intake Control: Participants continue their current diet for 24 months
Measure Participants	143	75
Mean (Standard Deviation) [Kcal/day]	-83 (10)	-1 (13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caloric Restriction (CR), Ad Libitum
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-82
	Confidence Interval	(2-Sided) 95%; -103.8 to -60.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.12
	Estimation Comments

4. Primary Outcome

Title	Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition
Time Frame	Baseline, 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Caloric Restriction (CR)	Ad Libitum
Arm/Group Description	25% caloric restriction Caloric Restriction (CR): Participants follow a diet with 25% fewer calories than calculated at baseline over a period of 24 months	Ad libitum energy intake Control: Participants continue their current diet for 24 months
Measure Participants	143	75
Mean (Standard Deviation) [Kcal/day]	-71 (12)	-7 (16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caloric Restriction (CR), Ad Libitum
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-64
	Confidence Interval	(2-Sided) 95%; -90.5 to -37.5
	Parameter Dispersion	Type: Standard Deviation; Value: 13.5
	Estimation Comments

5. Secondary Outcome

Title	Change in Tumor Necrosis Factor-α (TNF-α), Baseline to 12 Months
Time Frame	change baseline to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Caloric Restriction (CR)	Ad Libitum
Arm/Group Description	25% caloric restriction Caloric Restriction (CR): Participants follow a diet with 25% fewer calories than calculated at baseline over a period of 24 months	Ad libitum energy intake Control: Participants continue their current diet for 24 months
Measure Participants	143	75
Mean (Standard Deviation) [pg/mL]	-0.30 (0.09)	-0.34 (0.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caloric Restriction (CR), Ad Libitum
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

6. Other Pre-specified Outcome

Title	Change in Fat Mass
Description	Difference in change in Fat Mass between prescribed 25% Caloric Restriction (CR) and Ad Libitum (AL) at 12 and 24 months as measured by dual X-ray absorptiometry (DXA) using the Hologic 4500A, Delphi W or Discovery A, by a standardized protocol according to a standardized protocol. Fat Mass (FM) was determined for the whole body.
Time Frame	change 0 to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prescribed 25% Caloric Restriction	Ad Libitum
Arm/Group Description	2 years of prescribed 25% Caloric Restriction	Usual caloric intake
Measure Participants	143	75
Mean (Standard Deviation) [kg]	-6.1 (0.22)	-0.2 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caloric Restriction (CR), Ad Libitum
	Comments	Difference in change in Fat Mass between prescribed 25% Caloric Restriction (CR) and Ad Libitum (AL) at 12 and 24 months as measured by dual X-ray absorptiometry (DXA) using the Hologic 4500A, Delphi W or Discovery A, by a standardized protocol according to a standardized protocol. Fat Mass (FM) and Fat Free Mass (FFM) were determined for the whole body.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.9
	Confidence Interval	(2-Sided) 95%; -6.5 to -5.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.31
	Estimation Comments

7. Other Pre-specified Outcome

Title	Change in Fat Mass
Description	Difference in change in Fat Mass between prescribed 25% Caloric Restriction (CR) and Ad Libitum (AL) at 12 and 24 months as measured by dual X-ray absorptiometry (DXA) using the Hologic 4500A, Delphi W or Discovery A, by a standardized protocol according to a standardized protocol. Fat Mass (FM) was determined for the whole body.
Time Frame	baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prescribed 25% Caloric Restriction	Ad Libitum
Arm/Group Description	2 years of prescribed 25% Caloric Restriction	Usual caloric intake
Measure Participants	143	75
Mean (Standard Deviation) [Kg]	-6.1 (0.22)	-0.3 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caloric Restriction (CR), Ad Libitum
	Comments	Comparison of change in FM in 2 groups over at 24 mos, controlling for site, sex, BMI group, and baseline FM. A repeated measures Mixed Model was employed for the analysis. For any outcome, Type I error was controlled using a hierarchical gatekeeping strategy testing, first, the GroupXTime interaction, and, if non-significant, the main effects of these two factors. Bonferroni corrections were employed for non-significant effects. All tests were at p<0.05
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.9
	Confidence Interval	(2-Sided) 95%; -6.4 to -5.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.26
	Estimation Comments

Adverse Events

Time Frame	0 to 24 months
Arm/Group Title	Caloric Restriction (CR)		Ad Libitum
Arm/Group Description	25% caloric restriction Caloric Restriction (CR): Participants follow a diet with 25% fewer calories than calculated at baseline over a period of 24 months		Ad libitum energy intake Control: Participants continue their current diet for 24 months
All Cause Mortality
	Caloric Restriction (CR)		Ad Libitum
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/143 (0%)		0/75 (0%)
Serious Adverse Events
	Caloric Restriction (CR)		Ad Libitum
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/143 (0.7%)		7/75 (9.3%)
Gastrointestinal disorders
intestinal abscess	0/143 (0%)	0	1/75 (1.3%)	1
small intestinal obstruction	0/143 (0%)	0	1/75 (1.3%)	1
Injury, poisoning and procedural complications
pneumothorax	0/143 (0%)	0	1/75 (1.3%)	1
Musculoskeletal and connective tissue disorders
scoliosis	0/143 (0%)	0	1/75 (1.3%)	1
spinal osteoarthritis	0/143 (0%)	0	1/75 (1.3%)	1
Pregnancy, puerperium and perinatal conditions
spontaneous miscarriage	1/143 (0.7%)	1	0/75 (0%)	0
Reproductive system and breast disorders
leiomyoma	0/143 (0%)	0	1/75 (1.3%)	1
Vascular disorders
atrial septal defect	0/143 (0%)	0	1/75 (1.3%)	1
Other (Not Including Serious) Adverse Events
	Caloric Restriction (CR)		Ad Libitum
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	136/143 (95.1%)		72/75 (96%)
Blood and lymphatic system disorders
anemia	35/143 (24.5%)	99	17/75 (22.7%)	34
General disorders
dizziness	9/143 (6.3%)	48	10/75 (13.3%)	14
nasal congestion	19/143 (13.3%)	28	5/75 (6.7%)	14
constipation	18/143 (12.6%)	44	5/75 (6.7%)	11
toothache	6/143 (4.2%)	21	5/75 (6.7%)	12
pain	12/143 (8.4%)	20	5/75 (6.7%)	10
rash	9/143 (6.3%)	9	1/75 (1.3%)	1
Infections and infestations
gastrointestinal virus	13/143 (9.1%)	16	5/75 (6.7%)	5
urinary tract infection	4/143 (2.8%)	11	4/75 (5.3%)	6
Metabolism and nutrition disorders
diarrhea	20/143 (14%)	27	10/75 (13.3%)	16
Musculoskeletal and connective tissue disorders
muscle strain	3/143 (2.1%)	16	3/75 (4%)	4
Excessive bone loss	3/143 (2.1%)	3	0/75 (0%)	0
Reproductive system and breast disorders
dysmenorrhea	30/143 (21%)	78	11/75 (14.7%)	31
Respiratory, thoracic and mediastinal disorders
sinus congestion	23/143 (16.1%)	43	8/75 (10.7%)	17

Limitations/Caveats

The Caloric Restriction (CR) group fell short of achieving the 25% CR goal specified in the protocol. The completion rates differed between groups.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.