Wendy Bennett , elaborated on their research methods to MNT :. Participants from 3 health systems used the app for 6 months. We linked the app data with survey data with electronic health records. The researchers found that the timing from the first meal of the day to the last meal of the day was not associated with changes in weight.

However, they did find that eating more frequent, larger meals were associated with weight gain. While eating more medium or large meals is associated with weight gain over time.

And more smaller meals are associated with weight loss over time. Wendy Bennett. Katherine Saunders.

Data on intermittent fasting is still emerging, so no one study offers all the proof that the method is effective or ineffective. This particular study also had several limitations to consider.

First, researchers could only analyze data from study participants who downloaded and used the Daily24 app. This exclusion may have impacted the study population and results.

They only recruited participants from three health systems, meaning the results cannot necessarily be generalized. The study also had a relatively short follow-up time, leading to fewer weight measurements and declines in measurement precision.

The way researchers measured eating periods could not evaluate more complex fasting methods. Bennett noted to MNT. This study indicates that other methods of losing weight may be more effective than intermittent fasting. Regardless of weight goals, people can use various methods to stay healthy and manage weight.

Bennett said that self-monitoring was key to weight loss. Intermittent fasting is a diet plan that means consuming few to no calories on fasting day and eating normally on nonfasting days. We look at the…. There is a lot of hype around intermittent fasting, but what are its actual benefits, and what are its limitations?

We lay bare the myths and the…. In this edition of Medical Myths, we investigate 11 misconceptions about weight loss. We cover sugar and sweeteners, skipping meals, snacking, and…. Researchers say bariatric surgery can help with weight loss, but it can also help improve cognitive functions including memory.

Researchers say running can help with weight loss but only in the short term. This form of exercise does have other health benefits from maintaining…. My podcast changed me Can 'biological race' explain disparities in health?

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Medical News Today. Health Conditions Health Products Discover Tools Connect. Weight loss: Study finds calorie restriction more effective than intermittent fasting. By Jessica Freeborn on January 25, — Fact checked by Jennifer Chesak, MSJ. Share on Pinterest Intermittent fasting may not be as effective for some people as previously thought.

Help is available Eating disorders can severely affect the quality of life of people living with these conditions and those close to them. Many other resources are also available, including: The National Association of Anorexia Nervosa and Associated Disorders F. Was this helpful?

Too few calories can hamper your metabolism, sabotaging any goal to lose weight. The flip side of the coin, however, is that — as with everything in life — calorie cutting for weight loss requires balance. Reducing calories too drastically for too long can actually derail your efforts to slim down, and even cause health problems.

Healthy calorie cutting for weight loss shouldn't be a game of limbo as in, testing how low you can go , but more like a puzzle. It helps to understand that calories are energy, and energy plays multiple roles in the body. The remaining calorie intake should power your daily activities, or activity energy expenditure AEE.

Medical conditions, genetics, and age can all influence how quickly you reach a calorie deficit or surplus. Different types of foods may get processed differently, too. com and the author of Read It Before You Eat It — Taking You From Label to Table. For weight maintenance, the Dietary Guidelines for Americans — suggest a range of 1,—2, calories for women and 2,—3, for men — so you could consider anything below these numbers a low-calorie diet.

But some popular diet plans take users to extremely low levels. The HCG diet , for example, supplies as low as calories per day, and the Master Cleanse offers a range of , calories.

Other low-cal eating plans, like the TLC diet diet hover higher, near the 1, to 1,—calorie mark, or calculate a specific number based on your current weight and goal weight.

A low-calorie diet is a straightforward, research-confirmed path to weight loss, with plenty of journals, calculators, apps, and other resources available for calculating your progress.

That said, a slash-and-burn approach to calories may come with downsides. Meticulous tracking of numbers and portion sizes can be unhealthy territory for some people, ultimately creating disordered eating behavior.

Regardless of your mental health history, a super-low-calorie diet may not be sustainable in the long term. And plenty of research supports the notion that physical activity enhances weight loss by burning more calories. We all need calories for survival. If you cut back your calories too much, it hinders weight loss.

To prevent weight loss plateaus, Spiegel recommends a goal of 1 to 2 pounds lost per week. Before you start a low-cal diet, consider discussing your plan with a registered dietitian or other healthcare professional who specializes in weight loss.

Pankaj Kapahi, a researcher at the Buck Institute for Research on Aging, said that along with calorie restriction, exercise and eating a balanced diet are also important factors to consider for aging.

He was not involved in the research. Kapahi added that the study's findings do not mean people should starve themselves, saying that could lead to malnutrition and poor mental health. Valter Longo, a biochemist and director of the Longevity Institute at the University of Southern California, said that limiting calories for extended periods of time can be harmful.

Studies in animals, for example, have shown that long-term calorie restriction was found to be associated with a risk of reduced muscle strength, slower metabolism and an impaired immune system, said Longo, who was not involved in the study. Hadley cautioned against overinterpreting the results, saying calorie restriction may not be for everyone, including those with multiple underlying conditions.

He advised speaking with a doctor before undergoing a calorie-restricted diet. Berkeley Lovelace Jr. is a health and medical reporter for NBC News.

He covers the Food and Drug Administration, with a special focus on Covid vaccines, prescription drug pricing and health care. He previously covered the biotech and pharmaceutical industry with CNBC.

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Search Search. Profile My News Sign Out. Sign In Create your free profile. Sections U. tv Today Nightly News MSNBC Meet the Press Dateline. In addition, during the initial 13 weeks of the study intervention, participants in DCR and ADF were not provided any behavioral weight loss support and were provided all meals, limiting real-world applicability.

Furthermore, participants were instructed to not change their PA, which is not consistent with current guidelines for obesity treatment [ 17 ]. Headland et al.

In addition, the behavioral support was minimal, with participants receiving initial advice from a dietitian, but no ongoing individual or group-based support. Finally, while participants were given a PA goal of 10, steps per day, between-group differences in PA levels were not reported.

Lastly, Carter et al. Participants received individualized behavioral support sessions with a dietician biweekly for the first 3 months and every 2—3 months for the remaining 9 months, with no guidance to increase PA.

However, this weight loss intervention did not meet the obesity treatment guidelines regarding either behavioral support or PA recommendations.

Furthermore, adults with type 2 diabetes mellitus typically have a more difficult time losing weight as compared to adults without diabetes [ 23 ], which limits the generalizability of results. Thus, additional, longer-term randomized trials are needed to evaluate the effectiveness of IMF as compared to DCR on changes in weight, EI, and PA, when these approaches are delivered using guideline-based behavioral support and PA prescriptions.

Provision of a comprehensive behavioral support program will likely enhance adherence to IMF and result in greater weight loss and improvement in metabolic outcomes in IMF than observed in prior studies. The D aily C aloric R estriction vs. I ntermittent F asting Trial DRIFT was designed to compare weight loss generated by IMF vs.

DCR in adults with overweight or obesity enrolled in a week comprehensive behavioral weight loss intervention. This study will provide translatable clinical data on the effectiveness of a novel dietary weight loss intervention IMF as compared to the current standard of care DCR over 52 weeks.

In addition, this study will use rigorous, objective methods to measure EI and PA, so that adherence to the dietary and PA prescriptions can be compared between IMF and DCR. The aims of DRIFT are to 1 compare changes in body weight primary outcome , body composition, and metabolic parameters induced by IMF and DCR; 2 evaluate the impact of IMF vs.

DCR on EI and dietary adherence; and 3 evaluate the impact of IMF vs. DCR on energy expenditure EE and patterns of PA. Informed by our prior IMF pilot study that suggested that IMF may be better for long-term weight loss maintenance vs. DCR [ 15 ], our a priori hypotheses are that IMF will generate greater weight loss primary outcome , greater decreases in fat mass, improved maintenance of lean mass, and greater improvements in metabolic parameters fasting lipids, insulin sensitivity, blood pressure at 52 weeks.

While these hypotheses are contrary to recently published data from long-term studies, these data were not available at the time the study was designed. We also will use the National Institutes of Health NIH Accumulating Data to Optimally Predict obesity Treatment ADOPT framework to evaluate selected biologic, behavioral, environmental, and psychosocial predictors of weight loss response [ 24 , 25 , 26 , 27 , 28 ].

DRIFT is designed as a two-arm randomized controlled trial. Eligible participants will be randomized into one of two study arms: IMF or DCR. This study was powered as a superiority trial.

However, if superiority cannot be established, power was also performed for non-inferiority, a priori see item There are no planned interim analyses.

Outcome measures will take place at baseline and weeks, 13, 26, 39, and Selected follow-up measures obtained 26 weeks after completion of the week intervention i. This is not a primary study outcome timepoint, but rather a week post-primary outcome follow-up.

Healthy men and women with overweight or obesity will be recruited from the region around Denver, Colorado. All participants will be recruited and studied at a single site, the University of Colorado Anschutz Medical Campus CU-AMC.

in past 3 years for any reason except post-partum weight loss; 29 urinary incontinence or retention to a degree that would interfere with planned doubly labeled water DLW measures; or 30 prescription medication s that must be taken with food that would preclude the ability to adhere to the IMF intervention.

Females will also be excluded if they are currently pregnant or lactating, were pregnant within the past 26 weeks, are planning to become pregnant in the next 52 weeks, or are sexually active and not using contraception.

Volunteers will be initially assessed for eligibility via a preliminary online screening questionnaire or telephone interview.

Potential participants will be asked general eligibility questions regarding age, height, weight, and medical history and receive a brief explanation of the purpose of the study and study expectations, including participant responsibilities and potential risks related to study participation.

Interested individuals will be scheduled for a consent and screening visit to determine eligibility. Study coordinators will review the consent form with participants in a private setting. After providing written informed consent, potential participants will undergo a detailed health history and physical examination with the study physician.

Body weight and height will be measured to confirm the self-reported BMI. Resting blood pressure and heart rate will be measured, and a resting lead electrocardiogram will be obtained.

A fasting venous blood sample will be drawn for measurement of a complete blood count, comprehensive metabolic panel, lipid profile, hemoglobin A1c, and TSH. A urine pregnancy test will be performed in women.

Laboratory values available within the past 52 weeks may be substituted for these screening labs at the discretion of the study physician except for the urine pregnancy test.

Participants will also complete the Physical Activity Readiness Questionnaire [ 29 ] to assist in screening for exclusionary medical conditions. Prior to randomization, all eligible participants will undergo a test fast day to ensure they understand the requirements of the IMF intervention.

Study staff will discuss the test fast experience with participants and confirm their willingness to be randomized to the study. During informed consent, participants will be provided an opportunity to consent for additional, optional ancillary studies and storage of data and biological specimens including blood and stool to be used in future research, including genetic research.

We chose to compare IMF to DCR as DCR is the current standard-of-care dietary weight loss intervention. Both groups will receive a guideline-based PA prescription [ 34 ] and a comprehensive, group-based behavioral weight loss intervention consistent with current guidelines for obesity treatment [ 17 ].

Weight maintenance energy requirements will be calculated as resting energy expenditure REE measured by indirect calorimetry multiplied by an activity factor of 1. On fed days, IMF participants will eat ad libitum, but will be encouraged to make healthy food and portion choices.

Sample fast day menus and individualized fast day calorie goals will be provided to assist in achieving EI targets. On fast days, participants will be encouraged to consume their calories in their dinner meal.

However, they will be allowed to consume their fast day calories at other times of the day if they have difficulty with the recommendation to consume all calories at dinner. A previous study using a similar IMF protocol [ 36 ] found that altering times of caloric intake during the modified fast day i.

Participants in this group will be instructed in calorie counting and food logging but will be asked to count calories and log food intake only on fast days. We chose a modified IMF paradigm rather than a zero-calorie IMF paradigm i.

First, our review of the scientific and lay literature revealed that the strategy largely endorsed is a modified IMF protocol rather than a zero-calorie IMF protocol ; thus, we felt a modified IMF protocol was the most clinically relevant paradigm to study.

Second, in a prior study of a zero-calorie IMF intervention, the level of self-reported hunger remained high throughout the study [ 37 ].

In contrast, in studies using a modified IMF approach, hunger decreased [ 38 , 39 ] or remained unchanged [ 40 , 41 ] compared to pre-intervention levels, suggesting that long-term compliance may be better with a modified IMF protocol. Results suggested that a modified fast day produces a similar energy deficit as a zero-calorie fast day over a 3-day period because there is less compensatory increase in EI on the post-fast day with the modified fast [ 42 ].

As in the IMF group, weight maintenance energy requirements will be determined as measured REE × activity factor of 1. This target is consistent with current PA guidelines for weight management [ 34 , 43 ].

Participants will be instructed in how to use a relative intensity scale [ 34 ] to achieve the target of moderate intensity. To improve adherence to the interventions, both groups will receive a week group-based behavioral weight loss program with equivalent contact and support see Table 2 for a list of weekly behavioral support topics.

The programs will fulfill all recommendations for behavioral interventions for treatment of obesity outlined in current guidelines [ 17 ]. Randomized groups will meet separately. Curriculum for DCR will be based on the Colorado Weigh behavioral weight loss program which was developed at CU-AMC in and uses a skills-based approach and cognitive behavioral strategies for lifestyle modification with a dietary focus on DCR [ 44 , 45 ].

Curriculum for IMF will also be based on the Colorado Weigh behavioral weight loss program and features similar weekly curriculum themes as used in DCR but adapted by the study PI VC with input from a registered dietitian KB and a behavioral psychologist AC to focus on behavioral support specific to IMF.

Group meetings will be taught by a registered dietitian with experience in leading group-based behavioral weight loss interventions. Groups will meet weekly during weeks 0—13 and every 2 weeks during weeks 14— Weight will be obtained at each group meeting.

Group sessions will last ~60 min and the curriculum will be delivered using a mix of large group discussion, small breakout discussions, visual demonstrations, and written exercises. Participants in the DCR group will be instructed in specific strategies to support DCR with a focus on daily calorie counting and food logging.

Topics covered in both groups during the first 26 weeks include realistic weight loss goal setting, self-monitoring strategies, mindful eating, stress management, cognitive restructuring, improving personal food environments and social networks, and strategies to overcome barriers to healthy eating and increasing PA.

Later in the curriculum weeks 27—52 , topics will focus on strategies for weight loss maintenance and include impact of weight loss on EE and propensity for weight regain, relapse prevention, and identifying motivation for long-term dietary and PA changes.

Participants will also be provided two 10—15 min phone calls with their group leader during the initial 26 weeks of the intervention for individualized dietary goal setting using a standardized protocol. Participants will also be provided a 20—min in-person PA support session and a 10—min follow-up telephone call with an exercise specialist during the initial 26 weeks of the intervention for individualized PA goal setting using a standardized protocol.

IMF participants will be guided in strategies to adjust exercise duration on fast days if needed and still meet weekly PA targets. Participants will be provided access to the CU-AMC Anschutz Health and Wellness Center Fitness Center for the duration of the intervention.

Adherence to the prescribed dietary interventions for both randomized groups DCR, IMF will be monitored via 1 7-day diet diaries, 2 monthly dietary adherence surveys, and 3 the DLW intake-balance method.

Participants will not be withdrawn for non-adherence in this intent-to-treat study. Participants in both groups will be encouraged to adhere to the dietary prescriptions without modification for the initial 2 weeks as a prior study suggests individuals with obesity become habituated to IMF after ~2 weeks [ 38 ].

IMF participants will be allowed to reduce fasting to 2 days per week i. Participants will be allowed to continue these strategies for 2 weeks and will then be asked to re-try the original dietary prescription. If they are still unable to tolerate the original dietary prescription after a second attempt, they will be allowed to continue at the modified levels for the study duration.

Percentage of participants in each group requiring sustained intervention modification will be recorded. The allocated interventions will not be modified other than as described above. Participants will not be provided any compensation if they experience harm or injury from participating in the study.

Participants will continue to have access to the printed behavioral weight loss program materials that will be provided during the intervention after completion of study participation. Participants will be asked to complete assessment visits at baseline and weeks 13, 26, 39, and 52 during the intervention as well as a follow-up assessment 26 weeks after completion of the week study intervention i.

See Table 3 for assessments by study timepoint. Body weight, measured in the clinic, is the primary study outcome. Among participants allocated to IMF, outcomes will be measured after a fed day.

Body weight will be measured using a digital scale in the CU-AMC Anschutz Health and Wellness Center clinic accurate to ±0. Participants will also be given a smart scale ©BodyTrace smart scales Palo Alto, CA for daily home weighing use during the week study intervention.

These daily weights will be transmitted via wireless cellular network to a secure website. Height will be measured to the nearest 1 mm with a stadiometer at baseline. Blood pressure will be measured with a manual sphygmomanometer average of 2 seated values taken after 5 min rest at baseline and weeks 13, 26, 52, and Waist circumference cm will be measured at baseline and weeks 13, 26, 52, and 78 with a tape measure parallel to the floor, just superior to the iliac crest.

Fat mass and lean mass will be measured using dual-energy x-ray absorptiometry DXA at baseline and weeks 26, 52, and At baseline and weeks 26 and 52, REE will be measured using indirect calorimetry Parvo Medics TrueOne , Salt Lake City, UT in the AM in a thermoneutral 68—74 °F quiet room after a h overnight fast and h abstention from exercise.

For the duration of the test, the participant will be asked to remain motionless and awake. Prior to each measurement, the pneumotach flowmeter will be calibrated using a 3-L calibration syringe Hans Rudolph Inc. REE will be measured for 20 min and the average of the last 15 min of the measurement will be used to calculate REE using the Weir equation [ 46 ].

TDEE will be measured using the DLW method at baseline and at weeks 26 and Participants will arrive in the AM after a h fast. Participants will consume a dose based on body weight and an estimation of total body water.

Delivered doses will range from 0. The dosing cup will be rinsed twice with 30 mL of water and the rinsing dose consumed. The exact time of dosing will be recorded.

Urine will be collected after a 4-h and 5-h post-dose equilibrium period and then again on day 8 at the same time points. Frozen urine samples will be thawed and prepared by centrifugation and analyzed for 18 O and 2 H 2 enrichment by Off-Axis Integrated Cavity Output Spectroscopy OA-ICOS, Los Gatos Research Inc, Mountain View CA , as previously described [ 47 ].

TDEE will be determined using the two-point method according to Speakman et al. EI will be calculated using the intake-balance method. Change in body composition determined by DXA scan will be used to calculate change in energy stores ΔES using 9.

However, because DLW cannot quantify macronutrient intake or provide information on patterns of EI on fed and fast days, 7-day diet records will also be collected at baseline and weeks 13, 26, 52, and Diet records will be analyzed by Colorado Clinical and Translational Sciences Institute Nutrition Core personnel blinded to study group assignment using Nutrition Data System for Research software University of Minnesota.

The activPAL TM micro activPAL4, PALTechnologies, Glasgow, Scotland will be used to estimate time spent in moderate-to-vigorous PA MVPA , light activity, and sedentary behavior over a 7-day period at baseline and weeks 13, 26, 52, and The activPAL4 micro is a small The device is attached to the anterior thigh and is waterproofed by wrapping in a nitrile sleeve.

Thus, it can be worn during bathing and overnight, allowing for h measurement of wake and sleep behavior. Raw activPAL.

datx files will be processed using PALBatch software using the CREA — h wear protocol allows for 4 hours of non-wear per day and auto-correcting for inverted wear PAL Technologies Ltd. The algorithm will be used to determine time spent engaging in sedentary behavior, light activity, and MVPA.

Many studies have validated the activPAL for use in adults and report very high levels of accuracy Participants will also be asked to record all exercise and sleep times i. Self-reported dietary adherence and ratings of effort to adhere to the prescribed study diets will be obtained on a monthly basis during weeks 1—52 using methodology described by Dansinger et al.

Participants will be asked to rate on a 1—10 Likert scale: 1 how adherent they were to the prescribed study diet over the past week, 2 how hard was it to adhere to the prescribed study diet over the past week, and 3 how likely they feel they can adhere to the prescribed diet for the next month.

Participants in the IMF group will be asked to report the number of fast days over the past week. During weeks 53—78, monthly dietary follow-up questionnaires will be administered to evaluate participant efforts to continue weight loss or weight maintenance after the week intervention has ended.

A h fasting blood sample will be obtained for assessment of glucose, insulin, hemoglobin A1c, lipid panel, leptin, ghrelin, peptide YY, and highly sensitive C-reactive protein hs-CRP at baseline and weeks 26, 52, and Circulating nutrients and hormonal regulators of fuel metabolism glucose, insulin, triglycerides, free fatty acids, beta-hydroxybutyrate, and cortisol will be measured at baseline after both a fed i.

Labs will be analyzed by the UCHealth Clinical Laboratory beta-hydroxybutyrate or the Clinical Translational Research Institute CTRC, all other labs. Insulin sensitivity homeostasis model assessment of insulin resistance, HOMA-IR will be calculated as [insulin] × [fasting glucose × 0.

To measure psychosocial, behavioral, and environmental constructs which may predict weight loss response, several validated questionnaires and computer-based tasks will be administered to participants.

Selection of measures was informed by the recommendations of the NIH ADOPT Core Measures Project [ 24 , 27 , 28 ]. Questionnaires will be administered at baseline and at weeks 13, 26, 52, and 78 see Table 4. Each month, participants will also be asked to report any changes in their home or work address, to capture changes in their built, social, and community food environments.

Executive control will be assessed using computerized task-based measures of executive function i. The battery of computerized tasks to assess key domains of executive function will be deployed locally on a secure study computer and iPad coded by participant ID.

See Table 3 for the schedule of enrollment, randomization, interventions, and assessments for study participants. An a priori power calculation was performed for the primary outcome weight using nQuery 7. Standard deviation SD of weight loss used in this calculation was 5.

There are no previous data for us to estimate the effect size for any of the outcomes at 52 weeks. If superiority of IMF to DCR cannot be established, we will perform a non-inferiority test using 2.

Potential participants will be recruited from the Denver Metro area. We will recruit using CU-AMC campus wide e-mails, flyers, and research website which maintains an updated list of available studies performed on campus which is also accessible to the general population.

We will also provide flyers to the University of Colorado Primary Care practices as well as other local primary care practices including Denver Health Medical Center which serves low-income and minority populations.

The trial is registered at ClinicalTrials. We will also employ social media advertising strategies including the use of BUMP Digital Marketing. BUMP uses social media networks Facebook, Instagram, etc. to target a population of interest using an appealing advertisement for the study. The advertisement will include a link to a study landing page providing more information about the study, including a brief description of the study requirements and eligibility criteria.

Interested individuals will be provided a link to a screening questionnaire. The randomization assignment will be generated by the study biostatistician ZP using a computer-generated block randomization performed within strata defined by sex. Allocation of treatment will take place after all eligible participants for each cohort have completed baseline measures, based on the a priori randomization list.

The study biostatistician will generate the allocation sequence. After all participants have completed screening and baseline assessments, participants will be notified of the randomization assignment on the first day of group class for the intervention.

This process will take place separately within each cohort. Due to the nature of the intervention, it is not plausible to blind participants. However, participants will be blinded to the study hypothesis.

Due to the nature of the group-based behavioral intervention, it is also not plausible to blind study staff who enroll participants and deliver or monitor intervention delivery. However, the following personnel will be blinded to study group assignment: 1 staff performing laboratory analyses, 2 DLW assessment core staff performing analysis of the DLW samples, and 3 Colorado Clinical and Translational Sciences Institute Nutrition Core personnel who will be using Nutrition Data System for Research software to analyze the 7-day diet diary data.

Lastly, all data analyses and reporting will be completed by study investigators who are blinded to study arm assignments. Study personnel who are responsible for analyzing data and reporting results will remain blinded throughout the study period.

Outcome measures will be assessed during in-person clinic visits with trained, research staff. We will use detailed data collection forms to promote data quality and reduce assessor error. Weight, blood pressure, and waist circumference will be measured twice and the average of the two measures will be used in analyses.

Questionnaires will be administered online using REDCap survey or Qualtrics. Scores from questionnaire responses will be calculated directly within REDCap using hidden, calculated fields. See Table 4 for a list of each study questionnaire and the questionnaire references.

The study coordinators will be responsible for establishing and maintaining contact with participants throughout the study. If study appointments are missed, the study coordinator will follow-up with a telephone call to reschedule.

If participants miss two group-based support classes in a row without prior communication, study coordinators will contact participants to discuss attendance. In our experience, the most important characteristics of high retention is frequent and high-quality interaction with key study staff.

We will ensure continuity of key staff during the entire study so that participants build a relationship with study personnel, to provide inspiration and increase accountability.

Participants will also be compensated for completing study outcome measures. Field and range checks will be programmed to minimize data entry errors. Data distribution will be checked periodically, and outliers verified; missing data will be tracked and checked.

All data will be entered into the REDCap database and will be sight verified by a second study staff member. The key linking participant name and participant identifier code is kept in a secured location, with only key personnel having direct access to the list.

Participant identifier codes will be used for all data entry and data analyses. The investigative team will be trained in accordance to both the Colorado Multiple Institutional Review Board COMIRB and the Health Insurance Portability and Accountability Act HIPAA compliance issues and will act to maintain confidentiality and protect health information.

Electronic data will be stored on secure servers with a high level of security, controlled access, daily back-up, and long-term retention of back-up files.

Access to all study data will be restricted to the principal investigator and research personnel. Stool samples will be self-collected by study participants at baseline and weeks 13, 26, 52, and 78 using the Alpco EasySampler Stool Collection Kit.

Baseline characteristics will be summarized by treatment groups using descriptive statistics. Normality assumptions will be evaluated, and transformations used e. Body weight is the primary outcome variable and others are secondary or exploratory outcomes. Consequently, no adjustment for multiple outcomes will be applied.

Any imbalance in baseline characteristics between groups that could potentially be a confounding factor for the outcome will be adjusted for in the statistical model.

Each continuous outcome will be analyzed using a linear mixed effects model. The fixed effects of the linear mixed effects model will consist of treatment group IMF or DCR and time of measurement i.

Time of measurement will be treated as a continuous or categorical variable, as appropriate. Test of the interaction assesses the difference in post-intervention change from baseline between two groups and is used to quantify the effectiveness of the intervention. Among factors with a significant three-level interaction, we will further use post-intervention weight loss as the outcome and multiple linear regression to examine their association with the outcome and its interaction with intervention.

Similar multiple logistic regression analysis will also be conducted with the outcome dichotomized as responder and non-responder using clinical criteria. Although not formally powered to examine sex differences, results will be reported separately for men and women to enhance transparency and inform data interpretation.

All randomized participants will be analyzed. We expect that missingness condition is either missing completely at random MCAR or missing at random MAR. A linear mixed effects model will serve as the primary method to handle missing values.

The primary and secondary outcomes will be further examined using various sensitivity analyses including analysis of completers using the above statistical models; imputing missing values using baseline-observation-carried-forward, and then assessing efficacy by analyzing the change score from baseline using two sample t -tests or linear regression model while adjusting for other covariates; and finally imputing missing values using Markov chain Monte Carlo multiple imputation to create 20 imputed data sets and then analyzing the data using the linear mixed effects model.

This paper provides the full protocol. Interested individuals should contact the study principal investigator VC if interested in other data or documentation of the study.

This single-site randomized trial does not have a coordinating center or trial steering committee. The trial will be supervised by the PI VC with input from study co-investigators co-authors EM, DB, PM, and ZP. Additional oversight will be provided by an independent Safety Officer who will review study conduct and progress on an annual basis as outlined in our NIH-approved Data and Safety Monitoring Plan DSMP.

The screening medical history and physical exams will be performed by the PI VC , co-investigator DB , and co-author AZ , all of whom are MDs with current board certification.

The PI and the study PRAs will meet weekly to discuss trial conduct and progress including recruitment and retention. Co-investigator meetings will be held monthly during the study startup phase and then as needed to discuss any issues that arise with trial conduct.

The intervention and measurement protocols pose minimal risk to participants. Because of this low-risk status, the data safety monitoring plan for this trial focuses on close monitoring by the principal investigator an MD with current board certification in Endocrinology in conjunction with an independent Safety Officer, along with prompt reporting of excessive adverse events and any serious adverse events to the NIH and to COMIRB.

The Safety Officer will review the reports prepared by the study coordinator at the annual Safety Officer meeting and will determine whether there is any corrective action, trigger of an ad hoc review, or stopping rule violation that should be communicated to the study investigator, COMIRB and the study sponsor.

We plan to collect adverse event data on a case-by-case basis. Adverse events will be reviewed, collated, and evaluated by the PI within 72 h. All serious adverse events will be evaluated by the Safety Officer and the PI within 24 h. A summary table of adverse events Safety Report will be compiled on an ongoing basis and will be provided to the independent safety officer at the annual meeting.

The summary table will include a description of the adverse event, the date of onset, severity, action taken, outcome, whether the adverse event was expected or unanticipated, and a determination of the relationship of the adverse event to study procedures.

Adverse event reports and annual summaries will not include identifiable material and participants will be identified only by study ID number. To review study conduct throughout the trial period, study team meetings, led by the PI VC , will occur on a weekly basis.

The independent Safety Officer will review trial conduct and progress annually, as outlined in our NIH-approved DSMP. An annual report will be submitted for continuing review per COMIRB requirements. Lastly, an annual progress report will be submitted to the study sponsor NIH. Any protocol changes that impact study procedures or risk to human subjects will be approved by COMIRB and reflected in a revised consent form that will be reviewed and signed by all active participants.

Protocol changes will also be reported to NIH at the annual progress reports. Findings from this study will be shared publicly and disseminated mainly by publication in peer-reviewed journals and conference presentations.

Journal articles will be submitted to PubMed Central in compliance with NIH access guidelines. Main outcomes are planned to be submitted for publication during — Peer-reviewed findings will also be disseminated through CU-AMC social media outlets. Research data, which documents, supports, and validates research findings, will be made available after the main findings from the final research data set have been accepted for publication.

No research data with personal identifiers will be published under this project. Although weight loss interventions based on DCR lead to modest weight loss success in the short-term, there is wide inter-individual variability in weight loss and poor long-term weight loss maintenance.

IMF may represent a promising dietary strategy to help more people achieve weight loss and improve their metabolic health. However, the current evidence base has significant limitations including lack of a standard-of-care DCR control, failure to provide guideline-based behavioral support, and failure to rigorously evaluate dietary and PA adherence using objective measures.

To date, only three longer-term week trials have evaluated IMF as a weight loss strategy [ 19 , 20 , 21 ]. Thus, greater scientific rigor is required from interventional trials than found in the current literature and well-designed trials are needed to demonstrate long-term effectiveness and to understand the impact of IMF on energy balance.

DRIFT will fill this gap in the literature by examining the effectiveness of IMF as a dietary strategy to achieve weight loss compared to DCR, the current standard-of-care, within the context of a week, guideline-based behavioral support program for obesity treatment.

We will use objective methods to measure EI DLW intake-balance method and PA activPAL device to allow for an accurate comparison of adherence to the dietary and PA prescriptions between the IMF and DCR groups. This trial is also unique in that it will be one of the first obesity treatment trials to implement the recommendations from the NIH ADOPT framework to evaluate selected biologic, behavioral, environmental, and psychosocial predictors of weight loss response [ 24 , 25 , 26 , 27 , 28 ].

Our findings may have significant public health implications as this study will generate robust data regarding long-term weight loss effectiveness of IMF as compared to DCR. We anticipate that results will further our understanding of the impact of IMF on energy balance and will provide preliminary insight into predictors of weight loss response within IMF and DCR.

This study protocol was based on version date February 18, We were unable to submit our protocol manuscript prior to completing participant recruitment due to the substantially increased investigator and research staff burden necessitated by COVIDrelated clinical research shutdown activities, followed by COVIDrelated clinical research reactivation activities including developing, obtaining approval for, and implementation of protocols to safeguard clinical research staff and participants as required by CU-AMC.

The additional research burden related to COVID protocols was compounded by frequent staff quarantines and limited access to research offices which required us to focus all investigator and research staff effort on study conduct.

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