Study setting
The study is conducted in the centre for cardiovascular rehabilitation in the city of Leichlingen, North Rhine-Westphalia, Germany. While Leichlingen is a more rural town, the catchment area of the centre is the largest metropolitan area of Germany, a population of over 8 million people within a 50-km radius, including big cities like Cologne (population: 1 million) and Duesseldorf (population: 600.000), but also very rural areas.
Eligibility criteria
The inclusion criteria for this study are the following: male sex and age between 18 and 60years, a diagnosis of coronary heart disease (CHD) and a body mass index (BMI) between at least 27kg/m2 and 38.9kg/m2.
The study exclusion criteria are as follows: a NYHA (New York Heart Association Classification) Functional Class IV, severe obesity (BMI > 39kg/m2), oncological diseases, gastric or duodenal ulcers and insulin dependent diabetes. Patients with an intellectual disability, a current eating disorder or other psychiatric disorders (psychotic disorders, bipolar disorder, substance dependence, or anxiety and depressive disorders) are excluded.
However, we decided to exclude women because of the following reasons: first, some evidence indicates that intermittent fasting may have negative effects on reproduction and blood sugar levels in some women [3, 8, 17]. In all likelihood, such an intervention would produce different results not only in men and women but also in pre- and postmenopausal women [19, 23].
Secondly, female patients are generally underrepresented in cardiac rehabilitation (female-to-male ratio 1:4)Footnote 1 as well as in our study centre. In 2022, only 15% of all patients with CD were female. Therefore, to enroll an adequate number of patients in reasonable time, we solely recruited male patients. Over and beyond, only few studies on lifestyle changing interventions such as intermittent fasting address men. Since men are underrepresented relative to women in current research concerning intermittent fasting, this trial still enriches the existing state of research [9, 10].
Who will take informed consent?
Two qualified and appropriately trained members of the research team are responsible for obtaining consent. Informed consent involves giving information to the potential participant and clarifying the information. In obtaining and documenting informed consent, the research team complies with good clinical practice (GCP) and with the ethical principles of the Declaration of Helsinki [27].
Additional consent provisions for collection and use of participant data and biological specimens
No additional consent is provided for collection and use of participant data who withdraw; this study does not involve collecting biological specimens for storage.
Interventions
Explanation for the choice of comparators
The primary outcome of this study is difference in mean weight loss between baseline and end of inpatient rehabilitation after 4weeks (short-term effectiveness). This outcome has been selected as the primary outcome, because intermittent fasting addresses weight as a main risk factor for cardiovascular disease.
Intervention description
The InterVFast intervention was designed by a cooperation of researchers and clinicians from the fields of epidemiology, cardiology and rehabilitation medicine and nutritional advice. The specific contents of the intervention are as follows:
16:8-intermittent fasting
The intervention consists of a 16:8-intermittent fasting programme during the 4-week inpatient rehabilitation. 16:8-intermittent fasting involves fasting for 16h a day and consuming all calories during the remaining 8h. For example, a participant starts eating at 11:00 am and stops eating at 7:00pm. The fasting window is individually adapted to the wishes and needs of the participants.
The fasting programme includes an introduction to the concept of fasting by a nutritionist providing information on the health benefits, practical implementation and fasting tips. Participants in the IG document periods of fasting and meals eaten in a paper-based fasting diary.
A fasting consultation is provided by a trained nutritionist twice a week to answer questions and to track individual progress. Purpose of the consultation can be wants, requests, intentions, preferences or expectations. Besides that, the inpatient rehabilitation programme is carried out as usual.
Standard treatment
During 4-week rehabilitation period, the CG receives standard treatment. Regarding eating behaviour, the standard programme includes “healthy-eating” training (2h), shopping tips for healthy eating (1h), a teaching kitchen of 3h, and daily food and beverage buffet training (30min).
Criteria for discontinuing or modifying allocated interventions
Criteria for discontinuing or modifying allocated interventions are any changes in the patient’s condition that justify the discontinuation of treatment in the clinician’s opinion, and participant withdraws consent and confirmation of non-eligibility after registration.
Strategies to improve adherence to interventions
During inpatient rehabilitation, a trained nutritionist held regular fasting visits to improve adherence to the fasting programme.
Relevant concomitant care permitted or prohibited during the trial
There are no restrictions regarding concomitant care during the trial.
Provisions for posttrial care
Participants are able to contact the research team during the study period as well as after the end of participation.
Outcomes
The primary outcome of this study is difference in weight loss between baseline and end of inpatient rehabilitation after 4weeks (short-term effectiveness). Secondary outcomes are difference in weight loss between baseline and 3 and 12months after inpatient rehabilitation (long-term effectiveness), changes in blood pressure, fasting blood glucose and lipids and changes in diet as well as patients’ acceptance.
Weight, blood samples and clinical data are routinely collected as part of the initial and final examination. During inpatient rehabilitation, participants note daily periods of fasting as well as practicability (rating scale from 0 — very bad to 5 — very easy) in a fasting diary. They record all food and drinks, type of meal (breakfast, lunch, dinner, or snack), type of food and portion size. In addition, we carry out interviews about perceived advantages and disadvantages and acceptance with all participants in the IG.
After initial examination at admission (baseline, t0), three follow-up times are provided: final examination at the end of inpatient rehabilitation after 4weeks (t1), as well as two follow-up times after inpatient rehabilitation after 3 and 12months. The World Health Organization-Five Well-Being Index (WHO-5) is used for self-reported measure of current mental wellbeing at t0 and t1. A standardized follow-up examination (weight, blood samples) will be carried out by the family doctor at t2 and t3 for valid information. A financial incentive will be paid to family doctors for examination and data transfer.
Sociodemographic characteristics and comorbidities at baseline will be collected as moderating variables. Stable covariables (e.g. sociodemographic characteristics) will be collected only at baseline, while changeable variables will be measured at baseline and follow-up.
Participant timeline
Eligibility screening took place at initial admission examination (t0) involving medical history review, physical exams and laboratory tests. Figure1 shows the schedule of enrolment, intervention and assessments.
Schedule of enrolment, intervention and assessments
Patients who met the inclusion criteria were invited to provide study information at the beginning of the inpatient rehabilitation in a personal conversation. We explained the study’s purpose, procedures and potential risks and benefits to the patient. Each patient received appropriate written participant information and an informed consent form.
Sample size
A before-and-after comparison between the intervention group (IG) and the control group (CG) will be used for the evaluation. Follow-up values were assessed at t1, t2 and t3. Regarding the primary outcome, the intervention is considered effective if mean difference in weight loss after 4weeks (t1) in the IG is at least 2% higher than in the CG compared to baseline (t0). The standard deviation of mean difference is estimated at 3.5kg. The significance level should be 5%. In order to demonstrate difference in weight with a power of 80%, a two-tailed t-test requires a total of 100 patients (50 per group).
Recruitment
Based on an estimated participation rate of 20%, a period of 6months was planned for the implementation of the intervention and patient enrollment.
Assignment of interventions: allocation
Sequence generation
As soon as the patient gave written consent, randomization was performed. Randomization took place at individual level, i.e. every single patient was assigned either to the IG or to the CG. A statistician who is not involved in the study generated the randomization list using computer-generated random numbers.
Concealment mechanism
The research team member recruiting the patients contacted the randomization office by phone or secure computer after the patient was enrolled in the study (central randomization).
Implementation
After eligibility screening took place at initial admission examination (t0) involving medical history review, physical exams and laboratory tests, two trained members of the research team enrolled patients. To minimize the effect of bias, the random allocation sequence remained concealed from those enrolling patients into the study.
Assignment of interventions: blinding
Considering the nature of the intervention, participants and therapists cannot be blinded. So, the design of the study is open label; therefore, unblinding will not occur.
The statistician was not blinded, because, to our mind, the statistician should have a good knowledge of the topic of cardiovascular rehabilitation and the intervention. The statistician was not involved in the intervention and data collection.
Data collection and management
Plans for assessment and collection of outcomes
The primary outcome of this study is difference in weight loss between baseline and end of inpatient rehabilitation after 4weeks.
Secondary outcomes are difference in weight loss between baseline and 3 and 12months after inpatient rehabilitation, changes in blood pressure, fasting blood glucose and lipids and changes in diet as well as patients’ acceptance.
Weight, blood samples and clinical data are routinely collected as part of the initial and final examination. During inpatient rehabilitation, participants note daily periods of fasting as well as practicability (rating scale from 0 — very bad to 5 — very easy) in a fasting diary. They record all food and drinks, type of meal (breakfast, lunch, dinner, or snack), type of food and portion size.
After initial examination at admission (baseline, t0), three follow-up times are provided: final examination at the end of inpatient rehabilitation after 4weeks (t1), as well as two follow-up times after inpatient rehabilitation after 3 and 12months. The World Health Organization-Five Well-Being Index (WHO-5) is used for self-reported measure of current mental wellbeing at t0 and t1. A standardized follow-up examination (weight, blood samples) will be carried out by the family doctor at t2 and t3 for valid information.
Plans to promote participant retention and complete follow-up
To assure participant retention and completion of follow-up for t2 und t3, we send a reminder about completing the survey to participants who have not yet participated in the follow-up evaluation. A financial incentive will be paid to family doctors for follow-up examination and data transfer.
All baseline data is collected also for participants who discontinue or deviate from intervention protocols.
Data management
We perform double data entry and range checks for data values. Data quality management also includes data cleansing (completeness, consistency, duplicates) and validation of data against standard statistical measures. Co-investigator meetings were held monthly during the recruitment phase and then quarterly.
Onsite-research team
The members of the onsite-research team facilitate and coordinate the study activities in the rehabilitation centre. They provide intervention measures and collect data as required by the protocol. They provide information for the PI and the team members who are responsible for administration, randomization and analysis.
Confidentiality
For the statistical analysis, personalized data is documented only in the rehabilitation centre. Solely, pseudonymized data is sent to the Institute for Medical Informatics, Biometry and Epidemiology (IMIBE) for analysis. All employees are familiar with quality-assured data collection, data monitoring and documentation.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use
This study does not involve collecting and storing biological specimens for storage in the current trials and for future use in ancillary studies.
Patient/public involvement
We conduct structured patient interviews to evaluate the patient’s experience with the intervention. Public involvement takes place in the course of dissemination of generally understandable study results.
Statistical methods
Statistical methods for primary and secondary outcomes
The statistical evaluation is carried out using the statistical software SPSS (IBM SPSS Statistics, version 29). The confirmatory analysis to measure the effect of the intervention will be carried out as an intention-to-treat analysis, i.e. all participants who are randomized are included in the statistical analysis and analysed according to the group they were originally assigned. Additional analyses will focus on secondary outcomes as well as associations between independent and dependent variables.
Fasting diaries will be analysed using in-house nutrition information. The mean daily caloric intakes will be computed.
The WHO-5 uses a 6-point Likert scale ranging from 0 = “at no time” to 5 = “all of the time”. The sum of these answers is multiplied by 4; scores of 50 or lower suggest that participants might suffer from depression.
Between-group differences at baseline will be tested using analysis of variance (ANOVA). To answer the primary research question, the mean difference in weight loss between the two groups is compared using analysis of variance (ANOVA), a two-tailed t-test, or Spearman’s correlation coefficient, respectively. Chi-square tests are used to compare proportions. All continuous outcomes will be modelled using linear regression. We will analyse the effect of fasting while taking into account periods of fasting and calorie intake from the fasting diaries. All statistical tests assume a two-sided significance level of 0.05.
Guided interviews are transcribed and coded by two independent researchers along an open coding scheme using qualitative content analysis by Mayring [14] via the software MAXQDA (VERBI GmbH, Berlin, Germany). Qualitative content analysis aims at classifying qualitative data into categories of similar connotation.
Interim analyses
This randomized trial does not incorporate interim analyses to stop the study for futility. Coming from experience, we neither assume not to reach the full planned sample size nor that early data would suggest that an important treatment effect is unlikely to be found, even if the study continues to its full planned sample size.
Methods for additional analyses
We will analyse the effect of sociodemographic and clinical variables on the primary outcome as well as the effect of periods of fasting and calorie intake. Additionally, stratified analysis will be performed for those who completed t2 and t3 follow-up. All statistical tests assume a two-sided significance level of 0.05.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data
We use the ITT approach; all randomized patients are included in the analysis, based on the groups to which they were initially randomly assigned. To assess the bias of your data due to non-response, we will perform a non-response bias analysis.
Plans to give access to the full protocol, participant level-data and statistical code
There are no plans to grant access to full protocol, participant-level dataset or statistical code.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee
All investigators are steering committee members, including an external independent expert member. Investigator meetings are held regularly to monitor and supervise the progress of the study towards its short-term and overall objectives and adherence to the protocol.
Composition of the data monitoring committee, its role and reporting structure
We did not implement a special data monitoring committee, because the members of the data research team working on data management are well versed. We performed internal monitoring to verify data within the constraints of the regulatory requirements two times during the data collection phase. A data monitoring committee was not considered as this was a low-risk intervention co-investigator meetings including auditing trial conduct which was held monthly during the recruitment phase and then quarterly.
Adverse event reporting and harms
It is the responsibility of the investigators to report serious adverse events. An adverse event is defined as any untoward medical occurrence in a subject without regard to the possibility of a causal relationship. Adverse events will be collected after the subject has provided consent and enrolled in the study. All adverse events occurring after entry into the study and until rehabilitation discharge will be recorded.
Based on our experience with comparable trials, no adverse events related to the intervention are expected.
Frequency and plans for auditing trial conduct
To assess and assure the reliability and integrity against all relevant written standards, a systematic internal examination is conducted twice a year (three times in total). We will verify the following variables for all patients: initials, date of birth, sex, signed informed consent, eligibility criteria, date of randomization, treatment assignment, adverse events and endpoints. The process is independent from the funder.
Plans for communicating important protocol amendments to relevant parties
Important protocol modification changes will be reported to the ethical committee and other relevant parties.
Dissemination plans
We developed a publication strategy to select appropriate content, formats and audiences. The trial results will be reported to participants and the public in a public-centred research report. Healthcare professionals and the scientific community will be informed via peer-reviewed journal publications and conference proceedings.
According to the guiding principle of the PI’s affiliation, research publications are not influenced or controlled by funders or investigators. We will publish both positive and negative outcomes in an equitable manner.
