Patient and public involvement

Due to the study being planned as a single-centre study and the inability to establish a structure that would represent the population, patient and public involvement was not planned during the design, conduct and reporting stages of this study. However, after the study results are reported, they will be shared with patients and the public.

Trial design

The study is a single-centre, parallel-group (1:1), open-label, randomised controlled trial. Patients who are eligible and agree to participate will be randomly assigned to one of two groups for the 12-week intervention (I. MIND Diet and II. Standard Diet). The intervention duration is 12 weeks. Outcome measures will be assessed immediately before and after the 12-week intervention period.

Trial setting

The study will be conducted as a single-centre study at the Neurology Outpatient Clinic of Muğla Training and Research Hospital in Muğla Province, Türkiye. Participants will be determined among RRMS patients registered at the hospital and attending for routine follow-up visits, in accordance with the principle of voluntariness. The measurements and procedures to be performed during the patients’ initial and final visits (anthropometric measurements, administration of the MSQOL-54 questionnaire, the MFIS scale, the BICAMS battery and the brain fog scale) will be carried out in a room allocated by the institution. The patients’ blood tests are performed by the Neurology Outpatient Clinic of Muğla Training and Research Hospital during routine follow-up visits and are analysed in the hospital laboratory in accordance with standard clinical procedures. The preparation of the patients’ dietary interventions (I. MIND Diet, II. Standard Diet) will be explained via an online video call planned to last 30–45 min on the evening of the initial visit day, and the diet will be sent by e-mail to the patient or their relative (child, sibling, etc.).

Sample size

The study population consists of 327 RRMS patients registered at the hospital. Patients will be included in the study on a voluntary basis. A power analysis was conducted to determine the sample size, and calculations were performed using the G * Power program (version 3.1.9.2, Universität Düsseldorf, Düsseldorf, Germany). To support the sample size assumption, the mean (sd) values reported in the reference study^{(Reference Moravejolahkami, Paknahad and Chitsaz16)} for the 3-month General Quality of Life subscale of the MSQOL-54 (intervention group: 63·2 (sd 5·0); control group: 52·7 (sd 12·8)) were taken as the basis, and the standardised effect size derived from these values was calculated as Cohen’s d = 1·05; this value corresponds to a large effect according to Cohen’s classification (d ≥ 0·80). However, adopting a more conservative assumption, an effect size of d = 0·80 was used for the sample size calculation^{(Reference Cohen27)}. Accordingly, for a two-arm parallel-group (1:1) design, assuming a two-sided significance level of α = 0·05 and statistical power of 1 − β = 0·80 for comparing the means of two independent groups using a two-sided independent-samples t test, the minimum required sample size was determined as n ₁ = 26 and n ₂ = 26 (total n 52). Considering the potential for data loss, an additional 20 % attrition rate (5 patients per group) was included, and the target sample size was planned as a total of 62 RRMS patients (n ₁ = 31 and n ₂ = 31)^{(Reference Cohen28)}.

Participant eligibility criteria

The eligibility of RRMS patients who apply to the Neurology Outpatient Clinic will first be assessed by the investigator physician (diagnostic criteria, medication use and Expanded Disability Status Scale score). Patients deemed eligible by the investigator physician will be referred to the principal investigator, and their eligibility for the study will be checked (BMI, adherence to a special diet, use of dietary supplements). The criteria for determining participants’ eligibility and the criteria for withdrawal from the study are as follows.

Inclusion criteria;

1. Adult RRMS patients aged between 18 and 64 years

2. Having been diagnosed with RRMS at least three months prior

3. No change in disease-modifying therapy within the past 6 months

4. Patients who use their medications regularly

5. An Expanded Disability Status Scale score ≤ 6

6. Patients with a BMI between 18·5 and 29·9 kg/m²

Exclusion criteria;

1. RRMS patients who are pregnant or in the lactation period

2. Presence of another chronic metabolic disease

3. Individuals with limb deficiency

4. Individuals following a specific diet

5. Individuals using antidepressants or mood stabilisers

6. Individuals using nutritional supplements or dietary support products

Criteria for withdrawal from the study;

1. In at least three (25 %) of the weekly interviews, inability to reach the patient, inability to obtain the dietary intake record and/or determination of low adherence to the MIND diet (≤ 5 points)

2. Experiencing a relapse during the intervention

3. Change in disease-modifying therapy during the intervention

4. Initiation of any form of medical nutrition therapy for any reason during the intervention

5. Diagnosis of any chronic metabolic disease or cancer during the intervention

6. Pregnancy occurring during the intervention period

Participant recruitment

The patient recruitment strategy for the study will be that the neurologist investigator refers patients who are eligible in terms of diagnosis, medication and disability to the principalinvestigator. The BMI values of the patients referred to the investigator will be calculated, and their use of dietary supplements and whether they follow a special diet will be questioned. Patients who are eligible in terms of these conditions will be informed about the study. Interested individuals will be given the informed consent form (Appendix 3). A summary of the schedule of activities for participants is provided in Figure 1, and the full schedule is provided in Appendix 4.

Figure 1.

Timing of screening, intervention and assessments. Primary and secondary outcomes will be assessed at baseline and week 13.

Randomisation

Block randomisation will be applied for allocating individuals who meet the inclusion and exclusion criteria and who consent to participate in the study to the study groups. ‘The Permuted Block Randomisation’ stage will be performed using a computer program by an independent researcher who does not have access to participants’ personal information. As the program randomly determines the order of participants using different block sizes (4 and 6), the principle of unpredictability will be achieved more strongly than in randomisation performed with fixed block sizes. The risk of selection bias with this method is minimal.

In accordance with the principle of voluntariness, each participant who meets the inclusion and exclusion criteria will be numbered in the order of enrollment and allocated to the intervention and control groups at a 1:1 ratio. Allocation information will be kept by another researcher who is not part of the study team. The principal investigator who will deliver the dietary intervention will remain unaware of the allocation until anthropometric measurements and the pre-test are completed. Allocation information – limited to the numbers of participants enrolled that day – will be disclosed at the end of each day by the researcher who holds the randomisation information to the researcher who will deliver the dietary intervention, immediately before the initiation of the dietary intervention. With this procedure, it is aimed to minimise potential allocation bias.

In order to preserve the between-group balance and the integrity ensured by randomisation, no additional participant recruitment is planned to replace participants who withdraw from or are excluded from the study during the post-randomisation intervention period. The loss-to-follow-up (missing data) rate was set at 20 % to maintain the statistical power of the study.

Blinding

Blinding” will not be performed due to the distinguishable nature of the dietary intervention for both participants and researchers, and the study will be conducted as an open-label randomised controlled trial. Statistical analyses will be carried out by a researcher independent of the research team. During the analysis process, groups will be coded in the dataset as ‘Group 1’ and ‘Group 2’, thereby blinding the researcher conducting the statistical analyses with respect to group allocation. After the analyses of the primary outcome measures are completed and reported, the group labels will be unblinded and blinding will be lifted.

Interventions and comparator

The intervention of this study is the MIND diet program for the intervention group and the standard diet program for the control group. Any occurrence of the situations listed in the withdrawal criteria section will affect the outcome outputs. In addition, for the same reason, initiating a new exercise program or starting nutritional or herbal supplements will not be recommended, and maintaining the current status will be requested.

MIND diet

The MIND diet was developed in 2015 by nutritional epidemiologist Martha Clare Morris with the aim of preserving and enhancing cognitive function. It combines the principles of the Mediterranean diet and the Dietary Approaches to Stop Hypertension guidelines and has been suggested to be effective in reducing the risk of developing neurodegenerative diseases⁽²²⁾. Unlike the Mediterranean diet, the MIND diet emphasises increased consumption of fruits and green leafy vegetables while limiting cheese intake. The MIND diet consists of fifteen components, ten of which are considered brain-healthy and five of which are considered unhealthy⁽²²⁾. The principles and portion sizes of the MIND diet are presented in Table 1 ^{(Reference Morris, Tangney and Wang20)}.

Table 1.

Principles and portion sizes of the MIND diet

Each patient’s diet will be individually prepared, and their energy requirements will be calculated using the Harris–Benedict Equation and the appropriate activity factor^{(Reference Mousavi-Shirazi-Fard, Mazloom and Izadi29)}. Of the total daily energy intake, 55 % will be obtained from carbohydrates, 15 % from proteins and 30 % from fats. The distribution of the diet throughout the day will be planned in accordance with the principles of the MIND diet to achieve the prescribed portion amounts. The diet plans will consist of three main meals and one snack.

Standard diet

The standard diet program to be applied to the control group was planned in accordance with the Türkiye Dietary Guidelines (TÜBER)⁽³⁰⁾. The patients’ energy requirements will be calculated using the Harris–Benedict Equation with the addition of an activity factor^{(Reference Mousavi-Shirazi-Fard, Mazloom and Izadi29)}, and an isocaloric diet containing 55 % carbohydrates, 15 % protein and 30 % fat will be provided. The distribution of daily nutritional requirements across meals will be arranged in accordance with the principles outlined in TÜBER and tailored to individuals’ requirements (Table 2). Diet plans will be structured as three main meals and one snack. Participants will be asked to adhere to the planned diet for 12 weeks.

Table 2.

Foods and portion sizes recommended for consumption according to TÜBER

TÜBER, Türkiye Dietary Guidelines.

Delivery of dietary interventions and monitoring of compliance

The individually planned MIND diet and standard diet will be explained to the patients on the evening of the initial visit through an online video consultation lasting approximately 30–45 min, and the diet plan will be sent to the patient or their relative (child, sibling, etc.) via e-mail. Patients will be asked to adhere to their diets for 12 weeks. The primary goal is always to ensure optimal adherence to the diet. Therefore, participants will be regularly monitored through weekly online motivational interviews lasting approximately 30 min to assess their dietary compliance. Motivational interviewing is not merely a set of techniques but a communication method. Through motivational interviewing, it is possible to enhance an individual’s intrinsic motivation and focus on problem-solving^{(Reference Miller and Rose31)}. In this way, it also helps facilitate behavioural change^{(Reference Suire, Kavookjian and Feiss32)}. It is considered an important approach because it enables the adoption of desired nutritional behaviours and enhances adherence to the diet^{(Reference Pepe, Lottenberg and Fujiwara33)}.

During the weekly online motivational interviews, a retrospective 24-h dietary recall will be obtained from all participants. In addition, the MIND diet score will be applied to the patients in the MIND diet group to assess adherence to the diet^{(Reference Morris, Tangney and Wang20)}.

A list will be provided to each patient, listing alternative foods that are consistent with the dietary principles applied, physically accessible and economically affordable, together with their portion sizes. At this stage, patients will be encouraged to consume seasonal vegetables and fruits, which are more cost-effective within the framework of the dietary principles.

During the weekly online motivational interviews, all participants will be asked about the difficulties they experience regarding dietary adherence, and these difficulties will be recorded systematically. Personalised recommendations to increase dietary adherence will be provided for these difficulties (e.g. lists of physically and economically accessible foods, practical recipes, alternative suggestions for eating out, appropriate recipes for cravings for sweets, etc.).

Dietary intake record

Through the dietary intake record, the daily and meal-based energy and macronutrient intake of the patients will be determined. To accurately assess the quantity and content of foods, the visual portion sizes included in the TÜBER 2022 report will be used. The patients’ energy and macronutrient intake levels will be calculated by the researcher using the BeBIS computer program (Ebispro for Windows, Stuttgart, Germany; Turkish Version BeBIS, Nutrition Information System, Version 9). Any patient who cannot be contacted during at least three of the weekly sessions or whose dietary intake record cannot be obtained for any reason will be excluded from the study.

Assessment of adherence to the MIND diet

Adherence to the MIND diet will be determined based on the patient’s self-report using the MIND diet score. Each of the fifeen items is scored between 0 and 1 according to the degree of compliance with the principles of the MIND diet. The total score ranges from 0 to 15 points (Table 3). Higher scores are considered to indicate higher adherence. There are no definitive cut-off points for the MIND diet score. Tertile classifications (low, moderate and good adherence) based on participants’ MIND diet scores are performed at the analysis stage^{(Reference Morris, Tangney and Wang20)}. However, for the purpose of monitoring adherence in this study, participants with a MIND diet score ≤ 5 will be classified as having ‘low adherence’, and additional support procedures aimed at increasing adherence will be implemented.

Table 3.

MIND diet scoring

Data collection

Data will be collected through face-to-face interviews conducted twice: at the beginning of the implementation for the intervention and control groups (T0) and at the end of the 12-week intervention (T1). The data collection procedure consists of completion of the MSQOL-54^{(Reference Vickrey, Hays and Harooni34)} Questionnaire, MFIS^{(Reference Ritvo, Fischer and Miller35)}, the BICAMS^{(Reference Benedict, Amato and Boringa36,Reference Langdon, Amato and Boringa37)} battery and the Brain Fog scale^{(Reference Atik and İnel Manav38)}; performing anthropometric measurements and recording, from the patient file, the results of blood tests routinely requested by the Muğla Training and Research Hospital Neurology Outpatient Clinic.

First, participants’ anthropometric measurements will be taken by the researcher at the Muğla Training and Research Hospital Neurology Outpatient Clinic. Height will be measured in the Frankfort plane using a portable stadiometer.

Patients’ body composition will be determined using a Tanita brand BC 418 model bioelectrical impedance analysis (BIA) device with a measurement precision of 0·1 kg. The Tanita BC 418 model BIA device is a non-invasive professional product with easy-to-use features that can perform total body analysis. However, to obtain a highly reliable measurement with BIA, certain conditions must be met (Table 4)^{(Reference Son, Han and Bennett39)}. For participants who accept to participate in the study but do not meet any of these conditions, an appointment will be scheduled for another date, and the BIA measurement will be performed on that day.

Table 4.

Requirements prior to BIA measurement

BIA, bioelectrical impedance analysis.

Circumference measurements will be taken from three regions – neck, waist and hip – using a non-stretchable tape measure with a width of 0·5 cm. Neck circumference will be measured horizontally just below the larynx. Waist circumference will be measured at the midpoint between the last rib and the iliac bone. Hip circumference will be measured, while the patient is standing, from the patient’s right side, horizontally at the widest part of the hips when viewed from the side. All circumference measurements will be repeated twice.

Following completion of the anthropometric measurements, the MSQOL-54 questionnaire, MFIS, the BICAMS battery and the brain fog scale will be completed with the assistance of the researcher.

MS patients attend routine follow-up visits at the neurology outpatient clinic at 3-month intervals. During these visits, blood tests routinely requested by the Muğla Training and Research Hospital Neurology Outpatient Clinic are performed. These blood tests include hemogram; biochemical parameters (glucose, HDL-cholesterol, LDL-cholesterol, total cholesterol, aspartate aminotransferase, alanine aminotransferase, albumin); C-reactive protein; thyroid hormones including T3, T4, and thyroid-stimulating hormone; and folate, vitamin B₁₂, and vitamin D levels. The results of these blood tests will be obtained from the patient file and recorded in the data collection form. Data collection for each patient is planned to be completed within approximately 45 min.

Study outcomes

The primary outcomes of the study are the assessment of quality of life using the MSQOL-54 questionnaire and perceived fatigue using the MFIS questionnaire, cognitive functioning level using the BICAMS battery and brain fog status using the Brain Fog Scale. The secondary outcomes of the study are the assessment of anthropometric measurements and the status of blood parameters. Both primary and secondary outcomes will be recorded and evaluated twice, at the beginning of the intervention and at the end of the intervention. For each outcome, the analysis will be conducted based on change from baseline.

Adverse effects and harms

During the study, all adverse events reported by participants will be recorded and reported to the data monitoring committee and the ethics committee. The systematically conducted weekly interviews will facilitate the documentation of adverse effects and events. In the event of any harm related to the research, its treatment and associated costs will be covered by the investigators.

Data management and access

All data will be collected using participant identification numbers, with personal identifiers kept confidential and securely stored^{(Reference Regulation40)}. Printed documents, such as informed consent forms and questionnaires, will be stored in a locked cabinet accessible only to the research team. Data will be entered into an electronic database by the principal investigator through periodic follow-ups. To enhance data quality, the data will be checked using a double-check method by other researchers in the research team, independently of data entry and missing and outlier data will be monitored regularly. After the study is reported and published, anonymised data will be shared with other researchers upon ethically appropriate request.

Data monitoring and auditing

Data monitoring and oversight of the study will be conducted by the senior investigators and the supervisory team, D.T. and M.A.C., through meetings held every 6 months (Appendix 2). No interim analysis is planned for this study.

Statistical analysis method

Analyses will be conducted using IBM SPSS Statistics software. The significance level and type I error rate will be accepted as α = 0·05. In addition, effect sizes will be calculated and reported to determine the clinical significance of the observed effects.

After the data collection process is completed, the data will be checked and cleaned using descriptive statistics and data visualisation. Participants’ baseline demographic characteristics, lifestyle habits and clinical features will be summarised for each group using appropriate descriptive statistics (mean (sd) for normally distributed variables; median and interquartile range for non-normally distributed variables; frequency and percentage for categorical variables).

The homogeneity of demographic and baseline characteristics between the experimental and control groups will be assessed using χ ² test or Fisher’s exact test for categorical variables and independent samples t test or Mann–Whitney U test for continuous variables.

The internal consistency reliability of the scales used in the study will be assessed using Cronbach’s alpha coefficient.

The normality of continuous variables will be assessed by examining skewness and kurtosis coefficients. Variables with skewness and kurtosis values within the range of ±2 will be considered normally distributed.

For between-group comparisons (experimental v. control), the independent samples t test will be used for normally distributed variables, while the Mann–Whitney U test will be applied for non-normally distributed variables. For within-group comparisons (pre-test v. post-test), the paired samples t test will be used for normally distributed variables, while the Wilcoxon signed-rank test will be applied for non-normally distributed variables.

When all parametric assumptions are met, a mixed-design repeated measures analysis of variance (mixed RM-ANOVA) will be performed to examine the main effects of group (experimental/control) and time (pre-test/post-test), as well as their interaction effect.

The primary analyses will be conducted according to the intention-to-treat approach, including all randomised participants regardless of protocol adherence or missing data. Missing data will be handled using appropriate methods such as Expectation-Maximisation algorithm or multiple imputation. Additionally, a per-protocol analysis will be performed including only participants who completed the study protocol without major deviations. Both analyses will be compared to assess the robustness and sensitivity of the intervention effects.

Data reporting and publication plan

The study will be reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines^{(Reference Moirangthem, Deshpande and Patil41)}. The results of the study will be disseminated to a wide range of stakeholders – including researchers, participating patients, other individuals with MS and healthcare providers – through websites, reports, presentations and peer-reviewed journal articles.

Ethical approval of the study

This study will be conducted in accordance with the guidelines set forth in the Declaration of Helsinki. The conduct of the research at Muğla Training and Research Hospital was approved by the hospital administration, and institutional permission was granted on 8 January 2025. Ethical approval for the study was obtained from the Selçuk University Faculty of Health Sciences Non-Interventional Clinical Research Ethics Committee on 30 April 2025, with decision number 2025/643. During the conduct of this study, adverse events will be recorded and reported to the ethics committee. No major change is planned to the study protocol; however, any changes to the protocol will be reported and submitted as an amendment for ethical approval. Written informed consent will be obtained from all patients (Appendix 3). Participants will be informed that they may withdraw from the study at any time without providing any reason, and if they choose to provide a reason, it will be recorded. This research design was registered in the ClinicalTrials.gov database under the identifier NCT07057999 on 8 July 2025, prior to the commencement of data collection (https://clinicaltrials.gov/study/NCT07057999). This protocol was updated to Version 3 on 2 September 2025.

Study status

The data collection process began on 14 July 2025 and is planned to be completed in January 2026. The study results are expected to be reported and presented by July 2026.