Multiple Sclerosis, Relapsing-RemittingNCT06715436
Multiple Sclerosis and the Effects of Ketogenic Diet Therapy
A study testing Mediterranean Diet and Ketogenic Diet in people with Multiple Sclerosis, Relapsing-Remitting, run by IRCCS National Neurological Institute "C. Mondino" Foundation at 1 site in Italy.
Trial summary
Multiple sclerosis (MS) is an inflammatory and immune-mediated neurological disease with multifactorial etiology. The specific etiopathogenetic mechanisms of MS are still unknown but it is clear that it results from a combination of genetic and environmental factors. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Multiple Sclerosis, Relapsing-Remitting
- What is being tested?
- Mediterranean Diet and Ketogenic Diet
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 111 participants
- Where
- 1 siteItaly
- Study dates
- 15 Mar 2024to 15 Sep 2025
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Diagnosis of relapsing-remitting MS (RRMS) or progressive MS (PMS)
- Age between 18 and 60 years
- BMI between 18.5 kg/m2 and 39.9 kg/m2
- If on disease-modifying drugs, stable for 6 months, or no use of drugs in the previous 6 months
- Ability to give verbal and written consent
Who cannot join
- Patients actively engaged in a weight loss program or other specific diet (e.g. vegetarian, vegan); patients not willing to follow the assigned dietary pattern or patients with high adherence to MedDiet (MediLite score > 14)
- Pregnancy or breastfeeding
- Relapse or cortisone treatment within 30 days before study entry
- Clinically relevant metabolic, progressive or malignant diseases
- Intake of > 1 g/day of omega-3 fatty acid supplements
- Underweight (BMI<18.5 kg/m2) or severe obesity
Show all 14Show fewer
- Significant cognitive-cooperative impairment
- Insulin-dependent diabetes mellitus (type I)
- Weight loss greater than 5 kg within 2 months prior to study entry
- Diagnosis or suspicion of an eating disorder
- Kidney stones
- Oral anticoagulant therapy
- Known alcohol and drug abuse
- Telephonic interviews will be performed monthly to evaluate adherence to the dietary treatment and/or whether any changes in supplements use, physical activity, nutrition habits.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site, 1 recruiting
- Recruiting
U.O.Sclerosi Multipla
Pavia, 27100
Eleonora Tavazzi, MD, 0382380385 ext. 0039, eleonora.tavazzi@mondino.it
Cinzia Fattore, MD, 0382380385 ext. 0039, cinzia.fattore@mondino.it
About this study
Official title: The Effects of Ketogenic Diet Therapy Versus the Mediterranean Diet on Quality of Life in a Group of Patients With Multiple Sclerosis - the KETOMED-MS Study
Multiple sclerosis (MS) is an inflammatory and immune-mediated neurological disease with multifactorial etiology. The specific etiopathogenetic mechanisms of MS are still unknown but it is clear that it results from a combination of genetic and environmental factors. Several studies have reported the possible role of diet as a risk factor for MS and its progression. To date, many dietary patterns and their association with MS have been studied, but data is still limited and inconclusive. Mediterranean Diet (MedDiet) has been associated with a lower risk of developing MS, compared to a Western-style diet. In one of investigators' studies, higher MedDiet adherence was associated with a 6-fold greater likelihood of having lower disease severity than those with low adherence. A significant restriction of carbohydrates (up to ketogenesis) can have beneficial effects on various parameters (inflammatory markers, oxidative stress, altered glucose metabolism) which are altered in subjects with MS. Ketogenic diet therapies (KDTs) have been recommended mainly for children with drug-resistant epilepsy, but in recent years they have been applied to Multiple Sclerosis. Preclinical studies in animal models evaluating the efficacy of KDTs in experimental autoimmune encephalomyelitis (EAE) found a beneficial effect of diet in slowing of disease progression, improvement of motor disability, reduction of inflammatory cytokines and reactive oxygen species. In a randomized study, improvements in health-related quality of life (HRQL) scores and a slight decrease in EDSS scores were found. An open-label, single-arm study of 20 patients with RRMS also reported that, after 6 months of MAD, no subjects had new or enlarging FLAIR/T2 lesions, with a significant improvement in the EDSS score, the Modified Fatigue Impact Scale subscales and arm. A 3-arm parallel-arm randomized controlled pilot study was planned to determine the effectiveness of a modified Atkins diet (MAD) compared to a Mediterranean diet (MedDiet) on quality of life in a population with MS.
Read the detailed description
Multiple sclerosis (MS) is an inflammatory and immune-mediated neurological disease with multifactorial etiology. MS is one of the most important causes of disability in young adults and affects more women than men (with a male-female incidence ratio between 1.5:1 and 2.5:1). The specific etiopathogenetic mechanisms of MS are still unknown but it is clear that it derives from a combination of genetic and environmental factors. Several studies have reported the possible role of diet as a risk factor for MS and its progression. The possible role of dietary components on neuroinflammation, one of the main pathogenetic mechanisms of MS, has attracted a lot of interest. Diet and dietary components can be beneficial not only on MS symptoms but also on disease progression and disability status. To date, many dietary patterns and their association with MS have been studied, but the data is still limited and inconclusive. Notably, previous observational studies have found that MS patients tend to have a less healthy or more pro-inflammatory diet, compared to controls. Recently, Alfredsson and colleagues evaluated the risk of MS based on adherence to different dietary patterns (Western, Mediterranean and vegan/vegetarian diets). The authors reported that the Mediterranean Diet (MedDiet) was associated with a lower risk of developing MS, compared to a Western-style diet, while no significant associations were described between the vegetarian/vegan diet and the risk of MS. The positive association between MedDiet adherence and improved MS severity was recently confirmed by our study, in which high MedDiet adherence was associated with a 6-fold greater likelihood of having a lower severity of disease compared to those with low adherence to the MedDiet. Over the years, researchers have studied not only the neurological aspects of the disease but also the metabolic characteristics of MS patients. Insulin resistance, inflammatory markers, oxidative stress have been and are currently the main topics of interest. Studies have highlighted that MS is associated with altered glucose and insulin metabolism, which can negatively influence cognitive decline and dysfunction. All of these mechanisms can be modified through significant carbohydrate restriction that decreases glycemia and insulin levels and leads to ketogenesis. Dietary interventions aimed at inducing therapeutic ketosis are called ketogenic diet therapies (KDTs) and include different dietary regimes: the classic ketogenic diet (cKD), the medium chain triglyceride (MCT) diet, the modified Atkins diet (MAD). These protocols have been recommended mainly for children with drug-resistant epilepsy, but in recent years they have been applied to several other neurological pathologies such as Alzheimer's, Parkinson's and, recently, Multiple Sclerosis. Preclinical studies in animal models evaluating the efficacy of KDTs in experimental autoimmune encephalomyelitis (EAE) found a beneficial effect of diet. In particular, KDT slowed disease progression, improved motor disability, reduced inflammatory cytokines and reactive oxygen species. Choi et al. (2016) enrolled 60 patients with relapsing-remitting MS (RRMS) in a randomized, parallel 3-arm study to evaluate the safety and feasibility of a 6-month KDT or fasting-mimicking diets (FMD) on patients' quality of life. The study reported improvements in health-related quality of life (HRQL) scores of both the KDT group and the FMD group, at 3 and 6 months. Furthermore, a slight decrease in EDSS scores was reported in the FMD and KDT groups. An open-label, single-arm study tested a modified Atkins diet (MAD) for 6 months in a group of 20 patients with RRMS with the aim of evaluating the feasibility and safety of the diet. The study reported that, after 6 months of MAD, no subjects had new or enlarging FLAIR/T2 lesions, with significant improvement in EDSS score, Modified Fatigue Impact Scale (MFIS) subscales, and arm function (assessed through the Nine-Hole Peg Test). Similarly, in their phase II study, Brenton and colleagues confirmed their initial findings and described an improvement in depression (Beck Depression Inventory, BDI) and quality of life (Multiple Sclerosis Quality of Life-54, MSQoL -54).
Given this context, a 3-arm parallel-arm randomized controlled pilot study was planned to determine the effectiveness of a modified Atkins diet (MAD) compared to a Mediterranean diet (MedDiet) on quality of life, measured by the physical health subscale (CPH ) of MSQoL -54, in a population with MS followed at the Mondino Foundation Institute of Pavia, Italy. Safety, feasibility and general neurological, nutritional, motor and clinical outcomes were also assessed.
- Conditions
- Multiple Sclerosis, Relapsing-Remitting
- Being tested
- Mediterranean Diet, Ketogenic Diet, Control group
- Keywords
- Multiple Sclerosis, Ketogenic Dietary Therapy, Mediterranean diet
- Medical subject headings
- Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Mediterranean DietDietary supplement
The MedDiet will be planned according to the Mediterranean diet pyramid
Ketogenic DietDietary supplement
Modified Atkins diet with a maximum of 20 g of carbohydrates per day.
Control groupDietary supplement
The control group will be asked to continue their dietary and lifestyle habits
| Study group | Role | What they receive |
|---|---|---|
| Mediterranean Diet | Other | The MedDiet will be planned according to the Mediterranean diet pyramid. Energy prescriptions will be tailored to each patient's specific needs. The initial calorie prescription will be calculated taking into account usual dietary intake REE and physical activity level (PAL). Changes to calorie prescriptions will be made as needed during the course of follow-up. A minimum of 0.8-1 g of animal protein (e.g. eggs, milk, meat, poultry and fish) per kilogram of body weight per day will be given. Receives: Dietary Supplement: Mediterranean Diet |
| Ketogenic Diet | Experimental | Modified Atkins diet with a maximum of 20 g of carbohydrates per day. Fat-rich foods of plant origin will be encouraged in order to reach the prescribed daily caloric intake. Energy prescriptions will be tailored on each patient's specific requirements. The initial calorie prescription will be based on an average between the pre-diet intake, REE and physical activity levels. A minimum of 0.8-1 g of protein from animal sources (e.g. eggs, milk, meat, poultry and fish) per kilogram of body weight per day will be given. Receives: Dietary Supplement: Ketogenic Diet |
| Control group | Other | The control group will be asked to continue their dietary and lifestyle habits. Receives: Dietary Supplement: Control group |
What is being measured
The primary outcome is the main question the study is designed to answer.
The CPH subscale of the Multiple Sclerosis Quality of Life-54 (MSQoL -54)
Quality of life will be assessed in terms of physical health referring to the CPH subscale of the MSQoL -54 after 6 months of treatment. ITS consists of 52 items grouped in 12 subscales plus two single items.
All scores are transformed to scale from 0-100 and then added within each subscale to obtain the subtotal. By dividing the subtotal by the number of responses, the final score of the subscale is obtained. The scores final are in turn multiplied by a specific number at each subscale; adding the scores transformed in this way there is a value for "physical health" and one for "mental health". These two values, added, give the final score of the MSQoL-54. The higher scores demonstrate better HRQoL in patients.
Measured: Evaluation at baseline and after 6 months
Secondary outcomes (5)
Expanded Disability Status Scale (EDSS)
Degree of disability, measured with the EDSS. Scores are based on examination by a neurologist, and climb by half unit increments from 0 to 10 as level of disability increases.They are based on the level of neurological impairment of eight functional systems in the brain: pyramidal, cerebellar, brainstem, sensory, bowel and bladder function, visual function, cerebral functions, other.
Measured: Evaluation at baseline and after 6 months
Multiple Sclerosis Functional Composite (MSFC)
It is a 3-part, standardized, quantitative assessment instrument for use in clinical studies, particularly clinical trials, of multiple sclerosis: Timed 25-Foot Walk (T25W) for leg function and ambulation, 9-Hole Peg Test (9HPT) for arm and hand function, and Paced Auditory Serial Addition Test (PASAT-3) for cognitive function.
For these instruments there are not the minimum and the maximum values. Execution time is calculated. Longer time corresponds to worse outcome.
Measured: Evaluation at baseline and after 6 months
Modified Fatigue Impact Scale (MFIS)
This instrument provides an assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning. The full-length MFIS consists of 21 items. MFIS total score can range from 0 to 84.
MFIS score > 38 indicates moderate to severe fatigue.
Measured: Evaluation at baseline and after 6 months
The Pittsburgh Sleep Quality Index
The Pittsburgh Sleep Quality Index (PSQI) is a widely used self-report questionnaire that assesses sleep quality over a one-month time interval. Nineteen individual items generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these seven components yields one global score. Pittsburg scale's total score ranges from 0-21; where a higher score describes poorer sleep quality (score >5= inadequate sleep, score <5= adequate sleep)
Measured: Evaluation at baseline and after 6 months
The Beck Depression Inventory
The inventory contains 21 self-report items which individuals complete using multiple choice response formats. It is composed of items relating to symptoms of depression such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest in sex. BDI score can vary from 0 to 63. A BDI score of < 9 is considered normal, a score of 11-16 mild mood disturbance, and 21-30 mild-moderate depression, >30 severe depression.
Measured: Evaluation at baseline and after 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2024
- Study start15 Mar 2024
- Primary completion15 Mar 2025 (estimated)
- Study completion15 Sep 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (23)Papers the sponsor has linked to this study.
- Other trials for Multiple Sclerosis, Relapsing-RemittingStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 111 participants (estimated)
Sponsor and investigators
- Lead sponsor
- IRCCS National Neurological Institute "C. Mondino" Foundation
- Sponsor type
- University, hospital or other
- Collaborators
- University of Pavia
- Responsible party
- Sponsor
- Investigators
- Eleonora Tavazzi, MD, Principal investigator, U.O. Sclerosi Multipla
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06715436
- Sponsor's protocol ID
- KETOMED-MS-2024
- Status last verified
- Nov 2024
- First submitted
- 28 Nov 2024
- Last updated
- 20 Dec 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Alfredsson L, Olsson T, Hedstrom AK. Inverse association between Mediterranean diet and risk of multiple sclerosis. Mult Scler. 2023 Aug;29(9):1118-1125. doi: 10.1177/13524585231181841. Epub 2023 Jun 27.
PubMed 37366345Ascherio A. Environmental factors in multiple sclerosis. Expert Rev Neurother. 2013 Dec;13(12 Suppl):3-9. doi: 10.1586/14737175.2013.865866.
PubMed 24289836Ayromlou H, Hosseini S, Khalili M, Ayromlou S, Khamudchiyan S, Farajdokht F, Hassannezhad S, Amiri Moghadam S. Insulin resistance is associated with cognitive dysfunction in multiple sclerosis patients: A cross-sectional study. J Neuroendocrinol. 2023 Jun;35(6):e13288. doi: 10.1111/jne.13288. Epub 2023 Jun 15.
PubMed 37317829Azary S, Schreiner T, Graves J, Waldman A, Belman A, Guttman BW, Aaen G, Tillema JM, Mar S, Hart J, Ness J, Harris Y, Krupp L, Gorman M, Benson L, Rodriguez M, Chitnis T, Rose J, Barcellos LF, Lotze T, Carmichael SL, Roalstad S, Casper CT, Waubant E. Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry. 2018 Jan;89(1):28-33. doi: 10.1136/jnnp-2017-315936. Epub 2017 Oct 9.
PubMed 28993476Black LJ, Rowley C, Sherriff J, Pereira G, Ponsonby AL, Lucas RM. A healthy dietary pattern associates with a lower risk of a first clinical diagnosis of central nervous system demyelination. Mult Scler. 2019 Oct;25(11):1514-1525. doi: 10.1177/1352458518793524. Epub 2018 Aug 7.
PubMed 30084751Brenton JN, Banwell B, Bergqvist AGC, Lehner-Gulotta D, Gampper L, Leytham E, Coleman R, Goldman MD. Pilot study of a ketogenic diet in relapsing-remitting MS. Neurol Neuroimmunol Neuroinflamm. 2019 Apr 12;6(4):e565. doi: 10.1212/NXI.0000000000000565. eCollection 2019 Jul.
PubMed 31089482Brenton JN, Lehner-Gulotta D, Woolbright E, Banwell B, Bergqvist AGC, Chen S, Coleman R, Conaway M, Goldman MD. Phase II study of ketogenic diets in relapsing multiple sclerosis: safety, tolerability and potential clinical benefits. J Neurol Neurosurg Psychiatry. 2022 Jun;93(6):637-644. doi: 10.1136/jnnp-2022-329074. Epub 2022 Apr 13.
PubMed 35418509Choi IY, Piccio L, Childress P, Bollman B, Ghosh A, Brandhorst S, Suarez J, Michalsen A, Cross AH, Morgan TE, Wei M, Paul F, Bock M, Longo VD. A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. Cell Rep. 2016 Jun 7;15(10):2136-2146. doi: 10.1016/j.celrep.2016.05.009. Epub 2016 May 26.
PubMed 27239035Esposito S, Bonavita S, Sparaco M, Gallo A, Tedeschi G. The role of diet in multiple sclerosis: A review. Nutr Neurosci. 2018 Jul;21(6):377-390. doi: 10.1080/1028415X.2017.1303016. Epub 2017 Mar 24.
PubMed 28338444International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2; Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S, Gray E, Booth DR, Potter SC, Goris A, Band G, Oturai AB, Strange A, Saarela J, Bellenguez C, Fontaine B, Gillman M, Hemmer B, Gwilliam R, Zipp F, Jayakumar A, Martin R, Leslie S, Hawkins S, Giannoulatou E, D'alfonso S, Blackburn H, Martinelli Boneschi F, Liddle J, Harbo HF, Perez ML, Spurkland A, Waller MJ, Mycko MP, Ricketts M, Comabella M, Hammond N, Kockum I, McCann OT, Ban M, Whittaker P, Kemppinen A, Weston P, Hawkins C, Widaa S, Zajicek J, Dronov S, Robertson N, Bumpstead SJ, Barcellos LF, Ravindrarajah R, Abraham R, Alfredsson L, Ardlie K, Aubin C, Baker A, Baker K, Baranzini SE, Bergamaschi L, Bergamaschi R, Bernstein A, Berthele A, Boggild M, Bradfield JP, Brassat D, Broadley SA, Buck D, Butzkueven H, Capra R, Carroll WM, Cavalla P, Celius EG, Cepok S, Chiavacci R, Clerget-Darpoux F, Clysters K, Comi G, Cossburn M, Cournu-Rebeix I, Cox MB, Cozen W, Cree BA, Cross AH, Cusi D, Daly MJ, Davis E, de Bakker PI, Debouverie M, D'hooghe MB, Dixon K, Dobosi R, Dubois B, Ellinghaus D, Elovaara I, Esposito F, Fontenille C, Foote S, Franke A, Galimberti D, Ghezzi A, Glessner J, Gomez R, Gout O, Graham C, Grant SF, Guerini FR, Hakonarson H, Hall P, Hamsten A, Hartung HP, Heard RN, Heath S, Hobart J, Hoshi M, Infante-Duarte C, Ingram G, Ingram W, Islam T, Jagodic M, Kabesch M, Kermode AG, Kilpatrick TJ, Kim C, Klopp N, Koivisto K, Larsson M, Lathrop M, Lechner-Scott JS, Leone MA, Leppa V, Liljedahl U, Bomfim IL, Lincoln RR, Link J, Liu J, Lorentzen AR, Lupoli S, Macciardi F, Mack T, Marriott M, Martinelli V, Mason D, McCauley JL, Mentch F, Mero IL, Mihalova T, Montalban X, Mottershead J, Myhr KM, Naldi P, Ollier W, Page A, Palotie A, Pelletier J, Piccio L, Pickersgill T, Piehl F, Pobywajlo S, Quach HL, Ramsay PP, Reunanen M, Reynolds R, Rioux JD, Rodegher M, Roesner S, Rubio JP, Ruckert IM, Salvetti M, Salvi E, Santaniello A, Schaefer CA, Schreiber S, Schulze C, Scott RJ, Sellebjerg F, Selmaj KW, Sexton D, Shen L, Simms-Acuna B, Skidmore S, Sleiman PM, Smestad C, Sorensen PS, Sondergaard HB, Stankovich J, Strange RC, Sulonen AM, Sundqvist E, Syvanen AC, Taddeo F, Taylor B, Blackwell JM, Tienari P, Bramon E, Tourbah A, Brown MA, Tronczynska E, Casas JP, Tubridy N, Corvin A, Vickery J, Jankowski J, Villoslada P, Markus HS, Wang K, Mathew CG, Wason J, Palmer CN, Wichmann HE, Plomin R, Willoughby E, Rautanen A, Winkelmann J, Wittig M, Trembath RC, Yaouanq J, Viswanathan AC, Zhang H, Wood NW, Zuvich R, Deloukas P, Langford C, Duncanson A, Oksenberg JR, Pericak-Vance MA, Haines JL, Olsson T, Hillert J, Ivinson AJ, De Jager PL, Peltonen L, Stewart GJ, Hafler DA, Hauser SL, McVean G, Donnelly P, Compston A. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011 Aug 10;476(7359):214-9. doi: 10.1038/nature10251.
PubMed 21833088Jelinek GA, Hadgkiss EJ, Weiland TJ, Pereira NG, Marck CH, van der Meer DM. Association of fish consumption and Omega 3 supplementation with quality of life, disability and disease activity in an international cohort of people with multiple sclerosis. Int J Neurosci. 2013 Nov;123(11):792-800. doi: 10.3109/00207454.2013.803104. Epub 2013 Jun 3.
PubMed 23713615Katz Sand I. The Role of Diet in Multiple Sclerosis: Mechanistic Connections and Current Evidence. Curr Nutr Rep. 2018 Sep;7(3):150-160. doi: 10.1007/s13668-018-0236-z.
PubMed 30117071Keykhaei F, Norouzy S, Froughipour M, Nematy M, Saeidi M, Jarahi L, Amiri F, Malek Ahmadi M, Norouzy A. Adherence to healthy dietary pattern is associated with lower risk of multiple sclerosis. J Cent Nerv Syst Dis. 2022 May 6;14:11795735221092516. doi: 10.1177/11795735221092516. eCollection 2022.
PubMed 35558004Kobelt G, Thompson A, Berg J, Gannedahl M, Eriksson J; MSCOI Study Group; European Multiple Sclerosis Platform. New insights into the burden and costs of multiple sclerosis in Europe. Mult Scler. 2017 Jul;23(8):1123-1136. doi: 10.1177/1352458517694432. Epub 2017 Feb 1.
PubMed 28273775Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, Buchhalter JR, Caraballo RH, Cross JH, Dahlin MG, Donner EJ, Guzel O, Jehle RS, Klepper J, Kang HC, Lambrechts DA, Liu YMC, Nathan JK, Nordli DR Jr, Pfeifer HH, Rho JM, Scheffer IE, Sharma S, Stafstrom CE, Thiele EA, Turner Z, Vaccarezza MM, van der Louw EJTM, Veggiotti P, Wheless JW, Wirrell EC; Charlie Foundation; Matthew's Friends; Practice Committee of the Child Neurology Society. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open. 2018 May 21;3(2):175-192. doi: 10.1002/epi4.12225. eCollection 2018 Jun.
PubMed 29881797
Study at a glance
From the registry record, last updated by the sponsor on 20 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Ketogenic Diet Therapy Versus the Mediterranean Diet on Quality of Life in a Group of Patients With Multiple Sclerosis - the KETOMED-MS Study
- ClinicalTrials.gov ID
- NCT06715436
- Acronym / sponsor ID
- KETOMED-MS-2024
- Conditions
- Multiple Sclerosis, Relapsing-Remitting
- Keywords
- Multiple Sclerosis, Ketogenic Dietary Therapy, Mediterranean diet
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 111 participants (estimated)
- Lead sponsor
- IRCCS National Neurological Institute "C. Mondino" FoundationUniversity, hospital or other
- Collaborators
- University of Pavia
- Study start
- 15 Mar 2024 (actual)
- Primary completion
- 15 Mar 2025 (estimated)
- Study completion
- 15 Sep 2025 (estimated)
- First posted
- 4 Dec 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Multiple sclerosis (MS) is an inflammatory and immune-mediated neurological disease with multifactorial etiology. The specific etiopathogenetic mechanisms of MS are still unknown but it is clear that it results from a combination of genetic and environmental factors. Several studies have reported the possible role of diet as a risk factor for MS and its progression. To date, many dietary patterns and their association with MS have been studied, but data is still limited and inconclusive. Mediterranean Diet (MedDiet) has been associated with a lower risk of developing MS, compared to a Western-style diet. In one of investigators' studies, higher MedDiet adherence was associated with a 6-fold greater likelihood of having lower disease severity than those with low adherence. A significant restriction of carbohydrates (up to ketogenesis) can have beneficial effects on various parameters (inflammatory markers, oxidative stress, altered glucose metabolism) which are altered in subjects with MS. Ketogenic diet therapies (KDTs) have been recommended mainly for children with drug-resistant epilepsy, but in recent years they have been applied to Multiple Sclerosis. Preclinical studies in animal models evaluating the efficacy of KDTs in experimental autoimmune encephalomyelitis (EAE) found a beneficial effect of diet in slowing of disease progression, improvement of motor disability, reduction of inflammatory cytokines and reactive oxygen species. In a randomized study, improvements in health-related quality of life (HRQL) scores and a slight decrease in EDSS scores were found. An open-label, single-arm study of 20 patients with RRMS also reported that, after 6 months of MAD, no subjects had new or enlarging FLAIR/T2 lesions, with a significant improvement in the EDSS score, the Modified Fatigue Impact Scale subscales and arm. A 3-arm parallel-arm randomized controlled pilot study was planned to determine the effectiveness of a modified Atkins diet (MAD) compared to a Mediterranean diet (MedDiet) on quality of life in a population with MS.
Detailed description
Multiple sclerosis (MS) is an inflammatory and immune-mediated neurological disease with multifactorial etiology. MS is one of the most important causes of disability in young adults and affects more women than men (with a male-female incidence ratio between 1.5:1 and 2.5:1). The specific etiopathogenetic mechanisms of MS are still unknown but it is clear that it derives from a combination of genetic and environmental factors. Several studies have reported the possible role of diet as a risk factor for MS and its progression. The possible role of dietary components on neuroinflammation, one of the main pathogenetic mechanisms of MS, has attracted a lot of interest. Diet and dietary components can be beneficial not only on MS symptoms but also on disease progression and disability status. To date, many dietary patterns and their association with MS have been studied, but the data is still limited and inconclusive. Notably, previous observational studies have found that MS patients tend to have a less healthy or more pro-inflammatory diet, compared to controls. Recently, Alfredsson and colleagues evaluated the risk of MS based on adherence to different dietary patterns (Western, Mediterranean and vegan/vegetarian diets). The authors reported that the Mediterranean Diet (MedDiet) was associated with a lower risk of developing MS, compared to a Western-style diet, while no significant associations were described between the vegetarian/vegan diet and the risk of MS. The positive association between MedDiet adherence and improved MS severity was recently confirmed by our study, in which high MedDiet adherence was associated with a 6-fold greater likelihood of having a lower severity of disease compared to those with low adherence to the MedDiet. Over the years, researchers have studied not only the neurological aspects of the disease but also the metabolic characteristics of MS patients. Insulin resistance, inflammatory markers, oxidative stress have been and are currently the main topics of interest. Studies have highlighted that MS is associated with altered glucose and insulin metabolism, which can negatively influence cognitive decline and dysfunction. All of these mechanisms can be modified through significant carbohydrate restriction that decreases glycemia and insulin levels and leads to ketogenesis. Dietary interventions aimed at inducing therapeutic ketosis are called ketogenic diet therapies (KDTs) and include different dietary regimes: the classic ketogenic diet (cKD), the medium chain triglyceride (MCT) diet, the modified Atkins diet (MAD). These protocols have been recommended mainly for children with drug-resistant epilepsy, but in recent years they have been applied to several other neurological pathologies such as Alzheimer's, Parkinson's and, recently, Multiple Sclerosis. Preclinical studies in animal models evaluating the efficacy of KDTs in experimental autoimmune encephalomyelitis (EAE) found a beneficial effect of diet. In particular, KDT slowed disease progression, improved motor disability, reduced inflammatory cytokines and reactive oxygen species. Choi et al. (2016) enrolled 60 patients with relapsing-remitting MS (RRMS) in a randomized, parallel 3-arm study to evaluate the safety and feasibility of a 6-month KDT or fasting-mimicking diets (FMD) on patients' quality of life. The study reported improvements in health-related quality of life (HRQL) scores of both the KDT group and the FMD group, at 3 and 6 months. Furthermore, a slight decrease in EDSS scores was reported in the FMD and KDT groups. An open-label, single-arm study tested a modified Atkins diet (MAD) for 6 months in a group of 20 patients with RRMS with the aim of evaluating the feasibility and safety of the diet. The study reported that, after 6 months of MAD, no subjects had new or enlarging FLAIR/T2 lesions, with significant improvement in EDSS score, Modified Fatigue Impact Scale (MFIS) subscales, and arm function (assessed through the Nine-Hole Peg Test). Similarly, in their phase II study, Brenton and colleagues confirmed their initial findings and described an improvement in depression (Beck Depression Inventory, BDI) and quality of life (Multiple Sclerosis Quality of Life-54, MSQoL -54).
Given this context, a 3-arm parallel-arm randomized controlled pilot study was planned to determine the effectiveness of a modified Atkins diet (MAD) compared to a Mediterranean diet (MedDiet) on quality of life, measured by the physical health subscale (CPH ) of MSQoL -54, in a population with MS followed at the Mondino Foundation Institute of Pavia, Italy. Safety, feasibility and general neurological, nutritional, motor and clinical outcomes were also assessed.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Mediterranean Diet | Other | Dietary Supplement: Mediterranean DietThe MedDiet will be planned according to the Mediterranean diet pyramid. Energy prescriptions will be tailored to each patient's specific needs. The initial calorie prescription will be calculated taking into account usual dietary intake REE and physical activity level (PAL). Changes to calorie prescriptions will be made as needed during the course of follow-up. A minimum of 0.8-1 g of animal protein (e.g. eggs, milk, meat, poultry and fish) per kilogram of body weight per day will be given. |
| Ketogenic Diet | Experimental | Dietary Supplement: Ketogenic DietModified Atkins diet with a maximum of 20 g of carbohydrates per day. Fat-rich foods of plant origin will be encouraged in order to reach the prescribed daily caloric intake. Energy prescriptions will be tailored on each patient's specific requirements. The initial calorie prescription will be based on an average between the pre-diet intake, REE and physical activity levels. A minimum of 0.8-1 g of protein from animal sources (e.g. eggs, milk, meat, poultry and fish) per kilogram of body weight per day will be given. |
| Control group | Other | Dietary Supplement: Control groupThe control group will be asked to continue their dietary and lifestyle habits. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- Diagnosis of relapsing-remitting MS (RRMS) or progressive MS (PMS)
- Age between 18 and 60 years
- BMI between 18.5 kg/m2 and 39.9 kg/m2
- If on disease-modifying drugs, stable for 6 months, or no use of drugs in the previous 6 months
- Ability to give verbal and written consent
Key exclusion criteria (14 listed)
- Patients actively engaged in a weight loss program or other specific diet (e.g. vegetarian, vegan); patients not willing to follow the assigned dietary pattern or patients with high adherence to MedDiet (MediLite score > 14)
- Pregnancy or breastfeeding
- Relapse or cortisone treatment within 30 days before study entry
- Clinically relevant metabolic, progressive or malignant diseases
- Intake of > 1 g/day of omega-3 fatty acid supplements
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Mediterranean DietThe MedDiet will be planned according to the Mediterranean diet pyramid | Dietary supplement | Mediterranean Diet |
| Ketogenic DietModified Atkins diet with a maximum of 20 g of carbohydrates per day. | Dietary supplement | Ketogenic Diet |
| Control groupThe control group will be asked to continue their dietary and lifestyle habits | Dietary supplement | Control group |
Primary outcome
The CPH subscale of the Multiple Sclerosis Quality of Life-54 (MSQoL -54)
Time frame: Evaluation at baseline and after 6 months
Quality of life will be assessed in terms of physical health referring to the CPH subscale of the MSQoL -54 after 6 months of treatment. ITS consists of 52 items grouped in 12 subscales plus two single items. All scores are transformed to scale from 0-100 and then added within each subscale to obtain the subtotal. By dividing the subtotal by the number of responses, the final score of the subscale is obtained. The scores final are in turn multiplied by a specific number at each subscale; adding the scores transformed in this way there is a value for "physical health" and one for "mental health". These two values, added, give the final score of the MSQoL-54. The higher scores demonstrate better HRQoL in patients.
5 secondary outcomes
Expanded Disability Status Scale (EDSS)
Time frame: Evaluation at baseline and after 6 months
Multiple Sclerosis Functional Composite (MSFC)
Time frame: Evaluation at baseline and after 6 months
Modified Fatigue Impact Scale (MFIS)
Time frame: Evaluation at baseline and after 6 months
The Pittsburgh Sleep Quality Index
Time frame: Evaluation at baseline and after 6 months
The Beck Depression Inventory
Time frame: Evaluation at baseline and after 6 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Dec 2024.
- Background: PubMed 37366345Alfredsson L, Olsson T, Hedstrom AK. Inverse association between Mediterranean diet and risk of multiple sclerosis. Mult Scler. 2023 Aug;29(9):1118-1125. doi: 10.1177/13524585231181841. Epub 2023 Jun 27.
- Background: PubMed 24289836Ascherio A. Environmental factors in multiple sclerosis. Expert Rev Neurother. 2013 Dec;13(12 Suppl):3-9. doi: 10.1586/14737175.2013.865866.
- Background: PubMed 37317829Ayromlou H, Hosseini S, Khalili M, Ayromlou S, Khamudchiyan S, Farajdokht F, Hassannezhad S, Amiri Moghadam S. Insulin resistance is associated with cognitive dysfunction in multiple sclerosis patients: A cross-sectional study. J Neuroendocrinol. 2023 Jun;35(6):e13288. doi: 10.1111/jne.13288. Epub 2023 Jun 15.
- Background: PubMed 28993476Azary S, Schreiner T, Graves J, Waldman A, Belman A, Guttman BW, Aaen G, Tillema JM, Mar S, Hart J, Ness J, Harris Y, Krupp L, Gorman M, Benson L, Rodriguez M, Chitnis T, Rose J, Barcellos LF, Lotze T, Carmichael SL, Roalstad S, Casper CT, Waubant E. Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry. 2018 Jan;89(1):28-33. doi: 10.1136/jnnp-2017-315936. Epub 2017 Oct 9.
- Background: PubMed 30084751Black LJ, Rowley C, Sherriff J, Pereira G, Ponsonby AL, Lucas RM. A healthy dietary pattern associates with a lower risk of a first clinical diagnosis of central nervous system demyelination. Mult Scler. 2019 Oct;25(11):1514-1525. doi: 10.1177/1352458518793524. Epub 2018 Aug 7.
- Background: PubMed 31089482Brenton JN, Banwell B, Bergqvist AGC, Lehner-Gulotta D, Gampper L, Leytham E, Coleman R, Goldman MD. Pilot study of a ketogenic diet in relapsing-remitting MS. Neurol Neuroimmunol Neuroinflamm. 2019 Apr 12;6(4):e565. doi: 10.1212/NXI.0000000000000565. eCollection 2019 Jul.
- Background: PubMed 35418509Brenton JN, Lehner-Gulotta D, Woolbright E, Banwell B, Bergqvist AGC, Chen S, Coleman R, Conaway M, Goldman MD. Phase II study of ketogenic diets in relapsing multiple sclerosis: safety, tolerability and potential clinical benefits. J Neurol Neurosurg Psychiatry. 2022 Jun;93(6):637-644. doi: 10.1136/jnnp-2022-329074. Epub 2022 Apr 13.
- Background: PubMed 27239035Choi IY, Piccio L, Childress P, Bollman B, Ghosh A, Brandhorst S, Suarez J, Michalsen A, Cross AH, Morgan TE, Wei M, Paul F, Bock M, Longo VD. A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. Cell Rep. 2016 Jun 7;15(10):2136-2146. doi: 10.1016/j.celrep.2016.05.009. Epub 2016 May 26.
- Background: PubMed 28338444Esposito S, Bonavita S, Sparaco M, Gallo A, Tedeschi G. The role of diet in multiple sclerosis: A review. Nutr Neurosci. 2018 Jul;21(6):377-390. doi: 10.1080/1028415X.2017.1303016. Epub 2017 Mar 24.
- Background: PubMed 21833088International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2; Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S, Gray E, Booth DR, Potter SC, Goris A, Band G, Oturai AB, Strange A, Saarela J, Bellenguez C, Fontaine B, Gillman M, Hemmer B, Gwilliam R, Zipp F, Jayakumar A, Martin R, Leslie S, Hawkins S, Giannoulatou E, D'alfonso S, Blackburn H, Martinelli Boneschi F, Liddle J, Harbo HF, Perez ML, Spurkland A, Waller MJ, Mycko MP, Ricketts M, Comabella M, Hammond N, Kockum I, McCann OT, Ban M, Whittaker P, Kemppinen A, Weston P, Hawkins C, Widaa S, Zajicek J, Dronov S, Robertson N, Bumpstead SJ, Barcellos LF, Ravindrarajah R, Abraham R, Alfredsson L, Ardlie K, Aubin C, Baker A, Baker K, Baranzini SE, Bergamaschi L, Bergamaschi R, Bernstein A, Berthele A, Boggild M, Bradfield JP, Brassat D, Broadley SA, Buck D, Butzkueven H, Capra R, Carroll WM, Cavalla P, Celius EG, Cepok S, Chiavacci R, Clerget-Darpoux F, Clysters K, Comi G, Cossburn M, Cournu-Rebeix I, Cox MB, Cozen W, Cree BA, Cross AH, Cusi D, Daly MJ, Davis E, de Bakker PI, Debouverie M, D'hooghe MB, Dixon K, Dobosi R, Dubois B, Ellinghaus D, Elovaara I, Esposito F, Fontenille C, Foote S, Franke A, Galimberti D, Ghezzi A, Glessner J, Gomez R, Gout O, Graham C, Grant SF, Guerini FR, Hakonarson H, Hall P, Hamsten A, Hartung HP, Heard RN, Heath S, Hobart J, Hoshi M, Infante-Duarte C, Ingram G, Ingram W, Islam T, Jagodic M, Kabesch M, Kermode AG, Kilpatrick TJ, Kim C, Klopp N, Koivisto K, Larsson M, Lathrop M, Lechner-Scott JS, Leone MA, Leppa V, Liljedahl U, Bomfim IL, Lincoln RR, Link J, Liu J, Lorentzen AR, Lupoli S, Macciardi F, Mack T, Marriott M, Martinelli V, Mason D, McCauley JL, Mentch F, Mero IL, Mihalova T, Montalban X, Mottershead J, Myhr KM, Naldi P, Ollier W, Page A, Palotie A, Pelletier J, Piccio L, Pickersgill T, Piehl F, Pobywajlo S, Quach HL, Ramsay PP, Reunanen M, Reynolds R, Rioux JD, Rodegher M, Roesner S, Rubio JP, Ruckert IM, Salvetti M, Salvi E, Santaniello A, Schaefer CA, Schreiber S, Schulze C, Scott RJ, Sellebjerg F, Selmaj KW, Sexton D, Shen L, Simms-Acuna B, Skidmore S, Sleiman PM, Smestad C, Sorensen PS, Sondergaard HB, Stankovich J, Strange RC, Sulonen AM, Sundqvist E, Syvanen AC, Taddeo F, Taylor B, Blackwell JM, Tienari P, Bramon E, Tourbah A, Brown MA, Tronczynska E, Casas JP, Tubridy N, Corvin A, Vickery J, Jankowski J, Villoslada P, Markus HS, Wang K, Mathew CG, Wason J, Palmer CN, Wichmann HE, Plomin R, Willoughby E, Rautanen A, Winkelmann J, Wittig M, Trembath RC, Yaouanq J, Viswanathan AC, Zhang H, Wood NW, Zuvich R, Deloukas P, Langford C, Duncanson A, Oksenberg JR, Pericak-Vance MA, Haines JL, Olsson T, Hillert J, Ivinson AJ, De Jager PL, Peltonen L, Stewart GJ, Hafler DA, Hauser SL, McVean G, Donnelly P, Compston A. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011 Aug 10;476(7359):214-9. doi: 10.1038/nature10251.
- Background: PubMed 23713615Jelinek GA, Hadgkiss EJ, Weiland TJ, Pereira NG, Marck CH, van der Meer DM. Association of fish consumption and Omega 3 supplementation with quality of life, disability and disease activity in an international cohort of people with multiple sclerosis. Int J Neurosci. 2013 Nov;123(11):792-800. doi: 10.3109/00207454.2013.803104. Epub 2013 Jun 3.
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- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Eleonora Tavazzi, MD principal investigator
U.O. Sclerosi Multipla
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Mediterranean Diet and Ketogenic Diet in people with Multiple Sclerosis, Relapsing-Remitting, run by IRCCS National Neurological Institute "C. Mondino" Foundation at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 20 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Eleonora Tavazzi, MD (0382380385 ext. 0039, eleonora.tavazzi@mondino.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The CPH subscale of the Multiple Sclerosis Quality of Life-54 (MSQoL -54) (time frame: Evaluation at baseline and after 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06715436, which also lists 23 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Dec 2024.