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Dietary Strategies for the Treatment of Fibromyalgia in Overweight and Obese Patients
Condition(s) studied
Fibromyalgia (FM)
Investigational drug(s) / intervention(s)
Very Low-Calorie Ketogenic DietMediterranean dietMediterranean diet enriched by GABA-producing probiotic
Very Low-Calorie Ketogenic Diet: The very low calorie ketogenic diet (VLCKD) is a diet characterized by a very low carbohydrate content and reduced calorie intake, while maintaining an adequate amount of protein. In this study, subjects will receive food kits and supplements prepared by SDM, a company belonging to the Pronokal group. The VLCKD involves three different phases of intervention: the 4-week attack phase (phase l), the transition phase (phase Il), and the maintenance phase (phase III). Phase I is characterized by an 800 kcal diet with 1.2 g/kg/ideal weight of protein, 10-15 g of lipids, and 45-70 g of carbohydrates. Phase Il (four weeks) aims to gradually reintroduce carbohydrates, increase calorie intake and reduce consumption of Pronokal products. Phase Ill involves maintenance through a low-calorie Mediterranean-style diet in line with the other arms interventions, of 1400 kcal/day for another 4 weeks.
Mediterranean diet: A standardized low-calorie diet of 1400 kcal/day will be drawn up. The macronutrient breakdown will follow the Reference Intake Levels for Nutrients and Enerav (LARN V edition), providing for: 0.9 g/day/kg of ideal body weight of protein, 48% carbohydrates, and 30-35% lipids. The daily calorie breakdown will be: 15% of calories for breakfast, 35-40% for lunch, 30-35% for dinner, and 10% of the remaining calories to be divided into two snacks. Each patient must follow the Mediterranean Diet for the entire duration of the treatment, i.e., 12 weeks, during which any necessary changes will be made to ensure full compliance with the diet plan.
Mediterranean diet enriched by GABA-producing probiotic: Standardized low-calorie diet of 1400 kcal/day characterized by: 0.9 g/day/kg of ideal body weight of protein, 48% carbohydrates, and 30-35% lipids. The daily calorie breakdown will be: 15% of calories for breakfast, 35-40% for lunch, 30-35% for dinner, and 10% of the remaining calories to be divided into two snacks. This diet will also be enriched with GABA-producing probiotics such as Bifidobacterium adolescentis PRL2019 (20 CFU/day) present in Gabapral produced by Pharmextracta S.p.A.
Study summary
Spontaneous, non-sponsored, interventional, controlled, randomized, parallel-arm clinical study.
Primary objective To assess the impact of specific dietary approaches (ketogenic diet, Mediterranean diet, or Mediterranean diet supplemented with GABA-producing probiotics, e.g., Bifidobacterium adolescentis PRL2019) on fibromyalgia (FM) severity-particularly pain, sleep quality, anxiety, and depression-using validated questionnaires in female patients with FM and overweight/class I obesity.
Secondary objectives
* Evaluate effects on anthropometric measures, metabolic profile, and body composition.
* Assess changes in gut microbiota composition and metabolomic analysis.
* Measure neurosteroids with positive allosteric activity on GABA-A or NMDA receptors in saliva and/or plasma.
* Exploratory pilot sub-study to quantify brain GABA and glutamate levels through magnetic resonance spectroscopy (MRS) in a subset of patients.
Methods Participants will be recruited from the Rheumatology Unit outpatient clinics of IRCCS Policlinico San Martino Hospital (Genoa). Eligible subjects will be adult women with FM and overweight/obesity, selected through protocol-defined criteria. Enrollment requires written informed consent.
At enrollment (baseline), participants will complete validated questionnaires assessing FM severity (pain, sleep quality, depression, anxiety, bowel function). Data collection will include sociodemographic information, Mediterranean diet adherence through PREDIMED questionnaire, basal metabolic rate, medical and dietary history, smoking status, blood pressure, and recent laboratory results. Stool, blood, and saliva samples will be collected for routine tests, metabolomics, and ELISA-based measurement of neuroactive steroids like cortisol, progesterone, DHEA.
Within 7 days T1, results will be reviewed and eligible participants randomized to one of three groups: hypocaloric ketogenic diet, Mediterranean diet, or Mediterranean diet plus probiotics. Individualized dietary plans will be provided with written and verbal instructions.
Anthropometric measurements (weight, height, BMI, waist circumference, waist-hip ratio) and body composition via bioelectrical impedance analysis BIA will be recorded at T0, T4, T8, and T12, together with biological sample collection.
Pilot MRS sub-study A subset of participants will undergo brain GABA and glutamate assessment through MRI spectroscopy performed on a 3T Siemens - Prisma magnet at the baseline, before dietary treatment and after 4 weeks. Results will be compared with spectra from control subjects screened through medical history to exclude relevant diseases.
Eligibility
Inclusion Criteria:
* Adult female patients with fibromyalgia, aged ≤ 65 years, who are overweight or obese (BMI 24.9 \< ≤34.9 kg/m2);
* Patients able to independently provide their written informed consent to participate in the study;
* Patients motivated to participate in the project and able to independently manage the dietary plans provided for in the study.
Exclusion Criteria:
* Lack of signature on informed consent form
* Age \< 18 and \> 65 years
* Male gender
* Patients with food allergies or celiac disease, type 1 diabetes mellitus and autoimmune forms of diabetes mellitus or with severe pancreatic beta cell dysfunction, undergoing treatment with SGLT2 inhibitors, with recent cardiovascular or cerebrovascular events, liver failure, moderate or severe renal failure, respiratory failure, episodes of gout, kidney stones, electrolyte disturbances, NYHA class III-IV heart failure, unstable angina, cardiac arrhythmias or myocardial infarction within the last 12 months, severe depression or any other psychiatric illness, drug, narcotic or alcohol abuse, frail patients, pregnancy and/or breastfeeding, patients about to undergo surgery or invasive procedures, rare diseases (porphyria, carnitine deficiency, carnitine palmitoyltransferase, carnitine acylcarnitine translocase and pyruvate carboxylase, mitochondrial beta oxidation disorders), treatment with diuretics.
* Use of prebiotics and/or probiotics not included in the study, or other dietary supplements in the month prior to enrollment
* Antibiotic treatment less than 3 months prior to enrollment
* Infections at the time of enrollment or any chronic gastrointestinal disorder (e.g., Crohn's disease)
* Significant eating problems (e.g., dysphagia).
Primary outcome measure(s)
- Assessing the impact of dietary approach on the severity of fibromyalgia, particularly on pain through the Widespread Pain Index (WPI) — Baseline, Week 4, Week 8, and at the end of treatment (up to 12 weeks).
Widespread Pain Index (WPI): this corresponds to the sum of the areas of pain present (ranging from 0 to 19).
- Assessing the impact of dietary approach on the severity of fibromyalgia, particularly on pain through the Symptom Severity Scale (SSS). — Baseline, Week 4, Week 8, and at the end of treatment (up to 12 weeks).
Symptom Severity Scale (SSS): this corresponds to the sum of the severity levels of three symptoms (fatigue, non-restorative sleep, cognitive problems), measured on a 4-point ordinal scale, and the presence or absence of three other symptoms (migraine, abdominal pain/cramps, depression). The maximum possible score is 12.
- Assessing the impact of dietary approach on the severity of fibromyalgia, particularly on pain through the Fibromyalgia Impact Questionnaire (FIQR). — Baseline, Week 4, Week 8, and at the end of treatment (up to 12 weeks).
The FIQR comprises 21 questions, structured on numerical rating scales ranging from 0 to 10. The questions are divided into three distinct domains: physical function (9 questions), relating to difficulty in performing common activities of daily living; general health status (2 questions), which investigates the impact of the condition on work performance; and self-assessment of the intensity/severity of condition-related symptoms (10 questions).
- Assessing the impact of dietary approach on the severity of fibromyalgia, particularly on pain through the PainDETECT (PD-Q). — Baseline, Week 4, Week 8, and at the end of treatment (up to 12 weeks).
The PainDETECT (PD-Q) consists of a series of questions designed to identify the type, location (including any radiating pain) and intensity of the pain.
It also includes an image of a figure shown from the front and back, on which the patient must indicate the area affected by the pain.The score ranges from 0 to 35 and is directly proportional to the likelihood of the pain being neuropathic. More specifically, a final score of less than 12 indicates that neuropathic pain is unlikely, whilst a score of more than 19 indicates that the pain is very likely to be neuropathic.
- Assessing the impact of dietary approach on the severity of fibromyalgia, particularly on anxiety and depression through The Hospital Anxiety and Depression Scale (HADS). — Baseline, Week 4, Week 8, and at the end of treatment (up to 12 weeks).
The Hospital Anxiety and Depression Scale (HADS) is a 14-item, self-report screening tool designed to detect emotional distress (anxiety and depression) in clinical settings, particularly for people with physical health conditions. It includes seven anxiety questions and seven depression questions, excluding physical symptoms to avoid overlapping with medical diagnoses: 14 items, with 7 assessing anxiety (HADS-A) and 7 assessing depression (HADS-D).
Each item is rated on a 4-point scale (0 to 3), resulting in subscale scores ranging from 0 to 21.Generally, scores \< = 7 are "normal", 8-10 are borderline and \>= 11indicate a "case" of significant psychological morbidity.
- Assessing the impact of dietary approach on the severity of fibromyalgia, particularly on sleep quality through the Pittsburgh Sleep Quality Index (PSQI). — Baseline, Week 4, Week 8, and at the end of treatment (up to 12 weeks).
Each component score of the PSQI ranges from 0 to 3, with 3 indicating the greatest dysfunction or disturbance. The seven component scores are then summed to obtain a global PSQI score, which ranges from 0 to 21. Higher scores indicate poorer sleep quality, with a score greater than 5 suggesting significant sleep difficulties.
- Assess the presence of functional gastrointestinal disorders, in particular Irritable Bowel Syndrome (IBS) through the Rome IV criteria and the Bristol Stool Scale. — Baseline, Week 4, Week 8, and at the end of treatment (up to 12 weeks).
The Rome IV Criteria are a standardized diagnostic questionnaire used to identify functional gastrointestinal disorders, such as irritable bowel syndrome (IBS), functional constipation, and functional diarrhea. Its a checklist-based system:
* Presence/absence of symptoms
* Frequency and duration
* Association with bowel habits.
The Bristol Stool Scale is a visual classification tool used to categorize stool form into 7 types.
The 7 Types Type 1 - Separate hard lumps (severe constipation) Type 2 - Sausage-shaped but lumpy (mild constipation) Type 3 - Like a sausage with cracks on the surface (normal) Type 4 - Smooth, soft sausage or snake (normal, ideal) Type 5 - Soft blobs with clear edges (lacking fiber) Type 6 - Fluffy pieces, mushy (mild diarrhea) Type 7 - Watery, no solid pieces (severe diarrhea) Evaluation Scale
It is a 7-point ordinal scale:
1-2 → Constipation 3-4 → Normal stool 5 → Borderline 6-7 → Diarrhea
Trial sites (1)
| Facility | City | Region | Status |
|---|
| Department of Internal and Medical Specialities (university of Genoa) |
Genova |
Genova |
|
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