Effectiveness of Therapeutic Fasting and Specific Diet in Patients With Rheumatoid Arthritis

Study Overview
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Brief Summary
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The aim of this trial is an evaluation of the effectiveness of fasting and a subsequent diagnosis-specific diet change in patients with rheumatoid arthritis in respect to improving rheumatic symptoms and further to investigate possible mechanisms of this improvement.

Detailed Description
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Rheumatoid arthritis is an inflammatory-destructive joint disease for which up to date etiopathogenetical causes are lacking. In recent years, numerous new therapeutic concepts have been developed in the form of targeted antibody therapies that can block various inflammatory mechanisms. Although better treatment successes in comparison with conventional therapies were achieved, patients respond to the new therapies in very different ways. As a result the optimal drug needs to be identified for each patient through individual treatment trials. So far, no healings have been achieved and the progression of the disease can be stopped only by permanent suppression of the inflammatory response. In addition to different immunological mechanisms and genetic predispositions, interactions with the microbiome of the intestine are increasingly being discussed in recent years. A dysbiotic intestinal flora, characterized by the loss of beneficial bacteria and a concomitant increase in potentially pathogenic microbes, is associated with chronic inflammatory syndromes. Modified fasting (up to 500 kcal energy intake per day) for 7-10 days leads to an improvement of the symptoms in many patients with rheumatoid arthritis and is regularly used by the applicants for the treatment of rheumatoid arthritis. Several clinical studies have shown that therapeutic fasting produces anti-inflammatory effects. However, so far no standardized method for long-term stabilization of corresponding effects after resumption of nutrition has been established. Recent transcriptome analyzes have not only revealed numerous new potential markers, but also increasingly allow conclusions to be drawn from these extensive datasets that suggest immunological relationships between specific genes. In preliminary studies within the framework of a project of the same study group, it was possible to identify inflammatory profiles of individual foods and to identify molecular markers of disease activity in rheumatoid arthritis whose diagnostic value has been tested and interpreted under the influence of fasting. These markers will now be clinically evaluated in this study in collaboration with both centers. The hypothesis is that a combination of fasting and subsequent diagnosis-specific diet change will improve the rheumatic symptoms. In this context, it will also be analyzed, which meaning of the changes 1) of the metabolism and 2) of the microbiome, mediated by fasting and nutrition, belongs. This will be demonstrated by using already identified markers for genotypic traits, gene expression traits, characteristics of protein expression, protein activities, and antigen-specific immunological response patterns. The present research project aims to combine the different aspects of a possible anti-rheumatic nutrition and to evaluate the nutritherapeutic concept in an RCT. We suggest that a part of the anti-inflammatory effects of fasting and best practice diets may be due to a change in the composition of the intestinal flora mediated. Thus this study contributes to the extended therapy of rheumatoid arthritis.

Official Title
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Effectiveness of Therapeutic Fasting and Specific Diet in Patients With Rheumatoid Arthritis: a Randomized Controlled Clinical Trial

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Other: Fasting and plant-based nutrition
* Other: Standard Nutrition Counselling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Rheumatoid arthritis free of any serious medical condition that precludes safe participation in an exercise program, such as coronary artery disease, severe hypertension, peripheral vascular disease, stroke, congestive heart failure, chronic obstructive pulmonary disease, insulin-dependent diabetes, psychiatric disease, renal disease, liver disease, active cancer other than skin cancer, and anemia Ability to understand the intervention concept and written consent to participate; Willingness to accept randomization and undergo the testing and intervention procedures and deliver stool, blood and urine samples for testing Age 18-70 years (inclusive) drug therapy was not started in the last 8 weeks before screening Exclusion Criteria: Gout or septic arthritis Psychiatric disease that interferes with the understanding and implementation of the intervention Pregnancy or breast feeding In the case of pronounced anemia (Hb <10 mg / dl) no inclusion in the examination or no additional blood sampling is carried out Underweight (BMI <18,5) or weight loss of >3kg/5kg in the last/last 3 month(s) Eating disorder (such as bulimia, anorexia nervosa) in the last 5 years Current vegan nutrition Non-existence of email address or internet access

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fasting and best practice nutrition<br>Initial fasting followed by 11 weeks plant-based diet | Other: Fasting and plant-based nutrition<br>* The experimental intervention is divided into an initial part with periodic fasting for 7-10 days on an outpatient basis, which is followed by a build-up phase. This group part then receives a diet change with a specific normocaloric nutrition including the concept of time restricted eating (TRE, 16/8h) and according to the following criteria: 1) plant-based, 2) rich in prebiotics, 3) enriched with kitchen spices and kitchen herbs known for their anti-mycotic and anti-inflammatory potential.<br>|
| Active Comparator: Standard Nutrition Counselling<br>12 weeks standard antiinflammatory diet | Other: Standard Nutrition Counselling<br>* The control group receives a diet considered to be fundamentally beneficial to health in the sense of the recommendations of the German Association for Nutrition (DGE), which contain a reduced intake of arachidonic acid and, as a result, modulate an anti-inflammatory effect.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health Assessement Questionnaire (HAQ) | Change from Baseline in the HAQ after 12 weeks, range from 0 to 3 while higher values meaning a higher grade of disability | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Activity Score 28 (DAS-28-CRP) | Change from Baseline in the DAS-28-CRP, range from 2.0 to 10.0 while higher values meaning a higher disease activity and below of 2.6 meaning remission | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| American College of Rheumatology (ACR) response criteria | Change from Baseline in fulfilling the ACR response criteria indicating therapy response rate in percent (none, ACR20, ACR50 or ACR70) | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Simplified Disease Activity Index Score (SDAI) | Change from Baseline in the SDAI, range from 0 to 86 with assumed range from 0.1 to 10mg/dL for CRP. Higher values mean a higher disease activity and below of 34 meaning remission. | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Bio-electrical impedance analysis (BIA) | Estimation of the body composition via bio-electrical impedance analysis (body fat and visceral fat in %) | Date of inclusion (baseline), after 6 and 12 weeks | 
| Bio-electrical impedance analysis (BIA) | Estimation of the body composition via bio-electrical impedance analysis (muscle mass in kg) | Date of inclusion (baseline), after 6 and 12 weeks | 
| Abdominal circumference |  | Date of inclusion (baseline), after 6 and 12 weeks | 
| Resting blood pressure |  | Date of inclusion (baseline), after 6 and 12 weeks | 
| Pulse rate |  | Date of inclusion (baseline), after 6 and 12 weeks | 
| Differential blood count |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Hepatic transaminases (GPT, GOT) and Gamma glutamyl transpeptidase (y-GT) | GPT in units per liter (U/L) GOT (U/L) y-GT (U/L) | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Total protein in grams per liter (g/L) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Creatinine in µmol per liter (µmol/L) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Creatine kinase (U/L) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Estimated glomerular filtration rate (eGFR) in milliliter per minute (mL/min) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Electrolytes | calcium in millimol per liter (mmol/L) potassium (mmol/L) sodium (mmol/L) | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/h) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| CRP in milligram per liter (mg/L) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| International normalized ratio (INR) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Partial thromboplastin time (PTT) in seconds (s) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Lactate dehydrogenase (LDH) (U/L) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Blood lipids and fasting glucose | triglycerides (mmol/L) total cholesterol (mmol/L) LDL (mmol/L) HDL (mmol/L) fasting glucose (mmol/L) | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Uric acid (µmol/L) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Rheumatoid factor (IgM) |  | Date of inclusion (baseline) | 
| Anti-cyclic citrullinated peptide (anti-CCP) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Phenotyping of immune cells | Determination of cytometric parameters that indicate changes in cell activation or quantitative changes in the absolute and/or relative size of subpopulations (e.g. classical/intermediate/non-classical monocytes, naïve and memory T-cells, B-cell differentiation to plasmablasts/-cells) Gene expression analysis of immune cells with Affymetrix whole genome microarrays and RNAseq to search for transcriptional patterns and markers that help to identify relevant immune cell (sub-)populations, which are not yet included in the cytometric phenotyping screen | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Metabolic plasma metabolites | Metabolic plasma metabolites of carbon metabolism with a blood spot extract using metabolomics (GC / MS) | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Urine analysis (10 ml midstream urine) |  | Date of inclusion (baseline), day 7, after 6 and 12 weeks | 
| Gut microbiome | Molecular typing of the extremely individual intestinal microbiota composition by sequencing of stool material (16S-, 18S-, ITS-amplicon sequencing, metagenomics, metatranscriptomics) and performing proteomics and metabolomics to characterize fasting and diet induced changes of the so far insufficiently characterized gut microbiota related molecular components in a subgroup of patients | Date of inclusion (baseline), day 7, week 6 and week 12 | 
| Sociodemographic Measurements | age, education level, household income, employment status, marital status, language spoken, complete family history of rheumatoid arthritis in first- and second-degree relatives, current and previous illness and co-morbidities, and current medications | Date of inclusion (baseline) | 
| Medication intake | Systematized documentation of medication, main and secondary diagnoses using CRF | Date of inclusion (baseline), after 6 and 12 weeks | 
| Analgetics intake | Systematized documentation of analgetic medication on a daily basis using a diary | Up to 12 weeks | 
| Documentation of Behavioral Factors | Documentation of digestion, menstruation, compliance on diet and extraordinary events on a daily basis using a diary | Up to 12 weeks | 
| Quantification of Behavioral Factors | Documentation of occupational stress, domestic stress, interpersonal conflicts on a daily basis using a diary via visual analog scale (VAS), range from 0 to 10 while higher values meaning a higher grade of stress | Up to 12 weeks | 
| Quantification of Behavioral Factors | Nicotine, Alcohol, Physical Inactivity, Coffee and Media Consumption via Likert Scales, range from 0 to 5 while higher values meaning a higher grade of agreement | Date of inclusion (baseline), after 6 and 12 weeks | 
| Food selection | Nutritional history via dietary record (each for 3 days) | Date of inclusion (baseline), after 4 and 9 weeks | 
| Dietary Behaviour | Modified FFQ recording dietary behaviour such as mealtimes, frequency of food intake, food preferences, fasting experiences | Date of inclusion (baseline), after 6 and 12 weeks | 
| The Hannover Functional Ability Questionnaire (Funktionsfragebogen Hannover, FFbH-R) | Change from Baseline in the FFbH-R, range from 0 to 100 % while higher values meaning a higher grade of functional capacity | Date of inclusion (baseline), after 6 and 12 weeks, after 6 months | 
| Mood questionnaire (Profile of Mood States, POMS) | Change from Baseline in Emotional Distress will be measured using the German Version of the Profile of Mood States (POMS) short version (35 items, 7-point Likert scale; 0=not at all, 6=extremely). It has 65 items and 6 domains: depression [range 0 - 98], vigour-activity [range 0 - 49], fatigue [range 0 - 49], and anger-hostility [range 0 - 49]. The total mood disturbance score is derived by subtracting the vigour-activity score from the the sum of scores from the other subscales. Lower scores indicate more stable mood profiles. | Date of inclusion (baseline), after 6 and 12 weeks, after 6 months | 
| Stress questionnaire (Cohen Perceived Stress Scale, CPSS) | Change from Baseline in the CPSS, range from 0 to 4 in each item. Scores are obtained by reversing responses (e.g., 0 = 4, 1 = 3, 2 = 2, 3 = 1 & 4 = 0) to the positively stated items and then summing across all scale items while higher values meaning a higher grade of perceived stress. | Date of inclusion (baseline), after 6 and 12 weeks, after 6 months | 
| Quality of Life questionnaire (WHO-5) | Change from Baseline in the WHO-5, range from 0 to 100 % while higher values meaning a higher grade of well-being | Date of inclusion (baseline), after 6 and 12 weeks, after 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fasting, Vegan, Plant based, Randomized Trial