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

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

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.

Study Overview

• Status: Terminated
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Other: Fasting and plant-based nutrition; Other: Standard Nutrition Counselling

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14163
    • Charité Hochschulambulanz für Naturheilkunde, Immanuel Krankenhaus Berlin
  • Berlin, Germany
    • Charité University, Berlin, Department of Rheumatology and Clinical Immunology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Rheumatoid arthritis
2. 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
3. Ability to understand the intervention concept and written consent to participate;
4. Willingness to accept randomization and undergo the testing and intervention procedures and deliver stool, blood and urine samples for testing
5. Age 18-70 years (inclusive)
6. drug therapy was not started in the last 8 weeks before screening

Exclusion Criteria:

1. Gout or septic arthritis
2. Psychiatric disease that interferes with the understanding and implementation of the intervention
3. Pregnancy or breast feeding
4. In the case of pronounced anemia (Hb <10 mg / dl) no inclusion in the examination or no additional blood sampling is carried out
5. Underweight (BMI <18,5) or weight loss of >3kg/5kg in the last/last 3 month(s)
6. Eating disorder (such as bulimia, anorexia nervosa) in the last 5 years
7. Current vegan nutrition
8. Non-existence of email address or internet access

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fasting and "best practice" nutrition; Initial fasting followed by 11 weeks plant-based diet	Other: Fasting and plant-based nutrition; 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.
Active Comparator: Standard Nutrition Counselling; 12 weeks standard antiinflammatory diet	Other: Standard Nutrition Counselling; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Final questionnaire to record tolerability of fasting and nutrition, adverse effects	Measurement of tolerability of fasting and nutrition as well as adverse effects via Likert Scales, range from 0 to 5 while higher values meaning a higher grade of agreement	after 12 weeks

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: Luxembourg Centre for Systems Biomedicine; Braunschweig Integrated Centre of Systems Biology (BRICS), Germany
• Investigators: Principal Investigator: Andreas Michalsen, Prof. Dr., Charité Hochschulambulanz für Naturheilkunde, Immanuel Krankenhaus Berlin

Publications and helpful links

General Publications

• Hartmann AM, Dell'Oro M, Kessler CS, Schumann D, Steckhan N, Jeitler M, Fischer JM, Spoo M, Kriegel MA, Schneider JG, Haupl T, Kandil FI, Michalsen A, Koppold-Liebscher DA. Efficacy of therapeutic fasting and plant-based diet in patients with rheumatoid arthritis (NutriFast): study protocol for a randomised controlled clinical trial. BMJ Open. 2021 Aug 11;11(8):e047758. doi: 10.1136/bmjopen-2020-047758.

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2019
• Primary Completion (Actual): April 8, 2021
• Study Completion (Actual): July 7, 2021

Study Registration Dates

• First Submitted: January 24, 2019
• First Submitted That Met QC Criteria: February 25, 2019
• First Posted (Actual): February 27, 2019

Study Record Updates

• Last Update Posted (Actual): February 7, 2022
• Last Update Submitted That Met QC Criteria: January 24, 2022
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Fasting; Vegan; Randomized Trial; Plant based
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: NutriFast

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The study protocol is to be published open access. On publishing the outcomes, the anonymized individual participant data that underlie the reported results, as well as the statistical code, will be made available to scientific investigators who issue a methodologically sound proposal.
• IPD Sharing Time Frame: 10 years after publication of primary results
• IPD Sharing Access Criteria: scientific objective (non-commercial); sound methodology
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No