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

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ClinicalTrials.gov Identifier: NCT03856190
Recruitment Status : Active, not recruiting
First Posted : February 27, 2019
Last Update Posted : July 6, 2021
Sponsor:
Collaborators:
Braunschweig Integrated Centre of Systems Biology (BRICS), Germany
Luxembourg Centre for Systems Biomedicine
Information provided by (Responsible Party):
Andreas Michalsen, Charite University, Berlin, Germany

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Other: Fasting and plant-based nutrition Other: Standard Nutrition Counselling Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 53 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Effectiveness of Therapeutic Fasting and Specific Diet in Patients With Rheumatoid Arthritis: a Randomized Controlled Clinical Trial
Actual Study Start Date : March 18, 2019
Actual Primary Completion Date : April 23, 2021
Estimated Study Completion Date : September 30, 2021

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Health Assessement Questionnaire (HAQ) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
    Change from Baseline in the HAQ after 12 weeks, range from 0 to 3 while higher values meaning a higher grade of disability


Secondary Outcome Measures :
  1. Disease Activity Score 28 (DAS-28-CRP) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
    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

  2. American College of Rheumatology (ACR) response criteria [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
    Change from Baseline in fulfilling the ACR response criteria indicating therapy response rate in percent (none, ACR20, ACR50 or ACR70)

  3. Simplified Disease Activity Index Score (SDAI) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
    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.

  4. Bio-electrical impedance analysis (BIA) [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks ]
    Estimation of the body composition via bio-electrical impedance analysis (body fat and visceral fat in %)

  5. Bio-electrical impedance analysis (BIA) [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks ]
    Estimation of the body composition via bio-electrical impedance analysis (muscle mass in kg)

  6. Abdominal circumference [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks ]
  7. Resting blood pressure [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks ]
  8. Pulse rate [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks ]
  9. Differential blood count [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  10. Hepatic transaminases (GPT, GOT) and Gamma glutamyl transpeptidase (y-GT) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
    • GPT in units per liter (U/L)
    • GOT (U/L)
    • y-GT (U/L)

  11. Total protein in grams per liter (g/L) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  12. Creatinine in µmol per liter (µmol/L) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  13. Creatine kinase (U/L) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  14. Estimated glomerular filtration rate (eGFR) in milliliter per minute (mL/min) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  15. Electrolytes [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
    • calcium in millimol per liter (mmol/L)
    • potassium (mmol/L)
    • sodium (mmol/L)

  16. Erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/h) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  17. CRP in milligram per liter (mg/L) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  18. International normalized ratio (INR) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  19. Partial thromboplastin time (PTT) in seconds (s) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  20. Lactate dehydrogenase (LDH) (U/L) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  21. Blood lipids and fasting glucose [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
    • triglycerides (mmol/L)
    • total cholesterol (mmol/L)
    • LDL (mmol/L)
    • HDL (mmol/L)
    • fasting glucose (mmol/L)

  22. Uric acid (µmol/L) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  23. Rheumatoid factor (IgM) [ Time Frame: Date of inclusion (baseline) ]
  24. Anti-cyclic citrullinated peptide (anti-CCP) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  25. Phenotyping of immune cells [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
    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

  26. Metabolic plasma metabolites [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
    Metabolic plasma metabolites of carbon metabolism with a blood spot extract using metabolomics (GC / MS)

  27. Urine analysis (10 ml midstream urine) [ Time Frame: Date of inclusion (baseline), day 7, after 6 and 12 weeks ]
  28. Gut microbiome [ Time Frame: Date of inclusion (baseline), day 7, week 6 and week 12 ]
    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

  29. Sociodemographic Measurements [ Time Frame: Date of inclusion (baseline) ]
    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

  30. Medication intake [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks ]
    Systematized documentation of medication, main and secondary diagnoses using CRF

  31. Analgetics intake [ Time Frame: Up to 12 weeks ]
    Systematized documentation of analgetic medication on a daily basis using a diary

  32. Documentation of Behavioral Factors [ Time Frame: Up to 12 weeks ]
    Documentation of digestion, menstruation, compliance on diet and extraordinary events on a daily basis using a diary

  33. Quantification of Behavioral Factors [ Time Frame: Up to 12 weeks ]
    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

  34. Quantification of Behavioral Factors [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks ]
    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

  35. Food selection [ Time Frame: Date of inclusion (baseline), after 4 and 9 weeks ]
    Nutritional history via dietary record (each for 3 days)

  36. Dietary Behaviour [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks ]
    Modified FFQ recording dietary behaviour such as mealtimes, frequency of food intake, food preferences, fasting experiences

  37. The Hannover Functional Ability Questionnaire (Funktionsfragebogen Hannover, FFbH-R) [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks, after 6 months ]
    Change from Baseline in the FFbH-R, range from 0 to 100 % while higher values meaning a higher grade of functional capacity

  38. Mood questionnaire (Profile of Mood States, POMS) [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks, after 6 months ]
    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.

  39. Stress questionnaire (Cohen Perceived Stress Scale, CPSS) [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks, after 6 months ]
    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.

  40. Quality of Life questionnaire (WHO-5) [ Time Frame: Date of inclusion (baseline), after 6 and 12 weeks, after 6 months ]
    Change from Baseline in the WHO-5, range from 0 to 100 % while higher values meaning a higher grade of well-being


Other Outcome Measures:
  1. Final questionnaire to record tolerability of fasting and nutrition, adverse effects [ Time Frame: after 12 weeks ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03856190


Locations
Layout table for location information
Germany
Charité Hochschulambulanz für Naturheilkunde, Immanuel Krankenhaus Berlin
Berlin, Germany, 14163
Charité University, Berlin, Department of Rheumatology and Clinical Immunology
Berlin, Germany
Sponsors and Collaborators
Charite University, Berlin, Germany
Braunschweig Integrated Centre of Systems Biology (BRICS), Germany
Luxembourg Centre for Systems Biomedicine
Investigators
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Principal Investigator: Andreas Michalsen, Prof. Dr. Charité Hochschulambulanz für Naturheilkunde, Immanuel Krankenhaus Berlin
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Andreas Michalsen, Principal Investigator, Charite University, Berlin, Germany
ClinicalTrials.gov Identifier: NCT03856190    
Other Study ID Numbers: NutriFast
First Posted: February 27, 2019    Key Record Dates
Last Update Posted: July 6, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Analytic Code
Time Frame: 10 years after publication of primary results
Access Criteria:
  • scientific objective (non-commercial)
  • sound methodology

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Andreas Michalsen, Charite University, Berlin, Germany:
Fasting
Vegan
Plant based
Randomized Trial
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases