An Exploratory Clinical Study on Autophagy During Fasting

• ClinicalTrials.gov Identifier: NCT04739852
• Recruitment Status: Recruiting
• First Posted: February 5, 2021
• Last Update Posted: February 24, 2021
• Sponsor: Charite University, Berlin, Germany
• Collaborator: Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Bonn AöR
• Information provided by (Responsible Party): Andreas Michalsen, Charite University, Berlin, Germany

Study Description

Brief Summary:

Autophagy is considered one of the key molecular mechanisms for the broad preventive and therapeutic effects of periodic fasting. While it is generally known that fasting induces autophagy, there are no human studies that focus on the size and temporal kinetics of autophagy and its association with fasting specific signaling pathways. The kinetics of autophagy in patients with chronic diseases will now be compared with the kinetics of autophagy in healthy subjects, who both fast according to the same scheme; and further changes in metabolic and inflammatory parameters will be investigated.

Condition or disease	Intervention/treatment	Phase
Arthritis, Rheumatoid; Syndrome, Metabolic; Healthy	Other: Fasting	Not Applicable

Detailed Description:

Therapeutic fasting has been used for many decades in naturopathy and integrative medicine clinically successfully in the treatment of chronic diseases and pain syndromes. In particular, fasting therapy is used for chronic rheumatic, inflammatory, and metabolic diseases with increasing patient demand in specialized clinical facilities (fasting clinics).

Within the various historically developed forms of fasting, the fasting program according to the Buchinger Wilhelmi method has established itself worldwide as the most frequently applied method. This involves a subtotal caloric restriction with a daily caloric intake (200-400kcal/day) in the form of liquid components over a defined period of at least 10 days, accompanied by supporting measures of a health-promoting lifestyle program with elements such as exercise therapy, manual procedures, stress reduction and hydro-balneotherapy.

In early randomized studies and a systematic review, the effectiveness of inpatient fasting therapy for patients with rheumatoid arthritis was proven with 1a evidence. For the other indications, there is mainly empirical evidence or data from observation or prospective uncontrolled studies. In recent years, extensive basic science research activity has developed in the area of caloric restriction and intermittent fasting. In this context, a large number of favorable animal experimental findings have been demonstrated by defined fasting periods, including reductions in insulin, IGF-1, increases in adiponectins, insulin sensitivity, neurotrophic factors, and, over longer observation periods, a decrease in the incidence of cardiovascular, inflammatory, and metabolic, and more recently oncological diseases in a wide variety of animal species.

Numerous experimental studies have demonstrated that fasting or total or subtotal caloric restriction is a potent inducer of cellular autophagy. For autophagy, numerous beneficial effects on chronic diseases or disease defense functions have now been experimentally documented and also hypothesized for humans, including neurodegenerative and metabolic diseases, but also acute infections and inflammatory diseases. Unclear to date is the kinetics of the autophagy enhancing effect of fasting. In theoretical transfer from animal experimental data, an increase is postulated between 12 and 36h of fasting and possibly a decrease after several days.

Against this background, autophagy will now be investigated for the first time in blood samples from fasting healthy and diseased individuals in an exploratory clinical study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 3 groups of different inclusion criteria (healthy, metabolic syndrome or rheumatoid arthritis) undergoing the same intervention
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: The Kinetics of Autophagy During Periodic Fasting in Healthy People and Patients With Rheumatoid Arthritis or Metabolic Syndrome - an Exploratory Clinical Study
• Actual Study Start Date: February 1, 2021
• Estimated Primary Completion Date: February 1, 2022
• Estimated Study Completion Date: July 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Healthy Participants	Other: Fasting; Patients undergo a 5-10 day fasting period with a dietary energy supply 350-400kcal per day with fruit and vegetable juices or, if not feasible, an established fasting-mimicking diet of 600-800 kcal according to Longo et al.
Active Comparator: Metabolic Syndrome	Other: Fasting; Patients undergo a 5-10 day fasting period with a dietary energy supply 350-400kcal per day with fruit and vegetable juices or, if not feasible, an established fasting-mimicking diet of 600-800 kcal according to Longo et al.
Active Comparator: Rheumatoid Arthritis	Other: Fasting; Patients undergo a 5-10 day fasting period with a dietary energy supply 350-400kcal per day with fruit and vegetable juices or, if not feasible, an established fasting-mimicking diet of 600-800 kcal according to Longo et al.

Outcome Measures

Primary Outcome Measures :

1. Exploratory Proteomics of Autophagy Processes I [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
   - Change in protein levels of autophagy biomarkers (LC3II & p62) of isolated PBMCs (peripheral blood mononuclear cells) by Western Blotting, change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
2. Exploratory Proteomics of Autophagy Processes II [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
   - Change in protein levels and protein phosphorylation by untargeted mass spectrometry-based proteomics and phosphoproteomics of isolated PBMCs (peripheral blood mononuclear cells), change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up

Secondary Outcome Measures :

1. Muscle mass [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
   Estimation of the body composition via bio-electrical impedance analysis (muscle mass in kg)
2. Body fat [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
   Estimation of the body composition via bio-electrical impedance analysis (body fat and visceral fat in %)
3. Resting blood pressure [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
4. Cutaneous carotenoid level (CCL) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
   Cutaneous carotenoid level (CCL), correlating with the overall antioxidant status, measured with a noninvasive skin carotenoid sensor (Biozoom®)
5. Heart rate [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
6. Waist to Hip Ratio [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
7. Body Mass Index (kg/m2) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
8. Disease Activity Score 28 (DAS-28-CRP) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
   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
9. Health Assessement Questionnaire (HAQ) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
   Change from Baseline in the HAQ, range from 0 to 3 while higher values meaning a higher grade of disability
10. Simplified Disease Activity Index Score (SDAI) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    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.
11. Stress questionnaire (Cohen Perceived Stress Scale, CPSS) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    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, higher values meaning a higher grade of perceived stress.
12. Mindful Attention Awareness Scale (MAAS) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Assessing full scale, range from 15 to 90, higher score values meaning a better outcome.
13. Numerical Analog Scales [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Assessing stress, back pain, headache, shoulder/neck tension, sleep quality and duration, exhaustion, nervousness, digestive complaints, mood on 0-10 points each.
14. Quality of Life questionnaire (WHO-5) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Change from Baseline in the WHO-5, range from 0 to 100 %, higher values meaning a higher grade of well-being
15. Hospital Anxiety and Depression Scale (HADS) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Assessing full scale, range 0-42, lower score meaning a better outcome
16. General Self-efficacy Short Scale (ASKU) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Assessing full scale, range 3-15, higher score meaning a better outcome
17. Mood questionnaire (Profile of Mood States, POMS) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Change from Baseline in Emotional Distress will be measured using the German Version of the Profile of Mood States (ASTS) short version (19 items, 7-point Likert scale; 0=not at all, 6=extremely). Lower scores indicate more stable mood profiles.
18. Sociodemographic Measurements [ Time Frame: Day 1 (baseline) ]
    Age, gender, education level, household income, employment status, marital status, language spoken, complete family history, current and previous illness and co-morbidities, and current medications
19. Behavioral Factors [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Physical inactivity, coffee, health promoting activities via Likert Scales, range from 0 to 5 while higher values meaning a higher grade of agreement
20. Behavioral Factors: alcohol consumption [ Time Frame: Day 1 (baseline), after 2 and 6 weeks ]
    Number of alcoholic beverages on average per week in the last month
21. Behavioral Factors: smoking [ Time Frame: Day 1 (baseline), after 2 and 6 weeks ]
    Number of cigarettes on average per week in the last month
22. Behavioral Factors: fasting experience [ Time Frame: Day 1 (baseline) ]
    Type, definition, duration and date of previous fasting experiences
23. Expectation questions [ Time Frame: Day 1 (baseline) ]
    For fasting on a 5-point likert scale from 1 (nothing at all) to 5 (very strong)
24. Creatinine in µmol per liter (µmol/L) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
25. Estimated glomerular filtration rate (eGFR) in milliliter per minute (mL/min) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
26. Electrolytes [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    potassium (mmol/L) sodium (mmol/L)
27. Blood lipids and fasting glucose [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    triglycerides (mmol/L) total cholesterol (mmol/L) LDL (mmol/L) HDL (mmol/L) fasting glucose (mmol/L)
28. Insulin (mU/L) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
29. ß-Hydroxybutyrate [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Evaluate change in ketone body production by POCT
30. CrP (mg/L) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Evaluate change in CrP levels in participants with RA
31. Erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/h) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Evaluate change in ESR in participants with RA
32. Rheumatoid factor (RF, IgM) (U/mL) [ Time Frame: Day 1 (baseline) ]
    Evaluate RF status in participants with RA
33. Anti-cyclic citrullinated peptide (ACPA) (U/mL) [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Evaluate change in ACPA levels in participants with RA
34. Metabolic processes [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Targeted and quantitative analysis by mass spectrometry of change in metabolites of plasma, change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
35. Lipid profiling [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Targeted and quantitative analysis by mass spectrometry of change in plasma lipids, change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
36. Transcription expression patterns [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Change of the gene expression profile by RNA sequencing of isolated PBMCs (peripheral blood mononuclear cells), change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
37. Proteome/phosphoproteome/ubiquitinome patterns [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Evaluate proteome expression patterns through blood based proteome, phosphoproteome, and ubiquitinome analysis assessed prior to intervention (pre) vs. after 5-day fasting, day 2 of refeeding and 7 days post intervention
38. Epigentic patterns [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Evaluate epigentic methylation patterns through blood based epigenome analysis assessed prior to intervention (pre) vs. after 5-day fasting, day 2 of refeeding and 7 days post intervention
39. Exosomal protein patterns [ Time Frame: change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up ]
    Evaluate exosomal protein content through blood based metabolome analysis assessed prior to intervention (pre) vs. after 5-day fasting, day 2 of refeeding and 7 days post intervention

Other Outcome Measures:

1. Final questionnaire to record tolerability of fasting and nutrition, adverse effects [ Time Frame: After 6 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• One of the following diagnoses: rheumatoid arthritis, metabolic syndrome OR healthy volunteer
• Beginning (first 24h) inpatient treatment or hospital stay at Immanuel Hospital Berlin, Department of Naturopathy OR healthy volunteer
• Present written declaration of consent

Exclusion Criteria:

• Insufficient linguistic communication
• Dementia or other cognitive disorder
• Pregnancy or lactation
• Simultaneous participation in another clinical trial

Contacts and Locations

Contacts

Contact: Nadine Sylvester; +4930 80505 734; nadine.sylvester@immanuelalbertinen.de

Locations

Germany

Hochschulambulanz für Naturheilkunde der Charité-Universitätsmedizin Berlin am Immanuel-Krankenhaus; Recruiting

Berlin, Germany, 14109

Contact: Miriam Rösner, Study nurse 00493080505682 miriam.roesner@immanuel.de

Principal Investigator: Andreas Michalsen, Prof. Dr.

Sponsors and Collaborators

Charite University, Berlin, Germany

Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Bonn AöR

Investigators

• Principal Investigator: Andreas Michalsen, Prof. Dr.; Charite - Universitätsmedizin Berlin
• Study Director: Nils Gassen, Dr.; Department of Psychiatry and Psychotherapy University Bonn, Clinical Centre

More Information

• Responsible Party: Andreas Michalsen, Prof. Dr. med., Charite University, Berlin, Germany
• ClinicalTrials.gov Identifier: NCT04739852
• Other Study ID Numbers: Autophagy Fasting
• First Posted: February 5, 2021
• Last Update Posted: February 24, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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; Autophagy

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Metabolic Syndrome; Syndrome; Disease; Pathologic Processes; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases