An Exploratory Clinical Study on Autophagy During Fasting

Healthy Clinical Trial

Official title:

The Kinetics of Autophagy During Periodic Fasting in Healthy People and Patients With Rheumatoid Arthritis or Metabolic Syndrome - an Exploratory Clinical Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04739852
• Other study ID #: Autophagy Fasting
• Status: Recruiting
• Phase: N/A
• Start date: February 1, 2021
• Est. completion date: July 1, 2025

Study information

• Verified date: December 2023
• Source: Charite University, Berlin, Germany
• Contact: Nadine Sylvester
• Phone: +4930 80505 734
• Email: nadine.sylvester[@]immanuelalbertinen.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: July 1, 2025
• Est. primary completion date: February 1, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Healthy
• Metabolic Syndrome
• Syndrome
• Syndrome, Metabolic

Intervention

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.

Locations

Country	Name	City	State
Germany	Hochschulambulanz für Naturheilkunde der Charité-Universitätsmedizin Berlin am Immanuel-Krankenhaus	Berlin

Sponsors (2)

Lead Sponsor	Collaborator
Charite University, Berlin, Germany	Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Bonn AöR

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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 6 weeks
Primary	Exploratory Proteomics of Autophagy Processes I	- 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	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Primary	Exploratory Proteomics of Autophagy Processes II	- 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	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Muscle mass	Estimation of the body composition via bio-electrical impedance analysis (muscle mass in kg)	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Body fat	Estimation of the body composition via bio-electrical impedance analysis (body fat and visceral fat in %)	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Resting blood pressure		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Cutaneous carotenoid level (CCL)	Cutaneous carotenoid level (CCL), correlating with the overall antioxidant status, measured with a noninvasive skin carotenoid sensor (Biozoom®)	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Heart rate		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Waist to Hip Ratio		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Body Mass Index (kg/m2)		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	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	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Health Assessement Questionnaire (HAQ)	Change from Baseline in the HAQ, range from 0 to 3 while higher values meaning a higher grade of disability	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	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.	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	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, higher values meaning a higher grade of perceived stress.	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Mindful Attention Awareness Scale (MAAS)	Assessing full scale, range from 15 to 90, higher score values meaning a better outcome.	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Numerical Analog Scales	Assessing stress, back pain, headache, shoulder/neck tension, sleep quality and duration, exhaustion, nervousness, digestive complaints, mood on 0-10 points each.	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Quality of Life questionnaire (WHO-5)	Change from Baseline in the WHO-5, range from 0 to 100 %, higher values meaning a higher grade of well-being	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Hospital Anxiety and Depression Scale (HADS)	Assessing full scale, range 0-42, lower score meaning a better outcome	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	General Self-efficacy Short Scale (ASKU)	Assessing full scale, range 3-15, higher score meaning a better outcome	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	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 (ASTS) short version (19 items, 7-point Likert scale; 0=not at all, 6=extremely). Lower scores indicate more stable mood profiles.	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Sociodemographic Measurements	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	Day 1 (baseline)
Secondary	Behavioral Factors	Physical inactivity, coffee, health promoting activities via Likert Scales, range from 0 to 5 while higher values meaning a higher grade of agreement	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Behavioral Factors: alcohol consumption	Number of alcoholic beverages on average per week in the last month	Day 1 (baseline), after 2 and 6 weeks
Secondary	Behavioral Factors: smoking	Number of cigarettes on average per week in the last month	Day 1 (baseline), after 2 and 6 weeks
Secondary	Behavioral Factors: fasting experience	Type, definition, duration and date of previous fasting experiences	Day 1 (baseline)
Secondary	Expectation questions	For fasting on a 5-point likert scale from 1 (nothing at all) to 5 (very strong)	Day 1 (baseline)
Secondary	Creatinine in µmol per liter (µmol/L)		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Estimated glomerular filtration rate (eGFR) in milliliter per minute (mL/min)		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Electrolytes	potassium (mmol/L) sodium (mmol/L)	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Blood lipids and fasting glucose	triglycerides (mmol/L) total cholesterol (mmol/L) LDL (mmol/L) HDL (mmol/L) fasting glucose (mmol/L)	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Insulin (mU/L)		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	ß-Hydroxybutyrate	Evaluate change in ketone body production by POCT	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	CrP (mg/L)	Evaluate change in CrP levels in participants with RA	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/h)	Evaluate change in ESR in participants with RA	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Rheumatoid factor (RF, IgM) (U/mL)	Evaluate RF status in participants with RA	Day 1 (baseline)
Secondary	Anti-cyclic citrullinated peptide (ACPA) (U/mL)	Evaluate change in ACPA levels in participants with RA	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Metabolic processes	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	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Lipid profiling	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	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Transcription expression patterns	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	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Proteome/phosphoproteome/ubiquitinome patterns	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	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Epigentic patterns	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	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Secondary	Exosomal protein patterns	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	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up