An interventional study of Resonance frequency breathing with heart rate variability biofeedback training and Anti-Stress program in Prediabetes, sponsored by Johannes Gutenberg University Mainz. Recruiting at 2 sites in Germany. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-08-05.
Sponsored by Johannes Gutenberg University Mainz · Not applicable, Interventional, and Treatment
Approximately 20% of adults have prediabetes in Germany. Prediabetes is defined as a condition with glucose levels outside the normal range but not yet meeting the criteria for type 2 diabetes. The pathogenesis of prediabetes, as well as of type 2 diabetes, involves whole-body insulin resistance associated with inadequate insulin secretion. These two central processes of glucose regulation are modulated by the brain. The brain communicates via the autonomic nervous system (ANS) with metabolically important organs in the periphery to modulate insulin sensitivity and insulin secretion. These processes are impaired in individuals with prediabetes and diabetes. An ANS sympathovagal imbalance has also been observed in individuals with prediabetes. There are no specific therapeutic approaches to improve ANS sympathovagal imbalance. It is assumed that resonant frequency breathing (RFB) maximizes heart rate variability (HRV) through rhythmization of breathing, heartbeat, and blood pressure. Through this state of coherence, the activity of the parasympathetic nervous system is upregulated, and the activity of the sympathetic nervous system is suppressed, leading to an increase in modulation of ANS activity. Several studies have demonstrated that heart rate variability-biofeedback (HRV-BF) interventions improve HRV, reduce stress and anxiety, and alleviate symptoms in patients with various medical conditions. To the best of current knowledge, no study has investigated the effect of HRV-BF-RFB on glucose metabolism. Therefore, the proposed randomized controlled non-blinded trial aims to gain evidence about the effect of HRV-BF-RFB compared to an anti-stress program on glucose metabolism in individuals with prediabetes. Glucose metabolism is characterized using the 75 g oral glucose tolerance test. There are two potential mechanisms by which HRV-BF-RFB may improve glucose metabolism in individuals with prediabetes: (a) a 0°-phase relationship between heart oscillations and breathing, maximizing the amplitude of respiratory sinus arrhythmia (RSA), and (b) activation of the cholinergic anti-inflammatory pathway. The investigators hypothesized that in individuals with prediabetes, the HRV-BF-RFB intervention will improve glucose metabolism and glucose variability.
918 studies on the registry are indexed under Prediabetic State; 232 are open to participants now.
This study's planned enrollment of 60 is close to the median of 62 across 762 interventional studies indexed under Prediabetic State.
Browse Prediabetic State studies →Johannes Gutenberg University Mainz is the lead sponsor of 156 studies on the registry; 20 are open to participants now.
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Presence of prediabetes Fasting glucose: 100-125 mg/dl (5.6-6.9 mmol/L) and/or in %: 5.7-6.4 (39-47 mmol/mol ) and/or 2-hour value of the 75 g OGTT: 140-199 mg/dl (7.8-11.0 mmol/L)
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
HbA1c
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The mobile system "eSense Pulse" by Mindfield Biosystems Ltd. (Gronau, Germany) was used for RFB-HRV-BF training. The participants sat in an upright position, started the training via the eSense app on their smartphone, and were instructed to practice breathing at their individually determined resonance frequency.During training, a ball that expands (breathe in) and shrinks (breathe out) on the screen specified the breathing frequency goal to a value of six cycles per minute (five seconds inspiration, five seconds expiration). The HRV was visualized by new symbols varying in color depending on the respectively measured values, which appeared every ten seconds.
Behavioral: Resonance frequency breathing with heart rate variability biofeedback training
The mobile system eSense Pulse from Mindfield Biosystems is used for the digital anti-stress program. To do this, the participants put on a chest strap with a sensor and can start training via the eSense app. The anti-stress program is carried out using a procedure generated for the study. During the anti-stress program units, the participants receive application-related information and tips to better understand the topic of stress, identify stressors in their own lives and reduce stress. The active control intervention of the anti-stress program was selected to investigate the effect of a specific stress level reduction without the direct modulation of physiological mechanisms of action as with HRV-BF-RFA.
Behavioral: Anti-Stress program
During training, a ball that expands (breathe in) and shrinks (breathe out) on the screen specified the breathing frequency goal to a value of six cycles per minute (five seconds inspiration, five seconds expiration). The HRV was visualized by new symbols varying in color depending on the respectively measured values, which appeared every ten seconds. When the participants achieved the specified breathing frequency, resulting in an increased sinus arrhythmia, the symbols appearing on the smartphone display were green. When the participants did not achieve the specified breathing frequency, the symbols appeared in yellow (non-significant deviation), orange (significant deviation), or red (very significant deviation). The participants were instructed to adjust their breathing frequency to reach emergence of as many green symbols as possible for the entire training session.
Also known as: RFB-HRV-BF
The mobile system eSense Pulse from Mindfield Biosystems is used for the digital anti-stress program. To do this, the participants put on a chest strap with a sensor and can start training via the eSense app. The anti-stress program is carried out using a procedure generated for the study. During the anti-stress program units, the participants receive application-related information and tips to better understand the topic of stress, identify stressors in their own lives and reduce stress. The active control intervention of the anti-stress program was selected to investigate the effect of a specific stress level reduction without the direct modulation of physiological mechanisms of action as with HRV-BF-RFA.
Also known as: ASP
Glucose metabolism
Glucose metabolism was assessed through a frequently-sampled 75 g oral glucose tolerance test (OGTT) starting at 8:00 a.m. after an overnight fast. After basal blood sampling, the participants drank a 75 g glucose solution, with further blood samples taken at 30, 60, 90, and 120 minutes after glucose ingestion. Areas under the curve were calculated based on the trapezoid method.
Time frame: Baseline, four weeks, and eight weeks.
Glucose stimulated insulin secretion
Glucose stimulated insulin secretion was assessed as oral Disposition Index and as ratio of the areas under the C-peptide curves and the areas under the glucose curves during the first 30 minutes of the OGTT (AUC C-peptid0-30/AUC glucose0-30). For the estimation of insulin sensitivity, HOMA-IR was used for the fasting state and Matsuda Index \[29\] for the post-glucose load situation. Insulin clearance was estimated by the ratio of the areas under the C-peptide and insulin curves during the OGTT (AUC C-peptide0-120/AUC insulin0-120).
Time frame: Baseline, four weeks, and eight weeks.
Interstitial fluid glucose levels in mg/dL
The daily profiles of the interstitial fluid glucose levels are recorded using continuous glucose measurement systems (FreeStyle Libre Pro iQ). These data enable the calculation of indices to assess glucose variability (standard deviation, coefficient of variation, MAGE index, MODD index) and glucose tolerance (daily mean values, AUC). Each measurement period lasted 14 days, as per the sensor lifespan.
Time frame: Two weeks before the intervention, two weeks after the intervention
Cytokines
The cytokine profile is quantified using 48 analytes measured as a multiplex assay (proximity extension assay, Olink Proteomics, 2021). The 45 immune-related proteins (in pg/mL) are: IL-18, HGF, CCL19, CCL2, MMP12, LTA, FLT3LG, TNF, IL17A, IL2, ILF17F, CSF3, IL1B, OLR1, TNFSF12, CXCL10, VEGFA, IL33, TSLP, IFNG, CCL4, TGFA, IL13, CXCL8, CCL8, IL6, CCL13, CSF2, CCL7, IL4, TNFSF10, OSM, MMP1, EGF, IL7, IL15, CSF1, CXCL9, CXCL11, IL17C, CXCL12, CCL11, IL10, CCL3, EBI3\_IL27.
Time frame: Baseline, four weeks, and eight weeks.
Plan to share: No — There is not a plan to make IPD available.
Started May 2025 (actual). Primary completion is estimated for Dec 2026, 19 months after the start.
Of 378 non-industry interventional studies with no phase under Prediabetic State, half reached primary completion within 25 months of starting (the median), counting those still running; a quarter within 12 and three quarters within 39. This study's planned 19 months is below that.
Counting every sponsor, half of 424 studies reached it within 23 months; a quarter within 11 and three quarters within 37.
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