Chronic liver disease eventually results in liver cirrhosis and is associated with an increasing deterioration in patients' physical fitness. As there is currently limited evidence regarding the effects of a home-based exercise program in patients with liver cirrhosis awaiting OLT, and physical frailty rates are particularly high in this patient population, this group has the investigators specific interest. The primary aim of this study is to assess the effect of a semi-supervised home-based bimodal lifestyle program, consisting of interval and endurance training and peripheral resistance training on aerobic capacity in patients with liver cirrhosis awaiting OLT

Rationale: Patients with liver cirrhosis who are on the waiting list for orthotopic liver transplantation (OLT) encounter all key components of physical frailty, i.e., decreased functional capacity, impaired aerobic capacity and sarcopenia, which all lead to fatigue, diminished quality of life, increased hospitalization and pre- and post-transplantation morbidity and mortality. An exercise program in combination with nutritional support has proven to improve all key components of physical frailty and quality of life in various surgical patient populations. Although small studies have demonstrated similar positive effects of exercise training in patients on the waiting list for OLT, to date no large studies supported the effects of exercise training and nutritional support on (the longevity of) the increase in aerobic capacity in OLT patients.

Objective: The primary objective of this study is to assess the effect of a semi-supervised home based bimodal lifestyle intervention on aerobic capacity (measured by VO2 at the Ventilatory anaerobic threshold (VAT) and VO2peak in ml/kg/min) in patients with liver cirrhosis on the waiting list for OLT. Secondary objectives are to evaluate individual patients' responses to the bimodal lifestyle intervention on sarcopenia, anthropometry, functional mobility, quality of life, perceived fatigue, incidence of hepatic encephalopathy, number of unplanned hospital admissions, change in liver frailty index score and change in microbiome composition at six, 12 and 18 weeks, or until transplantation. Finally, the feasibility (participation rate, reasons for non-participation, adherence/compliance, dropout rate, reasons for dropout and adverse event) will be assessed.

Study design: This study is an investigator-initiated, single center, single arm, prospective clinical trial. It will take place at the University Medical Center Groningen, the Netherlands. Eligible patients will participate in the bimodal lifestyle program, which comprises two home-based training periods of six-weeks each (12 weeks training in total, or until transplantation). After 18 weeks (i.e., six weeks after termination of the program) a final assessment will take place to evaluate the longevity of the expected effects of the lifestyle program on predefined study outcomes.

Study population: Adult patients diagnosed with liver cirrhosis and screened for OLT, with a VO2 at the VAT ≤13ml/kg/min and/or VO2peak ≤18ml/kg/min will be screened for potential eligibility. Patients with no contraindications to physical exercise training and the ability to work out on a cycle ergometer can participate in the bimodal lifestyle intervention.

Intervention: Patients will participate in a home-based bimodal lifestyle program. The program comprises semi-supervised high intensity interval and endurance training on an advanced cycle ergometer (Lode Corival Home+ , Lode BV, Groningen, The Netherlands), combined with nutritional support consisting of protein, vitamin and mineral supplementation. Moreover, to improve functional mobility and muscle function patients will perform peripheral resistance training of the large muscle groups of the upper and lower extremities. Finally, to improve respiratory performance after surgery and potentially reduce pulmonary complications, patients will perform breathing exercises. The program will be patient personalized and compromises three training sessions per week. The cycle ergometer used for this program will upload training results of the interval and endurance training sessions to an online platform, enabling remote monitoring of patients' adherence and training progress. Furthermore, a community physical therapist will visit the patient at least weekly to monitor progress and to optimize the training intensity.

Main study parameters/endpoints: The main study parameter/endpoint is the progression in aerobic capacity after 6 weeks. Hereto, before and after the first training period a CPET will performed to determine the difference in VO2 at the VAT and VO2peak in ml/kg/min. A secondary parameter/endpoint of this study is the progression in aerobic capacity after the second training period, and six weeks after termination of the program. Hereto, after 12 and 18 weeks another CPET will be performed. Other secondary parameters/endpoints are the evaluation of differences in sarcopenia, anthropometry, functional mobility, quality of life, perceived fatigue, incidence of hepatic encephalopathy, number of unplanned hospital admissions, change in liver frailty index score and change in microbiome composition at six, 12 and 18 weeks, or until transplantation. Furthermore, postoperative outcomes up to twelve months post-OLT will be collected.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Because the exercise program is situated at home (both the cycle ergometer as the community physiotherapist will come to the patient) the investigators make things as accessible as possible for the patient to participate. Supervision by the physiotherapist during the training sessions is arranged three times in the first week and at least once a week thereafter. At the start of the program a CPET with continuous ECG monitoring will be executed under guidance of trained employees to assess baseline cardiorespiratory fitness, as well as to rule out strain related cardiac ischemia and other contraindications for physical exercise training during the consecutive exercise program. Hence, patient's safety in the exercise program is guaranteed. To minimize the burden of this study, the majority of the visits, withdrawal of blood samples, physical examinations and other study procedures, are combined with regular outpatient clinic visits.

Inclusion Criteria:

• Aged at least 18 years;
• Diagnosed with end-stage liver disease / liver cirrhosis (regardless of etiology);
• On the waiting list for OLT;
• VO2 at the VAT ≤13 ml/kg/min and/or VO2peak ≤18 ml/kg/min;
• Speaks the Dutch language;
• Understands the purpose of the study and has given written informed consent to participate in the study.

Exclusion Criteria:

• Experienced a MACE (e.g., myocardial infarction) in the past six months;
• Experienced a cerebrovascular incident in the past six months;
• Medical history of an uncontrolled heart rhythm disorder;
• Hepatic encephalopathy grade 3 or 4;
• Acute liver failure;
• Acute on chronic liver failure;
• Hospitalization at start of the study;
• Non-treated esophageal varices (i.e., variceal eradication endoscopy and/or adequately dosed NSBB);
• MELD score ≥30;
• Not capable of cycling on a cycle ergometer;
• No available community physical therapist in the living area of the patient.
• Patients refusing or unable to sign informed consent