The Importance of Additional Protein to Benefit More From Training During and After Hospitalization (PEPOP)

A Protein-enriched, Milk-based Supplement to Counteract Sarcopenia in Acutely Ill Geriatric Patients Offered Resistance Exercise Training During and After Hospitalisation - a Double-blinded, Randomized Controlled Trial

University of Copenhagen, The Danish Dairy Research Foundation, Denmark, Arla Foods, Glostrup University Hospital, Copenhagen, University Hospital, Gentofte, Copenhagen

The purpose of the study is to investigate if an increased protein intake, in the form of a protein-enriched, milk-based supplement, can enhance the beneficial effect of resistance training, offered during hospitalization and 12 weeks post discharge, in older patients. This will in part be evaluated from measures of muscle strength, muscle mass and physical functioning. Also, the study population's acceptance of the intervention product will be assessed along with measures related to 'cost-effectiveness'. A sub-study will be performed in a sub-group (n=30) to investigate if bio-impedance analysis (BIA) correlates with Dual-Energy X-ray absorptiometry (DXA) at single time points, and to see if it is possible to track changes in lean body mass. In addition, the reliability of the bio-impedance analyzer will be evaluated. Also, the prevalence and classification of sarcopenia will be assessed at baseline, and correlations to nutritional status will be investigated (n=120).

Main study: The study design is a block randomised, double-blind, placebo-controlled, multicentre intervention study. A total of 120 hospitalized older adults, above 70 years, will be recruited consecutively from the medical departments of three Hospitals in the Capital Region of Denmark (n=40 each place). Participants will be randomized into two groups - one group receives protein-enriched, milk-based supplements and the other group receives iso-energetic placebo products. Both groups participate in the same standardized resistance training program, and will be blinded to the supplement content. One training session consists of three exercises of the lower extremities (3 sets of 10 repetitions, pursuing an intensity of 8-12 repetition maximum (RM)). While admitted, supervised resistance training is offered daily. After discharge, the participants are encouraged to perform the same program as self-training four times per week.To ensure progression (or regression if necessary) the participants receive follow-up home visits by a physiotherapist, and thus after discharge the participants are closely monitored. All participants, irrespective of allocation, will get a daily vitamin D supplement. The study duration for each participant starts while admitted to hospital and lasts until 12 weeks after discharge. Endpoint assessments will be performed at baseline (> 72-h after admission to hospital), after discharge (> 72-h) and 12 weeks (± 2 days) after discharge. A few endpoints will be collected during follow-up (6 months post intervention). Data will be collected by study investigators blinded to the allocation of the participants. Sub-study: 'Validation of a portable bio-impedance analyzer in a population of older adults ≥ 70 years for the assessment of muscle mass and changes in muscle mass over time' A sub-study will be performed to investigate if the portable InBody-230 BIA correlate with DXA at single time points in 30 hospitalized older people ≥ 70 years, and to see if it is possible to track changes in LBM during the 12-week intervention. Total LBM, total fat mass, and percent LBM will be measured and compared as well as appendicular and trunk LBM. In addition, the reliability of the portable bio-impedance analyzer will be evaluated by assessing the degree of agreement between two subsequent measurements. In continuation of recruitment to the primary study, a subset of participants (n=30) will be asked if they want to participate in this sub-study, irrespective of their allocation in the main study. The measurements are going to be performed twice, while hospitalized and 12 weeks after discharge (± 5 days). Sub-study: 'Prevalence of sarcopenia and investigation of the relationship between nutritional status and the EWGSOP conceptual stages for sarcopenia in hospitalized older patients > 70 years'. The prevalence and classification of sarcopenia among Danish hospitalized older patients ≥ 70 years old (n=120) will be evaluated, according to the EWGSOP definition (Hand-grip-strength, 4-m gait speed, Bio-Impedance analysis). Also, examination of the relationship between measurements of nutritional status and the EWGSOP stages for sarcopenia (i.e. no sarcopenia, pre-sarcopenia, sarcopenia and severe sarcopenia) will be assessed at baseline. Nutritional status will be assessed according to BMI (< 18.5, 18.5-20.5, 20.5-25, > 25), Mini Nutritional Assessment (MNA) (no MN, risk of MN, MN), Malnutrition Universal Screening Tool (MUST) (low risk of MN, medium risk of MN, high risk of MN), and NRS-2002 (no MN, mild MN, moderate MN, severe MN) Results will be communicated to the general population and published in peer-reviewed journals.

Sarcopenia, Muscular atrophy, Frailty, Acute illness, Ageing, Protein supplementation, Whey protein, Resistance training, Strength training

Daily supervised resistance training offered while hospitalized, and encouragement of self-training 4 times per week for duration of 12 weeks after discharge (standardized training program, which will be monitered). Daily intake of 2 x 125 ml protein-enriched, milk-based supplements (whey protein), in the same period (additional ~25 g protein and 1953 kJ per day). Daily vitamin D supplements.

Daily supervised resistance training offered while hospitalized, and encouragement of self-training 4 times per week for duration of 12 weeks after discharge (standardized training program, which will be monitered). Daily intake of 2 x125 ml iso-energetic placebo-supplements, in the same period. Daily vitamin D supplements.

Resistance training (offered daily while hospitalized, and encouragement of 4 x/week as self-training after discharge)

Aiming at a dose of 20 ug/day. 20 ug/day will be handed out to study participants who do not get vitamin D supplements from the hospital while admitted and to those who are not already taking vitamin D supplements themselfes e.g. as part of a combination tablet.

Lean body mass (kg and percent) evaluated by bio-impedance analysis (portable, dual-frequency, 8-Point Tactile Electrode System).

Appendicular lean body mass (kg and percent) evaluated by bio-impedance analysis (portable, dual-frequency, 8-Point Tactile Electrode System).

Trunk lean body mass (kg and percent) evaluated by bio-impedance analysis (portable, dual-frequency, 8-Point Tactile Electrode System).

Lean body mass (total, appendicular, and trunk) evaluated by whole-body dual energy x-ray absorptiometry (DXA)-scanning.

Total mass. Evaluated by whole-body dual energy x-ray absorptiometry (DXA)-scanning and bio-impedance analysis (BIA).

According to Mini Nutritional Assessment (MNA) (no malnutrition, risk of malnutrition, malnutrition).

According to Malnutrition Universal Screening Tool (MUST) (low risk of MN, medium risk of MN, high risk of MN)

Inclusion Criteria: Men and women aged ≥ 70 years old Able to speak and understand Danish Expected length of stay > 3 days (evaluated by medical staff at department) Ability to stand independently without walking aids Admitted to the medical departments of Gentofte or Herlev Hospital or Rigshospitalet-Glostrup Exclusion Criteria: Active cancer Renal insufficiency (eGFR < 30 mL/min/1.73m2) Cognitive impairment (not able to comprehend the purpose of the study/give informed consent) Terminal disease Exclusively receiving enteral or parenteral nutrition Milk/lactose allergy or intolerance Planning to lose weight/go on a special diet Planned transfer to other hospitals/departments Pacemaker/other implanted electrical stimulants (due to Bio-Impedance Analysis (BIA) measurements) Not being able to lie still in seven minutes (only an exclusion criteria in the sub-study) Withdrawal criteria: Death during admission (does not apply to subsequent admissions) Withdrawal criteria: Discharge/transfer from the medical department before the intervention has started

Gade J, Beck AM, Andersen HE, Christensen B, Ronholt F, Klausen TW, Vinther A, Astrup A. Protein supplementation combined with low-intensity resistance training in geriatric medical patients during and after hospitalisation: a randomised, double-blind, multicentre trial. Br J Nutr. 2019 Nov 14;122(9):1006-1020. doi: 10.1017/S0007114519001831.

Gade J, Beck AM, Bitz C, Christensen B, Klausen TW, Vinther A, Astrup A. Protein-enriched, milk-based supplement to counteract sarcopenia in acutely ill geriatric patients offered resistance exercise training during and after hospitalisation: study protocol for a randomised, double-blind, multicentre trial. BMJ Open. 2018 Feb 1;8(2):e019210. doi: 10.1136/bmjopen-2017-019210.