PROMO: Protein Supplementation to Improve Muscle Mass in Malnourished Elderly via Oral Nutritional Supplements.

The prevalence of malnutrition in The Netherlands is well over 20% among people
aged 75 or older. Malnourishment significantly and negatively impacts clinical
parameters such as weight loss, wound healing, reduced physical performance,
lethargy and depression, impaired immune function, and secondary complications.
One of the major direct effects of disease-related malnutrition is muscle loss
which impairs function, mobility and independence. Malnutrition can be detected
by low body weight and by involuntary weight loss, but also by atrophy of
muscle tissue leading to reduced strength and thus impaired mobility. In older
adults the age-related progressive loss of skeletal muscle mass and strength
(sarcopenia), leads to the loss of functional capacity and an increased risk of
developing chronic metabolic disease. Improving the nutritional status of
patients will lead to a better physical condition which is very relevant for a
quicker recovery from the underlying disease.

This study aims to investigate the impact of a newly developed oral nutritional
supplementation (ONS_01) primary on body weight and lean body mass and
secondary on physical performance, muscle health and immune function in
malnourished elderly people versus a nutritional supplement (ONS_2) which is
the standard of care in The Netherlands for the treatment of malnutrition.

The present proposal consists of a 12 week, randomized and controlled
intervention trial with 3 treatments in parallel: Treatment 1: ONS01 (n=40), 2x
65 gram Vital01 dissolved in minimal 60 ml of a liquid (27,6g protein,
600kcal); Treatment 2 (reference): ONS02 (n=40), 2x 200ml Nutridrink (24g
protein, 600kcal);

All subjects will receive an oral nutritional supplement for 12 weeks, to
improve their nutritional status. Subjects will be randomly assigned to one of
the two treatments, ONS_01 and ONS_02.

The nutritional supplements used in this study will be: ONS_01: Vital01,
VitalNext B.V., Amersfoort, The Netherlands; ONS_02(reference): Nutridrink,
Nutricia Advanced Medical Nutrition, Danone, Schiphol, The Netherlands. ONS_01
is a newly developed nutrition for medical purposes, ONS_02 is an already
existing product.

Participants in this study can have benefits, since the participants are all at
risk for malnourishment, or already malnourished. This intervention using two
types of ONS will result in a better nutritional state. Both ONS are in
compliance with the appropriate law. The risks involved in participating in
this study are minimal. Adverse effects of using ONS might be nausea or
diarrhea. Other risks are blood sampling which occasionally can cause a local
haematoma or bruise and some participants may report pain or discomfort.
Furthermore, when participants choose to undergo a muscle biopsy this will be
performed, under local anaesthesia, by an experienced physician, and proper
precautions will be taken to minimize the risk of complications. Taking an
tissue biopsy can generate mild discomfort and result in local bruising. Since,
the elderly subjects will receive extra dietary protein, their estimated
glomular filtration rate (EFGR) will be screened and checked throughout the
study.

Both ONS have been notified at the Netherlands Food and Consumer Product Safety
Authority (NVWA, Nederlandse Voedsel en Warenautoriteit) and are thus safe for
consumer use.

Ursolic acid, a ubiquitously occurring pentacyclic triterpenoid, appears safe
for human consumption. This is substantiated by its natural presence in common,
daily consumed food products like fruit, herbs, and vegetable oil and the
numerous studies on ursolic acid showing a lack of toxicity in animal models
and humans. Because of its high safety profile, and through its action on
reducing muscle atrophy and stimulation of muscle protein synthesis, ursolic
acid can be expected to render beneficial effects in the treatment of
malnutrition, especially when used in combination with branch-chained amino
acids and vitamin D3 in the context of other essential components such as
protein, carbohydrates, lipids, and vitamins. With a targeted bioavailability
of 4% in Vital01, the effective daily dose of ursolic acid would be 16 mg of
ursolic acid. This amount is more than tenfold lower than the maximum tolerated
dose of 180 mg as determined by Wang et al.(2013) and Zhu et al. (2013),
thereby providing an additional and comprehensive safety margin.