The Efficacy of TRH in Intensive Care patients; a dose finding study

A broad variety of illnesses is known to induce a set of profound changes in
thyroid hormone metabolism, collectively known as non-thyroidal illness
syndrome (NTIS). Its main characteristics are decreased plasma levels of
circulating thyroid hormone (TH) in the absence of an increase in thyroid
stimulating hormone (TSH), indicating a major change in feedback regulation of
the hypothalamic-pituitary-thyroid axis (HPT axis). Some investigators have
hypothesized that the persistent down-regulation of the HPT axis has
detrimental effects on clinical outcome in patients with prolonged critical
illness, but this has not been adequately tested to date. There is a clear need
for randomized clinical trials addressing this issue (for review see Fliers et
al, 2015). We intend to perform a randomised controlled study in patients with
prolonged critical illness using protirelin, the pharmaceutical form of
thyrotropin releasing hormone (TRH), to restore plasma TH to within the
reference range. Protirelin is registered for use as a diagnostic test for
thyroid and pituitary function. As a first step, we will perform a dose finding
study with protirelin in critically ill patients aimed at restoring plasma TH
concentrations.

To determine the minimal dose of protirelin that is effective and safe to
normalize plasma thyroid hormone levels in patients with prolonged critical
illness.

Phase II dose finding study, open label with a step-up design.

Subjects will receive protirelin (TRH) intravenously until the end of their
stay in the intensive care but with a minimum treatment duration of 5 days and
a maximum treatment duration of 2 weeks. Up to three doses will be tested in a
step-up design (1, 1.5 & 2 µg/kg/h) in 8 patients. 8 patients will be included
as controls without an intervention.

The burdens associated with this study are frequent blood sampling and
intravenous infusion of protirelin. Protirelin will be administered
intravenously by continuous infusion over an in situ venous catheter inserted
for routine clinical purposes. Blood (18ml) will be drawn daily from an in situ
arterial catheter inserted for clinical purposes.
Protirelin is a registered drug with no known severe side effects. Previous
studies have been performed using protirelin in similar doses in critically ill
patients (see references 8-11). Furthermore the effects of TRH administration
on serum TH levels are self-limiting. The risk of participation in this study
is therefore regarded as minimal and acceptable, even in this vulnerable
patient population.