Ghrelin treatment of comatose patients after cardiac arrest:
A phase 2 clinical trial to estimate safety and efficacy of ghrelin to promote cerebral recovery

Comatose patients after cardiac arrest have an insecure prognosis
Anoxic brain damage after cardiac arrest is one of the most common causes of
coma worldwide. In the Netherlands alone, approximately 5000 patients are
admitted, yearly. Epidemiologic studies have predicted a rising incidence,
because of an increasing prevalence of cardiovascular risk factors and the
aging population. Postanoxic encephalopathy is the most common cause of death
in patients that survive cardiac arrest to hospital admission. As opposed to
increased survival of cardiopulmonary resuscitation, outcome of postanoxic coma
has improved only little over the past years. Despite treatment on an intensive
care unit, approximately half of all comatose patients never regain
consciousness as a result of severe hypoxic-ischemic brain damage.1,21,2 In the
other half, there is a large probability of lasting brain damage with
functional and cognitive impairments. There is limited knowledge of the
pathophysiology of brain damage in postanoxic coma and hardly any insight into
the severity of brain damage in individual patients.

Treatments are not available
Effective treatments to improve brain recovery in postanoxic coma are
unavailable. Over the past years, there has been no substantial scientific
progress. The only general treatment of presumed benefit is has been cooling
the brain to 32°C. This was based on evidence from two small trials in 2002.
However, , although its gainthe benefit of cooling has become uncertain since
the recent large Targeted Temperature Management trial, where cooling to 32°C
was associated with the same outcome as cooling to 36°Cand mechanisms of action
are unclear.33 Currently, most experts believe that prevention of hyperthermia
(fever) is more important than induction of hypothermia. An important rationale
behind all studied, but ineffective, neuroprotective strategies, including
hypothermia, has been prevention of secondary damage by inhibition of neuronal
activation. The presumption is that this should preserve the remaining energy
in order to maintain basic cellular processes. However, we observed that
hypoxia causes wide spread inhibition of neuronal activity in itself.44 We
established that insufficient neuronal activity during more than 24 hours is an
independent predictor of absence of recovery to physiological activity patterns
in vitro55 and in patients with postanoxic coma.6,76,7 This association was
unrelated to the duration of the initial circulatory arrest or to the actual
oxygen level. This suggests that, after the initial insult, it is not only the
lack of energy, but also lack of neuronal activity, which may lead to secondary
irreversible damage or recovery. None of the previously tested neuroprotective
modalities by inhibition of activation were of proven benefit.88

Ghrelin was effective in animal models
Contrary to previous attempts, we now propose a treatment modality with mild
neuronal activation. We found a massive increase of physiological neuronal
activity and formation of new synapses by mild neuronal activation with Ghrelin
in vitro.99 Furthermore, Ghrelin prevented apoptosis in living rats after
cardiac arrest, with improved neurological recovery.1010 In more than ten rat
studies on focal cerebral ischemia and reperfusion (mainly by intraluminal
vessel occlusion), ghrelin improved neuronal survival and functional recovery
without exception, where in most studies it was assumed that ghrelin prevented
apoptosis.1111

Ghrelin is a naturally occurring hormone and mildly excitatory
neurotransmitter. The presumed mechanism of action is slowing down of
apoptosis.12*1512*15 Since hypoxia induced neuronal inactivity was
independently associated with progression towards irreversible damage, both in
vitro1616 and in patients,6,76,7 we assume that the beneficial effects of
ghrelin are mediated by mild neuronal activation, preventing ill-fated neuronal
inactivity.55 This is perpendicular to the classical view of neuroprotection by
inhibition, which is currently applied in all comatose patients after cardiac
arrest.

Ghrelin seems safe
Ghrelin has been tested in over one hundred human studies, including studies in
healthy volunteers and patients with cardiopulmonary diseases, neuro-endocrine
diseases, psychiatric diseases, and neurodegenerative diseases. Serious adverse
events (pneumonia, enteritis, lung cancer) were extremely rare and difficult to
attribute to ghrelin administration.17
Ghrelin has been administered as an infusion or a bolus in a variety of doses
to at least 1850 study participants, including healthy participants and
patients with obesity, prior gastrectomy, cancer, pituitary disease, diabetes
mellitus, eating disorders, cardiovascular disease and neurodegenerative
disease (for reviews please see17,18). Taken together: there is strong evidence
that ghrelin stimulates appetite and increases circulating GH, ACTH, cortisol,
prolactin, and glucose in various patient populations. There is a paucity of
evidence regarding the effects of ghrelin on LH, FSH, TSH, insulin, lipolysis,
body composition, cardiac function, pulmonary function, the vasculature, and
sleep (review17).
At the doses evaluated in the 66 published studies with adverse event
reporting, ghrelin demonstrated an excellent short-term safety profile with few
adverse effects.17 Serious adverse events such as pneumonia, enteritis, and
lung cancer were extremely rare and difficult to attribute biologically to
ghrelin administration. Most of the severe adverse events derived from 1 study
of ghrelin v.s placebo administration in severely ill patients with pulmonary
cachexia, a group that is vulnerable to developing additional medical
problems.19 Mild adverse events occurred in approximately 20% of participants
receiving ghrelin. The most common effect was transient flushing, which
occurred in 10% of volunteers, but resulted in discontinuation of study
medication in only 3 of the 939 participants in whom adverse event collection
was reported.20*22 There was no difference in the percentage of participants
experiencing flushing between bolus and infusion routes of administration.
Larger ghrelin doses may increase the risk of flushing, as indicated by the
higher rate of flushing in the 2 ghrelin bolus studies that employed the
largest tested dose (10*g/kg/dose). The most common gastrointestinal side
effect was gastric rumbles, which occurred in 22 participants (2.3%) and was
never severe enough to lead to ghrelin discontinuation. Gastrointestinal side
effects and increased thirst were more common in volunteers who received
continuous ghrelin infusions, perhaps due to the longer duration of exposure to
ghrelin. Few participants developed neurocognitive effects including
somnolence, fatigue, vertigo, or change in mood (26 subjects, 2.8%). These
effects were more common in subjects who received ghrelin bolus, potentially
due to the rapid ghrelin delivery.17 For more details please see investigators
brochure.

First effective neuroprotective treatment in cerebral ischemia?
We propose to estimate study the effect of ghrelin on neurological recovery of
comatose patients after cardiac arrest based on the large probability of a poor
outcome in this patient group, lack of effective treatments to promote brain
recovery, consistent beneficial effects of ghrelin under experimental in vitro
and in vivo conditions, and substantial evidence of safety.

If mild stimulation of neurons with Ghrelin provides clinically relevant
improvement of recovery after hypoxic-ischemic brain damage in postanoxic coma,
this will be the first identified effective treatment. This will be of large
relevance for patients, families, and society given the high incidence and
large impact of the disease, and the large probability of a poor outcome
without adjunctive treatment. Apart from the evident potential clinical value,
the first effective neuroprotective treatment in hypoxic-ischemic brain damage
will be of conceptual value, and may be translated to other patients with
cerebral ischemia, such as patients with ischemic stroke.

We know of no patents or other initiatives aiming at testing effects of ghrelin
or other modalities based on neuronal activation in postanoxic coma.

Primary objective:
We aim to measure safety and efficacy of intravenous treatment with
acyl-ghrelin to promote cerebral recovery in comatose patients after cardiac
arrest. Safety will be monitored throughout hospitalization and during
follow-up using all AEs reported, and by interim analyses by an independent
DSMB. Efficacy will be measured by the primary outcome measure, i.e. functional
recovery as measured by the Cerebral Performance Category (CPC) scale at six
months after cardiac arrest.

Secondary objective:
1. Case fatality
2. Time to awaken (time interval between resuscitation and Glasgow Coma Scale
(GCS) score of 14)
3. Long term outcome: CPC and cognitive functioning at 12 months
4. Cardiovascular measures:
Mean arterial blood pressure day 1-7 (mean, highest, lowest)
Heart rate day 1-7 (mean, highest, lowest)
Arrhythmia day 1-7: yes / no. If yes: type of arrhythmia
Cumulative dose of vasopressive medication day 1-7
Cumulative dose of inotropic medication day 1-7
Sequential Organ Failure Assessment score day 1-7
Kidney function day expressed as GFR day 1-7
CVVH day 1-7: yes / no
Assist devices day 1-7: yes / no
5. Biomarkers:
Cardiac: troponine and CK / CK-MB ratio at day 0, 1, 2 or 3
Neurological: NSE day 1, 2, 3
Endocrinological: cortisol, growth hormone, prolactine, ACTH, IGF-1 day 1, 2, 3
6. Gastro-intestinal: gastric residual volume (day 1-7, during ICU admission)

This will be a phase 2 multicenter, double blind, placebo controlled randomized
clinical trial.

Intravenous treatment with acylated ghrelin 600 micro gram twice daily for 1
week vs. placebo (the highest tested and safe dosage regime in human subjects).
Treatment duration of one week is chosen because (i) ill-fated neuronal
inactivity is mainly observed in the acute phase (first days) after cardiac
arrest and (ii) previous phase 0 and 1 studies have proven safety with a
treatment duration of one week.

Risk analysis is described in chapter 11 of the study protocol.