Randomized, double-blind, placebo-controlled trial to evaluate the efficacy of continuous subcutaneous apomorphine infusion in Parkinson*s disease patients with refractory visual hallucinations

Visual hallucinations occur frequently in Parkinson*s disease (PD). The
prevalence of visual hallucinations ranges from 22 to 38% (Fénelon and Alves,
2010), increasing after long-term follow-up to more than 60% (Goetz et al.,
2010). The occurrence of visual hallucinations is predictive for progression to
more severe forms of PD psychosis and development of PD dementia (Fénelon and
Alves, 2010) reducing quality of life (Gibson et al., 2013). Risk factors for
visual hallucinations are older age (Fénelon and Alves, 2010; Gallagher et al.,
2011), longer disease duration (Fénelon and Alves, 2010; Gallagher et al.,
2011; Kalaitzakis et al., 2009), disease severity (Gallagher et al., 2011), and
cognitive impairment (Gallagher et al., 2011). Visual hallucinations are
associated with sleeping problems, depression and anxiety (Gibson et al., 2013).

The genesis of visual hallucinations in PD is related to impaired visual
processing. Collerton and colleagues have proposed the perception and attention
deficit (PAD) model, suggesting that visual hallucinations are caused by
disruption of either the bottom-up and/or top-down visual processing (Collerton
et al., 2005). Impaired bottom-up and top-down visual processing in patients
with PD and visual hallucinations is supported by structural and functional
imaging (Lenka et al., 2015; Meppelink, 2015), and clinic-pathological studies
(Gallagher et al., 2011; Harding et al., 2002; Kalaitzakis et al., 2009;
Papapetropoulos et al., 2006). Higher cortical visuoperception and attention
are impaired in PD patients with visual hallucinations compared to their PD
patients without visual hallucinations (Barnes et al., 2003; Gallagher et al.,
2011; Grossi et al., 2005; Meppelink et al., 2008; Ramírez-Ruiz et al., 2008).
The PAD model linked the genesis of visual hallucinations in PD to cholinergic
dysfunction (Collerton et al., 2005). However, it is suggested that
dysfunctional mono-amine neurotransmitters could also be linked to the
occurrence of visual hallucinations.

In treating visual hallucinations very few therapeutic options are available in
PD. The use of classic anti-psychotics is complicated by their extra-pyramidal
side effects. Some atypical anti-psychotics like quetiapine and clozapine do
not worsen parkinsonism and are now being most used. Only clozapine has been
shown to be efficacious in randomized controlled trials, and is therefore
considered as first choice (Ballard et al., 2013). However, the use of
clozapine is associated with an increased risk of agranulocytosis (Ballard et
al., 2013; Seppi et al., 2011), requiring careful follow-up of leucocytes. So
treatment options are limited and cumbersome, stressing the need of alternative
therapies.

An alternative therapeutic option might be continuous apomorphine infusion
(CAI). CAI is now being used successfully in PD patients with motor
fluctuations. In contrast to other dopamine agonists, apomorphine is
well-tolerated in advanced PD patients with visual hallucinations (Borgemeester
et al., 2016). Moreover, there is growing anecdotal evidence that CAI may
improve non-motor symptoms, such as visual hallucinations (Borgemeester et al.,
2016; García Ruiz et al., 2008; Martinez-Martin et al., 2011, 2015).

Two studies have investigated the role of apomorphine on visual hallucinations
in PD patients in particular. Ellis and colleagues showed that 12 PD patients
of whom 8 with visual hallucinations and 2 with confusion, had no worsening of
psychotic symptoms after initiation of apomorphine treatment (Ellis et al.,
1997). Above that, in most patients hallucinations disappeared completely, even
after long-term follow-up (range 8-72 months). The efficacy of apomorphine on
visual hallucinations is investigated in one small open-label trial (van Laar
et al., 2010). After a follow-up of six weeks, a significant improvement on the
neuropsychiatric inventory questionnaire was shown in eight PD patients with
visual hallucinations. In summary, apomorphine is suggested to have a
beneficial effect, however the number of patients is limited and both studies
lacked a control group.

The suggested beneficial effect of apomorphine could be linked to the
piperidine moiety incorporated in the structure of apomorphine and other
anti-psychotics (van Laar et al., 2010). The piperidine moiety has specific
binding sites with dopaminergic and serotonergic receptors (Nematollahi et al.,
2014), possible related to the potential anti-hallucinogenic effect of
apomorphine.

To investigate the efficacy of continuous subcutaneous apomorphine infusion
compared to placebo in PD patients with visual hallucinations.

This study is designed as a randomized, placebo-controlled, double-blind trial.
Subjects will be matched by age and cognition.

Patients will be treated with either apomorphine 5 mg/ml or placebo (saline)
for four weeks.
Apomorphine will be infused subcutaneously during the waking day using a
apomorphine pump.
Titration of apomorphine will be conducted by telephone contact.

Benefit
The benefit lies in the possibility of a positive therapeutic effect on visual
hallucinations, and with their participation subjects will contribute to the
scientific understanding of apomorphine in patients with PD and visual
hallucinations.

Risks
The main risk for subjects is related to the use of apomorphine. Apomorphine
will be used off-label. Based on previous experience with apomorphine, a common
side effect is the development of subcutaneous nodules. Other side effects are
rare, but more serious and adequate measures are known and provided.

Burden
In this randomized, placebo-controlled trial subjects have to visit the
out-patient clinic three times (i.e. a screening, baseline and follow-up
visit). At screening, a blood sample and ECG will be performed. Before
initiation of apomorphine or placebo, subjects will be pre-treated with
domperidone 10 mg tid to avoid peripheral side effects of apomorphine such as
nausea and orthostatic hypotension. Several questionnaires will be filled out
at baseline and at follow-up. The burden for subjects is kept low given the
short study duration of only four weeks.