Multicenter, parallel-group, double-blind, placebo-controlled phase III study to evaluate the efficacy and safety of apomorphine subcutaneous infusion in Parkinson's disease patients with motor complications not well controlled on medical treatment.

Parkinson`s Disease (PD) is one of the most frequent neurodegenerative
disorders. 100-200/100.000 people are affected by PD in Germany. Prevalence
increases with age; in the German population >65 years, the prevalence is
elevated to 1.800/100.000 (Eggert et al., 2012). Across Europe, prevalence
estimates range between 108 and 257/100.000 (von Campenhausen et al., 2005). PD
affects both sexes approximately equally.
Patients with PD suffer from muscle rigidity, resting tremor, postural
instability and bradykinesia or akinesia. Flexed posture and freezing (motor
blocks) have also been included among the classical features of parkinsonism
(Jankovic, 2008). Primarily, the motor symptoms of PD result from the death of
dopaminergic neurons in the substantia nigra, leading to striatal dopamine
deficiency (Dauer und Przedborski, 2003). The neurotransmitter dopamine
modulates post-synaptic signaling in the striatum, influencing motor behavior.
Oral administration of the dopamine precursor levodopa (L-3,
4-dihydroxyphenylalanine, L-dopa) reduces the classical motor symptoms. L-dopa
is converted to dopamine in the presynaptic dopaminergic nerve endings
(Ribaric, 2012). The replacement therapy with L-dopa restores terminal dopamine
levels in the striatum. The antiparkinsonian effect is mediated by the
stimulation of postsynaptic D2 receptors (Ribaric, 2012). After significant
initial improvement, the progression of PD is often accompanied by a
progressive shortening of the clinical response to L-dopa. These fluctuations
in motor function have been termed ON/OFF fluctuations. Progressive
degeneration of the dopaminergic transmission results in a reduced capacity of
taking up exogenously administered L-dopa and its conversion to dopamine for
storage and release (Chase et al., 1993; Varanese et al., 2011). Erratic
gastrointestinal absorption may contribute to the clinical problem of
unpredictable motor response or failure of individual doses of L-dopa to induce
an ON phase. Complex postsynaptic changes in the striatal expression of
neuropeptides and in firing patterns are thought to underlie the formation of
dyskinesias, or involuntary movements, which occurs in many of the patients
with advanced PD (Obeso et al., 2000).
Motor fluctuations and dyskinesia develop in 50% of patients after 5 years and
in 80% of patients after 10 years of L-dopa treatment (Chase et al., 1993;
Schrag und Quinn, 2000). Advanced and end-stage PD patients experience an
enhanced sensitivity to small changes in plasma L-dopa levels (Lang und Lozano,
1998; Varanese et al., 2011). The transition from good motor (ON state) to poor
motor (OFF state) function occurs when brain L-dopa falls below the threshold
needed to adequately stimulate striatal dopamine receptors (Dewey et al.,
2001). The reduction in the dose of L-dopa often improves dyskinesias, but
increases the duration and severity of the OFF periods (Deleu et al., 2004).
The dopamine agonist apomorphine has shown good effect on the ON-OFF
phenomenon. Apomorphine directly stimulates the striatal presynaptic and
postsynaptic dopamine D1 and D2 receptors (Ribaric, 2012). In contrast to
L-dopa, apomorphine is not concentrated and converted in the presynaptic
dopaminergic endings. Its motor effects are therefore not dependent on the
presence of functional presynaptic nerve endings (Ribaric, 2012).
Two principle approaches are applied for the treatment of patients with
fluctuating PD: intermittent subcutaneous *rescue* injections of apomorphine
and continuous diurnal subcutaneous apomorphine infusions (Poewe und Wenning,
2000). Intermittent subcutaneous injections produce antiparkinsonian benefit
comparable to L-dopa and the efficacy of apomorphine injections has been
demonstrated in placebo-controlled, randomized studies, both as single doses
and in a longer-term (4 weeks) study, which showed that 95% of OFF periods
could be terminated using apomorphine, compared with 23% on placebo (Dewey et
al., 2001).
Continuous subcutaneous apomorphine infusion has been shown to be a highly
effective treatment in patients with motor fluctuations in several studies,
some of which were long-term (up to 5 years of follow-up). Level 1 evidence
from randomized studies, however, is still lacking (Fox et al., 2011).
Clinical practice has shown that, for PD patients with severe motor
fluctuations who are poorly controlled by conventional treatment, continuous
apomorphine infusion can be an effective and well-tolerated option. It has been
noted that this nonaggressive technique is easy to perform and relatively easy
to control (Garcia Ruiz et al., 2008).

The primary objective of the trial is to investigate the efficacy of
apomorphine subcutaneous infusion compared to placebo in PD patients with motor
fluctuations not well controlled on medical treatment. The secondary objective
is to investigate the safety and tolerability of apomorphine subcutaneous
infusion therapy.

This clinical trial is designed as a randomized, multicenter, multi-national,
parallel-group, double-blind and placebo-controlled phase III study in
approximately 102 patients. The trial consists of a double-blind treatment
phase followed by an open-label phase.
The study will comprise 2 screening visits to confirm patients* eligibility and
their ability to handle diary completion followed by hospital admission at
baseline with a maximum stay between 5 and 10 days. During the 3-month
treatment period, 8 weekly control visits are scheduled. Discontinuation of the
blinded drug will be performed at the End of Blinded Treatment Visit. Patients
will be offered the possibility to enter the open-label phase starting with the
titration of apomorphine at the next visit according to the local standards.
The open-label phase is planned for a maximum of 12 months, including 4 control
visits after 12, 24, 36 and 52 weeks and 4 telephone contacts after 6, 18, 30
and 44 weeks .
All efforts should be made to encourage 12 weeks of blinded treatment. Patients
discontinuing the blinded treatment of the study due to lack of efficacy (per
investigator discretion) prior week 12 will be offered a possibility to enter
the open-label phase.
The study will be performed in hospitals specialized in the treatment of PD.

Pretreatment prior and during hospitalization

Antiemetic premedication will be administered according to local standards.
Recommended pre-treatment use of domperidone is 10 mg tid starting 3 days prior
to the infusion. ECGs will be repeated at Baseline and at hospital discharge.
If these ECGs show QTc > 430 ms for male and >450 ms for female, domperidone
can be reduced stepwise to 10 mg bid or totally withdrawn, at the discretion of
the investigator. ECG will be repeated at week 2. It is recommended to perform
ECG before any dose increase and after per investigator discretion. At any time
if QTc is > 450 ms a cardiology opinion must be obtained and the decision for
continuation or discontinuation of domperidone treatment (QTc > 430 ms for male
and >450 ms for female) should be made in accordance with the cardiologist.

Trial medication and adjustments in oral/transdermal antiparkinsonian medication

The hourly flow rate is adjusted during the initial in-patient stay and during
the first 4 weeks of treatment, to doses of 3 mg/hour up to 8 mg/hour,
depending on individual tolerability and efficacy.
The target dose is each patient*s individual optimized dose or the maximum dose
of 8 mg/hour.
Patients will be admitted to hospital on the day of the Baseline visit. On that
day, patients will be on their regular medical treatment. On the day following
Baseline, patients will take their regular medication and the pump will be
initiated.

Each patient will receive a starting dose for apomorphine or placebo as
subcutaneous infusion of 1 mg/hour during the first day of infusion.
If no adverse effects occur, the hourly flow rate will then be increased in the
following manner:
- During in-patient stay the hourly flow rate will be increased daily by
0.5-1.0 mg/hour until the maximum dose of 8 mg/hour or the highest tolerated
dose has been reached, whichever occurs first.
- At the weekly visits up to week 4, the hourly flow rate will be increased by
0.5 to 1 mg/hour per visit until the maximum dose of 8 mg/hour or the highest
tolerated dose has been reached, whichever occurs first.

A gradual reduction of concomitant medication is driven by the occurrence of
possible adverse events (AEs). During the titration phase (i.e. in the first 4
weeks) concomitant antiparkinsonian medication can be reduced in case of newly
emergent or worsened dopaminergic AEs - in particular dyskinesias, nausea,
orthostatic hypotension, or sleepiness. Therefore, if dopaminergic adverse
effects occur, concomitant medication should be decreased first and the study
drug flow rate should be maintained. Upon resolution of the adverse event, the
next increase in flow rate should be undertaken.
The investigator will adjust concomitant treatment in a hierarchical way,
aiming at the reduction and discontinuation of any oral/transdermal dopamine
agonist first.

Risks and side effects of apomorphine administration

Apomorphine hydrochloride should be given with caution to patients with renal,
pulmonary or cardiovascular disease and persons prone to nausea and vomiting.
Extra caution is recommended during initiation of therapy in elderly and/or
debilitated patients.
Since apomorphine may produce hypotension, even when given with domperidone
pretreatment, care should be exercised in patients with pre-existing cardiac
disease or in patients taking vasoactive medicinal products such as
antihypertensives, and especially in patients with pre-existing postural
hypotension (Licher MT GmbH, 2012).
Since apomorphine, especially at high dose, may have the potential for QT
prolongation, caution should be exercised when treating patients at risk for
torsades de pointes arrhythmia (Licher MT GmbH, 2012).
Apomorphine may be associated with local subcutaneous effects. Most patients
experience injection site reactions, particularly with continuous use. These
may include subcutaneous nodules, induration, erythema, tenderness and
panniculitis. Various other local reactions (such as irritation, itching,
bruising and pain) may also occur.
These can sometimes be reduced by the rotation of injection sites or possibly
by the use of ultrasound (if available) to areas of nodularity and induration.
Hemolytic anemia and thrombocytopenia have been reported in patients treated
with apomorphine. Hematology tests should be undertaken at regular intervals.
Caution is advised when combining apomorphine with other medicinal products,
especially those with a narrow therapeutic range.
Neuropsychiatric problems co-exist in many patients with advanced PD. There is
evidence that for some patients neuropsychiatric disturbances may be
exacerbated by apomorphine. Special care should be exercised when apomorphine
is used in these patients.
Apomorphine has been associated with somnolence, and other dopamine agonists
can be associated with sudden sleep onset episodes, particularly in patients
with PD. Pathological gambling, hypersexuality and impulsive eating or buying
have been reported in patients treated with dopamine agonists for PD, including
apomorphine.
Apomorphine (APO-Go PFS) 5 mg/ml solution for infusion in pre-filled syringe
contains sodium metabisulphite which may rarely cause severe allergic reactions
and bronchospasm.

Precautions and Preventive Measures

The abdominal skin must be checked at each visit. Any skin changes must be
documented (counted and described).
Indurations:
- Number
- Size
- Signs of inflammation in these:
o If yes, in how many
o Degree of inflammation: mild, moderate or severe
Ulcerations
Necrosis
Abscess

Before starting the infusion and at each visit, patients are to be reminded of
the following measures:
- strict hygiene,
- massages after removing the needle,
- rotation of insertion site, making use of the whole abdomen (if comfortable
to the patient),
- do not leave needle in for >18 hours.

If nodule formation is suspected to interfere with the absorption of the study
drug, patients should be re-trained in
identifying suitable insertion sites. When necessary and depending on local
availability, the following additional methods
are permitted:
- ultrasound
- silicon patches or
- massage devices including creams, as recommended by the national provider of
apomorphine or by national treatment
guidelines.

Laboratory tests are performed at Screening, Baseline and at weeks 4, 8, 12 and
during open-label phase at weeks 12, 24, 36 and 52. These will include full
blood count with differential blood count, haptoglobin, bilirubin and LDH.
In the case of a drop of hemoglobin by >=1.5 g/dl compared to the previous test,
hemolytic anemia must be ruled out. The urgency of intervention depends on the
degree of the changeand whether there are any concomitant laboratory changes
suggestive of hemolytic anemia and must be judged by the investigator in charge
of reviewing the blood test results.
The patient must be asked to come for an unscheduled safety visit and have the
following assessments:
- clinical assessment for symptoms and signs of anemia,
- full blood count with differential blood count,
- Coombs test,
- haptoglobin,
- bilirubin,
- LDH.

If any findings suggest hemolytic anemia, an internist / hematologist must be
consulted. If hemolytic anemia is confirmed, apomorphine must be stopped and
the patient must be managed as advised by the consulted internist /
hematologist. The patient must be discontinued from the study.

Anticipated Benefits

For the patients randomized to treatment the benefit lies in the possibility of
a positive therapeutic effect, and with their participation in the trial all
patients contribute to the scientific understanding of the properties and
impacts of apomorphine.