Effectiveness of penfluridol (oral long acting neuroleptic) as compared to second generation oral neuroleptics in psychotic disorder patients: an open label randomized controlled trial.

Schizophrenia and its psychotic spectrum disorders are chronic remitting and
disruptive disorders associated with significant abnormalities and the
progressive deterioration of a wide variety of cognitive, psychosocial,
vocational, and behavioural functioning.(Chien and Yip 2013) The fifth edition
of the Diagnostic and Statistical Manual of Mental disorders (DSM-V) defines
schizophrenia as a syndrome characterized by delusions, hallucinations,
disorganized speech, disorganized or catatonic behaviour and negative symptoms,
with social dysfunctioning and sometimes mood problems, all for a long
duration.(Tandon, Gaebel et al. 2013) Life-time prevalence of schizophrenia is
1%, typically manifesting in late adolescence or early adulthood.(Insel 2010)
With respect to mortality, a substantial gap exists between the health of
people with schizophrenia and the general community.(Saha, Chant et al. 2007)
Suicide contributes to this increased mortality, however increased mortality
risks are also attributable to a wide range of somatic conditions and to
reduced access to medical treatment.(Saha, Chant et al. 2007)

To reduce patients* illness episodes and symptoms, as well as to improve their
functioning and quality of life in the longer term, comprehensive and
multimodal treatment approaches are tested.(Chien and Yip 2013) Antipsychotics
are considered the best treatment for schizophrenia and other psychotic
disorders.(Miyamoto, Duncan et al. 2005) They are mainly categorized into
first-generation antipsychotics (FGA) and second-generation antipsychotics
(SGA) and share a similar pharmacological mechanism in blocking the dopamine D2
receptor.(Miyamoto, Duncan et al. 2005)

While pharmacological treatment is the cornerstone and essential component of
treatment for schizophrenia and other psychotic disorders(Miyamoto, Duncan et
al. 2005), compliance constitutes a major problem in these patients. Most
studies indicate that 40-75% of patients stop using their oral neuroleptic
during a period of one year.(Lacro, Dunn et al. 2002) (Lieberman, Stroup et al.
2005; Kahn, Fleischhacker et al. 2008) Reasons for non-compliance include lack
of insight into the disease, cognitive problems, side effects and negative drug
attitude with medication or treatment.(Fleischhacker, Oehl et al. 2003)
Non-compliance leads to higher incidence of relapse, hospitalizations,
incarcerations, drug and alcohol consumption and suicide.(Acosta, Hernandez et
al. 2012)

When second-generation antipsychotics were introduced, this new class of drugs
was heralded as the first major advance in the therapeutics of schizophrenia
for 40 years.(Lewis and Lieberman 2008) The second-generation drugs appeared to
have important advantages over their first-generation predecessors, including
better efficacy and improved tolerability.(Lewis and Lieberman 2008) It was
also claimed that the higher costs of these drugs would be offset by saving
results from decreased use of healthcare services.(Lewis and Lieberman 2008)
None the less, the global antipsychotic drug market has increased 30-fold since
the late 1980s to more than US 15 billion dollars per year.(Lewis and Lieberman
2008) And meta-analyses and reviews have provided limited support for the
superiority of second-generation antipsychotics.(Lewis and Lieberman 2008)
(Davis, Chen et al. 2003; Leucht, Wahlbeck et al. 2003) Also large trials did
not find this superiority.(Lieberman, Stroup et al. 2005) (Jones, Barnes et al.
2006) As a result, healthcare policy makers on both sides of the Atlantic faced
a dilemma with respect to rising costs of mental healthcare and the lack of
demonstrably improved outcomes in psychotic disorder patients.(Lewis and
Lieberman 2008)

Penfluridol (brand name: acemap) has been available since 1970 as a *unique*
neuroleptic used for the treatment of patients with schizophrenia and other
psychotic disorders.(Soares and Lima 2006) It is a typical antipsychotic drug
and it is unique in the sense that it can be taken orally once a week; all
other oral neuroleptics have to be taken daily, while other long acting
neuroleptics need to be injected intramuscularly.(van Praag, Schut et al. 1971;
Soares and Lima 2006) Therefore penfluridol is very suitable for patients who
have compliance problems, but who refuse intramuscular injections. Penfluridol
has a superior effect compared to placebo, and when compared to other typical
antipsychotics it shows similar efficacy and tolerance.(Soares and Lima 2006)
Compared to depot medication, patients using penfluridol drop out less often,
so there is better compliance.(Soares and Lima 2006)

Despite the great advantage of penfluridol regarding compliance, the original
pharmaceutical company that produced penfluridol (Janssen Cilag), stopped
producing this first-generation antipsychotic in 2009. True reasons for this
decision are not known, however it is believed that the production has stopped
because the drug lack commercial potential. Janssen Cilag is also a producer of
second-generation antipsychotics (risperidone), which has an economic advantage
for the manufacturer. Income from oral risperidone are 2.5 times as high as for
penfluridol and income from risperidone long acting injections are even 26
times higher as for penfluridol calculated for one year of treatment. Also, in
addition to the possible advantage regarding compliance, penfluridol is cheaper
than oral second-generation neuroleptics mostly used today (including
olanzapine, quetiapine, aripiprazole). Possibly due to these lower financial
gains, penfluridol has not been promoted by pharmaceutical companies. From an
economical perspective, production of an old antipsychotic that is cheaper than
any second-generation antipsychotic is not attractive to other pharmaceutical
companies as well. They rather invest in a new medicine with patent that is
more profitable.

Considering the clinical importance of penfluridol, the Medicines Evaluation
Board (MEB) in The Netherlands has ensured that the production of penfluridol
is guaranteed by ordering a pharmaceutical company in the Netherlands.
Therefore, penfluridol is still prescribed in the Netherlands in patients with
schizophrenia and other psychotic disorders, and is prescribed most frequently
in patients who have compliance problems. The use of penfluridol in the
Netherlands has increased by 30% in the years 2006 * 2010. The reason for this
increase in the use of penfluridol may be that (some) psychiatrists favour
penfluridol over other oral neuroleptics, because patients may show better
compliance with penfluridol. Penfluridol is also available in other European
countries, including Austria, Belgium, France and Germany as well as in some
developing countries (Haiti, Philippines) and it is expected that there will be
a worldwide interest in this compound because of its low costs and weekly oral
dosage scheme.

Because almost all studies on the effectiveness of penfluridol were carried out
in the 1970s and 1980s, it is unknown whether penfluridol differs in
compliance, efficacy, safety and tolerability, and healthcare costs compared to
second-generation neuroleptics.(Soares and Lima 2006) In case penfluridol leads
to increased compliance, we can expect less relapses, higher quality of life,
lower number of suicides, less (severe) crisis situations, less incarcerations,
and less (in)voluntary hospitalizations. The latter may be the most important
financial gain of penfluridol over other oral neuroleptics, since
hospitalization costs constitute the largest part of the mental health services
budget.(Hoof, Knispel et al. 2012)

This project will provide evidence for the effectiveness of penfluridol as
compared to second-generation neuroleptics, which can help in improving
compliance and reducing overall costs for the treatment of psychotic disorder
patients.

Primary Objective: The aim of this study is to determine the time to all-cause
discontinuation of penfluridol (acemap; oral long acting neuroleptic) as
compared to second-generation oral neuroleptics (olanzapine, risperidone) using
an open label randomized controlled trial design in 180 patients.

Secondary Objective(s): Secondary objectives include the reason for treatment
discontinuation, efficacy, safety and tolerability, drug attitude, subjective
well-being, insight, healthcare related costs and quality of life.

We hypothesize that there will be significant differences in time to
discontinuation and overall effectiveness of penfluridol as compared to oral
second-generation neuroleptics (olanzapine and risperidone) that reflect
variations in compliance, safety and tolerability and costs. We hypothesize
that penfluridol as compared to oral second-generation neuroleptics (olanzapine
and risperidone), will show better compliance (primary outcome) and therefore
lower healthcare costs. Also we hypothesize that higher level of symptom
severity, more side effects, poor insight, negative drug attitude and worse
subjective well-being would predict poorer adherence associated with more
relapses and crises leading to more healthcare use and higher costs.

Design: Open label, randomized controlled trial in 180 patients
Duration: 4 years
Follow-up: 12 months
Setting: This is a multicenter randomized controlled trial in the Netherlands,
supported by the Dutch Psychosis Consortium. Eight mental health institutions
collaborate: Academic Medical Center (Amsterdam), Bavo Europoort (Rotterdam),
Delta Psychiatric Center (Poortugaal), GGZ Breburg Group (Tilburg),GGZ Noord
Holland Noord (Heiloo), GGZ Westelijk Noord Brabant (Halsteren), Maastricht
University Medical Center (Maastricht) and Yulius (Rotterdam). Together these
centers treat over 6000 psychotic disorder patients.

The psychiatrists prescribing the neuroleptics as well as the patients cannot
be blind to the treatment condition (open label study) due to the different
dosing schemes of the neuroleptics (weekly versus daily). But although
theoretically this problem may be surmountable, we have chosen to do an open
label study because of the important advantages. An open clinical trial with as
little exclusion criteria as possible most closely reflects real life clinical
practice.(Fleischhacker, Keet et al. 2005) When patients and their treating
psychiatrists are unmasked for the assigned treatment, this reflects routine
clinical practice, increasing the trial*s external validity; it will also
improve the trial*s acceptability for patients and psychiatrists, leading to a
group of patients, that is representative of a normal psychiatric case load,
which further increased the trial*s external validity.(Kahn, Fleischhacker et
al. 2008)
Also, the complicated logistics of a double-blind trial would jeopardize the
feasibility of this study, leading to the inclusion of only a selected group of
patients. As this selection bias is one of the most serious problems when
interpreting and attempting to generalize findings from the available double
blind randomized controlled trials(Fleischhacker, Keet et al. 2005), this open
randomized design hopefully overcomes this bias problem.

Despite the open label characteristics of the study, we will be able to
generate valid results, which do have consequences for clinical practice. All
medications used have been shown to have beneficial antipsychotic effects. We
have no reasons to believe that clinicians or patients think that one of these
substances has more effects on positive symptoms than the others, thereby
minimizing the placebo effect. In addition, research data on efficacy, safety
and tolerability, drug attitude, subjective well-being, insight, healthcare
related costs and quality of life will be collected by trained raters who will
be blind for the intervention condition at baseline, at three month and at
12-month follow-up. Demographic characteristics will be registered at baseline
including age, sex, country of birth (patient, father and mother),
socioeconomic status, level of education, age of onset and duration of
untreated psychosis. In addition, psychiatric diagnosis (DSM-V), including
comorbid diagnoses such as addiction disorders, of patients will be registered
on all five axis by the psychiatrist responsible for the treatment of the
patient, as well as date of first contact with mental health services.
At 2, 4, 6, 8, 10, 12 weeks and 6, 9 and 12 months, information about adherence
will be collected from the participating centres. Adherence will be measured by
pill count in the healthcare setting, where pills remaining in the medication
box are counted prior to refill. Besides, the Brief Adherence Rating Scale
(BARS)(Byerly, Nakonezny et al. 2008) is used, which will be administered by
nurse practitioners who are blinded to electronic monitoring adherence results.
They cannot be blinded for the intervention condition since it is necessary to
know which medication was used in order to score these variables. This is
because penfluridol is taken on a weekly basis, whereas the other drugs are
taken daily. Given these facts, total blinding of this rating is not feasible.
Importantly, all raters will be independent, not being clinicians treating the
patients or one of the researchers involved. Medication blood level analysis
will be used to assess adherence at baseline, three month and twelve month
follow-up.

Randomization
Computer generated randomization will be done per site, with help of the
randomization program Research Randomizer (www.randomizer.org)(Urbaniak and
Plous 2013) following a 2:1:1 procedure into 3 groups: (a) penfluridol group,
(b) olanzapine and (c) risperidone group. On the basis of a power analysis (see
paragraph 4.4 sample size calculation) 90 patients shall be randomized in group
(a) and 90 patients shall be randomized in group (b) or group (c). When
patients use olanzapine they cannot be randomized in group (b) and will be
randomized in group (a) penfluridol weekly or group (c) risperidone daily. The
same applies when patients use risperidone; they cannot be randomized in group
(c) and will be randomized to either group (a) penfluridol weekly or (b)
olanzapine daily.

One group (a) receives penfluridol orally once weekly, group (b) receives
olanzapine orally once daily and group (c) receives risperidone orally once
daily as prescribed by the treating psychiatrist, according to the prescribing
guidelines.
If dosage modifications are needed according to the prescribing psychiatrist,
these are allowed within the window of prescribing guidelines.

Patients participating in this study, undergo three additional examinations
beside their regular check-ups. These consist each of an interview, physical
examination and blood sampling. In Appendix 4 of E1. Patient Information
leaflet, there is a flowchart with all additional examinations that will take
place. At 2, 4, 6, 8, 10, 12 weeks and 6, 9 and 12 months, information about
adherence will be collected from the participating centres.

The load of this study is minimal because the additional examinations are
scheduled after regular check-ups. The risks of this study are minimal because
the study medication used, concerns medication which is also used in regular
treatment of patients with a psychotic disorder. Side effects are well known by
al the treating psychiatrisct and treatment of this side effects is possible
when nessecary.