We propose to investigate the effect of administering a broad-acting, potent immune suppressive agent early in the course of the disease as this may prevent neuronal damage caused by low-grade inflammatory processes in the brain. It is expected that…
ID
Source
Brief title
Condition
- Central nervous system infections and inflammations
- Schizophrenia and other psychotic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in 'Positive and Negative Symptom Scale (PANSS)' total score compared to
baseline.
Secondary outcome
Secundary objectives concern the comparison of the 2 groups with regards to
changes in:
- Positive and Negative Symptom Scale (PANSS) subscales
- Cognitive performance (tested by the 'Brief assessment in cognition', BACS)
- General functioning (tested by Global Assessment of Functioning, GAF)
- Depressive symptoms (tested by Calgary Depression Scale for Schizophrenia)
- Safety data will be evaluated by comparing incidences (number and % of
subjects with at least one occurrence) of key SAEs and SUSARs (e.g.
hospitalisations).
- Changes in immune profile, measured by blood markers.
Background summary
Schizophrenia is a severe mental disorder with a worldwide prevalence of around
1%, placing significant burnden on global health. Although the introduction of
antipsychotic medications in the 1950s has substantially improved clinical
symptoms of schizophrenia, the disease is still causing considerable morbidity
and mortality. Also patients are affected by substantial impairment in multiple
domains of life. Therefore the need for better treatment paradigms is hampered
by insufficient knowledge on the underlying disease mechanisms. The
pathogenesis of schizophrenia is still far from elucidated. Different lines of
evidence now suggest that low grade inflammation in the central nervous system
is involved in the pathogenesis of schizophrenia. Such inflammation could cause
increased gray matter loss and consequently contribute to more severe negative
and cognitive symptoms.
Study objective
We propose to investigate the effect of administering a broad-acting, potent
immune suppressive agent early in the course of the disease as this may prevent
neuronal damage caused by low-grade inflammatory processes in the brain. It is
expected that symptom severity will be improved. Prednisolone predominantly has
glucocorticoid capacities and only slight mineralcorticoid potency. It
interferes with almost all primary and secondary immune cells, inculding
monocytes, microglia cells, T-cells and granulocytes. Furthermore prednisolone
can easily pass the blood-brain-barrier, which is a prerequisite to induce
immune modulation in the brain. Finally, there is ample clinical experience
with prednisolone and its side-effects and safety profiles are well known.
Therefore, we propose to investigate the effects of administering the
corticosteroid prednisolone versus placebo on psychotic symptoms in addition to
standard antipsychotic medication in patients with early stage schizophrenia or
related disorders.
Study design
In the current 'proof of concept' study, we aim to investigate the effect of
additional treatment with prednisolone on cognition, symptomatic improvement,
global functioning and on immunological parameters in patients with early-stage
psychotic disorder, applying a randomized double-blind placebo-controlled
design. A placebo-controlled design was chosen in order to differentiate
between clinical effects of prednisolone and effects associated with
experimental treatment, such as induced expectations of participants.
Randomization is applied to minimize bias. All 90 patients will be randomized
1:1 to either prednisolone or placebo daily for 6 weeks. During the treatment
period, patients will be seen at weekly intervals to assess symptom severity,
depressive mood and suicidal ideation, global functioning and side effects.
After 6 weeks of treatment, 2 follow-up assessments take place at 4, 6 and 12
months after a patient entered the study.
Intervention
The main investigational product used in this trail is prednisolone, which is
approved for systemic treatment of disorders in rheumatology, pulmonology,
gastroenterology, endocrinology, hematology, oncology, neurology, dermatology
and ophtalmology. Also it is used topically in dermatology and rheumatology.
Furthermore, it is used as an immunosuppressant in organ transplantation. In
the current study, prednisolone will be administered for six weeks; during the
first week patients will use 40mg for 3 days and 30mg for 4 days. In each
following week, the dose will be decreased with 5 mg, so patients will use 5mg
per day in week 6. In the last 4 days of week 6 they will use 5 mg every other
day ((0 mg * 5 mg * 0 mg * 5 mg). After this week they can stop using
prednisolone. Additionally, a placebo product is used consisting of an inactive
substance (filler), which is visually identical to the prednisolone tablet.
Study burden and risks
The total burden and risks for the patients is based on the following factors:
1. Time investment: the complete study involves 10 visits, with a total time
investment of 11 hours. A detailed overview of all protocol procedures and
questionnaires can be found in Table 1 of the protocol.
2. Risks due to protocol procedures: these risks are limited to the known risks
for venapunction.
3. Side effects of prednisolone. Despite the fact that not all patients will
experience side effects, the nature of prednisolones side effects shoudl not be
underestimated. All side effects are listed in the SPC as well as an appendix
to the Informed Consent Document.
Risks are minimized through:
- Elaborate in- and exclusion criteria
- Implementation of appropriate, pro-active safety measures (e.g. strict
monitoring of onset and course of specific side effects)
- Applying specific 'stopping rules', which means that in case patients seem to
develop specific side effects, they will be dropped out of the study, after
which appropriate follow-up take splace as well as treatment if necessary.
- Prednisolone use is limited to 6 weeks. Of these 6 weeks, the maximum dosage
will be given for 1 week. Patients will take 40 mg/daily during 3 days and 30
mg/daily during 4 days.
- Annual review of patient safety and study progress information by the
independent Data Safety Monitoring Board.
A complete consideration of risks and burden on the one hand and benefits on
the other is provided in section 13.2 'Synthesis' of the structured risk
analysis of the protocol.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
1. DSM-IV-R diagnosis of 295.x (schizophrenia, schizophreniform or schizoaffective disorder) or 298.9 (psychosis NOS).;2. Start of first psychosis no longer than 7 years ago.;3. Age 18-70 years.;4. Patients use a stable dosis of antipsychotic medication for at least 3 weeks.;5. Written informed consent is obtained.;6. Female patients of childbearing potential need to utilize a proper method of contraception in case of sexual intercourse during the study.
Exclusion criteria
1. Presence of any of the contra-indications of prednisolone as reported in the SPC.;2. Presence of diabetes mellitus or random (non-fasting) glucose levels exceeding 11 mmol/L at screening, severe heart failure, severe osteoporosis or systemic fungal infections.;3. Body Mass Index (BMI) of >30.0;4. Current or chronic use of systemic glucocorticosteroids (temporary use is permitted, if stopped 1 month before start of treatment trial);5. Chronic use of non-steroidal anti-inflammatory drugs (2 months or more of continuous use) ;6. Pregnancy or breast-feeding. ;7. Concurrent use of carbamazepine, riphampicine, primidone, barbiturates and phenytoine ;8. Concurrent use of HAART medication (both HIV protease inhibitors and (non)-nucleoside reverse transcriptase inhibitors), especially efavirenz, ritonavir and lopinavir;9. Current use of telaprevir and boceprevir in treatment of Hepatitis C.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000520-14-NL |
| CCMO | NL46653.041.14 |
| Other | submissie bij www.clinicaltrial.gov is geinitieerd |