2.1 Overview
The study procedures described in this paper are comparable to procedures described in a previously published paper by our group related to another Randomized Clinical Trial (RCT) (36). However, there are essential differences between both studies, such as treatment duration, duration of the trial itself and an interview used to determine the diagnosis of the participant as well as the intervention.
This study, being a proof of concept trial, was designed as a double-blind placebo-controlled trial, to be able to differentiate between clinical effects of prednisolone addition and placebo effects. Prednisolone or placebo is provided in addition to current antipsychotic medication as it is not the intention to replace existing antipsychotic treatment. Finally, by applying the placebo arm and urging treating physicians to keep the antipsychotic dose as stable as possible during the 6 week period, the effect of prednisolone addition can be measured.
In this study, 90 patients with schizophrenia, schizoaffective or schizophreniform disorder, or psychotic disorder NOS (not otherwise specified) will be included, with an age of 18-70 years and a time interval between the onset of psychosis and study entry not exceeding seven years. Patients will continue their antipsychotic medication and (if applicable) other psychotropic drugs throughout the treatment period of 6 weeks. Doses are preferably kept stable, but dose adjustments of up to 25% of the initial dose are allowed. Changes in dosage of antipsychotic medication or benzodiazepines of 25% or more (relative to the screening visit), will be regarded as a secondary outcome measure.
For this proof of concept study, a treatment period of 6 weeks was considered appropriate. We hypothesize that if prednisolone carries the expected effect, this will be apparent within this period of time. The study does not intend to assess the therapeutic potential of prednisolone as a possible augmentation therapy for these patients. Rather, the results may strengthen the case for immune-modulatory treatment and encourage further research in this direction.
2.2 Aims
This study aims to investigate the effect of prednisolone augmentation to antipsychotic pharmacotherapy in patients with a psychotic disorder. The following outcome variables will be investigated within this study;
- Primary:
- Reduction of symptom severity of the PANSS total score
- Secondary:
- Improvement of global functioning (GAF)(37) and cognition (BACS)
- Prediction of treatment response to prednisolone therapy using immune markers (blood samples)
- Insight in psychosis and inflammation in the brain using Magnetic Resonance Imaging (MRI)
2.3. Allocation
All 90 patients will be randomized 1:1 to either prednisolone or placebo for six weeks study medication use, in addition to their current antipsychotic medication as prescribed by their treating physician. Stratification will be applied for country, center and gender. The study staff will not have access to the trial treatment randomization codes. These will be stored in the pharmacy in the University Medical Centre Utrecht (The Netherlands), Ziekenhuis Netwerk Antwerpen (Belgium) and Haukeland University Hospital (Norway) in case emergency unblinding is needed. In case of serious adverse events (SAEs) in which knowledge regarding the assigned treatment is important to decide on medical management of the event emergency unblinding is permitted..
2.4 Inclusion criteria
- A DSM-IV-TR diagnosis of: 295.x (schizophrenia, schizophreniform disorder, or
schizoaffective disorder) or 298.9 (psychosis NOS)
- Onset of psychosis no longer than 7 years ago
- Minimum total PANSS score of 60.
- Age 18 -70 years.
- Patients are treated with antipsychotic medication (stable dosage for at least 3 weeks)
- Written informed consent is obtained
- Female patients of childbearing potential need to utilize a proper method of contraception
(contraceptive pill, vaginal ring, hormonal patch, intrauterine device, cervical cap, condom,contraceptive injection, diaphragm) in case of sexual intercourse during the study.
Additional inclusion criteria for patients included in Norway are enlisted in Additional file 1:
2.5 Exclusion criteria
- Presence of any of the contra-indications of prednisolone as reported in the summary of product characteristics (SPC).
- Presence of diabetes mellitus or random glucose levels exceeding 11 mmol/L at screening in a non-fasting condition or 7 mmol/L in a fasting condition, severe heart failure, severe osteoporosis or systemic fungal infections.
- Body Mass Index (BMI) of >30.0.
- Current or chronic use of systemic glucocorticosteroids (temporary use is permitted, if stopped 1 month before start of treatment trial)
- Chronic use of NSAIDs, defined as daily use during more than 2 months. Intermittent use is permitted, if stopped at least 1 month before start of treatment trial.
- Pregnancy or breast-feeding. A urine pregnancy test will be performed at screening.
- Concurrent use of certain types of medication:
- carbamazepine, riphampicine, primidone, barbiturates and phenytoine
- HAART medication (both HIV protease inhibitors and (non)-nucleoside reverse transcriptase inhibitors), especially efavirenz, ritonavir and lopinavir.
- telaprevir and boceprevir in treatment of Hepatitis C
Additional exclusion criteria for patients included in Norway are enlisted within Additional file 1:
2.6 Interval assessments
In total, 11 visits will be conducted throughout a period of one year. The patients are using study medication for 6 weeks and will be followed up for another 46 weeks. The informed consent procedure and the eligibility check will be conducted during the screening visit. When the patient is eligible for study participation, the patient will be randomized to either prednisolone or placebo. During the six weeks of study medication intake, the patient will be reviewed weekly by a study physician for adverse events. The symptom severity, which is the primary outcome of this study, will be measured by conducting the PANSS interview, assessed by a trained researcher. Additionally, the GAF score, the Calgary Depression Scale for Schizophrenia (CDSS) (38) score, drug and alcohol use and cognition by using the BACS score will be measured. Blood will be withdrawn at five occasions throughout the study, for metabolic and immunological measurements. The patients in Norway will be invited to the optional MRI procedures. An overview of the assessments per visit can be found in Table 1.
2.7 Training and inter-rater reliability
All involved researchers will be trained in the PANSS interview by an experienced PANSS trainer, using instructional videos and assessment of a test video in a classroom setting. After passing an exam, researchers can perform PANSS ratings for this study. PANSS raters will be assigned to patients in order to limit the bias in PANSS assessment in patients. Proper conduct of The Comprehensive Assessment of Symptoms and History (CASH - (39)) interview (demographics, alcohol and drugs only), Mini International Neuropsychiatric Interview 5.0.0 Plus (M.I.N.I. 5.0.0 Plus) (40) and cognitive testing will also be trained by experts. Study team members will be carefully selected and extensively informed and trained regarding Good Clinical Practice (GCP).
2.8 Treatment
All patients included in the study will use the study medication in addition to their current antipsychotic medication as prescribed by their treating physician at the time of inclusion. Study medication will be tapered-off within six weeks in the following schedule: 40mg/day for 3 days and 30mg/day for 4 days, followed by a decrease of 5mg/day per week during the remaining 5 weeks; in the second week, patients will use 25 mg/day, in the third week 20 mg/day is used etc. In the last week the patients will only take prednisolone on day 1-3 and day 5 and 7; a tapering scheme in line with the treatment guidelines for Inflammatory Bowel Diseases (2008). To prevent loss of bone mass, we will provide calcium supplementation (calciumcarbonate 500 mg daily) and vitamin D supplementation (cholecalciferol 400ie daily). Pantroprazole will be actively provided to patients with a history of ventricular/duodenal ulcer.
2.9 Outcome variables
2.9.1. Primary outcome variables
Clinical outcome measure
Our main study parameter is overall symptom severity as measured with the PANSS total score. We will compare the effect of prednisolone versus placebo, both given in addition to antipsychotic medication, with regards to change in overall symptom severity, measured after 6 weeks of treatment compared to baseline.
2.9.2. Secondary outcome variables
Symptom severity
Secondary study parameters include PANSS total scores 4, 6 and 12 months after start of the treatment. Furthermore, general functioning will be evaluated using the GAF comparing patients treated with prednisolone versus placebo.
Cognitive assessment
Neurocognitive functioning as measured with the BACS will be used to measure the possible improvement over the treatment and the 6 months follow-up period. The BACS consists of the following domains:
- Verbal memory: List Learning
- Working memory: Digit Sequencing Task
- Motor speed: Token Motor Task
- Verbal fluency: Category Instances
- Verbal fluency: Controlled Oral Word Association Test
- Attention and speed of information processing: Symbol Coding
- Executive functions: Tower of London
Laboratory assessments
Immunological and metabolic parameters will be assessed four times over the one year study period. We will investigate inflammatory processes that may be involved in a subpopulation of patients with psychotic disorders using prednisolone augmentation (29). To investigate immunological biomarkers that predict treatment response to prednisolone therapy we will collect serum and RNA of all patients at baseline, 3, 6 and 26 weeks after the start of the study medication use. The laboratory assessments will contain the following analyses:
- Multiplex immunoassay
- Infectious disease profiling
- Flow cytometry
- Selective reaction monitoring (SRM)
Brain imaging (optional in Norway)
Information regarding the brain imaging part of the study conducted in Norway can be found in Additional file 2.
2.9.3. Other objectives
Severity of depression will be assessed and compared between groups using the CDSS. The need to adjust current antipsychotic medication with 25% or more is compared between groups. Finally, safety data will be assessed by comparing incidences (number and % of subjects with at least one occurrence) of key SAEs and Suspected Unexpected Serious Adverse Reactions (SUSARs) between both groups, e.g. hospitalisations.
2.10 Safety assessment
Safety measurements
At each visit a study physician will review the possible adverse events, medication use and any contraindications for prednisolone use. After the screening visit, the blood results will be reviewed by a study physician regarding the inclusion and exclusion criteria. After the baseline visit at which patients start study medication, safety parameters will be checked by a study physician who is not conducting the PANSS interview. Based on blood assessment, presence of adverse events and contraindications for prednisolone use, it will be determined if it is still safe to use the study medication.
Stopping rules
Several events that may jeopardize the patient's health will prompt clinicians to end the study and start tapering the patient off the study medication immediately in line with the treatment guidelines for Inflammatory Bowel Diseases (2008). These events include the patient developing:
- A blood glucose exceeding 7.0 mmol/L. In case a non-fasting glucose level was determined: a blood glucose level exceeding 11 mmol/L
- Suicidal ideations assessed by the CDSS, the following cut-off are applicable based on item 8: Suicidal ideations within the CDSS
- Score of 0: no action (no suicidal ideation).
- Score of 1: consult with clinician (passive suicidal ideation).
- Score of 2/3: potential cause to stop study medication treatment – consult with clinician (active suicidal ideation).
- The PANSS positive subscore which increase by 10 or more points without a clear reason (i.e. medication non-adherence)
- The PANSS item G6 (depression) exceeding a score of 4
- The need for coercive treatment
- Pregnancy
- Oral systematic infectious disease.
Adverse events (AE)
Any undesirable experience occurring to a subject during the study is defined as AEs, regardless of any relatedness to the study medication. All AEs reported spontaneously by the subject or observed by the investigator or study team members conducting the visit will be recorded. AEs will be checked by a study physician every visit by asking an open question how the patient is doing and if the patient was suffering from any AE. Furthermore, the study physician will assess a standardized questionnaire which includes all potential prednisolone-related AEss. If an AE requires follow-up, the study physician will inform the general practitioner, will examine and monitor the AE him/herself or if necessary will liaise with a medical specialist. In case SAEs have taken place, the applicable authorities will be informed as described in the study protocol following the guidelines.
2.11 Power calculation and statistical analysis
A two group t-test with a 0.050 two-sided significance level will have 80% power to detect an effect size of 0.610 when the sample sizes in the two groups are 44 and 44, respectively (a total sample size of 88) (text generated by nQuery Advisor). Subsequently the sample size can be reduced by the data with an Ancova instead of analyzing a t-test (41). The level of reduction depends on the correlation (r) between baseline and follow up measurements: N-ANCOVA = ((1-r2) * N-t-test) + 1.From a previous study in this hospital (OPTiMiSE trial) where a PANSS was performed at baseline and after 6 weeks, r = 0.48 was found. Therefore, N-ANCOVA = ((1 – 0.482) * 88) + 1 = 68.7248. Moreover in this study we will use a mixed model, however since we do not estimate a linear change in this analysis, the increase in efficiency compared to the ANCOVA and therefore the reduction in sample size will not be immense and this calculation will suffice. Lastly we expect a considerable number of drop-out. Assuming a drop-out rate of 30 % the definitive sample size is calculated at 68.7248 * 1.3 = 89.34224, which makes a total of N = 90 patients.
2.12 Study procedures
2.12.1 Screening visit
Interested potential study participants will be informed regarding all study procedures. They will be provided with an information letter and will be given sufficient time to read all information, ask any questions to the investigator and to liaise with family and friends. Participation into this study is completely voluntarily. When a potential study participant agrees to take part in this study, written informed consent will be obtained by study physician. After the informed consent procedure has been completed, eligibility criteria will be checked to assess the patient’s eligibility for participation within the study. The M.I.N.I. 5.0.0 Plus will be assessed to confirm the inclusion diagnosis. Additionally the PANSS and GAF will be assessed, which both relate to the past week. Additionally, several demographical and clinical variables will be assessed, including date of birth, sex, educational level, prior psychiatric disorders, duration of untreated psychosis and use of drugs and alcohol. The CASH will be used to document the sociodemographic data and drug and alcohol use. Furthermore, the use of concomitant medication, medical history and current medical conditions will be recorded. The maximum period between screening visit and baseline visit is 12 weeks. If the patient uses co-medication at the screening visit which is not allowed, it can be washed out during this period. Additionally physical examination will be conducted by a study physician, including BMI, blood pressure and temperature. Any abnormality will be discussed with the patient’s treating physician. To rule out pregnancy in female patients, a urine pregnancy test will be performed. Electrocardiogram (ECG) examination will be conducted in all patients above 60 years old, patients with congenital heart defects and patients with plausible familial heart disorders and patients with a medical history of collapse e causa ignora, cardiac arrythmias, use of antiarrythmic medication, angina pectoris, heartfailure, (recent) myocardial infarction, or myocarditis (Cahn et al. 2008). Signs of lipodystrophy will be observed. Additionally, blood will be drawn to determine and to rule out hyperglycaemia as well as signs of systemic infection as these are special warnings for the use of prednisolone. Additionally several blood parameters (blood differentiation, electrolytes, thyroid, liver and renal function) will be checked at screening to identify serious other diseases. Patients need to meet all inclusion criteria and none of the exclusion criteria to be regarded as eligible to participate.
2.12.2 Baseline visit
At baseline, PANSS and GAF will be administered, in addition to the CDSS and the BACS. If the time between screening and baseline is less than 2 weeks the PANSS will not be repeated at baseline. Additionally, the presence of any exclusion criteria for the current study will be checked as well as suicidal ideation. Subsequently, the patient will be randomized and the study medication will be dispensed for the first time. Patients will be instructed on medication use, with regards to contraindicated co-medications. Blood will be drawn to assess immunological parameters. A study letter will be send to the treating psychiatrist, general practitioner and pharmacist regarding the patient’s participation.
2.12.3 Treatment visits
After the baseline visit, patients will be assessed weekly for six weeks. During various visits, a trained study team member will interview them using the PANSS, GAF (every other week; visit 2-4-6-8) and CDSS questionnaires (weekly). At each visit, presence of suicidal ideation is carefully examined. Co-medication use will be noted as well as side effects and treatment compliance. Except for visit 8, study medication will be dispensed during each visit during the treatment period. Alcohol and drug use will be assessed using the alcohol/drug use section of the CASH during visits 5 and 8. At visit 2, 5 and 8 blood draws intended for immunological assessments will be performed. After the blood draw the patients need to remain within the hospital (when possible) until the laboratory values are checked by a physician in case follow-up treatment is necessary. Furthermore, pill boxes were returned to the study centers each week to assess compliance to study medication. Cognitive testing will take place at the end (six weeks) of the treatment period.
2.12.4 Follow-up visits
After 16, 26 and 52 weeks (relative to baseline), follow-up visits will take place, during which the PANSS, CDSS and GAF are assessed. Additionally, the current use of medication and adverse events will be noted. At visit 10, blood will be drawn to assess immunological parameters and the BACS will be repeated once more.
2.12.5 Patient safety
The participants’ treating physician remains responsible for the day-to-day. . Prednisolone has minor mineral-corticosteroid potencies and is able to adequately pass the BBB. The side effects and safety profile of prednisolone are well known. The principal investigator will be responsible for the medical and safety concerns related to study participation. Study members can be contacted at the telephone number provided on the emergency card provided during the first study medication dispense and letters patients receive during the study. This emergency card includes a telephone number from the pharmacy in case emergency unblinding is necessary outside office hours.
2.12.6 Patient withdrawal
Subjects can quit study participation at any time for any reason without any consequences, if they wish to do so. The investigator can decide to withdraw a subject from the study for urgent medical reasons.
Reasons to terminate a patient’s participation include but are not limited to the following instances:
- The patient withdraws her/his consent
- Intolerance to the study medication
- Start of the use of NSAIDs, HAART, telaprevir, boceprevir, riphamicine, primidone, barbiturates and phenytoine
- Administration of a live vaccine is needed
- Any of the stopping rules provided in section 2.9
In case a patient or the investigator decides to terminate a patient’s participation, the patient needs to be followed until the patient has completely tapered-off the study medication. This tapering-off scheme will be decided by a study physician based on the patients’ situation. If needed, the study physician will liaise with a medical specialist (e.g. endocrinologist).
2.13 Data collection
Data will be collected on paper during the study visits and will be inserted in an electronic case report form (eCRF). Data collected during visits with study participants will be pseudonymized and will be treated as confidential.
2.14 Ethical and regulatory standards
Medical Ethical Review Board
Ethical approval was obtained from the research and ethics committee of the University Medical Center Utrecht (UMCU), the Netherlands, protocol number 14-110, Ziekenhuis Netwerk Antwerpen (ZNA), Belgium and Haukeland University Hospital, Norway. The trial is registered in the ClinicalTrails.gov database (identifier NCT02949232) and the European Clinical Trials Database (EudraCT number 2014-000520-14 for the Netherlands and Belgium and 2017-000163-32 for Norway).
Data and Safety Monitoring Board (DSMB)
The safety of the study will be judged by an independent committee of experts (DSMB) on regular basis, at a frequency of at least once a year. The members of this board will have access to all safety and progress information (e.g. inclusion and drop-out rates). If deemed necessary, the DSMB members may review the unblinded study data. The DSMB will meet each time after 10 additional patients are recruited, but meetings may be more frequent depending on trial events causing safety concerns, the enrolment rate (much slower or faster than anticipated) or when the DSMB deems this to be appropriate for other reasons. The DSMB may suggest changes to the protocol or provide an altered judgement of feasibility if information from the annual safety report or new information about the study medication becomes available. No interim analyses are planned. The tasks and responsibilities of the DSMB, as well as premature termination criteria, are described in a separate DSMB charter.
Declaration of Helsinki
The study will be conducted in accordance with this protocol as well as the principles of the Declaration of Helsinki (64th WMA general assembly; Fortaleza, Brazil, October 2013), the ICH-GCP guidelines and other applicable laws and regulations.