Conditions: Psychosis Acute Psychosis Schizophrenia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
In this double blind randomized clinical trial the investigators are going to exam influence of adjuvant Aspirin therapy on soft neurological signs (Heidelberg scale), positive and negative symptoms (PANSS), cytokine profile and inflammatory factors, as well as on cognition (MoCA) in young psychotic patients.

Detailed description:
Schizophrenia as psychiatric paradigm is one of the most mysterious mental illness, for decades remains a challenge to many clinicians and researchers with its complex, fundamental mechanisms.

Soft neurological signs (SNS) are described as non-localized neurological abnormalities that cannot be associated with damage of a specific brain region. It is believed that they are not part of a well-defined neurological syndrome. They include neurological abnormalities with deficits in sensory integration, motor coordination and sequencing of complex motor acts. They have a higher prevalence in schizophrenic patients compared to healthy population. Moreover, SNS have been consistently demonstrated in neuroleptic naive patients in the first episode of illness. There is also an increased prevalence in non- schizophrenic relatives of patients with schizophrenia. It is considered that they are not potentiated by antipsychotics. For all these reasons it is believed that they are the inherent quality of schizophrenia - "trait" marker, or endophenotypes.

According to the so-called "Two hit" hypothesis in the development of schizophrenia, there are two periods of increased vulnerability. The first one is in a fetal age when it comes to the interaction of genetic and environmental factors such as infection and inflammatory processes who may also serve this function. The second period of vulnerability is a period of adolescence, or early adult age when the influence of environmental factors leads to clinical manifestations of the disease. It is thought that cytokines have key role in the first strike.

Cytokines are mediators of communication between the neural elements in all aspects of the development of the nervous system. Until now, numerous studies indicated modification of specific cytokines in psychotic disorders and their possible role in the proposed concept of "microglial hypothesis" of schizophrenia. Hypothesis of activation Th1 and Th2 immune response, with a predominance of Th2 immune response is proposed in schizophrenia. Type-17 cytokines are important in mediating tissue damage in autoimmune diseases. Regulatory cytokines suppress immune responses and maintain self-tolerance.

Consequently, the question is whether the combination of antipsychotic drugs with anti-inflammatory drugs is more useful than independent antipsychotic therapy? Laan and colleagues in 2010. carried out a randomized, double- blind, placebo - controlled study to determine if the adjuvant aspirin therapy could be useful for patients who are already taking antipsychotics. They concluded that the therapy antipsychotic + aspirin was significantly superior to placebo + antipsychotic therapy. PANSS score was significantly lower in the aspirin group.

The aim of the study would be to determine the effects of adjuvant aspirin therapy on Soft Neurological Signs, PANSS and the cytokine profile. The investigators expect the reduction of PANSS scores in both groups of patients (aspirin group and placebo group). If there is no significant changes of SNS between groups, the results would support SNS as trait characteristics of schizophrenia.

The research would be done on hospitalized patients at the Clinic for Psychiatric Disorders "Dr Laza Lazarevic" in Belgrade. Part of the study (immunology) will be done on Medical Faculty University of Kragujevac.

The study would be a randomized, double-blind, placebo controlled in two parallel groups of 50 to 60 patients who are neuroleptic naive or previously minimally medicated (in the past 6 months without any antipsychotic treatment) with the duration of the illness up to seven years. The study would involve the patients of both sexes, aged 18 to 28 years, according to ICD 10 (10th revision of the International Statistical Classification of Diseases and Related Health Problems) criteria to satisfy diagnosis F 20 to F 29. Each patient who enters the hospital and meets the inclusion criteria would be taken into consideration. If patient satisfies exclusion criteria and sign consent, then s/he would be randomized into two groups: Experimental group (antipsychotic + aspirin) and Control group (antipsychotic + placebo). Patients in experimental group (EG) would receive 1,000 mg of aspirin pro die and pantoprazole 40 mg pro die in two doses for gastric protection.

Only one researcher would know in which group patient belongs (would be responsible only for randomization, would not be rater or treating psychiatrist). The same researcher would give boxes with medications marked with the patient's name. In fact, all medications (aspirin, pantoprazole, and placebo) would be packaged in the same looking capsules.

The protocol would consist of three planned visits for patients in both groups. On the first visit blood samples would be taken for the implementation of immunological tests as well as for laboratory inflammatory factors; patients would be subjected to clinical psychiatric and physical examination, BMI measurement; PANSS scale will be done. After calming the signs of acute psychosis, on 3rd day, patients would be examined with Heidelberg and MoCA scale; patients would start to take Aspirin or Placebo. At the end of 6th week from the second visit (+/- 3 days), on the third visit, blood samples would be taken again for analyzing cytokine profile and inflammatory factors. PANSS, Heidelberg and MoCA scales would be performed again.

The investigators would consider the following factors: patient sex, age of the patients, clinical characteristics, the role of heredity, type of therapy/ prescribed typical or atypical antipsychotic; side effects of treatment and type of treatment response. Serum concentrations of cytokines will be examined with commercial ELISA tests.

Arms:
arm 1: Aspirin 1000 mg/pd per os in two doses

Pantoprazole 40 mg/pd per os in two doses for gastric protection arm 2: Two pills in the morning and two in the evening

All pills (aspirin, pantoprazole an placebo) will be the same looking- in the same capsules.

Interventions: intervention 1: Aspirin intervention 2: Placebo intervention 3: Pantoprazole
Intervention descriptions: intervention 1: 1000 mg pd in two doses intervention 2: two pills twice a day (instead of aspirin and pantoprazole) intervention 3: Pantoprazole 40 mg/pd in two doses, for gastric protection

Protocol document:
Prot_SAP_ICF_001.pdf: 
Official Title: Aspirin as Adjuvant Therapy in Young Psychotic Patients 
NCT number: NCT02685748 
 
 
 
 
Study Protocol and Statistical Analysis Plan 
 
 
 
 
 
Effect of adjuvant aspirin therapy on neurological soft signs and PANSS 
in young psychotic patients 
 
A randomized, interventional, double-blind, placebo-controlled clinical trial 
 
 
 
 
Protocol name: 
Aspirin2016.2 
 
Date: 
25 October 2016. 
 
Donor: 
Stanley Medical Research Institute, 8401 Connecticut 
Avenue, Suite 200, Chevy Chase, MD 20815, SAD 
 
Sponsor: 
Clinic for Mental Diseases “Dr Laza Lazarević”, 
Višegradska 26, 11000 Belgrade, Serbia 
 
Principal Investigator, Grant Holder: 
MD Dragana Pavićević, psychiatrist 
 
Co-investigators: 
MD/PhD Slavica Đukić Dejanović, neuropsychiatrist 
MD Đorđe Ćurčić, psychiatrist 
MD Nebojša Živković, psychiatrist 


Background: 
The clinical trial team would conduct a randomized, interventional, double-blind, 
placebo-controlled study in two parallel groups of patients who were neuroleptically naive or 
previously minimally medicated (who did not take antipsychotics during the previous 6 months) 
with the illness duration of up to seven years. Patients of both sexes, ages 18 to 28, would 
participate in the trial, in accordance with the tenth revision of the International Classification of 
Diseases (ICD10), they would meet the diagnostic criteria for the illnesses ranging from F 20 to 
F 29. After meeting the inclusion and exclusion criteria and having signed an informed consent 
form, the patients would be randomized into two groups: 
Experimental group – EG: antipsychotic + Aspirin 
and 
Control group – CG: antipsychotic + placebo. 
The EG patients would be administered 1000 mg aspirin pro die with gastric protection 
pantoprazole 40 mg pro die, both medicines in two doses during 6 weeks of hospital treatment at 
Clinic form Mental Disorders “Dr Laza Lazarevic”. The trial would last for 18 months and 
would include the total of 100 to 120 patients. 
 
 
Objective and hypotheses: 
 
The objective of the trial would be to determine the effect of adjuvant aspirin therapy on 
neurological soft signs, positive and negative syndrome in schizophrenia, cognition, 
inflammatory factors and cytokine profile. 
Working hypotheses: 
 
1. Changes in PANSS and MoCA scores as well as inflammation factors in both patient 
groups, more in the experimental group. 
2. Changes in the cytokine profile in both patient groups. 
3. In case of significant change of SNS and cytokine profile in the experimental group - 
the results would support the cytokine hypothesis. If there were no significant 
changes in the SNS in the experimental group, the results would support the SNS as a 
trait of schizophrenia. 
 
Clinical Trial Design: 
 
A randomized, interventional, double-blind, placebo-controlled clinical trial in two 
parallel groups of patients who were neuroleptically naive or previously minimally medicated 
(who did not take antipsychotics during the previous 6 months) with the illness duration of up to 
seven years. Patients of both sexes, ages 18 to 28, would participate in the trial, in accordance 


with the tenth revision of the International Classification of Diseases, would meet the diagnostic 
criteria for the illnesses ranging from F20 to F29. Upon fulfilment of inclusion and exclusion 
criteria and signed Informed consent form, they would be randomized in two groups: 
experimental (EG) and control group (CG). Patients belonging to the control group would be 
administered antipsychotic therapy and placebo, whereas patients in the experimental group 
would be administered regular antipsychotic therapy and aspirin. EG patients would be 
administered 1000 mg aspirin pro die with gastric protection- pantoprazole 40 mg pro die, both 
medicines in two doses in duration of 6 weeks. 
 
A software application specialized in the randomization of subjects for clinical trials - 
Sealed Envelope - will be used for randomization. The obtained list will be in possession of one 
co-investigator and only he or she will know which group the patient belongs to. Only upon 
completion of the trial, after taking the serum samples from the last patient, and cytokine profile 
analysis (cytokine profile analysis would be performed at the end of the trial, after the serum 
sample from the last patient was taken at both test times) would the patient’s belonging to the EG 
or CG group be revealed. 
The co-investigator in charge of randomization would give out the medicine boxes and 
the medicines would all look identical - packed in the same capsules for overcapsulation by the 
company Capsugel. Placebo tablets would be manufactured by Galenika A.D. The patient would 
be administered Bayer’s Aspirin tbl. á 500 mg and Nolpaza tbl. á 20 mg produced by Krka- 
Farma D.O.O. 
 
Three visits are planned. The first visit after admission to the Clinic. If the patient fulfils the 
inclusion criteria and none of the exclusion criteria (anamnestic data, somatic and psychiatric 
examination), and after the Informed consent form has been signed, PANSS scale test and blood 
sample would be taken for laboratory analysis. Laboratory analysis would be complete blood count 
(RBC, WBC, PTC, Hgb, Hct), sedimentation, C reactive protein, blood biochemical analysis 
(glycaemia, cholesterol, triglycerides, transaminases, CK, bilirubin, uric acid, creatinine, urea), and 
electrolytes (Na, K). Th1, Th2 and Th17 cytokines would be subject to the immunological assays. 
Each patient would be given an identification number (from one upwards) and the tubes with serum 
for the cytokine profile would be labelled with the same number, in terms of x/y, where x is the 
patient’s identification number and y- may be “1” or “2” (“a” or “b”), where “1” or “a” would 
mean the first blood draw (at the beginning of the trial) and the number “2” or “b” - the second 
blood draw (at the very end of the trial). 
After calming down of the acute signs of psychosis, between the third and fifth day of 
hospitalization, the second visit would be made when testing of the neurological soft signs would 
be performed according the Heidelberg Soft Neurological Signs Scale, the MoCA Cognitive 
Assessment Scale, and then the patient would be randomized to an experimental or control group if 
he/she meets the inclusion and no-exclusion criteria, if there are no somatic contraindications (with 
a stable ECG), and if he/she still wishes to participate in the trial. 
 
The staff of the ward where the patient would be accommodated would be given two boxes 
of medicines labelled “Clinical Trial Medication 1” and “Clinical Trial Medication 2” that would 
be administered to patients – one medicine from each box, in the morning and in the evening. 


After 6 weeks from the second visit (+/- 3 days), the third visit would be made when the 
patient would be examined, the PANSS, MoCA and Heidelberg scales testing repeated, and the 
blood sample taken again for laboratory analyses - inflammatory factors and cytokine profiles. 
 
Control laboratory analyses would be performed on each patient on days 14th and 28th from 
the second visit. If patients received high dose valproic acid in therapy, valproatemia control would 
be performed, and if they received antidepressants from the SSRI group, bleeding time would be 
controlled. 
 
Serums administered to patients would be transported in a cold chain to the Centre for 
Molecular Medicine and Stem Cell Research at the Faculty of Medical Sciences, University of 
Kragujevac, where they would be stored at -70°C until analyses were performed. 
 
 
Criteria for Trial Termination: 
 
The criteria for trial termination for individual subjects, parts of the trial or the whole trial 
would be defined as follows: the subject may voluntarily leave the trial at any moment. In the 
event that side effects of adjuvant aspirin therapy occur, the patient would be excluded from the 
trial. Occurrence of bleeding from the nose or gums, bruising, bleeding in the GIT or brain, and 
confusion, anaphylactic reactions or acute renal failure would imply the immediate exclusion of 
subjects from the trial. If there is an increase in valproatemia (in patients taking valproic acid in 
therapy) - the dose of the medicine would be adjusted. In case of significant deviation in the 
laboratory analyses - the subject would be excluded from the trial. The entire trial would be 
discontinued by the emergence of a large number of complicated side effects, as well as by 
compromising drug storage. 
 
 
Selection and inclusion of subjects: 
 
➢ Inclusion criteria: 
• 
Age 18 to 28 
• 
Diagnostic categories from F 20 to F 29 
• 
Illness duration ≤ 7 years 
 
➢ Exclusion criteria: 
o PAS abuse 
o Primary cognitive impairment 
o Contraindications and special caution for acetylsalicylic acid and pantoprazole: 
• Hypersensitivity to acetylsalicylic acid and other NSAIDs (possible cross- 
reaction) 
• Gastric ulcer and/or duodenum ulcer, gastritis 
• Pregnancy 
• Haemophilia, bleeding disorders 
• Gout 


• Asthma, COPD, NSAID-induced bronchospasm 
• Angioedema, urticaria 
• Haemolytic anaemia 
• Use of warfarin, methotrexate 
• Diabetes 
• Decreased liver and / or kidney function 
• Heart failure 
• Surgical/dental intervention 
• Interactions with specific psycho-pharmaceuticals 
• Sensitivity to pantoprazole 
 
 
Statistical analysis plan: 
Statistical data analysis will be done in the programme IBM SPSS Statistics v.20. 
 
Continuous variables will be displayed descriptively using the minimum and maximum values, 
mean values and standard deviation. Categorical variables will be presented descriptively using 
absolute and relative frequency as well as graphically using a pie chart. 
 
Kolmogorov-Smirnov or Shapiro-Wilk test, depending on sample size, will be used to check the 
normality of data distribution, as well as graphical method of using histogram. If the data follow 
the normal distribution, parametric tests will be used for the statistical analysis of the data; 
otherwise the corresponding non-parametric tests will be used. 
 
For the analysis of significant continuous variables over time, the Paired Samples t Test will be 
used if the data follow a normal distribution or the Wilcoxon test if the data do not follow the 
normal distribution. Significant results will be presented graphically using a bar chart or boxplot. 
 
For the analysis of significant difference of continuous variables between the control and 
experimental groups, the Independent Samples t Test will be used if the data follow a normal 
distribution or the Mann-Whitney test if the data do not follow the normal distribution. Significant 
results will be presented graphically using a bar chart or boxplot. 
 
For the analysis of the dependence between two continuous variables, the value of Pearson's or 
Spirman's correlation coefficient will be interpreted. In the case of strong correlations, the 
dependence will be shown both by the regression equation and graphically using the scatterplot. 
 
For the analysis of the dependence between the two categorical variables, a Chi-squared test, that 
is, a Fisher's exact-dependency test will be used. The results will be presented graphically using a 
bar cluster graph. 
 
The results will be considered statistically significant if the p value is less than 0.05. 


SUBJECT INFORMED CONSENT, second version, 11.07.2016. 
 
SUBJECT INFORMED CONSENT 
Effect of adjuvant aspirin therapy on Soft Neurological Signs and 
PANSS 
in young psychotic patients 
A double-blind, randomized, interventional clinical trial 
(Second version, 11/07/2016) 
We invite you to participate in our study to examine the impact of additional 
aspirin therapy on mental illnesses’ symptoms and signs. If you agree to participate 
in the trial while taking your regular psychiatric treatment you would receive aspirin 
and pantoprazole or placebo (depending on randomization). Aspirin is a drug from 
the group of the so-called antirheumatics – they soothe pain and inflammation, and 
pantoprazole is administered to protect the gastric mucosa during aspirin therapy. 
 
You need to understand why this study is conducted, what is demanded of 
you, and take the time to carefully read the following information to decide whether 
or not you want to participate in it. It is also advisable to ask if something is not clear 
to you or if you need further clarification. 
 
The aim of the study is to determine whether additional aspirin therapy will 
result in a faster and essential improvement of mental illness - signs and symptoms 
of the illness. 
 
If you agree to participate in this study/trial, you are expected to take the 
prescribed therapy regularly and to fill-in the tests (it will take approximately 90 
minutes) at the beginning and end of the trial. Also, you would have been taken 
blood sample from your vein twice for laboratory tests - at the beginning and at the 
end of the trial. A 5 ml sample of venous blood sample would be sent (subject to 
randomization) to determine additional biological markers (analysis) in the USA at 
the Stanley Neurobiology Laboratory at Johns Hopkins University. 
As with any medicines, there are contraindications related to the use of 
Aspirin and pantoprazole, as well as possible side effects that you should 
consider. 
• 
Aspirin should not be used by person who are allergic to NSAIL (salicylate, 
ibuprofen, naproxen). 
• 
Particular attention should be paid to patients suffering from asthma, gastric 
ulcer, mild diabetes, gastritis, haemophilia, persons suffering from kidney 
diseases, hyperuricemia or gout. 
• 
Even in people without these difficulties, there is still a risk of internal bleeding 
in the gastrointestinal system if aspirin is taken after consuming alcohol or 
warfarin; it can cause haemolytic anaemia in people with G6PD genetic 
disorder. It increases the risk of Reye’s syndrome. 
• 
Hypersensitivity to pantoprazole. 
 
 
 
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SUBJECT INFORMED CONSENT, second version, 11.07.2016. 
 
You need to inform the investigator of any previous and present illnesses and 
treatment. 
If you choose to participate, the data collected during the trial (personal and 
medical data) would be recorded and stored in the NIMH database (National Institute 
of Mental Health Data Archive, USA) and published in accordance with applicable 
personal data protection regulations by persons conducting trial and other 
investigators who may access the database. A description of this clinical trial will be 
available http://www.ClinicalTrials.gov, in accordance with the US law. This website 
will not include information by which you may be identified. At best, the website will 
include a summary of the results. You may search the website at any time. 
 
Your participation will not entail additional costs on your part, nor will you 
receive material compensation for participation. 
 
Your full compliance with the investigator’s requests and instructions is 
expected. Information will be made available during the trial that may affect your 
willingness to continue participating within a reasonable time. 
 
Participation in a study/trial is voluntary and you can terminate it at any time, 
without any sanction and without losing any benefit to which you are entitled. 
TO BE FILLED-IN BY A SUBJECT by putting the sign ×: 
□ 
I have read and understood this information and the subject informed consent 
form. 
□ 
I was given the opportunity to ask additional questions; I am satisfied with the 
answers I obtained. 
□ 
I hereby authorize investigators to submit the trial data and results to the 
NIMH database and to the website http://www.ClinicalTrials.gov, and publish 
the results in accordance with applicable personal data protection regulations. 
□ 
I confirm that I have received a copy of the signed document. 
□ 
I am aware that my participation is entirely voluntary and confirm that I am 
aware of the terms of participation. 
□ 
I fully understand that signing of this document also means accepting all 
views stated in the Subject Informed Consent Form with full notice. 
 
Subject: 
 
Name and Surname 
Date 
Signature 
 
 
Investigator: 
 
 
Name and Surname 
Date 
Signature 
 
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