Controlled, Double-blind, Randomized Clinical Trial for Prophylaxis of Postoperative Delirium in High Risk Surgical Patients With Quetiapine
Phase: PHASE3
Conditions: Postoperative Delirium
Sponsor: Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
 
"CONTROLLED, DOUBLE-BLIND, ANDA RANDOMIZED CLINICAL TRIAL FOR 
QUETIAPINE PROPHYLAXIS OF POSTOPERATIVE DELIRIUM IN AT-RISK 
SURGICAL PATIENTS." 
 
 
 
 
 
PROMOTER: IBSAL-Instituto de Investigación Biomédica de Salamanca 
PROTOCOL CODE: QUEPRO 
EudraCT No.: 2016-004117-27 
VERSION  2.0,  dated  April 3, 2019 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
2 
 
 
 
 
PROTOCOL SIGNATURES PAGE 
 
Promoter's Statement: 
PROTOCOL TITLE: RANDOMIZED, DOUBLE-BLIND, CONTROLLED CLINICAL 
TRIAL FOR QUETIAPINE PROPHYLAXIS OF POSTOPERATIVE DELIRIUM IN AT-
RISK SURGICAL PATIENTS 
PROTOCOL CODE: QUEPRO 
EudraCT No.: 2016-004117-27 
Representative of the promoter: Rogelio González Sarmiento 
 
 
Company 
Date 
 
 
Signature of the Coordinating Researcher: 
PROTOCOL TITLE: RANDOMIZED, DOUBLE-BLIND, CONTROLLED CLINICAL 
TRIAL FOR QUETIAPINE PROPHYLAXIS OF POSTOPERATIVE DELIRIUM IN AT-
RISK SURGICAL PATIENTS 
PROTOCOL CODE: QUEPRO 
EudraCT No.: 2016-004117-27 
Researcher Coordinator of the Study: Elisa Sánchez Barrado. 
 
 
 
Company 
Date 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
3 
 
 
 
 
Principal Investigator's Signature Page 
PROTOCOL CODE: QUEPRO 
EudraCT No.: 2016-004117-27 
 
CONFIDENTIALITY AND DECLARATIONOF CONFORMITY OF CBS 
  
I have read the protocol of the previous clinical study entitled: "RANDOMIZED, 
DOUBLE-BLIND, 
CONTROLLED 
CLINICAL 
TRIAL 
FOR 
QUETIAPINE 
PROPHYLAXIS OF POSTOPERATIVE DELIRIUM IN AT-RISK SURGICAL 
PATIENTS" and agree that it contains all the information necessary to conduct the 
study. 
  
I hereby confirm that I have thoroughly read and understood this clinical study protocol, and I  
agree that my staff and I will conduct the study in accordance with the protocol and 
comply with its requirements, including ethical and safety considerations.  
I understand that if the Promoter decides to terminate or suspend the study 
prematurely for any reason, such decision  will be communicated to me in writing. On 
the contrary, if I decide to withdraw from the execution of the study, I will immediately 
communicate this decision to the Promoter.  
I agree not to publish any part of the results of the study conducted under this clinical 
study protocol without the prior written consent of the Sponsor. 
 
 
Principal Investigator ____  
 
Hospital Center ____ 
 
 
 
Company 
 
 
Date 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
4 
 
 
 
 
ABBREVIATIONS 
 
AA 
Adverse Event 
AAG 
Serious adverse event 
AEMPS 
Spanish Agency for Medicines and Health Products 
APACHE II 
Acute Physiology And Chronic Health Evaluation II 
AUC 
Area under the curve 
Good 
Blood Urea Nitrogen 
C.A.U.S.A 
University Assistance Complex of Salamanca 
CAM 
Confussion Assessment method 
CDR 
Data Collection Notebook 
CEIm 
Committee on the Ethics of Research with Medicinal 
Products 
IC 
Confidence interval 
CI 
Informed consent 
CTCAE 
Common Toxicity Criteria for NCI Adverse Event 
Cro 
Contract research organisation 
DRS-R-98 
Delirium Rate Scale-Revised-98 
DSM IV 
Diagnostic and Statistical  Manual of Mental Disorders 
EVA 
Visual Analog Scale 
GBPC 
Good Clinical Practice Guide 
IBSAL 
Biomedical Research Institute of Salamanca 
Me 
Resident Intern 
NCI 
National Cancer Institute 
p.e. 
For example 
PCR 
 C-reactive protein 
RAGI 
Serious 
and 
Unexpected 
Adverse 
Reaction 
RASS 
Richmond Agitation sedation  Scale 
REec 
Spanish Registry of Clinical Studies 
SF-36 
Health-Related Quality of Life Questionnaire 
SNC 
Central nervous system 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
5 
 
 
 
 
1. SUMMARY AND GENERAL INFORMATION 
1.1TYPE OF APPLICATION 
 
Non-commercial low-intervention clinical trial 
 
1.2IDENTIFICATION OF THE PROMOTER 
Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León (IECSCYL)- Instituto 
de Investigación Biomédica de Salamanca (IBSAL).  
IECSCYL-IBSAL Foundation. 
 
1.3TITLE OF THE CLINICAL TRIAL 
Randomized, double-blind, controlled clinical trial for quetiapine prophylaxis of postoperative 
delirium in at-risk surgical patients. 
1.4PROTOCOL CODE  
 
QUEPRO 
 
1.5COORDINATING AND PRINCIPAL INVESTIGATOR 
Elisa Sánchez Barrado.  Anesthesia, rehabilitation and pain treatment service. C.A.U.S.A 
 
1.6CENTRES WHERE THE STUDY IS PLANNED 
 
University Assistance Complex of Salamanca 
 
1.7CEIM 
 
Committee on Research Ethics with medicines Salamanca Health Area 
 
1.8RESPONSIBLE FOR MONITORING  
 
Monitor: Esperanza López Franco 
Coordinator in the Promoter: Carmen Arias De La Fuente. Clinical Trials Area.  IBSAL 
RESPONSIBLE FOR PHARMACOVIGILANCE: 
Patricia Rodríguez Fortúnez (UICEC H. Universitario de Canarias) 
 
1.9.DESCRIPTIONOF STUDY PRODUCTS. 
Experimental treatment and control 
 
Quetiapina (experimental)  vs placebo (control) 
Route of administration: oral 
Experimental: quetiapine  25 mg gelatin capsule-coated tablets. Cada tablet contains 25 mg 
of q uetiapina (as quetiapine fumarate). Excipient: lactose 18.5 mg 
Therapeutic group: N05A H04. Antipsychotics: diazepines, oxacepines and thiazepines. 
Anatomical Group: (N) Nervous system 
 
Placebo: gelatin capsule. 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
6 
 
 
 
 
 
1.10 CLINICAL TRIAL PHASE 
 
 Phase III 
 
10.11OBJECTIVES 
Main: to know the incidence of postoperative delirium in patients at risk, over 65 years of age, 
treated early with prophylactic quetiapine compared to those treated with placebo. 
 
Side: 
1. Evaluate the safety and tolerability of the medication applied 
2. To compare the efficacy of medication versus placebo in relation to:  
- 
length of hospital stay 
- 
perceived quality of life 
- 
all-cause mortality at discharge and 28±2 days from initiation (1st dose) of 
quetiapine treatment.  
3 
In cases where delirium develops, know: 
- 
Time of appearance 
- 
the duration and severity of the same 
- 
Total dose of treatment with other antipsychotics. 
 
 
1.12STUDY DESIGN 
 Prospective low-level non-commercial, balanced, randomized, double-blind clinical trial 
(phase III) clinical trial. 
 
1.13STUDY DISEASE 
Delirium  developed during the period after surgery. 
Delirium is an acute alteration of consciousness accompanied by inattention, disorganization 
of thought and alterations of perception that fluctuate in a short period of time (DSM IV). It is 
one of the most frequent complications of surgery and develops characteristically between 0-
96 h after the intervention. It is associated with worse prognosis in the short and long term.  
 
1.14STUDY VARIABLES 
A. The main variable is the proportion of patients diagnosed with delirium (number of 
delirium cases/total number of patients) in the first 4 postoperative days in both 
branches. 
B. Secondary variables: 
1. number of days from the start of treatment to the onset of delirium, if it appears, 
2. duration of delirium, in days, 
3. severity of delirium measured with validated scale (DRS-R-98) 
4. total dose (mg) haloperidol or another antipsychotic to control symptoms of 
delirium, 
5. Security variables: 
• 
degree of sedation: by RASS scale,  
• 
QTc prolongation: increase in mseg on the control ECG. 
• 
presence or absence of extrapyramidal symptoms (tremor, involuntary 
movements, stiffness) 
6. days of hospital stay since surgery, 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
7 
 
 
 
 
7. perceived quality of life (through SF36 validated questionnaire) 28±2 days after 
initiation of treatment, 
8. All-cause mortality at discharge and 28±2 days after initiation of treatment 
 
 
1.15STUDY POPULATION AND TOTAL NUMBER OF PATIENTS 
Patients older than or equal to 65 years of age who are going to undergo major non-cardiac 
surgery and who have a score equal to or greater than 5 on the Delphi scale:  
- 
Age: 70-79 years: 1 point; >80 years: 2 points 
- 
Physical activity: need for assistance, not self-sufficient: 2 pointss 
- 
Alcoholism: 1 point 
- 
Hearing deficit: 1 point 
- 
History of delirium: 2 points 
- 
Urgent surgery: 1 point 
- 
Non-laparoscopic surgery: 2 points 
- 
Admission to Critical Care Units: 3 points 
- 
 C-Reactive Protein (CRP) value > 10 mg/dL: 1 point 
 
The necessary sample size will be 350 patients, 175 patients per branch (control and 
experiment). 
 
1.16DURATION OF PROCESSING 
The duration of the treatment will be three days included in the early postoperative phase.  
Quetiapine will be administered  orally  to the patientsof the experimental group 60 minutes 
after arrival at Resuscitation/Post-Anesthetic Recovery Unit and thereafter every 12 hours until 
the 3rd postoperative day. Subjects in the control group will be given placebo in the same time 
and form as subjects in the experimental group. 
1.17 
CLINICAL TRIAL SCHEDULE. 
The total duration of the clinical trial will be approximately 3 years.  They include  the period 
for  approvals and coordination of the project, period of recruitment and  monitoring, period or 
analysis of  results and a final period for the publication of results.  
 
1.18COLLABORATING   INVESTIGATORS OF THE TRIAL 
Dr. José María Calvo Vecino. Head of Service Anesthesiology, resuscitation and pain 
management. C.A.U.S.A - Biomedical Research Institute of Salamanca (IBSAL) 
Dr. Luis Mario Vaquero Roncero.  Medical assistant to the  Anesthesiology, Resuscitation and 
Pain Treatment Service. C.A.U.S.A.  - Biomedical Research Institute of Salamanca (IBSAL). 
Dr. Domingo Bustos García.  Medical assistant to the Anesthesiology, Resuscitation and Pain 
Treatment Service.  C.A.U.S.A. 
Dr. Azucena Hernández Valero.  Medical assistant to the  Anesthesiology, Resuscitation and 
Pain Treatment Service.  C.A.U.S.A. 
Dr.  Miguel Vicente Sánchez Hernández. Head of section of the  Anesthesiology, Resuscitation 
and Pain Treatment Service.  C.A.U.S.A. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
8 
 
 
 
 
Dr. Antonio Rodríguez Calvo.  Medical assistant to the  Anesthesiology, Resuscitation and 
Pain Treatment Service.  C.A.U.S.A. 
Dr. Carolina Jambrina.  Medical assistant to the  Anesthesiology, Resuscitation and Pain 
Treatment Service.  C.A.U.S.A. 
Dr. María del Carmen Vargas. Assistant Physician Anesthesiology, Resuscitation and Pain 
Treatment Service.  C.A.U.S.A. 
Dr. Cristina Morales.  Medical assistant to the Anesthesiology, Resuscitation and Pain 
Treatment Service.  C.A.U.S.A. 
Dr. Isabel Pingarrón.  Medical assistant to the  Anesthesiology, Resuscitation and Pain 
Treatment Service.  C.A.U.S.A. 
Dr. David Sánchez Poveda.  Medical assistant to the Anesthesiology, Resuscitation and Pain 
Treatment Service.  C.A.U.S.A. 
Dr. María Pilar Arribas Pérez. Medical assistant to the Anesthesiology, Resuscitation and pain 
treatment service. C.A.U.S.A. 
 
 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
9 
 
 
 
 
2 
INDEX 
PROTOCOL ................................................................................................................................ 22 2 
SIGNATURE PAGE 
ABBREVIATIONS ....................................................................................................................... 44 4 
1.SUMMARY AND GENERAL INFORMATION ..................................................................... 55
 
 ............................................................................................................................................ 5 
1.1Type of Application ................................................................................................... 55
 
 .......................................................................................................................................... 5 
1.2Identification of the promoter ...................................................................................... 55
 
 .......................................................................................................................................... 5 
1.3Title of clinical trial .................................................................................................... 55
 
 .......................................................................................................................................... 5 
1.4Protocol Code .......................................................................................................... 55
 
 .......................................................................................................................................... 5 
1.5Coordinating and principal investigator ........................................................................ 55
 
 .......................................................................................................................................... 5 
1.6Centres where the study is planned to be conducted .................................................... 55
 
 .......................................................................................................................................... 5 
1.7CEIm ...................................................................................................................... 55
 
 .......................................................................................................................................... 5 
1.8Responsible for monitoring ........................................................................................ 55
 
 .......................................................................................................................................... 5 
1.9.Description of study products.  .................................................................................. 55
 
 .......................................................................................................................................... 5 
1.10 Clinical trial phase .......................................................................................................... 66 6 
1.11Objectives.............................................................................................................. 66
 
 .......................................................................................................................................... 6 
1.12Design of Studio ..................................................................................................... 66
 
 .......................................................................................................................................... 6 
1.13Study disease ........................................................................................................ 66
 
 .......................................................................................................................................... 6 
1.14Study variables ....................................................................................................... 66
 
 .......................................................................................................................................... 6 
1.15Study population and total number of patients ............................................................ 77
 
 .......................................................................................................................................... 7 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
10 
 
 
 
 
1.16Duration of processing ............................................................................................ 77
 
 .......................................................................................................................................... 7 
1.17Clinical trial schedule.  ............................................................................................. 77
 
 .......................................................................................................................................... 7 
1.18Collaborating investigators of trial ............................................................................. 77
 
 .......................................................................................................................................... 7 
2 
 ........................................................................................................................................... 9. 
 
9 INDEX .................................................................................................................. 99
 
 ............................................................................................................................................ 9 
3 
 ......................................................................................................................................... 13. 
 
13 JUSTIFICATION .................................................................................................. 
 
1312 ....................................................................................................................... 13 
4 
 ......................................................................................................................................... 15. 
 
15 HYPOTHESES AND OBJECTIVES ....................................................................... 
 
1514 ....................................................................................................................... 15 
5 15.        ........................................................................................ 15CLINICAL TRIAL DESIGN. 15 
15 15 
5.1Description of variables ............................................................................................. 
 
1515 ..................................................................................................................... 15 
5.2Study design and control method.  .............................................................................. 
 
1616 ..................................................................................................................... 16 
5.3Allocation of patients and identification codes.  ............................................................ 
 
1616 ..................................................................................................................... 16 
5.4Description of trial treatments ..................................................................................... 
 
1716 ..................................................................................................................... 17 
5.5Masking techniques and opening of masking codes.  .................................................... 
 
1717 ..................................................................................................................... 17 
5.6Identification of the data to be recorded.  ..................................................................... 
 
1817 ..................................................................................................................... 18 
5.7End of essay ............................................................................................................ 
 
1817 ..................................................................................................................... 18 
6 
 ......................................................................................................................................... 18. 
 
18 PATIENT SELECTION AND WITHDRAWAL ........................................................... 
 
1818 ....................................................................................................................... 18 
6.1Inclusion criteria.  ..................................................................................................... 
 
1818 ..................................................................................................................... 18 
6.2Exclusion criteria.  .................................................................................................... 
 
1818 ..................................................................................................................... 18 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
11 
 
 
 
 
6.3Number of patients.  ................................................................................................. 19 
6.4Expected criteria for withdrawal of study subjects.  ....................................................... 
 
1919 ..................................................................................................................... 19 
6.5Follow-up of study patients.  ...................................................................................... 
 
1919 ..................................................................................................................... 19 
6.6Premature discontinuation of the study.  ...................................................................... 
 
2019 ..................................................................................................................... 20 
7.TREATMENT OF PATIENTS.  ......................................................................................... 
 
2020 ....................................................................................................................... 20 
7.1Clinical trial materials.  .............................................................................................. 
 
2020 ..................................................................................................................... 20 
7.2  .................................................................................. 20Schedule of visits and procedures 
 
2020 ..................................................................................................................... 20 
7.3 Concomitant and prohibited processing ......................................................................... 23 
7.4Storage, storage and dispensing of medication ............................................................ 24 
8.  
EFFECTIVENESS ASSESSMENT ................................................................................... 24 
8.1Efficacy variables. .................................................................................................... 24 
8.2Evaluation methods.  ................................................................................................ 24 
 
9.ADVERSE EVENTS. SAFETY RATING ........................................................................ 25 
9.1Definitions. .............................................................................................................. 26 
9.2Qualification of an adverse event.  .............................................................................. 26 
9.3Procedures for registration of  .................................................................................... 28 
9.3.1Responsibility for notification.  ............................................................................... 28 
9.3.2Notification to Health Authorities and Ethics Committees.  ........................................ 29 
9.3Number and contact persons ..................................................................................... 29 
10.STATISTICAL ANALYSIS .............................................................................................. 30 
11.ETHICAL ASPECTS ..................................................................................................... 30 
11.1Informed consent .................................................................................................... 31 
11.2Confidentiality / Data protection.  .............................................................................. 31 
11.3Acquisition and dispensing of the medication under study.  .......................................... 32 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
12 
 
 
 
 
11.4Audit and monitoring.  ............................................................................................. 32 
11.5Breach of protocol.  ................................................................................................. 32 
 
12.FINANCING AND INSURANCE .................................................................................. 33 
 
13.PUBLICATION POLICY ............................................................................................... 33 
13.1Publication of results.  ............................................................................................. 33 
13.2Amendments to the protocol.  ................................................................................... 33 
 
14.BIBLIOGRAPHY .......................................................................................................... 33 
 
 
ANEXO 1: 
SCALE OF VALUATIONN CAM.................................... 37 
ANNEX 2: 
SCALE RASS.................. 39th 
ANNEX 3:  
SCALE DRS-R-98.................... 40th 
ANNEX 4: SCALE  
SF-36................. 48 
ANEXO 5: THE CLAVIEN-DINDO CLASSIFICATION........................................................ 51
 
 
 
ANNEX 6:COMPLICATIONS NOT RELATED TO DELIRIUM.......... .. ............ 52 
ANNEX 7: ADVERSE REACTIONS TO QUETIAPINE ( SMPC)................ 53 
 
 
 
 
 
3 
JUSTIFICATION 
According to the DSM-IV, delirium is an acute alteration of consciousness accompanied by inattention, 
disorganization of thought and alterations of perception that fluctuate in a short period of time. 
Postoperative delirium is one of the most common complications of surgery, with an incidence ranging 
from 10-51% in elderly patients at risk and up to 80% in those requiring critical care (1). It develops 
characteristically between 0 and 96 hours after the intervention (2) and is associated with a worse 
prognosis in the short and long term, with an increase in mortality and hospital stay and,  therefore, an 
increase in economic expenses (3,4). The antipsychotic of choice for treatment is haloperidol (5,6), 
although its efficacy is limited in part by its side effects (mainly extrapyramidalism and prolongation of 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
13 
 
 
 
 
the QTc interval) and lack of response in some patients. To solve these problems,  second-generation 
or atypical antipsychotics appear, which have a more favorable safety profile with similar efficacy in 
clinical response (7). However, despite treatment, the prognosis does not seem to improve once 
delirium is triggered (4,8), so prophylaxis may be essential. Thus, although non-pharmacological 
prophylaxis measures (respect for wake-sleep cycle, pain control, early mobilization, providing visual 
and auditory aids...) have shown efficacy in reducing the incidence of delirium in this type of patients 
(4), this decrease is closely related to the complete follow-up of all measures, which implies a very 
important work overload without evidence of improvement in fundamental  variables at discharge, such 
as functional or cognitive status (9). Therefore, pharmacological prophylaxis is gaining interest (4), 
although the evidence in the literature is limited. It seems logical to think that,  just as antipsychotics 
are effective for the treatment of delirium, they will also be effective for pharmacological prophylaxis. 
In this regard, a number of studies with haloperidol and atypical antipsychotics have presented variable 
results, possibly related to the quality of the studies, variability in the tools used for the diagnosis of 
delirium and the selection of high-risk patients. The first large randomized clinical trial was conducted 
in 430 postoperative hip replacement patients. It failed to demonstrate a reduction in the incidence of 
delirium when 1.5 mg haloperidol was administered orally divided into three doses, but the severity 
and duration of delirium decreased (10). Larsen (11), in  2010,  tested olanzapine 5 mg orally in 400 
patients and managed to demonstrate that the risk of developing delirium in the intervention group was 
lower (RR 0.36, 95% CI 0.24 to 0.52), although episodes of delirium were longer lasting and severe. 
In 2014,  Fukata (12) administered 121 patients 2.5 mg of intravenous haloperidol daily after general, 
trauma or other surgery, and could not demonstrate a decrease in the incidence of delirium in the 
intervention group. And yet,  Wang (1), using haloperidol in patients undergoing noncardiac surgery, 
demonstrated clinically significant incidence decreases. Despite the risk of bias in these studies, there 
was no evidence of adverse effects with the use of these antipsychotics at low doses. 
We think that, within the group of atypical antipsychotics, quetiapine, due to its pharmacological profile 
(low affinity for dopamine receptors and μ receptors; high affinity for serotonergic receptors), could be 
useful in the prophylaxis of delirium and provide sedation without causing too many extrapyramidal 
effects (3) or precipitating acute episodes of delirium. In the current literature, there are no clinical trials 
with quetiapine for postoperative delirium prophylaxis but there are for the treatment of delirium. A 
series of randomized trials (7, 13,14) and one open-label trial (3) suggest that quetiapine may be 
effective and safe. Studies show faster resolution of symptoms than with placebo and find the same 
efficacy of other antipsychotics such as haloperidol, with low incidence of side effects, mainly 
drowsiness, without finding significant differences. The average dose used in these studies ranges 
from 40 mg to 200 mg, because they use increasing doses until symptoms are controlled. But there 
are studies that show efficacy with lower doses: 25-40 mg / day. They are studies carried out in the 
medical population and in critical care, and have certain limitations: n small, assessment of the 
effectiveness of treatment with quetiapine with different scales ... Even so, they would justify the use 
of quetiapine as prophylaxis at doses lower than those used for treatment. In this sense,  there are 
two international clinical trials underway on postoperative delirium prophylaxis in the population at risk 
in critical care units, with an initial dose of quetiapine 12.5mg, in one of them adjusting for patient 
weight and the other with increasing doses as needed (15,16). Taking into account, in addition, that 
the clearance of the drug in patients over 65 years of age is decreased and,  therefore, the  half-life of 
the drug is extended in this population, we believe that the use of doses of quetiapine of 25 mg every 
12 hours during the first three days of the postoperative period in patients at risk is justified.  
 
One aspect to take into account is to determine the population at risk (in which we would suppose 
greater benefit of prophylactic measures), which can be complicated since until now there is no reliable 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
14 
 
 
 
 
tool to detect patients at risk of developing delirium during the postoperative period (17). More and 
more risk factors for this condition are known that seem to be based on three variables (18): the first 
is the speed of onset of surgical aggression. Thishas been demonstrated in orthopedic surgery, where 
several studies show that urgent surgery is associated with increased risk of delirium. The second 
variable is severity: the greater the surgical aggression (for example aorta surgery or neurosurgery) 
and the longer the intervention, the greater the risk of delirium. Although there is little evidence linking 
increased risk of delirium with a drug or anesthetic technique, it currently appears that anesthetic depth 
plays an important role in the development of postoperative delirium with sufficient evidence (17,19). 
The last variable is the patient, in whom several risk factors have been identified: age (the older the 
older the greater the risk of delirium), cognitive deficit or dementia, depression, use of psychotropic 
drugs, associated comorbidity, degree of functionality (independent for activities of daily living)... (17-
20). 
 
In the work on the prophylaxis of delirium with antipsychotics, different tests have been used to identify 
patients at risk of developing delirium after surgery. One of the first was used by Kalisvaar to identify 
patients at risk of developing delirium after hip replacement surgery (21). Based on a scale of a study 
on delirium prophylaxis in patients undergoing general surgery, it used 4 items: visual deficit 
(measured with the Snellen test), APACHE II >16, Minimental Test > 24 and dehydration 
(BUN/creatinine ratio > 18). In this way, it classified patients with intermediate risk (if they had 1 or 2 
items) or high risk if they had 3 or 4 (AUC 0.73). In 2014, Harasawa (22) used a new scale to predict 
the development of postoperative delirium in patients undergoing cerebrovascular surgery with a 
sensitivity of 71% and a specificity of 85.7%, area under the curve 0.844. It considers five variables: 
underlying disease (comorbidity), dehydration (nitrogen/creatinine index> 18), age >70 years, 
alterations in consciousness (Glasgow scale) and presence of depression-anxiety. Patients with a 
score greater than 12 were at increased risk of delirium. In that same year, in the  published protocol 
of the HARPOON study (9), a  multicenter trial that assesses the efficacy and safety of haloperidol 
prophylaxis in the prevention of delirium in elderly medical and surgical patients, they  used three 
simple questions to identify patients at risk of developing delirium: about the patient's mental state (do 
they have memory problems?),  on the degree of functionality (have you required help for your personal 
care in the last 24 hours?) and on the background (have you presented a state of transitory confusion 
during admissions or previous illnesses?). Each positive response scores as 1, and a score equal to 
or greater than 1 identifies a patient at risk. Except in this last study, the use of delirium risk predictor 
scales is complicated by the incorporation of other scales that hinder and slow down their realization. 
In this sense, in 2016 a delirium prediction scale was published to identify high-risk patients based on 
clinical data from the perioperative period: it is the Delphi method (23). The predictors used are: age, 
dependence for physical activities, alcoholism, hearing deficit, history of delirium, urgent surgery, open 
surgery, C-reactive protein value > 10 (mg/mL) and admission to critical care unit. A score equal to or 
greater than 7 classifies the patient as at high risk of developing delirium during the postoperative 
period. This predictor scale presents an area under the curve of 0.938 (95% CI: 0.91-0.97) and 
identifies the patient at high risk of developing delirium with a sensitivity of 80.8% and a specificity of 
95.7%. It is simple, fast and easy to perform. 
 
Given the importance of this condition, its prevalence and its consequences, we think that prophylaxis 
in the population at risk (patients >65 years postoperative for non-cardiac surgery) during the first 72 
hours after surgery with small doses of quetiapine can provide great benefits (decreased incidence, 
decreased duration and severity delirium) with a low level of risk since it has a favorable safety profile.  
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
15 
 
 
 
 
4 
HYPOTHESES AND OBJECTIVES 
 
Hypothesis: The prophylactic administration of an antipsychotic with fewer side effects,  such as 
quetiapine, in patients identifiedwith a validated scale decreases the incidence of delirium during the 
postoperative period compared to placebo administration. 
 
The main objective of the study is to determine the incidence of postoperative delirium in patients at 
risk, over 65 years of age, treated early with prophylactic quetiapine compared to those treated with 
placebo. 
 
The secondary objectives are:  
• 
eassess the safety and tolerability of the medication applied. 
• 
cCompare the efficacy of medication versus placebo in relation to:  
- 
the length of hospital stay. 
- 
perceived quality of life at 28±2 days from the start (1st dose) of quetiapine treatment.  
- 
all-cause mortality at discharge and 28±2 days from initiation (1st dose) of quetiapine 
therapy.  
• 
In cases where delirium develops, know: 
- 
Time of  appearance. 
- 
the duration and severity of the same. 
- 
  total treatment with other antipsychotics. 
 
5 
CLINICAL TRIAL DESIGN. 
5.1 . DESCRIPTION OF VARIABLES 
The main variable is  the proportion of patients diagnosed with delirium (number of delirium 
cases/total number of patients) in the first 4 postoperative days.  We will use  a validated scale   
based on the DSM-IV definition of delirium,  CAM: Confusion Assessment Method scale  
(17,24-27). 
 
The secondary variables are: 
1. Numberof days from the start of treatment to the onset of delirium, if it appears. 
2. duration of delirium, in days. 
3. severity of theirium measured with validated scale (DRS-R-98). 
4. D  Total osis (mg) haloperidol or another antipsychotic tocontrol the symptoms of 
delirium. 
5. Security Costs: 
- 
Sedation degree: using RASS scale. 
- 
QTc prolongation: increase in mseg in the control ECG. 
- 
presence or absence of  extrapyramidal symptoms (tremor, involuntary 
movements, rigidity).  
6. Days ofhospital stay ofthe surgical intervention. 
7. perceived quality of life (through validated questionnaire SF36 or SF 12) 28±2 days 
after initiation of treatment. 
8. mortality from all causes at discharge and 28±2 days after initiation of treatment. 
 
Additional variables that will also be collected: 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
16 
 
 
 
 
- 
Baseline variables: demographic data,  comorbidity, ASA classification,  preoperative 
medication (sleep medication, antidepressants, opiates, corticosteroids), vital signs, 
previous  baseline analysis with CRP, previous physical function (independent for 
daily life activities-Barthel index), previous cognitive function (assessed with 
MINIMental). 
- 
 Intraoperative variables: type of intervention and specialty, type of anaesthesia, 
intraoperative medication  related in previous studies with delirium, duration of 
anaesthesia (min), anesthetic depth and regional cerebral oxygen saturation 
whenever possible, blood  transfusion, degree of pain ( by VAS scale) and 
postoperative medication related in previous studies with delirium and / or  analgesic 
techniques usedin this period. 
- 
Complications not associated with delirium that require medical intervention (from 
grade II on the Clavien-Dindo scale  – ANNEX 5).  They will be collected  at the time 
of the patient's discharge and 28± 2 days after the start of treatment, in percentage.  
They must be registered in the corresponding section of the CRD, indicating the start 
date and severity according to the Clavien-Dindo scale. The list of complications to be 
collected is detailed in ANNEX 6 of this protocol. Inaddition, all those events that in 
the opinion of the researcher are relevant to the development of the study and patient 
safety should be collected.  
 
5.2 STUDY DESIGN AND CONTROL METHOD. 
Prospective  low-intervention,  non-commercial, balanced, randomized, double-blind clinical 
study  (phase III).  
 
5.3 PATIENT ASSIGNMENT AND IDENTIFICATION CODES. 
Patientswill be identified with a code  that will be generated with protocol code (QUEPRO) + 
correlative number, according to orrdin inclusion in the study.  Example: The first patient 
included in the trial will receive the identification code QUEPRO-001; the second QUEPRO-
002 and so on. 
Once the patient accepts participation in the study by signing the informed consent, his 
participation has been correctly recorded in his medical history and it has been verified that 
he meets all the inclusion criteria and none of the exclusion criteria, the subject will be 
assigned an identification code and will be centrally randomized by the sponsor with a 1:1 ratio 
in one of the two arms of the study,  placebo (control group) or quetiapine (experimental group) 
in a consultation prior to surgery (selection visit), in such a way that proportional groups with 
equal probability of permanence are generated. 
 
5.4 DESCRIPTION OF TRIAL TREATMENTS 
Quetiapine is a drug belonging to the group of atypical antipsychotics with extensive 
experience of use in humans. Generic presentation is currently available. The smallest dose 
marketed in Spain is 25 mg in the form of film-coated tablets whose composition is: 25 mg 
quetiapine as quetiapine fumarate and 18.5 mg lactose as excipient.  It is administered orally 
or enterally by crushing it previously. 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
17 
 
 
 
 
For the realization of this clinical trial we will use doses of 25 mg every 12 hours for 3 days, 
so the total dose used per patient will be 150 mg of quetiapine.  
 
Adverse reactions reported for quetiapine:  
According to the Summary of Product Characteristics published by Normon S.A. revised in 
July 2018, themost frequently reported adverse drug reactions (ADRs) with quetiapine (≥10%) 
are drowsiness, dizziness, dry mouth, headache, withdrawal symptoms (discontinuation), 
elevated serum triglyceride levels, elevated total cholesterol (predominantly LDL cholesterol),  
decreased HDL cholesterol, weight gain, decreased hemoglobin, and extrapyramidal 
symptoms.  ANNEX 7 details the ADRs associated with quetiapine treatment and their 
corresponding indications.  The frequencies of adverse events are classified as Very common 
(≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), 
very rare (<1/10,000) and not known (cannot be estimated from the available data). 
 
The placebo is prepared in hard gelatin capsules in such a way  that the capsules are identical 
to those containing  active ingredient so that it is impossible to differentiate. Placebo consists  
of microcrystalline cellulose and magnesium stearate. 
 
5.5 MASKING TECHNIQUES AND OPENING OF MASKING CODES. 
This work is designed as double-blind, so that neither the patient nor the  researcher know the 
branch of the study assigned to each patient.  
At the pre-intervention screening visit,  the patient is assigned a code (identification code) and 
randomization is performed, all centrally.   Upon arrival at Resuscitation / Post-anesthetic 
Recovery Unit after the intervention, the pharmacy is requested  to prepare the medication 
corresponding to that code. The preparation will be  marked as quetiapine/placebo, which will 
be what the doctor in charge of the patient's care writes in the treatment orders, thus respecting 
the masking. The active drug/placebo will be coated with an identical gelatin capsule so that 
neither the patient nor the patient's attending physician can identify which of the products they 
are administering. 
The cecum will be maintained until after the data analysis is performed. The blind for a specific 
patient should only be broken when information about the patient's treatment protocol is 
considered necessary  and essential.  The unmasking procedure shall be requested only by 
the principal investigator and/or his/her representative and with the consent of the sponsor.  If  
an urgent intervention is necessary so as not to compromise the safety and/or life of the 
patient, the blind can break without the  express authorization of the sponsor, but must be 
notified within a maximum period of 24 hours. 
 
5.6 IDENTIFICATION OF THE DATA TO BE RECORDED. 
The patient data necessary to obtain the primary, secondary and complementary variables will 
be collected in the paper data collection notebooks (CRD) and must be documented in 
accordance with the guide of Good Clinical Practice, confidentiality and data protection law.  
The data included in the CRD, which are derived from source documents, must be consistent 
with those documents or otherwise justify the discrepancies. 
Retention of documentation: the investigator will keep the original clinical documents of  each 
patient in the study, which consist of all medical and demographic information including 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
18 
 
 
 
 
laboratory data, electrocardiograms, etc., and a copy of the signed informed  consent form, 
for as long as established by the legislation in force after the end or suspension of the study. 
Uponsigning the protocol, the researcher agrees to follow the procedures for preserving 
documents. 
 
5.7 END OF ESSAY 
The end of the trial will be considered the day of the final visit of the last patient included in 
the study. 
6 
PATIENT SELECTION AND WITHDRAWAL 
6.1 INCLUSION CRITERIA. 
Patients older than or equal to 65 years of age who are going to undergo major non-cardiac  
surgery  and who have a score equal to or greater than 5 on the Delphi scale:  
- 
Age: 70-79 years: 1 point; >80 years: 2 points. 
- 
Physical activity: need for assistance, not self-sufficient: 2 pointss 
- 
Alcoholism: 1 point. 
- 
Hearing deficit: 1 point. 
- 
History of delirium: 2 points. 
- 
Urgent surgery: 1 point. 
- 
Non-laparoscopic surgery: 2 points. 
- 
Admission to Critical Units: 3 points. 
- 
 C-Reactive Protein (CRP) value > 10 mg/dL: 1 point. 
6.2 EXCLUSION CRITERIA. 
× 
the lergia the quetiapine. 
× 
lactose intolerance. 
× 
patients with a score of less than 5 on the Delphi scale. 
× 
Diagnosis of delirium on admission. 
× 
Cardiological diseases: QTc >460 msec in men, >470 msec in women, AMI or recent 
cardiac decompensation, AV block 2-3º or history of torsades de pointes arrhythmias or 
ventricular arrhythmias, bradycardia (<45 bpm). 
× 
hipopotasemia <3 mEq/CLK. 
× 
history of drug use. 
× 
Patients on antipsychotic or antidopaminergic treatment (chlorpromazine, clozapine, 
olanzapine, risperidone, haloperidol, quetiapine, paliperidone, amisulpride). 
× 
Parkinson's disease. 
× 
Minimental < 24. 
× 
vascular dementia or Levi's bodies. 
× 
Disorder of movements hipokinéticos. 
× 
History of neuroleptic malignant syndrome. 
× 
Central anticholinergic syndrome. 
× 
epilepsy. 
× 
patients weighing   less than  50 or more than 200 kg. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
19 
 
 
 
 
× 
Patients participating in or having participated in a study of an investigational drug or 
device within four weeks prior to administration of the first dose of study treatment. 
 
6.3 NUMBER OF PATIENTS. 
Taking into account the current published literature, the estimated incidence of delirium in this 
type of population is 20-25%(2). We consider that a reduction in the absolute risk of delirium 
of 12% is clinically relevant  , being similar to the reduction of absolute risk with non-
pharmacological measures (10).  Therefore, a sample size  of  350 patients  is estimated, with  
175 subjects per treatment branch (significance level 95%, power 80%, expected losses of 
5%).  
 
6.4 EXPECTED CRITERIA FOR WITHDRAWAL OF STUDY SUBJECTS. 
1. Voluntary patient abandonment: patients have the right to withdraw from the study at 
any time and for any reason, being able to express it personally or through their 
representative. 
 
2. By medical criteria (safety and efficacy): 
a. Admission to critical care units for postoperative complications. 
b. Significant prolongation of the QTc interval: prolongation greater than 60 
miliseconds or QTc greater than 500 msec (1.28) during the study or 
appearance of ventricular tachycardias / torsades de pointes. 
c. When, for any reason, the treatment is no longer safe for the patient (for 
example, the patient has an allergic reaction to it), it may aggravate his 
disease, endanger his life or have serious consequences for him. 
 
3. For non-compliance or violation of the rules contained in the protocol: when the patient 
no longer complies with the rules or proceduresestablished in this protocol or there is 
loss of follow-up. 
6.5 FOLLOW-UP OF STUDY PATIENTS. 
The monitoring of the pacientis will be done from the signing of the informed consent (CI) until 
the last view marked by protocol. In the case of retired patients, follow-up will be done until the 
date of withdrawal that will be documented in the clinical history with the reason for it, 
whenever possible, and a premature withdrawal visit will be made.   
 
6.6 PREMATURE DISCONTINUATION OF THE STUDY. 
This study may be stopped prematurely if in the opinion of the sponsor or regulatory authorities 
there is sufficient reasonable cause. The investigator will receive written notice that the 
terminating party documents the reason for the suspension of the study.  
The circumstances justifying the suspension of the present study include, but are not limited 
to:  

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
20 
 
 
 
 
a) Identification of unforeseen, significant or unacceptable risks to patients.  
b) Inability to enroll an acceptable number of patients.  
c) Insufficient compliance with protocol requirements.  
d) Plans for modification, suspension or discontinuation of study drug development.  
e) Administrative reasons that the promoter could not solve with the health authorities.  
 
If the trial ends early or is suspended for any reason, the investigator shall promptly inform the 
trial subjects, ensuring appropriate treatment and follow-up of the trial and, where required by 
applicable law, inform the regulatory authority. 
If the investigator terminates or suspends a trial without the prior agreement of the sponsor, 
he or she shall promptly inform the institution, and the investigator/institution shall promptly 
inform thesponsor  and the CEIm and provide them with written justification of the cause of 
such termination or suspension. 
If the sponsor terminates or suspends a trial, the investigator must inform the institution where 
the trial is conducted and the investigator/institutionmust promptly inform  the CEIm by 
providing written justification of the reasons for the termination or suspension. 
If the Ethics Committee (CEIm)  terminates or withdraws the favourable opinion of a trial, the 
investigator shall inform the institution and the  investigator/institution shall promptly inform the 
sponsor and provide written justification for the cause oftermination or suspension. 
7 PATIENT TREATMENT. 
7.1 CLINICALTRIAL MATERIALS. 
The active drugwill be supplied by the promoter (IBSAL). 
The manufacture of the medication will be entrusted to an independent company 
(LABORATORIUM SANITATIS, S.L.)  which will generate identical capsules for active drugs 
and placebo under rules of good manufacture of medication according to current legislation.  
Subsequently, they will be sent  to the pharmacy service of the C.A.U.S.A.  Theperson in 
charge of dispensing the medication will be the only one who knows if the treatment is the 
active drug or is the placebo.  All the medication that the patient will receive together will be 
dispensed, in a bottle containing the 6 corresponding capsules.  The treating physician will 
leave reflected in the treatment orders: administrar quetiapine/placebo 1 capsule orally every 
12 hours. The first  dose of active drug/placebo will be administered  60 minutes after arrival 
at the resuscitation unit and every 12 hours thereafter for the first 3 postoperative days. 
 
7.2 SCHEDULE OF VISITS AND PROCEDURES.  
 
See Figure 1: Outline procedures in each visit. 
 
I. 
Pre-selection visit: where the patient is selected by assessing the inclusion and exclusion 
criteria. Itwill explain what the clinical trial consists of and give youthe documentation 
(information sheet and informed consent). 
 
II. 
Selection visit: it will be carried out during the pre-anesthesia consultation or the day 
before the surgical intervention. Thefollowing procedures shall be carried out: 
- signature of CI. 
- Verification of compliance with selection criteria. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
21 
 
 
 
 
- Demographics.  
- Relevant medical history: Preoperative comorbidity.  
- ASA classification. 
- Preoperative medication: sleep medication, antidepressants, opiates, 
corticosteroids... 
- vital signs. 
- complete analysis with PCR. 
- previous physical function: independent for activities of daily living (Barthel 
index). 
- Basal cognitive function (valued with MINIMental o 6 ICT). 
- CAM scale. 
- ECG and QTc measurement.  
 
III. 
Postoperative visits: A daily personal clinical visit will be made to all randomized patients 
during the first four days of the postoperative period or during the duration of their 
admission if it is less than 4 days.  In this case, the last visit during admission will be the 
visit to discharge.  
Theseclinical visits will be listedin corresponding to the postoperative day: visit 1st day 
post, visit 2nd day post... so on until the 4th postoperative day.  
 
Procedures to be performed: 
- CAM scale. 
- RASS scale. 
- Extrapyramidal symptoms. 
- vital signs.  
- ECG and QTc measurement (after administration of the 4th dose). 
- Complete laboratory tests (at least one during the first four days after surgery). 
- VAS scale and analgesia received (opiates). 
 
In addition, during the 1st postoperative visit, the intraoperative variables will be 
collected: 
- Type of surgical intervention and specialty. 
- urgent ly programmed. 
- anesthetic technique performed. 
- Drugs used, doses and routes of administration(benzodiazepines,  opiates, 
glucocorticoids, atropine). 
- Measurement of anesthetic depth and/or regional brain oxygen saturation 
where possible. 
- Duration anesthesia . 
- EVA upon admission to URPA/Resuscitation. 
- Analgesia: IV or by regional techniques( drug used, dose and administration). 
- blood transfusion. 
 
If the patient develops delirium , the daily visit will continue until the clinic disappears. In 
this case, the following will also be collected: 
- severity of the picture using DRS scale -R- 98 
- Drug used for its treatment, dose and route of administration. 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
22 
 
 
 
 
IV. 
Discharge visit: when the patient meets criteria and is discharged.  The following will be 
collected: 
- Reason for hospital discharge. 
- CAM. 
- RASS. 
-  vital signs. 
- Extrapyramidal symptoms. 
- Hospital evolution including complications that have appeared and that have 
required medical treatment (≥ grade II Clavien-Dindo scale): blood 
transfusion, surgical reoperation, pneumonia ... . 
- mortality. 
- complete anal itatic if it has not been collected in the postoperative visits. 
- If you have developed delirium:  
× duration. 
× Severity. 
× Dosage and route of administration of the drug used for its treatment. 
 
V. 
Premature withdrawal visit: all patients who, regardless of the cause and phase of  the 
study in which they are, prematurely and permanently stop treatment, must complete the 
premature withdrawal visit, which will take place in the following 24-48 hours from the 
time the withdrawal is known.  During the same the following procedures will be carried 
out: 
- reason de premature interruption. 
- vital signs. 
- CAM. 
- RASS. 
- sextrapyramidal symptoms. 
- Hospital evolution including complications that have appeared and that have 
required medical treatment (≥ grade II Clavien-Dindo scale): blood 
transfusion, surgical reoperation, pneumonia ... . 
- if you have developed delirium:  
× duration. 
× severity. 
× Dosage and route of administration of the drug used for its treatment. 
 
 
VI. 
Final visit: It will be carried out at 28± 2 days from the start of treatment.  A personal, 
telephone or mail follow-up will be carried out   to determine the vital status (mortality) 
and quality of life in relation to health through the SF 36 questionnaire. Complications that 
have appeared during this period and that have required medical treatment (≥ grade II 
Clavien-Dindo scale) will  also be collected. 
 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
23 
 
 
 
 
 
Figure 1: Outline procedures in each visit.  * At least one complete analysis during the period of 
admission. 
 
 
7.3 CONCOMITANT AND PROHIBITED TREATMENTS 
All types of anesthetic drugs and analgesic techniques are allowed according to the needs of 
each patient, and  must be reflected in the data record book: the anesthetic technique 
performed, the anesthetic depth and regional brain oxygen saturation, if it has been possible 
to measure it, and the drugs used that in previous studies have been related to delirium 
(benzodiazepines,  opiates, corticosteroids and atropine). 
The use of drugs for adequate control of pain, heart rate and blood pressure is recommended 
as needed, including opioids and regional analgesic techniques, leaving the drug used 
recorded. 
According to the Technical Label ofthe investigational medicinal product, concomitant 
administration of cytochrome P450 3A4 inhibitors, such as HIV protease inhibitors, azole-type 
antifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated. 
Considering the main effects of quetiapine on the central nervous system, quetiapine should 
be used with caution in combination with other centrally acting drugs and alcohol. 
Preselección
Selección
1 -post
2-post
3-post
4-post
Alta
Final          
(28± 2 días)
Retirada 
prematura
Criterios de selección
x
x
Entrega de 
documentación
x
Firma CI
x
Variables 
demográficas
x
Comorbilidad
x
ASA
x
Medicación 
preoperatoria
x
CAM
x
x
x
x
x
x
x
BARTHEL
x
MINIMETNTAL
x
ECG con QTc
x
x
RASS
x
x
x
x
x
x
Constantes vitales
x
x
x
x
x
x
x
Síntomas 
extrapiramidales
x
x
x
x
x
x
Variables 
intraoperatorias
x
EVA y analgesia 
x
x
x
x
Complicaciones no 
relacionadas con 
delirio
x
x
x
Mortalidad
x
x
SF-36
x
Datos analíticos
x
x*
x*
x*
x*
x
Severidad del delirio
x
x
x
x
x
x
Tratamiento del delirio
x
x
x
x
x
x
Duración del delirio
x
x
VISITAS

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
24 
 
 
 
 
In case of developing delirium,  the usual treatment will be carried out not intervening in it, 
leaving reflected in the CRD drug used and dosage.  In this case, if it develops during  the first 
3 days, the  study medication will be discontinued  . 
 
7.4 STORAGE, CONSERVATION AND DISPENSING OF MEDICATION 
Quetiapine is a drug already marketed and with generic presentation. For our work it will be 
supplied free  ofcharge by the promoter and manufactured by LABORATORIUM SANITATIS, 
S.L. 
The manufacturer of the medication, will send it to the pharmacy service of the C.A.U.S.A. that 
will be responsible forthe storage, conservation and  dispensing. 
It shall be stored and kept in accordance with the particularsspecified in the data sheet and 
as specified by the manufacturing undertaking.  The dispensing will be carried out following 
the randomization list provided by the promoter to the Pharmacy service. 
8 
N-ASSESSMENTOF EFFECTIVENESS 
 
8.1 EFFICACY VARIABLES. 
The efficacy of the treatment is given by the main variable: incidence of delirium during the 
postoperative period in the first 4 days in both intervention groups. 
The secondary variables will be collected: number of days free of delirium, duration and 
severity of delirium if it finally develops; hospital stay, adverse effects, mortality at discharge 
and 28± 2 days, perceived quality of life at 28± 2 days. 
8.2 EVALUATION METHODS. 
To obtain the main variable we will use the CAM scale (Confusion Assessment Method) as a 
method of diagnosis of the appearance of delirium. It is a scale based on the DSM IV definition 
of delirium (29) and with demonstrated internal and external validity for surgical patients 
(17,24-27). It consists of an interview of the clinician consisting of six items: two addressed to 
the closest caregiver (family member or nursing technician) with which information is obtained 
on the beginning of the picture and the presence of fluctuations. The remaining four items are 
to ask the patient, to determine their cognitive impairment that evaluates attention, thinking 
and consciousness. In the second part of the instrument, the clinician answers a questionnaire 
of 4 questions (yes / no), based on the evaluation made. The diagnosis of delirium is 
established around the presence of its two fundamental criteria (abrupt onset with fluctuations 
of symptoms and loss of attention) and one of the two secondary criteria (disorganized thinking 
and altered level of consciousness). We will use the same scale to rule out the presence of 
delirium in the initial assessment of the patient and to determine the duration of the picture 
during the follow-up period. The assessment of the response will be carried out daily in both 
study groups, during the first 4 days of admission or until the patient's discharge. 
We will use the RASS scale (Richmond Agitation sedation scale) to assess the degree of 
sedation or agitation presented by the patient. It is a 10-point scale, very intuitive in its 
description since the positive values indicate agitation and the negative values are used to 
quantify sedation, in such a way that level 0 corresponds to a calm and awake patient, level 4 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
25 
 
 
 
 
to the situation of maximum agitation and level -5 to the highest depression of the level of 
consciousness. It also has a good correlation with the appearance of delirium when the 
presence or absence of attention is detected (30). It will be administered prior to CAM during 
the follow-up period, if -4/-5 values are obtained, it will be repeated again after two hours until 
it decreases to -3 values onwards. In case of development of delirium, daily follow-up (through 
CAM and RASS scales) will be carried out until resolution of the patient's condition or 
discharge and the drugs used for symptom control and the necessary doses will be recorded 
in the CRD. 
The severity of delirium developed will be determined by the DRS-R-98  scale (31,32). Itis a 
scale of 16 items scored by the clinician with two sections (severity and diagnosis) and a score 
sheet. The 13 items in the severity section can be scored separately from the 3 items in the 
diagnostic section. The severity section functions as a standalone scale for repeated 
measurements during an episode of delirium. All items are accompanied by descriptions that 
serve as a guide for scoring along a continuum that moves between normality and severe 
involvement, scoring between 0 and 3. All available sources of information can be used for 
patient assessment: family, visitors, hospital staff, even the roommate can contribute more 
information. Some items are scored based on test and medical history, while others 
incorporate standardized questions (e.g., language and cognitive items). The items assessed 
are: circadian rhythm alteration, alteration in perception and hallucinations, delusions, affective 
lability, language alterations, alterations in the course of thought, agitation or motor slowdown, 
orientation, attention, short and long-term memory, visuospatial capacity. Only the severity 
section of the scale will be administered  once a day for as long as you develop delirium. 
At 28±2 days, the final visit (personal, telephone or email) will be made, reflecting the patient's 
vital status (mortality) and health-related quality of life, assessed through the SF-36 
questionnaire. It is a questionnaire that should preferably be self-administered, although it is 
also acceptable to administer it through personal and telephone interviews, not changing its 
internal consistency. It consists of 36 items covering 8 scales: physical function, physical role, 
body pain, general health, vitality, social function, emotional role, and mental health (33,34). 
 
9 
ADVERSE EVENTS. SAFETY ASSESSMENT. 
The researchers of the study will record the hospital evolution of the patients including complications 
and the treatments derived from them, both pharmacological and non-pharmacological through the 
daily visit to collect the variables during the first four days of admission or until hospital discharge. 
Safety oversight in the trial will comply with the provisions of Royal Clinical Trials Decree1090/2015 
on the registration, evaluation and reportingof adverse events (A A).  
The sponsor, through the principal investigator of the study, will assess Serious Adverse Events 
(SAAs) with the safety documents of the products and will notify those AGAs that meet expedited 
notification criteria (serious, unexpected and treatment-related), to the Health Authorities. The 
notification to the competent authorities (AEMPS, CEIm, competent bodies of the Autonomous 
Communities) and principal investigators of any notifiable event will also be the responsibility of the 
sponsor,who will do so  within the  time limits established by the Spanish regulations in force (namely: 
serious and unexpected adverse reactions (RAGI) will be notified within a maximum period of 15 
calendar days from when the sponsor becomes aware of it,  and within 7 days if the unexpected serious 
adverse reaction has resulted in death or endangering the subject's life).  

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
26 
 
 
 
 
 
9.1 DEFINITIONS. 
• 
Adverse Event (AA):  
Any incident harmful to health that occurs to a subject to whom a medicinal product 
has been administered, even if it does not necessarily have a causal relationship with 
it. 
 
• 
Serious adverse event (SAA):  
Any incident harmful to health which, at any dose, necessitates hospitalisation or 
prolongation, results in permanent or significant disability or disability, results in a 
congenital anomaly or malformation, endangers life or results in death. 
Interventions scheduled prior to study inclusion will not be considered as 
SAAs. Nor the complications derived from the surgical process itself. 
For reporting purposes, suspected AA or RA that is considered medically important 
but does not meet the above criteria, including major medical events requiring 
intervention to prevent any of the consequences described above, shall also be 
treated as serious. 
 
• 
Adverse reaction (AR):  
Any harmful and unintended response to a medicine. 
• 
Serious and unexpected adverse reactions (RAGI):  
A serious adverse reaction whose nature, severity or outcome is not consistent with 
the baseline safety information. 
 
9.2 QUALIFICATIONOF AN ADVERSE EVENT. 
The degree of intensity of anA A provides a qualitative assessment of the extent or intensity 
of an adverse event, determined by the investigator or reported by the patient. The degree of 
intensity does not reflect the clinical severity of the event, but only the degree or extent of grief 
or incidence (e.g., severe nausea, mild crisis) and does not reflect the relationship to study 
medication. 
 
• Degree of intensityof an adverse event 
The researcher will assess the intensity of A A and A AG. AA intensity will be rated on 
a scale of 1 through 5 according to the latest version of the National Cancer Institute 
(NCI) Common Toxicity Criteria for Adverse Events (CTCs), which are available online 
at NCI: http://ctep.cancer.gov/reporting/ctc.html. 
If a particular event is not listed on the NCI CTCAE toxicity scale, the following table will 
be used for classification: 
 
 
   Degree Definition  
 
 
n___ 
1 Mild.The patient reports the sign, symptom or event, which is usually temporary 
and does not require special treatment or interfere with usual 
daily activities.  
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
27 
 
 
 
 
2 Moderate. Discomfort that interferes with usual activities but usually improves 
with basic therapeutic measures. 
3 Intense.Incapacitates and does not make it possible to perform usual activities or 
that significantly affects the clinical state and guarantees 
therapeutic intervention. Hospitalization may or may not be 
necessary. 
4 Life-threatening. Risk of imminent death requiring hospitalization and clinical 
intervention.  
5 Death. 
 
 
 
• Relationship of adverse events and serious adverse events with study treatment.  
Imputability criteria. 
The sponsor will classify adverse events, based on their causal relationship with the 
drug, according to the Karch and Lasagna Algorithm (1977), as: 
• Definitive:• there is a reasonable time sequence between the administration of the 
drug and the appearance of AA. This event coincides with the RA described for the 
drug, improves with its suppression, reappears after its readministration and cannot 
be explained by alternative causes.  
• Probable:• there is a reasonable time sequence between drug administration and 
the onset of AA. This event coincides with the RAs described for the drug, improves 
after discontinuation of treatment and cannot be explained by other alternatives.  
• Possible:• there is a reasonable time sequence between the administration of the 
drug and the appearance of AA. This event coincides with the RA described for the 
drug but can be explained by alternative causes.  
• Conditional or •Unlikely: there is a reasonable time sequence between the 
administration of the drug and the appearance of AA. This event does not coincide 
with the ARs described for the drug and can be explained by alternative causes.  
• Unrelated:• there is no reasonable time sequence between drug 
administration and the onset of AA. This event does not coincide with the ARs 
described for the drug and can be explained by alternative causes.  
For expedited notification purposes, the definitive, probable and possible categories of 
Karch and Lasagna's (1977) algorithm will be considered as related and the conditional 
or improbable category of said algorithm as unrelated.  
The determination of the possible relationship to the treatment of the study is the 
responsibility of the principal investigator of the research center or the person 
designated by it. 
 
• Actions to be taken inresponse to an adverse event 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
28 
 
 
 
 
The measures to be takenbefore an RA are described on a numerical scale, from 0 to 
5, which covers different possibilities. One or more of them must be selected. 
0 =None 
1 =Temporary dose adjustment/interruption of study medication 
2 =Study medication is permanently discontinued due to AA 
3 =Concomitant medication administration 
4 =Administration of non-pharmacological treatment 
5 =Hospitalization/prolongation of hospitalization 
 
9.3 PROCEDURES FOR THE REGISTRATION OF AA. 
All serious adverse events (SAAs) occurring during the clinical trial from the  first dose  of 
the drug until 28±2 days thereafter will be recorded in the CRD. For serious adverse events, 
registration should be extended until the SAA is resolved or considered clinically stable at 
medical discretion 
. 
To the extent possible, each adverse event shall also be described in terms of: 
- 
its duration (start and end dates) 
- 
the degree of intensity (grade 1, 2, 3, 4 or 5) 
- 
the severity of AA (severe or non-severe) 
- 
Study drug(s) with which a causal relationship is suspected.  
- 
the action(s) taken. 
 
9.3.1 
Responsibility for notification. 
Any serious adverse events (SAAs) occurring afteradministration of the first dose and 
up to 28 days thereafter should be reported. 
The investigator shall inform the sponsor of the AAG without undue delay and within 
24 hours of becoming aware of such events, even if they do not appear to be related 
to the drug under study. The investigator shall, where appropriate, send the sponsor 
a follow-up report to enable the sponsor to assess whether the serious adverse event 
has an impact on the benefit-risk balanceof the clinical trial. 
All AGAs should be monitored until one of the following occurs: 
 
- 
Resolution of the event. 
- 
Stabilization of the event 
- 
Restoration of the baseline of the event, if a baseline value is available. 
- 
The event may be attributed to products other than the study medication or to 
factors unrelated to the conduct of the study. 
- 
Further information is unlikely (subject or primary care physician refuses to 
provide additional information, loss to follow-up after demonstration of due 
diligence with follow-up efforts) 
 
AllAGs that have not been resolved  at the end of the study, or that have not been 
resolved with withdrawal from study participation, will be monitored until any of the 
above situations occur. Thefollow-up information of an AG shall be communicated in 
the same manner as  the original Serious  Adverse Event, including the date of when 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
29 
 
 
 
 
the initial report was reported. The new information will be sent in a form from AAG 
(indicating that it is a follow-up and the new date noted). Follow-up should describe 
whether the event has resolved or continued, whether and how it was treated, and 
whether or not the patient remained in the study. Both the form and the shipping 
confirmation sheet must be archived.  
The cause of death of a subject in a clinical study, whether the expected event or not, 
and whether or not the event is relatedto the drug under study, is considered a serious 
adverse event communicable within 24 hours.  
The investigator should keep a copy of allinformation relating to AG.  
9.3.2 
Notification to Health Authorities and Ethics Committees. 
The sponsor will communicate to the competent Health Authorities (when appropriate) 
and to the Ethics Committees all the relevant information on serious and unexpected 
adverse reactions (RAGI) that are suspected to be related to the study drug and that 
are fatal or life-threatening, as soon as possible and in any case, within a maximum 
period of seven days from the moment the case is known. Follow-up information 
relevant to these cases shall subsequently be notified within a further period of eight 
days. 
For the evaluation of esperability , the quetiapine summary of product characteristics 
shall be used. 
The responsibility for assessing adverse events lies with the sponsor of the study, 
always taking into account the opinion of the investigator.  Each AAG should be 
evaluated for expectability, and if it is an unexpected AGR and should be notified 
accordingly.  
The annual safety reports that will include the RAGIs and AAGs collected in the study, 
will be sent by the sponsor to the AEMPS (Clinical Trials Area of the General 
Subdirectorate of Medicines for Human Use), to the CEIm and CCAA, within the 
deadlines established in current legislation.  
 
 
9.4 NUMBER AND CONTACT PERSON  IN TERMS OF PHARMACOVIGILANCE. 
 
In the event of a SAA that needs to be notified to the Pharmacovigilance Unit, or a case of 
pregnancy is collected, a member of the research team shall complete and sign the AAG or 
pregnancy notification form to be faxed immediately and always within 24 hours of becoming 
aware of the event to:  
PhD Patricia Rodríguez Fortúnez 
Head of Pharmacovigilance UICEC of the University Hospital of the Canary Islands 
Telephone: 922 678 117 Fax: 922 677 284 
Email: patricia.rodriguez@scren.es 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
30 
 
 
 
 
The Pharmacovigilance Unit shall review the form received and, if appropriate, request 
additional information from the investigator. Whenadditional information on the AAG is 
obtained, or resolves or is unlikely to change, a follow-up report should be completed and 
fax/e-mail also sent to the Pharmacovigilance Unit. 
 
10 STATISTICAL ANALYSIS 
 
A statistical analysis will be carried out after the development of a basis for the collection of patient 
data, by protocol and in accordance with the principle of "intention to treat". 
After identifying extreme data, a subsequent analysis will be carried out to assess the normality of the 
variables. All variables related to efficacy and safety will be analyzed for both treatment arms.  
Categorical variables shall be expressed in percentages and number of observations. Continuous 
variables shall be expressed as mean and standard deviation or medians and interquartile ranges (25 
– 75) and/or minimum and maximum. Relative risks of the estimated effect and its 95% confidence 
intervals shall be calculated and presented. For the comparison of categorical variables, the Chi-
square test or the Fisher's test will be used, when necessary. For the comparison of the continuous 
variables, the Student's "t" test or Mann-Whiteney U test will be used for both simple and paired data, 
or other non-parametric tests, if necessary. Multivariate and survival analyses will be used to determine 
whether the association between the intervention and theprimary (or secondary) objective is free from 
confusion. Covariates in each model will be considered as those that in the univariate analysis show 
a value of p <0.1 
All analyses will be performed with hypothesis contrast of 2 tails and a significance level of 5%. 
The statistical program used will be SPSS® 21.0. 
Intermediate analyses are not planned except those indicated by the Safety Committee in order to 
safeguard the health of patients included in the study. 
 
11 ETHICAL ASPECTS 
 
This clinical trial will  not  start until the Spanish Agency for Medicines and Health Products (AEMPs) 
and the  CEIm consider that all the conditions present in article 3 of RD 1090/2015 on the general 
requirements of clinical trials are met.  
This study should be developed in accordance with the protocol and the Good Clinical  Practice (GCP) 
standards, as described in: ICH Harmonized Tripartite Standards for Good Clinical Practice 
(CPMP/ICH/135/95), according to current Spanish legislation (RD1090/2015) and European  
regulation EU 536/2014 (Good Clinical Practice Standards for trials on medical devices in the 
European Community) . It will also be guided in accordance with the Declaration of Helsinki on Ethical 
Principles for Medical Research on Human Subjects, approved by the General Assembly of the World 
Medical Association (Fortaleza, Brazil, 2013) and taking into account the Oviedo Convention for the 
Protection of Human Rights and Dignity of the Human Being with regard to the Applications of Biology 
and Medicine,  as well as any other rules that may be applicable. 
It 
can 
be 
accessed 
through 
the 
website 
of 
the 
World 
Medical 
Organization 
http://wma.net/es/30publications/10policies/b3. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
31 
 
 
 
 
The researcher agrees, with the signature of this protocol, to follow the instructions and procedure 
described therein and therefore will comply with the principles of Good Clinical Practice on which it is 
based.  
11.1 INFORMED CONSENT 
The obtaining and content of informed consent will follow the provisions of Article 29 of 
Regulation (EU) No. 536/2014 of the European Parliament and of the Council, of April 16, 
2014, as  well as Articles 8 and 9 of Law 41/2002, of November 14, as set out in RD 
1090/2015 on clinical trials.  
The investigator must explain to each patient (or legally authorized representative) the nature 
of the study, its purposes, procedures, expected duration, and the potential risks and benefits 
associated with participating in the study, as well as any inconvenience the study may pose. 
Each participant should be advised that their participation in the study is voluntary and that 
they may leave the study at any time, without affecting their subsequent medical treatment 
or their relationship with the treating physician. Informed consent will be provided by means 
of a standard writing, in language easily understood by the participant. The patient must write 
his/her name and that of the reporting physician in  his/her own handwriting and  date and 
sign the informed consent, as well as receive a copy of the signed document. If the subject 
cannot read or sign the documents, an oral presentation may be made or the signature of 
the subject's authorized legal representative may be obtained, provided that it is witnessed 
by a witness not involved in the study and mentioned in the same document and/or medical 
history. No patient may be included in the study without prior informed consent.  
 
11.2  CONFIDENTIALITY / DATA PROTECTION. 
By signing the protocol, the researcher undertakes to keep all the information provided by 
the Sponsor in strict confidentiality and to insist on the maintenance of it by his team. The 
study documents provided by the Sponsor (protocols, data sheet, CRDs and other materials) 
must be kept appropriately to ensure their confidentiality. Information provided by the 
Sponsor to the investigator may not be disclosed to third parties without the direct written 
permission of the investigator, except to the extent necessary to obtain the informed consent 
of patients who wanted to participate in this trial.  Patients will be informed that all study data 
will be archived and treated in a strictly confidential manner, according to the Organic Law 
on the Protection of Personal Data (Organic Law 3/2018, of December 5, on the Protection 
of Personal Data and guarantee of digital rights) and its implementing regulations, as well as 
current European regulations on the matter.  
The monitor will also assume respect for this confidentiality when, in the course of the trial, 
it carries out the obligatory reviews and verifications of the study data. 
 
11.3  ACQUISITION AND DISPENSING OF THE MEDICATION UNDER STUDY. 
Quetiapine is a drug alreadymarketed and comes in generic form.  The promoter is 
responsible for supplying the drug under study, ensuring that the rules of good 
manufacturing, packaging and labeling have been met. 
It shall be stored and stored in accordance with theparticulars specifiedin the data sheet.  
The preparation will be carried out by the pharmacy service in accordance with the 
indications reflected in  the protocol in section 8.1.  

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
32 
 
 
 
 
All  unused and unaltered study drugs  may  be returned to whomever the sponsor 
designates or destroyed in the center's Pharmacy Service if authorized. Any of the 
procedures should be well documented. 
 
11.4  AUDIT AND MONITORING. 
Regulatory authorities, the CEIm, and the  sponsor or a designated representative may 
request access to all original documents, patient data collection notebooks, and other study 
documentation to conduct an on-site audit or inspection. The researcher must ensure direct 
access to these documents and collaborate at all times in carrying out these activities. In 
such procedures, due protection of private personal identification data will be attended to in 
accordance with the data protection law. 
Monitoring. 
Before starting the study, at the start visit of each center or at a meeting of researchers, a 
representative of the Sponsor will review the protocol and the data collection notebooks with 
the researchers and other personnel involved in the study.  During the study, the monitor will 
regularly visit the center, to compare  the data collected in the CRD with the source 
documents, check adherence to the protocol and the Standards of Good Clinical Practice. 
The investigator and trial personnel should be available to assist the monitor during these 
visits.  
No data revealing the identity of patients should leave the participating center.  
 
11.5  FAILURE TO COMPLY WITH PROTOCOL. 
Serious breaches of the authorised protocol should be reported to the sponsor without undue 
delay and at the latest within three calendar days from the date on which it became aware 
of the non-compliance. The sponsor will communicate it to the Spanish Agency of Medicines 
and Health Products and the CEIm. For these purposes, a serious non-compliance is one 
that may significantly compromise the safety and rights of the subjects or the reliability and 
robustness of the data obtained in the clinical trial.  
Where immediate deviation from the protocol is required to avoid immediate risks to patients, 
the investigator shall contact the sponsor, circumstances permitting, to discuss planned 
action. Any deviation from the protocol should be documented in detail in the CRD and in  
the original documentation. 
 
12 FINANCINGAND INSURANCE 
This is a non-commercial study. The trial will be funded for the most part by the Spanish Multimodal 
Rehabilitation Group. In addition, thepromoter will try to obtain funding through several calls and / or 
public scholarships to  cover the expenses associated with the implementation and development of 
the study that may not be covered  as well as obtain necessary material for it. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
33 
 
 
 
 
 
Sure. 
Because the clinical trial has been requested as a low-intervention clinical trial, the sponsor takes 
advantage of the insurance coverage established by RD 1090/2015, of December 4, for this type of 
trial. 
 
13 PUBLICATION POLICYN 
13.1  PUBLICATION OF RESULTS. 
Both positive and negative results of  this clinical trial will be communicated in scientific 
congresses and/or published in scientific  journals, regardless of the obligations to publish 
the report of the results in the Spanish Registry of Clinical Studies (REec) and the provisions 
of Regulation (EU) No 536/2014 of the European Parliament and of the Council,  of 16 April 
2014. 
The final results of the trial and a manuscript of the publication will be sent by the coordinating 
investigator of the trial to the sponsor at least 60 days before their submission for publication. 
Posters, abstracts or other oral or written material related to the trial will also be 
communicated to the sponsor at least 5 days before submission. 
 
13.2  AMENDMENTS TO THE PROTOCOL. 
All changes to the protocol will be specified in the form of an amendment. The method of 
carrying out the amendments will follow the standardized procedures according to 
RD1090/2015. The protocol should not be modified without the consent of both the 
coordinating investigator and the sponsor. 
 
 
14. BIBLIOGRAPHY 
 
1. 
Wang W, Li HL, Wang DX et al. Haloperidol prophylaxis decreases delirium incidence in elderly 
patients after noncardiac surgery: A randomized controlled trial. Crit Care Med 2012;40 (3):731-
739. 
2. 
Avidan MS, Fritz AB, Maybrier HR. The prevencion of delirium and complications associated 
with surgical treatments (PODCAST) study: protocol for an international multicenter randomized 
controlled trial. BMJ open 2014;4:e005651 
3. 
Hawkins SB, Bucklin M, Muzyk AJ. Quetiapine for the treatment of Delirium. Journal of Hospital 
medicine 2013;8: 215-220 
4. 
Fok MC, Sepehry AA, Frisch L. Do antipsychotics prevent postoperative delirium? A systematic 
review and meta-analysis. Int J Geriatr Psychiatry 2015;30: 333-344. 
5. 
Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of 
sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30:119-141. 
6. 
Cook IA: Guideline Watch: Practice guideline for the treatment of patients with delirium. 
Arlington, VA: American Psychiatric Association, 2004. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
34 
 
 
 
 
7. 
Devlin JW, Roberts RJ, Fong JJ, et al . Efficacy and safety of quetiapine in critically ill patients 
with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot 
study. Crit Care Med  2010; 38:419-427. 
8. 
Delirium: Diagnosis, prevention and management CG103. London. National Institute for Health 
and Clinical Excellence,2010. 
9. 
 Schrijver EJM, De Vries OJ, Verburg A. Efficacy and safety of haloperidol prophylaxis for 
delirium prevention in older medical and surgical at-risk patients acutely admitted to hospital 
through the emergency department: study protocol of a multicenter, randomised, double-blind, 
placebo-controlled clinical trial. BMC Geriatrics 2014, 14:96. 
10. Kalisvaart KJ, De Jonghe JFM, Bogaards MJ. Haloperidol Prophylaxis for Elderly Hip-surgery 
patients at risk for delirium: A randomized Placebo-controlled study. J Am Geriatr Soc 53:1658-
1666,2005. 
11. Larsen KA, Min D, Kelly SE, et al. Administration of olanzapine to prevent postoperative delirium 
in elderly joint-replacement patients: a randomized, controlled trial.  Psychosomatics 2010; 
51(5):409–18. 
12. Fukata S, Kawabata Y, Fujisiro K, et al. Haloperidol prophylaxis does not prevent postoperative 
delirium in elderly patients: a randomized, open-label prospective trial.  Surgery Today 2014; 
44(12): 2305–13. 
13. Tahir TA,Eeles E, Karapareddy V, et al. A radomized controlled trial of quetiapine versus 
placebo in the treatment of delirium. Psychosom Res 2010;69:485-490. 
14. Maneeton B, ManeetonN, and Srisurapanont M, et al. Quetiapine versus haloperidol in the 
treatment of delirium: a double-blind, randomized, controlled trial. Drug Design, Development 
and Therapy 2013:7 657-667. 
15. Daley B. Quetiapine for delirium prophylaxis in High-risk Critically ill patients. ClinicalTrials.gov 
Identifier: NCT02612948. 
16. Prophylactic quetiapine on delirium Prevention in Critically ill patients. clinicalTrials.gov 
Identifier: NCT02297763. 
17. Schenning KJ, Denier SG. Postoperative delirium in the geriatric Patient. Anesthesiology Clin 
2015; 33: 505-516 
18. Noimark D. Predicting the onset of delirium in the post-operative patient. Age and ageing 
2009;38:368-373. 
19. Leungg,JJ. An update on delirium in the postoperative setting: prevention, diagnosis and 
management. Best pract res clin anaesthesiol 2012;26(3): 327-43. 
20. Dasgupta M, Drumbell AC. Preoperative risk assessment for delirium after noncardiac surgery. 
A systematic review. J am Geriatr Soc 2006;54:1578-1589. 
21. Kalisvaart KJ, Vreeswijk R,De Jonghe JFM. Risk Factors and Prediction of Postoperative 
Delirium in Elderly Hip-Surgery Patients: Implementation and Validation of a Medical Risk Factor 
Model. J Am Geriatr Soc 2006; 54: 817–822. 
22. Harasawa N, Mizuno T. A novel scale predicting postoperative delirium (POD) in patients 
undergoing cerebrovascular surgery. Archives of gerontology and geriatrics 2014: 59;  264-271 
23. Min young K, Ui Jun Park, Hyoung Tae K. Delirium Prediction Based on Hospital Information 
(Delphi) in general surgery patients. Medicine 95(12): e3072. 
24. Inouye SK, Van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI Clarifying confusion: the 
confusion assessment method. A new method for detection of delirium. Ann Intern Med. 
1990;113(12):941–948. 
25.  Wong CL, Holroyd-Leduc J, Simel DL, Straus SE. Does this patient have delirium? : value of 
bedside instruments. JAMA. 2010; 304(7):779–786. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
35 
 
 
 
 
26. Steiner LA. Postoperative Delirium. Part 2: detection, prevention and treatment. Eur J 
Anaesthesiol 2011;28:723-732. 
27.  Rathier MO, Baker WL. A Review of Recent Clinical Trials and Guidelines on the Prevention 
and Management of Delirium in Hospitalized Older Patients. Hospital Practice 2011, 39:4, 96-
106. 
28. Roden DM. Drug induced prolongation of the QT interval. N Engl J Med2004;350:1013-22. 
29. American Psychiatric Association. Diagnostic and Statistical Manual of mental disorders 4th ed. 
Text revision. Washington , DC: American Psychiatric Press; 2000. 
30. Chamorro c, Martínez-Melgar JL, Barrientos R. Monitoring sedation. Intensive Med 2008; 32, 
suppl1:45-52. 
31. Trzepacz PT, Mittal D, Torres R. validation of the delirium Rating Scale-revised-98: Comparison 
with the delirium rating scale and the cognitive test for delirium. J neuropsychiatry Clin neurosci 
2001;13: 229-242. 
32. Fonseca F, Bulbena A, Navarrete R. Spanish version of the delirium rating scale-revised-98: 
reability and validity. J Psycho res 2005 ;59: 147-151. 
33. López-García E, Banegas JR, Graciani Pérez-Regadera A.   Reference values of the Spanish 
version of the SF-36 Health questionnaire in the adult population over 60 years of age. MED 
Clin (Barc) 2003;120: 568-73. 
34. Vilagut G, Ferrer M, Rajmil L. The Spanish SF-36 health questionnaire: a decade of experience 
and new developments. Gac sanit 2005; 19(2):135-50. 
35. Karch F, Lasagna L. Toward the operational identification of adverse drug reactions. Clin 
Pharmacol Ther. 1977 Mar;21(3):247-54. 
 
 
 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
36 
 
 
 
 
ANNEX 1 
STOPOVER CAM-S 
This instrument consists of two parts: an interview with questions to be asked to the patient and his 
closest caregiver (familymember and/or nurse) and a set of questions that the clinician must 
answerbased on the evaluation carried out. 
 
Part One (interview) 
A. Ask the closest caregiver (family member and/or nurse): 
A1. "Have you noticed any changes in patient behaviorin the last 24 hours?"  ( 
assessbehavioral and/or mental cambios) 
YES NO 
 
A 2. "These changes, do they vary throughout the day?"  (assess fluctuations in the course of 
the day)  
YES NO 
 
 
B. Ask the patient: 
B1. "Tell us why you are admitted here. 
"Do youfind me currently?" 
Let the patient talk for one minute. 
Is the patient unable to follow the course of the conversation and give 
Andclear and logical explanations?  
 
OTHERWISE  
B2. "Tell me: the day, the date, the m is, the season of the year  , and the year we are in now." 
Is there more than one wrong answer?  
OTHERWISE  
B3. "Tell me the hospital (or  place), plant (or service), city, province and country." 
Is there more than one wrong answer?  
OTHERWISE  
B4. "Repeat these numbers: 5-9-2 , now repeat them backwards" 
Is the answer wrong?  YES  
NO 
 
Part Two (phase in which the clinician must respond to what is observed to define the 
presence or absence of Delirium) 
1. The patient presents with a change in baseline mental status of acute onset and 
fluctuating course throughout the day. 
To answer rely on Item A.1 and A.2. YES--- NO--- 
2. The patient has difficulty maintaining attention, is easily distracted . 
To answer based on item B.1 and B.4 YES--- NO--- 
3. The patient presents a disorganized thought. 
It will be positively valued if at any timeof the interview there is difficulty in organizing the 
thoughts reflected in: 
Frequent topic changes 
S.A.D.  
Interruptions or disconnections of speech 
Loss of speech logic (confused and/or delusional speech) 
To answer rely especially on item B.1. YES--- NO--- 
4. The patient presents alteration of the level of consciousness: 
Alteration of consciousness is considered to be any alteration of the ability to react 
appropriately to stimuli. 
Vigil (normal consciousness) 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
37 
 
 
 
 
S.A. Hyperalert (vigilant, hyperreactive) 
 
Sleepy (falls asleep easily) 
Stupor (responds to verbal stimuli) 
A coma (responds to painful stimuli) 
To answer based on item B.1- B.2 and B.3 YES--- NO--- 
Algorithm: The instrument will be positive for Delirium if in the second part the first two 
items and the third or fourth are positive. 
 
DELIRIUM: YES NO 
 
 
 
 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
38 
 
 
 
 
ANNEX 2 
RICHMOND AGITATION AND SEDATION SCALE: RASS 
 
 
Score Term Description 
 
 
 
+4  
 
Combative Combative,  
 
violent, immediate danger to the 
group  
 
 
 
 
 
+3 
 
Very agitated   
The tubes or catheters are removed; aggressive 
+2  
 
Agitated  
 
Frequent and purposeless movement, struggle  
 
 
 
 
 
with fan 
+1 
 
Restless  
 
Anxious but no aggressive or vigorous movements
 
 
 
 
 
 
 
0  
 
Alert and calm 
-1  
 
Drowsy 
 
Not fully alert, but stays  
 
 
 
 
 
awake  (openingand eye contact) to the  
 
 
 
 
 verbal  call (≥ 10 seconds) 
-2  
 
Mild sedation   
Briefly wakes up to the verbal call with   
 
 
 
eye  
contact (< 10 seconds) 
-3  
 
Moderate sedation  
Eye movement or opening at theverbal   
 
 
 
 
call (but no eye contact) 
-4  
 
Deep sedation  
No response to verbal call, but there is   
 
 
 
 
eye movement or opening to the physical stimulus 
-5 No   
response  
 
No response to voice or physical stimulus. 
 
If RASS is -4 or - 5, stop and reassess the patient later. 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
39 
 
 
 
 
ANNEX 3 
DELIRIUM RATING SCALE-REVISED-98 
 
ITEMS OF SEVERIDAD. 
1. Disruption of the circadian rhythm. 
Value the sleep-wake pattern using all sources of information, including family, caregivers, 
nursing information and the patient himself. Try to distinguish sleep from rest with your eyes 
closed. 
0. Do not present. 
1. Slight disturbance of sleep continuity during the night or occasional daytime sleepiness. 
2. Moderate disorganization of the sleep-wake rhythm (e.g. falling asleep during 
conversations, taking naps during the day or several brief awakenings during the night with 
confusion or changes in behavior or little sleep time during the night). 
3. Severe: alteration of the sleep-wake cycle (e.g. reversal of the sleep-wake cycle, or 
circadian fragmentation with multiple periods of sleep and wakefulness or severe 
insomnia). 
2. Alterations of perception and hallucinations. 
Illusions and hallucinations can belong to any sensory modality. Alterations in 
sensoperception are "simple" when they do not have a single dimension, such as a sound, 
noise, color, spot, or lights, and can be "complex" when they are multidimensional, such as 
voices, music, people, animals, or scenes. Note if they are referred by the patient or caregiver 
or if they are inferred during observation. 
0. In the gifts. 
1. Slight perceptual alterations (e.g. feelings of derealization or depersonalization, or the 
patient cannot distinguish dreams from reality). 
2. Presence of illusions. 
3. Presence of hallucinations. 
3. Delusions. 
Delusions can be of any kind, but persecutory delusions are more frequent. Write down if 
they are referred by the patient, family, or caregiver. Value as delusional ideas that are 
unlikely to be true and that the patient presents an absolute certainty of their veracity and 
that resistance cannot be overcome with logical argumentation. Delusions cannot be 
explained by the patient's cultural context or religious background. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
40 
 
 
 
 
0. Do not present. 
1. Slightly suspicious, hypervigilant or worried. 
2. Unusual or overrated ideas that do not reach delusional proportions or may be plausible. 
3. Delusions. 
4. Affective lability. 
Value the patient's affection as the form of manifestation and not a description of how the 
patient feels. 
0. Absent. 
1. Affection slightly altered or incongruous with the situation; changes during the course of 
hours; Emotions are basically under control. 
2. Affection is generally inappropriate to the situation and changes intermittently within 
minutes; Emotions are not under control although they can be directed by others. 
3. Disinhibition of emotions in a severe and consistent way; Affection changes rapidly, is 
inappropriate to the context, and cannot be directed by others. 
5. Language. 
Assess abnormalities of oral, written or sign language that cannot be attributed to dialect or 
stuttering. Research fluency, grammar, comprehension, semantic content and naming. 
Value comprehension and naming non-verbally if necessary by administering commands 
that the patient should follow or point to objects. 
0. Normal language. 
1. Slight alteration including difficulties in finding words or naming or fluency problems. 
2. Moderate alteration including difficulties in understanding or deficits in communication 
(semantic content). 
3. Severe alteration including meaningless semantic content, "word salad", mutism or 
severely reduced understanding. 
6. Alteration of the course of thought. 
Assess the alterations of the course of thought based on verbal or written language. If the 
patient does not speak and write, do not rate this item. 
0. Normal course of thought. 
1. Tangential or circumstantial thinking. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
41 
 
 
 
 
2. Occasional loss of partnerships, but still understandable. 
3. Loss of partnerships most of the time. 
 
7. Psychomotor agitation. 
Assess through observation, including from other sources of observation such as visitors, 
family and health personnel. Do not include dyskinesia, tics or chorea. 
0. No restlessness or agitation. 
1. Light restlessness with rude movements or nervousness. 
2. Moderate restlessness including significant limb movements, nervousness and trying to 
start the tracks. 
3. Severe psychomotor agitation, such as aggression or need for containment or isolation. 
8. Psychomotor slowdown. 
Assess movements through direct observation or through other sources of observation such 
as family, visitors or clinical staff. Do not assess components caused by parkinsonism. Do 
not value drowsiness or sleep. 
0. No slowing down of voluntary movements. 
1. Slight reduction of the frequency, spontaneity or speed of movements to a degree that 
may interfere in some way with the evaluation. 
2. Moderate reduction in the frequency, spontaneity or speed of movements to a degree 
that interferes with self-care activities. 
3. Severe psychomotor slowing with few spontaneous movements. 
 
9. Guidance. 
Patients who cannot speak may be given the hearing test or visually with multiple-choice 
responses. Allow the patient to make mistakes up to 7 days instead of 2 if the admission is 
longer than 3 weeks. Disorientation in person means not recognizing familiar people and it is 
not scored if the patient recognizes the person even if he has made a mistake in the name. In-
person disorientation is more severe if the person does not recognize themselves and is rare. 
Disorientation in person appears after disorientation in space and/or time. 
0. Oriented in time, space and person. 
1. Disoriented in time (e.g. more than 2 days or wrong month or year) or space. 
(e.g. name of building, city or state) but not both. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
42 
 
 
 
 
2. Disoriented in time and space. 
3. Disoriented in person. 
10. Attention. 
Patients with sensory deficits or who are intubated or those with limited hand movement should 
be evaluated with tests that do not require writing. Attention can also be assessed during the 
interview (e.g. verbal perseverances, distractibility and difficulty in changing the subject) and/or 
through the use of specific tests. 
0. Alert and attentive. 
1. Slightly distracted or slight difficulties in maintaining attention, but with the ability to focus 
it again on warning you. In tests only minor errors without significant slowing down in the 
answers. 
2. Moderate inattention with difficulty focusing and maintaining attention. In tests it presents 
numerous errors or requires help to finish the task. 
3. Severe difficulty focusing and maintaining attention with numerous incorrect or 
incomplete answers or inability to follow directions. Distracted by noises or environmental 
events. 
11. Short-term memory. 
Defined as the retrieval of information (e.g. 3 items presented verbally or visually) after 2 or 3 
minutes. When it is assessed with a standardized test, it is necessary that it has previously 
been properly registered. The number of trials until the information is recorded, as well as the 
effect of giving clues can be noted on the answer sheet. The patient cannot rehearse during 
the waiting time and must be distracted in this period of time. The patient can speak or 
communicate nonverbally with the examiner to identify the correct items. Short-term deficits 
can also be picked up during the interview. 
 
0. Intact short-term memory. 
1. Remember 2/3 items; You may be able to remember the third item with clues. 
2. Remember 1/3 items; May be able to remember the other items after clues. 
3. Remember 0/3 items. 
12. Long-term memory. 
It can be assessed formally or through the interview remembering part of your past life (e.g. 
medical history or information that can be corroborated by someone else) or general 
information that has had relevance. When evaluating with standardized tests use 3 items that 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
43 
 
 
 
 
can be presented verbally or visually, make sure they are correctly recorded and ask at least 
5 minutes later. The patient should not rehearse during the waiting period. Make concessions 
in patients with less than 8 years of education or with mental retardation in terms of general 
information. The assessment of the severity of deficits includes a judgment of all long-term 
memory modalities that have been evaluated, including long-term and short-term memory 
evaluated informally during the interview and also formally tested. 
0. No significant long-term memory disturbances. 
1. Recalls 2/3 items and/or has minor difficulties in remembering details of long-term 
information. 
2. Recalls 1/3 items and/or has moderate difficulty remembering long-term information 
details. 
3. Remembers 0/3 items and/or has severe difficulties. 
13. Visuospatial capacity. 
Value it formally and informally. Consider the patient's difficulty in managing in their 
environment (e.g. getting lost). Formally evaluate by drawing, copying a design, assembling a 
puzzle, or drawing a map and identifying major cities, etc. Take into account visual problems 
that may interfere with the performance of the test. 
0. No alteration. 
1. Slight alteration so that most of the design, most details or parts are correct; and/or there 
is a small difficulty in managing around them. 
2. Moderate alteration with distorted design appreciation and/or various errors in details or 
parts; and/or repeated need to redirect to avoid getting lost in a nine environment despite 
having familiar objects around. 
3. Serious alteration in formal tests, and / or repeated questions or lost in the middle. 
 
DRS-R-98 OPTIONAL ITEMS 
These 3 items can be used for the differential diagnosis of delirium from other diseases as well as 
for diagnostic or research purposes. They are NOT included in the total severity score. 
Temporary onset of symptoms. 
Assess the speed of onset of the symptoms of the current episode, do not valuethe time of 
evolution. Distinguish the onset of symptoms attributable todelirium when they occur 
concomitantly with other pre-existing psychiatric pathologies. For example, if a patient with major 
depression is evaluated during an episode of delirium for an overdose, assess the speed  of onset 
of delirium symptoms. 
0. No significant change from baseline. 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
44 
 
 
 
 
1. Gradual onset of symptoms, over a period of weeks or months. 
2. Acute change in behavior orpersonhood occurring within days or a week. 
3. Abrupt change in behavior orbehavior, occurring over  a period of hours or a day. 
 
Fluctuating in symptom severity. 
Assess the oscillations of the symptoms individually or grouped during the chosen period of time. 
It is usually applied to cognition, affect, intensity  of hallucinations, alteration  of thought and 
alteration of language. Keep in mind that perceptual disturbances usually appear intermittently, 
but can have moments of greaterintensity when the other symptoms fluctuate in severity. 
0. No fluctuation of symptoms. 
1. Symptoms fluctuate in severity over hours. 
2. Symptoms fluctuate in severity within minutes. 
 
Medical illness 
Assess the degree to which a physiological, medical or pharmacological problemmay be the 
cause of the symptoms evaluated. Many patients have these problems but there may not be a 
cause-and-effect relationship . 
0. None present or active. 
1. presence of any physical problems that interfere with mental state 
2. medication, infection, metabolic disturbance, CNS injury, or any other medical problem 
that may specifically be involved in the cause of altered consciousness or mental status. 
 
 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
45 
 
 
 
 
DRS-R-98 SPANISH VERSION 
 
SEVERITY SCORE: _______ TOTAL SCORE: _______ 
 
Severity item ScoreAdditional information 
 
 
Sleep-wake cycle 0 1 2 3 ❑ 
 
 
 
naps ❑only nocturnal disturbance 
 
 
 
 
 
 
 
❑Night-day investment 
 
Alterations of perception 0 1 2 3 Sensory type of illusion or hallucination: 
 
 
 
 
 
 
 
 
 
 
❑auditory  ❑visual  ❑olfactory ❑tactile 
 
 
 
 
 
 
 
Form of illusion or hallucination: 
 
 
 
 
 
 
 
❑simple ❑complex 
 
Delusions 0 1 2 3 Type of delirium: ❑ persecution 
 
 
 
 
 
 
 
 
 
 
 
 
 
❑grandiosity ❑somatic 
 
 
 
 
 
 
 
Form: ❑little systematized  
 
 
 
 
 
 
 
 
❑structured 
 
Affective Lability 0 1 2 3 Type:  
 
 
 
 
 
 
 
 
 
 
 
 
❑anger  ❑anxiety  ❑sadness-dysphoria 
❑hyperthymia 
 
 
 
 
 
 
 
 
❑irritability 
 
Language 0 1 2 3 Intubation, mutism, etc.   
 
 
 
 
❑ 
 
Course of thought0 1 2 3 Intubation, mutism, etc.  
 
 
 
 
❑ 
 
Motor agitation 0 1 2 3 In contention  
 
 
 
 
 
 
❑ 
 
 
 
 
 
 
 
Containment type: 
 
Psychomotor retardation 0 1 2 3 In containment  
 
 
 
 
❑ 
 
 
 
 
 
 
 
Containment type: 
 
Orientation 0 1 2 3 Date:  
 
 
 
 
 
 
 
 
 
 
 
 
Place: 
 
 
 
 
 
 
 
Person: 
Attention 0 1 2 3  
 
 
 
 
Short-term memory 0 1 2 3  
 
 
 
 
❑Number of trials until items are 
memorized 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
❑Able to remember with help 
 
Long-term memory 0 1 2 3  
 
 
 
 
❑Indicate if you are able to remember 
with help 
 
 
 
 
 
 
 
 
Visuospatial capacity0 1 2 3  
 
 
 
 
❑Indicate if you are unable to use your 
hands 
 
 
 
 
 
 
 
 
 
Diagnostic item ScoreAdditional information 
 
 
 
How to start the 
Symptoms0 1 2 3  
 
 
 
 
 
❑Indicate if the symptoms may belong 
to another psychopathology 
 
 
 
 
 
 
 
 
 
 
 
Fluctuation in the severity of 
symptoms0 1 2   
 
 
 
 
❑Indicate if there are symptoms that only appear 
during the night  
 
 
 
 
 
 
 
Medical pathology 0 1 2 Diseases involved  
 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
46 
 
 
 
 
ANNEX 4  
SF-36 HEALTH STATUS QUESTIONNAIRE 
 
1. In general, you would say that your health is: 
 
Excellent 1 
 
 
Very good2 
 
 
Good 3  
 
 
Regular4 
 
 
 
Bad 5  
 
 
2. How would you say your health is compared to a year ago? 
 
Much better now than a year ago 1 
 
 
 
Somewhat better now than a year ago 2 
 
 
 
More or less the same now as a year ago 3 
 
 
Worse now than a year ago4 
 
 
 
Much better now than a year ago 5 
 
 
 
3. The following questions refer to activities or things you might do on a typical day. Does 
your current health limit you from doing those activities or things? If so, how much? 
 
 
 
 
 
 
 
 
Yes, yes, no 
 
 
 
 
 
 
 
 
 
 
       limits me it  
       does not limit 
         
me  
 
 
 
 
 
 
        Much 
        a little 
          limits 
 
 
 
 
 
 
 
 
 
 
           nothing 
 
 
 
Activities 
Intense efforts, such as running, lifting  
1 
 
2 
 
3 
heavy objects or participating in sports 
Strenuous 
Moderate efforts, such as moving a  
 
table,1  
2 
 
3 
vacuuming, bowling or walking 
more than an hour  
Picking up or carrying the shopping bag  
 
1 
 
2 
 
3 
Climbing severalfloors up the stairs  
 
 
1 
 
2 
 
3 
Climbing a single floor up the staircase   
 
1 
 
2 
 
3 
Bending or kneeling  
 
 
 
1 
 
2 
 
3 
Walking one kilometre or more  
 
 
1 
 
2 
 
3 
Walk several blocks (several hundred 
 
1 
 
2 
 
3 
of meters)  
Walking a single block (about 100 meters) 
 
1 
 
2 
 
3 
Bathingor dressing oneself  
 
 
1 
 
2 
 
3 
 
 
4. During the last four weeks, have you had any of the followingproblems at work or in your 
daily activities because of your physical health? 
 
 
 
 
 
 
 
 
 
 
Yes No  
 
Did you have to reduce the time spent at work or in your 
activities of daily living?  
 
 
 
 
 
 
1 
 
2 
Did he do less than hewould have wanted to do?   
 
 
 
1 
 
2 
Did you have to stop doing some tasks at your job or in your 
activities of daily living?  
 
 
 
 
 
 
1 
 
2 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
47 
 
 
 
 
Did you have difficulty doing your job or activities? 
everyday (for example, did it cost you more than usual)?   
 
 
1 
 
2 
 
5. During the past four weeks, have you had any of the following problemsat work  or in your 
daily activities because of any emotional problems(such as being sad, depressed, or 
nervous)? 
 
 
 
 
 
 
 
 
 
Yes No  
 
Did you have to reduce the time spent at work or in your 
Everyday activitiesfor any emotional problems?   
 
 
1 
 
2 
Did he do less than he would have wanted to do, 
Orany emotional problems?   
 
 
 
 
1 
 
2 
Didn't you do your job or your day-to-day activities so 
carefully as usual, 
for any emotional problem? 1 2  
 
 
 
 
 
 
 
 
6. Over the past four weeks, to what extent have your physical health or emotional problems 
hindered your usual social activities with the family, friends, neighbours or others? 
Nothing 1 
 
 
A poco2 
 
Teamlar 
 
3 
Pretty much. 4  
Mucho5 
 
 
 
7. Did you have pain anywhere in your body during the past four weeks? 
No, none 1 
 
Yes, very little 2 
Yes, a little  
3 
Yes, moderate 4 
Yes, a lot 
5 
Yes, very much6 
 
 
8. Over the past four weeks, how much has the pain made it difficult for you to do your usual 
job (including work outside the home and household chores)? 
Nothing 
1 
A little 2 
Regular  
3 
LowAunt  
4 
Mucho  
5 
 
9. The questions that follow relate to how you have felt andhow things have gone over the 
past four weeks. In each question, answer what most closely resembles how you have felt . 
During the last four weeks, how long...? 
 
 
 
 
 
 
 
 
Always     Almost      many     some     only      never 
 
 
 
 
 
Always  timessome   times 
 
 
 
 
 
 
 
 
 
 
 
 
time 
Felt full of vitality 1 23 456 
 
 
 
 
 
 
 
 
 
He was very nervous   
1 
 
2 
3 
4 
 
5 
6 
I feel so low morale 1 2 3 4 5 6  
 
 
 
 
 
 
 
that nothing could encourage him 1 2 3 4 5 6 
 
 
 
 
 
 
 
 
Felt calm and calm 1 2 3 4 5 6  
 
 
 
 
 
 
 
Had a lot of energy 1 2 3 4 5 6  
 
 
 
 
 
 
 
 
Felt discouraged and sad 1 2 3 4 5 6 
 
 
 
 
 
 
 
 
Felt exhausted 1 2 3 4 5 6 
 
 
 
 
 
 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
48 
 
 
 
 
Felt happy 1 2 3 4 5 6  
 
 
 
 
 
 
 
 
 
Felt tired1 2 3 4 5 6 
 
 
 
 
 
 
 
 
 
 
10. Over the past four weeks, how often have physical health oremotional problems hindered 
your social activities (such as visiting friends or family)? 
Always  
1 
Almost always  
2 
Sometimes  
 
3 
Only once 
4 
Never 5 
 
 
 
11. Please say whether each of the following phrases seems true or false to you: 
 
 
 
 
 
 
 
 
 
Totally Quite  
Totally  
 
 
 
 
true 
 true 
I know false false 
 
 
 
I think I get sick more 
easily than other people 1 2 3 4 5 
 
 
 
 
 
 
 
 
I'm as healthy as anyone1 2 3 4 5 
 
 
 
 
 
 
 
I think my health is going to get worse 1 2 3 4 5  
 
 
 
 
 
 
My health is excellent 1 2 3 4 5  
 
 
 
 
 
 
 
 
 
 
INSTRUCTIONS: The above questions pertain to what you think about your health. Your 
answers will let you know how you are doing and to what extent you are able to do your usual 
activities. 
Answer each question as directed. If you are not sure how to answer a question, please answer 
what seems most true to you. Remember, you need to dial only one number per question. 
 
 
 TOTAL SCORE: 
 
 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
49 
 
 
 
 
ANNEX 5 
The Clavien-Dindo Classification 
The therapy used to correct a specific complication is the basis of this classification in order to rank a 
complication in an objective and reproducible manner. 
  
It consists of 7 grades (I, II, IIIa, IIIb, IVa, IVb and V). The introduction of the subclasses a and b allows 
a contraction of the classification into 5 grades (I, II, III, IV and V) depending on the size of the 
population observed or the of the focus of a study. 
  
Complications that have the potential for long-lasting disability after patient’s discharge (e.g.: paralysis 
of a voice cord after thyroid surgery) are highlighted in the present classification by a suffix (“d” for 
disability). This suffix indicates that a follow-up is required to comprehensively evaluate the outcome 
and related long-term quality of life. 
  
  
GRADES 
DEFINITION 
Grade I 
Any deviation from the normal postoperative course without the need for 
pharmacological treatment or surgical, endoscopic and radiological 
interventionsAllowed therapeutic regimens are: drugs as antiemetics, antipyretics, 
analgetics, diuretics and electrolytes and physiotherapy. This grade also includes 
wound infections opened at the bedside. 
Grade II 
Requiring pharmacological treatment with drugs other than such allowed for grade 
I complications.  
Blood transfusionsand total parenteral nutritionare also included. 
Grade III 
Requiring surgical, endoscopic or radiological intervention 
IIIa 
Intervention not under general anesthesia 
IIIb 
Intervention under general anesthesia 
Grade IV 
Life-threatening complication (including CNS complications)* requiring IC/ICU-
management 
VAT 
single organ dysfunction (including dialysis) 
IVb 
multiorgandysfunction 
Grade V 
Death of a patient 
  
*brain hemorrhage, ischemic stroke, subarrachnoidalbleeding,but excluding transient ischemic attacks 
(TIA);IC: Intermediate care; ICU: Intensive care unit. 
  
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
50 
 
 
 
 
ANNEX 6 
Complications not associated with delirium 
 
List of complications to collect in the CRD include, but are not limited to: 
1) Medical complications: 
- cardiovascular events: arrhythmias, myocardial injury after non-cardiac surgery (MINS), 
acute myocardial infarction (AMI), acute pulmonary edema (PAD), shock any etiology, cardiac 
arrest... 
- pulmonary: atelectasis, pleural effusion, respiratory failure, bronchoaspiration, adult 
respiratory distress syndrome (ARDS), fat embolism... 
- gastrointestinal:  paralytic ileus, diarrhea or colitis, acute dysgestive hemorrhage  (HDA), 
intestinal ischemia... 
- renal: acute retention urine, acute renal failure (classification according to AKIN scale)... 
- cerebrovascular: stroke, convulsions, malignant hyperthermia... 
- Infectious: urinary tract infection, pneumonia, sepsis/septic shock of any etiology... 
- thrombosis: deep vein thrombosis, pulmonary thromboembolism... 
-haemorrhage. 
- allergic reaction. 
2) Surgical complications: 
- Anastomos fugue. 
- Bleeding surgical site. 
- Surgical site infection: which can be superficial or deep infection, infection of an organ or 
space. 
 
 
All previous events that reach grade II Clavien-Dindo severity scale and  all those events that, at the 
discretion of the researcher, are relevant to the development of the study and patient safety  must be 
collected in the Data Collection Booklet, in the "Complications" section. 
 
 

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
51 
 
 
 
 
 
ANNEX 7 
Adverse reactions to quetiapine (SmPC) 
 
Sistema de 
clasificación de 
órganos
Muy 
frecuentes
Frecuentes
Poco 
frecuentes
Raras
Muy raras
Frecuencia no 
conocida
Trastornos de 
la sangre y del 
sistema 
linfático
Disminución 
de la 
hemoglobina
Leucopenia, 
disminución 
del recuento 
de neutrófilos, 
aumento de 
eosinófilos
Trombocito- 
penia, 
anemia, 
disminución 
del recuento 
de plaquetas
Agranulocitosis
Neutropenia
Trastornos del 
sistema 
inmunológico
Hipersensibi- 
lidad 
(incluyendo 
reacciones 
alérgicas en 
la piel)
Reacción 
anafiláctica
Trastornos 
endocrinos
Hiperprolac- 
tinemia, 
disminución 
de T4 total, 
disminución 
de T4 libre, 
disminución 
de T3 total, 
aumento de 
TSH
Disminución 
de T3 libre, 
hipotiroidism
o
Secreción 
inapropiada 
de la 
hormona 
antidiu- 
rética
Trastornos del 
metabolismo y 
de la nutrición
Elevación de 
los niveles de 
triglicéridos 
séricos; 
Elevación del 
colesterol total 
(predominan- 
temente 
colesterol LDL); 
Disminución 
de colesterol 
HDL, aumento 
de peso
Aumento del 
apetito, 
aumento de 
glucosa en 
sangre a 
niveles 
hiperglucé- 
micos
Hiponatre- 
mia, diabetes 
Mellitus
Síndrome 
metabólico
Exacerba- 
ción de la 
diabetes pre-
existente

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
52 
 
 
 
 
 
 
 
 
 
 
Sistema de 
clasificación de 
órganos
Muy 
frecuentes
Frecuentes
Poco 
frecuentes
Raras
Muy raras
Frecuencia no 
conocida
Trastornos 
psiquiátricos
Sueños 
anormales y 
pesadillas, 
ideación 
suicida y 
comporta- 
miento suicida
Sonambulismo y 
reacciones 
relacionadas 
tales como 
hablar dormido y 
desorden 
alimenticio 
relacionado con 
el sueño
Trastornos del 
sistema 
nervioso
Mareo, 
somnolencia, 
cefalea, 
síntomas 
extrapiramidal
es
Disartria
Convulsiónes, 
síndrome de 
piernas 
inquietas, 
discinesia 
tardía, 
Trastornos 
cardíacos
Taquicardia, 
palpitaciones
Prolongación 
del QT, 
Bradicardia
Trastornos 
oculares
Visión borrosa
Trastornos 
vasculares
Hipotensión 
ortostática
Tromboembo- 
lismo venoso
Trastornos 
respiratorios, 
torácicos y 
mediastínicos
Disnea
Rinitis
Trastornos 
gastrointes- 
tinales
Sequedad de 
boca
Estreñimien- 
to, dispepsia, 
vómitos
Disfagia
Pancreatitis, 
Obstrucción 
intestinal/Íleo
Trastornos 
hepatobilia- 
res
Elevación de la 
alanina-
aminotransfer
asa sérica 
(ALT), 
elevación de 
los niveles de 
gamma-GT
Elevación de 
la aspartato-
aminotransfer
asa sérica 
(AST)
Ictericia, 
hepatitis

Protocol  QUEPRO 
Version 2.0, April-3-2019 
EudraCT: 2016-004117-27 
 
 
53 
 
 
 
 
 
Sistema de 
clasificación de 
órganos
Muy 
frecuentes
Frecuentes
Poco 
frecuentes
Raras
Muy raras
Frecuencia no 
conocida
Trastornos de 
la piel y del 
tejido 
subcutáneo
Angioede- ma, 
síndrome de 
Stevens-
Johnson
Necrolisis 
Epidérmica 
Tóxica, 
Eritema 
Multiforme; 
Erupción 
medicamento
sa con 
eosinofilia y 
síntomas 
sistémicos 
(DRESS)
Trastornos 
musculoesquel
éticos y del 
tejido 
conjuntivo
Rabdomio- 
lisis
Trastornos 
renales y 
urinarios
Retención 
urinaria
Embarazo, 
puerperio y 
enfermedades 
perinatales
Síndrome de 
abstinencia 
neonatal de 
fármacos
Trastornos del 
aparato 
reproductor y 
de la mama
Disfunción 
sexual
Priapismo, 
galactorrea, 
hinchazón de las 
mamas, 
trastorno 
menstrual
Trastornos 
generales y 
alteraciones en 
el lugar de 
administra- 
ción
Síntomas de 
retirada 
(interrupción)
Astenia leve, 
edema 
periférico, 
irritabilidad, 
pirexia
Síndrome 
neuroléptico 
maligno, 
hipotermia
Exploraciones 
complementa- 
rias
Elevación de 
creatina-
fosfoquinasa en 
sangre