Simvastatin add-on to Escitalopram in Patients With Comorbid Obesity and Major Depression: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial
Phase: PHASE2
Conditions: Depressive Disorder, Major, Obesity
Sponsor: Charite University, Berlin, Germany



 
EudraCT-No: 2018-002947-27 
Protocol code: SIMCODE 
Version 1.2 vom 03.12.2019 
 
I 
Table of contents 
 
1. 
Synopsis ..................................................................................................................................... 1 
2. 
Synopse (Deutsch) ................................................................................................................... 12 
3. 
Flow-Chart ................................................................................................................................ 24 
4. 
Introduction ............................................................................................................................... 24 
4.1 
Introduction and background ............................................................................................. 24 
4.2 
Data on IMP-Application .................................................................................................... 25 
4.2.1 
Summary ............................................................................................................... 25 
4.2.2 
Physical, Chemical, and Pharmaceutical Properties and Formulation ................. 26 
4.2.3 
Nonclinical Studies ................................................................................................ 26 
4.2.4 
Effects in humans .................................................................................................. 27 
4.2.5 
Summary of Data and Guidance for the Investigator ............................................ 29 
4.3 
Rationale ............................................................................................................................ 29 
5. 
Study objectives ....................................................................................................................... 30 
5.1 
Primary objective ............................................................................................................... 30 
5.1.1 
Primary efficacy (confirmatory) endpoint .............................................................. 31 
5.2 
Secondary objectives ......................................................................................................... 31 
5.2.1 
Secondary efficacy (exploratory) endpoints .......................................................... 31 
5.2.2 
Other secondary (exploratory) endpoints .............................................................. 31 
6. 
Study population ....................................................................................................................... 32 
6.1 
Number of patients ............................................................................................................. 32 
6.2 
Selection of patients ........................................................................................................... 33 
6.2.1 
Inclusion criteria ..................................................................................................... 33 
6.2.2 
Exclusion criteria ................................................................................................... 34 
6.2.3 
Contraception ........................................................................................................ 35 
6.2.4 
Follow up of pregnancy ......................................................................................... 35 
6.2.5 
Methods of avoiding simultaneous enrolment in other trials ................................. 35 
6.2.6 
Screening failures .................................................................................................. 36 
7. 
Plan for medical treatment ....................................................................................................... 36 
7.1 
Study design ...................................................................................................................... 36 
7.2 
Description of study medication ......................................................................................... 36 
7.2.1 
Investigational Medical product (IMP) ................................................................... 36 
7.2.2 
Standard medication ............................................................................................. 37 
7.2.3 
Control (Placebo)................................................................................................... 37 
7.2.4 
Treatment schedule / Dose regimen ..................................................................... 37 
7.2.5 
Adverse drug reactions and restrictions, contraindications, drug interactions ..... 38 
7.2.6 
Procedures in case of emergency ......................................................................... 39 
7.2.7 
Randomization ....................................................................................................... 40 
7.2.8 
Packaging, labelling, and blinding procedures...................................................... 40 
7.2.9 
Unblinding .............................................................................................................. 40 
7.2.10 
Storage requirements and administration (shipping and destruction) .................. 41 
7.2.11 
Treatment compliance ........................................................................................... 41 
8. 
Concomitant medication / concomitant therapy ....................................................................... 41 
9. 
Study procedures ..................................................................................................................... 42 
9.1 
Recruitment / Screening procedures ................................................................................. 42 
9.2 
Informed consent ............................................................................................................... 42 
9.3 
Patient identification / Generation of pseudonym .............................................................. 42 
9.4 
Visits schedule and evaluations......................................................................................... 43 
9.4.1 
Screening visit ....................................................................................................... 44 
9.4.2 
Randomization visit (Baseline) - Drug dispensation ............................................. 44 
9.4.3 
Examinations during trial ....................................................................................... 45 
9.4.4 
Final examination (End-of-study) .......................................................................... 46 
9.5 
Evaluations / Efficacy assessments .................................................................................. 47 

 
EudraCT-No: 2018-002947-27 
Protocol code: SIMCODE 
Version 1.2 vom 03.12.2019 
 
II 
9.5.1 
MADRS .................................................................................................................. 47 
9.5.2 
BDI-II ...................................................................................................................... 47 
9.6 
Evaluations / Safety assessments ..................................................................................... 47 
9.6.1 
Clinical examination .............................................................................................. 47 
9.6.2 
Laboratory safety ................................................................................................... 47 
9.6.3 
Electrocardiogram ................................................................................................. 48 
9.6.4 
MINI International Neuropsychiatric Interview ...................................................... 48 
9.7 
Evaluations / Other assessments ...................................................................................... 48 
9.7.1 
Patient reported outcome measures ..................................................................... 48 
9.7.2 
Laboratory assessments ....................................................................................... 49 
9.7.3 
Other procedures................................................................................................... 49 
10. Risk-benefit-assessment .......................................................................................................... 49 
11. Termination and subsequent treatment ................................................................................... 50 
11.1 
Premature termination of the individual participant ....................................................... 50 
11.2 
Premature termination of the clinical study ................................................................... 51 
11.3 
Follow-up and continuing treatment after regular / premature termination ................... 52 
12. Adverse events ......................................................................................................................... 52 
12.1 
Definitions ...................................................................................................................... 52 
12.1.1 
Adverse Event (AE) ............................................................................................... 52 
12.1.2 
Adverse Reactions (AR) ........................................................................................ 52 
12.1.3 
Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) ....................... 52 
12.1.4 
Exceptional rules ................................................................................................... 52 
12.1.5 
Suspected Unexpected Serious Adverse Reactions (SUSAR) ............................ 52 
12.2 
Treatment of (S)AEs ...................................................................................................... 53 
12.3 
Assessment of AEs and SAEs ...................................................................................... 53 
12.3.1 
Assessment of intensity ......................................................................................... 53 
12.3.2 
Assessment of causality ........................................................................................ 53 
12.4 
Documentation of AEs and SAEs .................................................................................. 54 
12.5 
Reporting of SAEs and SUSARs ................................................................................... 54 
12.5.1 
Reporting of SAEs / Contact for SAE reporting .................................................... 54 
12.5.2 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)...... 55 
12.5.3 
Other safety issues requiring expedited reporting ................................................ 55 
12.6 
Follow-up of adverse events .......................................................................................... 55 
12.7 
Data Monitoring Committee ........................................................................................... 55 
13. Documentation ......................................................................................................................... 56 
13.1 
Source Data and Study Files ......................................................................................... 56 
13.2 
Case Report Forms (CRF) ............................................................................................ 56 
13.3 
Investigator Site File (ISF) ............................................................................................. 56 
13.4 
Drug accountability / Flow of study medication ............................................................. 56 
14. Quality management ................................................................................................................ 56 
14.1 
Control of trial progress and data quality ....................................................................... 56 
14.1.1 
Monitoring, Data Quality Assurance ...................................................................... 56 
14.1.2 
Audits / Inspections ............................................................................................... 57 
14.2 
Standardisation and validation ...................................................................................... 57 
14.3 
Reference institutions .................................................................................................... 57 
15. Data entry und data management ............................................................................................ 57 
15.1 
Source Data and Study Files ......................................................................................... 58 
15.2 
Data collection / Case Report Form (CRF) ................................................................... 58 
15.3 
Data management ......................................................................................................... 58 
16. Statistical Analysis .................................................................................................................... 59 
16.1 
Hypotheses .................................................................................................................... 59 
16.1.1 
Primary hypothesis ................................................................................................ 59 
16.1.2 
Secondary hypotheses .......................................................................................... 59 
16.2 
Sample size estimation .................................................................................................. 59 

 
EudraCT-No: 2018-002947-27 
Protocol code: SIMCODE 
Version 1.2 vom 03.12.2019 
 
III 
16.3 
Definition of population for analysis ............................................................................... 60 
16.4 
Analysis of primary and secondary endpoints ............................................................... 60 
16.5 
Analysis of adverse events ............................................................................................ 61 
16.6 
Interim analyses and endpoints for premature study termination ................................. 61 
17. Reporting .................................................................................................................................. 61 
17.1 
Statistical report ............................................................................................................. 61 
17.2 
Final report ..................................................................................................................... 61 
17.3 
Publication (policy) ......................................................................................................... 61 
18. Ethical, legal and regulatory aspects ....................................................................................... 62 
18.1 
ICH-GCP-guidelines ...................................................................................................... 62 
18.2 
Legal requirements of the study .................................................................................... 62 
18.2.1 
Approval of Ethics Committee ............................................................................... 62 
18.2.2 
Approval of competent authority ........................................................................... 62 
18.2.3 
Notification to regional authorities ......................................................................... 62 
18.2.4 
Patient information and informed consent ............................................................ 62 
18.2.5 
Patient insurance ................................................................................................... 62 
18.2.6 
Data Privacy and confidentiality ............................................................................ 63 
18.3 
Archiving of data / Access to records ............................................................................ 63 
18.4 
Financing ....................................................................................................................... 63 
19. References ............................................................................................................................... 64 
20. Appendices ............................................................................................................................... 69 
20.1 
Stellungnahme zur Geschlechterverteilung................................................................... 69 
20.2 
Stellungnahme zur Weiterbehandlung nach Studienende ............................................ 69 
20.3 
Zusammenfassende Nutzen-Risiko-Abwägung ............................................................ 69 
20.4 
Ergänzende Informationen zum Prüfpräparat ............................................................... 69 

 
EudraCT-No: 2018-002947-27 
Protocol code: SIMCODE 
Version 1.2 vom 03.12.2019 
 
IV 
Abbreviations 
 
ADL 
 
 
Activities of daily living 
AE 
 
 
Adverse Event  
ALT/GPT 
 
Alanine aminotransferase 
AMG  
 
Arzneimittelgesetz 
AR 
 
 
Adverse Reactions 
AST/GOT 
 
Aspartate transaminase 
BCRP  
 
Breast Cancer Resistance Protein 
BDI-II  
 
Beck Depression Inventory II 
BDNF  
 
Brain Derived Neurotrophic Factor 
Beta-HCG 
 
β-Subunit of hCG gonadotropin 
BfArM  
 
Bundesinstitut für Arzneimittel und Medizinprodukte 
BMBF  
 
Bundesministerium für Forschung und Bildung 
BMI 
 
 
Body-Mass-Index 
CD-ROM 
 
Compact Disc Read-Only Memory 
CDT   
 
Carbohydrate Deficient Transferrin 
CI 
 
 
Confidence interval 
CGI-I  
 
Clinical Global Impression scale – Improvement 
CGI-S  
 
Clinical Global Impression scale – Severity of illness 
CHD  
 
Coronary heart disease  
CK 
 
 
Creatine kinase 
CNS 
 
 
Central nervous system 
CONSORT 
 
Consolidated Standards of Reporting Trials 
CRF 
 
 
Case Report Form 
CRP 
 
 
C-reactive protein 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CYP3A4 
 
Cytochrome P450 3A4 
DMC  
 
Data Monitoring Committee 
DSM 5  
 
Diagnostic and Statistical Manual of Mental Disorders 5th Edition) 
DSMB  
 
Data and Safety Monitoring Board 
ECG/EKG 
 
Electrocardiography/Elektrokardiogramm 
eCRF  
 
Electronic case report form 
ECT 
 
 
Electroconvulsive therapy 
EDC 
 
 
Electronic data capture system 
EMA  
 
European Medicines Agency 
EQ-5D-3L 
 
EuroQol-5 Dimensions-3 Levels Questionnaire 
ESC 
 
 
Escitalopram 
EWR  
 
Europäische Wirtschaftsraum 
FACS  
 
fluorescence activated cell sorting 
FDA 
 
 
Food and Drug Administration 
Gamma-GT 
 
Gamma-glutamyltransferase 
GBD  
 
Global Burden of Disease 
GCP  
 
Good Clinical Practice 
GFR 
 
 
Glomerular filtration rate 
HbA1c  
 
Glycated hemoglobin 
HDI 
 
 
Haftpflichtverband der Deutschen Industrie 
HDL 
 
 
High-density lipoprotein 
HIV 
 
 
Human immunodeficiency virus 
iAS 
 
 
interActive Systems 

 
EudraCT-No: 2018-002947-27 
Protocol code: SIMCODE 
Version 1.2 vom 03.12.2019 
 
V 
 
ICD 
 International Statistical Classification of Diseases and Related Health 
Problems 
ICH 
 International Conference on Harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
ID 
 
 
Identity document 
IEC 
 
 
Independent Ethics Committee 
IL-1beta 
 
Interleukin 1 beta 
IL-6 
 
 
Interleukin 6 
IMP 
 
 
Investigational Medical Product 
IRB 
 
 
Institutional review board 
ISF 
 
 
Investigator site file 
ITT 
 
 
Intent to treat Population 
KKS 
 
 
Koordinierungszentrum für klinische Studien 
LDL 
 
 
Low-density lipoprotein 
LOCF  
 
last-observation-carried-forward 
MADRS 
 
Montgomery-Asberg-Depression Rating Scale 
MAO inhibitor  
Monoamine oxidase inhibitors 
MCH  
 
Mean corpuscular hemoglobin 
MCHC  
 
Mean corpuscular hemoglobin concentration 
MCID  
 
Minimal clinically important difference 
MCV  
 
Mean corpuscular volume 
MDD  
 
Major depressive disorder 
MDE  
 
Major depressive episode 
mg/d  
 
Milligram/day 
MINI 
 
 
Mini International Neuropsychiatric Interview 
MMRM 
 
Mixed Model for Repeated Measures 
MPV  
 
Mean platelet volume 
NCRC  
 
NeuroCure Clinical Research Center 
NMDA  
 
N-Methyl-D-aspartic acid 
PBMC  
 
peripheral blood mononuclear cells 
PGIC  
 
Patients’ Global Impression of Change Scale 
PI 
 
 
Principal Investigator*  
PLC 
 
 
Placebo Statistical analysis 
PPP 
 
 
Per protocol population 
qRT-PCR 
 
quantitative real-time polymerase chain reaction 
QTc 
 
 
corrected QT interval 
RCT 
 
 
Randomized controlled trial 
RDE 
 
 
Remote data entry 
RDW-CV 
 
Red blood cell distribution width 
SAE 
 
 
Serious Adverse Event 
SAR 
 
 
Serious Adverse Reaction 
SAS 
 
 
Statistical Analysis System 
SDV 
 
 
Source data verification 
SIM 
 
 
Simvastatin 
SIMCODE 
 Simvastatin add-on to Escitalopram in patients with comorbid obesity 
and major depression: A multicenter, randomized, double-blind, pla-
cebo-controlled trial 
SOFAS 
 
Social and Occupational Functioning Assessment Scale  
SSL 
 
 
Secure data transfer-protocol 
SSRI  
 
Selective Serotonin Reuptake Inhibitor 
                                               
* will be used as a synonym for Representative of Sponsor. 

 
EudraCT-No: 2018-002947-27 
Protocol code: SIMCODE 
Version 1.2 vom 03.12.2019 
 
VI 
 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
TG 
 
 
triglyceride 
TMF 
 
 
trial master file 
TNF 
 
 
tumor necrosis factor 
YLD 
 
 
Years lived with disability 
ULN 
 
 
upper limit normal 
VLDL  
 
Very-low-density lipoprotein 
 

 
EudraCT-No: 2018-002947-27 
Protocol code: SIMCODE 
Version 1.2 vom 03.12.2019 
 
Page 1 of 70 
1. Synopsis 
Study title 
Simvastatin add-on to Escitalopram in patients with comorbid obesity and 
major depression: A multicenter, randomized, double-blind, placebo-con-
trolled trial (SIMCODE) 
Type of project 
Randomized, placebo-controlled, double-blind multicenter trial with paral-
lel-group design, Phase II 
Sponsor 
Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin 
(Principal) investi-
gator (PI) 
Prof. Dr. Christian Otte 
Charité - Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychothe-
rapie, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin  
Tel: 030-450517531; Fax: 030-450 517942 
Email: christian.otte@charite.de 
Administrative 
support by 
NeuroCure Clinical Research Center (NCRC), Charité - Universitätsmedi-
zin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin 
Koordinierungszentrum für Klinische Studien (KKS Charité), Charité - Uni-
versitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 
1, 13353 Berlin 
Study Centers 
Coordinating investigator: Prof. Dr. Christian Otte, Charité - Universitäts-
medizin Berlin, Klinik für Psychiatrie und Psychotherapie, Campus Benja-
min Franklin 
Investigational centers: 8 centers located in Germany. 
Data and Safety Monitoring Board (DSMB): 
- Prof. Dr. Brenda Penninx, Vrije Universiteit Amsterdam 
- Prof. Dr. Falk Kiefer, Zentralinstitut für Seelische Gesundheit, Mann-
heim 
- Prof. Dr. Carsten Spitzer, Fachklinik Universitätsmedizin Rostock 
- Mrs. Francoise Margue, Deutsche Depressionsliga 
Timetable 
Recruitment start / start of study: (first patient first visit) Q1 2020 
End of recruitment Q1 2023 
End of study1 (last patient last visit) Q2 2023 
Trial duration (for a patient): 12 weeks 
follow up: none 
Rationale 
Major depressive disorder (MDD) and obesity are major contributors to 
impaired health worldwide. Statins are among the most prescribed medi-
cations with well-established safety and efficacy. Statins are recom-
mended in primary prevention of cardiovascular disease, which has been 
linked to both MDD and obesity. Moreover, statins are promising candi-
dates to treat MDD because a meta-analysis of pilot randomized con-
trolled trials has found antidepressive effects of statins as adjunct therapy 
to antidepressants. However, no study so far has tested the antidepres-
sive potential of statins in patients with MDD and comorbid obesity 
                                               
1 2010/C 82/01, 2.5, 43. 

 
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Protocol code: SIMCODE 
Version 1.2 vom 03.12.2019 
 
Page 2 of 70 
Study objectives 
Primary objective 
To examine whether add-on 40 mg/d Simvastatin to standard antidepres-
sant medication (Escitalopram 20 mg/d) improves depression to a greater 
extent than adjunct placebo in patients with major depression and comor-
bid obesity 
Secondary objectives 
To examine whether add-on 40 mg/d Simvastatin to standard antidepres-
sant medication (Escitalopram 20 mg/d) improves response rates, remis-
sion rates, patients’ impression of change, clinicians impression of sever-
ity and change, quality of life, social functioning, self-report depression, 
lipid values, and immunometabolism / mitochondrial function to a greater 
extent than adjunct placebo in patients with major depression and comor-
bid obesity 
Hypotheses / end-
points 
Primary hypothesis: 
Simvastatin (40 mg/d) add-on to standard antidepressant Escitalopram 
(20 mg/d) will improve depression to a greater extent than add-on placebo 
in patients with comorbid obesity and major depression 
Primary efficacy (confirmatory) endpoint 
Change score from baseline to week 12 in Montgomery-Asberg-Depres-
sion Rating Scale (MADRS) 
Secondary Hypotheses: 
Add-on Simvastatin (40 mg/d) to standard antidepressant Escitalopram 
(20 mg/d) will improve 
1)  response rates and remission rates 
2)  patients’ impression of change, clinicians’ impression of severity 
and improvement, quality of life, social functioning, self-report depres-
sion 
3)  lipid values 
4)  mitochondrial and cellular function of immune cells 
to a greater extent over 12 weeks than adjunct placebo in patients with 
major depression and comorbid obesity. 
Secondary efficacy (exploratory) endpoints 
1)  MADRS-response (50 % MADRS score reduction from baseline), 
MADRS-remission (MADRS score < 10), and MADRS-minimal clini-
cally important difference (MCID) 
2)  change Beck Depression Inventory (BDI-II) scores from baseline 
to week 12, and BDI-II-MCID 
Other secondary (exploratory) endpoints 
2)  change in Patients’ Global Impression of Change Scale (PGIC), 
change in Clinicians’ Global Impression of Severity of illness (CGI-S), 
Clinicians’ Global Impression of Improvement (CGI-I), EuroQol-5 Di-
mensions-3 Levels Questionnaire (EQ-5D-3L), and Social and Occu-
pational Functioning Assessment Scale (SOFAS) from baseline to 
week 12 
3)  change in high-density lipoprotein (HDL), low-density lipoprotein 
(LDL), and total cholesterol from baseline to week 12 

 
EudraCT-No: 2018-002947-27 
Protocol code: SIMCODE 
Version 1.2 vom 03.12.2019 
 
Page 3 of 70 
4)  change in mitochondrial and cellular function of immune cells from 
baseline to week 12 
Study design 
multicenter, randomized, double-blind, placebo-controlled, parallel-group 
Study medication / 
Therapeutical 
strategy 
Investigational Medical Product (IMP): Simvastatin (fixed dose 40 mg/d 
over 12 weeks) 
Standard-medication: Escitalopram (fixed dose 10 mg/d - week 1 – 2 and 
20 mg/d week 3 - 12) 
IMP or placebo will be provided as add-on medication to standard antide-
pressant treatment with Escitalopram 
Control therapy  
Placebo capsules (indistinguishable from IMP) over 12 weeks 
Total number of 
patients 
160 patients divided into 2 groups: 
- Group 1 (80 patients): Placebo add-on standard-medication 
- Group 2 (80 patients): IMP add-on standard-medication  
Study population 
Patients with comorbid obesity (body mass index ≥ 30) and major depres-
sion 
Inclusion criteria 
- 
Written informed consent is present  
- 
The patient has the capacity to give consent (He/she is able to un-
derstand the nature and anticipated effects/side effects of the pro-
posed medical intervention)  
- 
The patient has a major depressive episode according to DSM 5 
(Diagnostic and Statistical Manual of Mental Disorders 5th Edition) 
- 
The patient has a score of ≥ 18 in the Montgomery-Asberg Depres-
sion Rating Scale (MADRS)  
- 
The patient has a body mass index ≥ 30  
- 
The patient’s age is between 18 and 65 years (≥ 18 und ≤ 65) 
- 
The patient has not given childbirth within the 6 months prior to 
study entry and is not breastfeeding 
- 
In case of non-psychotropic medication:  
The patient received stable pharmacological medication for at least 
14 days prior to study entry (any changes in medication dose or 
frequency of therapy must be answered with no) 
- 
The patient did not take antidepressants during the last 7 days prior 
to study entry (discontinuation of effective medication to enable 
study participation is prohibited) 
- 
The patient did not receive prior treatment with Escitalopram in in-
dex episode 
- 
The patient had less than three (<3) trials with antidepressants in 
index episode  
- 
The patient does not have a history of non-response to Escital-
opram 
- 
The patient did not receive treatment with ketamine, electroconvul-
sive therapy (ECT) or other stimulatory treatments in index episode 
- 
The patient does not meet any of the following criteria: 
- 
schizophrenia 
- 
schizoaffective disorder 
- 
bipolar disorder 

 
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Page 4 of 70 
- 
The patient is not diagnosed with dementia and does not have mod-
erate or severe impairment of general cognitive function according 
to clinical impression  
- 
The patient does not have clinically relevant elevated liver enzymes 
[GOT or GPT > 3 x upper limit normal (ULN)] and does not have 
elevated Carbohydrate Deficient Transferrin (CDT) ≥ 2.4 % 
- 
The patient does not meet the criteria for alcohol use disorder 
(DSM-5: 303.90; ICD-10: F10.20) or substance use disorder (DSM-
5: 304; ICD-10: F11.20 – F19.20) in M.I.N.I. for DSM-5 and a 
urine/serum drug screening is negative (except for benzodiaze-
pines and opiates) 
- 
The patient does not have a history of suicide attempt 
- 
The patient does not have diagnosed epilepsy or increased bleed-
ing diathesis or a history of angle closure glaucoma or other glau-
comas 
- 
The patient did not have bariatric surgery prior to study entry  
- 
The patient does not have a known allergy or contraindication 
against Escitalopram or Simvastatin 
- 
The patient does not meet any of the following criteria: 
- 
hereditary muscle disease  
- 
known history of rhabdomyolysis  
- 
elevated creatine kinase (CK) outside of the sex-specific 
reference intervals 
- 
History of muscular symptoms under treatment with statins 
or fibrates 
- 
The patient does not have elevated TSH level outside of the age- 
and sex-specific reference intervals. 
- 
The patient does not have insulin-dependent diabetes mellitus 
- 
The patient does not have uncontrolled hepatic disorder, renal or 
cardiovascular disease 
- 
The patient does not have untreated hypothyroidism 
- 
The patient does not have a history of myocardial infarction or 
stroke  
- 
The patient does not have symptomatic peripheral arterial disease  
- 
The patient does not have monogenic familial hypercholesterole-
mia  
- 
The patient does not have clinically significant laboratory abnormal-
ities  
- 
The patient did not participate in other interventional trials during 
the 6 months before and at the time of this trial  
- 
The patient is not an employee of the investigator study site, or a 
family member of the employees or the investigator, or otherwise 
dependent on the sponsor, the investigator or the investigator study 
site. 
Exclusion criteria 
- 
The patient has current use of statins (for visits 2-6 applies: except 
for IMP Simvastatin) 
- 
The patient has current use of antidepressants (for visits 2-6 ap-
plies: except for standard medication Escitalopram)  
- 
The patient has acute suicidal tendencies (MADRS Item 10 > 4) 

 
EudraCT-No: 2018-002947-27 
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- 
The patient uses potent CYP3A4-inhibitors (e.g. clarithromycin, 
erythromycin, HIV protease inhibitors – see “Risks, adverse drug 
reactions, drug interactions, restrictions, contraindications, proce-
dures in case of emergency”)  
- 
The patient uses potent CYP3A4 inductors (carbamazepine, efavi-
renz, nevirapin, etravirine). 
- 
The patient uses Fibrates, Amiodaron, Amlodipin, Verapamil, Flu-
conazol, Diltiazem, Fusidic acid, Niacin or Lomitapid or BCRP-In-
hibtors (e.g. Elbasvir or Grazoprevir) 
- 
The patient uses Gemfibrozil, Ciclosporin or Danazol 
- 
The patient has known hypersensitivity to other ingredients of 
Simvastatin and Escitalopram [butylated hydroxyanisole, micro-
crystalline celluose, citric acid, starch, lactose, magnesium stea-
rate, hypromellose, talc, titanium dioxide, iron oxies, colloidal silicon 
dioxide, croscarmellose sodium, polyethylene glycol] 
- 
The patient uses medication that is associated with QTc-prolonga-
tion [antiarrhythmica class IA and III, antipsychotics (e.g. haloperi-
dol), phenothiazines, tricyclic antidepressants, antibiotics (e.g. 
moxifloxacin), and certain antihistaminergic drugs (e.g. astemizol, 
mizolastin)] 
- 
The patient has clinically significant abnormalities in 12-lead ECG 
(e.g. QTc-prolongation ≥ 500 ms or increase ≥ 60 ms from baseline 
visit) 
- 
The patient is pregnant  
- 
The patient with childbearing potential is not willing to use an ac-
ceptable form of contraception (defined as Pearl index < 1) 
- 
The patient has current use of psychotropic medication (e.g. anti-
psychotics, anticonvulsants, lithium or St. John's Wort) except for 
benzodiazepines, non-benzodiazepines and opiates  
- 
The patient uses nonselective, irreversible monoamine oxidase 
(MAO) inhibitor (e.g. Tranylcypromine) or selective, reversible in-
hibitor of monoamine oxidase A (e.g. Moclobemide) or the nonse-
lective, reversible monoamine oxidase inhibitor Linezolid 
- 
The patient is unwilling to consent to saving, processing and prop-
agation of pseudonymized medical data for study reasons 
- 
The patient is legally detained in an official institution 
Visit and docu-
mentation sched-
ule  
Maximum variation of ± 3 days is permitted for the scheduling of each study visit 
Assessments 
Scree
ning 
Basel
ine 
(Visit 
1) 
 
Visit 2 
 
Visit 
3 
 
Visit 
4 
 
Visit 
5 
End-of-
study 
(Visit 6) 
 
 
week 
0 
week 
1 
week 
2 
week 
4 
week 
8 
week 12 
Screening and consent 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion criteria  
 
X 
 
 
 
 
 
 
Exclusion criteria 
 
X 
X 
X 
X 
X 
X 
 
Medical history  
X 
 
 
 
 
 
 

 
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Treatment status 
 
X 
 
 
 
 
 
 
M.I.N.I – DSM-5 
X 
 
 
 
 
 
 
 
Urine/serum 
drug 
screening 
X 
 
 
 
 
 
 
 
Concomitant medica-
tion 
X 
 
 
 
 
 
 
Safety 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
X 
 
ECG  
X 
X 
X 
X 
X 
X 
X 
 
Blood 
pressure 
& 
heart rate 
X 
X 
X 
X 
X 
X 
X 
 
Safety laboratory 
(incl. Pregnancy test 
- women only) 
X 
X 
 
 
X 
X 
X 
 
Adverse events re-
cording 
 
 
X 
X 
X 
X 
X 
Effectiveness 
 
 
 
 
 
 
 
 
MADRS 
X 
X 
X 
X 
X 
X 
X 
 
BDI-II 
 
X 
X 
X 
X 
X 
X 
Social functioning and 
quality of life 
 
 
 
 
 
 
 
 
SOFAS 
 
X 
 
 
X 
 
X 
 
EQ-5D-3L 
 
X 
 
 
X 
 
X 
Other 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
BMI 
X 
X 
 
 
 
 
X 
 
Waist circumference 
 
X 
 
 
 
 
X 
 
PGIC 
 
 
X 
X 
X 
X 
X 
 
CGI-S 
 
X 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
 
Laboratory (lipid as-
sessment) 
 
X 
 
 
 
 
X 
 
Laboratory (immuno-
metabolism / mito-
chondrial function) 
 
X 
 
 
X 
X 
X 
 
Drug dispensation 
 
X 
 
X 
X 
X 
 
Note: Electrocardiography (ECG), Body-Mass-Index (BMI), Mini International Neuropsychiatric Inter-
view (MINI), Montgomery-Asberg Depression Scale (MADRS), Beck-Depressions-Inventar (BDI), Pa-
tient Global Impression of Change (PGIC), Clinicians’ Global Impression of Severity of illness (CGI-
S), Clinicians’ Global Impression of Improvement (CGI-I), Social and Occupational Functioning As-
sessment Scale (SOFAS), Generic Quality of Life Questionnaire (EQ-5D-3L) 
Safety 
Assessment of safety: Assessment of blood pressure and heart rate at 
every visit. Assessment of laboratory parameters – safety laboratory (incl. 
pregnancy test – women only) at screening, baseline, week 4, week 8 and 
week 12; physical examination at screening and end-of-study; ECG at 
every visit.  
Standard procedures for reporting of adverse events will be used. Adverse 
events will be assessed at every visit starting at visit 2.   
Discontinuation 
criteria 
Discontinuation of individual patient 

 
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Patients are free to withdraw from participation in the study at any time 
without specifying any reasons. An investigator may discontinue or with-
draw a participant from the study for the following reasons: 
- If any clinical adverse event (AE), laboratory abnormality, or other med-
ical condition occurs such that continued participation in the study 
would not be in the best interest of the participant (see also 11.1) 
Discontinuation of the trial 
According to the German Fachinformation for Simvastatin, the combined 
incidence for myopathy/rhabdomyolysis in 41.413 patients treated for at 
least 4 years was 0.08% for 40mg/d Simvastatin. Severe symptomatic hy-
ponatremia (serum sodium [SNa] <125 mmol/L) is a rare but potentially fa-
tal complication of Escitalopram. Signs and symptoms of hyponatremia 
include headache, difficulty concentrating, memory impairment, confu-
sion, weakness, and unsteadiness and can be as severe as hallucination, 
syncope, seizure, coma, respiratory arrest, and death. Therefore, the 
whole study may be discontinued at the occurrence of the treatment-re-
lated serious adverse event (SAE) “myopathy/rhabdomyolysis” as defined 
by the German Fachinformation for Simvastatin [muscle pain, tenderness 
or weakness with creatine kinase (CK) above ten times the upper limit of 
normal (ULN)] in more than 5 participants or the treatment-related SAE 
“severe symptomatic hyponatremia” (serum sodium [SNa] <125 mmol/L) in 
more than 5 participants. In addition, an early discontinuation of the trial 
may be decided if new scientific data during the course of the trial changes 
the risk-benefit-balance significantly. If such data emerges, recruitment 
and treatment of currently treated patients will be paused immediately. A 
final decision on continuation or termination of the trial will then made by 
the Sponsor/PI based on the recommendation of the Data and Safety 
Monitoring Board (DSMB).  
Statistical analy-
sis 
Primary efficacy (confirmatory) endpoint: 
The primary analysis will compare MADRS change from baseline to week 
12 between the Simvastatin and placebo group by Gaussian linear models 
for repeated measures (so-called MMRM) with intervention, center, time 
(week 1, 2, 4, 8, and 12), and intervention-by-time interaction as factors, 
and baseline MADRS score as covariate. The primary analysis population 
will be the intention-to-treat (ITT) population. 
Secondary efficacy (exploratory) endpoints: 
The secondary efficacy endpoints include the percentages of MADRS-re-
sponse, MADRS-remission, and MADRS-MCID within 12 weeks that will 
be analyzed by logistic regression models with intervention and center as 
factors and baseline MADRS as covariate. The analyses of secondary ef-
ficacy endpoint BDI-II will follow the same lines as the primary outcome.  
The analyses of safety parameters and all secondary endpoints will have 
an exploratory character. 
Pharmacological-
toxicological eval-
uation 
Both Simvastatin and Escitalopram are approved for several indications 
since decades. The respective “latest version of German Fachinformation” 
for each medication are in the Investigator site file (ISF).  
Risks, adverse 
drug reactions, 
drug interactions, 
Simvastatin is the IMP that will be tested versus placebo as add-on to 
standard antidepressant medication with Escitalopram, which will be given 
open label to each patient. We list the risks and potential adverse drug 

 
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restrictions, con-
traindications, 
procedures in 
case of emer-
gency 
effects for both medications. See for further information the latest version 
of German “Fachinformation”.  
 
Simvastatin: Simvastatin is approved for several indications since dec-
ades and has in general proven to be a safe medication. The risks and 
adverse effects listed below are all taken from the latest version of German 
“Fachinformation”. 
The most prominent risk of statin use is myopathy, associated with muscle 
pain, muscle tenderness, muscle weakness and increases of creatine ki-
nase (CK). The most severe form of myopathy is rhabdomyolysis with or 
without acute renal failure secondary to myoglobinuria that occurs very 
rarely and is dose-dependent. The combined incidence for myopa-
thy/rhabdomyolysis in 41.413 patients treated for at least 4 years was 
0.03% for 20mg/d, 0.08% for 40mg/d, and 0.61% for 80 mg/d Simvastatin. 
Thus, to minimize the risk of Simvastatin, we will use it in a medium dose 
(40mg/d) and not a high dose (80mg/d). In addition to safety laboratory 
values at screening, baseline, week 4, and week 12, It will be explicitly 
asked if the patient experienced unexplained muscle pain or dark urine as 
a sign of rhabdomyolysis. 
Other adverse effects are listed below and the information is taken from 
the latest version of German “Fachinformation” and classified as follows: 
Very often: (>1/10); often (> 1/100); sometimes (> 1/1000), rarely (> 1/10.000), 
very rarely (< 1/10.000); not known (cannot be determined on basis of available 
data) 
Very often: none 
Often: none 
Sometimes: none 
Rarely: Anemia, headache, dizziness, paresthesia, peripheral neuropa-
thy, obstipation, stomach ache, flatulence, dyspepsia, diarrhea, nausea, 
emesis, pancreatitis, hepatitis/icterus, rash, pruritus, alopecia, myopa-
thy, rhabdomyolysis, myalgia, muscle cramps, asthenia 
Very rarely: insomnia, memory complaints, liver failure 
Not known: depression, interstitial lung disease, tendinopathy, immune-
mediated myopathy, erectile dysfunction 
Medication that is contraindicated with Simvastatin due to inhibition of 
CYP3A4 will not be permitted (Itraconazol, Ketoconazol, Posaconazol, 
Voriconazol, Erythromycin, Clarithromycin, Telithromycin, HIV protease 
inhibitors (e.g. Nelfinavir), Boceprevir, Telaprevir, Nefazodon, Cobicistat, 
Ciclosporin, Danazol, Gemfibrozil). 
Further, medication that is not recommended to use in parallel to Simvas-
tatin in a dosage of 40 mg/d will not be permitted (Fibrates, Amiodaron, 
Amlodipin, Verapamil, Fluconazol, Diltiazem, Fusidic acid, Niacin, Lo-
mitapid). 
Finally, patients will be noticed that they should not drink grapefruit juice 
during Simvastatin treatment due to inhibition of CYP3A4 and correspond-
ing increases in Simvastatin plasma levels. 

 
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In turn, medication that induces CYP3A4 leading to decreased Simvas-
tatin levels will also not be permitted (Carbamazepine, Efavirenz, Nevira-
pin, Etravirine). 
Patients with contraindications for Simvastatin will not be included or ex-
cluded from the study in case of later occurrence (see under inclusion cri-
teria).  
In case of an emergency the blind will be broken immediately and the pa-
tient will receive immediate medical care. 
 
Escitalopram: The most prominent risk of Escitalopram is QTc-Prolonga-
tion in the ECG that can lead to ventricular arrhythmia (torsade des 
pointes). To exclude patients with QTc-prolongation an ECG will be con-
ducted at screening. Furthermore, an additional safety ECG will be con-
ducted at every visit.  
Other adverse effects are listed below and the information is taken from 
the latest version of German “Fachinformation” and classified as follows: 
Very often: (>1/10); often (> 1/100); sometimes (> 1/1000), rarely (> 1/10.000), 
very rarely (< 1/10.000); not known (cannot be determined on basis of available 
data) 
Very often: headache, nausea 
Often: decreased appetite, increased appetite, weight gain, anxiety, 
restlessness, nightmares, decreased libido, anorgasmia, insomnia, fa-
tigue, dizziness, paresthesia, tremor, sinusitis, yawning, diarrhea, obsti-
pation, emesis, dry mouth, hyperhidrosis, arthralgia, myalgia, delayed 
ejaculation, erectile dysfunction, fever 
Sometimes: weight loss, bruxism, agitation, nervousness, panic at-
tacks, confusion, disturbed taste, insomnia, syncope, mydriasis, blurred 
vision, tinnitus, tachycardia, epistaxis, gastrointestinal bleeding, urticar-
ial, alopecia, rash, pruritus, metrorrhagia, menorrhagia, edema 
Rarely: anaphylaxis, aggression, depersonalization, hallucination, ser-
otonin syndrome, bradycardia 
Very rarely: none 
Not known: thrombocytopenia, inadequate ADH-secretion, hypo-
natremia, anorexia, mania, suicidality, dyskinesia, seizures, akathisia 
(psychomotor restlessness), QTc-prolongation in the ECG, orthostasis, 
hepatitis, increased liver enzymes, ecchymosis, angioedema, urinary 
retention, galactorrhea, priapism 
Medication that is contraindicated with Escitalopram will not be permitted, 
which includes all irreversible MAO-inhibitors and medication that is asso-
ciated with QTc-prolongation [antiarrhythmica class IA and III, antipsychot-
ics (e.g. haloperidol), phenothiazines, tricyclic antidepressants, antibiotics 
(e.g. moxifloxacin), and certain antihistaminergic drugs (e.g. astemizol, mi-
zolastin)]. 
Patients with contraindications for Escitalopram will not be included 
(please see under inclusion criteria).  
Risk-benefit analy-
sis 
Both medications (Simvastatin, Escitalopram) are approved for several in-
dications since decades and have overall been proven to be safe. All de-
pressed patients enrolled in the trial will be continuously treated with a 

 
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gold standard antidepressant (Escitalopram) as described by the National 
Disease Management Guideline (“Nationale Versorgungsleitlinie”) for the 
treatment of MDD. For Escitalopram a dose-response relationship has 
been suggested. Especially for patients with severe depression the high 
standard dose of 20 mg/d was shown to be superior compared to 10 mg/d 
[1]. A fixed-dose of 10 mg/d Escitalopram for the entire study duration of 
12 weeks would therefore not allow the optimal treatment for some pa-
tients. Thus, we consider this option ethically not justifiable. A dose in-
crease from 10 mg/d to 20 mg/d based on individual patient response 
would however interfere with comparability of the treatment group and pla-
cebo group, because a strong decrease in depressive symptoms in the 
treatment group compared to placebo group could potentially be masked 
by a higher percentage of Escitalopram dose escalation in the placebo 
group. Therefore, we will increase Escitalopram to 20 mg/d after giving a 
low standard dose of 10 mg/d in the first two weeks. In case of adverse 
reactions related to Escitalopram, we will follow the instructions for dose 
adjustment described in 7.2.4 Treatment schedule / Dose regimen. 
IMP Simvastatin is offered in an “add-on” design, thus there will be virtually 
no drug-free patients in this trial. Invasive interventions beyond ordinary 
sampling of peripheral venous blood will not be performed within this trial, 
therefore the risks associated with trial participation are mainly attributable 
to IMP Simvastatin that has already been shown in depressed patients to 
be safe and well tolerated in combination with an SSRI (Selective Seroto-
nin Reuptake Inhibitor) [2]. 
It has been suggested that both for the lipid-lowering effects and for the 
pleiotropic effects of statins a high dose is more effective than a low dose 
[3-5]. Especially in studies examining effects of statins on diseases of the 
central nervous system such as multiple sclerosis and mild cognitive dis-
order a high dose of Simvastatin (60 – 80 mg/d) has been administered 
[6-8]. One of the most important side effects of Simvastatin is dose-de-
pendent risk of myopathy. The combined incidence for myopathy/rhabdo-
myolysis under Simvastatin was 0.03% for 20 mg/d, 0.08% for 40 mg/d 
and markedly went up to 0.61% for 80 mg/d according to latest version of 
German “Fachinformation”. To minimize the risk of Simvastatin and exam-
ine the pleiotropic effects of Simvastatin in depression, we will use it in a 
medium dose (40 mg/d) and not a high dose (80 mg/d). In addition to as-
sessing safety laboratory values including creatine kinase (CK) at screen-
ing, baseline, at week 4, week 8 and week 12, it will be explicitly asked 
during each visit if the patient experienced unexplained muscle pain or 
dark urine as a sign of rhabdomyolysis. Furthermore, we will not include 
particularly vulnerable patients (e.g. patients with renal impairment, un-
treated hypothyroidism or history of muscle toxicity under statins or fi-
brates) to our study. To exclude patients with QTc-prolongation an ECG 
will be conducted at screening. Furthermore, an additional safety ECG will 
be conducted at every visit.  
According to a meta-analysis of small, randomized controlled trials, a ben-
eficial antidepressive effect of Simvastatin is to be expected [2]. Many de-
pressed patients with comorbid obesity might additionally benefit from 
Simvastatin in terms of primary prevention of cardiovascular disease. 

 
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In summary, the potential benefits of the study by far outweigh the risks 
associated with Escitalopram and Simvastatin. Importantly, a recent ex-
tensive literature review on parallel SSRI and statin use concluded the 
following: “Escitalopram, Citalopram, and Paroxetine are almost certain to 
be safe with all statins” [9]. 
 
 

 
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2. Synopse (Deutsch) 
Titel der Studie 
Simvastatin als Zusatztherapie zur antidepressiven Medikation mit Esci-
talopram bei Patienten mit Depression und Adipositas: Eine multizentri-
sche, randomisierte, doppelt-verblindete, Placebo-kontrollierte Studie 
(SIMCODE) 
Art des Vorhabens  Randomisierte, Placebo-kontrollierte, doppelt-blinde Multicenterstudie mit 
Parallelgruppen- Design. Phase II 
Sponsor  
Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin 
Sponsorvertreter 
und Prüfer / Leiter 
der Prüfgruppe 
(PI) 
Prof. Dr. Christian Otte 
Charité – Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychothe-
rapie, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin  
Tel: 030-450517531; Fax: 030-450 517942 
E-Mail: christian.otte@charite.de 
Administration 
NeuroCure Clinical Research Center (NCRC), Charité – Universitätsme-
dizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin 
Koordinierungszentrum für Klinische Studien (KKS Charité), Charité – Uni-
versitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 
1, 13353 Berlin 
Prüfzentren 
Koordinierender Prüfer: Prof. Dr. Christian Otte, Charité – Universitätsme-
dizin Berlin, Klinik für Psychiatrie und Psychotherapie, Campus Benjamin 
Franklin 
Prüfzentren: 8 Zentren in Deutschland. 
Data and Safety Monitoring Board (DSMB): 
- Prof. Dr. Brenda Penninx, Vrije Universiteit Amsterdam 
- Prof. Dr. Falk Kiefer, Zentralinstitut für Seelische Gesundheit, Mann-
heim 
- Prof. Dr. Carsten Spitzer, Fachklinik Universitätsmedizin Rostock 
- Mrs. Francoise Margue, Deutsche Depressionsliga 
Zeitplan 
Rekrutierungsstart / Beginn der Studie (first patient first visit): Q1 2020 
Ende der Rekrutierung: Q1 2023 
Ende der Studie2 (last patient last visit): Q2 2023 
Studiendauer (für einen Patienten): 12 Wochen 
Katamnese: keine 
Fragestellung auf-
bauend auf wis-
senschaftlichem 
Hintergrund 
Major Depression (MDD) und Adipositas gehören zu den häufigsten Er-
krankungen weltweit. Statine gehören zu den meist verschriebenen Medi-
kamenten und ihre Sicherheit und Effektivität ist etabliert. Statine werden 
empfohlen in der primären Prävention von kardiovaskulären Krankheiten, 
die sowohl mit MDD als auch mit Adipositas in Verbindung gebracht wur-
den. Darüber hinaus zeigte eine Metaanalyse, dass Statine außerdem 
vielversprechend als Ergänzungstherapie zur herkömmlichen antidepres-
siven Therapie sein könnten, da sich antidepressive Effekte zeigten. 
                                               
2 2010/C 82/01, 2.5 43. 

 
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Nichtsdestotrotz hat bis jetzt keine Studie die potentielle antidepressive 
Wirkung von Statinen bei Patienten mit MDD und komorbider Adipositas 
getestet.  
Studienziele 
Primäres Ziel 
Untersuchung, ob eine Simvastatin (40 mg/d) Zusatztherapie zur antide-
pressiven Medikation mit Escitalopram (20 mg/d) zu einer zusätzlichen 
Verbesserung der Depression im Vergleich zu einer Zusatzbehandlung 
mit Placebo bei Patienten mit Major Depression und komorbider Adiposi-
tas führt 
Sekundäres Ziel 
Untersuchung, ob eine Simvastatin (40 mg/d) Zusatztherapie zur antide-
pressiven Medikation mit Escitalopram (20 mg/d) zu einer zusätzlich ver-
besserten Ansprechrate, Remissionsrate, Veränderungseinschätzung 
durch Patienten, Schwere- und Veränderungseinschätzung durch Be-
handler, Lebensqualität, Sozialem Funktionsniveau, selbstberichtete De-
pression, Lipidwerten und Immunometabolismus / mitochondrialer Funk-
tion im Vergleich zur Zusatzbehandlung mit Placebo bei Patienten mit 
Majo Depression und komorbider Adipositas führt 
Hypothesen / End-
punkte 
Primäre Hypothese: 
Simvastatin (40 mg/d) als Zusatztherapie zur konventionellen Antidepres-
siva-Standardtherapie mit Escitalopram (20 mg/d) führt zu einer zusätzli-
chen Verbesserung der Depression im Vergleich zu einer Zusatzbehand-
lung mit Placebo bei Patienten mit Major Depression und komorbider Adi-
positas 
Primärer (konfirmatorischer) Endpunkt 
Veränderungsscore von Baseline zur Woche 12 in der Montgomery-As-
berg-Depression Rating Skala (MADRS) 
Sekundäre Hypothesen: 
Simvastatin (40 mg/d) als Zusatztherapie zur konventionellen Antidepres-
siva-Standardtherapie mit Escitalopram (20 mg/d) führt nach 12 Wochen 
zu einer zusätzlich verbesserten 
1)  Ansprech- und Remissionsrate 
2)  Veränderungseinschätzung durch Patienten, Schwere- und Verän-
derungseinschätzung durch Behandler, Lebensqualität, Sozialem 
Funktionsniveau, selbstberichtete Depression 
3)  Lipidwerte 
4)  Immunometabolismus / mitochondriale Funktion 
im Vergleich zur Behandlung mit Placebo bei Patienten mit Major Depres-
sion und komorbider Adipositas 
Sekundäre (explorative) Endpunkte (Effektivität) 
1)  Ansprechrate (Reduktion der Punkte im MADRS um 50 % zur Base-
line), Remission (MADRS Punkte < 10) und MADRS geringster klinisch 
relevanter Unterschied (MCID) 
2)  Veränderung in den Beck Depression Inventory (BDI-II) Punkten von 
Baseline zu Woche 12 und geringster klinisch relevanter Unterschied 
(MCID) 

 
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Weitere sekundäre (explorative) Endpunkte  
2)  Veränderung in der Patients’ Global Impression of Change Scale 
(PGIC), Veränderung in der Clinicians’ Global Impression of Severity of 
illness (CGI-S), Clinicians’ Global Impression of Improvement (CGI-I), 
EuroQol-5 Dimensions-3 Levels Questionnaire (EQ-5D-3L), Social and 
Occupational Functioning Assessment Scale (SOFAS) von Baseline zu 
Woche 12 
3)  Veränderung in high-density lipoprotein (HDL), low-density lipopro-
tein (LDL) und total Cholesterin von Baseline zu Woche 12 
4)  Veränderung in der respiratorischen Reserve von Monozyten und T 
Zellen und andere zelluläre Funktionen von Baseline zu Woche 12 
Studiendesign 
multizentrisch, randomiziert, doppel-blind, Placebo-kontrolliert, Parallel-
gruppen  
Studienmedika-
tion / Behand-
lungsstrategie 
IMP: (Investigational Medical Product): Simvastatin (feste Dosierung 40 
mg/d für 12 Wochen) 
Standardmedikation: Escitalopram (Dosierung 10 mg/d in den ersten 
zwei Wochen, dann feste Dosierung 20 mg/d bis Woche 12) 
Simvastatin oder Placebo werden als Zusatztherapie zur konventionellen 
Antidepressiva-Standardtherapie mit Escitalopram zur Verfügung gestellt. 
Vergleichsthera-
pie 
Placebo-Kapseln (nicht unterscheidbar zur IMP) für 12 Wochen 
Gesamtzahl Pati-
enten 
160 Patienten unterteilt in zwei Gruppen: 
- Gruppe 1 (80 Patienten): Placebo plus Standardmedikation 
- Gruppe 2 (80 Patienten): IMP plus Standardmedikation 
Studienpopulation Patienten mit komorbider Adipositas (body mass index ≥ 30) und Major 
Depression 
Einschlusskrite-
rien 
- 
Eine unterschriebene Einwilligungserklärung ist vorhanden 
- 
Der Patient ist einwilligungsfähig [Er erfasst klar Art, Bedeutung 
und Tragweite (Risiken) der ärztlichen Maßnahme] 
- 
Der Patient hat eine Episode einer Majoren Depression nach DSM 
5 
- 
Der Patient hat einen Montgomery-Asberg Depression Rating 
Scale (MADRS) Score von ≥ 18 
- 
Der Patient hat einen Body Mass Index von ≥ 30 
- 
Das Alter des Patienten liegt zwischen 18 und 65 Jahren (≥ 18 und 
≤ 65) 
- 
Die Patientin hat in den vergangenen 6 Monaten nicht entbunden 
und befindet sich nicht in der Stillzeit 
- 
Im Falle einer nicht-psychotropen Medikation: 
Der Patient erhält eine stabile pharmakologische Medikation für 
mind. 14 Tage vor Studienbeginn (jegliche Veränderungen der Do-
sis oder Einnahmefrequenz müssen mit nein beantwortet werden) 
- 
Der Patient hatte in den letzten 7 Tagen vor Studieneinschluss 
keine Einnahme von Antidepressiva (Das Absetzen einer wirksa-
men Vormedikation, um Patienten zur Studienteilnahme zu qualifi-
zieren, ist ausdrücklich untersagt) 
- 
Der Patient hat keine vorherige Behandlung mit Escitalopram in der 
aktuellen Major depressive episode (MDE) 

 
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- 
Der Patient hatte weniger als drei (< 3) Behandlungsversuche mit 
Antidepressiva in der aktuellen MDE 
- 
Der Patient besitzt keine frühere Non-Response auf Escitalopram 
- 
Der Patient wurde in der aktuellen MDE nicht mit Ketamin, elektro-
konvulsiver Therapie (EKT) oder anderen Stimulationsbehandlun-
gen behandelt 
- 
Der Patient erfüllt keine der folgenden Kriterien: 
- 
Schizophrenie 
- 
schizoaffektive Störung 
- 
bipolare Störung 
- 
Der Patient hat keine diagnostizierte Demenz und besitzt nach dem 
klinischen Eindruck keine moderaten oder schweren generellen 
kognitiven Funktionseinschränkungen  
- 
Der Patient hat keine klinisch relevanten erhöhten Leberwerte 
[GOT oder GPT > 3 x obere Normgrenze (ULN)] und hat keinen 
erhöhten CDT-Wert (Carbohydrate-deficient Transferrin) ≥ 2,4 %  
- 
Der Patient erfüllt nicht die Kriterien von Alkoholkonsumstörung 
(DSM-5: 303.90; ICD-10: F10.20) bzw. Substanzkonsumstörung 
(DSM-5: 304; ICD-10: F11.20 – F19.20) im M.I.N.I für DSM-5 und 
ein Urin oder Serum-Drogenscreening-Test ist negativ (ausgenom-
men Benzodiazepine und Opiate) 
- 
Der Patient hat keine Suizidversuche in der Vorgeschichte 
- 
Der Patient hat keine bekannte Epilepsie oder Blutungsneigung o-
der ein Engwinkelglaukom oder ein Glaukom in der Vorgeschichte  
- 
Der Patient hatte keine bariatrische Chirurgie in der Vorgeschichte 
- 
Der Patient besitzt keine bekannten Allergien oder Kontraindikatio-
nen bzgl. Escitalopram oder Simvastatin 
- 
Keine der folgenden Punkte treffen für den Patienten zu: 
- 
Erblich bedingte Muskelerkrankungen  
- 
Bekannte Vorgeschichte von Rhabdomyolyse  
- 
erhöhte Kreatininkinase (CK) außerhalb der geschlechts-
spezifischen Referenzintervalle 
- 
muskuläre Symptomatik unter Behandlung mit Statinen o-
der Fibraten in der Vorgeschichte 
- 
Der Patient hat keinen erhöhten TSH-Wert (TSH basal) außerhalb 
der alters- und geschlechtsspezifischen Referenzintervallen 
Der Patient hat keinen Insulin-abhängigen Diabetes Mellitus 
- 
Der Patient besitzt keine unkontrollierte Leberfunktionsstörung, 
Nieren- oder Herz-Kreislauf-Erkrankungen 
- 
Der Patient besitzt keine unbehandelte Hypothyreose 
- 
Der Patient hatte keinen Myokardinfarkt oder Schlaganfall in der 
Vorgeschichte 
- 
Der Patient besitzt keine symptomatische periphere arterielle Ver-
schlusskrankheit  
- 
Der Patient besitzt keine monogene familiäre Hyperlipidämie  
- 
Der Patient hat keine klinisch signifikanten Auffälligkeiten im Si-
cherheitslabor 
- 
Der Patient nimmt derzeit und nahm innerhalb der letzten 6 Monate 
an keiner anderen interventionellen Studie teil  
- 
Der Patient ist kein Mitarbeiter eines Studienzentrums oder Famili-
enmitglied eines Mitarbeiters oder eines Prüfers oder anderweitig 
abhängig vom Sponsor, von einem der Prüfer oder Prüfzentren. 

 
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Page 16 of 70 
Ausschlusskrite-
rien 
- 
Der Patient hat eine aktuelle Einnahme von Statinen (für Visiten 2-
6 gilt der Zusatz: mit Ausnahme der IMP Simvastatin) 
- 
Der Patient hat eine aktuelle Einnahme von Antidepressiva (für Vi-
siten 2-6 gilt der Zusatz: mit Ausnahme der Standardmedikation 
Escitalopram) 
- 
Beim Patienten bestehen akute suizidale Tendenzen (MADRS Item 
10 > 4) 
- 
Der Patient benutzt potente CYP3A4-Inhibitoren (z.B. Clarithromy-
cin, Erythromycin, HIV Proteaseinhibitoren – siehe „Mögliche Risi-
ken, Nebenwirkungen, Kontraindikationen, Maßnahmen, die bei 
eventuellen Zwischenfällen zu ergreifen sind“) 
- 
Der Patient benutzt potente CYP3A4-Induktoren (Carbamazepine, 
Efavirenz, Nevirapin, Etravirine) 
- 
Der Patient benutzt Fibrate, Amiodaron, Amlodipin, Verapamil, Flu-
conazol, Diltiazem, Fusidinsäure, Niacin oder Lomitapid oder 
BCRP-Inhibtoren (z.B. Elbasvir oder Grazoprevir) 
- 
Der Patient benutzt Gemfibrozil, Ciclosporin oder Danazol 
- 
Der Patient hat eine bekannte Überempfindlichkeit gegen sonstige 
Bestandteile von Simvastatin und Escitalopram [Butylhydroxya-
nisol, 
mikrokristalline 
Cellulose, 
Citronensäure-Monohydrat, 
Stärke, Lactose, Magnesiumstearat, Hypromellose, Talkum, Titan-
dioxid, Eisen(III)-oxid, hochdisperses Siliciumdioxid, Croscarmel-
lose-Natrium, Macrogol (Polyethylenglycol)] 
- 
Der Patient benutzt Medikation, die mit QTc-Verlängerung assozi-
iert ist [Antiarrhythmika Klasse IA and III, Antipsychotika (z.B. Hal-
operidol), Phenothiazine, trizyklische Antidepressiva, Antibiotika 
wie z.B. Moxifloxacin, und einige antihistaminerge Medikation (z.B. 
Astemizol, Mizolastin)]  
- 
Der Patient hat klinisch signifikante Auffälligkeiten im 12-Kanal 
EKG (z.B. Verlängerung des QTc-Intervalls ≥ 500 ms oder QTc ≥ 
60 ms zu Baseline-Visite) 
- 
Die Patientin ist schwanger   
- 
Die Patientin im gebärfähigen Alter zeigt eine fehlende Bereitschaft 
für die Anwendung einer effektiven Verhütungsmethode (definiert 
als Pearl-Index < 1) 
- 
Der Patient nimmt psychotrope Medikation (z.B. Antipsychotika, 
Antikonvulsiva, Lithium oder Johanniskraut) mit Ausnahme von 
Benzodiazepinen, Non-Benzodiazepinen oder Opiaten ein 
- 
Der Patient benutzt nicht selektive, irreversible MAO-Hemmer (z.B. 
Tranylcypromin) oder selektive, reversible MAO-A Hemmer (z.B. 
Moclobemid) oder den reversiblen nicht selektiven MAO-Hemmer 
Linezolid 
- 
Der Patient zeigt eine fehlende Bereitschaft zur Speicherung, Ver-
arbeitung und Weitergabe pseudonymisierter Studiendaten im 
Rahmen der klinischen Prüfung 
- 
Der Patient ist aufgrund behördlicher oder gerichtlicher Anordnung 
in einer Anstalt untergebracht  
Visiten und Doku-
mentationszeit-
punkte 
Für die Planung der einzelnen Visiten ist eine maximale Abweichung von 
± 3 Tagen zulässig. 

 
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Page 17 of 70 
Erhebungen 
Scree-
ning 
 
Baseline 
Visit 1 
 
 
Visit 2 
 
 
Visit 3 
 
 
Visit 4 
 
 
Visit 5 
Studien-
ende 
Visit 6 
 
 
Woche 
0 
Woche 
1 
Woche 
2 
Woche 
4 
Woche 
8 
Woche 
12 
Screening und Ein-
willigung 
 
 
 
 
 
 
 
 
Einwilligungser-
klärung 
X 
 
 
 
 
 
 
 
Einschlusskrite-
rien  
 
X 
 
 
 
 
 
 
Ausschlusskrite-
rien 
 
X 
X 
X 
X 
X 
X 
 
Medizinische 
Anamnese  
X 
 
 
 
 
 
 
 
Aktueller 
Be-
handlungsstatus 
 
X 
 
 
 
 
 
 
M.I.N.I – DSM-5 
X 
 
 
 
 
 
 
 
Urin/Serum Dro-
genscreening 
X 
 
 
 
 
 
 
 
Begleitmedika-
tion 
X 
 
 
 
 
 
 
Sicherheit 
 
 
 
 
 
 
 
 
Körperliche Un-
tersuchung 
X 
 
 
 
 
 
X 
 
EKG  
X 
X 
X 
X 
X 
X 
X 
 
Blutdruck- 
und 
Herzfrequenz-
messung 
X 
X 
X 
X 
X 
X 
X 
 
Sicherheitslabor 
(inkl. Schwan-
gerschaftstest - 
nur für Frauen) 
X 
X 
 
 
X 
X 
X 
 
Registrierung 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Effektivität 
 
 
 
 
 
 
 
 
MADRS 
X 
X 
X 
X 
X 
X 
X 
 
BDI-II 
 
X 
X 
X 
X 
X 
X 
Soz. 
Funk-
tionsniveau 
und 
Lebensqualität 
 
 
 
 
 
 
 
 
SOFAS 
 
X 
 
 
X 
 
X 
 
EQ-5D-3L 
 
X 
 
 
X 
 
X 
Andere 
 
 
 
 
 
 
 
 
Demographische 
Daten 
X 
 
 
 
 
 
 
 
BMI 
X 
X 
 
 
 
 
X 
 
Bauchumfang 
 
X 
 
 
 
 
X 
 
PGIC 
 
 
X 
X 
X 
X 
X 
 
CGI-S 
 
X 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
X 

 
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Page 18 of 70 
 
Labor - Lipid  
 
X 
 
 
 
 
X 
 
Labor - Immun-
metabolismus / 
mitochondriale 
Funktion 
 
X 
 
 
X 
X 
X 
 
Medikamenten-
ausgabe 
 
X 
 
X 
X 
X 
 
Anmerkung: Elektrokardiographie (EKG), Body-Mass-Index (BMI), Mini International Neuropsychiatric 
Interview (MINI), Montgomery-Asberg Depression Scale (MADRS), Beck-Depressions-Inventar (BDI), 
Patient Global Impression of Change (PGIC), Clinicians’ Global Impression of Severity of illness (CGI-
S), Clinicians’ Global Impression of Improvement (CGI-I), Social and Occupational Functioning As-
sessment Scale (SOFAS), Generic Quality of Life Questionnaire (EQ-5D-3L). 
Sicherheit 
Beurteilung der Sicherheit: Beurteilung des Blutdrucks und der Herzfre-
quenz zu jeder Visite. Beurteilung der Laborparameter - Sicherheitslabor 
(inklusive Schwangerschaftstest) zum Screening, Baseline, Woche 4, Wo-
che 8 und Woche 12. Körperliche Untersuchung zu Screening und zum 
Studienende. EKG zum Screening und zu jeder weiteren Visite. Das Stan-
dardprozedere für die Meldung von „adverse events“ wird angewendet. 
„Adverse events“ werden ab der Visite 2 zu jeder Visite erfasst.  
Abbruchkriterien 
Abbruchkriterien für individuelle Patienten 
Jeder Teilnehmer kann ohne Angabe von Gründen aus der Studie aus-
scheiden. Zwingende Gründe für einen Abbruch sind:  
- Adverse Events (AE), klin. sign. auffällige Laborbefunde oder andere 
Krankheitsfälle, bei denen eine weitere Studienteilnahme dem Wohler-
gehen des Patienten schaden würde (siehe auch 11.1) 
- Wenn Patienten Ausschlusskriterien erfüllen (entweder neu entwickelt 
oder nicht zuvor erkannt) die einer weitere Studienteilnahme ausschlie-
ßen 
Abbruchkriterien für Studie 
Laut der deutschen Fachinformation für Simvastatin war die kombinierte 
Inzidenz für Myopathie/Rhabdomyolyse bei 41.413 Patienten, die mindes-
tens 4 Jahre behandelt wurden, 0,08 % für die Dosierung von 40 mg pro 
Tag Simvastatin. Die schwere symptomatische Hyponatriämie (Serum 
Natrium [SNa] <125 mmol/L) ist eine seltene, jedoch potenziell fatale Kom-
plikation von Escitalopram. Symptome von Hyponatriämie reichen von 
Kopfschmerzen, Konzentrationsstörungen, Gedächtnisstörungen, Ver-
wirrtheit, Schwäche, unsicherer Gang und Stand bis zu Halluzination, 
Synkope, Krampfanfälle, Koma, Atemstillstand und Tod. Daher werden wir 
die gesamte Studie vorzeitig abbrechen, wenn das Vorkommen von be-
handlungs-assoziierten SAE „Myopathie/Rhabdomyolyse“ wie definiert in 
der deutschen Fachinformation für Simvastatin (Muskelschmerzen, -emp-
findlichkeit oder –schwäche verbunden mit Erhöhungen der Kreatinkinase 
(CK) über das 10-Fache des oberen Normwertes) oder das Vorkommen 
vom behandlungs-assoziierten SAE „schwere symptomatische Hyponat-
riämie“ (Serum Natrium [SNa] <125 mmol/L) jeweils bei mehr als 5 Stu-
dienteilnehmern auftritt. Weiterhin wird ein vorzeitiges Studienende in Er-
wägung gezogen, wenn neue wissenschaftliche Erkenntnisse verfügbar 
werden, welche die Risiko-Nutzen-Abwägung signifikant verändern. Soll-
ten solche Erkenntnisse verfügbar werden, wird die Rekrutierung und Be-
handlung sofort unterbrochen. Eine finale Entscheidung bzgl. einer Wei-

 
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Page 19 of 70 
terführung oder Beendigung der Studie wird durch den Sponsor/PI getrof-
fen basierend auf der Empfehlung des Data and Safety Monitoring Board 
(DSMB). 
Statistische Aus-
wertung 
Effektivität (Primärer, konfirmatorischer Endpunkt) 
In der primären Analyse soll mithilfe von Gaussian linear models for repea-
ted measures (s.g. MMRM) die MADRS Veränderung von der Baseline 
zur Woche 12 zwischen der Simvastatin- und Placebo-Gruppe verglichen 
werden. Hierbei sollen die Faktoren Intervention, Zentrum, Zeit (Woche 1, 
2, 4, 8, und 12) und die Interaktion Intervention x Zeit berechnet werden. 
Als Kovariat werden die Baseline MADRS Punkte berücksichtigt. Die pri-
märe zu analysierende Population ist die intention-to-treat (ITT) Popula-
tion.  
Effektivität (Sekundäre, explorative Endpunkte) 
Die zentralen sekundären Endpunkte, die Ansprechrate in Prozent, Re-
missionsrate und MCID sollen mithilfe von logistischen Regressionsmo-
dellen analysiert werden, mit Intervention und Zentrum als Faktoren und 
dem MADRS Baseline Score als Kovariate. Die Analyse von kontinuierli-
chen sekundären Endpunkten soll identisch mit der Analyse des primären 
Ergebnisses erfolgen. Die Analyse der Sicherheitsparameter und der se-
kundären Endpunkte soll einen exploratorischen Charakter haben.  
Pharmakologisch-
toxikologische 
Prüfung 
Sowohl Simvastatin als auch Escitalopram sind für mehrere Indikationen 
seit Jahrzehnten zugelassene Medikamente. Die jeweiligen aktuellsten 
Versionen der deutschen Fachinformationen befinden sich im Investigator 
site file (ISF). 
Mögliche Risiken, 
Nebenwirkungen, 
Kontraindikatio-
nen, Maßnahmen, 
die bei eventuel-
len Zwischenfällen 
zu ergreifen sind 
Simvastatin ist das IMP (Investigational Medical Product), welches gegen 
ein Placebo als Zusatztherapie zur konventionellen Antidepressiva-Stan-
dardtherapie mit Escitalopram („open label“) jedem Teilnehmer verab-
reicht wird. Im Folgenden sind die Risiken und möglichen unerwünschten 
Ereignisse für beide Medikamente aufgelistet. Siehe für weitere Informati-
onen die aktuellste Version der deutschen Fachinformation.  
 
Simvastatin: Simvastatin ist seit mehreren Jahrzehnten für mehrere Indi-
kationen zugelassen und ist als sichere Medikation anerkannt. Die folgen-
den Risiken und unerwünschten Ereignisse sind der aktuellsten Version 
der deutschen Fachinformation entnommen. 
Simvastatin ruft gelegentlich eine Myopathie hervor, die sich in Muskel-
schmerzen, -empfindlichkeit oder –schwäche verbunden mit Erhöhungen 
der Kreatinkinase (CK) äußert. Die schwerwiegendste Form von Myopa-
thie ist Rhabdomyolyse mit oder ohne akutem Nierenversagen aufgrund 
von Myoglobinurie, welche sehr selten vorkommt und dosisabhängig ist. 
Die kombinierte Inzidenz für Myopathie/Rhabdomyolyse in 41.413 Patien-
ten, die mind. 4 Jahre behandelt wurde, war 0,03 % für 20 mg/d, 0,08 % 
für 40 mg/d, und 0,61 % für 80 mg/d Simvastatin. Um die Risiken von Sim-
vastatin zu minimieren, werden wir die mittlere Dosis (40 mg/d) und nicht 
die hohe Dosis (80 mg/d) verwenden. Zusätzlich zu einem Sicherheitsla-
bor, welches zum Screening, zur Baseline, Woche 4 und Woche 12 aus-
geführt wird, wird explizit danach gefragt, ob der Patient unter anderweitig 
unerklärlichen Muskelschmerzen oder dunklem Urin als Hinweis für Rhab-
domyolyse gelitten hat/leidet. 

 
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Page 20 of 70 
Andere unerwünschte Ereignisse werden im Folgenden aufgelistet. Sie 
sind der aktuellsten Version der deutschen Fachinformation entnommen 
und wie folgt klassifiziert: 
Sehr häufig (> 1/10), häufig (> 1/100), gelegentlich (> 1/1.000), selten (> 
1/10.000), sehr selten (< 1/10.000), nicht bekannt (kann auf Grundlage der ver-
fügbaren Daten nicht abgeschätzt werden) 
Sehr häufig: keine 
Häufig: keine 
Gelegentlich: keine 
Selten: Anämie, Kopfschmerzen, Parästhesien, Schwindel, periphere 
Neuropathie, Obstipation, Bauchschmerzen, Flatulenz, Dyspepsie, 
Diarrhö, Übelkeit, Erbrechen, Pankreatitis, Hepatitis/Ikterus, Hautaus-
schlag, Juckreiz, Alopezie, Myopathie, Rhabdomyolyse, Myalgie, 
Muskelkrämpfe, Asthenie 
Sehr selten: Schlaflosigkeit, Beeinträchtigung des Erinnerungsvermö-
gens, Leberversagen 
Nicht bekannt: Depression, interstitielle Lungenkrankheit, Tendinopa-
thie, immunvermittelte nekrotisierende Myopathie, erektile Dysfunk-
tion 
Folgende Medikamente sind kontraindiziert bei Einnahme von Simvasta-
tin, aufgrund der CYP3A4 Inhibition: (Itraconazol, Ketoconazol, Posaco-
nazol, Voriconazol, Erythromycin, Clarithromycin, Telithromycin, HIV Pro-
tease Inhibitoren (z.B. Nelfinavir), Boceprevir, Telaprevir, Nefazodon, 
Cobicistat, Ciclosporin, Danazol, Gemfibrozil).  
Folgende Medikamente, bei denen von einer gleichzeitigen Anwendung 
mit Simvastatin (Dosis 40 mg/d) abgeraten wird, sind nicht zugelassen 
(Fibrates, Amiodaron, Amlodipin, Verapamil, Fluconazol, Diltiazem, Fusi-
dinsäure, Niacin, Lomitapid). 
Patienten werden außerdem darauf hingewiesen, dass sie keinen Grape-
fruitsaft im Zeitraum der Behandlung mit Simvastatin zu sich nehmen sol-
len, aufgrund der Inhibition von CYP3A4 und dem korrespondierenden 
Anstieg der Simvastatin-Plasmakonzentration. 
Medikamente, welche CYP3A4 induzieren und demnach zu erniedrigten 
Simvastatin-Plasmalevel 
führen, 
werden 
auch 
nicht 
zugelassen 
(Carbamazepin, Efavirenz, Nevirapin, Etravirin). 
Patienten, die eine Kontraindikation bzgl. Simvastatin aufweisen, werden 
nicht in die Studie eingeschlossen oder bei späterem Auftreten von der 
Studie ausgeschlossen (siehe Einschlusskriterien). 
Im Falle eines Notfalls wird die Verblindung unmittelbar aufgehoben, und 
der Patient erhält eine medizinische Versorgung.  
 
Escitalopram: Das bedeutendste Risiko von Escitalopram stellt eine QTc-
Verlängerung im EKG dar, welche zu ventrikuläre Arrhythmien (Torsade 
de Pointes) führen kann. Um Patienten mit einer QTc-Verlängerung aus-
zuschließen, wird vor Studieneinschluss ein EKG geschrieben. Zusätzli-
che Sicherheits-EKGs werden bei jeder Visite ausgeführt.  

 
EudraCT-No: 2018-002947-27 
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Version 1.2 vom 03.12.2019 
 
Page 21 of 70 
Andere unerwünschte Ereignisse werden im Folgenden aufgelistet. Sie 
sind der aktuellsten Version der deutschen Fachinformation entnommen 
und wie folgt klassifiziert: 
Sehr häufig (> 1/10), häufig (> 1/100), gelegentlich (> 1/1.000), selten (> 
1/10.000), sehr selten (< 1/10.000), nicht bekannt (kann auf Grundlage der ver-
fügbaren Daten nicht abgeschätzt werden) 
Sehr häufig: Kopfschmerzen, Übelkeit 
Häufig: Verminderter Appetit, gesteigerter Appetit, Gewichtszunahme, 
Ängstlichkeit, Ruhelosigkeit, anormale Träume, verringerte Libido, An-
orgasmie, Schlaflosigkeit, Schläfrigkeit, Schwindel, Parästhesie, Tre-
mor, Sinusitis, Gähnen, Diarrhoe; Obstipation; Erbrechen, Mundtro-
ckenheit, Vermehrtes Schwitzen, Arthralgie, Myalgie, Ejakulationsstö-
rungen, Impotenz, Fieber 
Gelegentlich: Gewichtsabnahme, Nächtliches Zähneknirschen, Agi-
tiertheit, Nervosität, Panikattacken, Verwirrtheit, Geschmacksstörun-
gen, Schlafstörungen, Synkope, Mydriasis, Sehstörungen, Tinnitus, 
Tachykardie, Nasenbluten, Gastrointestinale Blutungen, Urtikaria, 
Haarausfall, Ausschlag, Juckreiz, Metrorrhagie, Menorrhagie, Ödeme 
Selten: Anaphylaktische Reaktion, Aggression, Depersonalisation, 
Halluzinationen, Serotonin-Syndrom, Bradykardie,  
Sehr selten: keine 
Nicht bekannt: Thrombozytopenie, Inadäquate ADH-Sekretion, Hy-
ponatriämie, Anorexie, Manie, suizidale Gedanken, suizidales Verhal-
ten, Dyskinesien, Bewegungsstörungen, Krämpfe, psychomotorische 
Unruhe/Akathisie, Elektrokardiogramm: QT-Verlängerungen im EKG, 
Orthostatische Hypotonie, Hepatitis, erhöhte Leberenzyme, Ekchymo-
sen, Angioödem, Harnretention, Galaktorrhoe, Priapismus,  
Medikation die bei Einnahme von Escitalopram kontraindiziert ist, wird 
nicht zugelassen, darunter alle irreversiblen MAO-Inhibitoren und Medika-
mente die mit QT-Verlängerungen assoziiert sind [Antiarrhythmika Klasse 
IA und III, Antipsychotika (z.B. Haloperidol), Phenothiazin, trizyklische An-
tidepressiva, Antibiotika (z.B. Moxifloxacin) und bestimmte Antihistami-
nika (z.B. Astemizol, Mizolastin)].  
Patienten, die eine Kontraindikation bzgl. Escitalopram aufweisen, werden 
nicht in die Studie eingeschlossen bzw. bei späterem Auftreten aus der 
Studie ausgeschlossen (siehe Ausschlusskriterien).  
Risiko-Nutzen-Ab-
wägung 
Beide Medikamente (Simvastatin, Escitalopram) sind seit Jahrzehnten für 
mehrere Indikationen zugelassen und haben sich insgesamt als sicher er-
wiesen. Alle depressiven Patienten, die in die Studie eingeschlossen sind, 
werden kontinuierlich mit einem Standard-Antidepressivum (Esci-
talopram) behandelt, welches durch die Nationale Versorgungsleitlinie als 
„Goldstandard“ für die Behandlung von MDD beschrieben wurde. Es gibt 
Hinweise für eine Dosis-Wirkungs-Beziehung von Escitalopram. Insbe-
sondere konnte für Patienten mit einer schweren Depression gezeigt wer-
den, dass sie von der höheren Standarddosierung von Escitalopram 20 
mg/d profitieren [1]. Eine fixe Dosierung von 10 mg/d Escitalopram für die 
gesamte Studienteilnahme von 12 Wochen würde daher einem Teil der 
Patienten nicht die bestmögliche Therapie ermöglichen und wäre aus un-
serer Sicht ethisch nicht vertretbar. Eine Aufdosierung von 10 mg/d auf 20 

 
EudraCT-No: 2018-002947-27 
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Page 22 of 70 
mg/d je nach individuellem Ansprechen würde hingegen die Vergleichbar-
keit der Verumgruppe mit der Plazebogruppe potentiell beeinträchtigen, 
da eine stärkere Abnahme der depressiven Symptomatik in der Verum-
gruppe im Vergleich zur Plazebogruppe möglicherweise durch den ver-
gleichsweise höheren Anteil an Escitalopram-Aufdosierungen in der Pla-
zebogruppe maskiert werden würde. Daher werden wir die Dosierung 
nach initialer Dosierung von 10 mg/d in den ersten beiden Wochen auf 20 
mg/d erhöhen bis zum Studienende. Dennoch ist bei Auftreten von Ver-
träglichkeitsproblemen eine langsamere Aufdosierung bzw. eine Dosisre-
duktion möglich mit folgendem Dosisänderungsschema (siehe Kapitel 
7.2.4).  
Simvastatin als IMP wird als Zusatztherapie verabreicht, sodass keine me-
dikamentenfreien Patienten in der Studie eingeschlossen sind. Invasive 
Interventionen, zusätzlich zur Entnahme von venösem Blut, werden in die-
ser Studie nicht angewandt. Die Risiken, die mit einer Studienteilnahme 
einhergehen, beziehen sich dementsprechend hauptsächlich auf Simvas-
tatin als IMP, welches bereits bei depressiven Patienten eingesetzt wurde 
und sich in Kombination mit SSRIs (Selective Serotonin Reuptake Inhi-
bitor) als gut verträglich erwiesen hat [2].  
Sowohl für die lipidsenkende Wirkung als auch für die pleiotropen Effekte 
von Statinen gibt es Hinweise, dass eine hohe Statindosis effektiver ist als 
die niedrige Standarddosis [3-5]. Insbesondere bei ZNS-Erkrankungen 
wie Multiple Sklerose und leichter kognitiver Störung wurde in bisherigen 
Studien die hohe Dosis von Simvastatin (60 – 80 mg/d) verabreicht [6-8]. 
Eine der wichtigsten Nebenwirkungen von Simvastatin ist die dosisabhän-
gige Myopathie. Die Myopathiehäufigkeit unter Simvastatin lag annährend 
bei 0,03 % unter 20 mg/d, bei 0,08 % unter 40 mg/d und steigt erst unter 
80 mg/d deutlich an auf 0,61 % laut aktuellster Version der deutschen 
Fachinformation. Um die Risiken von Simvastatin zu minimieren und 
gleichzeitig die pleiotropen Effekte von Simvastatin bei Depression zu un-
tersuchen, werden wir eine mittlere Dosis von 40 mg/d und nicht eine hohe 
Dosis von 80 mg/d verabreichen. Zusätzlich erheben wir Sicherheitspara-
meter inklusive Kreatininkinase (CK) im Blut zum Screening, zur Baseline 
und jeweils in Woche 4, 8 und 12. Ferner wird der Patient zu jeder Visite, 
explizit nach unerklärlichen Muskelschmerzen und dunklem Urin gefragt 
als Zeichen für Rhabdomyolyse. Weiterhin schließen wir besonders ge-
fährdete Patientengruppen (z.B. Patienten mit Nierenfunktionsstörung, 
unbehandelter Hypothyreose oder muskulärer Symptomatik unter Be-
handlung mit Statinen oder Fibraten in der Anamnese) per Ein- und Aus-
schlusskriterien nicht in die Studie ein. Um Patienten mit einer QTc-Ver-
längerung auszuschließen, wird ein Sicherheits-EKG zum Screening und 
bei jeder anderen Visite ausgeführt.  
Basierend auf den Ergebnissen einer kürzlich erschienenen Metaanalyse, 
welche kleine RCTs umfasste, ist ein vorteilhafter antidepressiver Effekt 
von Simvastatin zu erwarten [2]. Viele Patienten mit komorbider Adiposi-
tas könnten zusätzlich, hinsichtlich einer primären Prävention von kardi-
ovaskulären Krankheiten, von der Einnahme von Simvastatin profitieren.  
Zusammenfassend überwiegt der potentielle Nutzen der Studie deutlich 
den potentiellen Risiken, die bei einer Einnahme von Simvastatin und 
Escitalopram auftreten könnten. Besonders zu betonen sind die Ergeb-

 
EudraCT-No: 2018-002947-27 
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nisse einer kürzlich erschienen Literaturrecherche zum parallelen Ge-
brauch von SSRIs und Statinen mit folgendem Fazit: „Escitalopram, Ci-
talopram und Paroxetin sind beinahe zweifelsfrei sicher in Kombination 
mit allen Statinen“ [9]. 
 
 
 

 
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3. Flow-Chart 
 
Figure 1: Study procedure 
4. Introduction 
4.1 Introduction and background 
The World Health Organization’s Global Burden of Disease (GBD) study just recently demon-
strated that of all diseases worldwide, major depressive disorder (MDD) is among the top 5 with 
regard to years lived with disability (YLD) [10]. Among all psychiatric disorders, MDD is by far the 
leading cause of disability [11]. The 12-months prevalence of MDD in Germany is 6% (women: 
8.1%; men: 3.8%) [12]. Mortality rates of MDD are twice as high compared to the general popu-
lation and translate to a reduced life expectancy of 14.0 years in men and 10.1 years in women 
[13]. 
The prevalence of obesity in the German population is 23.3% in men and 23.9% in women [14]. 
In patients with obesity, mortality rates are elevated and they increase in relation to BMI as re-
cently confirmed in a meta-analysis of 239 studies from four continents [15]. In the GBD study, 
obesity was estimated to cause 3.4 million deaths, 3.9% of years of life lost, and 3.8% of disabil-
ity-adjusted life years worldwide [16].  
MDD and obesity are both linked to a higher risk of cardiovascular disease and stroke, further 
increasing their public health and economic impact. Importantly, MDD and obesity frequently co-
occur and the presence of one condition increases the risk for developing the other [17]. 
Statins (3-hydroxy-3-methylglutaryl Co-A reductase inhibitors) are among the most prescribed 
medications worldwide with well-established safety and efficacy. Recent guidelines recommend 
use of statins in primary prevention of cardiovascular disease [18], which has been linked to both 
MDD and obesity.  
Moreover, statins are highly promising candidates to treat MDD as described in detail below. 
However, no randomized controlled study so far has tested the antidepressive potential of statins 
in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that 
often exhibits a chronic course of MDD and treatment resistance [19-22]. Given the enormous 
public health impact of MDD and obesity and given the evidence of antidepressive effects of 

 
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statins, a controlled trial of adjunct statin treatment in comorbid patients appears clearly war-
ranted. 
4.2 Data on IMP-Application 
4.2.1 Summary 
Simvastatin is a lipid-altering agent and one of the components of multiple risk factor intervention 
in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercho-
lesterolemia. Simvastatin administration is indicated as an adjunct to diet when the response to 
a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone 
has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, 
Simvastatin can be started simultaneously with diet. The indications listed below are taken from 
the prescribing information for Simvastatin (“Fachinformation SimvaHEXAL®, aktuellste Ver-
sion”). 
- 
Reductions in Risk of CHD Mortality and Cardiovascular Events. Simvastatin is indicated 
to 
o Reduce the risk of total mortality by reducing CHD deaths.  
o Reduce the risk of non-fatal myocardial infarction and stroke.  
o Reduce the need for coronary and non-coronary revascularization procedures.  
- 
Hyperlipidemia. Simvastatin is indicated to 
o Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol 
(LDL-C), apolipoprotein B (ApoB), and triglycerides (TG), and to increase high-
density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia 
(Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia 
(Fredrickson type IIb).  
o Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hy-
perlipidemia).  
o Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia 
(Fredrickson type lll hyperlipidemia). 
o Reduce total-C and LDL-C in patients with homozygous familial hypercholesterol-
emia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) 
or if such treatments are unavailable.  
- 
Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH). Simvas-
tatin is indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in ado-
lescent boys and girls who are at least one-year post-menarche, 10-17 years of age, with 
HeFH, if after an adequate trial of diet therapy the following findings are present:  
o LDL cholesterol remains 190 mg/dL; or 
o LDL cholesterol remains 160 mg/dL and  
o There is a positive family history of premature cardiovascular disease (CVD) or  
o Two or more other CVD risk factors are present in the adolescent patient.  
In patients with CHD or at high risk of CHD, Simvastatin can be started simultaneously with diet. 
For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel dis-
ease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 
mg/d. Lipid determinations should be performed after 4 weeks of therapy and periodically there-
after. 
Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year 
of treatment, use of the 80 mg/d dose of Simvastatin should be restricted to patients who have 
been taking Simvastatin 80 mg/d chronically (e.g., for 12 months or more) without evidence of 
muscle toxicity. Patients who are currently tolerating the 80 mg/d dose of Simvastatin who need 

 
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to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for 
Simvastatin should be switched to an alternative statin with less potential for the drug-drug inter-
action. Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80 
mg/d dose of Simvastatin, patients unable to achieve their LDL-C goal utilizing the 40 mg/d dose 
of Simvastatin should not be titrated to the 80 mg/d dose, but should be placed on alternative 
LDL-C-lowering treatment(s) that provides greater LDL-C lowering. 
For adverse drug reactions and restrictions, contraindications and drug interactions see 7.2.5.  
4.2.2 Physical, Chemical, and Pharmaceutical Properties and Formulation 
Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of 
Aspergillus terreus. After oral ingestion, Simvastatin, which is an inactive lactone, is hydrolyzed 
to the corresponding β -hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-co-
enzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to meva-
lonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. 
Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahy-
dro-4- hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β ,8β (2S*,4S*),-
8aβ ]]. The empirical formula of Simvastatin is C25H38O5 and its molecular weight is 418.57. Its 
structural formula is: 
 
Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble 
in water, and freely soluble in chloroform, methanol and ethanol. Simvastatin for oral administra-
tion contain the following inactive ingredients: ascorbic acid, citric acid, hydroxypropyl cellulose, 
hypromellose, iron oxides, lactose, magnesium stearate, microcrystalline cellulose, starch, talc, 
and titanium dioxide. Butylated hydroxyanisole is added as a preservative. 
Simvastatin should be stored between 5-25°C. 
4.2.3 Nonclinical Studies 
Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, 
after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A 
(HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, 
an early and rate limiting step in the biosynthetic pathway for cholesterol [23]. The primary mech-
anism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosyn-
thesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing 
the clearance of LDL-cholesterol (LDL-C) [24]. Simvastatin reduces very low-density lipoprotein 
(VLDL) and triglyceride (TG) and increases high-density lipoprotein cholesterol (HDL-C) [23].  
In addition, Simvastatin may exert cardiovascular protective effects that are independent of LDL-
C lowering called “pleiotropic” effects. Because statins inhibit the production of isoprenoid inter-
mediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small gua-
nosine triphosphate binding proteins such as Rho and Rac, and their downstream effectors such 
as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In 
cell culture and animal studies, these effects alter the expression of endothelial nitric oxide syn-
thase, the stability of atherosclerotic plaques, the production of pro-inflammatory cytokines and 

 
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reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy 
and fibrosis. [24]  
Simvastatin has antidepressant and anxiolytic effects in rats [25]. In addition, statin effects in 
animal models on several neurobiological processes and structures with relevance for MDD such 
as inflammatory markers, glucocorticoids and serotonin in the hippocampus, glutamatergic N-
Methyl-D-Asparte (NMDA) receptors, Brain Derived Neurotrophic Factor (BDNF) levels, and do-
pamine receptors have been demonstrated (for review of CNS effects of statins see [26]). 
Oral absorption of Simvastatin is rapid and the bioavailability low due to an extensive first-pass 
metabolism. Plasma protein binding is high for Simvastatin (> 95%). Simvastatin undergoes en-
terohepatic circulation and is recovered mainly in feces via bile, the extent of which is species-
dependent. Elimination is rapid with metabolism being the main elimination route. Metabolism 
varies with the animal species, particularly the beta-oxidation of the dihydroxy heptanoic side 
chain that occurs primarily in rodents. [27] The IC50 (the concentration resulting in 50% inhibition 
of cholesterol synthesis) value of Simvastatin varies from 1.0 to 23 nM in different experimental 
systems. [23] 
The administration of high dosages of Simvastatin has resulted in the production of toxicity in a 
variety of tissues and in a number of species. However, the investigative toxicology studies have 
indicated that many are mechanism-based phenomena occurring only at high dosage levels of 
Simvastatin and are the product of a profound, prolonged inhibition of the target enzyme that is 
not achieved at clinical dosages in humans. [28] On the other hand, muscle injury upon statin 
treatment has been confirmed and it has been shown that it can be prevented in a rat model by 
giving mevalonate, the product of the inhibited enzyme [29]. Simvastatin was not teratogenic in 
rats or rabbits, but in several teratology studies in the 1980s Lovastatin was found to produce 
fetal malformations in rats and atorvastatin at maternally toxic doses was linked to developmental 
toxicity [30-32].  
4.2.4 Effects in humans 
Elevated levels of serum cholesterol is associated with the development of atherosclerosis and 
increased cardiovascular risk [33]. Simvastatin decreases cholesterol biosynthesis and de-
creases serum LDL-C and triglyceride levels [34]. Landmark clinical trials have demonstrated the 
efficacy of Simvastatin for both primary and secondary prevention of coronary heart disease 
(CHD) [35]. In addition, there is cumulative evidence for pleiotropic effects in humans but its 
contribution to clinical outcomes in addition to LDL-C lowering remains unknown [24].  
Simvastatin showed antidepressive effects as adjunct treatment to Fluoxetin in one recent RCT 
[36] (see Figure 2). With regard to lipid levels, however, no change was reported during the 
course of the study (6 weeks). Concerning this, the effect of statin for prevention of depression 
was found to be independent of the cholesterol lowering effects of statins [37]. Furthermore, 
Simvastatin was superior to atorvastatin in depressed patients with heart disease [38]. According 
to a meta-analysis of small, randomized controlled trials with various statins, a beneficial antide-
pressive effect of Simvastatin is to be expected [2] (see Figure 3). Effects of Simvastatin on 
depressed patients with comorbid obesity is not known to our knowledge, but it is to be expected 
that they might additionally benefit from Simvastatin in terms of primary prevention. Simvastatin 
passes the blood-brain barrier [39]. 

 
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Figure 2: Randomized controlled trial examining the effect of add-on Simvastatin vs. add-on placebo to Fluoxe-
tine in patients with major depression (Gougol et al, J Psychopharmacol, 2015)[36]. 
Simvastatin undergoes oxidative metabolism, primarily by cytochrome P450 3A4, while simvas-
tatin acid is oxidised via CYP 3A4 and β-oxidation enzyme systems. Both the parent lactone form 
and the acid are normally present in very small amounts in plasma due to a high hepatic extrac-
tion ratio (∼ 95%). The major active metabolites of simvastatin present in human plasma are the 
β-hydroxyacid of simvastatin and its 6´-hydroxy, 6´-hydroxymethyl, and 6´-exomethylene deriva-
tives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 
2.4 hours postdose [32]. Simvastatin is cleared predominantly by the liver. Nevertheless, the 
plasma concentration of HMG-CoA reductase inhibitory activity is probably higher for Simvastatin 
in patients with severe renal insufficiency as it is for Lovastatin. Although simvastatin is a sub-
strate for CYP 3A4 simvastatin 80 mg inhibited neither hepatic nor intestinal CYP 3A4. Therefore, 
simvastatin can be given with other substrates of CYP 3A4 without concern over effects on their 
plasma levels. There is also no evidence that simvastatin inhibits other cytochrome isoforms. 
Furthermore, simvastatin is not known to cause any clinically significant change in the plasma 
levels of any other drug, regardless of its metabolism and clearance pathways. In addition, the 
plasma concentrations of simvastatin and its metabolites are too low to cause significant protein 
binding displacement reactions. [40] 
CYP 3A4 inhibitors can produce substantial increases in the plasma concentrations of the parent 
lactone form and the equivalent acid, although the absolute levels remain quite low. However, 
there are, in addition, three downstream oxidised active metabolites of simvastatin that together 
account for about 75% of the HMG-CoA reductase inhibitory activity in plasma. The only known 
consequence of drug interactions between certain CYP 3A4 inhibitors and simvastatin is an in-
crease in the risk of myopathy. [40]  
Except for rare cases of myopathy and marked but asymptomatic increases in hepatic transam-
inases, none of the adverse effects of simvastatin found in animals occur at human therapeutic 
doses [40]. The most severe form of myopathy is rhabdomyolysis with or without acute renal 
failure secondary to myoglobinuria that occurs very rarely and is dose-dependent. The combined 
incidence for myopathy/rhabdomyolysis in 41.413 patients treated for at least 4 years was 0.03% 
for 20 mg/d, 0.08% for 40 mg/d, and 0.61% for 80 mg/d Simvastatin [32]. In regard to drug inter-
actions with SSRI a recent extensive literature review concluded the following: “Escitalopram, 
Citalopram, and Paroxetine are almost certain to be safe with all statins” [9]. Increasing age, 
female gender, renal insufficiency, subclinical hypothyroidism, polypharmacy, high levels of 
physical activity, alcohol and drug abuse, HIV infection, severe trauma, surgery with increased 
metabolic demands, genetic factors and inherited mitochondrial diseases have been related to 
increased risk of statin-induced myopathy [41]. In a meta-analysis of randomized trials, statin 
therapy was found to be associated with a slightly increased risk of development of diabetes, but 

 
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the risk was considered low both in absolute terms and when compared with the reduction in 
coronary events [42]. A systematic review on the risks of statins in pregnancy couldn’t show a 
clear relationship of congenital anomalies with statin use in pregnancy and proposed that statins 
are probably not teratogenic [43].  
4.2.5 Summary of Data and Guidance for the Investigator 
Simvastatin is approved for several indications since decades and has in general proven to be 
an effective and safe medication in primary prevention of cardiovascular disease [18], which has 
been linked to both MDD and obesity. Preclinical and clinical data suggest that adjunctive treat-
ment with statins could be useful for the treatment of depressive symptoms. Therefore, in our 
study, we want to investigate whether add-on Simvastatin to standard antidepressant medication 
improves depression to a greater extent than adjunct placebo in patients with major depression 
and comorbid obesity.  
In randomized trials, statin therapy appears to cause only a slight increased risk of side effects 
compared with placebo, and no increased risk of discontinuation of therapy compared with pla-
cebo [44]. In 2017, a meta-analysis of 22 placebo-controlled trials on statin use involving nearly 
130,000 participants showed that 13.3 % of subjects receiving a statin discontinued the drug 
compared with 13.9 % of subjects on placebo (odds ratio [OR] 0.99, 95% CI 0.93-1.06) over a 
mean follow-up of 4.1 years [45]. The most prominent risk of statin use is myopathy, associated 
with muscle pain, muscle weak-ness and increases of creatine kinase (CK). The most severe 
form of myopathy is rhabdomyolysis with or without acute renal failure secondary to myoglobinu-
ria that occurs very rarely and is dose-dependent. Statin-induced myopathy appears to have a 
multi-factorial etiology that includes the effects that statins have on myocyte metabolism, the use 
of other concomitant drugs that increase statin blood levels, and genetic variables that predis-
pose some patients to myopathy. Still, the risk-to-benefit ratio for most dyslipidemic patients 
greatly favors treatment with statins [46]. In regard to drug interaction with our standard medica-
tion Escitalopram, no clinically significant pharmacokinetic interaction is expected. Nevertheless, 
due to the increased risk of muscle injury and the corresponding warning from the US Food and 
Drug Administration we will be using a dose of 40 mg/d Simvastatin in our study. Because in 
pregnancy Simvastatin is contraindicated, pregnant or breastfeeding women or women with 
childbearing potential without acceptable form of contraception will not be included in the study 
and a highly sensitive serum HCG test will be conducted at screening visit, baseline, week 4, 
week 8 and at the end-of-study for women of childbearing potential.  
4.3 Rationale 
Evidence for antidepressive effects of statins has accumulated from four independent lines of 
research:  
a) A meta-analysis [2] (see Figure 3) of three small pilot randomized controlled trials has found 
antidepressive effects of statins as adjunct therapy to standard antidepressant treatment and 
concluded: “Our results suggest that adjunctive treatment with statins could be useful for the 
treatment of depressive symptoms. Additional double-blind randomized, placebo-controlled 
trials are necessary to settle the matter” [2].  
Importantly, even though these pilot RCTs have shown antidepressive effects of statins, 
all of these studies suffered from small sample sizes and all of these studies were con-
ducted in the same county strongly limiting the generalizability of these findings. Thus, 
we propose to conduct this confirmative RCT including about the same number of de-
pressed patients as in all previous RCTs combined. No competing study is currently reg-
istered at clinicaltrials.gov and the International Clinical Trials Registry Platform of the 
World Health Organization. 

 
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Figure 3: Meta-analysis of three randomized controlled trials examining the effects of add-on statin vs. add-on 
placebo to SSRI in patients with major depression (Salagre et al, J Affect Dis, 2016)[4]. 
 
b) A nationwide population-based registry study that included all incident SSRI users in Den-
mark between 1997 and 2012 (n = 872.000) found that combined use of SSRI and statins (n 
= 113.000) was associated with a substantially reduced risk of MDD (adjusted hazard ratio 
0.64, 95% confidence interval 0.55 – 0.75) [47]. Importantly, Citalopram and Simvastatin was 
the most often used SSRI/statin combination and the authors concluded: “this specific com-
bination would be a good candidate for a head-to-head test against a Citalopram-placebo 
combination in a randomized controlled trial”. We will test the recommended combination in 
our study except using Escitalopram instead of Citalopram due to the lack of weight gain with 
Escitalopram compared to Citalopram [48]. 
c) A meta-analysis of prospective cohort studies [49] showed that statin users are less likely to 
develop MDD than non-users. One of the studies included in this meta-analysis was con-
ducted by the first applicant and found odds of MDD to be decreased by 38% in statin users 
vs. non-users [50]. These results were recently corroborated by two large Danish nation-wide 
population-based studies, which found that statin users were less likely to develop depression 
after acute coronary syndrome [51] or after stroke compared to non-users of statins [52] 
d) In animal models of MDD, antidepressive effects of statins have clearly been demonstrated. 
These studies have additionally confirmed statin effects on several neurobiological processes 
and structures with relevance for MDD such as inflammatory markers, glucocorticoids and 
serotonin in the hippocampus, glutamatergic N-Methyl-D-Asparte (NMDA) receptors, Brain 
Derived Neurotrophic Factor (BDNF) levels, and dopamine receptors (for review of CNS ef-
fects of statins see [26]). 
In summary, given a) the enormous public health impact of depression [53, 54] and obesity [15, 
16], b) the lack of remission in about 30% of depressed patients even after several antidepressive 
treatment attempts [55], c) the fact that obese MDD patients are especially prone to chronicity 
and non-response [19-21], d) the evidence of antidepressive effects of statins from four different 
sources (animal studies [26], meta-analysis of prospective cohort studies [49], meta-analysis of 
pilot controlled trials [2], nationwide cohort study [47]) and e) the established safety of statins, a 
confirmative controlled trial of add-on statin treatment in patients with MDD and comorbid obesity 
appears urgently warranted. 
5. Study objectives 
5.1 Primary objective 
To examine whether add-on 40 mg/d Simvastatin to standard antidepressant medication (Es-
citalopram 20 mg/d) improves depression to a greater extent than adjunct placebo in patients 
with major depression and comorbid obesity 

 
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5.1.1 Primary efficacy (confirmatory) endpoint 
As primary outcome variable we will use the change in Montgomery-Åsberg Depression Rating 
Scale (MADRS) [56] score from baseline to week 12.  
5.2 Secondary objectives 
To examine whether add-on 40 mg/d Simvastatin to standard antidepressant medication (Es-
citalopram 20 mg/d) improves response rates, remission rates, patients’ impression of change, 
quality of life, social functioning, self-report depression, lipid values, and immunometabolism / 
mitochondrial function to a greater extent than adjunct placebo in patients with major depression 
and comorbid obesity: 
5.2.1 Secondary efficacy (exploratory) endpoints 
As secondary outcome variables we will use  
 
MADRS response (defined as 50% MADRS score reduction from baseline),  
 
MADRS remission (defined as MADRS score < 10), and  
 
MADRS minimal clinically important difference (MCID). 
The MCID concept originated from studies of patient-reported outcomes, in which it represented 
the smallest improvement that was considered meaningful by the patient [57]. Empirically, the 
MCID using the MADRS has been identified as a change from baseline between 1.6 – 1.9 [58]. 
Also, we will assess as secondary outcome variables  
 
change scores in patients’ self-reported Beck Depression Inventory (BDI-II) as well as  
 
the MCID according to BDI [59] 
5.2.2 Other secondary (exploratory) endpoints 
We will additionally determine  
 
The clinician’s impression of the severity of illness (Clinical Global Impression scale – 
Severity of illness, CGI-S) [60], 
 
the clinician’s impression whether and to what extent symptoms have improved (Clinical 
Global Impression scale – Improvement, CGI-I) [60], 
 
the patient’s impression whether and to what extent symptoms have improved (Patients’ 
Global Impression of Change Scale, PGIC), 
 
social functioning (Social and Occupational Functioning Assessment Scale, SOFAS), 
 
quality of life (EuroQol-5 Dimensions-3 Levels Questionnaire, with a calculated MCID 
[61]),  
 
change scores in high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total 
cholesterol, 
 
and change scores in mitochondrial function (spare respiratory capacity) of immune cells 
and indicators of immune function. 
Please see Table 1 for characteristics and definitions of primary and secondary outcome varia-
bles. 
Table 1: Characteristics and definitions of primary and secondary endpoints. 
Outcome 
Instrument 
Rating 
Domain 
Exactly defined outcome 
Variable 
Primary 
MADRS 
Clinician-
rated 
Severity of 
Depression 
Mean Change from Baseline 
Continuous 

 
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Secondary / 
Efficacy (ex-
ploratory) 
MADRS 
Clinician-
rated 
Severity of 
Depression 
- Percentage response (>50 % 
reduction from baseline) 
- Percentage remission (MADRS 
score < 10 post-treatment) 
- Percentage minimal clinically 
important difference  
(MCID; change from  
baseline score > 1.9) 
Dichotomous 
 
Secondary / 
Efficacy (ex-
ploratory) 
BDI-II 
Self-rated 
Severity of 
Depression 
Mean Change from Baseline 
- Percentage MCID (> 17.5% 
change from baseline) 
Continuous 
Dichotomous 
Secondary 
Exploratory 
CGI-S 
Clinician-
rated 
Severity of 
illness 
Median Change from Baseline 
Ordinal 
Secondary 
Exploratory 
CGI-I 
Clinician-
rated 
Improve-
ment/wors-
ening of ill-
ness 
Response defined as “much im-
proved” or “very much improved” 
post-treatment 
Dichotomous 
Secondary 
Exploratory 
PGIC 
Self-rated 
Subjective 
Improvement 
Response defined as “much im-
proved” or “very much improved” 
post-treatment  
Dichotomous 
 
Secondary 
Exploratory 
SOFAS 
Clinician-
rated 
Social Func-
tioning 
Mean Change from Baseline 
Continuous 
Secondary 
Exploratory 
EQ-5D-3L 
Self-rated 
Quality of 
Life 
Mean Change from Baseline 
Percentage MCID (change from 
baseline score > 0.74) 
Continuous 
Dichotomous 
Secondary 
Exploratory 
HDL, LDL, to-
tal cholesterol 
Laboratory 
values 
Metabolism 
Mean Change from Baseline 
 
Continuous 
 
Secondary 
Exploratory 
Mitochondrial 
and cellular 
function of im-
mune cells 
Laboratory 
values 
Immune 
function 
Mean Change from Baseline 
Continuous 
 
The time point for the evaluation of the secondary endpoints is 12 weeks. The secondary efficacy 
endpoints MADRS-response and MADRS-remission within 12 weeks will be analyzed by logistic 
regression models with intervention and center as factors and baseline MADRS as covariate. 
The analyses of continuous secondary efficacy endpoint BDI-II, and continuous secondary ex-
ploratory endpoints SOFAS, and EQ-5D-3L will follow the same lines as the primary outcome. 
The analyses of safety parameters and all secondary endpoints will have an exploratory charac-
ter. 
6. Study population 
6.1 Number of patients 
The study will include 160 patients (8 centers located in Germany; approximately 20 to 25 pa-
tients per center) divided into 2 groups: 
- Group 1 (80 patients): Placebo add-on standard-medication 
- Group 2 (80 patients): IMP add-on standard-medication 

 
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6.2 Selection of patients 
We will include in- and outpatients with a major depressive episode according to DSM 5 (Diag-
nostic and Statistical Manual of Mental Disorders 5th Edition) and comorbid obesity (body mass 
index ≥ 30 as measured by weight and height). Patients will be recruited from the depression 
outpatient clinics and inpatient wards from each study site. In addition, we will use the existing 
and established networks of all sites within the psychiatric community to include depressed out-
patients from general practitioners and psychiatrists. Thus, we will ensure high generalizability of 
our study population. There will be no specific gender distribution as no gender specific differ-
ences concerning efficacy and safety of the IMP are expected.  
6.2.1 Inclusion criteria 
- 
Written informed consent is present  
- 
The patient has the capacity to give consent (He/she is able to understand the nature and 
anticipated effects/side effects of the proposed medical intervention)  
- 
The patient has a major depressive episode according to DSM 5 (Diagnostic and Statisti-
cal Manual of Mental Disorders 5th Edition) 
- 
The patient has a score of ≥ 18 in the Montgomery-Asberg Depression Rating Scale 
(MADRS)  
- 
The patient has a body mass index ≥ 30  
- 
The patient’s age is between 18 and 65 years (≥ 18 und ≤ 65) 
- 
The patient has not given childbirth within the 6 months prior to study entry and is not 
breastfeeding 
- 
In case of non-psychotropic medication:  
The patient received stable pharmacological medication for at least 14 days prior to study 
entry (any changes in medication dose or frequency of therapy must be answered with 
no) 
- 
The patient did not take antidepressants during the last 7 days prior to study entry (dis-
continuation of effective medication to enable study participation is prohibited) 
- 
The patient did not receive prior treatment with Escitalopram in index episode 
- 
The patient had less than three (<3) trials with antidepressants in index episode  
- 
The patient does not have a history of non-response to Escitalopram 
- 
The patient did not receive treatment with ketamine, electroconvulsive therapy (ECT) or 
other stimulatory treatments in index episode 
- 
The patient does not meet any of the following criteria: 
- 
schizophrenia 
- 
schizoaffective disorder 
- 
bipolar disorder 
- 
The patient is not diagnosed with dementia and does not have moderate or severe impair-
ment of general cognitive function according to clinical impression  
- 
The patient does not have clinically relevant elevated liver enzymes [GOT or GPT > 3 x 
upper limit normal (ULN)] and does not have elevated Carbohydrate Deficient Transferrin 
(CDT) ≥ 2.4 % 
- 
The patient does not meet the criteria for alcohol use disorder (DSM-5: 303.90; ICD-10: 
F10.20) or substance use disorder (DSM-5: 304; ICD-10: F11.20 – F19.20) in M.I.N.I. for 
DSM-5 and a urine/serum drug screening is negative (except for benzodiazepines and 
opiates) 
- 
The patient does not have a history of suicide attempt 
- 
The patient does not have diagnosed epilepsy or increased bleeding diathesis or a history 
of angle closure glaucoma or other glaucomas 

 
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- 
The patient did not have bariatric surgery prior to study entry  
- 
The patient does not have a known allergy or contraindication against Escitalopram or 
Simvastatin 
- 
The patient does not meet any of the following criteria: 
- 
hereditary muscle disease  
- 
known history of rhabdomyolysis  
- 
elevated creatine kinase (CK) outside of the sex-specific reference intervals 
- 
History of muscular symptoms under treatment with statins or fibrates 
- 
The patient does not have elevated TSH level outside of the age- and sex-specific refer-
ence intervals. 
- 
The patient does not have insulin-dependent diabetes mellitus 
- 
The patient does not have uncontrolled hepatic disorder, renal or cardiovascular disease 
- 
The patient does not have untreated hypothyroidism 
- 
The patient does not have a history of myocardial infarction or stroke  
- 
The patient does not have symptomatic peripheral arterial disease  
- 
The patient does not have monogenic familial hypercholesterolemia  
- 
The patient does not have clinically significant laboratory abnormalities  
- 
The patient did not participate in other interventional trials during the 6 months before and 
at the time of this trial  
- 
The patient is not an employee of the investigator study site, or a family member of the 
employees or the investigator, or otherwise dependent on the sponsor, the investigator or 
the investigator study site 
Please note that having type 2 diabetes will not offend inclusion criteria (except if insulin-depend-
ent) because large beneficial effects of Simvastatin 40 mg/d have been shown on cardiovascular 
endpoints in these patients [62].  
6.2.2 Exclusion criteria 
- 
The patient has current use of statins (for visits 2-6 applies: except for IMP Simvastatin) 
- 
The patient has current use of antidepressants (for visits 2-6 applies: except for standard 
medication Escitalopram)  
- 
The patient has acute suicidal tendencies (MADRS Item 10 > 4) 
- 
The patient uses potent CYP3A4-inhibitors (e.g. clarithromycin, erythromycin, HIV prote-
ase inhibitors – see “Risks, adverse drug reactions, drug interactions, restrictions, contra-
indications, procedures in case of emergency”)  
- 
The patient uses potent CYP3A4 inductors (carbamazepine, efavirenz, nevirapin, et-
ravirine). 
- 
The patient uses Fibrates, Amiodaron, Amlodipin, Verapamil, Fluconazol, Diltiazem, 
Fusidic acid, Niacin or Lomitapid or BCRP-Inhibtors (e.g. Elbasvir or Grazoprevir) 
- 
The patient uses Gemfibrozil, Ciclosporin or Danazol 
- 
The patient has known hypersensitivity to other ingredients of Simvastatin and Escital-
opram [butylated hydroxyanisole, microcrystalline celluose, citric acid, starch, lactose, 
magnesium stearate, hypromellose, talc, titanium dioxide, iron oxies, colloidal silicon di-
oxide, croscarmellose sodium, polyethylene glycol] 
- 
The patient uses medication that is associated with QTc-prolongation [antiarrhythmica 
class IA and III, antipsychotics (e.g. haloperidol), phenothiazines, tricyclic antidepres-
sants, antibiotics (e.g. moxifloxacin), and certain antihistaminergic drugs (e.g. astemizol, 
mizolastin)] 
- 
The patient has clinically significant abnormalities in 12-lead ECG (e.g. QTc-prolongation 
≥ 500 ms or increase ≥ 60 ms from baseline visit) 

 
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- 
The patient is pregnant  
- 
The patient with childbearing potential is not willing to use an acceptable form of contra-
ception (defined as Pearl index < 1) 
- 
The patient has current use of psychotropic medication (e.g. antipsychotics, anticonvul-
sants, lithium or St. John's Wort) except for benzodiazepines, non-benzodiazepines and 
opiates  
- 
The patient uses nonselective, irreversible monoamine oxidase (MAO) inhibitor (e.g. 
Tranylcypromine) or selective, reversible inhibitor of monoamine oxidase A (e.g. Moclo-
bemide) or the nonselective, reversible monoamine oxidase inhibitor Linezolid 
- 
The patient is unwilling to consent to saving, processing and propagation of pseudony-
mized medical data for study reasons 
- 
The patient is legally detained in an official institution 
6.2.3 Contraception 
Highly effective contraception in women (defined as pearl index < 1), or complete abstinence of 
intercourse (during study participation). 
Female patients who are not either surgically sterile (tubal ligation/obstruction or removal of ova-
ries or uterus) or post-menopausal (no spontaneous menstrual periods for at least one year con-
firmed by a negative hormone panel) must commit to using one highly effective method (such as 
intrauterine device, sterilisation of one of the partners, hormonal birth control methods) for the 
duration of the study. 
Birth control methods which are considered as highly effective (low failure rate less than 1% per 
year) when used consistently and correctly include: 
• 
Established use of oral, injected or implanted hormonal methods of contraception. 
• 
Placement of an intrauterine device or intrauterine system. 
• 
Female bilateral tubal ligation. 
• 
Sexual abstinence: When this is in line with the preferred and usual lifestyle of the patient. 
Note: Periodic abstinence (e.g. calendar ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not highly effective methods of contraception 
Pregnancy testing: For women of childbearing potential, a highly sensitive serum HCG test will 
be conducted at screening visit, baseline, week 4, week 8 and at the end-of-study.  
6.2.4 Follow up of pregnancy 
A patient must immediately inform the investigator if she becomes pregnant during the study. 
The investigator will report all pregnancies to the Sponsor/Sponsor representative on the form 
provided within 24 h after knowledge. Every pregnant female will be excluded from the trial im-
mediately and referred to outpatient obstetrics and gynecology for further medical care. Following 
local regulation monitoring of the subject will continue until the conclusion of the pregnancy and 
until 3 months after the birth of the baby. For further information on premature termination of the 
individual participant see 11.1. 
6.2.5 Methods of avoiding simultaneous enrolment in other trials 
Patients who participated in other interventional trials during the 6 months before and at the time 
of this trial will not be included in the study. It is the duty of the recruiting investigator to rule out 
current participation in another trial. Patient information will explicitly state the impossibility to 
partake if already participating in another trial. 

 
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6.2.6 Screening failures 
Patients who sign an informed consent form but fail to meet the eligibility criteria are defined as 
screening failures. For all screening failures, the investigator is asked to maintain a screening log 
that documents the patient number, reason(s) for screening failure and justification for rescreen-
ing if applicable. A copy of this log should be retained in the investigator site file. The end of study 
form and other forms containing information needed to examine the inclusion- and exclusion 
criteria (e.g. demography, MADRS scale) leading to screening failure will be completed and doc-
umented using eCRF – secuTrial at each study site. In case of screening failures further treat-
ment will be offered in specialized outpatient clinics for depression and obesity. If screening fail-
ures occur due to medical reasons patients will be referred to specialized out- or inpatient clinics 
for the treatment of this medical condition.  
 
7. Plan for medical treatment 
7.1 Study design 
We will conduct a randomized, placebo-controlled, double-blind multicenter trial with parallel-
group design (Phase II). Subjects will be randomized 1:1 to IMP or placebo based on separate 
randomization lists for each study site provided by the biostatistician. The randomization will be 
based on a permuted block procedure stratified by center. 
Subinvestigators and patients will be blinded to the treatment. Simvastatin is an effective serum 
lipid-lowering drug that can decrease lipid levels. In order to ensure continued blinding, laboratory 
assessment will be divided into safety laboratory, laboratory (lipid assessment) and laboratory 
(immunometabolism/mitochondrial function). Laboratory (lipid assessment) will be conducted 
only at V1 and V6 to minimize the risk for unblinding of investigators/subinvestigators by revealing 
the lipid profile. Particularly LDL-cholesterol is expected to be lower in the treatment group. At 
the same time, not assessing the lipid status of patients during the entire study participation would 
not represent current practice where lipid status is an important part of cardiovascular risk as-
sessment. No unblinding of the subinvestigators due to specific side effects of Simvastatin treat-
ment is to be expected (see 9.5).  
7.2 Description of study medication 
Each patient in this study will be treated with Escitalopram - a well-established standard-antide-
pressant, which is readily available because it is commonly used as generic drug in Germany. 
Adjunct placebo serves as the control condition for adjunct Simvastatin (40 mg/d fixed dose). 
Simvastatin and placebo will be provided by the pharmacy of the Charité and will be administered 
in a double-blind fashion. Patients will receive IMP or placebo at baseline (visit 1), at visit 4 and 
visit 5. Patients will receive 10 mg Escitalopram at baselie (visit 1) and then 20 mg Escitalopram 
at visit 3, visit 4, and visit 5 (see 7.2.4 for treatment schedule and instructions for dose adjust-
ments). Please see Figure 1 for scheme of intervention. 
7.2.1 Investigational Medical product (IMP) 
Among the available stains, we decided to use Simvastatin (SimvaHEXAL®) in a dosage of 40 
mg/d based on the following considerations: Simvastatin was used in this dose in one of three 
RCTs showing evidence vs. placebo as adjunct treatment to SSRI [36]; it was superior to atorvas-
tatin in depressed patients with heart disease [38]; it passes the blood-brain barrier [39], and it is 
available as generic drug (costs for 40 mg/d Simvastatin = 0.24 Euro/day = 87.6 Euro/year). We 
decided against using a dose of 80 mg/d Simvastatin due to the increased risk of muscle injury 

 
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and the corresponding warning from the US Food and Drug Administration [63]. See for further 
information on risk-benefit assessment 10.  
7.2.2 Standard medication 
Escitalopram will be provided by the pharmacy of the Charité, stored and dispensed at each 
study site in a non-blinded fashion.  
Current treatment with antidepressants is an exclusion criterion. Study participation may be per-
mitted in case of wash-out of prior antidepressants for at least 7 drug-free days prior to inclusion. 
This will be permitted only if the depression severity had not sufficiently improved under the prior 
antidepressant regime as shown by a MADRS score ≥ 18 at screening visit. Discontinuation of 
effective medication to enable study participation is prohibited. 
7.2.3 Control (Placebo) 
IMP and placebo indistinguishable in form, color, and taste will be provided by the pharmacy of 
the Charité (see 7.2.8) and will be administered in a double-blind fashion. 
In order to measure blinding, we will ask patients which treatment they believe they have been 
assigned at the end of study.  
7.2.4 Treatment schedule / Dose regimen 
Instructions for application: 
IMP - Simvastatin: The majority of cholesterol synthesis appears to occur at night, presumably 
reflecting the effects of a fasting state. For this reason, it is typically recommended that the statins 
with shorter half-lives including Simvastatin be administered in the evening or at bedtime. Pa-
tients should not drink grapefruit juice during Simvastatin treatment. IMP will be administered 
orally in a fixed dosage of 40 mg once a day at bedtime. IMP can be taken with or without food, 
but patients are recommended to take it with a glass of water.  
Control - Placebo: Placebo will be administered orally once a day at bedtime. Placebo can be 
taken with or without food, but patients are recommended to take it with a glass of water.  
Standard medication - Escitalopram: Escitalopram will be administered orally in a fixed dosage 
of 10 mg once a day in the morning for the first two weeks, then increased to 20 mg once a day 
in the morning until the end of study. Escitalopram can be taken with or without food, but patients 
are recommended to take it with a glass of water.  
Table 2 treatment schedule 
 
morning 
lunchtime 
evening 
night 
Simvastatin, orally 
0 
0 
0 
40 mg 
Placebo 
0 
0 
0 
1 
Escitalopram, orally 
20 mg (10 mg for 
first two weeks) 
0 
0 
0 
 
Instructions for dose adjustment: 
Simvastatin (IMP): fixed dose 40 mg/d during 12 weeks without dose-adjustment 
 
Placebo: not applicable 
 
Escitalopram (standard antidepressant that each patient will receive): 
- 10 mg/d for first two weeks, then increase to 20 mg/d until end of study 

 
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- If side effects occur in the first two weeks, 10 mg/d Escitalopram can be reduced to 5 mg/d 
until the next visit, then ideally increased to 10 mg/d again unless side effects persists. 
- If side effects occur after the increase to 20 mg/d, Escitalopram can be reduced to 10 mg/d 
until next visit, then ideally increased to 20 mg/d again unless side effects persists. 
7.2.5 Adverse drug reactions and restrictions, contraindications, drug interactions 
In randomized trials, statin therapy appears to cause only a slight increased risk of side effects 
compared with placebo, and no increased risk of discontinuation of therapy compared with pla-
cebo [44]. In 2017, a meta-analysis of 22 placebo-controlled trials on statin use involving nearly 
130,000 participants showed that 13.3 % of subjects receiving a statin discontinued the drug 
compared with 13.9 % of subjects on placebo (odds ratio [OR] 0.99, 95% CI 0.93-1.06) over a 
mean follow-up of 4.1 years [45].   
Simvastatin is the IMP that will be tested versus placebo as add-on to standard antidepressant 
medication with Escitalopram, which will be given open label to each patient. In the following, we 
list the risks and potential adverse drug effects for both medications. 
Simvastatin 
Simvastatin is approved for several indications since decades and has in general proven to be a 
safe medication. The risks and adverse effects listed below are all taken from the latest version 
of German “Fachinformation”. 
The most prominent risk of statin use is myopathy (rarely), associated with muscle pain, muscle 
tenderness, muscle weakness and increases of creatine kinase (CK). The most severe form of 
myopathy is rhabdomyolysis with or without acute renal failure secondary to myoglobinuria that 
occurs very rarely and is dose-dependent. The combined incidence for myopathy/rhabdomyoly-
sis in 41.413 patients treated for at least 4 years was 0.03% for 20 mg/d, 0.08% for 40 mg/d, and 
0.61% for 80 mg/d Simvastatin. Thus, to minimize the risk of Simvastatin, we will use it in a 
medium dose (40 mg/d) and not a high dose (80 mg/d). In addition to safety laboratory values at 
screening, baseline, week 4, and week 12, it will be explicitly asked if the patient experienced 
unexplained muscle pain or dark urine as a sign of rhabdomyolysis. 
Other adverse effects are listed below, taken from the latest version of German “Fachinformation” 
and classified as follows: 
Very often: (>1/10); often (> 1/100); sometimes (> 1/1000), rarely (> 1/10.000), very rarely (< 
1/10.000); not known (cannot be determined on basis of available data) 
Very often: none 
Often: none 
Sometimes: none 
Rarely: Anemia, headache, dizziness, paresthesia, peripheral neuropathy, obstipation, stom-
ach ache, flatulence, dyspepsia, diarrhea, nausea, emesis, pancreatitis, hepatitis/icterus, 
rash, pruritus, alopecia, myopathy, rhabdomyolysis, myalgia, muscle cramps, asthenia 
Very rarely: insomnia, memory complaints, liver failure 
Not known: depression, interstitial lung disease, tendinopathy, immune-mediated myopathy, 
erectile dysfunction 
 
Medication that is contraindicated with Simvastatin due to inhibition of CYP3A4 will not be per-
mitted (Itraconazol, Ketoconazol, Posaconazol, Voriconazol, Erythromycin, Clarithromycin, Teli-
thromycin, HIV protease inhibitors (e.g. Nelfinavir), Boceprevir, Telaprevir, Nefazodon, Cobi-
cistat, Ciclosporin, Danazol, Gemfibrozil). 

 
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Further, medication that is not recommended to use in parallel to Simvastatin in a dosage of 40 
mg/d will not be permitted (Fibrates, Amiodaron, Amlodipin, Verapamil, Fluconazol, Diltiazem, 
fusidic acid, Niacin, Lomitapid). 
Finally, patients will be noticed that they should not drink grapefruit juice during Simvastatin treat-
ment due to inhibition of CYP3A4 and corresponding increases in Simvastatin plasma levels. 
In turn, medication that induces CYP3A4 leading to decreased Simvastatin levels will also not be 
permitted (Carbamazepine, Efavirenz, Nevirapin, Etravirine). 
Patients with contraindications for Simvastatin will not be included or excluded from the study in 
case of later occurrence (see under inclusion criteria).  
Escitalopram 
The most prominent risk of Escitalopram is QTc-Prolongation in the ECG that can lead to ven-
tricular arrhythmia (torsade des pointes). To exclude patients with QTc-prolongation an ECG will 
be conducted at screening. Furthermore, an additional safety ECG will be conducted at every 
visit.  
Other adverse effects are listed below, taken from the latest version of German “Fachinformation” 
and classified as follows: 
Very often: (>1/10); often (> 1/100); sometimes (> 1/1000), rarely (> 1/10.000), very rarely (< 
1/10.000); not known (cannot be determined on basis of available data) 
Very often: headache, nausea 
Often: decreased appetite, increased appetite, weight gain, anxiety, restlessness, nightmares, 
decreased libido, anorgasmia, insomnia, fatigue, dizziness, paresthesia, tremor, sinusitis, 
yawning, diarrhea, obstipation, emesis, dry mouth, hyperhidrosis, arthralgia, myalgia, delayed 
ejaculation, erectile dysfunction, fever 
Sometimes: weight loss, bruxism, agitation, nervousness, panic attacks, confusion, disturbed 
taste, insomnia, syncope, mydriasis, blurred vision, tinnitus, tachycardia, epistaxis, gastroin-
testinal bleeding, urticarial, alopecia, rash, pruritus, metrorrhagia, menorrhagia, edema 
Rarely: anaphylaxis, aggression, depersonalization, hallucination, serotonin syndrome, brad-
ycardia 
Very rarely: none 
Not known: thrombocytopenia, inadequate ADH-secretion, hyponatremia, anorexia, mania, 
suicidality, dyskinesia, seizures, akathisia (psychomotor restlessness), QTc-prolongation in 
the ECG, orthostasis, hepatitis, increased liver enzymes, ecchymosis, angioedema, urinary 
retention, galactorrhea, priapism 
 
Medication that is contraindicated with Escitalopram will not be permitted, which includes all irre-
versible MAO-inhibitors and medication that is associated with QTc-prolongation [antiarrhythmica 
class IA and III, antipsychotics (e.g. haloperidol), phenothiazines, tricyclic antidepressants, anti-
biotics (e.g. moxifloxacin), and certain antihistaminergic drugs (e.g. astemizol, mizolastin)]. 
Patients with contraindications for Escitalopram will not be included (please see under inclusion 
criteria).  
7.2.6 Procedures in case of emergency 
In case of emergency supposedly due to application of the medication, they will be immediately 
discontinued. The blinding will be broken immediately, and the patient will receive immediate 
medical care (see 7.2.9). No specific antidote to Simvastatin or Escitalopram are currently known, 
therefore treatment is limited to symptom management. Regulatory reporting duties apply. 

 
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7.2.7 Randomization 
We will conduct a randomized, placebo-controlled, double blind multicenter study (RCT). Sub-
jects will be randomized 1:1 to Simvastatin or placebo based on separate randomization lists for 
each study site provided by the biostatistician. The randomization will be based on a permuted 
block procedure stratified by center. We will additionally collect data on prognostic variables (e.g. 
chronicity of depression, number of prior treatment attempts, etc.) as recommended by EMA [64] 
but will not stratify for these variables because a) there are a several predictive variables and it 
is not feasible to stratify randomization for all of them and b) we expect that these predictive 
variables will not systematically differ between the two treatment groups because of randomiza-
tion. The Charité pharmacy will be instructed in proper allocation concealment. Based on the 
randomization codes, the pharmacy will centrally provide for each center sequentially numbered, 
tamper-proof containers, which are equal in weight and similar in appearance containing IMP or 
placebo. The pharmacy keeps the randomization lists unavailable to investigators and the Spon-
sor/Sponsor representative until the end of study.  
7.2.8 Packaging, labelling, and blinding procedures 
Charité Pharmacy encapsulates and packages IMP and placebo in identical vials with a medica-
tion ID. The IMP/placebo vials will be provided by the Charité pharmacy to study sites. Medication 
is prepared and concealed by Charité Pharmacy. Concealment will not be broken until completion 
of the study, therefore double-blinding remains intact. 
Emergency envelopes for the unblinding are enclosed in the packages sent to the investigator 
site and are stored by the local investigator. Envelopes are only to be opened in case of emer-
gency and if treatment decisions depend on knowledge of application of IMP. Patient information 
contains contact information to ensure possibility of unblinding after treatment if necessary. 
7.2.9 Unblinding 
In case of an emergency the blinding will be broken immediately, and the patient will receive 
immediate medical care. 
Premature Unblinding 
Premature unblinding happens at the discretion of the local investigator in case of a medical 
emergency, where treatment is based on the knowledge whether IMP has been applied. When 
emergency envelopes are opened prematurely, date, time, reason for opening and name of the 
person opening have to document in source data and CRF. After unblinding the patient has to 
be immediately excluded from the study.   
An identical copy of the emergency envelopes for the unblinding will be sent to the Sponsor 
representative and stored securely at the coordinating site (Charité - Universitätsmedizin Berlin). 
This way the coordinating staff is additionally available for immediate unblinding in case of a 
medical emergency, where treatment is based on the knowledge whether IMP has been applied. 
The same rules apply as for the premature unblinding by the local investigator. 
Regular Unblinding 
After completion of the study and data base closure, Charité pharmacy is requested by the Spon-
sor/Sponsor representative to send the randomization lists and all participants will be unblinded. 
Furthermore, the Data Monitoring Committee (DMC) is granted access to limited randomization 
lists of the subjects they are currently reviewing. 

 
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7.2.10 Storage requirements and administration (shipping and destruction) 
Study medication will be delivered to the study sites by the Charité pharmacy for each individual 
participant after successful screening visit. Receipt will be confirmed via an acknowledgement of 
receipt dated and signed by site study staff, which will be stored in the investigator site file (ISF). 
At the investigator sites, IMP/placebo must be kept separate from regular medication in a locka-
ble cupboard with access only to study staff.  
Upon distribution/application of study medication (IMP/placebo, and standard medication) to the 
patient, exact amount, date, medication ID and randomization number are documented in the 
ISF (drug account). It is the investigator’s obligation to assure correct documentation. The same 
procedure applies if medication is returned. The monitor will regularly check the drug account 
logs. Only after this check unused medication (IMP/placebo) will be returned to Charité pharmacy 
and destroyed. Charité pharmacy documents retrieval and destruction of IMP not applied. This 
documentation will be filed in the TMF. 
7.2.11 Treatment compliance 
Patients will receive study medication for four weeks at baseline and then at week 4, and at week 
8. Standard medication will be distributed for two weeks at baseline and then at week 2, at week 
4, and at week 8. Patients are instructed to bring back the medication package and compliance 
will be determined by count of the remaining pills and patients will be considered compliant if 
they report taking more than 90 % of their drug (as in previous studies with Simvastatin in central 
nervous system diseases [7, 65]).  
8. Concomitant medication / concomitant therapy 
Medication that is contraindicated with Simvastatin, and Escitalopram will not be permitted (see 
7.2.5). 
- 
Use of potent CYP3A4-inhibitors (e.g. clarithromycin, erythromycin, HIV protease inhibitors). 
- 
Use of potent CYP3A4 inductors (carbamazepine, efavirenz, nevirapin, etravirine). 
- 
Medication that is associated with QTc-prolongation [antiarrhythmica class IA and III, anti-
psychotics (e.g. haloperidol), phenothiazines, tricyclic antidepressants, antibiotics (e.g. mox-
ifloxacin), and certain antihistaminergic drugs (e.g. astemizol, mizolastin)]. 
- 
Use of nonselective, irreversible monoamine oxidase inhibitor (e.g. Tranylcypromine) or se-
lective, reversible inhibitor of monoamine oxidase A (e.g. Moclobemide) or the nonselective, 
reversible monoamine oxidase inhibitor Linezolid. 
Concomitant treatment with antidepressants other than Escitalopram will not be permitted. In 
case of current treatment with antidepressants at study entry a wash-out of prior antidepressants 
for at least 7 drug-free days prior to inclusion may be permitted. However, discontinuation of 
effective medication to enable study participation is prohibited. 
Other psychotropic drugs (including antipsychotics, anticonvulsants, lithium, or St. John’s Wort) 
are not permitted during the study period with the following exceptions.  
- 
In case of sleep difficulties, benzodiazepine or nonbenzodiazepine hypnotics (e.g. zolpidem, 
zopiclone) will be allowed on an “as needed basis”. 
- 
In case of acute anxiety or agitation, a benzodiazepine (preferably lorazepam) may be pre-
scribed not exceeding 3 mg/d (other benzodiazepines at the equivalent dosage). 
- 
Opiates for pain relief. 
Any clinical exacerbation requiring a higher benzodiazepine regimen or prescription of antipsy-
chotics (“rescue medication”) will be considered as a serious adverse event. 

 
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In case of non-psychotropic medication stable pharmacological medication for at least 14 days 
prior to study entry will be permitted. Patients with any changes in medication dose or frequency 
of therapy during the 14 days prior to study entry will not participate in the study (see 6.2.1). 
Concomitant use of statins will not be permitted.  
9. Study procedures 
To ensure that the study is conducted according to the study protocol, to current laws and to 
guidelines, a training of all investigators/subinvestigators will be conducted prior to initiation. The 
trial will be initiated by a monitor. 
The investigator will be responsible for collecting the following information: laboratory lipid as-
sessment comprised of LDL, HDL and total cholesterol. Otherwise the investigator will not have 
any other information about evaluations and efficacy assessments and will not perform drug dis-
pensation.  
The subinvestigator, independently from the investigator, will perform the following evaluations: 
informed consent and medical history, treatment status, inclusion/exclusion criteria, concomitant 
medication, physical exam, ECG interpretation, assessment of blood pressure and heart rate, 
adverse events recording, all efficacy assessments (see 9.5), all safety assessments (see 9.6), 
drug dispensation, laboratory assessment immuno-metabolism/mitochondrial function, and other 
procedures (see 9.7.3). 
9.1 Recruitment / Screening procedures 
Based on the power calculation described in chapter 16, we aim to recruit a total of 160 patients 
at several study sites within Germany. The time allotted for recruitment is 39 months. All centers 
intended for participation are specialized tertiary depression clinics, where large numbers of de-
pressed in- and outpatients are routinely seen in both clinical care and research contexts. Pa-
tients will be recruited from the depression outpatient clinics and inpatient wards from each study 
site. In addition, we will use the existing and established networks of all sites within the psychiatric 
community to include depressed outpatients from general practitioners and psychiatrists. All con-
tacted investigators have extensive experience with screening, recruiting, and assessing patients 
with MDD for clinical trials. Recruitment estimations are based on current reviews of the hospital 
records of patients with MDD at each of these institutions. Before initiation of the trial, recruitment 
capabilities will again be assessed during scheduled pre-trial visits to all sites, after which a final 
decision for inclusion of a given site in the trial will be made. 
9.2 Informed consent  
Patients will be informed about the conduction of the trial in a personal conversation by the in-
vestigator/subinvestigator. They will receive the written patient information (“Information zur 
Studie”) and be given time to read it thoroughly and without haste. If further questions arise, the 
investigator/subinvestigator will answer them openly and correctly. The patients’ consent to par-
ticipate in the study will be documented by signature and dating of the consent form (“Einwil-
ligungserklärung”) which will be countersigned by the investigator/subinvestigator. 
9.3 Patient identification / Generation of pseudonym 
Patient related data will be recorded in study files (source data) under the participant`s real name. 
The information required by the protocol will be entered onto the electronic case report forms 
(eCRF - secuTrail) under a pseudonym. Pseudonyms will be generated by secuTrail and will be 
comprised of a combination of numbered and lettered sequence without the use of initials and 

 
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date of birth. Every patient will receive a patient number / pseudonym which will be unique for 
this individual patient. The investigator will compile a confidential list (patient identification log), 
which relates these patient numbers to the patient’s full name. This list will only be accessible to 
the study staff and the monitor. The investigator must print the patient identification log and store 
it with other study documents, e.g. the protocol, and any protocol amendments, in a secure place. 
The databank will contain only pseudonymized data. Re-identification of patients will only be 
possible through the confidential list.  
9.4 Visits schedule and evaluations 
 
Table 3: Overview and frequencies of trial examinations 
Assessments 
Screen-
ing 
Base-
line 
(Visit 1) 
 
Visit 2 
 
Visit 3 
 
Visit 4 
 
Visit 5 
End-of-study 
(Visit 6) 
 
 
week 0 
week 1 
week 2 
week 4 
week 8 
week 12 
Screening and consent 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion criteria  
 
X 
 
 
 
 
 
 
Exclusion criteria 
 
X 
X 
X 
X 
X 
X 
 
Medical history  
X 
 
 
 
 
 
 
 
Treatment status 
 
X 
 
 
 
 
 
 
M.I.N.I – DSM 5 
X 
 
 
 
 
 
 
 
Urine/serum drug screening 
X 
 
 
 
 
 
 
 
Concomitant medication 
X 
 
 
 
 
 
 
Safety 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
X 
 
ECG  
X 
X 
X 
X 
X 
X 
X 
 
Blood pressure & heart rate 
X 
X 
X 
X 
X 
X 
X 
 
Safety laboratory (incl. Preg-
nancy test - women only) 
X 
X 
 
 
X 
X 
X 
 
Adverse events recording 
 
 
X 
X 
X 
X 
X 
Effectiveness 
 
 
 
 
 
 
 
 
MADRS 
X 
X 
X 
X 
X 
X 
X 
 
BDI-II 
 
X 
X 
X 
X 
X 
X 
Social functioning and quality 
of life 
 
 
 
 
 
 
 
 
SOFAS 
 
X 
 
 
X 
 
X 
 
EQ-5D-3L 
 
X 
 
 
X 
 
X 
Other 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
BMI 
X 
X 
 
 
 
 
X 
 
Waist circumference 
 
X 
 
 
 
 
X 
 
PGIC 
 
 
X 
X 
X 
X 
X 
 
CGI-S 
 
X 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
 
Laboratory (lipid assessment) 
 
X 
 
 
 
 
X 

 
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Laboratory (immunometabo-
lism / mitochondrial function) 
 
X 
 
 
X 
X 
X 
 
Drug dispensation 
 
X 
 
X 
X 
X 
 
Note: Electrocardiography (ECG), Body-Mass-Index (BMI), Mini International Neuropsychiatric Interview (MINI), Montgomery-Asberg 
Depression Scale (MADRS), Beck-Depressions-Inventar (BDI), Patient Global Impression of Change (PGIC), Clinicians’ Global Im-
pression of Severity of illness (CGI-S), Clinicians’ Global Impression of Improvement (CGI-I), Social and Occupational Functioning 
Assessment Scale (SOFAS), Generic Quality of Life Questionnaire (EQ-5D-3L). 
 
Maximum variation of ± 3 days is permitted for the scheduling of each study visit.  
 
9.4.1 Screening visit 
After informed consent, we will assess the severity of depressive episode, duration of the de-
pression and of the index episode, number of episodes, previous treatment as requested by the 
EMA guideline on clinical trials in depression [64].  
During screening the following procedures will be performed:  
 
Medical history, concomitant medication, and physical examination  
 
M.I.N.I for DSM-5 
 
Body weight, height (for determination of body mass index) 
 
Blood pressure, heart rate  
 
ECG  
 
Laboratory (safety) 
 
Pregnancy test (women only) 
 
Urine/serum drug screening 
 
Demographics 
 
MADRS 
9.4.2 Randomization visit (Baseline) - Drug dispensation 
Patients will be examined for inclusion and exclusion criteria in the randomization visit. Patients 
fulfilling all inclusion criteria and no exclusion criterion based on information assessed at the 
screening visit will be randomized in the two treatment groups (IMP vs. placebo). Randomization 
is carried out by the biostatistician. In addition, we will further characterize the sample with regard 
to eating behavior by a well-validated questionnaire, the “Three-Factor-Eating-Questionnaire” 
[66]. Patients will not be explicitly asked to pursuit weight loss during the study participation. We 
will assess the treatment status of the patient (inpatient/day-care/outpatient). 
 
During Baseline (visit 1 – week 0) the following procedures will be performed:  
 
Assessment of in- and exclusion criteria 
 
Blood pressure, heart rate  
 
ECG 
 
Laboratory (safety) 
 
Pregnancy test (women only) 
 
MADRS 
 
BDI-II 
 
SOFAS, EQ-5D-3L 
 
CGI-S 
 
Determination of body mass index and measurement of waist circumference 
 
Laboratory (lipid assessment) 
 
Laboratory (immunometabolism / mitochondrial function) 
Furthermore, patients will receive IMP or placebo for four weeks and Escitalopram 10 mg/d for 
two weeks. 

 
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9.4.3 Examinations during trial 
Visit 2 (week 1) 
During visit 2 – week 1 the following procedures will be performed:  
The exclusion criteria will be reassessed. 
Safety examinations during the trial include: 
 
Blood pressure, heart rate  
 
ECG 
 
Adverse events recording 
Efficacy examinations during the trial include: 
 
MADRS  
 
BDI-II 
Other examinations during the trial include: 
 
PGIC 
 
CGI-S 
 
CGI-I 
Visit 3 (week 2) - Drug dispensation 
During visit 3 – week 2 the following procedures will be performed:  
The exclusion criteria will be reassessed. 
Safety examinations during the trial include: 
 
Blood pressure, heart rate 
 
ECG 
 
Adverse events recording 
Efficacy examinations during the trial include: 
 
MADRS  
 
BDI-II 
Other examinations during the trial include: 
 
PGIC 
 
CGI-S 
 
CGI-I 
 
Patients will receive Escitalopram 20 mg/d for two weeks. 
Visit 4 (week 4) - Drug dispensation 
During visit 4 – week 4 the following procedures will be performed:  
The exclusion criteria will be reassessed. 
Safety examinations during the trial include: 
 
ECG 
 
Blood pressure, heart rate 
 
Laboratory (safety) 
 
Pregnancy test (women only) 
 
Adverse events recording 
Efficacy examinations during the trial include: 
 
MADRS  
 
BDI-II 
Other examinations during the trial include: 
 
SOFAS, EQ-5D-3L, and PGIC 
 
CGI-S 
 
CGI-I 

 
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 
Laboratory (immunometabolism / mitochondrial function) 
Patients will receive IMP or placebo and Escitalopram 20 mg/d for four weeks. 
Visit 5 (week 8) - Drug dispensation 
During visit 5 – week 8 the following procedures will be performed:  
The exclusion criteria will be reassessed. 
Safety examinations during the trial include: 
 
Blood pressure, heart rate 
 
ECG  
 
Laboratory (safety) 
 
Pregnancy test (women only) 
 
Adverse events recording 
Efficacy examinations during the trial include: 
 
MADRS  
 
BDI-II 
Other examinations during the trial include: 
 
PGIC 
 
CGI-S 
 
CGI-I 
 
Laboratory (immunometabolism / mitochondrial function) 
Patients will receive IMP or placebo and Escitalopram 20 mg/d for four weeks. 
9.4.4 Final examination (End-of-study) 
During Final examination (visit 6 – week 12) the following procedures will be performed:  
The exclusion criteria will be reassessed. 
Safety examinations during the trial include: 
 
Physical examination 
 
ECG 
 
Blood pressure, and heart rate 
 
Laboratory (safety) 
 
Pregnancy test (women only) 
 
Adverse events recording 
Efficacy examinations during the trial include: 
 
MADRS  
 
BDI-II 
Other examinations during the trial include: 
 
SOFAS, EQ-5D-3L, and PGIC 
 
CGI-S 
 
CGI-I 
 
Determination of body mass index and measurement of waist circumference 
 
Laboratory (lipid assessment) 
 
Laboratory (immunometabolism / mitochondrial function) 

 
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9.5 Evaluations / Efficacy assessments 
9.5.1 MADRS 
As primary outcome variable we will use the change in Montgomery-Åsberg Depression Rating 
Scale (MADRS) score from baseline to week 12. All subinvestigators will be trained to use the 
MADRS according to the published structured interview guide to enhance inter-rater reliability 
[67]. 
The MADRS is a clinician rated interview to measure the severity of depression within the last 
seven days [56]. It consists of 10 items that can be ranked on a 7-point scale ranging from 0 to 
6. This variable is explicitly recommended by the European Medicines Agency (EMA) as a pri-
mary outcome to determine efficacy in the treatment of depression: “Improvement should be 
documented as the difference between baseline and post-treatment score in signs and/or symp-
toms, but should also be expressed as the proportion of responders” (page 9 of EMA guideline 
on clinical investigation of medicinal products in the treatment of depression)[64]. The German 
version of the MADRS has been shown to be a valid instrument with high internal consistency 
and high sensitivity for change [68]. All subinvestigators will be trained to use this scale and 
interviews will be conducted according to the specific interview guide that has been developed 
for the MADRS [67]. MADRS will be conducted at every visit during the study by the subinvesti-
gator.  
9.5.2 BDI-II 
The Beck Depression Inventory (BDI)-II is a well-established self-report questionnaire to meas-
ure depressive symptoms [69]. Patients will be asked to fill out the BDI-II at every visit except for 
screening. 
9.6 Evaluations / Safety assessments 
9.6.1 Clinical examination 
Physical examination 
The physical examination comprises a routine medical examination including neurological and 
cognitive assessments. The following body systems will be examined: HEENT (head, eyes, ear, 
nose, and throat), urological, cardiovascular, respiratory, lymphatic, gastrointestinal, musculo-
skeletal, dermatological, and venous system. The physical examination will take place at screen-
ing and at end-of-study by the subinvestigator.  
Blood pressure, and heart rate (vital signs) 
The following vital signs will be assessed at each visit by the subinvestigator: 
 
Systolic (SBP) and diastolic (DBP) blood pressure (mmHg) 
 
Heart rate (beats per minute [bmp]) 
Blood pressure (SBP and DBP) and heart rate will be measured using a semi-automatic blood 
pressure recording device with an appropriate cuff size. Supine blood pressure and heart rate 
will be measured after the patient has rested in a supine position for at least 5 minutes. 
9.6.2 Laboratory safety 
Safety laboratory will be performed at screening, baseline, visit 4, visit 5 and at the end-of-study. 
Components of the laboratory panels include tests for the following: 
 

 
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 
Blood count (leukocytes, erythrocytes, hemoglobin, hematocrit, MCV, MCH, MCHC, 
RDW-CV, thrombocytes, MPV) and differential blood count (neutrophiles, granulocytes, 
lymphocytes, monocytes, eosinophiles, basophiles, neutrophiles) 
 
Clinical chemistry [sodium, potassium, creatinine, estimated GFR, GOT (AST), GPT 
(ALT), gamma-GT  
 
Creatine kinase (CK) 
 
CRP 
 
Basal glucose and HbA1c 
 
Beta-HCG (women only). 
At screening visit thyroid-stimulating hormone (TSH) and Carbohydrate-deficient Transferrin 
(CDT) will be additionally determined. 
Sample collection will take place at each investigator site by the subinvestigator. The sample is 
obtained by using a needle to draw off blood from veins into collection tubes and then immedi-
ately transported to the local laboratory. Blood samples will be stored until all analyses are com-
pleted. Safety laboratory results will be evaluated by the subinvestigator. 
9.6.3 Electrocardiogram 
12-lead ECG will be obtained at every visit. After the subject has rested in a supine position for 
at least 5 minutes, 12-lead ECG will be performed and interpreted by the subinvestigator. Meas-
urements that deviate substantially from previous readings will be reported. The most prominent 
risk of Escitalopram is QTc-Prolongation in the ECG that can lead to ventricular arrhythmia (tor-
sade des pointes). To exclude patients with QTc-prolongation an ECG will be conducted at every 
visit. If QTc reaches or exceeds 500 ms or increased ≥ 60 ms from baseline, subject will be 
immediately discontinued [70].  
9.6.4 MINI International Neuropsychiatric Interview 
MINI International Neuropsychiatric Interview (German for Germany Translation Version 7.0.2) 
will be performed at screening visit by the subinvestigator to assess psychiatric comorbidities 
and evaluate inclusion and exclusion criteria [71].  
9.7 Evaluations / Other assessments 
9.7.1 Patient reported outcome measures 
PGIC 
The Patient Global Impression of Change (PGI-C) measures the patient’s subjective improve-
ment [72]. Patients will be asked to fill out the PGIC at every visit except for screening and base-
line. 
EQ-5D-3L 
Quality of life will be determined with the EuroQol-5 Dimensions-3 Levels Questionnaire [73]. 
Patients will be asked to fill out the EQ-5D-3L at baseline, week 4 and end-of-study. 

 
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9.7.2 Laboratory assessments 
Lipid assessment 
Sample collection will take place at each investigator site by the subinvestigator. The sample is 
obtained by using a needle to draw off blood from veins into collection tubes and then immedi-
ately transported to the local laboratory. Blood samples will be stored until all analyses are com-
pleted. 
 
High-density lipoprotein (HDL) 
 
Low-density lipoprotein (LDL) 
 
Total cholesterol 
Immunometabolism / mitochondrial function 
At selected sites in Hamburg and Berlin, additional blood samples (80 ml heparin blood samples 
and 5 ml serum sample) for assessments of immunometabolism / mitochondrial function will be 
analyzed within the internal research laboratories and will be stored for a maximum of 10 years. 
Heparin blood samples (80 ml) will be immediately processed using established procedures (see 
[74, 75]) for isolation and cryopreservation of peripheral blood mononuclear cells (PBMCs). The 
protocols for sample processing are harmonized between the labs. PBMCs will be frozen at a 
concentration of 107 cells/ml at -80°C in a pre-cooled freezing container. After 24-48 hours, cells 
were transferred to liquid nitrogen and stored at -196°C until analysis. Serum samples (5 ml) will 
be centrifuged, aliquoted, and stored at -20°C until analysis. 
 
Mitochondrial function of monozytes and T cells 
 
Cell-specific gene expression relevant for intracellular stress hormone signaling by qRT-PCR 
 
Phenotyping of monozytes and T cells by fluorescence activated cell sorting (FACS) 
 
Serum concentrations of cytokines incl. IL-6, TNF, IL-1beta 
9.7.3 Other procedures 
CGI  
The CGI consists of 2 sub-scales: CGI-S and CGI-I. Clinical Global Impression scale – Severity 
of illness (CGI-S) and Clinical Global Impression scale - Improvement (CGI-I) will be used to 
assess patient’s overall severity and improvement/worsening of depression [60]. CGI-I of the 
current visit will be assessed compared to a CGI-I score of the last visit. CGI-S will be conducted 
at visit 1, 2, 3, 4, 5 and 6, whereas CGI-I will be conducted at visit 2, 3, 4, 5 and 6 by the subin-
vestigator. 
SOFAS 
The Social and Occupational Functioning Assessment Scale (SOFAS) will be used to determine 
social functioning [76] and will be conducted at baseline, week 4 and end-of-study by the subin-
vestigator. 
BMI, measurement of waist circumference 
Body-Mass-Index will be determined by measuring weight at screening, baseline and end-of-
study by study staff. Height will be measured only once at screening. Waist circumference will be 
measured at baseline and end-of-study by study staff. 
10. 
Risk-benefit-assessment 
Both medications (Simvastatin, Escitalopram) are approved for several indications since decades 
and have overall been proven to be safe. All depressed patients enrolled in the trial will be con-
tinuously treated with a gold standard antidepressant (Escitalopram) as described by the National 

 
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Disease Management Guideline (“Nationale Versorgungsleitlinie”) for the treatment of MDD. For 
Escitalopram a dose-response relationship has been suggested. Especially for patients with se-
vere depression the high standard dose of 20 mg/d was shown to be superior compared to 
10mg/d [1]. A fixed-dose of 10 mg/d Escitalopram for the entire study duration of 12 weeks would 
therefore not allow the optimal treatment for some patients. Thus, we consider this option ethi-
cally not justifiable. A dose increase from 10 mg/d to 20 mg/d based on individual patient re-
sponse would however interfere with comparability of the treatment group and placebo group, 
because a strong decrease in depressive symptoms in the treatment group compared to placebo 
group could potentially be masked by a higher percentage of Escitalopram dose escalation in the 
placebo group. Therefore, we will increase Escitalopram to 20 mg/d after giving a low standard 
dose of 10 mg/d in the first two weeks. In case of adverse reactions related to Escitalopram, we 
will follow the instructions for dose adjustment described in 7.2.4 Treatment schedule / Dose 
regimen. 
IMP Simvastatin is offered in an “add-on” design, thus there will be virtually no drug-free patients 
in this trial. Invasive interventions beyond ordinary sampling of peripheral venous blood will not 
be performed within this trial, therefore the risks associated with trial participation are mainly 
attributable to IMP Simvastatin that has already been shown in depressed patients to be safe 
and well tolerated in combination with an SSRI.[2] 
It has been suggested that both for the lipid-lowering effects and for the pleiotropic effects of 
statins a high dose is more effective than a low dose [3-5]. Especially in studies examining effects 
of statins on diseases of the central nervous system such as multiple sclerosis and mild cognitive 
disorder a high dose of Simvastatin (60 – 80 mg/d) has been administered [6-8]. One of the most 
important side effects of Simvastatin is dose-dependent risk of myopathy. The combined inci-
dence for myopathy/rhabdomyolysis under Simvastatin was 0.03% for 20 mg/d, 0.08% for 
40 mg/d and markedly went up to 0.61% for 80 mg/d according to latest version of German 
“Fachinformation”. To minimize the risk of Simvastatin and examine the pleiotropic effects of 
Simvastatin in depression, we will use it in a medium dose (40 mg/d) and not a high dose 
(80 mg/d). In addition to assessing safety laboratory values including creatine kinase (CK) at 
screening, baseline, at week 4, week 8 and week 12, it will be explicitly asked during each visit if 
the patient experienced unexplained muscle pain or dark urine as a sign of rhabdomyolysis. Fur-
thermore, we will not include particularly vulnerable patients (e.g. patients with renal impairment, 
untreated hypothyroidism or history of muscle toxicity under statins or fibrates) to our study. To 
exclude patients with QTc-prolongation an ECG will be conducted at screening. Furthermore, 
additional safety ECGs will be conducted at every visit.  
According to a meta-analysis of small, randomized controlled trials, a beneficial antidepressive 
effect of Simvastatin is to be expected [2]. Many depressed patients with comorbid obesity might 
additionally benefit from Simvastatin in terms of primary prevention of cardiovascular disease. 
In summary, the potential benefits of the study by far outweigh the risks associated with Escital-
opram and Simvastatin. Importantly, a recent extensive literature review on parallel SSRI and 
statin use concluded the following: “Escitalopram, Citalopram, and Paroxetine are almost certain 
to be safe with all statins” [9]. 
11. 
Termination and subsequent treatment 
11.1 Premature termination of the individual participant 
Patients are free to withdraw from participation in the study without specifying any reasons. An 
investigator may discontinue or withdraw a participant from the study for the following reasons: 
- If any clinical adverse event (AE), laboratory abnormality, or other medical condition occurs 

 
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such that continued participation in the study would not be in the best interest of the partici-
pant. In particular the following AE, laboratory abnormality, or other medical condition will lead 
to immediate discontinuation of the individual participant: 
o report of any unexplained muscle pain, tenderness or weakness if accompanied 
by malaise or fever 
o hyperbilirubinemia or jaundice 
o interstitial lung disease 
o QTc prolongation ≥ 500 ms or ≥ 60 increase from baseline visit  
o seizures 
o activation of mania/hypomania 
o abnormal bleeding event (e.g. ecchymoses, purpura) 
o serotonin syndrome 
o angle closure glaucoma 
o clinically significant worsening of depression severity operationalized as a CGI-
I change score of 6 or 7 (“much worse” or “very much worse”) in two successive 
visits.  
o clinically significant laboratory abnormalities such as  
 
elevated creatine kinase greater than 5fold upper limit of normal (ULN) 
 
elevated GOT or GPT greater than 3fold upper limit of normal (ULN) 
 
severe symptomatic hyponatremia (serum sodium [SNa] <125 mmol/L)  
 
elevated thyroid-stimulating hormone outside of the age- and sex-spe-
cific reference intervals 
o acute suicidal ideation (MADRS item 10 > 4) 
o pregnancy 
 
In the case of premature termination, the reason for withdrawal must be entered on the appropri-
ate case report form (eCRF) page and the patient must be followed for safety and efficacy until 
the end of the study (week 12).  
11.2 Premature termination of the clinical study 
According to the German Fachinformation for Simvastatin, the combined incidence for myopa-
thy/rhabdomyolysis in 41.413 patients treated for at least 4 years was 0.08% for 40mg/d Simvas-
tatin. Severe symptomatic hyponatremia (serum sodium [SNa] <125 mmol/L) is a rare but poten-
tially fatal complication of Escitalopram. Signs and symptoms of hyponatremia include headache, 
difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness and can be 
as severe as hallucination, syncope, seizure, coma, respiratory arrest, and death. Therefore, the 
whole study may be discontinued at the occurrence of the treatment-related serious adverse 
event (SAE) “myopathy/rhabdomyolysis” as defined by the German Fachinformation for Simvas-
tatin [muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper 
limit of normal (ULN)] in more than 5 participants or the treatment-related SAE “severe sympto-
matic hyponatremia” (serum sodium [SNa] <125 mmol/L) in more than 5 participants. In addition, 
an early discontinuation of the trial may be decided if new scientific data during the course of the 
trial changes the risk-benefit-balance significantly. If such data emerges, recruitment and treat-
ment of currently treated patients will be paused immediately. A final decision on continuation or 
termination of the trial will then made by the Sponsor/PI based on the recommendation of the 
Data and Safety Monitoring Board (DSMB). 

 
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11.3 Follow-up and continuing treatment after regular / premature termination 
After completing all the protocol treatment and visits, patients will continue with regular visits 
according to usual practice. In case of response or remission, Escitalopram will be continued 
while the study medication Simvastatin (IMP) will be discontinued in any event.  
In case of non-response or non-remission, Esctalopram will be definitely discontinued. The in-
vestigator will ensure a gradual dose reduction of Escitalopram over at least one or two weeks 
because of potential symptoms associated with abrupt discontinuation of Escitalopram. Patients 
with non-response or non-remission will be offered at least one additional clinical appointment at 
the psychiatric outpatient clinic of the study center after termination of the individual study partic-
ipation for the gradual discontinuation of Escitalopram. 
12. 
Adverse events 
12.1 Definitions 
12.1.1 Adverse Event (AE)  
An adverse event is an untoward medical occurrence in a patient or clinical trial subject admin-
istered a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE could be diseases, signs or symptoms which occur or worsen after enrolment 
of the patient in the clinical trial. 
12.1.2 Adverse Reactions (AR) 
Adverse reactions are all untoward and unintended responses to an investigational medicinal 
product related to any dose administered. 
12.1.3 Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) 
A serious adverse event or serious adverse reaction is an untoward medical occurrence or effect 
that at any dose  
 
results in death,  
 
is life-threatening,  
 
requires hospitalisation or prolongation of existing hospitalisation,  
 
results in persistent or significant disability or incapacity,  
 
or is a congenital anomaly or birth defect; 
 
requires a higher benzodiazepine regimen or prescription of antipsychotics (“rescue med-
ication”). 
12.1.4 Exceptional rules 
In this clinical trial the following AEs/SAEs are excluded from the notification requirement:  
- Serious or unexpected events which occur after enrolment, but before treatment was initiated  
- Events with hospitalization planned before the inclusion to the trial (i.e. scheduled surgery) 
12.1.5 Suspected Unexpected Serious Adverse Reactions (SUSAR)  
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is any suspected adverse reaction 
related to the study treatment that is both serious and unexpected.  
“Unexpected” means that the nature and severity of the adverse reaction are not consistent with 
the information about the study medication in question set out in the reference safety information. 

 
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12.2 Treatment of (S)AEs 
All AEs should be treated appropriately. Such treatment may include changes in study drug treat-
ment including possible interruption or discontinuation, starting or stopping concomitant treat-
ments, changes in the frequency or nature of assessments, hospitalization or any other medically 
required intervention. 
12.3 Assessment of AEs and SAEs 
As far as possible, each AE should be evaluated to determine: 
- the severity grade (assessment of intensity) 
- whether it constitutes a SAE (see 12.1.3) 
- its relationship to the study drug (assessment of causality) 
- its duration (start and end dates or if continuing at final exam) 
- action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study drug 
permanently discontinued due to this AE; hospitalization) 
12.3.1 Assessment of intensity 
We will apply the following definitions according to the Common Terminology Criteria for Adverse 
Events (CTCAE) grading: 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appro-
priate instrumental ADL (Activities of daily living).  
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL.  
Grade 4 Life-threatening consequences; urgent intervention indicated.  
Grade 5 Death related to AE. 
Seriousness (severity grade) shall be determined according to the definition above. Furthermore, 
medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. Examples of such events are intensive treatment in an emer-
gency room, or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalisation, or development of drug addiction or drug abuse. 
12.3.2 Assessment of causality 
To assess causality between administration of the IMP and the Adverse Event the following def-
initions apply:  
Sure: The reaction comprehensively follows the administration of the IMP in the right 
timeframe or can be measured in body tissues or fluids or represents a known or expected 
response to the study medication or disappears after discontinuation or dose reduction and 
reoccurs after re-exposure. 
Probable: The reaction comprehensively follows the application of the IMP in the right 
timeframe or represents a known or expected response to the study medication or disap-
pears after discontinuation or dose reduction and cannot be explained by known charac-
teristics of the patient’s disease. 

 
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Possible: The reaction comprehensively follows the application of the IMP in the right 
timeframe or represents a known or expected response to the study medication, but could 
easily be caused by other factors.  
Not related: Adequate Information supporting the assumption that there is no causality  
Cannot be evaluated: The causality cannot be determined. 
12.4 Documentation of AEs and SAEs 
All AE and SAEs will be documented, no matter if the investigator suspects a causal connection 
to the IMP or not. The event will be recorded in the eCRF. 
Out of normal range laboratory data and ECG abnormalities will be analyzed concerning their 
clinical relevance by the subinvestigator – and if relevant documented as an AE itself. Related 
signs, symptoms, and laboratory changes will be summarized to a specific disease. The docu-
mentation will include the type of event, start, duration, severity, causality, and action taken. 
SAEs need to be documented on a separate SAE form (see 12.5.1). All SAEs need to be followed 
until they subside or stabilize.   
The Sponsor/Sponsor representative will carefully document all Adverse Events (AEs) reported 
by the investigator.  
12.5 Reporting of SAEs and SUSARs 
12.5.1 Reporting of SAEs / Contact for SAE reporting 
Every event will be documented on a record form and will immediately be sent to the given ad-
dress. If at that point all required information is not available, succeeding records will be sent. In 
the event of death, a copy of the autopsy record should be added.  
The investigator shall promptly (at the latest within 24 h) notify the Sponsor/Sponsor representa-
tive of the occurrence of a Serious Adverse Event after becoming aware and subsequently pro-
vide the Sponsor/Sponsor representative with a detailed written report3.  
Contact details for SAE reports: 
 
Charité Universitätsmedizin Berlin 
Koordinierungszentrum für klinische Studien /KKS Charité 
Central Pharmacovigilance KKS Charité 
Fax number: 030 4507553856 
Email: pharmacovigilance-kks@charite.de 
 
Personal data shall be pseudonymized before transmission using the identification code of the 
data subject.  
The report must include the following minimal criteria: 
- Patient-ID 
- Name of reporter/investigator 
- Information on event (term, case narrative, duration) 
- Assessment of severity and causality (relationship to study drug/study procedure/concomitant 
medication/other circumstances) 
                                               
3 GCP-V §12 (4), and 2011//C 172/01 (CT-3), 4.3.1, 29. 

 
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12.5.2 Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Before reporting a SUSAR (Suspected Unexpected Serious Adverse Reactions) the subject will 
be unblinded. The Sponsor/Sponsor representative will report all suspicious cases of SUSARs 
which had been occurred in one of clinical trials conducted by the same Sponsor with the same 
drug substance/IMP to the relevant Ethics Committee, the relevant regulatory authorities and to 
relevant regulatory authorities of other European member states and other contracting states of 
the EWR agreement, if the study is run in their territory immediately, at the latest 15 days after it 
becomes known. He will also inform all investigators involved in the trial.  
In case of a fatal or life threatening SUSAR the Sponsor/Sponsor representative will report all 
information relevant for judging the event immediately, at the latest 7 days after the event be-
comes known to the relevant Ethics Committee, the relevant regulatory authorities and to relevant 
regulatory authorities of other European member states and other contracting states of the EWR 
agreement, if the study is run in their territory as well as to all investigators involved in the trial. 
After a further 8 days all further relevant information must be available.   
12.5.3 Other safety issues requiring expedited reporting 
The Sponsor/Sponsor representative will immediately, at the latest 15 days after it becomes 
known report all circumstances that require a revision of the risk-benefit analysis to the relevant 
Ethics Committee, the relevant regulatory authorities and to relevant regulatory authorities of 
other European member states and other contracting states of the EWR agreement, if the study 
is run in their territory. This especially includes:   
- Singular cases of expected severe adverse events with an unexpected outcome.  
- Increased incidence of expected severe adverse events that are judged as being clinically 
relevant.  
- Events related to study procedures or development of the study medication, which could affect 
a subject’s safety.  
All person-related data will always be transmitted pseudonymized.  
12.6 Follow-up of adverse events 
Once an AE is detected, it will be followed until its resolution or stabilization, and assessment will 
be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study, the interventions required to treat it and the outcome. 
Follow-up information is sent to the same address to which the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported SAE 
and giving the date of the original report. Each re-occurrence, complication, or progression of the 
original event will be reported as a follow-up to that event regardless of when it occurs. The 
follow-up information will describe whether the event has resolved or continues, if and how it was 
treated, whether the patient continued or withdrew from study participation.  
For a follow-up report to the authorities, the investigator may be required to collect further infor-
mation for a detailed description and a final evaluation of the case, including copies of hospital 
reports, autopsy reports, or other relevant documents. 
12.7 Data Monitoring Committee 
We will seek advice from independent experts in the field who have agreed to serve on the Data 
and Safety Monitoring Board (DSMB): 
 
Prof. Dr. Brenda Penninx (methods expert/epidemiologist), Vrije Universiteit Amsterdam 

 
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 
Prof. Dr. Falk Kiefer (clinician), Zentralinstitut für Seelische Gesundheit, Mannheim 
 
Prof. Dr. Carsten Spitzer (clinician), Klinik für Psychosomatik und Psychotherapeutische 
Medizin Universitätsmedizin Rostock 
 
Mrs. Francoise Margue (patient representative), Deutsche Depressionsliga 
To ensure that the patients’ perspective will be present at all DSMB meetings as recommended 
by the European Patient Academy [77], Mrs. Francoise Margue, vice-chair of the “Deutsche De-
pressionsliga” has kindly agreed to serve on the DSMB. The DSMB will regularly (once a year) 
assess safety data during the course of this study and their primary interest is the safety of study 
participants and integrity and validity of collected data. 
13. 
Documentation 
13.1 Source Data and Study Files 
The investigator must maintain source documents for each patient in the study (see 15.1). 
13.2 Case Report Forms (CRF) 
Investigators or their designee must enter the information required by the protocol onto the elec-
tronic case report forms - eCRF (see 15.2).  
13.3 Investigator Site File (ISF) 
All essential documents will be kept in the Investigator Site File, which will be stored at the study 
sites in accordance with ICH GCP chapter 8.   
13.4 Drug accountability / Flow of study medication 
Study medication will be provided by Charité pharmacy. Receipt of study medication will be doc-
umented in each study site (date, number of medication received, charge-ID, etc.) by the inves-
tigator. The individual patient will receive the medication from the subinvestigator. This will be 
documented in the drug account (date, charge-ID). Medication that is not used and empty medi-
cation boxes will be stored until final closure of the drug account by the clinical study monitor. 
14. 
Quality management 
14.1 Control of trial progress and data quality 
The study sites will be monitored by a clinical study monitor to ensure the quality of the data 
collected. The objectives of the monitoring procedures are to ensure that the trial subject’s safety 
and rights as a study participant are respected, that accurate, valid and complete data are col-
lected, and that the trial is conducted in accordance with the trial protocol, the principles of GCP 
and local legislation. 
14.1.1 Monitoring, Data Quality Assurance 
All investigators agree that the monitor regularly visits the study site and assure that the monitor 
will receive appropriate support in his activities at the study site. The declaration of informed 
consent includes a statement to the effect that the monitor has the right – while observing the 
provisions of data protection legislation – to compare the case report forms (eCRFs) with the trial 

 
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subject’s study files (doctor’s notes, ECGs, laboratory printouts etc.). The investigator will secure 
access for the monitor to all necessary documentation for trial-related monitoring. The aims of 
the monitoring visits are as follows: 
- To check the declarations of informed consent. 
- To monitor trial subject safety (occurrence and documentation/reporting of AEs and SAEs). 
- To check the completeness and accuracy of entries on the eCRF. 
- To validate the entries on the eCRF against those in the source documents (source data ver-
ification, SDV). 
- To evaluate the progress of the trial. 
- To evaluate compliance with the trial protocol. 
- To assess whether the trial is being performed according to GCP at the study site. 
- To discuss with the investigator aspects of trial conduct and any deficiencies found. 
A monitoring visit report is prepared for each visit describing the progress of the clinical trial and 
any problems (e.g. refusal to give access to documentation). 
The investigators allow the monitor to have access to any or all of the study materials needed for 
source data verification and proper review of the study progress. At all times, the Sponsor/inves-
tigators/monitors will maintain the confidentiality of the study documents. Furthermore, problems 
with inconsistent and incomplete data will be discussed. By signing the declaration of informed 
consent, the participants allow access to their documents.  
14.1.2 Audits / Inspections 
Authorized representatives of the Sponsor, a regulatory authority, or an Independent Ethics Com-
mittee (IEC) may visit the center to perform audits or inspections, including source data verifica-
tion. The purpose of a Sponsor audit or inspection is to systematically and independently exam-
ine all study related activities and documents to determine whether these activities were con-
ducted, and data were recorded, analyzed, and accurately reported according to the protocol, 
Good Clinical Practice (GCP), guidelines of the International Conference on Harmonisation 
(ICH), and any applicable regulatory requirements. 
With the signature in the protocol, the investigators confirm that auditors and health authority 
inspectors may have access to the study documentation and accordant medical records. Auditors 
and inspectors are bound by professional confidentiality and may not pass on any personal in-
formation that comes to their knowledge. In the course of audits or inspections, data in the case 
report forms will be compared with the data for medical records. All the documentation held by 
the investigators within the scope of the clinical trial, as well as the drug logs of the study medi-
cations will be verified. 
14.2 Standardisation and validation 
All rating scales have previously been standardized and validated.  
14.3 Reference institutions 
Not applicable. 
15. 
Data entry und data management 
Patient related data will be recorded in study files (source data) under the participant`s real name. 
The information required by the protocol will be entered onto the electronic case report forms 

 
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(eCRF - secuTrial) under a pseudonym. Every patient will receive a patient number / pseudonym 
which will be unique for this individual patient (see 9.3).  
15.1 Source Data and Study Files 
The investigator must maintain source documents for each patient in the study, consisting of all 
demographic and medical information, including laboratory data, electrocardiograms, and all as-
sessments and keep them together with the signed informed consent form in designated study 
files. The information in original documents and records defined as Source Data will be reviewed 
by the Monitor for Source Data Verification. 
15.2 Data collection / Case Report Form (CRF) 
Investigators or their designee must enter the information required by the protocol onto the elec-
tronic case report forms (eCRF - secuTrial®). Data items from the eCRF are entered into the 
study database. All entries to the eCRF must be made as described in the electronic case report 
form manual. All information on eCRF must be traceable to source documents in the study file.  
A clinical study monitor will review the eCRF and compare the content to the source data. In 
addition, the investigator or designated colleague will provide access to designated Sponsor rep-
resentative(s) for the periodic review of source documents (e.g. hospital and clinic records) to 
assure accuracy and completeness of the eCRF.  
15.3 Data management 
Data required for the analysis will be acquired and transferred electronically to a central database 
at the KKS Charité by means of an electronic data capture system (EDC) - secuTrial®. 
The secuTrial® Software solution of interActive Systems (iAS) is a worldwide reachable web-
based system (remote data entry [RDE]). The system operates according to the principle of 
online data capture and is in compliance with the FDA 21 CFR Part 11 and ICH-GCP. In addition, 
it contains further functions to perform plausibility, consistency and range checks of the study 
data. 
The log-in in the system requires a previous authentication for access and runs by a secure data 
transfer-protocol (SSL) to exclude any improper manipulation of data by unauthorized parties. 
The system will automatically keep an audit trail of all entries and corrections to the eCRF. 
The secuTrial® Software solution is based on an Oracle database that does not allow direct ac-
cess. All access rights of study staff will be defined according to their trial functions. The defined 
access rights will e.g. allow to read or to enter study data depending on their functions (Monitor, 
clinical investigator, etc.). 
Query management is an integrated part of this RDE system. This function allows the communi-
cation between the Monitor and study staff. In case of errors or improper data, the responsible 
person of study staff will get queries (messages) to correct the errors or to check improper data 
on the eCRF. 
The trial data will be stored digitally on a remote server with daily backups. After end of study all 
data will be exported for checks of consistency and plausibility. After performing the checks, the 
data matrix will be transferred in pseudonymized form for the statistical evaluation. 

 
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16. 
Statistical Analysis 
16.1 Hypotheses 
16.1.1 Primary hypothesis 
Simvastatin (40 mg/d) add-on to the standard antidepressant Escitalopram (20 mg/d) improves 
depression to a greater extent over 12 weeks than add-on placebo in patients with comorbid 
obesity and major depression 
16.1.2 Secondary hypotheses 
Add-on Simvastatin (40 mg/d) to standard antidepressant Escitalopram (20 mg/d) will improve: 
1) response rates, and remission rates, 
2) patients’ impression of change, clinician’s impression of severity and change, quality of 
life, social functioning, self-report depression, 
3) lipid values, 
4) mitochondrial and cellular function of of immune cells 
to a greater extent over 12 weeks than adjunct placebo in patients with major depression and 
comorbid obesity. 
16.2 Sample size estimation 
So far, there are three small pilot RCTs in depressed patients (sample sizes ranging from n = 48 
to n = 68) that have all found statistically significant beneficial effects of add-on statins vs. placebo 
with large, clinically relevant effect sizes. A meta-analysis [2] of these trials has found a stand-
ardized mean difference between add-on statins and add-on placebo of -0.73 (95 % confidence 
interval -1.04 to -0.42, p < 0.001). However, it is well-known that initial studies tend to overesti-
mate the true effect size [78]. Therefore, we conservatively assume a standardized treatment 
difference (also known as Cohen’s d) of 0.5, which is supported by the findings of all pilot RCTs 
[36, 79, 80]. Given a standard deviation of 6-8 points on the MADRS, as commonly observed in 
RCTs in this population [81-83], a standardized effect size of 0.5 translates into a mean difference 
of 3-4 points, which is considered clinically relevant because it is about twice as large as the 
minimal clinically important difference of 1.6 to 1.9 points that has been reported [84]. Thus, a 
sample size of 64 patients per group gives a power of 80% for a comparison of the mean changes 
in MADRS score from baseline to week 12 between the two treatment groups using a two-sample 
t-test at the usual two-sided level of 5%. As the analyses will be adjusted for baseline scores the 
actual power is likely to be higher; this will be confirmed in a blinded sample size review once 
50% of the patients have reached week 12 [85]. Accounting for about 20% dropout, we aim to 
recruit 80 patients per group (i.e. 160 patients in total). Based on sex-specific prevalence rates 
and recruitment in our earlier studies [86, 87], we expect that about two thirds of the sample will 
be women. This will allow gender-specific analyses. 
 

 
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Figure 4: Study flow chart according to CONSORT. We assume that we need to screen N = 1125 patients aged 
18 - 65 with major depression according to Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 and 
obesity (body mass index ≥ 30) for eligibility at 8 recruiting centers to randomize n = 160 participants. The sam-
ple size and assumed dropout rate (20%) is conservatively based on three earlier pilot RCTs of add-on statin to 
SSRI treatment in depressed patients [1-3].  
16.3 Definition of population for analysis 
The primary analysis population will be the intention-to-treat (ITT) population. The ITT population 
will include all randomized patients. We will repeat the analyses in the per-protocol sample. 
16.4 Analysis of primary and secondary endpoints 
The primary analysis will compare MADRS changes from baseline to week 12 between the 
Simvastatin and placebo group by Gaussian linear models for repeated measures (so-called 
MMRM) with intervention, center, time (week 1, 2, 4, 8, and 12), and intervention-by-time inter-
action as factors, and baseline MADRS score as covariate. The error terms are assumed to follow 
a multivariate normal distribution with unstructured covariance. Least squares mean changes 
from baseline will be reported for both groups with 95% confidence interval (CI) as well as the 
difference between the least squares treatment group means with 95% CI and p-value testing 
the null hypothesis of no treatment effect. Although the model described above is robust to a 
certain extend to missing data, sensitivity analyses will be performed as supporting analyses 
including multiple imputation and last-observation-carried-forward (LOCF). The latter will also 
facilitate comparison with previous trials.  
The analyses of all secondary endpoints and safety parameters will have an exploratory charac-
ter and will therefore not be adjusted for multiple testing. The secondary efficacy endpoints 
MADRS-response and MADRS-remission, and MADRS-MCID within 12 weeks will be analyzed 
by logistic regression models with intervention and center as factors and baseline MADRS as 
covariate. The treatment effects will be reported as odds ratios with 95% CI and p-values testing 
the null hypotheses of no treatment effect. The analyses of continuous secondary efficacy end-
point as well as SOFAS, and EQ-5D-3L will follow the same lines as the primary outcome. 

 
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We will repeat the analyses in the per-protocol sample. 
All details of the statistical analyses including definitions of the analyses populations will be spec-
ified in the statistical analysis plan, which will be finalized before database lock and unblinding. 
All statistical analyses will be carried out using SAS software (SAS Institute Inc., Cary, NC, USA) 
or the R package. 
16.5 Analysis of adverse events 
All adverse events (AE; any undesirable experience occurring to a participant during the trial, 
whether or not considered related to the study medication) reported by the subject or observed 
by the investigators will be recorded at each visit. Standard procedures for reporting of (serious) 
adverse events will be used. (Serious) adverse events will be summarized as frequencies and 
percentages by treatment group. For recurrent events and to account for variable follow-up times 
event rates will be reported with rate ratios comparing Simvastatin with add-on placebo control 
and 95% confidence intervals. We will use Poisson regression models with adjustment for over 
dispersion (or negative binomial regression models) with offset for follow-up time and possibly a 
mixture component to account for zero-inflation. For events of particular interest Kaplan-Meier 
curves stratified by treatment group will be computed and compared by log-rank tests. 
16.6 Interim analyses and endpoints for premature study termination 
As the analyses will be adjusted for baseline scores the actual power is likely to be higher than 
80 %. To confirm this in an interim analysis, a blinded sample size review will be carried out once 
50 % of the patients have reached week 12. Based on blinded estimates of the mean square 
error and the dropout rate the required sample size will be recalculated and the sample size will 
be adjusted up to a maximum total sample size of 240 patients, if necessary. 
17. 
Reporting 
17.1 Statistical report 
The statistical analysis and the biometrical report will be provided by the biostatistician Prof. Dr. 
Tim Friede, Universitätsklinikum Göttingen, in cooperation with the Sponsor representative / Prin-
cipal investigator. All data in this report is confidential.   
17.2 Final report 
The composition of a final integrated report will be conducted in accordance with ICH E3: Struc-
ture and Contents of Clinical Study Reports. After termination of the biometrical analysis, the 
biostatistician will compose an integrated report. This report contains a clinical record, a statistical 
record, single value tables and conclusions. It will be signed by the principal investigator and the 
biostatistician.  
17.3 Publication (policy) 
The study results will be published irrespective of the study outcome.  

 
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18. 
Ethical, legal and regulatory aspects 
18.1 ICH-GCP-guidelines 
This trial will be conducted in accordance with the current ICH-GCP-guidelines. Good Clinical 
Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, 
recording and reporting trials that involve the participation of human subjects. Compliance with 
this standard provides public assurance that the rights, safety and well-being of trial subjects are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical trial data are credible. 
18.2 Legal requirements of the study 
18.2.1 Approval of Ethics Committee 
Study protocol, patient information (Information zur Studie) and consent form (Einwilligungserklä-
rung) will be presented to the relevant Ethics Committees for survey. The study will only start 
after ethics approval has been granted. The Ethics Committee will immediately be informed (by 
the Sponsor/Sponsor representative) of all changes to the protocol (according to GCP-V § 10) 
and of all events that could affect a patient’s safety. The Ethics Committee will also be informed 
of all suspected SUSARs and of regular or premature termination of the study. We will register 
our study in the ClinicalTrials.gov database and German Clinical Trials Register (DRKS) before 
we enroll any patients.  
18.2.2 Approval of competent authority 
The trial will be submitted to the relevant federal authorities (BfArM) for approval. The trial will 
only start after approval has been granted.  
18.2.3 Notification to regional authorities 
The trial will be submitted to the relevant state authorities by the Sponsor representative / Prin-
cipal investigator before we enroll any patients. The Sponsor/Sponsor representative and all in-
vestigators will be reported by full name. 
18.2.4 Patient information and informed consent 
Patient Information  
Before enrolment every patient will receive full oral and written information about the nature, 
purpose, expected advantages and possible risks of the trial.  
Consent to participation in the trial:  
The patient will agree to participation in the trial by signing the informed consent form. Patients 
must be given an opportunity to enquire about details of the study. After a sufficient period of 
time for the individual’s consideration and decision, comprehension and consent shall be docu-
mented on the consent form by the dated signature of the patient and the investigator/subinves-
tigator. Design and language will be adjusted to the study site’s needs. The final versions of 
patient information and consent will be presented to the Ethics Committee. Both the patient in-
formation and the patient consent form are prepared in duplicate. One of each form for the in-
vestigator, a duplicate will be handed to the patient. 
18.2.5 Patient insurance 
For participating patients, an insurance (according to AMG § 40 Absatz 1 Satz 3 No. 8) was 

 
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obtained with the 
HDI Global SE 
HDI-Platz 1, 30659 Hannover 
Tel. 0211 - 74820 
Policy number 43125625 03680 
The insurance is limited to a maximum of 500.000 Euro per patient and 50.000.000 Euro for the 
whole study. A copy of the insurance policy and the insurance terms and conditions will be 
handed to the participants. 
18.2.6 Data Privacy and confidentiality 
The participants’ data will be saved in a pseudonymous form, which will neither contain initials 
nor full date of birth. All regulative requirements applying to data protection will be met. Re-iden-
tification of a participant subject’s name is possible from the patient identification log, which is 
kept in a locked research office at the study site where access is only possible by the investigator 
or persons authorized by the investigator.  
Patients will be informed that their disease-related data will be saved for scientific purpose (pub-
lication, etc.) using a pseudonym. Consenting patients have got the right to be informed about 
the data recorded. Patients will also be informed that their pseudonymized data will be forwarded 
to the federal authorities (BfArM) and to the Ethics Committee responsible, in accordance with 
legal notification obligation for drug safety. Patients, who disagree with this process of data trans-
fer, are not allowed to participate in this study.  
Blood samples will be pseudonymized and sent to the local laboratories for analysis. They will 
be destroyed after analysis (laboratory safety, laboratory assessment lipid) or will be stored for a 
maximum of 10 years (laboratory assessment immunometabolism / mitochondrial function). The 
pseudonymized data will be transferred to the study site. 
18.3 Archiving of data / Access to records 
Essential documents, as listed below, must be retained by the investigator for as long as needed 
to comply with national and international regulations. The investigator agrees to adhere to the 
document retention procedures by signing the protocol. Essential documents include: 
- IRB/IEC approvals for the study protocol and all amendments 
- All source documents and laboratory records 
- Patient identification log 
- CRF copies (paper copies or electronic copies on a CD-ROM) 
- Signed patient informed consent forms 
- Any other pertinent study document. 
Originals of all study-related report (incl. original data of study patient - medical records) forms 
will be stored in each study site for at least 10 years after completion of the trial. 
A list allowing patient identification will be kept for 10 years. 
18.4 Financing 
The study is funded by the Bundesministerium für Forschung und Bildung (BMBF; Federal Min-
istry of Education and Research) within the call „Klinische Studien mit besonderer Relevanz für 
die Patientenversorgung“  
 
 

 
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19. 
References 
1. 
Bech, P., et al., Escitalopram dose-response revisited: an alternative psychometric 
approach to evaluate clinical effects of escitalopram compared to citalopram and placebo 
in patients with major depression. Int J Neuropsychopharmacol, 2004. 7(3): p. 283-90. 
2. 
Salagre, E., et al., Statins for the treatment of depression: A meta-analysis of randomized, 
double-blind, placebo-controlled trials. J Affect Disord, 2016. 200: p. 235-42. 
3. 
Wang, C.-Y., P.-Y. Liu, and J.K. Liao, Pleiotropic effects of statin therapy: molecular 
mechanisms and clinical results. Trends in molecular medicine, 2008. 14(1): p. 37-44. 
4. 
de Lemos, J.A., et al., Early intensive vs a delayed conservative simvastatin strategy in 
patients with acute coronary syndromes: phase Z of the A to Z trial. Jama, 2004. 292(11): 
p. 1307-16. 
5. 
Wu, C.K., et al., Statin use reduces the risk of dementia in elderly patients: a nationwide 
data survey and propensity analysis. J Intern Med, 2015. 277(3): p. 343-352. 
6. 
Vollmer, T., et al., Oral simvastatin treatment in relapsing-remitting multiple sclerosis. 
Lancet, 2004. 363(9421): p. 1607-8. 
7. 
Chataway, J., et al., Effect of high-dose simvastatin on brain atrophy and disability in 
secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, 
phase 2 trial. Lancet, 2014. 383(9936): p. 2213-21. 
8. 
ClinicalTrials.gov. Identifier NCT00842920, Trial of Simvastatin in Amnestic Mild 
Cognitive Impairment (MCI) Patients (SIMaMCI).  2019 May 23]; Available from: 
https://clinicaltrials.gov/ct2/show/NCT00842920. 
9. 
Andrade, C., Selective serotonin reuptake inhibitor drug interactions in patients receiving 
statins. J Clin Psychiatry, 2014. 75(2): p. e95-9. 
10. 
Abajobir, A.A., et al., Global, regional, and national incidence, prevalence, and years 
lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a 
systematic analysis for the Global Burden of Disease Study 2016. The Lancet. 390(10100): 
p. 1211-1259. 
11. 
Whiteford, H.A., et al., Global burden of disease attributable to mental and substance use 
disorders: findings from the Global Burden of Disease Study 2010. Lancet, 2013. 
382(9904): p. 1575-86. 
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20. 
Appendices 
20.1 Stellungnahme zur Geschlechterverteilung 
Based on sex-specific prevalence rates and recruitment in our earlier studies [86, 87], we expect 
that about two thirds of the sample will be women. This will allow gender-specific analyses. 
20.2 Stellungnahme zur Weiterbehandlung nach Studienende 
After completing all the protocol treatment and visits, patients will continue with regular visits 
according to usual practice. In case of response or remission, Escitalopram will be continued 
while the study medication Simvastatin (IMP) will be discontinued in any event. In case of non-
response or non-remission, Esctalopram will be definitely discontinued. The investigator will en-
sure a gradual dose reduction of Escitalopram over at least one or two weeks because of poten-
tial symptoms associated with abrupt discontinuation of Escitalopram. Patients with non-re-
sponse or non-remission will be offered at least one additional clinical appointment at the psychi-
atric outpatient clinic of the study center after termination of the individual study participation for 
the gradual discontinuation of Escitalopram. 
 
In the case of premature termination, the reason for withdrawal must be entered on the appropri-
ate case report form (eCRF) page and the patient must be followed for safety and efficacy until 
the end of the study (week 12).  
20.3 Zusammenfassende Nutzen-Risiko-Abwägung 
See 10. Risk-benefit-assessment 
20.4 Ergänzende Informationen zum Prüfpräparat  
See 4.2 Data on IMP-Application