Conditions: Major Depressive Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
This study's primary objective is to compare the efficacy and tolerability of switching patients with inadequate relief on generic SSRIs to levomilnacipran versus adding a new treatment (quetiapine) to the participants' existing treatment with people diagnosed with depression (major depression disorder).

The secondary objective is to examine the response and remission rates following the switch from a generic SSRI to levomilnacipran ER and augmentation with quetiapine along with examining changes in neurocognitive and apathy measures after the switch.

Detailed description:
1. Study Design 1) An 8-week, randomized rater blinded parallel group, 2-arm trial 2) Trial duration - 9 weeks 3) Drug doses

   * Levomilnacipran ER; Switching to a flexible dose regime of levomilnacipran ER 40-120 mg/day after initial dose of 20mg.
   * Quetiapine XR; Adjunct a flexible dose regimen of quetiapine XR 150-300 mg/day after initial dose of 50mg.
2. Objective 1) To compare the efficacy and tolerability of switching to levomilnacipran ER (40-120 mg/d) versus augmentation with quetiapine XR 150-300 mg/day to the patients' existing treatment for patients with inadequate relief on generic SSRIs in patients with MDD.

2\) To examine the response following the switch from generic SSRI to levomilnacipran ER and augmentation with quetiapine XR.

3\) To examine changes in neurocognitive and apathy measures after switching from SSRI to levomilnacipran ER and after augmentation with quetiapine XR in MDD

Arms:
arm 1: Levomilnacipran ER is switched from SSRI. arm 2: Quetiapine XR is added in addition to current SSRI.

Interventions: intervention 1: Levomilnacipran intervention 2: Quetiapine
Intervention descriptions: intervention 1: treating major depression. A flexible dose regime of levomilnacipran ER 20-120 mg/d mg per day starting at 20 mg/d on Days 1-2, increasing to 40 mg/d on Days 3-7 in week 1, then flexibly dosed between 40 mg/d -120 mg/d during weeks 2 through 8 intervention 2: Quetiapine will be started at 50 mg/d on Day 1-2, increasing to 150 mg/d on Days 3-7 in Week 1 and then flexibly dosed between 150-300 mg/d during Weeks 1 through 8 along with their current antidepressant.

Protocol document:
Prot_SAP_000.pdf: 
Levomilnacipran versus quetiapine augmentation Patkar et al  
1 
Version 6  
 
July 18, 2017 
NCT02720198 
 
Study Proposal Full Protocol 
Title: A randomized, rater-blinded trial comparing efficacy and tolerability and changes 
in neurocognition and apathy of a switch to levomilnacipran extended release (ER) versus 
adjunctive quetiapine extended release for patients who have shown inadequate relief 
with Selective Serotonin Reuptake Inhibitors (SSRIs) in Major Depressive Disorder 
(MDD). 
Principal Investigator (PI):   
Ashwin A Patkar, MD 
Professor of Psychiatry  
Duke University Medical Center 
2218 Elder Street, suite 127, Durham, NC 27705 
Tel #: 919-668-3626 
Fax #: 919-668-5418 
E-mail: Ashwin.Patkar@duke.edu 
 
Sub_Investigators 
Angelo Sambunaris, M.D.,  
Atlanta Institute of Medicine & Research 
5901 Peachtree Dunwoody Rd Suite A2:  
Atlanta, GA 30328 / (770) 817-9200 (Office) 
a.sambunaris@atlanta-institute.com 
 
Prakash S Masand, MD 
26 East 63rd St., Apt. 11-F, New York, NY 10065 
Tel: 212-633-0003 
Email: pmasand2001@yahoo.com, 


Levomilnacipran versus quetiapine augmentation Patkar et al  
2 
Version 6  
 
July 18, 2017 
TABLE OF CONTENTS 
I. 
BACKGROUND AND RATIONALE 
 
 
 
 
 
II. 
STUDY OBJECTIVES 
III.   
STUDY DESIGN AND PLAN 
 
A. Methodology 
IV.   
STUDY POPULATION 
A. 
Number of Subjects 
B. 
Subject Recruitment 
C. 
Inclusion Criteria 
D. 
Exclusion Criteria  
V. 
STUDY PROCEDURES 
A.  
Blinding and Controls 
B. 
Dosage Regimen 
C. 
Visit-Specific Treatment and Evaluation Sequence 
D. 
Concomitant Medication and Therapy 
VI.   
STUDY MEDICATION 
A.        Description and Dispensing 
B. 
Storage 
VII. 
CLINICAL ASSESSMENTS 
VIII. STATISTICAL EVALUATION 
A. 
Power Analysis 
B. 
Randomization Method 
C. 
Outcome Measures and Planned Analyses 
D. 
Definition of Evaluable Subject (safety and efficacy) 


Levomilnacipran versus quetiapine augmentation Patkar et al  
3 
Version 6  
 
July 18, 2017 
IX : ETHICAL AND REGULATORY CONSIDERATIONS  
X : REFERENCES 
XI : STUDY TIMELINES 
XII : PUBLICATION PLAN 
XIV : SCHEDULE OF EVENTS 
  
 


Levomilnacipran versus quetiapine augmentation Patkar et al  
4 
Version 6  
 
July 18, 2017 
I.  BACKGROUND AND RATIONALE:   
As increasing number of antidepressants has become generically available, the generic 
penetration of the antidepressant market in the US has increased from about 41% in 2004 
to about 73% in 2010 (Ventimiglia and Kalali, 2010).  Although generic SSRIs are 
widely used, they continue to suffer from several limitations including variability of 
response, intolerable side effects and high discontinuation rates. In real world settings, 
clinicians frequently switch patients between different antidepressants for efficacy and/or 
tolerability reasons. 
 
The efficacy of extended-release (ER) levomilnacipran has been established for major 
depressive disorder (MDD) in doses ranging from 40 mg/day to 120 mg/day (Sambunaris 
et al, 2014; Asnis et al, 2013). Levomilnacipran is the most noradrenergically active of 
the SNRI class of antidepressant drugs. Levomilnacipran was found to have twofold 
greater potency for norepinephrine relative to serotonin reuptake inhibition, and 17 and 
27 times higher selectivity for norepinephrine reuptake inhibition compared with 
venlafaxine and duloxetine, respectively (Auclair et al, 2013).   
 
Cognitive dysfunction in MDD is common and associated with greater impairment in 
functioning and quality of life.  Given the similarities in mechanisms of action, it is 
possible for levomilnacipran to have beneficial effects on neurocognition. Apathy is 
considered a disorder of motivation and can occur in neuropsychiatric syndromes as well 
as depression. It is associated with neurocognitive disturbances and functional 
impairment. It remains understudied in depression.  
 
Augmentation by adjunctive atypical antipsychotics is recommended as one of the 
clinical strategies on par with antidepressant switch in the APA guidelines to treat MDD.  
Quetiapine (extended release) is an atypical antipsychotic approved as adjunct to 
antidepressants for treatment of MDD in doses between 150-300 mg/day and has been 
extensively used in clinical practice. 
 


Levomilnacipran versus quetiapine augmentation Patkar et al  
5 
Version 6  
 
July 18, 2017 
Needs assessment: There is a significant unmet clinical need in terms of patients with 
MDD who show inadequate response and remission with SSRI treatment. Scientific 
evidence that guides appropriate treatment strategies in terms of further steps of 
switching or augmentation of medications will improve clinical care in patients with 
MDD who do not show adequate response to SSRIs. 
 
II. STUDY OBJECTIVE(S):  
Primary:  
1. To compare the efficacy and tolerability of switching to levomilnacipran ER (40-
120 mg/d) versus augmentation with quetiapine 150-300 mg/day to the patients’ 
existing treatment for patients with inadequate relief on generic SSRIs in patients 
with MDD.  
 
Secondary:  
1. To examine the response and remission rates following the switch from generic 
SSRI to levomilnacipran ER and augmentation with quetiapine.  
2. To examine changes in neurocognitive and apathy measures after switching  from 
SSRI to levomilnacipran and after augmentation with quetiapine in MDD 
 
III. STUDY DESIGN and PLAN:   
Methodology:   
This is an 8-week, randomized rater blinded parallel group, 2-arm trial to comparing a 
switch to levomilnacipran ER versus augmentation with quetiapine.  
 
Participants who meet inclusion/exclusion criteria for inadequate response to existing 
antidepressants will be randomly assigned (1:1 ratio) to either levomilnacipran ER or 
augmentation with quetiapine and their existing antidepressants in the same dose for 8 
weeks. A flexible dose regime of levomilnacipran ER 40-120 mg/d mg per day will be 
employed with titrating doses starting at 20 mg/d on Days 1-2, increasing to 40 mg/d on 
Days 3-7 in week 1, then flexibly dosed between 40 mg/d -120 mg/d during weeks 2 
through 8. FDA approved package insert guidelines will be followed for the adjunctive 


Levomilnacipran versus quetiapine augmentation Patkar et al  
6 
Version 6  
 
July 18, 2017 
quetiapine dosing. Quetiapine will be started at 50 mg/d on Day 1-2, increasing to 150 
mg/d on Days 3-7 in Week 1 and then flexibly dosed between 150-300 mg/d during 
Weeks 1 through 8 along with their current antidepressant. Patients who cannot tolerate 
the higher dose of levomilnacipran ER or quetiapine will have their dose reduced to a 
lower dose per the investigator’s judgment.  The primary efficacy measure rating will be 
performed by a blinded rater. 
 
IV. STUDY POPULATION:  
     A.  A total of 60 subjects (n=30 in each group) will be studied at 2 sites. A total of 40  
           subjects will be screened for a total of 30 eligible subjects to be enrolled at Duke.  
     B.  Potential participants will be identified by self-referral via the printed ad, phone  
Script, the patients’ physicians, local health providers, mental health providers, or 
Duke providers; if not self-referred, the potential participant will have the study 
introduced by a care provider known to them as meeting the inclusion criteria will 
be offered basic information about the protocol by the PI or Study Coordinator 
and if interested, provided with an appointment for the purposes of obtaining 
informed consent and screening assessments. 
 
During the phone screen interview the study coordinator will collect specific 
protected health information (PHI) for ascertaining subject eligibility and to 
determine if an appointment should be set up. If the is ineligible to participate or 
decides not to participate in the study, the PHI will be destroyed.  The PI or Study 
Coordinator will also clearly explain to them that a refusal to participate in the 
study will not affect their participation to treatment at their regular treating 
physician or Duke University Medical Center (DUMC). 
 
C.  Inclusion Criteria 
• Male or Female - ages 18-65 years of age inclusive 
• Current diagnosis of Major Depressive Disorder based on DSM-IV criteria 


Levomilnacipran versus quetiapine augmentation Patkar et al  
7 
Version 6  
 
July 18, 2017 
• Able to understand study rules and procedures and willing to sign written 
informed consent for study participation 
• Inadequate response to antidepressants:  having a score of ≥14 on the 17-item 
HAMD and not having a ≥ 50% reduction in HAMD or CGI-S scores from 
baseline after a retrospective confirmation of an adequate trial of a single 
antidepressant (defined as a minimum 6-week trial of acceptable therapeutic 
dose (daily dose ≥ 40 mg of fluoxetine, 40 mg of paroxetine, 20 mg of 
citalopram, 10 mg of escitalopram, 37.5 mg of paroxetine CR, 150 mg of 
sertraline, 100 mg of fluvoxamine). 
If female, nonpregnant/nonlactating status 
• Duration of current MDD ≥ 4 weeks and < 24 months 
Not more than 2 treatment failures of adequate antidepressant trials for 
current episode of MDD 
D.  Exclusion Criteria 
• Has previously participated in a levomilanacipran ER or quetiapine XR or 
quetiapine clinical study in previous 12 months 
• Has 1 or more the following: Current or past history of: manic or hypomanic 
episode, schizophrenia or any other psychotic  disorder defined in the DSM- 5                  
• Diagnosis of alcohol or other substance use disorder (except nicotine and 
caffeine) as defined in the DSM-5 that has not been in sustained full remission 
for at least 6 months  prior to screening (participant must also have negative 
urine drug screen prior to baseline). 
• Presence or history of a clinically significant neurological disorder (including 
epilepsy) 
• Poorly controlled Hypertension or Diabetes 
• uncontrolled narrow-angle glaucoma 
• hypersensitivity to levomilnacipran, milnacipran , quetiapine or quetiapine XR 
• Neurodegenerative disorder. 
• Has a thyroid stimulating hormone value outside the normal range at the 
Screening Visit that is deemed clinically significant by the investigator. 


Levomilnacipran versus quetiapine augmentation Patkar et al  
8 
Version 6  
 
July 18, 2017 
• Has clinically significant abnormal vital signs as determined by the 
investigator. 
• Has a clinical significant abnormal electrocardiogram. 
• Has screening laboratory values greater than 2.5 times the upper or lower 
limits of normal range or judged to be clinically significant 
• Has a disease or takes medication that, in the opinion of the investigator, 
could interfere with the assessments of safety, tolerability, or efficacy or 
prevent the individual from completing the study. Female subjects of 
childbearing potential not on adequate contraception methods in the opinion 
of the investigator 
o If the female is childbearing, she must agree to use appropriate 
contraceptive measures for the duration of the study and for one month 
afterwards.  Medically acceptable contraceptives include: (1) surgical 
sterilization (such as tubal ligation of hysterectomy), (2) approved 
hormonal contraceptives (such as birth control pills, patches, implants, or 
injections), (3) barrier methods (such as condom or diaphragm) used with 
a spermicide, or (4) an intrauterine device (IUD). Contraceptive measures 
such as Plan B ™, sold for emergency use after unprotected sex, are not 
acceptable methods for routine use. If the female does become pregnant 
during this study she must inform the study physician immediately. 
 
• Has a significant risk of suicide according to Columbia Suicide Severity 
Rating Scale (CSSRS) or in the clinical judgment of the investigator 
• History of suicide attempt in the previous 12 months 
• MDD with postpartum onset, psychotic features or seasonal features 
• Hamilton Anxiety Scale (HAM-A) baseline score  ≥ 24 
• Failure of ≥ 3 adequate trials of different antidepressants for the current 
episode of MDD 
• ≥ 3 episodes major depression in previous 12 months or ≥ 8 lifetime episodes 
of MDD 
• Current or previous use of an atypical or typical antipsychotic agent for 
augmentation of major depression or treatment of psychotic depression, mania 
psychosis, or agitation. Previous use of antipsychotics for insomnia will be 
permitted. 


Levomilnacipran versus quetiapine augmentation Patkar et al  
9 
Version 6  
 
July 18, 2017 
V.  STUDY PROCEDURES 
     A.  Blinding and Controls:  
The study will be rater blinded, randomized, parallel study.   Patients will be 
randomized in 1:1 ratio to levomilnacipran ER switch arm or adjunctive 
quetiapine arm. Subjects will be instructed not to discuss any clinical issue with 
the blinded rater. The blinded rater will be specifically instructed to perform 
specified ratings only and not to address or ask any other study related questions. 
    
  B.  Drugs, Dosages, and Regimens:  
All allowed concomitant medications will be unchanged throughout the study. 
Other psychotropic medications will require a 2-4 week washout, depending on 
the half life of the applicable medication after the subject is deemed eligible after 
the screening visit. Subjects will be monitored weekly by phone for side effects or 
symptom worsening during the taper.   Subjects randomized to the 
Levomilnacipran switch arm will have their SSRI tapered over 2-4 weeks after 
they are determined to be eligible for the study to avoid risk of discontinuation 
syndrome.  Subjects randomized to the adjunctive quetiapine arm will have their 
pre-existing antidepressants continue unchanged at baseline. A flexible dose 
regime of levomilnacipran ER 40-120 mg/d mg per day will be followed with the 
FDA approved package insert. Initial titration dose will bet 20 mg/d Days 1-2, 
increasing to 40 mg/d from Days 3-7 in week 1, flexibly dosed between 40 mg/d -
120 mg/d week 2 to week 8. FDA approved package insert guidelines will be 
followed for adjunctive quetiapine dosing. Adjunctive quetiapine will be started at 
50 mg/d Day 1-2, increasing to 150 mg/d Days 3-7 and flexibly dosed between 
150-300 mg/d week 1-8. Patients who cannot tolerate the higher dose of 
levomilnacipran ER or quetiapine will have their dose reduced to the lower dose 
per the investigator’s judgment.  At the end of the 8-week trial, subjects in each 
group will have 1-week taper of study drug.  A week 9 follow up safety 
assessment will be performed.  Subjects will be told how to safely restart their 


Levomilnacipran versus quetiapine augmentation Patkar et al  
10 
Version 6  
 
July 18, 2017 
prior medication or can be provided with a referral for continued treatment as 
needed. 
 
Any new medication started during the study will be evaluated by the investigator 
to determine its effect on study integrity and subject safety.  Subjects and primary 
raters will be blinded to study drug and doses. 
Arm I: Levomilnacipran ER flexible dose regime (40-120 mg/d): titration dose of 
20 mg po once a day from days 1-2, then 40 mg po once a day, 80mg po once a 
day or 120 mg once a day.  
      Arm II: Quetiapine flexible dose regime: 50 mg po once a day as initiating       
dose, 150 mg po once a day (during the period that the subjects will be titrated on 
150 mg; they will be given 1-50mg tab and 1-100 mg tab with instructions to be 
taking once per day) (, then 300 mg po once a day. 
 
C. Visit specific procedures and sequence: 
     This is an 8-week trial with a 1 week (week 9) safety follow up visit. Visits will be     
     planned to occur at the screening visit and weeks 0, 1, 2, 3, 4, 6, 8 and 9.  
The following activities and/or assessments will be performed at/during the 
Screening visit (Week -4 to Week 0):  
• Obtain written informed consent prior to performing any of the formal 
screening procedures.  
• Administer the M.I.N.I  
• Administer the C-SSRS, MADRS, ASEX, HAM-D, HAM-A, DSST, 
CGI-S, RVLT, Spontaneous Reported AEs and Sheehan Disability  
• Record demographic information 
• Obtain medical and surgical and psychiatric history 
• Record prior and concomitant medications  
• Record vital signs (temperature, heart rate, supine and orthostatic blood 
pressure), body height and body weight 
• Perform a complete physical examination 
• Perform a 12-lead ECG 


Levomilnacipran versus quetiapine augmentation Patkar et al  
11 
Version 6  
 
July 18, 2017 
• Collect blood and urine samples for evaluation of standard laboratory 
safety test (chemistry, hematology, and urinalysis) 
• Assess all applicable inclusion and exclusion criteria 
• Schedule the baseline visit for those subjects that do not require washout 
of prohibited medications 
• Subjects requiring washout of prohibited medication will be provided 
washout requirements  
o Subjects in adjunctive quetiapine arm will be permitted to continue 
their pre-existing antidepressants if FDA approved for depression;  
if not FDA approved, they will be switched to an FDA approved 
medication for the duration of the study but will undergo washout 
of other prohibited medications 
• Provide instructions on washout of prohibited medication(s), including the 
duration of the washout period (if needed) 
• Assess for and record AEs and concomitant medications 
 
Once potential eligibility is confirmed, the investigator, or a person designated by the 
investigator, will contact the subject by telephone at or during the 
Randomization/Baseline (Week 0): 
• Determine appropriate duration of the washout period of prohibited 
medication(s), taking into account any labeling requirements for tapering of 
medication dose(s), as well as the minimal washout requirements 
o Weekly phone calls will include a Symptom Checklist, consistent with 
symptoms of Major Depression, suicidal risk and adverse events, 
which the Study Coordinator will review with the subject. Any 
potential concerns will be reviewed with the subject.  Any potential 
concerns will be discussed with the PI and appropriate interventions 
for subject safety will be planned. The same symptom checklist and 
monitoring plan for the subjects will be used at the Duke and the non-
Duke site.  
• Assess all applicable inclusion and exclusion criteria 


Levomilnacipran versus quetiapine augmentation Patkar et al  
12 
Version 6  
 
July 18, 2017 
• Administer the C-SSRS, MADRS, ASEX, HAM-A, DSST, CGI-S, RVLT, 
AES, Spontaneous Reported AEs and Sheehan Disability 
• Assess for and record AEs and concomitant medications 
• Dispense study medication 
 
    The following activities and/or assessments will be performed at Weeks 1 through    
    Weeks 6: 
• Assess for and record AEs and concomitant medications 
• Administer the C-SSRS, MADRS, ASEX, HAM-A, DSST, CGI-S, RVLT, AES, 
Spontaneous Reported AEs and Sheehan Disability 
• Collect study medication and review medication compliance 
• Dispense study medication 
 
    The following activities and/or assessments will be performed at Week 8: End of Study   
   or Early Termination:  
• Assess for and record AEs and concomitant medications 
• Collect study medication and review medication compliance 
• Record vital signs (temperature, heart rate, supine and orthostatic blood pressure), 
and body weight 
• Collect blood and urine samples for evaluation of standard laboratory safety tests 
• Administer the C-SSRS, MADRS, ASEX, HAM-A, DSST, CGI-S, RVLT, AES, 
Spontaneous Reported AEs and Sheehan Disability 
• Perform a 12-lead ECG 
 
The following activities and/or assessments will be performed at the Week 9/ Safety 
Follow-Up Visit: 
• Assess for and record AEs and concomitant medications 
• Administer the C-SSRS, Spontaneous Reported AEs and the DSST 
 
After all study assessments has been completed or if the participant completes an early 
term visit, the participants will be referred back to their outpatient treating physician for 


Levomilnacipran versus quetiapine augmentation Patkar et al  
13 
Version 6  
 
July 18, 2017 
psychiatric care. Participants who are uninsured will be referred to Lincoln Community 
Health Center or Durham Access.  Results of the subject's participation will not be 
available to the subject before they return to their treating doctor. 
 
Patient termination will occur if the patient experiences a clinically significant worsening 
of MADRS scores in two successive visits or any worsening on CSSRS on two 
consecutive visits, or based on clinician judgment or patient preference.   
 
  
D. Concomitant Medications and Therapy:  
All medications for pre-existing medical conditions will be permitted to continue 
unchanged provided subjects are on a stable dose of at least 12 weeks.  Subjects on 
prohibited concomitant mood stabilizers or atypical antipsychotics will require a 2-4-
week washout of the prohibited medication after the subject meets all eligibility criteria at 
the screening visit.  Washout of prohibited medication will be determined by the ½ life of 
the drug. Subjects on a minimum of 3 months of stable dose of hypnotics (e.g. zolpidem 
10 mg per day or benzodiazepine dose of ≤ 2 mg per day of lorazepam or trazodone ≤ 
100 mg per day) will be allowed to continue their hypnotic medication at the same dose. 
Over the counter medications will be permitted if in the opinion of the investigator, they 
are not considered to have any significant impact on the study. Any medication that has 
the potential to cause a clinical significant drug interaction with levomilnacipran ER or 
quetiapine in the judgment of the investigator will require a washout. 
 
VI. STUDY MEDICATION 
A. Description and Dispensing 
      a. Description and Dispensing 
          Levomilnacipran and quetiapine will be dispensed/administered at specified study   
          visits.   
      b. Storage 
 
All study medications will be stored in a double-locked cabinet in the Civitan    
            Building. With available access only to the study investigator and research  
            coordinator. 


Levomilnacipran versus quetiapine augmentation Patkar et al  
14 
Version 6  
 
July 18, 2017 
VII. CLINICAL ASSESSMENTS 
Diagnostic Evaluation:   The Mini-International Neuropsychiatric Interview (MINI) 
(version 6.6) for DSM-5 Axis I Disorders to establish diagnosis.  
 
Study Parameters/Efficacy: 
Efficacy:  
The primary outcome measure will be: 
Change from Baseline to end of treatment in Montgomery-Åsberg Depression Rating 
Scale (MADRS) Total Score.  
 
Secondary outcome will be: 
Change from baseline to end of treatment in  
Clinical Global Impression Scale- Severity (CGI-S) and Improvement (CGI-I) scores  
Hamilton Anxiety Rating Scale (HAM-A) scores 
Hamilton Depression Rating Scale (HAM-D) scores 
Sheehan Disability Scale (SDS) total score.  
Scores on Digit symbol substitution test (DSST)  
Scores on Reyes Verbal Learning Test (RVLT).  
Scores on Apathy Evaluation Scale (AES). 
 
Safety/Tolerability:   
Safety and tolerability will be assessed by spontaneously reported adverse events, 
Columbia Suicide Severity Rating Scale (CSSRS) Arizona Sexual Experience Scale 
(ASEX) scores, vital signs, weight and BMI measurements and clinical laboratory 
assessments and evaluating reasons for dropout from the trial. 
 
Adverse event: any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
Suspected adverse reaction: any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event 


Levomilnacipran versus quetiapine augmentation Patkar et al  
15 
Version 6  
 
July 18, 2017 
Serious Adverse Event (SAE) 
A serious adverse event is one that: 
• 
Results in death 
• 
Is an immediate threat to life? 
• 
Requires inpatient hospitalization, or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect. 
 
Causality Assessment 
For all AEs, the Investigator must provide an assessment of causal relationship to the IP. 
Causal relationship must be assessed by answering the following question: 
Is there a reasonable possibility the IP caused the event? 
Yes: 
There is a possible or probable relationship (i.e., there is a reasonable or strong 
temporal relationship, and the events are unlikely to be attributable to other drugs, 
underlying diseases, or other factors). Challenge and/or rechallenge (if available) is 
positive. 
No: 
The relationship is unlikely or nonexistent (i.e., there is no strong temporal 
relationship and/or the use of other drugs, underlying diseases, or other factors provide 
plausible explanations for the event), or the patient did not take the IP. 
 
Reporting of Adverse Events: 
All spontaneously reported and observed adverse events will be recorded in the source 
and CRF documents. The Principal Investigator will inform Actavis/Forest Global Drug 
Safety of all SAEs within 24 hours of first knowledge of any AE that meets one of the 
criteria for an SAE, on a SAE report form. If, during follow-up, any nonserious AE 
worsens and eventually meets the criteria for an SAE, that AE will be recorded as a new 
SAE. 
The study centers will transmit the SAE report form to the SAE fax number (631) 858-
7906) within 24 hours of first awareness of the event at the study center. Supplemental 
information will be submitted as soon as available and may include laboratory results, 


Levomilnacipran versus quetiapine augmentation Patkar et al  
16 
Version 6  
 
July 18, 2017 
radiology reports, progress notes, hospital admission and emergency room notes, holding 
and observation notes, discharge summaries, autopsy reports, and death certificates. 
 
Reporting of Pregnancy to Allergan, Inc. / Forest Research Institute 
Study center personnel will report every pregnancy on a pregnancy report form as soon as 
possible (within 24 hours of first awareness of the pregnancy to the Allergan, Inc. 
pregnancy fax number, (631) 858-7906), even if no AE has occurred, and follow it to 
term. If, however, the pregnancy is associated with an SAE (e.g., if the mother is 
hospitalized for dehydration), in addition to the pregnancy report form, a separate SAE 
report form will be filed.  
Any Serious Adverse Event will also be reported to the Duke IRB, to the FDA within 24 
hours. The FDA Adverse Event Reporting System (AERS) is a computerized information 
database designed to support the FDA's post-marketing safety surveillance program for 
all approved drug and therapeutic biologic products. The FDA uses AERS to monitor for 
new adverse events and medication errors that might occur with these marketed products. 
 
VII. STATISTICAL EVALUATION 
A.  Power analysis: 
The proposed design levomilnacipran switch has never previously been studied in either a 
randomized or open-label design. Thus no direct pilot data exist upon which to base a 
power analysis.  As is recommended for cases where pilot data are absent or minimal, 
clinical trials can be powered to detect clinically meaningful effect sizes.  What is 
clinically meaningful depends on the illness and outcome being studied.  According to 
mainstream resources, such as British National Institute for Health and Clinical 
Excellence (NICE), it is generally accepted that small effect sizes are not clinically 
meaningful, while medium effect sizes are.  If one uses standardized effect sizes 
(Cohen’s d) to determine clinical significance, the British National Institute for Health 
and Clinical Excellence (NICE) has suggested that d=0.50 should be the standard general 
threshold for "clinical significance" in drug treatments (www.nice.org.uk).  This standard 
has been applied to assessing efficacy in RCTs with antidepressants in MDD (Kirsch et 
al., 2008). 


Levomilnacipran versus quetiapine augmentation Patkar et al  
17 
Version 6  
 
July 18, 2017 
Sample Size calculations for two-sided log rank test in survival analysis 
Power 
Proportion Response: 
Drug 
Proportion Response: 
Placebo 
Alpha 
Number in each 
group 
0.90 
.33 
.17 
0.05 
44 
0.80 
.33 
.17 
0.05 
28 
0.90 
.45 
.27 
0.05 
48 
0.80 
.45 
.27 
0.05 
31 
 
Using Cohen’s d effect size to determine sample size, in Cohen’s standard text on 
statistical power (Cohen, 1988), using the NICE definition of a d=0.5 or larger, we obtain 
an estimated sample size (given a two-sided alpha = 0.05 and 1 – Beta = 0.800) of n= 30 
per arm or 60 for the study. A power analysis was also conducted based on an effect size 
estimate derived from the drug-placebo difference in primary outcome of MADRS scores 
in published levomilnacipran trials (Citrome, 2013). The summary of Least square mean 
change between drug and placebo at 95% CI was -4.9 (p<.0001). With a two-tailed   
alpha= =0.05, a sample size of n= 60 provides a power of 0.80.  
 
B.  Randomization Method   
Randomization will occur with randomly generated computer lists held at the Duke site.  
This group will assign subjects according to a computer-generated the randomization 
sequence (without blocking or stratification) for each site. After the study coordinator 
determines eligibility, the participant will be randomized to one of two different arms. 
Drug capsules will be placed in standard medicine bottles. Each bottle will be dispensed 
individually by the study coordinator at the appropriate visit. Rater unblinding will be 
done at the end of the study after data lock. In case of any AEs or SAEs or other 
emergencies that require the blind to be broken, the pharmacy will have a 24-hour on call 
support service. 
 
Power analysis was performed using an internet based software program. The results 
showed that a sample size of n=60 (n=20 in each of the 3 groups) could detect a strong 
effect with α = .05, unless the true mean difference is quite minimal. 
 


Levomilnacipran versus quetiapine augmentation Patkar et al  
18 
Version 6  
 
July 18, 2017 
C.  Plan of Data analysis  
Subjects will be defined as able to be evaluated by two methods.  The primary method 
will be an intent-to-treat analysis, including those who discontinue drug due to lack of 
efficacy or due to side effects.  The secondary method will be completer analysis.  The 
intent-to-treat (ITT) group will include randomly assigned patients receiving study drug 
with a post baseline efficacy assessment. The safety population will comprise all patients 
receiving study drug with a post baseline safety assessment. 
 
Primary efficacy analysis will be conducted in the ITT population using the last-
observation-carried-forward (LOCF) method. Treatment group comparisons will base on 
changes in MADRS from baseline to week 8/end of treatment from repeated measures 
ANOVA or analysis-of-covariance (ANCOVA) model containing treatment site, gender 
and baseline MADRS score included as a covariate.  
 
Secondary efficacy analysis: Repeated measures ANOVA or ANCOVA models will be 
used to analyze change from baseline in secondary measures.  Response and remission 
rates at end of treatment will be compared using the Cochran-Mantel- Haenszel test. No 
formal hypothesis testing will be performed on safety data. Safety outcomes will be 
summarized by treatment group and study visit (observed cases) using descriptive 
statistics. Any clinically significant findings among patients who terminated early will be 
discussed separately. All analyses will be conducted using SAS Version 9.1.3 (SAS 
Institute, Inc.; Cary, North Carolina). Statistical comparisons of efficacy outcomes will 
be 2-sided and considered significant at P < .05. Comparisons for secondary endpoints 
will be not adjusted for multiplicity. 
 
D.  Definition of Evaluable Subject (Safety and Efficacy) 
Subjects will be defined as able to be evaluated by two methods.  The primary method 
will be an intent-to-treat analysis, including those who discontinue drug due to lack of 
efficacy or due to side effects.  The secondary method will be completer analysis.  
 
 


Levomilnacipran versus quetiapine augmentation Patkar et al  
19 
Version 6  
 
July 18, 2017 
XI:  ETHICAL AND REGULATORY CONSIDERATIONS  
A. 
Institutional Committee Approval 
Duke University Health Systems Institutional Review Board (DUHS IRB) will 
need to approve the protocol at the Duke site. Dr Sambunaris’ site will use an 
external IRB (e.g. Copernicus, Western) and provide Duke with a copy of its 
approval. 
B. 
Informed Consent 
Participation in this study is voluntary and at no cost to the subjects.  All potential 
participants interested in this study must be thoroughly informed of the details of 
the study.  Prior to study participation in this trial, each subject will have an 
opportunity to ask questions and will sign an approved informed consent form.  
The signed consent forms will be filed with the investigator’s copies of the Case 
Report Forms for each subject and a copy provided to the subject.  Any subject 
may voluntarily withdraw from the study at any time without prejudicing 
treatment. 
C. 
Document Storage and Retention 
Documents will be stored at the offices of the respective Principal Investigator Dr. 
Patkar at Duke and Dr Sambunaris at Atlanta. Medical records will be kept in 
accordance with Duke University Medical Center requirements.  All research 
records and information obtained in this study will be kept in locked files and will 
be available only to research staff, Duke Institutional Review Board, the FDA, 
and personnel from Allergan, Inc. Computers will be password protected. Except 
when required by law, subjects will not be identified by name, social security 
number, address, telephone number, or any other direct personal identifier in 
study records disclosed outside of Duke University Health System (DUHS).  
 
The study results will be retained in the subject’s research record for at 6 years 
after the study is completed, whichever is longer.  At that time either the research 
information not already in the subject’s medical record will be destroyed or 
information identifying the subject will be removed from such study results at 


Levomilnacipran versus quetiapine augmentation Patkar et al  
20 
Version 6  
 
July 18, 2017 
DUHS.  Any research information in the subject’s medical record will be kept 
indefinitely. 
D. 
Protocol Amendments 
Any protocol amendments will be accompanied by IRB approval and appropriate 
revisions of consent form documents. 
E. 
Confidentiality of Data and Subject Records 
Subject research charts will only be identifiable by initials and numbers when 
disclosed outside of the study site.  No subjects will be identifiable in any 
published data produced from this study. HIPPA compliant deidentification 
procedures will be followed for any data analysis or dissemination. 
F.   
Monthly Protocol Communication 
Before subject enrollment, the PI’s at Duke and the non-Duke site will plan a 
schedule of monthly teleconferences to review the following: Subject Enrollment, 
Screening Issues, Subject Compliance, Assessment Scales and Primary/Secondary 
Efficacy and Safety Measures, Adverse Events and Serious Adverse Events, 
Study Drug Storage and Dispensing, Data Collection and Data Entry. 
 
Any potential concerns that may impact on subject safety, or study integrity, will 
be reviewed to decide if any protocol modifications and/or urgent communication 
with sites are necessary. If required, a Modified Protocol and Consent Form will 
be submitted to IRB for approval. The teleconferences will also include 
discussion of interim blinded data analysis and results. 
 
ADDITIONAL INFORMATION REGARDING STUDY CONDUCT 
A. 
Case Report and Other Forms 
All case report and other forms will be contained in the study research chart of 
each subject. 
B. Quality Assurance Audits 
     Charts will be made available as requested to the sponsor, the participating site IRBs,  
      sponsor and the FDA or other federal regulatory bodies for quality assurance  
      purposes. 


Levomilnacipran versus quetiapine augmentation Patkar et al  
21 
Version 6  
 
July 18, 2017 
C.  Study Discontinuation/Termination 
Patients will be discontinued from the study for the following reasons: 
1. 
Initiation of any concomitant medications that are excluded from the trial 
2. 
Development of any psychiatric or medical condition that are exclusion criteria. 
3. 
Development of any side effects or adverse events that are sufficiently clinically 
significant in the opinion of the investigator to warrant discontinuation. 
4. 
Clinical worsening sufficient to require hospitalization or other medication 
interventions in the judgment of the investigator. 
5. 
Patient noncompliance with medications or appointments 
6. 
Patient voluntarily withdraws consent or is lost to follow up. 
 
X: REFERENCES:doi:10.192/bjp.134.4.382 PubMed 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental 
Disorders. Fifth Edition, Text Revision. Washington, DC: American Psychiatric 
Association; 2014. 
 
Auclair AL, Martel JC, Assié MB, et al. Levomilnacipran (F2695), a norepinephrine-
preferring SNRI: profile in vitro and in models of depression and anxiety. 
Neuropharmacology. 2013; 70:338-347. 
 
Asnis GM, Bose A, Gommoll CP, Chen C, Greenberg WM. Efficacy and safety of 
levomilnacipran sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: 
a phase 3, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013; 
74:242-248. 
 
CItrome L Levomilnacipran for major depressive disorders. A systematic review of the 
efficacy and safety profile of this newly approved antidepressant. What is the number 
needed to treat and number needed to harm. Int J Clin Practice 2013; 67:1089-1104 
 
Guy W. Clinical Global Impressions (028-CGI). In: ECDEU Assessment Manual for 
Psychopharmacology. Rockville, MD: National Institute of Mental Health; 1976:216–
222. 
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 
1960;23(1):56–62. doi: 
10.136/jnp.23.1.56 PubMed 
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 
1959;32(1):50–55. 
 


Levomilnacipran versus quetiapine augmentation Patkar et al  
22 
Version 6  
 
July 18, 2017 
Hawley CJ, Gale TM, Sivakumaran T; Hertfordshire Neuroscience Research group. 
Defining remission by cut off score on the MADRS: selecting the optimal value. J Affect 
Disorder. 2002; 72(2):177–184. do 
 PubMed 
Hindmarch I, et al:  Pharmacodynamics of milnacipran in young and elderly 
volunteers.Br. J. Clin. Pharmacology. 2000; 49: 118–125. 
 
Kanetani K, et al: Therapeutic effects of milnacipran (serotonin noradrenalin reuptake 
inhibitor) on depression following mild and moderate traumatic brain injury. J. Nippon 
Med. Sch. 2003; 70: 313–320. 
 
Marin RS, Biedrycki RC, Firiciogullari S. Reliability and validity of the apathy 
evaluation scale. Psychiatry Res 1991; 38:143–162. 
 
McGahuey CA, Gelenberg AJ, Laukes CA, Moreno FA, Delgado PL, McKnight KM, 
Manber R. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex 
Marital Therapy 2000 Jan-Mar; 26(1):25-40. 
 
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. 
Br J Psychiatry. 1979; 134(4):382–389 
 
Zimmerman M, Posternak MA, Chelminski I. Defining remission on the Montgomery-
Asberg Depression Rating Scale. J Clin Psychiatry. 2004; 65(2):163–168. : 
10.408/JCP.v65n0204 PubMed16/S0165-0327(01)0451-7 PubMed 
Posner K, Brent D, Lucas C, et al. Columbia-Suicide Severity Rating Scale (C-SSRS). 
http://www.cssrs.columbia.edu/docs/ C-SSRS_1_14_09_Baseline.pdf. Accessed 
September 22, 2011. 
 
Sambunaris, A., Bose, A.,Gommoll, C., Chen, C., Greenberg, WM, Sheehan,  DV. A 
Phase III Double-blind, Placebo-Controlled, Flexible-Dose Study of Levomilnacipran ER 
in Patients with Major Depressive Disorder. J Clinical Psychopharmacology 2014 34; 1. 
 
Rickels K, Athanasiou M, Robinson D, Gibertini M, Whalen H, Reed C. Evidence for 
efficacy and tolerability in the treatment of major depressive disorder: A randomized, 
double-blind, placebo-controlled trial. J Clin Psychiatry 2009; 70(3):326-333. 
 
Ventimiglia J, Kalali A. Generic penetration in the retail antidepressant market. 
Psychiatry (Edgmont) 2010; 7(6):9-11.   
 
 
 
 


Levomilnacipran versus quetiapine augmentation Patkar et al  
23 
Version 6  
 
July 18, 2017 
XI: STUDY TIMELINE:   
A startup period of 3 months for contract and IRB approval is anticipated. The projected 
enrollment is to be completed in 12 months, at a rate of 4 patients/month. With an 
8 week trial, it will take 2 additional months for the last subject to complete last 
visit. It will take 2 additional months for the study data to be analyzed and ready 
for presentation. We anticipate he total time period for the trial to be 18 months. 
 
All data will be analyzed by the Duke site.  The PI and Co-Is are solely responsible for 
data analysis, interpretation of results, presentation and publication of data 
produced by this study.  The results of this study will be presented at national 
Conferences (APA, NCDEU) and published in peer reviewed journals (Journal of 
Clinical Psychiatry). 
 
 
XII:  PUBLICATION PLAN:   
Presented at APA Annual meeting 2017, NCDEU annual meeting 2017 and article 
submitted to Journal of Clinical Psychiatry end 2016. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Levomilnacipran versus quetiapine augmentation Patkar et al  
24 
Version 6  
 
July 18, 2017 
XIV. SCHEDULE OF EVENTS: 
STUDY VISIT SCHEDULE 
 
 
Test 
Week -4 
Screening 
Week 0: 
Randomization/
Baseline  
Week 
1 
Week 
2 
Week 
3 
Week 
4  
Week 
6 
Week 8: 
End of 
Study or 
ET 
Week 9: 
Safety 
Follow-
Up 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
X 
 
Vital Signs 
X 
 
 
 
 
 
 
X 
 
Blood Samples & 
Laboratory  tests 
X 
 
 
 
 
 
 
X 
 
Urine Samples Collect. 
X 
 
 
 
 
 
 
X 
 
ECG 
X 
 
 
 
 
 
 
X 
 
Psychiatric History/MINI 
X 
 
 
 
 
 
 
 
 
Prior/concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Washout instructions 
X 
X 
 
 
 
 
 
 
 
MADRS 
X 
X 
X 
X 
X 
X 
X 
X 
 
Columbia Suicide 
Severity Rating Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ASEX 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAM-A 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAM-D 
X 
 
 
 
 
 
 
 
 
RVLT 
X 
X 
X 
X 
X 
X 
X 
X 
 
Spontaneous Reported 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DSST 
X 
X 
X 
X 
X 
X 
X 
X 
 
Sheehan Disability 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-I and CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug 
Dispense/Account/Adjust 
 
X 
X 
X 
X 
X 
X 
X