Conditions: Major Depressive Disorder
Keywords: Major Depressive Disorder bupropion XL Wellbutrin XL
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 74
Healthy volunteers: no

Brief summary:
Determine bioequivalence between branded and generic bupropion extended release (XL) products (and between generic products) at steady state in patients with major depressive disorder.

Detailed description:
The protocol is a prospective, randomized, double-blinded, crossover study with Major Depressive Disorder (MDD) receiving bupropion HCl 300mg XL (branded or generic).

Subjects will be studied in 4 phases for a total of approximately 28 weeks:

Phase 1: an approximately 4-week lead-in phase during which participants remain on their existing bupropion product Phases 2 - 4: randomized cross-over phases of approximately 6 weeks on each of the four bupropion study drugs (brand and 3 generics).

Arms:
arm 1: Subjects will be studied for 28 weeks in a sequential cross-over study: a

Subjects will be studied in 4 phases for a total of approximately 28 weeks:

Phase 1: an approximately 4-week lead-in phase during which participants remain on their existing bupropion product Phases 2 - 4: randomized cross-over phases of approximately 6 weeks on each of the four bupropion study drugs (brand and 3 generics).

Interventions: intervention 1: Bupropion XL 300
Intervention descriptions: intervention 1: Subjects will be studied in 4 phases for a total of approximately 28 weeks:

Phase 1: an approximately 4-week lead-in phase during which participants remain on their existing bupropion product Phases 2 - 4: randomized cross-over phases of approximately 6 weeks on each of the four bupropion study drugs (brand and 3 generics).

Protocol document:
Prot_SAP_000.pdf: 
Bioequivalence of Generic Bupropion 
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1 
RESEARCH PROTOCOL 
 
 
 
 
Bioequivalence and Clinical Effects of Generic and Brand Bupropion 
 
Principal Investigator:  Evan D. Kharasch, M.D., Ph.D. 
Russell D. and Mary B. Shelden Professor of Anesthesiology 
Director, Division of Clinical and Translational Research 
Washington University School of Medicine 
Department of Anesthesiology 
660 S. Euclid Ave., Campus Box 8054 
St. Louis, MO 63110 
Voice: (314) 362-8796 
Fax: (314) 747-3371 
E-mail: kharasch@wustl.edu 
 
Co-Investigator:  Eric J. Lenze, MD 
Professor of Psychiatry 
Washington University School of Medicine 
Department of Psychiatry 
660 S. Euclid Ave., Campus Box 8134 
St. Louis, MO 63110 
Voice: (314) 362-1671 
E-mail: lenzee@wustl.edu 
 
 
 
Washington University Human Research Protection Office 
FWA00002284 
Washington University in St. Louis 
660 S. Euclid Ave., Campus Box 8089 
St. Louis, MO 63110 
 
 
 
Sponsor:  US Food and Drug Administration 
 
 
 
Original Version: October 31, 2013 
 
Version 1.01: January 5, 2015  (Includes Amendment 1) 
Version 1.02: November 19, 2015 (Includes Amendment 2) 
 


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1.  SYNOPSIS 
Study Title 
Bioequivalence and clinical effects of generic and brand bupropion  
Objective 
Determine 1) steady-state bioequivalence between branded and three generic 
300mg XL bupropion products in patients with major depressive disorder, 2) 
patients’ perception of differences in release patterns, clinical effectiveness, and 
adverse events between drug products, 3) patients' clinical response using 
validated objective measures of depression 
Study Period 
Planned enrollment duration: Approximately 2 1/2 years 
Planned study duration: Approximately 28 weeks per subject 
Number of Patients 60 evaluable patients diagnosed with major depressive disorder (up to 75 enrolled) 
Study Medication 
Administration 
Subjects will be studied for 28 weeks: a 4 week lead-in phase during which 
participants remain on their existing bupropion product, and then four randomized 
cross-over phases of 6 weeks on each of the four bupropion study drugs (brand 
Wellbutrin 300mg XL and 3 generics) 
Study Design 
Prospective, randomized, double-blinded, single-center crossover study in patients 
with major depressive disorder currently taking bupropion 300 XL 
Inclusion and 
Exclusion Criteria 
Inclusion Criteria 
1. Adult outpatients age 18-75 years 
2. Currently on once daily bupropion HCl 300mg XL (brand or any generic) for a 
minimum of 4 months 
3. Diagnosis of major depressive disorder in partial or full remission for ≥4 months, 
confirmed by Structured Clinical Interview for DSM Axis I Disorders (SCID) 
4. Ability to understand and willingness to comply with study procedures, and to 
provide written informed consent 
Exclusion Criteria 
1. Remission from depression not clearly attributed to bupropion treatment 
2. Current severe side effects attributable to bupropion 
3. Poor adherence to bupropion treatment per patient self-report and history of refill 
persistence 
4. History of active seizure disorder, or seizure treatment within past year 
5. History of significant hepatic or renal disease, based on physician assessment 
6. Currently taking drugs or natural products known to influence cytochrome 
P450B6 (CYP2B6) activity 
7. Currently taking drugs for hepatitis C or multiple sclerosis, due to their ability to 
cause depression 
8. Dementia or other significant cognitive impairment, per diagnosis or 
investigative team’s assessment 
9. Lifetime diagnosis of schizophrenia, schizoaffective or schizophreniform dis-
order, delusional disorder, or current psychotic symptoms diagnosed by SCID 
10. Abuse of or dependence on alcohol or other substances within the past 6 months 
as determined by SCID, and confirmed by study physician interview 
11. Current suicidal ideation 
Measurements 
Plasma and urine samples obtained over 24 hr during each study drug treatment (4 
times).  Bupropion and metabolite (hydroxybupropion, erthrohydrobupropion, 
threohydrobupropion) concentrations determined by stereoselective LC-MS-MS.  
Depression outcomes measured using the Montgomery-Asberg Depression Rating 
Scale (MADRS). Drug side-effects assessed with the self-report Antidepressant 
Side-Effect Checklist.  Subjects’ daily reports of side effects and symptoms using 
smart phone-based Ecological Momentary Assessments (EMA).  
Statistical 
Methodology 
Primary: Plasma and urine Cmax and AUC ratios for racemic bupropion, 
hydroxybupropion, erthrohydrobupropion, threohydrobupropion. 
Additional pharmacokinetic/bioequivalence endpoints: 


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1. Plasma Cmax and AUC0-24 for R- and S- bupropion 
2. Plasma Cmin, Cav, Ctrough, CL/F, %PTF, and swing for RS-, R- and S-bupropion 
3. Plasma AUC0-t for RS-, R- and S-bupropion 
4. Plasma Cmax, AUC0-24, Cmin, Cav, Ctrough %PTF, CLf and swing for 
hydroxybupropion, erythrohydrobupropion, and threohydrobupropion; racemate 
and their individual isomers (enantiomers/diastereomers) 
5. Plasma AUC0-24 hydroxybupropion/bupropion for racemate and individual 
enantiomers 
6. Formation clearance of hydroxybupropion, erythrohydrobupropion, 
threohydrobupropion and glucuronides; racemate and individual isomers 
 
Secondary Endpoints: 
1. Relapse of MDD 
2. Change in symptoms of depression 
3. Change in side effects of medication  
 
 
 


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Bioequivalence and Clinical Effects of Generic and Brand Bupropion 
 
Amendment 2 
 
November 19, 2015 
Purpose 
 
Administrative clarification 
 
Changes 
 
A.  Additions:   
 
2.7.1 Primary Assessments 
 
From:  Additional pharmacokinetic/bioequivalence endpoints: 6. Formation clearance of hydroxybupropion, 
erythrohydrobupropion, and threohydrobupropion, racemate and individual isomers 
 
To:  Additional pharmacokinetic/bioequivalence endpoints: 6. Formation clearance of hydroxybupropion, 
erythrohydrobupropion, threohydrobupropion, erythrohydrobupropion glucuronide, threohydrobupropion glucuronide:  
racemate and individual isomers 
 
Rationale:  Additional urine metabolites discovered during assay development (Change also made to Synopsis) 
 
B.  Deletions:  None 
 
C.  Changes:  
 
2.7.3.3 Objective evaluation of antidepressant effectiveness 
 
From:  The main clinical outcome is relapse of depression, defined using the MADRS and SCID depression module. 
Patients with a 2 point or greater increase from their average baseline open-label lead-in phase MADRS score, on two 
consecutive evaluations, will have the SCID depression module conducted.  If the SCID reveals current MDD, they will 
be considered to have relapsed.  Physician adjudication (by study Psychiatrist, who is blinded to randomization 
assignment) will be utilized as well.2 
 
To:  The main clinical outcome is relapse of depression, defined using the MADRS and SCID depression module. Patients 
with a 2 point or greater increase from their average baseline open-label lead-in phase MADRS score, on two consecutive 
evaluations, and/or MADRS score of 15 or greater will have the SCID depression module conducted.  If the SCID reveals 
current MDD, they will be considered to have relapsed.  Physician adjudication (by study Psychiatrist, who is blinded to 
randomization assignment, who interviews participant at time of relapse) will be utilized as well.2 
 
Rationale:  This was a previously undetected word processing error.  It would be infeasible to require two consecutive 
elevated MADRS scores because this measure is done only twice during each randomized phase, and, a subject may be 
withdrawn for relapse of depression after a single episode of elevated MADRS score and SCID.  Also to also further 
clarify the exact relapse assessment process. 
 
 
 
 


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Bioequivalence and Clinical Effects of Generic and Brand Bupropion 
 
Amendment 1 
 
January 5, 2015 
 
Purpose 
 
Administrative clarification, per FDA. 
 
Changes 
 
A.  Additions:  None 
 
B.  Deletions:  None 
 
C.  Changes 
 
2.6.7 Study Drug and Doses 
 
From: …application will be made to the RIHSC for approval to use after the expiration date  
 
To: application will be made to FDA for approval to use after the expiration date  


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2.  STUDY PROTOCOL 
2.1 Background and Significance 
Major depressive disorder (MDD) is one of the most common mental disorders and is currently the leading cause of 
disability in the world. One of the most important actions of antidepressant drugs is relapse prevention; that is, for 
patients with MDD who are stabilized (i.e., remitted or partially remitted) with an antidepressant, are far less likely to 
suffer a relapse or recurrence of depression if they are maintained on this medication.  Relapse of depression is an adverse 
outcome with significant deleterious consequences, including not only the suffering, burden, and suicide risk during 
each episode, but also that each additional depressive episode is likely to become more chronic and treatment-resistant.1 
 
Bupropion is an antidepressant efficacious in the treatment of major depressive disorder for both acute treatment 
and relapse prevention. Bupropion is commonly prescribed, because effectiveness and tolerability are equivalent to 
SSRIs, but with advantages of less somnolence, sexual dysfunction, and weight gain.  Bupropion is commonly used both 
as monotherapy and in combination with other antidepressants, typically with SSRIs. Many individuals cannot tolerate, 
or do not respond to, SSRIs, and for them bupropion is a first-line switch agent. Bupropion XL is a once-daily 
formulation, leading to better medication adherence. 
 
One principle of relapse prevention is “the dose that gets you well, keeps you well.”  That is, a patient stabilized on 
bupropion XL 300mg will be at elevated risk of depression relapse if the effective dose is diminished (either dose 
reduction or reduced bioavailability), and whether bupropion is used as monotherapy or in combination therapy.2 , 3  
Bioequivalence of generic bupropion is particularly critical, because a switch between non-bioequivalent forms could 
cause relapse (if bioavailability decreases) or toxicity (if bioavailability increases). 
 
2.1.1 Generic Drugs 
The public health importance and economic impact of generic drugs, to patients individually and to the US 
healthcare system in aggregate, are manifest.4-6  Total US drug expenditure was $320B in 2011. Generic drugs 
accounted for 80% of prescriptions dispensed, and were dispensed 94% of the time that they were available. The 
economic value of generics is staggering: While over 80% of prescriptions are for generic drugs, they account for just 
27% of total drug spending. Generic drug use has saved the US health care system an estimated $1.07 trillion over 
the past decade (2002-2011), with $193B saved in 2011 alone. Generic market share has risen substantially, from 
47% of prescriptions in 1999, to 67% in 2007, 74% in 2009, and 80% in 2011. Cost savings have also risen, from $60B in 
2002, to $101B in 2007, and $193B in 2011, and this trend is only expected to escalate. 
 
Aside from obvious cost advantages attendant to branded-generic switching, generic-generic switching also occurs 
due to availability, stocking from a specific manufacturer, pharmacy-negotiated costs, and requirements by third-party 
payers.7  Switching decisions may be made by prescribers, pharmacists, or patients. Interchangeability of generic drugs 
influences drug prescribability (whether a patient is treated for the first time with a branded vs a generic drug) and 
drug switchability (when a branded drug is switched to a generic, or there is a change from one generic to another).8 
 
The key underlying premise on which rests patient safety, medical therapeutics, healthcare economics, and the public 
trust, is that generic drugs are therapeutically equivalent to the branded innovator, and to each other. Therapeutic non-
equivalence can have profound health, ethical, cost, and broad economic implications. 
 
2.1.2 FDA Bioequivalence, Pharmaceutical, Therapeutic, Clinical Equivalence  
FDA evaluation of generic drugs uses bioequivalence as a surrogate for therapeutic equivalence, obviating the need for 
generic drugs to undergo clinical testing.9-11  A generic drug is considered bioequivalent to the reference (or branded drug) 
if the active compound or moiety exhibits the same rate and extent of absorption (more generally, systemic exposure).  
Systemic exposure is determined from plasma Cmax and AUC (area under the curve), and the entire 90% confidence 
interval for the geometric mean of the log-transformed  generic-to-reference Cmax and AUC ratios must be within the 
bioequivalence limit of 80 to 125%. Generic drugs must also show pharmaceutical equivalence (same active ingredients, 
route of administration, dosage, form, and strength as the branded drug). Drugs are considered "therapeutic 
equivalents", without the need for clinical data, if they are both pharmaceutical equivalents and show bioequivalence. 
While this is reasonable and usually accurate, non-therapeutic equivalence can occur despite bioequivalence, for both 


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7 
conventional and narrow therapeutic index drugs.12,13  More importantly, it is now clear that single-dose studies in 
healthy volunteers may not predict steady- state bioequivalence in patients, particularly for modified release forms.13,14 
 
2.1.3 Branded and Generic Bupropion 
GlaxoSmithKline (GSK) was the innovator of bupropion (Wellbutrin®), first i n  immediate release (IR) form (TID 
dosing), then Wellbutrin SR® (sustained release, BID dosing), then Wellbutrin XL® (extended release, once daily 
dosing). Introduction of generic bupropion IR was followed by generic bupropion SR, then generic bupropion XL. 
 
Approval of the first bupropion XL 300mg generic (Budeprion XL, 2006) was based on a prior bioequivalence study 
of 150mg Budeprion XL and Wellbutrin XL in healthy subjects, which were then extrapolated to the 300mg 
product.15,16 The pharmacokinetic profile was not expected to differ between 300mg and 150mg bupropion XL; FDA 
decided not to test bioequivalence of t h e  300mg products. 
 
Shortly thereafter, FDA received numerous reports of clinical issues when switching from Wellbutrin XL to Budeprion 
XL.  In 2010, FDA sponsored a single-dose crossover bioequivalence study in healthy subjects comparing 300mg 
Budeprion XL to Wellbutrin XL, completed in August, 2012.15,17 Budeprion XL failed bioequivalence testing. Based on 
these results, Budeprion XL 300mg was withdrawn from the market in October, 2012.  In fact, none of the currently 
available 300mg XL generics has undergone bioequivalence or clinical equivalence testing.  
 
2.1.4  Bupropion Disposition and Clinical Effect 
Bupropion pharmacokinetics have been well-described for branded Wellbutrin IR, SL and XL.18  Steady-state for all three 
formulations was reached in 8d.  Bupropion is extensively metabolized.  The three major metabolites are 
hydroxybupropion (via cytochrome P4502B6, CYP2B6), and erythrohydrobupropion and threohydrobupropion (by 
carbonyl reductase).  Metabolite exposure is considerably higher than that of parent drug.  At steady-state, 
hydroxybupropion, threohydrobupropion and erythrohydrobupropion Cmax are 6-fold greater, 5-fold greater, and 
comparable to that of bupropion.  Bupropion is racemic, and bupropion and metabolite disposition are stereoselective.19-24 
 
Bupropion metabolism is important for therapeutic effectiveness.  In mice, the activity of hydroxybupropion is 
approximately 50% of the parent drug.25-29  While R- and S-bupropion have similar antidepressant activity,30 only (S,S)-
hydroxybupropion, but not (R,R)-hydroxybupropion, is pharmacologically active.  Accordingly, (S,S)-hydroxybupropion 
is now considered the most active metabolite of bupropion, and the mediator of pharmacologic effect.  Thus, bupropion 
hydroxylation is a bioactivation pathway. 
 
Bupropion reduction to erythrohydrobupropion and threohydrobupropion is an inactivation pathway.  The specific human 
carbonyl reductase(s) which catalyze bupropion reduction are unknown.  There are hundreds of known carbonyl 
reductase(s).31,32  Recent evidence suggests the relevant reductase(s) are microsomal, and that one of them, 11ß-
hydroxysteroid dehydrogenase 1, can convert bupropion to threohydrobupropion but not erythrohydrobupropion.33  Other 
reductases have not been identified. 
 
2.1.5 CYP2B6, Genetics and Bupropion Metabolism and Disposition 
There is extensive interindividual variability in CYP2B6 activity, due to variability in protein expression, susceptibility 
to inhibitors (clopidogrel, ticlopidine, thiotepa) and inducers (rifampin, phenobarbital, phenytoin),34-36 and CYP2B6 
genetic polymorphisms.36,37  Moreover, CYP2B6 is highly polymorphic, with 37 haplotypes (star alleles) identified to 
date, several of which have major clinical importance.36,37  Bupropion hydroxylation is diminished, both in expressed 
CYP2B6.6 compared with wild-type CYP2B6.1,38,39 and in human liver microsomes from CYP2B6*6 carriers.39,40  After 
7 days of sustained-release bupropion dosing, CYP2B6*6 and *18 carriers had significantly reduced plasma 
hydroxybupropion concentrations, with no effects on bupropion.41,42 
 
2.2 Preliminary Studies 
We conducted the first ever investigations showing the stereoselective disposition of bupropion and 
hydroxybupropion.20,22-24 Although the influence of CYP2B6 polymorphisms on the disposition of bupropion was 
recently reported, the studies evaluated steady-state dosing and did not use a stereoselective assay.41,42 We 


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t h e r e f o r e  determined the influence of CYP2B6*6 genetic polymorphisms on the disposition of bupropion and 
hydroxybupropion using a single 150mg immediate-release dose, to evaluate metabolism and clearance, and that 
of bupropion and hydroxybupropion isomers.  To date, 46 subjects have been enrolled, of genotypes 
CYP2B6*1/*1 (n=17), CYP2B6*1/*6 (n=20), CYP2B6*6/*6 (n=6).  CYP2B6 genotype had no effect on R-, S-, or total 
bupropion plasma concentrations.  In contrast, CYP2B6*6 significantly influenced hydroxybupropion concentrations 
(R,R- more than S,S-), and there was a gene-dose effect.  These results demonstrate the interaction between CYP2B6 
genetics and stereoselective bioactivation of bupropion to hydroxybupropion. 
 
2.3 Objective 
1) Determine bioequivalence between branded and generic bupropion extended release (XL) products (and between 
generic products) at steady state in patients with major depressive disorder. 
2) Compare patients’ self-reported clinical differences (release patterns, antidepressant effectiveness, and adverse events) 
between four bupropion 300mg XL products (brand vs. generics, and between generics). 
3) Compare objective evaluations of patients’ clinical response between each bupropion 300mg XL product evaluated, 
using standard, well-validated measures of depression response and side effects. 
 
2.4 Study Drug Selection 
Bioequivalence of branded Wellbutrin SR® and generic bupropion SR in all dosages has been established. 
Bioequivalence of 150mg Wellbutrin XL® and all 150mg bupropion XL generics has also been established.  In contrast, 
no 300mg bupropion XL generic has undergone bioequivalence testing.  This is the bupropion XL dose used for 
depression, hence the public health importance of testing clinical equivalency of 300mg bupropion XL is significant.  
Thus, the unmet need is to evaluate branded and generic 300mg bupropion XL products.  Therefore bioequivalence of (1) 
branded Wellbutrin XL® 300mg (Valeant Pharmaceuticals, initially developed by GSK), (2) generic bupropion XL 
300mg (Mylan Pharmaceuticals) (3) generic bupropion XL 300mg (Anchen/Par Pharmaceuticals), and (4) generic 
bupropion XL 300mg (Watson Labs) will be compared.   
 
To ensure full double-blinding, all four drug products in the randomized portion will be over-encapsulated with the same 
opaque capsule (DBcaps® overencapsulation capsules, Capsugel Inc, or equivalent) to conceal product identity from 
investigators and patients, and to conceal the occurrence of a product switch from patients. Over-encapsulation will begin 
at the start of the lead-in phase, to avoid symptom reporting due to expectancy effects from change in appearance of the 
medication after randomization. An IND is not required for the conduct of this study. 
 
2.5 Patient Selection 
An estimated 75 subjects with MDD in partial or full remission who are currently taking bupropion 300mg XL (branded 
or generic) will be enrolled.  The target enrollment is 60 evaluable subjects.  A 25% drop-out rate is conservatively 
assumed.  Subjects must be on stable therapy (minimum of 4 months on bupropion 300mg XL).  Subjects will be recruited 
from the Washington University patient population, by referrals from community physicians, and by public 
advertisements.  Potential subjects will also be contacted by the pharmacy benefit manager Express Scripts, given a brief 
description of the study, and invited to contact the investigators for further information and potential 
recruitment/enrollment.  The study will be posted on clinicaltrials.gov, once reviewed and approved by the Research 
Involving Human Subjects Committee (RIHSC), the FDA’s Institutional Review Boards (IRB).  Subjects will be screened 
with the Structured Clinical Interview for DSM Axis I Disorders (SCID) to determine eligibility.43 SCID assesses current 
and lifetime depression, as well as other psychiatric disorders, and is used to clarify psychiatric inclusion and exclusion 
criteria.  Participants must have MDD which is in partial or full remission.  All risks and benefits will be explained, and 
subjects will sign an informed consent form.  After enrollment a blood sample will be obtained, coded for deidentification 
(see 3.3.4 below) and stored at -80°C in the PIs lab for later DNA analysis.  DNA is stored until all reports and 
manuscripts are completed and accepted. 
 
2.5.1 Inclusion Criteria 
Each subject must meet all of the following criteria: 
1. Adult outpatients age 18-75 years 
2. Currently on once daily bupropion HCl 300mg XL (brand or any generic), for a minimum of 4 months 


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3. Major depressive disorder (MDD), in partial or full remission for at least 4 months, as confirmed by the SCID. 
Spontaneous relapse of depression unrelated to medication changes is less likely – about 5% chance per year – after 
remission has been maintained for at least 4 months.2 
4. Ability to understand and willingness to comply with study procedures, and to provide written informed consent 
 
2.5.2 Exclusion Criteria 
Subjects will not be enrolled if any of the following criteria exist: 
1. Remission from depression not clearly attributed to bupropion treatment 
2. Current severe side effects attributable to bupropion 
3. Poor adherence to bupropion treatment per patient self- report and history of refill persistence 
4. History of active seizure disorder, or seizure treatment within past year 
5. History of significant hepatic or renal disease, based on physician assessment 
6. Currently taking drugs or natural products known to influence cytochrome P450B6 (CYP2B6) activity 
7. Currently taking drugs for hepatitis C or multiple sclerosis, due to their ability to cause depression 
8. Dementia or other significant cognitive impairment, per diagnosis or investigative team’s assessment 
9. Lifetime diagnosis of schizophrenia, schizoaffective or schizophreniform dis-order, delusional disorder, or current 
psychotic symptoms diagnosed by SCID 
10. Abuse of or dependence on alcohol or other substances within the past 6 months as determined by SCID, and 
confirmed by study physician interview 
11. Current suicidal ideation 
 
2.6 Design and Procedures 
2.6.1 Study Design 
The protocol is a prospective, randomized, double-blinded, crossover study in 75 subjects (target, 60 evaluable) with 
Major Depressive Disorder (MDD) receiving bupropion HCl 300mg XL (branded or generic).  Subjects will be studied 
for a total of approximately 28 weeks: an approximately 4 week lead-in phase during which participants remain on their 
existing bupropion product, and then four randomized cross-over phases of approximately 6 weeks on each of the four 
bupropion study drugs (brand and 3 generics).  For each of the four bupropion products, subjects will have (a) formal 
pharmacokinetic evaluation (24 hr plasma and urine) at steady-state, (b) every 3-week in-person standard structured 
clinical evaluations of depressive symptoms and side effects, and (c) once daily smart phone-based assessments to capture 
information on symptoms and side effects.  See Figure 1 for a pictorial description. 
 
 
 
 


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2.6.2 Randomization 
The order of the four study drugs will be randomized and balanced across the study.  The randomization table will be 
generated by the Barnes-Jewish Hospital Investigational Pharmacy.  Each subject will be assigned the next available 
number. Subjects, investigators, and all study team members will be blinded to drug treatment.  In the case of dropouts 
(either subject- or investigator-initiated), subjects will be replaced, to provide the required number of subjects.  
Randomization of replacements will be as follows: 
1.  Subjects withdrawn prior to randomization (before or during the lead-in) will simply be replaced in that former 
subject’s randomization, and receive that subject’s order of drug products 
2.  Subjects withdrawn after randomization, while receiving the study drugs, will be replaced using the next scheduled 
randomization sequence. 
 
2.6.3 Enrollment Timeline 
Figure 2 conceptually illustrates the anticipated enrollment timeline for the randomized 4-way crossover.  For illustration 
purposes, subjects are shown to be randomized in blocks, however study drug order will be individually randomized and 
balanced across the study. 
 
 
Figure 2: Protocol schematic for the clinical trial of 4 bupropion products 
 
2.6.4 Initial Lead-in Period 
Subjects will enter the study after reviewing and signing the informed consent document.  They will remain on their 
current bupropion product for the initial 4 weeks.  Their specific supply will be turned over to the investigators and 
replaced by the identical product, now over-encapsulated during the run-in to minimize expectancy (3.4.2).  During this 
period, subjects will undergo daily smart phone-based self-report assessments.  At the end of the 4 week period, subjects 
will visit the study clinic at Washington University Medical Center for objective assessments of depression and side 
effects.  These procedures will familiarize subjects with assessment approaches, and also provide baseline data against 
which to compare similar data when subjects take the same bupropion product during the blinded portion of the study.  
Non-adherent subjects will be excluded from further participation. At the end of the prestudy period, subjects will be 
randomized and then receive their first study drug in the sequence, without washout. 
 
 
 
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3
3
3
3
4 subjects
4
4
4
4
3 subjects
3
3
3
3
4 subjects
4
4
4
4
3 subjects
3
3
3
3
4 subjects
4
4
4
4
3 subjects
3
3
3
3
4 subjects
4
4
4
4
3 subjects
3
3
3
3
4 subjects
4
4
4
4
3 subjects
3
3
3
3
4 subjects
4
4
4
4
3 subjects
3
3
3
3
4 subjects
4
4
4
4
3 subjects
3
3
3
3
3 subjects
3
3
3
3
2 subjects
2
2
2
2
Total
Enrolled subj/month
75
# Subj On Study
# PK sessions
300
Each column M1-M36 represents the month of the study; Each row is a cohort of 3-4 subjects
Grey box represents the drug product at the time of enrollment and entry into the study
Each drug product is administered for 6 weeks
M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M13 M14 M15 M16 M17 M18 M19 M20 M21 M22 M23 M24 M25 M26 M27 M28 M29 M30 M31 M32 M33 M34 M35 M36
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
3
3
2
4
7
11
14
18
21
25
24
25
24
25
24
25
24
25
24
25
24
25
24
24
22
19
15
12
8
5
2
0
4
3
8
10
11
14
14
14
14
14
14
14
14
14
14
5
3
2
Each color box is a different bupropion XL drug product
Pharmacokinetic sessions are performed during the day 10-20 window on each drug product
The number in each box shows the time of the PK session (2nd-3rd week) and the number of subjects
14
14
14
14
14
13
13
9
9


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2.6.5 Randomized Study Period 
Subjects will take each 300mg bupropion XL product for 6 weeks, and then be switched to another product without 
washout, according to their randomization schedule.  During the 2nd-3rd week on each product, subjects will visit the study 
clinic for a bupropion pharmacokinetic session, an objective assessment of depression and side effects, and to receive 
another 3 week supply of study drug.  During the 6th week on each product, subjects will again visit the study clinic for 
objective assessments of depression and side effects.  Subjects will then be switched to their next scheduled drug product, 
and the sequence repeated for the four study drugs.  Each subject will therefore be studied for four 6-week study drug 
epochs.  Subjects will not be informed when they are being switched, in order to minimize bias.  A Medication Event 
Monitoring System, (MEMS 6 TrackCap, or equivalent) will be used to assess compliance and compile drug dosing 
histories for the quantitative analysis of adherence during each subject’s 28 week study period. 
 
The rationale for the timing of the pharmacokinetic assessments is as follows:  Subjects must be at steady-state on their 
new bupropion product.  Steady-state bupropion concentrations have been reported to occur by 8d for all formulations.18  
Nevertheless, to ensure that metabolites disposition is also at steady-state, and metabolite elimination is known to be 
somewhat slower than parent, at least 10d will be allowed before assessing pharmacokinetics.  Assessment should not 
wait too long, however, in case a patient reports loss of effectiveness or side effects after starting a new bupropion 
product, causing a product switch or other intervention, and this risk increases with time.  Therefore the 10-20 day 
window will be targeted for the bupropion pharmacokinetic session for each product. 
 
The rationale for not informing subjects of the timing and frequency of product switching is to minimize expectancy.  
Patients are more likely to report an increase in depressive symptoms or side effects if they identify a change in 
medication.  In previous relapse prevention studies, patient complaints about lack of efficacy increased, regardless of 
treatment (continued medication or taper to placebo), when their medication changed from pills to over-encapsulated.  In 
another, patients reported increased symptoms at the time of randomization, apparently from anticipation. Expectancy 
effects are particularly common in depression studies, and interfere with detection of product switch-related clinical 
effects.  Therefore: (1) participants will not be told when or how many times they are being crossed over; (2) all 
bupropion products will be over-encapsulated to look identical throughout the study, including during the lead-in phase.   
 
Particular attention will be paid to maximizing medication adherence.  To maximize adherence:  
 Patients will be carefully screened, to screen out those with low likelihood of good medication adherence.  Potential 
participants with known predictors of poor adherence (e.g. heavy drinking, dissatisfaction with their bupropion 
therapy, adverse side effects, perceived lack of benefit from bupropion) will not be enrolled. 
 Adherence and timing of medication will be evaluated during the lead-in phase; subjects showing non-adherence 
during the lead-in phase will be removed. 
 Subjects will receive daily reminders to take their pill, and reminders regarding the importance of exact adherence. 
 Adherence and timing of medication will be confirmed with the MEMS system (cap with a microprocessor, providing 
real-time data on container opening), in addition to self-reports and pill counts. 
 Patients showing non-adherence in the 7 days before bioequivalence testing will be rescheduled.  At other times, 
adherence will be corrected and reinforced using reminders, engaging participants and their support systems, and 
reassessing barriers and facilitators to adherence. 
 
After the fourth 6-week drug session and at the last study clinic visit, subjects will be returned to their original bupropion 
product, resupplied with their own medication to take, and thanked and provided positive feedback for their participation. 
 
2.6.5.1  Bupropion Pharmacokinetic Sessions 
Subjects will be studied in the Clinical Research Unit at Washington University-Barnes Jewish Hospital, and remain in 
the Unit for approximately 24 hours.  Subjects are instructed to 1) have nothing to eat or drink after midnight before the 
study session and 2) abstain from alcohol for 24 hours before each study period and until the last sample is collected.  
Because food increases plasma Cmax and AUC of bupropion extended-release tablets by 11 and 17%, respectively 
(although changes were not statistically significant18), subjects will nonetheless be studied after an overnight fast to 
minimize potential variability.  They will take their study drug with 240ml of water, receive a standard meal 4 hours after 
bupropion dosing, and have free access to food and water thereafter.  An intravenous catheter will be placed by CRU 


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12 
nursing staff in an arm vein for blood sampling (5cc, EDTA) immediately before and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 
20 and 24 hr after dosing (15 samples, 75 cc per session, 300 cc over the entire study), and samples centrifuged to obtain 
plasma.  Urine will be collected for 24 hr, kept refrigerated, the volume measured, and aliquots frozen.  Samples will be 
stored at -80°C in the PIs lab.  At the end of the 24 study, the intravenous catheter is removed, and subjects leave the 
research unit.  Plasma and urine concentrations of bupropion, hydroxybupropion, erythrohydrobupropion, and 
threohydrobupropion will be determined using a chiral LC/MS/MS assay.   
 
2.6.5.2  Objective Depression and Side Effects Assessment Sessions 
Subjects will visit the medical center twice during each 6-week drug crossover (every 3 weeks).  The main outcome 
measurement for depression will be the Montgomery-Asberg Depression Rating Scale (MADRS).44  This is a 10-item 
checklist, where each item is rated on a scale from 0-6 with anchors at 2-point intervals.  It takes about 15 min to 
administer.  A MADRS score of <15 at baseline will establish study eligibility.  The MADRS was designed to assess 
treatment-sensitive changes in MDD, and can be used by both psychiatrists and non-psychiatrist raters. A structured 
interview will also be used, which provides high inter-rater reliability to maximize reliability.45  Side effects will be 
assessed with the self-report Antidepressant Side-Effect Checklist (ASEC).46  This well-validated scale has the advantage 
of being measurable via self-report (versus interview) and can be used in both in-person and EMA assessments. 
 
MADRS and ASEC are the standard clinical methods for depression care (and also research instruments) and will be the 
clinical metrics to determine if patients have a change in clinical response to bupropion, and if patients should be 
withdrawn for therapeutic reasons. 
 
2.6.5.3  Smart phone-based Assessments 
Standard clinical measures of depressive symptoms are sufficient for detecting relapse, but may be insufficiently sensitive 
for more subtle changes caused by nonequivalent medication versions. Measuring patients’ perspectives on complex, 
subjective, and often transient events such as symptoms or side effects is a methodological challenge, given both insight 
and memory biases that affect standard retrospective questionnaires.47,48 
Therefore, to gather more frequent and potentially more precise information, daily symptoms and side effects will be 
assessed via a validated smart phone-based program.  This approach (Ecological Momentary Assessments, EMA) is 
currently in use with other Washington University in St. Louis IRB-approved protocols.  Specific procedures include: 
 
In-person demonstration of the smart phone application with a practice phone at the start of the study. 
 
Phones will be provided by the study team, and run only the EMA program (i.e., no other applications or calls). 
 
Participants receive a daily trigger for an assessment, with reminder cues until it is completed. 
 
The daily assessment (approximately 20 items) will measure: (a) depressive symptoms, using 8 items from the 
MADRS (excluding the suicide item and the depression observational item), (b) 6 most common self-reported side 
effects of bupropion, as assessed in the Antidepressant Side-Effect Checklist: dry mouth, insomnia, headache, 
nausea, agitation and sweating, and (c) a short list (no more than 6) symptoms reported by patients who have 
reported problems with switching between forms of bupropion. 
 
Data are automatically uploaded to the University server.  They will be reviewed approximately weekly. 
Smart phone-based assessments are for research only, and will not be used to determine if patients have a change in clini-
cal response to bupropion, or if subjects should be withdrawn for therapeutic reasons.  This will be made clear to subjects. 
 
2.6.6 Post-Study Period 
After the fourth 6-week drug session and at the last study clinic visit, subjects will be returned to their original bupropion 
product, resupplied with their own medication to take, and thanked and provided positive feedback for their participation. 
 
2.6.7 Study Drug and Doses 
Four study drugs will be evaluated during the randomization period (no IND is needed): 
1) Wellbutrin XL® 300mg (Valeant Pharmaceuticals, NDC 64455-731, initially developed by GSK) 
2) generic bupropion XL 300mg (Mylan Pharmaceuticals, NDC 00378-2009, ANDA 090942) 
3) generic bupropion XL 300mg (Anchen/Par Pharmaceuticals, NDC 10370-102, ANDA 077284) 
4) generic bupropion XL 300mg (Watson Labs, NDC 00591-3332, ANDA 077715)   


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13 
A single lot number of each drug product will be used throughout the study, when available.  Lot numbers and expiration 
dates will be recorded.  Drugs will be stored at room temperature (59-77 °F, 15-25 °C) away from light and moisture, or 
as otherwise specified by the manufacturers.  All medications will be secured and maintained by Barnes Jewish Hospital 
Investigational Pharmacy.  Drug supply, dispensing, and accountability logs will be maintained. 
 
Each lot number of each drug product will be characterized with respect to identity, content, and purity.  Each lot number 
of each drug product will undergo appropriate dissolution testing.  Bupropion tablets will be over-encapsulated with the 
same opaque capsule to ensure full double-blinding.  Over-encapsulated bupropion tablets will also undergo dissolution 
testing.   
 
If the drug lot number expires prior to the inclusion and completion of all subjects in the study, the drug remaining will be 
re-characterized with respect to identity, content, and purity, and undergo appropriate dissolution testing.  If equivalence 
to the pre-study identity, content, purity, and dissolution is established (90-110%), in order to ensure that the product has 
the same quality, then application will be made to FDA for approval to use after the expiration date and extend the 
expiration date by 1 year. 
 
2.6.8 Genotyping 
Genotyping will be performed by PCR to determine relevant CYP2B6 SNPs.  Additional genotyping may be performed to 
evaluate effects of genetic variability in relevant pathways of bupropion disposition.  For example, if identities of the 
human enzymes responsible for bupropion reduction are published during this investigation, and clinically relevant 
mutants are identified, then additional SNPs may be evaluated. 
2.7  Observations and Measurements 
2.7.1 Primary Assessments 
The primary outcome measure will be Cmax and AUC0-24 for racemic bupropion, hydroxybupropion, 
erythrohydrobupropion and threohydrobupropion. 
Additional pharmacokinetic/bioequivalence endpoints: 
1. Plasma Cmax and AUC0-24 for R- and S- bupropion 
2. Plasma Cmin, Cav, Ctrough, CL/F, %PTF, and swing for RS-, R- and S-bupropion 
3. Plasma AUC0-t for RS-, R- and S-bupropion 
4. Plasma Cmax, AUC0-24, Cmin, Cav, Ctrough %PTF, CLf and swing for hydroxybupropion, erythrohydrobupropion, 
and threohydrobupropion; racemate and their individual isomers (enantiomers/diastereomers) 
5. Plasma AUC0-24 hydroxybupropion/bupropion for racemate and individual enantiomers 
6. Formation 
clearance 
of 
hydroxybupropion, 
erythrohydrobupropion, 
threohydrobupropion, 
erythrohydrobupropion glucuronide, threohydrobupropion glucuronide:  racemate and individual isomers 
Secondary Endpoints: 
7. Relapse of MDD 
8. Change in symptoms of depression  
9. Change in side effects of medication  
 
2.7.2 Pharmacokinetic Calculations 
Pharmacokinetic parameters will be determined essentially per FDA Guidance.10  The primary metrics will be 1) Peak 
drug exposure, assessed from maximum plasma drug concentration (Cmax) obtained directly from the data without 
interpolation; and 2) Total exposure, assessed as the area under the plasma concentration-time curve from time zero to 
time tau over the dosing interval at steady state (AUC0-tau), analyzed using non-compartmental methods, where tau is the 
dosing interval (24 hr, hence AUC0-24).  In addition: 
 
Trough plasma concentration (Ctrough) will be measured at the end of the dosing interval (24 hr) 
 
Minimum plasma concentration (Cmin) is the lowest concentration during the dosing interval 
 
Average plasma concentration (Cav) is AUC0-tau/tau (i.e. AUC0-24/24) 
 
As a measure of plasma concentration flux, %Peak-trough fluctuation (%PTF)=100%•(Cmax−Ctrough)/Cav and 
Swing =100%•(Cmax−Ctrough)/Ctrough will be used  


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14 
 
Time to peak plasma concentration (Tmax) will be recorded, for both parent and metabolites, although it is 
expected to be highly variable (variability in Tmax for extended release drugs at steady-state is recognized.13 
 
As an exploratory metric, and an index of early exposure (potential “dose-dumping”), various partial AUCs from 
0-t, and t-24 will be evaluated, with various cutoff times for t (including the population Tmax, while also 
recognizing Tmax as a potential source of error), as recently described by FDA,13,49 and for sustained-release 
bupropion.50 
 
Plasma hydroxybupropion AUC0-24//bupropion AUC0-24 will be used as an index of CYP2B6-mediated bupropion 
hydroxylation 
 
Apparent oral bupropion clearance(CL/F) will be determined as dose/AUC 
 
Metabolite formation clearance (CLf) will be calculated as the product of the molar fraction of the dose recovered 
in urine and CL/F. 
All results are determined for each subject and each drug product, and reported as arithmetic mean, SD, CV, and 
geometric mean (and Tmax as the median and range). 
 
Per FDA Guidance,10 all parameters will be determined for the parent drug released from the dosage form (RS-
bupropion).  Due to the unusual nature of bupropion (racemate, enantioselective bioactivation, and different 
pharmacologic effects of the metabolites and their stereoisomers) parameters will also be determined for the major 
metabolites (hydroxybupropion, erythrohydrobupropion, threohydrobupropion), and for both the individual stereoisomers 
and the racemate for each analyte. 
 
Additional exploratory analysis may be performed using a population pharmacokinetic approach.  In brief, multi-compart-
mental models will be defined and optimized for bupropion, and then for bupropion and hydroxybupropion simul-
taneously (and if identifiable, other metabolites).  The influence of covariates on the model parameters will be analyzed, 
where covariates will include age, sex, weight, race/ethnicity, bupropion XL drug product, and CYP2B6 genotype.  
Optimal models will be selected based on goodness-of-fit plots, precision of estimates, likelihood ratio test, and evaluation 
of population predicted estimates, conditional weighted residuals, and relative standard errors of population estimates. 
 
2.7.3   Statistical Methods 
2.7.3.1 Bioequivalence 
Bioequivalence will be determined essentially per FDA Guidance,9,10 using an average bioequivalence approach.  A 
repeated measures model will be fit for each parameter separately. Interpatient variability for each compound will be 
examined separately prior to assuming that they are all the same. It is anticipated that most parameters will be log-
transformed prior to statistical testing, but the distributional assumptions will be examined for each parameter and the 
most appropriate data transformation used.  Following the standard FDA guidance the two one-sided test procedure will 
be used to determine whether each generic product is significantly less bioavailable than Wellbutrin XL, and whether 
Wellbutrin XL is significantly less bioavailable than each generic product.  This is expressed as a limit of test 
average/reference average of 80% for the first statistical test and a limit of reference average/test average of 80% for the 
second statistical test.  In practice, the 90% confidence interval around the geometric means of the test/reference ratio for 
each parameter must be entirely between 0.80 and 1.25 for bioequivalence.   
 
Bioequivalence will be determined using the standard pharmacokinetic parameters (AUC and Cmax) and equivalence 
definition (90% CI of the generic/brand geometric mean is within 80-125%) for bupropion (primary), the active 
metabolite hydroxybupropion (secondary), and for the other metabolites (tertiary).  The test for each generic compound 
will not be adjusted for the other comparisons, e.g. to control the study-wide error rate.  Similarly, analysis will not 
control for multiple comparisons involved in testing each of the parameters. As an aid to interpretation of the results, 
however, the False Discovery Rate will be computed for the observed results.  The generics will also be evaluated using 
the criteria for bioequivalence for narrow therapeutic index drugs (90% CI of ratio within 0.95-1.05). 
 
The influence of CYP2B6 genetics on the disposition of bupropion, hydroxybupropion, and bioequivalence between brand 
and generic bupropion XL products will be determined through exploratory analyses to fit individual bioequivalency 
models by adding random effects for each agent and covariances between the responses.  Order effects (omitted in the 
model described above) will also be determined.  Predictors of overall response of each individual for each parameter, 


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15 
especially CYP2B6 genetics, will be evaluated, specifically the most common variant allele CYP2B6*6, comparing 
CYP2B6*1/*6 and CYP2B6*6/*6 genotypes with non-carriers of CYP2B6*6, and with true CYP2B6*1/*1 genotypes.  
 
The influence of stereochemistry on (i) bupropion disposition, (ii) bupropion bioactivation to hydroxybupropion, and (iii) 
bioequivalence between bupropion XL products will be examined by fitting an expanded model where both the 
enantiomers and diastereomers will be included by introducing an additional factor, examining the significance of this 
factor, and its interaction with the specific compound. 
 
2.7.3.2 Patient perception of antidepressant effectiveness and side effects 
Patients’ self-reported clinical differences (release patterns, antidepressant effectiveness, and adverse events) will be 
compared between all bupropion 300mg XL products (brand vs. generics, and between generics). 
 
Reports will be determined by the daily patient smart phone assessments.  Daily depressive symptom scores, side effect 
scores, and focus group-nominated symptoms (e.g., sensations regarding drug release) during each randomized bupropion 
phase will be compared with each other, and with those from the open-label lead-in period.  Repeated measures ANOVA 
analogues of the models described above for the pharmacokinetic parameters will be used for assessing patents’ 
perceptions.  Since there are no well-accepted criteria for the equivalence of scores using this method, any systematic 
effects of differences between patient’s responses to Wellbutrin XL and each generic product will be tested.   
 
Analysis will explore whether differences in smart phone-collected depression symptoms, side effects, and patient reports 
regarding release patterns are related to pharmacokinetics by augmenting the models above with pharmacokinetic 
parameters as covariates.  Analysis will determine if there are differences in bupropion products by correlating, on an 
individual basis, the ratio of the two pharmacokinetic parameters to the difference in symptoms or side effects. 
 
2.7.3.3 Objective evaluation of antidepressant effectiveness 
The main clinical outcome is relapse of depression, defined using the MADRS and SCID depression module.  Patients 
with a 2 point or greater increase from their average baseline open-label lead-in phase MADRS score, and/or MADRS 
score of 15 or greater, will have the SCID depression module conducted.  If the SCID reveals current MDD, they will be 
considered to have relapsed.  Physician adjudication (by study Psychiatrist, who is blinded to randomization assignment) 
will be utilized as well.2  An appropriate generalized linear model with a binomial link function will be used. Relapse of 
depression will also be considered an end-point in the study.   
 
Subjects suffering a relapse will be removed from the study and will return to their pre-study bupropion product.  Subjects 
will be advised to contact their treating physician for follow-up.  Data and specimens collected for these subjects will be 
included in the analysis. 
 
The secondary clinical outcomes are symptomatic change in depression (MADRS scores) and side effects (Antidepressant 
Side Effect Checklist scores) determined at the every 3-week interviews.  Repeated measures ANOVA analogues of the 
models described above will be used for each of these analyses.  Analysis will test for any systematic effects of 
differences between patient’s symptom/side effect levels with Wellbutrin XL and each generic preparation.    
 
2.7.4 Sample Size Justification 
Calculations for sample size and power of the proposed studies are based on information from the confidence intervals for 
the ratio of the pharmacokinetic parameters for the generic (Budeprion XL) to the innovator (Wellbutrin XL) which was 
recently reported by the FDA in their evaluation of Budeprion XL.51 
 
SAS 9.3’s Proc Power was used to conduct the correct power analysis for the two one-sided tests (TOST) approach per 
the FDA guidance on bioequivalence.  Using a 90% confidence interval and ratios needing to be between 0.80 and 1.25, 
the power for sample sizes ranging from a conservative estimate of 60 to the recruitment goal of 75 was computed.  If the 
comparators are indeed bioequivalent (ratio=1.0) then the study power would be >0.999 for a pharmacokinetic parameter 
such as AUC and 0.98 for a more variable parameter such as Cmax. If the generic is 10% under (or over), e.g. ratio=0.90, 


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16 
then for AUC the power would be 0.78=0.83 to declare a significant difference between the compounds at an alpha of .05 
even if the CI for the ration was still contained within the 0.80-1.25 bounds.  
 
The study is also powered in order to have a reasonable power of detecting clinical differences between compounds.  If 
one of the generics is non-equivalent with respect to symptom and it is assumed that 25% suffer a relapse on this generic 
versus 5% for Wellbutrin or other (equivalent) forms, then using a McNemar’s test for equality of proportions, a sample 
size of 60 and a 1-tailed alpha of 0.05, the power will be about 0.83. For continuous variables, there will be 0.80 power to 
detect a standardized difference of 0.37 (low-medium effect size). 
 
3.  MANAGEMENT OF INTERCURRENT EVENTS 
There is a naturalistic recurrence (relapse) rate of depression of about 5% yearly for patients who maintain adherence with 
a stable dose of medication to which they initially responded.  Thus, even if all forms of bupropion XL are clinically 
equivalent, about 3-4 participants may be expected to suffer a relapse during the trial.  Relapse of depression is considered 
an end-point in the study: patients who have suffered a relapse will be removed from the study and will return to their pre-
study medication formulation.  Study staff will ensure that relapsed study subjects restart their medication and receive 
timely follow-up with their treating physician or other appropriate mental health professional.  In the case that relapse of 
depression is associated with the emergence of suicidal ideation, this could include hospitalization.  Patients who 
prematurely discontinue or are non-adherent to study medication will be removed from the study.  The most likely 
outcome is for the patient to return to their pre-study medication formulation. Other risks are those that would follow a 
breach of confidentiality and the disclosure of clinical information.  In addition, it is recognized that depressed individuals, 
especially those with chronic illness and disability, can easily feel overwhelmed or fatigued by what would be minimally 
demanding tasks for others, and, therefore, this discomfort is included in the potential risks. The instruments to be used in this 
study have been used by the investigators in other studies of older depressed adults (including older frail adults). There are very 
few older adults who are unable to tolerate the length of the questionnaires.   
 
3.1 Adverse Events 
Significant drug-related adverse events are expected to be uncommon, as participants in this study are being continued on 
bupropion at a dose that they are currently tolerating well (study inclusion criterion).  Bupropion, tends to produce side 
effects early in treatment, so late-appearing side effects are unlikely, especially if bioequivalence is observed).  
Nevertheless, there is a rare risk for new, significant side effects, even with our procedures to select participants with low 
likelihood of these. The investigative team will closely monitor subjects for adverse events.  Adverse events will be 
reported to the RIHSC and to the Washington University IRB according to applicable guidelines.  Adverse events are 
followed until satisfactory resolution, as determined by the investigators.  The description of the adverse experience will 
include the description, date and time of onset, duration, intensity, etiology, relationship to the study drug (none, unlikely, 
possible, probable, highly probable), any treatment required, and any follow-up and/or treatment required. 
 
3.2 Premature Discontinuation 
If a subject withdraws or drops out from the study, or is withdrawn by the investigators, they will be replaced, to provide 
the required number of subjects.  Subjects will be withdrawn if the investigator decides that discontinuation is in the best 
interest of the subject, or the subject requests withdrawal from the study.  Subjects’  participation can be terminated by the 
investigator without regard to the subject’s consent.  Randomization of replacements will be as follows: 
1.  Subjects withdrawn or dropping out prior to randomization (before or during the lead-in) will simply be replaced in 
that former subject’s randomization, and receive that subject’s order of drug products 
2.  Subjects withdrawn or dropping out after randomization, while receiving the study drugs, will be replaced using the 
next scheduled randomization sequence. 
 
3.3 Potential Risks 
3.3.1 Potential risks from bupropion 
Adverse effects from bupropion: Bupropion is a widely used and efficacious antidepressant also used for smoking 
cessation. All enrolled subjects will currently be taking this drug under the management of their treating physician at the 
time of enrollment. Bupropion is generally well-tolerated.  In patients taking it chronically, it may cause agitation, anxiety 
or insomnia.  A rare effect of bupropion is seizures, which are partially dose-related, and the risk is also increased in 


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17 
patients with a history of seizure disorders or other predisposing factors. The incidence of seizure in patients receiving 
bupropion at doses <450mg daily is about 0.1-0.4%, similar to other antidepressants. The potential risks and side effects 
from versions of bupropion HCl manufactured by Valeant Intl (Wellbutrin), Anchen/Par Pharmaceuticals, Watson, and 
Mylan will be explored from this proposed research to determine if patients can perceive differences in release patterns, 
clinical effectiveness, and adverse events between drug preparations. 
 
3.3.2 Potential Risks from Drug Cross-Over 
The intent of the study is to determine whether the forms of bupropion 300mg XL are bio- and clinically-equivalent; 
therefore, there is some chance that some of the forms are not equivalent and patients will be switched to a form that is 
either ineffective or causes side effects.  The risk of this is unknown.  However, these risks are not unlike typical clinical 
care in which patients may be switched between generics for reasons of cost or availability at any refilling of medications. 
 
3.3.3 Potential Risks from Discomfort Related to Interviews And Questionnaires 
With respect to minimizing any discomfort that may result from the interview, raters have been or will be selected on the 
basis of personal attributes and interpersonal skills as well as substantive knowledge.  They will be further trained and 
periodically observed to ensure that they are respectful and sensitive to the needs and feelings of the subjects.  
Furthermore, they are trained to recognize signs of significant stress or irritability and will be instructed that they should 
gently terminate the interview whenever distress is observed. 
 
3.3.4  Potential Risks from Genotyping 
1) The relevant genes are not associated with any known disorder(s), syndrome(s), or adverse condition.  2) Samples will 
be kept confidentially. They will be coded, with a key to the code linking code numbers to names kept at a separate 
location, under lock and key.  3) The link to identifiers will be destroyed at the end of the study.  4) A disease/syndrome is 
not being studied, hence there is no issue of effective treatments to be administered as a result of genotyping.  There is no 
evidence that testing will provide evidence of previously undiagnosed or unrecognized illness, or susceptibility to illness.  
5) Samples will not be used for any purpose other than to study genes related to the disposition and response to study 
drugs.  6) Blood samples will not be used to establish permanent cell lines.  7) Data will be stored under lock and key 
(office, file cabinet) and only the investigators will have access. If data are published, there will be no link to identifiers. 
Study data will not be revealed to any organization, individuals other than the subjects, or the subjects themselves.  8) 
Genetic data will not be entered in subjects’ medical records.  9) Studies are not likely to result in findings that meet the 
National Bioethics Advisory Commission criteria for disclosure.  10) Genetics counseling will not be available to 
subjects, as they will not be informed of results and there are no know implications with respect to disease.  11) DNA 
samples will be deidentified (i.e., stripped of identifiers and given a separate code numbers unrelated to the subjects’ study 
identification numbers). The code key will be kept by the PI under lock and key.  DNA samples are used for this study 
only, and are not used for any other purpose or study. 
 
3.3.5 Other Potential Risks 
Intravenous catheter placement can cause a bruise. The amount of blood drawn will not constitute a risk to subjects (300 
cc over 7 months), since this is less than recommended limits.  Subjects may experience a loss of confidentiality.  
Investigators will keep subjects’ participation confidential to the extent permitted by law.  However, it is possible that 
others may become aware of subjects’ participation in this study and may inspect and copy records pertaining to this 
research.  Some of these records could contain information that personally identifies subjects. 
 
3.4 Procedures to Minimize Potential Risks 
The PI and co-investigator (a board certified adult and geriatric psychiatrist), will have primary responsibility for 
monitoring of all actively enrolled study subjects. Inclusion/exclusion criteria, screening interviews and assessments will 
be reviewed by the investigators at baseline and monitored throughout the study. Subjects will have access to a 24-hour 
answering service with physician availability. Study investigators, coordinators, and research staff will meet weekly to 
review recruitment, data accrual, data confidentiality, adherence to protocol design, subject compliance, subject status 
(clinical symptoms, side effects, any possible adverse events, intercurrent medical conditions) and complaints. At these 
meetings, any possible changes to the risk-benefit level will be discussed. 
 


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3.4.1 General 
Overnight study sessions will be conducted in the WU Clinical Research Unit (CRU) under the supervision of the PI, a 
board-certified anesthesiologist thoroughly trained and experienced in human subjects research, assessment of adverse 
effects, and treatment. Subjects will be monitored by trained research coordinators and (RN) nursing personnel. The CRU 
operates as an in-patient and out-patient clinical research unit for studies that require more “intense” nursing services or 
that require an inpatient stay, and has crash cart and ACLS staff available on the unit. Each room is equipped with wall 
suction, oxygen and standard hospital monitoring equipment. There is an emergency plan in place that assures direct 
access to emergency care if it would be required.  
 
3.4.2 Medication Risks 
Risks from study medications will be minimized by excluding individuals with elevated seizure risk from bupropion (e.g., 
any history of bupropion-related seizures, or eating disorder).  Since only individuals already taking bupropion stably for 
at least 4 months and tolerating it well will be enrolled, bupropion risks are likely low.  Additionally, the risk of clinical 
worsening will be mitigated by following participants closely for evidence of this and removing them from the study if 
they suffer a relapse or intolerable side effect, restarting them on their original form of bupropion XL.   
 
3.4.3 Genotyping 
With regard to the determination of CYP2B genotype:  1) CYP2B genes are not associated with any disorder(s), 
syndrome(s) or adverse condition.  2) Samples will be kept confidentially.  They will be coded, with a key to the code 
linking code numbers to names kept at a separate location, under lock and key.  3) The link to identifiers will be destroyed 
at the end of the study. 4)  A disease/syndrome is not being studied, hence there is no issue of effective treatments to be 
administered as a result of genotyping.  There is no evidence that testing will provide evidence of previously undiagnosed 
or unrecognized illness, or susceptibility to illness.  5) Samples will not be used for any purpose other than to study genes 
related to the disposition and response to study drugs.  6) Blood samples will not be used to establish permanent cell lines.  
7) Data will be stored under lock and key (office, file cabinet) and only the investigators will have access.  If data are 
published, there will be no link to identifiers.  Study data will not be revealed to any organization, individuals other than 
the subjects, or the subjects themselves. 8) Genetic data will not be entered in subjects' medical records.  9) Studies are not 
likely to result in findings that meet the National Bioethics Advisory Commission criteria for disclosure. 10) Genetics 
counseling will not be available to subjects, as they will not be informed of results and there are no know implications 
with respect to disease.  11) DNA samples will be anonymized (i.e., stripped of identifiers and given a separate code 
numbers unrelated to the subjects' study identification numbers).  The code key will be kept by the PI under lock and key.  
 
3.4.4. Suicide Risk Management 
Suicide is a risk of depression and not of the study per se. Patients who are identified as having suicidal ideation will be 
excluded from the study. Nevertheless, since the rate of completed suicide in the USA remains high (i.e., about twice the 
rate of homicide) and most Americans who commit suicide suffer from depression, all subjects eligible to participate in 
this study are statistically at a relatively higher risk for suicide than the general population. The subjects’ absolute risk for 
completing suicide during this brief study remains very low and participation in the study does not create or increase the 
risk of completed suicide. Furthermore, all participants will be formally assessed every 3 weeks during the study. If the 
study personnel identify that a subject has become acutely suicidal, this subject will be referred to a mental health 
professional for further evaluation and treatment. This may lead to a clinical intervention that is lifesaving and may not 
have occurred had the subject not been participating in the study. 
 
At each assessment point, trained research staff will probe for passive death wish, and suicidal ideation, intent or plan 
when they administer the MADRS. If a subject endorses suicidal ideation, intent, or plan, research staff is trained to 
follow an operationalized protocol developed to manage high-risk subjects in other studies of depressed subjects 
potentially at risk for suicide. This protocol has already been used successfully by the investigators to manage several 
acutely suicidal patients, and entails a specific determination of the suicidal risk and a prescribed set of actions. If a 
subject is determined to be at high and immediate risk, research staff is instructed to stay with the subject until a study 
psychiatrist has been contacted to discuss the situation. Coordinators will have cell phones and at least one study 
psychiatrist will be reachable at all times. In case of extreme emergency, coordinators are instructed to call their hospital 
security team or 911 for immediate help and to initiate commitment proceedings. 


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19 
3.4.5 Discomfort 
With respect to minimizing the discomfort that may result from interviews, coordinators will be selected on the basis of 
personal attributes, interpersonal skills, experience and substantive knowledge.  They will be further trained and 
periodically observed to ensure that they are respectful and sensitive to the needs and feelings of the subjects. 
Furthermore, they are trained to recognize signs of significant stress or irritability and will be instructed that they should 
gently terminate the interview whenever distress is observed. 
 
3.4.6 Data Integrity and Confidentiality 
Subjects will be interviewed specifically to obtain research data. In addition to training and close supervision of research 
staff described above, a formal quality control mechanism will provide a systematic check on the quality of interview 
data.  Of every 20 assessments, one will be selected for a random quality check. Selections will be made regardless of 
whether the interview was actually completed and will be random with the restriction that no more than two interviews 
will be checked for a given subject. Procedures designed to maintain confidentially include: (1) formal training sessions 
for all research staff emphasizing the importance of confidentiality; (2) specific procedures developed to protect subjects’ 
confidentiality, and (3) formal mechanisms limiting access to information that can link data to individual subjects. 
Identities of participants will not be revealed in the publication or presentation of any results from this project. Research 
staff and subjects will provide data through paper forms and electronically.  Smart-phone based data capture is transmitted 
immediately to a WU firewall-protected server at which point data are removed from the phone. All data capture by the 
device is encrypted and saved as numerics. In the event of difficulty with data transmission, encrypted data must be 
manually pushed to the server via a password protected user-interface. Only the research team would have access to the 
password for manual push of data, which then results in removal of stored data from the device. There are no patient 
identifiers saved to the devices. 
 
3.5 Plans for Ensuring Necessary Medical Intervention 
Subjects will remain under the care of the practitioner who is their treating physician. Subjects will be instructed to inform 
their treating physician of participation in the research study. Subjects will be told that in the event of a physical injury as 
the direct result of study procedures, they will be cared for by a member of the investigating team at no cost, within the 
limits of the Washington University compensation plan. Drug doses are chosen to be the same as currently used for 
medical management of depression. Side effects for each drug will be monitored daily by trained research personnel and 
the PIs. 
 
3.6   Data and Safety Monitoring Plan 
The specific monitoring plan for this investigation is commensurate with the risks and the size and complexity of the 
investigations planned.  The potential risks are attributable to the use of different bupropion 300mg XL drug products, as 
there is no change in subjects’ drug or drug dose, or medical management.  Based on these considerations the monitoring 
plan involves a (board certified psychiatrist trained in treatment of depression) not involved in the study to serve in a 
monitoring capacity.  Based on the small size and relatively low risks nature of the protocol, only a third person, rather 
than a full DSMB, is utilized.  This individual will review the annual summary of adverse events.  In addition, they will 
review all reports of a Serious Adverse Event, or an Unexpected Adverse Event.  This Plan is acceptable to our IRB, and 
has been used successfully by the PI for several years.   
 
In general, the PI has a specific set of Standard Operating Procedures (SOPs) for clinical research.  All individuals 
working under the PI are required to read and be totally familiar with and compliant with the SOPs, inclusive of the SOP 
for Adverse Event Reporting to the IRB (attached). 
 
3.7  Notification of Subjects of New Findings  
Significant findings developed during the course of the research which may relate to the subject’s willingness to continue 
participation will be provided to the subject. 
 
 
 


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20 
4.  HUMAN SUBJECTS RESEARCH 
4.1 Protection of Human Subjects 
4.1.1 Human Subjects Involvement and Characteristics 
The 28-week prospective, randomized, double-blinded, crossover study will involve enrollment of 75 subjects age 18-75 
yrs who volunteer and meet all inclusion/exclusion criteria. All subjects will have been diagnosed with Major Depressive 
Disorder (MDD) and be taking bupropion HCl, 300mg XL (branded or generic versions). After all study related 
procedures, risks and benefits are explained and discussed, potential subjects will be asked to sign an informed consent 
form approved by the Washington University Institutional Review Board (IRB) and will be enrolled. The randomization 
table will be generated and kept by the Barnes-Jewish Hospital Investigational Pharmacy.  Subjects will complete baseline 
research assessments conducted by trained research staff which include a) diagnostic and symptomatic measures of 
depression, b) review of medical conditions and medications, c) alcohol and drug use, and d) physical health.  Subjects 
will remain on their own medication for the initial 4 weeks of the study. During this time they will undergo daily 
monitoring with smart phone-based Ecological Momentary Assessments (EMA). Upon completion of this 4 week period, 
subjects will visit the clinic for assessment of depression and side effects. Non-adherent subjects will be withdrawn from 
the study. Ongoing study participation will include 6 weeks on each of the four bupropion products (brand and 3 generics) 
without washout between drug crossover. Subjects will participate in overnight pharmacokinetic sessions at the 
Washington University Clinical Research Unit (CRU) approximately 2-3 weeks following each drug crossover. These 
sessions will occur 4 times and involve collection of blood and urine samples for up to 24 hours.  Subjects will be 
provided with 3 weeks of study drug prior to discharge from the CRU.  Periodic (approximately every 3 weeks) 
interviews will be conducted at WU Medical Center research offices and include monitoring of drug compliance (MEMS 
6 TrackCap system), structured interview for assessment of depression symptoms, completion of Montgomery-Asberg 
Depression Rating Scale (MADRS) and assessment of drug effect(s). Subjects will receive an additional 3 week supply of 
study drug at each clinic visit.  Subjects will complete smart phone-based EMA daily for real-time capture of patient-
reported drug effects. Phones will also be used as a reminder to adhere to dosing instructions and provide instructions and 
trouble-shooting guidance. At the conclusion of the final session and last clinic visit, subjects will be returned to their 
original bupropion formulation and directed to resume their own medication.  All studies are conducted under the 
supervision of the PI, a Board-Certified and GCP-certified and clinically active anesthesiologist with extensive experience 
in the conduct of human volunteer studies. We will examine bioequivalence, clinical equivalence, stereoselectivity, 
genomics, and patient perspectives regarding switches between commercially available forms of bupropion 300mg XL. 
 
4.1.2 Criteria for Inclusion and Exclusion 
Inclusion criteria: 
1. Adult outpatients age 18-75 years 
2. Currently on once daily bupropion HCl 300mg XL (brand or any generic) for a minimum of 4 months 
3. Diagnosis of major depressive disorder in partial or full remission for ≥4 months, confirmed by Structured Clinical 
Interview for DSM Axis I Disorders (SCID) 
4. Ability to understand and willingness to comply with study procedures, and to provide written informed consent 
 
Exclusion criteria: 
1. Remission from depression not clearly attributed to bupropion treatment 
2. Current severe side effects attributable to bupropion 
3. Poor adherence to bupropion treatment per patient self report and history of refill persistence 
4. History of active seizure disorder, or seizure treatment within past year 
5. History of significant hepatic or renal disease, based on physician assessment 
6. Currently taking drugs or natural products known to influence cytochrome P450B6 (CYP2B6) activity 
7. Currently taking drugs for hepatitis C or multiple sclerosis, due to their ability to cause depression 
8. Dementia or other significant cognitive impairment, per diagnosis or investigative team’s assessment 
9. Lifetime diagnosis of schizophrenia, schizoaffective or schizophreniform dis-order, delusional disorder, or current 
psychotic symptoms diagnosed by SCID 
10. Abuse of or dependence on alcohol or other substances within the past 6 months as determined by SCID, and 
confirmed by study physician interview 
11. Current suicidal ideation 


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21 
4.1.3 Involvement of Special Subject Classes 
None 
 
4.1.4  Procedures for Assignment to Study Group 
Subjects will enter the study and remain on their current bupropion medication for the initial 4 weeks. The order of the 
four study drugs (all FDA-approved forms of bupropion XL 300mg) will be randomized and balanced across the study. 
The randomization table will be generated and kept by the Barnes-Jewish Hospital Investigational Pharmacy. Each 
enrolled subject will be assigned the next available number. Subjects, investigators, and all study team members will be 
blinded to drug treatment. 
 
4.2 Sources of Materials 
4.2.1 Research Material Obtained 
Specimens include blood and urine obtained exclusively for determining study drug bioequivalence, stereoselectivity, and 
CYP2B6 genomics. Subjects will not be informed of their genotype. Subject completion of EMA data will be transmitted 
directly from research smart phones to a secure designated server at WU. The research team will administer the 
Montgomery-Asberg Depression Rating Scale (MADRS) and conduct structured interviews at all clinic visits. Side effects 
will be assessed with a self-reported Antidepressant Side-Effect Checklist. Drug compliance will be recorded with the 
MEMS system. Other data include past health and medical information obtained exclusively for research purposes.  
 
4.2.2.  Data Recorded 
All research data will be recorded and saved to a secure password protected research designated server at WU. Data will 
be de-identified and stored under lock and key (secured building, locked office, locked cabinet) and only the research 
team will access.   
 
4.2.3.  Linkages to Subjects and Access to Identifiers 
Any information that is obtained in connection with research that can be identified with a subject will remain confidential. 
Medical information, case report forms, pharmacokinetic and genetic data will be given a code and only the research 
personnel will have access to this information. Statisticians involved in any of the projects will have access only to 
deidentified data for the purposes of analysis. The original informed consent forms will be kept by the PI and a copy will 
be given to all subjects. Genotyping samples will be coded, with the key to the code linking code numbers to names kept 
at a separate location, under lock and key, with access limited to research team members. 
 
4.2.4.  Method of Specimen Collection 
On study days, one IV catheter will be inserted for blood sampling. After administration of study medication, blood and 
urine samples are obtained for up to 24 hrs.  
 
4.3. Recruitment and Informed Consent 
4.3.1 Recruitment Strategy and Feasibility 
The projected enrollment is four participants per month, well within our recruitment abilities, based on previous 
experience in patients with MDD in clinical trials.  Potential subjects will be identified through IRB-approved processes.   
 
The main recruitment plan involves targeted screening of patients (potential subjects) taking bupropion: This strategy 
leverages collaboration with Express Scripts as a Pharmacy Benefits Manager (PBM) to identify and contact patients with 
stable use of bupropion XL 300mg (and no contraindicated medications).  Express Scripts has 3 years of prescription 
claims data readily accessible. Many clients have provided consent to Express Scripts allowing the use of their 
prescription and medical claims data for research purposes.  Prescription data provides the ability of Express Scripts to 
identify individuals taking 300mg XL bupropion products, their duration of use, and comorbid conditions which might 
preclude patients from inclusion in the study, based on the inclusion/exclusion criteria.  To date, more than one thousand 
bupropion XL 300mg users in the St Louis metro area have given consent for these research purposes.  Express Scripts 
will notify eligible subjects of the study, and subjects will contact the investigators if they are potentially interested.  
Investigators will not contact potential subjects without their prior permission.  This method alone will likely be sufficient 
to meet recruitment needs; only a 7% consent and randomization rate would be needed to obtain 75 participants. 


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22 
 
Should the above method be insufficient, three other robust strategies for recruitment are available: 
1.  Community Engagement Core of the Washington University CTSA: This service, provided at no cost for CTSA 
faculty, will engineer a study-specific plan to search the Core’s volunteer patient database, and advertise directly to the 
selected participant population. 
2.  Primary care and specialty care clinic screening and advertisements.  Screening staff will partner with several care 
networks, including Washington University clinics in primary and specialty medical care, psychiatry, geriatric psychiatry, 
and geriatric medicine, the Washington University Physician Network, and referrals from local psychiatric practitioners 
and the BJC Medical Group. Washington University psychiatry clinics alone have over 1000 patients. 
3.  Wide-based screening of self-nominated volunteers.  This involves large, current research registries (e.g., the 
“Volunteers for Health” registry at Washington University) to potentially identify and contact patients with depression 
history.  In addition, Washington University Public Affairs will engage local media for messaging the study, using 
newspaper or radio advertising.  Our prior clinical trials of depression have been able to recruit in the hundreds by these 
wide-based screening methods. 
 
4.3.2 Circumstances of Informed Consent 
Study volunteers will be consented for participation and enrolled by trained research personnel at Washington University 
School of Medicine. Subjects will be given verbal (initially) and then written descriptions of the study aims, procedures, 
risks, and benefits, and will be required to give written informed consent.  A member of the investigative team will 
provide all study descriptions, informed consent, and answer all questions. No placebo is required for the purposes of this 
study. Subjects will be informed verbally and in writing that participation is voluntary and they may refuse to participate 
and may withdraw from the study at any time without penalty.  
 
Subjects will be asked for permission to contact their psychiatrist or primary care physician (PCP) who is prescribing 
bupropion and to inform them that the patient is interested in participating in the study. If the psychiatrist or PCP believes 
that participation could endanger the patient, the patient will not be enrolled. Informed consent will be obtained before 
any study procedures are performed and before any private information is recorded. Proxy consent is not planned. 
 
4.4. Potential Benefits of the Proposed Research to the Subjects and Others 
Subjects will benefit by receiving medication at no cost during the duration of time on study treatment (28 weeks) and 
daily monitoring of signs and symptoms of depression and suicide (approximately 7 months).  
 
In case participants do suffer a relapse or side effect from change in formulations, their bupropion pharmacokinetics will 
be examined to determine bioequivalence.  If it can be determined that clinical worsening was attributable to a non-
bioequivalent switch, this information will be provided to the patient and their treating physician.  The patient and their 
treating physician will also be informed of the bupropion XL formulation associated with clinical worsening. Such 
participants would benefit from learning which bupropion products are less tolerated or ineffective for them.   
 
Society will benefit from a better understanding of the quality, bioequivalence and therapeutic equivalence of bupropion 
300mg XL products. 
 
4.4.1 Why Risks to Subjects Are Reasonable in Relation to Anticipated Benefits to Subjects 
In general, the risks to research subjects in this protocol are probably small and not different than the usual manner in 
which generic-generic switches occur. There will be no change to the subject’s prescribed medication. There is a small 
potential for clinical ineffectiveness, or new or worsening side effects, due to non-bioequivalence, but in such cases 
participants will benefit from acquiring the knowledge of which bupropion forms are non-equivalent for them. The overall 
anticipated benefit to society is improved bupropion 300mg XL dosing guidelines in treatment of depression. These 
potential benefits are substantial in comparison to the potential risks, hence the risks to subjects are reasonable in 
relationship to the anticipated benefits. 
 
4.5  Subject Compensation  


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Subjects are compensated for participation.  A subject will receive $150 for completing the 4 week lead-in, and $250 for 
completing each of four 6-week drug evaluation periods (up to $1150).  If they complete the entire protocol they will 
receive an additional $850.  Maximum total compensation is therefore $2000.  If a subject stops participating before the 
entire protocol is completed, they will receive the prorated amount for the number of sessions completed.   
 
4.6  Importance of the Knowledge to be Gained 
More than 3 billion generic drug prescriptions are filled annually in the US, and generic medicines save consumers and 
the U.S. healthcare system $190 billion annually.  Generic drugs are usually only approved after demonstration of 
bioequivalence to the innovator (branded) drug. Bupropion is taken by more than 1 million Americans annually. One 
generic formulation of bupropion was recently found to be non-bioequivalent and withdrawn from the market. It is 
important that the bioequivalence of other bupropion 300mg XL products be assessed and verified.   
 
4.7 Inclusion of Women 
There is no exclusion of any sex/gender or racial/ethnic group for these studies. Studies and their advertisements actively 
encourage the participation of women in the research.  The study goal is equivalent numbers of women and men. To 
ensure sufficient enrollment of both sexes, enrollment is typically closed once a sex quota is reached.  Women of 
childbearing 
potential 
are 
not 
excluded. 
 
Bupropion 
is 
not 
contraindicated 
during 
pregnancy 
(http://www.womensmentalhealth.org/use-of-wellbutrin-bupropion-during-pregnancy/).52,53  Subjects will be advised to 
follow the instructions of their bupropion-prescribing physician regarding pregnancy or pregnancy planning, and, per drug 
label, to inform the investigators and their treating physician if they become pregnant or intend to become pregnant during 
the course of the study. 
 
4.8 Inclusion of Minorities 
Studies and their advertisements actively encourage the participation of minorities in the research.  Minority recruiting 
typically matches the demographic composition of the Washington University community from which subjects will be 
recruited (44% white, 51% Black, 2% Asian, 2% Hispanic). 
 
4.9 Inclusion of Children 
Subjects <18 yr will not be studied in these investigations.  
 
4.10 Clincaltrials.gov requirements 
The proposed research will be registered in ClinicalTrials.gov once the protocol has been reviewed and approved by the 
FDA RIHSC. 
 
5.0 References 
 
1. Souery D, Oswald P, Massat I, Bailer U, Bollen J, Demyttenaere K, Kasper S, Lecrubier Y, Montgomery S, Serretti 
A, Zohar J, Mendlewicz J: Clinical factors associated with treatment resistance in major depressive disorder: results 
from a European multicenter study. J Clin Psychiatry 2007;68:1062-70 
2. Reynolds CF, 3rd, Dew MA, Pollock BG, Mulsant BH, Frank E, Miller MD, Houck PR, Mazumdar S, Butters MA, 
Stack JA, Schlernitzauer MA, Whyte EM, Gildengers A, Karp J, Lenze E, Szanto K, Bensasi S, Kupfer DJ: 
Maintenance treatment of major depression in old age. N Engl J Med 2006;354:1130-8 
3. Blier P, Ward HE, Tremblay P, Laberge L, Hebert C, Bergeron R: Combination of antidepressant medications from 
treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry 2010;167:281-8 
4. Association GP: Generic drug savings in the U.S. (Fourth annual edition: 2012), 2012 
5. Informatics IIfH: The use of medicines in the United States: Review of 2011, 2012 
6. van der Meersch A, Dechartres A, Ravaud P: Quality of reporting of bioequivalence trials comparing generic to brand 
name drugs: a methodological systematic review. PLoS One 2011;6:e23611 
7. Hottinger M, Liang BA: Deficiencies of the FDA in evaluating generic formulations: addressing narrow therapeutic 
index drugs. Am J Law Med 2012;38:667-89 
8. Williams RL, Chen ML, Hauck WW: Equivalence approaches. Clin. Pharmacol. Ther. 2002;72:229-37 


Bioequivalence of Generic Bupropion 
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11/19/2015 
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24 
9. Guidance for industry: Statistical approaches to establishing bioequivalence. US Food and Drug Administration, 
Center for Drug Evaluation and Research 2001: http/:www.fda.gov:downloads:Drugs:Guidances:ucm070244.pdf 
10. Guidance for industry: Bioavailability and bioequivalence studies for orally administered drug products - General 
considerations. US Food and Drug Administration, Center for Drug Evaluation and Research 2003: 
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070124.pdf 
11. Orange book: Approved drug products with therapeutic equivalence evaluations. US Food and Drug Administration, 
Center for Drug Evaluation and Research 2013:http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm 
12. Yamada M, Welty TE: Generic substitution of antiepileptic drugs: a systematic review of prospective and 
retrospective studies. Ann Pharmacother 2011;45:1406-15 
13. Endrenyi L, Tothfalusi L: Metrics for the evaluation of bioequivalence of modified-release formulations. AAPS J 
2012;14:813-9 
14. Garcia-Arieta A, Morales-Alcelay S, Herranz M, de la Torre-Alvarado JM, Blazquez-Perez A, Suarez-Gea ML, 
Alvarez C: Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products. 
Int J Pharm 2012;423:321-5 
15. Woodcock J, Khan M, Yu LX: Withdrawal of generic budeprion for nonbioequivalence. N Engl J Med 
2012;367:2463-5 
16. Review of therapeutic equivalence generic bupropion XL 300 mg and Wellbutrin XL 300 mg. Office of medical 
products 
and 
tobacco, 
US 
Food 
and 
Drug 
Administration 
(FDA) 
2012: 
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270 
17. Update:  Budeprion XL 300 mg not therapeutically equivalent to Wellbutrin XL 300 mg. Food and Drug 
Administration 
(FDA), 
Center 
for 
Drug 
Evaluation 
and 
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agreement by the recipient that no unpublished information contained herein will be published or disclosed without prior written approval. 
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26 
Bioequivalence and clinical effects of generic and brand bupropion:  Study Table 
 
Pre- 
randomIzation 
(4 weeks) 
Randomization Study Period (24 weeks) 
Entire 
Study 
Post 
Study 
Study Drug 1 
(6 wks) 
Study Drug 2 
(6 wks) 
Study Drug 3 
(6 wks) 
Study Drug 4 
(6 weeks) 
 
Procedure 
Phone 
Screen 
Initial clinic 
Lead-in 
Visit 0 
Random
ization 
Visit 1 
PK 
Session 
1 
Study 
clinic 
Visit 2 
PK 
Session 
2 
Study 
clinic 
Visit 3 
PK 
Session 
3 
Study 
clinic 
Visit 4 
PK 
Session 
4 
Close-out 
Clinic 
Visit 5 
 
Subject visit 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Subject contacts investigators.  Telephone description of study purpose, 
procedures, benefits, risks.  Screen potential eligibility.  (E)mail informed 
consent doc to subject.  Subject contacts investigators if interested 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review study purpose, procedures, benefits, risks.  Provide detailed orien-
tation to study procedures (daily smart phone assessments, medications) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Structured Clinical Interview for DSM‐IV Axis I Disorder (SCID) (as needed) 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
MADRS -Symptoms of depression questionnaire 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ASEC checklist (side effects) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Training: Daily smart phone assessments and MEMS 6 TrackCap use 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Determine and confirm eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Replace subject’s current bupropion product with same product, over-
encapsulated (4 wk supply) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Subject starts new crossover bupropion study drug 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Provide over-encapsulated study drug(3 wk supply) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Download MEMS compliance data 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Review smart phone, download  data (if required) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
DNA sample (blood) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
24 hour PK session, venous sampling (~15 samples, 75ml) 
 
X 
X 
 
X 
X 
 
24 hour urine collection 
 
X 
X 
 
X 
X 
 
Reinstruct subjects to all study related procedures 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subject performs daily smart phone-based assessments 
 
 
X 
Capture drug compliance and adherence (MEMS 6 TrackCap) 
 
 
X 
Occasional phone calls if warranted   
 
 
X 
24 access via pager to Research Team and Research MD 
 
 
X 
Return subjects’ original bupropion medication 
X
Remuneration for study participation (and completion) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Collect all study equipment (phone, MEMS 6 TrackCap) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
30 day telephone follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
X