Clinical trial NCT02593396
Conditions: Sexual Dysfunctions, Psychological Hypoactive Sexual Desire Disorder Erectile Dysfunctions
Keywords: sexual dysfunctions erectile dysfunctions hypoactive sexual desire dysfunctions
Sponsor: University of Malaya
Start date: 2015-12-01; Completion date: 2017-12-01
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the tolerability, safety, and efficacy of bupropion hydrochloride sustained-release in the treatment of sexual dysfunction in men on methadone maintenance therapy.

Detailed description:
This is a single-center (University Malaya Medical Centre), randomized, double-Blind, placebo-controlled versus bupropion hydrochloride sustained-releases study trial on 70 men who have methadone emergent sexual dysfunction. Bupropion hydrochloride sustained-release (Wellbutrin SR) 150mg once a day for 7 days then 150mg twice a day for 42 days. Taken orally by the subjects.The total duration of the study is expected to be 24 months. 20months for subject recruitment and 4 months for final subject follow-up.

The primary endpoint is Mean improvement in scores on the Clinical Global Impression Scale adapted for sexual Function (CGI-SF). Secondary endpoints are Change from baseline International Index of Erectile Function (IIEF-15) score. Mean improvement in scores on the sexual desire inventory 2 (SDI2). Other evaluation included: Montgomery-Åsberg Depression Rating Scale (MADRS- Malay version ), Mini International Neuropsychiatric Interview (M.I.N.I), Opiate Treatment Index (OTI), World health organization Quality of Life-Brief Scale (WHOQoL-Brief, Malay version), Malay Version of the Golombok-Rust Inventory of Marital State (Mal-GRIMS) and Rapid urine drug test. Safety evaluation included: Incidence of adverse events. Data will be analyzed using linear mixed-effects model.

Arms: arm 1: Placebo BD arm 2: Bupropion hydrochloride sustained-release 150mg BD
Interventions: intervention 1: Bupropion hydrochloride sustained-release intervention 2: placebo
Intervention descriptions: intervention 1: Up to 70 eligible patients will be randomly assigned to Bupropion Hydrochloride Sustained-Release or placebo treatment groups in a 1:1 ratio using a computer-generated table of random numbers through the use of the Randomization.com program. Subjects will be randomized to to Bupropion Hydrochloride Sustained-Release 150mg b.d. (n = 35) or placebo b.d (n = 35)The study drug will be repacked in the standard capsules by the research assistant who is not involved in the assessment of the study. The study drug and placebo will be packaged in sets of 11 (1 tablet per day for 3 days, followed by 2 tablets per day for 4 days.) for the first week. Subsequently, the study drug and placebo will be packaged in sets of 14 (2 tablets per day for 7 days.). intervention 2: Up to 70 eligible patients will be randomly assigned to Bupropion Hydrochloride Sustained-Release or placebo treatment groups in a 1:1 ratio using a computer-generated table of random numbers through the use of the Randomization.com program. Subjects will be randomized to to Bupropion Hydrochloride Sustained-Release 150mg b.d. (n = 35) or placebo b.d (n = 35)

Protocol documents:
Prot_SAP_000.pdf: 
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A Prospective, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial 
Of Bupropion Hydrochloride Sustained-Release In The Treatment Of Sexual 
Dysfunction In Men On Methadone Maintenance Therapy. 
 
 
 
 
 
 
Name of investigator:  
Yee Hway Ann @ Anne Yee 
Institution 
 
:   
Department of psychological medicine 
    
Faculty of Medicine 
   
Unversity Malaya  
 
50603, Kuala Lumpur 
 
Malaysia 
 
03-79494327 
 
Name of sponsor 
:   
University Malaya 
 
 
 
 
50603, Kuala Lumpur 
 
Malaysia 
 
03-79494327 
 
Study Product 
: 
Bupropion Hydrochloride Sustained-Release 
 
Protocol Number 
: 
AY001


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CONFIDENTIAL 
This document is confidential and the property of Dr Yee Hway Ann @ Anne Yee. No 
part of it may be transmitted, reproduced, published, or used by other persons without 
prior written authorization from the author. 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse effect 
b.d 
Twice per day 
CGI-SF 
Clinical Global Impression Scale adapted for Sexual Function  
ECG 
Electrocardiogram 
HIV 
Human immunodeficiency virus 
IIEF-15 
International Index of Erectile Function 
ITT 
Intention-to-treat analyses 
MADRS, Malay  
Montgomery-Åsberg Depression Rating Scale 
M.I.N.I 
Mini International Neuropsychiatric Interview 
OTI 
Opiate Treatment Index 
WHOQoL-Brief, 
Malay version 
World health organization Quality of Life-Brief Scale 
Mal-GRIMS 
Malay Version of the Golombok-Rust Inventory of Marital State 
SAE 
  
Serious Adverse Experiences 


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PROTOCOL SUMMARY 
TITLE 
Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial 
Of Bupropion Hydrochloride Sustained Release In The Treatment Of 
Sexual Dysfunction In Men On Methadone Maintenance Therapy. 
SHORT TITLE 
RCT Bupropion SR in SD among MMT men 
INVESTIGATOR 
Yee Hway Ann @ Anne Yee 
SYUDY PROTOCOL 
AY001 
Phase 
Phase II 
Study Center(s) 
Single-center (University Malaya Medical Centre) 
STUDY DESIGN 
Randomized, Double-Blind, Placebo-Controlled Study. 
OBJECTIVE 
To assess the therapeutic effect of bupropion hydrochloride sustained-
release in the treatment of sexual dysfunction in men on methadone 
maintenance therapy 
NUMBER OF 
SUBJECTS 
70 (35 for each arm) 
Diagnosis and Main 
Inclusion Criteria 
Adult had a diagnosis of opioid dependence base on Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) 
criteria, who were experiencing constant sexual dysfunction for ≥ 4 
weeks while taking a stable dose of methadone for ≥ 6 months.  
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Bupropion hydrochloride sustained-release (Wellbutrin SR) 150mg 
once a day for 7 days then 150mg twice a day for 35 days. Taken 
orally by the subjects. 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 63 days 
Screening:  up to 7 days(1 week) 
Treatment:  42days (6 weeks) 
Follow-up:  14 days (2 weeks) 
The total duration of the study is expected to be 24 months.  20months 
for subject recruitment and 4 months for final subject follow-up. 
EFFICACY 
EVALUATIONS 
 
PRIMARY ENDPOINT 
• Change from baseline International Index of Erectile Function 
(IIEF-15) score. 
SECONDARY 
ENDPOINTS 
• 
Mean improvement in scores on the Clinical Global Impression 
Scale adapted for sexual Function (CGI-SF) 
• 
Mean improvement in scores on the Arizona Sexual Experience 


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Scale (ASEX) 
• 
Safety and Tolerability 
OTHER 
EVALUATIONS 
• Montgomery-Åsberg Depression Rating Scale (MADRS- Malay 
version ) 
• Mini International Neuropsychiatric Interview (M.I.N.I), 
• Opiate Treatment Index (OTI)  
• World health organization Quality of Life-Brief Scale (WHOQoL-
Brief, Malay version) ,  
• Malay Version of the Golombok-Rust Inventory of Marital State 
(Mal-GRIMS) 
• Rapid urine drug test 
SAFETY 
EVALUATIONS 
Incidence of adverse events  
 
STATISTICS 
Primary Analysis Plan 
Data will be analyzed using linear mixed-effects model. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
Pg 
LIST OF ABBREVIATIONS 
3 
PROTOCOL SUMMARY 
4 
INTRODUCTION 
9 
1. 
BACKGROUND 
9 
1.1 
Investigational Agent 
10 
1.2 
Overview of Non-Clinical Studies 
10 
1.3 
Overview of Clinical Studies 
11 
1.4 
Risk / Benefit Assessment 
11 
1.4.1 Dose Rationale 
11 
1.4.2 Potential Risk 
11 
1.4.3 Potential Benefit 
11 
1.4.4 Risk Benefit Ratio 
11 
2 
STUDY RATIONALE 
12 
3 
STUDY OBJECTIVES 
12 
3.1 
Primary Objective 
12 
3.2 
Secondary Objectives 
12 
4 
STUDY DESIGN 
13 
4.1 
Design 
13 
4.2 
Procedure 
13 
4.3 
Project Timetable 
14 
5 
CRITERIA FOR EVALUATION 
14 
5.1 
Primary Efficacy Endpoint 
14 
5.2 
Secondary Efficacy Endpoints 
14 
5.3 
Safety Evaluations 
14 
6 
SUBJECT SELECTION 
15 
6.1 
Study Population 
15 
6.2 
Inclusion Criteria 
15 
6.3 
Exclusion Criteria 
15 
6.4 
Subject Recruitment and Screening 
15 
7 
EARLY WITHDRAWAL OF SUBJECTS 
16 
7.1 
When and How to Withdraw Subjects 
16 
7.2 
Data Collection and Follow-up for Withdrawn Subjects 
17 
8 
STUDY TREATMENTS 
17 
8.1 
Method of Assigning Subjects to Treatment Groups 
17 
8.2 
Blinding 
17 


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8.3 
Formulation of Test and Control Products 
18 
8.3.1 Description 
18 
8.3.2 Treatment Regimen 
18 
8.3.2.1 Route 
18 
8.3.2.2 Regime 
18 
8.4 
Preparation and Administration of Study Drug 
18 
8.5 
Prior and Concomitant Therapy 
18 
8.6 
Packaging and Labeling 
18 
8.7 
Receiving, Storage, Dispensing and Return 
19 
8.7.1 Receipt of Drug Supplies 
19 
8.7.2 Storage 
19 
8.7.3  Dispensing of Study Drug 
19 
8.7.4 Return or Destruction of Study Drug 
19 
8.8 
Measures of Treatment Compliance 
19 
9 
STUDY PROCEDURES AND GUIDELINES 
19 
9.1 
Clinical Assessments 
20 
9.1.1 Concomitant Medications 
20 
9.1.2 Demographics 
20 
9.1.3 Medical History 
20 
9.1.4 Physical Examination 
20 
9.1.5 Adverse Events 
20 
9.2 
Clinical Laboratory Measurements 
20 
9.2.1 Blood investigation 
20 
9.2.2 Urinalysis 
20 
10 
 EVALUATIONS BY VISIT  
21 
10.1 
Visit 0(Screening visit and Randomization) 
21 
10.2 
Visit 1 (week 1) 
21 
10.3 
Visit 2 (week 2) 
21 
10.4 
Visit 3 (week 3) 
21 
10.5 
Visit 4 (week 4) 
22 
10.6 
Visit 5 (week 5) 
22 
10.7 
Visit 6 (week 6) (end of study drug) 
22 
10.8 
Early Withdrawal Visit 
22 


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11 
STATISTICAL PLAN 
22 
11.1 
Sample Size Determination 
22 
11.2 
Statistical Methods 
22 
11.3 
Subject Population(s) for Analysis 
23 
11.4 
Data Management 
23 
12 
ADVERSE EXPERIENCE REPORTING AND 
DOCUMENTATION 
23 
12.1 
Adverse Events 
23 
12.2 
Serious Adverse Experiences (SAE) 
25 
13 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
28 
13.1 
Early Discontinuation of Study Drug 
28 
13.2 
Withdrawal of Subjects from the Study 
29 
14 
PROTOCOL VIOLATIONS 
29 
15 
DATA COLLECTION, RETENTION AND MONITORING 
30 
15.1 
Confidentiality 
30 
15.2 
Source Documents 
30 
15.3 
Data Quality Control and Reporting 
30 
15.4 
Records Retention 
30 
16 
STUDY MONITORING, AUDITING, AND INSPECTING 
30 
16.1 
Study Monitoring Plan 
30 
16.2 
Auditing and Inspecting 
30 
17 
ETHICAL CONSIDERATIONS 
31 
17.1 
Informed Consent Form 
31 
18 
STUDY FINANCES 
31 
18.1 
Funding Source 
31 
18.2 
Conflict of Interest 
32 
19 
PUBLICATION PLAN 
32 
APPENDIX 1 
33 
20 
REFERENCES 
34 
21         ATTACHMENTS 
35 
 
 
 
 
 
 
 


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INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted 
according to the international standards of Good Clinical Practice (International 
Conference on Harmonization guidelines), applicable government regulations and 
University Malaya Medical Centre research policies and procedures.  
 
1. BACKGROUND 
 Sexual dysfunctions, such as reduced libido or arousal and impairments in 
erectile, ejaculatory and orgasmic functions, are commonly found  in men among both the 
mentally ill as well as the healthy populations. The prevalence of sexual dysfunction 
among healthy men ranges from 20% to 35%, and in male populations with psychiatric 
illness, 50% to 65%. [1-5]  
 
Methadone maintenance treatment (MMT) is a comprehensive treatment program 
that involves the long-term prescribing of methadone as a substitution therapy for opioid 
dependence. Despite the effectiveness of the methadone maintenance therapy[6], the  
meta-analytical pooled prevalence for sexual dysfunction among methadone users  was  
52% (95% confidence interval [CI], 0.39–0.65). In this meta-analysis, hypoactive sexual 
desire and low libido were the most prevalent sexual dysfunctions compared to other 
sexual dysfunction, accounting for 51%[7] . Methadone-maintained patients, their partners 
and clinicians who were interviewed regarding the influence of sexual dysfunction 
perceived that that sexual dysfunction decreased quality of patient’s sexual life [8] and 
damaged intimate relationships, while at the same time possibly increasing risk of dropout 
from methadone maintenance therapy prematurely [9] and to use suboptimal methadone 
dose or other illicit drugs. [10] Management for methadone induced sexual dysfunction 
remain a challenge for the physicians because the reducing or stopping the methadone in 
this group of patients may not be always possible.  Hence, the physicians  need other 
stradegies to manage the sexual dysfunction  in this group of patients. 
 
 
Methadone is the slow-and-long acting opiate agonist that cause the  stimulation 
of mu opiate receptors in the various area of the brain.  There are few hypothesis that try 
to explain the correlation of methadone and sexual dysfunction. One of well known 
hypothesis was the neuroendocrinologic effects of methadone that exert on the tubero-
infundibular and hypothalamus-pituitary-gonadal (HPG) axis . The previous studies found 
that the patients in methadone therapy had alternation of the prolactin levels compared 
with the healthy subjects. Hence, the hypothesis that the  chronic stimulation of the μ 
opiate receptors by methadone, alters the functioning of the tubero-infundibular axis and 
the dopaminergic control of prolactin with the consequential impact on sexual functioning 
was formulated . [11] A high level of circulating prolactin causes inhibition of 
gonadotrophin releasing hormone which lowers levels of sex hormone, especially 
testosterone. Men with low testosterone levels may exhibit a decrease in sexual 
interest.[12]This is evidenced by aquantitative meta-analysis study, which showed that  
testosterone, free testosterone and  estradiol level was impaired and statistically associated 
with sexual dysfunction in the patients who were on methadone maintenance therapy.[13]   
However, in a recent study also showed that there were more than 50% of methadone 
maintennace therapy patients had sexual dysfunction ( 55% had erectile dysfunction and 


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65% had orgasm dysfunction), only 15% of them had hyperprolactinaemia.[14] Therefore, 
this hypothesis could not sorely explain the sexual dysfunction in this group of patients.  
 
The effects of the neurotransmitter dopamine on male sexual behavior have been 
discussed for centuries. The mesoaccumbens dopamine system has been implicated in the 
neural processes of  sexual motivation in many animal studies.[15] However, the first 
reconized dopamine-mediated enhancement of sexual behavior in human was when 
administration of l-dopa (3,4-dihydroxy-l-phenylalanine), the precursor to dopamine, to 
men suffering from Parkinson's disease resulted in increased libido and sexual potency. 
[16] In a recent imaging study showed that the methadone maintenance patients has 
reduced dopamine receptor 2 (D2) in the various part of the brain with the consequences 
of reduced  functioning of the dopaminergic system in brain.[17] There are studies also 
showed  methadone inhibit copulatory behaviour when given either acutely or chronically 
in animals and decrease socio-sexual interaction, apparently without interfering with 
locomotion.[18] Therefore, there are researchers proposed to use dopamine agonist such 
as bromocriptine or dopamine reuptake inhibitor such as bupuprion to treat sexual 
dysfunction in this group patients. There was an open-labelled, quasi-experimental study 
done by Tatari et al.  In 2013 [19], whereby 100mg of Bupropion was administered on 67 
methadone maintenance men who had erectile dysfunction for six weeks. In this study, 
Bupropion significantly improved the erectile function in this group of patients. However, 
the sample size of that study was small and with many methodological limitations. Hence, 
I aim to conduct a randomised controlled trial of Bupropion in the treatment of erectile 
dysfunction among men on methadone maintenance therapy 
 
1.1 
Investigational Agent 
Bupropion hydrochloride sustained-release (Trade name is Wellbutrin SR™), an 
antidepressant of the aminoketone class, is a inhibitor of the neuronal reuptake of 
norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Its structure 
closely resembles that of diethylpropion; it is related to phenylethylamines. It is 
designated as (±)-1-(3-chlorophenyl)-2-[(1,1- dimethylethyl)amino]-1-propanone 
hydrochloride. The molecular weight is 276.2. The molecular formula is 
C13H18ClNO•HCl.[20] 
Bupropion is extensively metabolized in humans. Three metabolites are active: 
hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of 
bupropion, and the amino-alcohol isomers, threohydrobupropion and 
erythrohydrobupropion, which are formed via reduction of the carbonyl group. The 
elimination half-life of metabolites are ranged from 20 hours to 37 hours. [20] 
1.2 
Overview of Non-Clinical Studies 
Carcinogenesis : Nodular proliferative lesions of the liver at doses of 100 to 300 
mg/kg/day (approximately 2 to 7 times the MRHD on a mg/m2 basis) was found in a rat 
study but not in the mouse study.  There were no increase in malignant tumors of the liver 
and other organs were seen in either study. Bupropion produced a positive response (2 to 
3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity assay. 


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Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone 
marrow cytogenetic studies.[20] 
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired 
fertility.[20] 
1.3 
Overview of Clinical Studies 
There was an open-labelled, quasi-experimental study done by Tatari et al.  In 2013 [19], 
whereby 100mg of Bupropion was administered on 67 methadone maintenance men who 
had erectile dysfunction for six weeks. In this study, Bupropion significantly improved the 
erectile function in this group of patients (IIEF score improved from 12.79±1.37 to 
15.94±2.14). However, the sample size of that study was small and with many 
methodological limitations.  
1.4 
Risk / Benefit Assessment 
1.4.1 
Dose Rationale 
In this study, the usual adult target dose for bupropion hydrochloride sustained-release is 
300 mg per day, given as 150 mg twice daily. Initiate dosing with 150 mg per day given 
as a single daily dose in the morning. After 3 days of dosing, the dose may be increased to 
the 300-mg-per-day target dose, given as 150 mg twice daily. This is based on a phase II, 
randomized, placebo controlled, adjunctive bupropion sustained-release (SR) on male 
sexual dysfunction (SD) induced by a selective serotonin reuptake inhibitor.  In this study, 
117 patients were randomly assigned to receive 12 weeks of bupropion SR 150 mg twice 
daily. 97.3% of the patients did not complain any adverse effects (AEs), the most 
commonly reported AEs were headache (8.5%), nasopharyngitis (6.8%), insomnia (6.0%) 
and dry mouth (6.0%).There were no severe AEs during the trial.[20] 
1.4.2 
Potential Risk 
The potential risks of this study include adverse reactions to bupropion hydrochloride 
sustained-release. Clinical condition of the subjects will be closely monitored by the study 
design 
1.4.3 
Potential Benefit 
Methadone induced sexual dysfunction that is experienced by the patients who are 
receiving study medication may be improved.Patients in the study will receive close 
psychiatric and medical attention. The potential benefits to the partners include 
improvement of the marital relationship with the patients 
1.4.4 
Risk Benefit Ratio 
The potential benefits of this study far outweigh the potential risks. Methadone induced 
sexual dysfunction in this group of patients by far does not have standard treatment. 
Literature reviews have shown that the lowering or stopping the methadone dosage 
increase the relapse risk in this group of patients. In contrast, bupropion as a adjunctive 
treatment was shown to have early positive effect on the treatment of erectile dysfunction 
in this group of patients. Patients accepted into the study will receive close medical and 


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psychiatric monitoring as well as treatment with methylphenidate that has a well-
documented safety profile. Patients will be screened prior to admission into the study. The 
subjects selected for participation will be monitored closely for adverse effects.  
 
2 
STUDY RATIONALE 
Sexual dysfunction is highly prevalent among methadone maintenance male patients. 
Previous studies found that sexual dysfunction decreased quality of patient’s sexual life 
[8] and damaged intimate relationships, while at the same time increased the risk of 
dropout from methadone maintenance therapy prematurely [9]. Although the sexual 
dysfunction is related to the methadone dose, some of the ex-opioid dependent patients 
relapsed after their methadone dosage became too low. Worse still, some of them used 
other illicit drugs, especially stimulants, to boost up their sex function [10]. Currently, 
there are no standard treatment to treat methadone induced sexual dysfunction. Therefore, 
we are using bupropion hydrochloride sustained-release to treat methadone induced sexual 
dysfunction. 
 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
3.1.1 To assess the clinical efficacy of bupropion hydrochloride sustained-release in the 
treatment of sexual dysfunction in men on methadone maintenance therapy. 
Hypothesis 
Bupropion hydrochloride sustained-release treated subjects will show significant 
improvement in Clinical Global Impression Scale adapted for Sexual Function 
(CGI-SF) then placebo treated subjects between baseline and week 6.   
 
3.2 
Secondary Objectives 
3.2.1 To assess the clinical efficacy of bupropion hydrochloride sustained-release in the 
treatment of erectile dysfunction in men on methadone maintenance therapy. 
Hypothesis 
Bupropion hydrochloride sustained-release treated subjects will show significant 
improvement in erectile function domain in International Index of Erectile 
Function (IIEF-15) and Arizona Sexual Experience Scale (ASEX)then placebo 
treated subjects between baseline and week 6. 


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3.2.2 To assess the clinical efficacy of bupropion hydrochloride sustained-release in the 
treatment of intercourse dissatisfaction in men on methadone maintenance therapy. 
Hypothesis 
Bupropion hydrochloride sustained-release treated subjects will show significant 
improvement in intercourse satisfaction domain in International Index of Erectile 
Function (IIEF-15) then placebo treated subjects between baseline and week 6. 
3.2.3 To assess the clinical efficacy of bupropion hydrochloride sustained-release in the 
treatment of orgasmic dysfunction in men on methadone maintenance therapy. 
Hypothesis 
Bupropion hydrochloride sustained-release treated subjects will show significant 
improvement in orgasmic function domain in International Index of Erectile 
Function (IIEF-15) then placebo treated subjects between baseline and week 6. 
3.2.4 To assess the clinical efficacy of bupropion hydrochloride sustained-release in the 
treatment of hypoactive sexual desire in men on methadone maintenance therapy. 
Hypothesis 
Bupropion hydrochloride sustained-release treated subjects will show significant 
improvement in sexual desire domain in International Index of Erectile Function 
(IIEF-15) then placebo treated subjects between baseline and week 6 
3.2.5 To assess the clinical efficacy of bupropion hydrochloride sustained-release in the 
treatment of overall dysfunction in men on methadone maintenance therapy. 
Hypothesis 
Bupropion hydrochloride sustained-release treated subjects will show significant 
improvement in overall satisfaction domain in International Index of Erectile 
Function (IIEF-15) then placebo treated subjects between baseline and week 6 
4 
STUDY DESIGN 
4.1 
Design 
This is a single center, phase II, randomized, double-blind, parallel-group, placebo-
controlled trial 
4.2 
Procedure 
 
All the male subjects who attended the methadone maintenance clinic will be approached. 
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all 


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inclusion criteria and none of the exclusion criteria will be entered into the study.  Sexual 
dysfunction will be measured by CGI-SF, IIEF-15 and ASEX, 
Seventy (70) of subjects will be randomized to one of two experimental treatments (35 
subjects per group): bupropion hydrochloride sustained or placebo. Bupropion 
hydrochloride sustained or placebo will be initiated after screening and continued for 42 
days of outpatient treatment. Efficacy will be take place at baseline, day 14(week 2), day 
28(week four) and day 42 (week 6).  
At the end of the 42 days, the continuation of treatment will be depends on the 
investigator’s clinical judgment and End of Medication Evaluation will be perform. Every 
effort will be made to continue to evaluate all subjects who are randomized even if they 
decide to discontinue the medication.  
4.3 
Project Timetable 
The project will take 2 years. The plan is to randomize 1 subject per week, taking about 18 
months to acquire 70 subjects. Follow-up evaluations will be completed 2 year from the 
start of the project.  
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
The primary endpoint to be measured in this study is: 
• CGI-SF at the baseline, day 14(week 2), day 28(week four) and day 42 (week 6). 
5.2 
Secondary Efficacy Endpoints 
• Erectile function (EF, questions 1–5 and 15) of IIEF-15   at the baseline, day 14(week 
2), day 28(week four) and day 42 (week 6). 
•  Intercourse satisfaction (questions 6–8) of IIEF-15   at the baseline, day 14(week 2), 
day 28(week four) and day 42 (week 6). 
• Orgasmic function (questions 9 and 10) of IIEF-15   at the baseline, day 14(week 2), 
day 28(week four) and day 42 (week 6). 
• Sexual desire (questions 11 and 12) of IIEF-15 at the baseline, day 14(week 2), day 
28(week four) and day 42 (week 6). 
• Overall satisfaction (questions 13 and 14) of IIEF-15 at the baseline, day 14(week 2), 
day 28(week four) and day 42 (week 6). 
• ASEX at the baseline, day 14(week 2), day 28(week four) and day 42 (week 6). 
5.3 
Safety Evaluations 
• The primary safety endpoint will be measurement and collection of any serious 
adverse event that occurs from initial study treatment through and including 28 days 
after cessation of study treatment. 


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6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with a diagnosis of opioid dependence base on Diagnostic and Statistical Manual 
of Mental Disorders, Fourth Edition (DSM-IV) criteria who meet the inclusion and 
exclusion criteria will be eligible for participation in this study.   
6.2 
Inclusion Criteria 
• Patients were eligible if they were aged 18–60 years 
• Had a diagnosis of opioid dependence base on Diagnostic and Statistical Manual of 
Mental Disorders, Fourth Edition (DSM-IV)  criteria   
• While taking a stable dose of methadone In UMMC (University Malaya Medica 
Centre)   and University Malaya centre of Addiction Science (UMCAS) outpatient 
clinic for ≥ 6 months 
• Were experiencing constant sexual dysfunction for ≥ 4 weeks 
• Were in a stable sexual relationship with a female partner for ≥ 6 months 
6.3 
Exclusion Criteria 
• 
Severe behavior disturbances or psychotic symptoms 
• 
Obvious organic illnesses caused the sexual dysfunction (such as diabetics or patients 
with heart and vascular disease) 
• 
Those with history of sexual dysfunction before methadone therapy 
• 
Receiving antiviral treatment for viral hepatitis or HIV, or androgen replacement               
treatment.  
• 
History of an eating disorder (eg, anorexia, bulimia) or seizures (eg, epilepsy) 
• 
Using other psychotropic medications other than methadone  
• 
Clinical significant abnormal laboratory values. 
• 
Clinically significant abnormal ECG. 
Documented history of other psychiatric diagnosis (schizophrenia, bipolar disorder, 
organic brain disorder, dementia etc.) 
• 
Refused to give participate.   
6.4 
Subject Recruitment and Screening 
Subjects are identified from the In UMMC (University Malaya Medica Centre)   and 
University Malaya centre of Addiction Science (UMCAS) outpatient clinic. Subjects will 
undergo an informed consent process in accordance with GCP (see section 11 Ethical 


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Considerations). To qualify for the study, subjects must meet all inclusion and none of the 
exclusion criteria as determined by pre-treatment battery measures. 
Laboratory and physical exam screening 
These include a complete medical history and physical exam; vital signs and weight; 
baseline ECG (12-lead); routine blood work (study laboratory tests) including renal 
function test, Liver function test, fasting lipid profile, fasting blood sugar,  total 
testosterone (TT), free testosterone (FT), estradiol (E2), luteinizing hormone (LH), and 
prolactin.), urinalysis (U/A) for opioid (non methadone), marijuana, methamphetamine 
and ecstasy. Study laboratory tests are specifically listed with normal cutoff values in 
Attachment.  
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria 
and scales measurement 
A M.I.N.I will be administered to rule out other psychiatric disorders. All medications 
taken by the patient for the 30 days prior to screening will be documented. They will 
complete the MADRS, Malay version , OTI, WHOQoL-Brief, Malay version and Mal-
GRIMS. 
The efficacy between the groups is assessed and compared using the measurement of 
CGI-SF, IIEF15 and the 5 domain, and ASEX 
Documentation of Screening 
Screening assessments will be performed to determine subject eligibility criteria, which 
will be documented on a case report form. The PI will confirm and sign off on the 
inclusion and exclusion criteria on a case report form (CRF) prior to the patient formally 
included in the study or given study medication. 
7 
EARLY WITHDRAWAL OF SUBJECTS 
7.1 
When and How to Withdraw Subjects 
Subjects will be withdrawn from the study in the following condition: 
• Report of clinical significant adverse events felt to be related to study drug 
• Failure of subject to adhere to protocol requirements 
• Subject withdraw consent or their authorization to use their protected health 
information 
• Subject is too ill to continue with the study procedure  
• Deemed by the principal investigator to be in their best interest 
Subjects discontinued from the clinical trial will be scheduled for a final evaluation. The 
investigator or sub-investigators will continue the care, consider alternative treatment or 
given appropriate treatment referrals for the subjects who withdraw from the study. 
 


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All subjects randomized into the study will be included in the final study analyses. 
Subjects are not dropped from all study activity unless they request not to be contacted or 
cannot be located for follow-up assessment. Subjects will be informed at the consent 
session that treatment may be discontinued due to:  
• Intolerable side effects; 
• Significantly abnormal laboratory values or  confirmed with a repeat testing;  
• Development or exacerbation of sexual dysfunction; 
• Clinical deterioration for any reason or any clinical status that necessitates IP 
admission;  
 
Reasons why subjects are discontinued from the clinical trial will be documented on the 
Study Termination Form, along with any referrals that are made. A final safety evaluation 
will be conducted as soon as possible on all randomized subjects who are discontinued. 
Every effort will be made to continue to collect data on every randomized subject for the 
entire study duration regardless of whether or not the subject continues to take study 
medication, assuming the subject has now withdrawn his/her authorization to obtain such 
information. 
7.2 
Data Collection and Follow-up for Withdrawn Subjects 
Even though subjects may be withdrawn prematurely from the study all adverse event data 
will continue to be collected through 14 days from cessation of study drug (with the 
subject’s permission). Subjects who have study drug discontinued for any reason, but are 
willing to complete study visits will have all assessments administered and collected. For 
the final measures, subjects will receive all assessments that were scheduled for the End of 
Study visit. 
 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Up to 70 eligible patients will be randomly assigned to Bupropion Hydrochloride 
Sustained-Release or placebo treatment groups in a 1:1 ratio using a computer-generated 
table of random numbers through the use of the Randomization.com program. Subjects 
will be randomized to to Bupropion Hydrochloride Sustained-Release 150mg b.d. (n = 35) 
or placebo b.d (n = 35) 
8.2 
Blinding 
Due to the objectives of the study, the identity of test and control treatments will not be 
known to investigators, research staff, or patients.  The following study procedures will be 
in place to ensure double-blind administration of study treatments.  Access to the 
randomization code will be strictly controlled. Besides, the packaging and labeling of test 


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and control treatments will be identical to maintain the blind. The study blind will be 
broken on completion of the clinical study and after the study database has been locked.  
During the study, the blind may be broken only in emergencies when knowledge of the 
patient’s treatment group is necessary for further patient management 
8.3 
Formulation of Test and Control Products 
8.3.1 Description 
Bupropion hydrochloride sustained-release (Wellbutrin SR™) tablets are biconvex purple 
film-coated with a white core. 
8.3.2 Treatment Regimen 
8.3.2.1 Route 
The drugs are taken orally 
8.3.2.2 Regime 
Bupropion hydrochloride sustained-release started at 150mg on morning (0800) from day 
1 to day 3. Dose increased to 150mg on morning (0800) and evening (1800) from day 4 
onwards. The dose can be reduced to 150mg/day if patients are not able to tolerate a 
higher dose. The treatment continues until day 42. 
8.4 
Preparation and Administration of Study Drug 
Study drug will be maintained and dispensed by the study coordinator. Tablets will be 
used as supplied, meaning that there is no further study drug preparation required. Study 
drug is administered orally. 
8.5 
Prior and Concomitant Therapy 
All prior and/or concomitant medical therapy will be documented 
Anxiolytic drugs (clonazepam, lorazepam, valium and alprazolam) and methadone are 
permitted for agitation, anxiousness or insomnia. 
All other medication which can improve the sexual function except the study drugs are not 
permitted during the study.  
8.6 
Packaging and Labeling 
The study drug will be repacked in the standard capsules by the research assistant who is 
not involved in the assessment of the study. The study drug and placebo will be packaged 
in sets of 11 (1 tablet per day for 3 days, followed by 2 tablets per day for 4 days.) for the 
first week. Subsequently, the study drug and placebo will be packaged in sets of 14 (2 
tablets per day for 7 days.). Each packet (kit) of study drug will be labeled with the 
required FDA warning statement, the protocol number, a treatment number, and directions 
for patient use and storage.   


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8.7 
Receiving, Storage, Dispensing and Return 
8.7.1 Receipt of Drug Supplies 
Upon receipt of the of the study drugs, an inventory will be performed and a drug receipt 
log filled out and signed by the person accepting the shipment. The designated staff will 
count and verify that the shipment contains all the items noted in the shipment inventory. 
Any damaged or unusable study drug in a given shipment (study drug or comparator) will 
be documented in the study files. The investigator will notify the Company of any 
damaged or unusable study treatments that were supplied to the investigator’s site. 
8.7.2 Storage 
Stock study drug and drug packaged in patient kits within the research centre and study 
drug that has been dispensed to the Investigator, will be stored in a locked cabinets with 
climate control maintaining the temperatures within a range of 20°-25° C. Access to study 
drug within the research centre will be controlled by the staff, and access to study drug 
dispensed to the Investigator will be controlled by the Investigator and the Investigator’s 
study staff. 
8.7.3  Dispensing of Study Drug 
All study drugs will be dispensed by investigator or their designated study staff.  
8.7.4 Return or Destruction of Study Drug 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the subject will be recorded on the 
Investigational Drug Accountability Record.  The study monitor will verify these 
documents throughout the course of the study. . Any discrepancies noted will be 
investigated, resolved, and documented prior to destruction of unused study drug. After 
appropriate accounting, unused study drug will be destroyed on site with the date of this 
action documented in the study files. 
8.8 
Measures of Treatment Compliance 
Subjects will be asked to keep a patient diary noting the day and date they take their study 
drug and any adverse events. They will be asked to bring their patient diary to each study 
visit along with all used and unused study drug containers. The research coordinator will 
conduct pill counts at each visit of all study subjects. Unused amounts will be 
documented. Proper drug dosing will be reviewed with subjects at each visit with clear 
instructions to take all study drugs as directed. 
 
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 


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Prior to conducting any study-related activities, written informed consent must be signed 
and dated by the subject 
9.1 
Clinical Assessments 
9.1.1 Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening and at Study Days and at early termination when applicable. Dose, 
route, unit frequency of administration, and indication for administration and dates of 
medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Screening. 
9.1.4 Physical Examination 
A complete physical examination will be performed by the investigator at Screening.   
Vital Signs, Body temperature, blood pressure, pulse and respirations will be performed 
after resting for 5 minutes at Baseline/Screening and at Study Days. 
9.1.5 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity, outcome, treatment and relation to study drug 
will be recorded on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements 
9.2.1 Blood investigation 
Approximately 20 ml (4 teaspoons) of blood will be collected at visit 0 (baseline) for a 
complete blood count (hemoglobin, white blood cell count, white blood cell differential, 
and platelet count), blood count, serum sodium, potassium, chloride, bicarbonate, 
creatinine,  fasting glucose, aspartate aminotransferase (AST/SGOT), alanine 
aminotransferase (ALT/SGPT), total testosterone (TT), free testosterone (FT), estradiol 
(E2), luteinizing hormone (LH), prolactin, Hepatitis B, C and HIV. Approximately 5ml(1 
teaspoon) of blood will be collected during visit 3 and 6 for liver function test: aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT).  
9.2.2 Urinalysis 
Urine will be obtained and tested for amphetamine, methamphetamine, marijuana and 
opioid in their urine by using F.A.C.T.S combo drug testing. The F.A.C.T.S combo drug 
testing is a competitive immunoassay utilizing highly specific reactions between 
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specimens. During the testing, the urine specimen migrates upward by capillary action. If 
a drug is present in the urine specimen above the cut-off concentration, it will saturate all 
the binding sites of the antibody, and the colored line will not form in the test line region. 
To serve as a procedural control, a colored line will appear at the control line region. 
Hence, positive test will only have one line and negative test will have two lines on the 
test strip. 
 
10  EVALUATIONS BY VISIT (REFER APPENDIX 1.) 
10.1 Visit 0(Screening visit and Randomization) 
Review the study with the subject and obtain written informed consent. Those who are 
willing to participate and consented will be screened for eligibility. A complete physical 
examination will be performed and blood will be collected for clinical laboratory tests. 
Urine will be collected for testing amphetamine, methamphetamine, marijuana and opioid. 
A Mini International Neuropsychiatric Inventory (MINI) will be administered to obtain 
DSM-IV diagnoses of opioid dependence and rule out other psychiatric disorders. 
MADRS, Malay version, OTI, WHOQoL-Brief, Malay version, Mal-GRIMS, CGI-SF, 
IIEF15, and ASEX will be completed. Eligible subjects will be scheduled for Visit 1 in 7 
days. 
10.2 Visit 1 (week 1) 
Eligible subjects will be randomized and started either the study drug or placebo. 
Concomitant medications will be reviewed; abbreviated physical examination will be 
performed, vital signs will be recorded, Urinalysis for illicit drug and electrocardiography 
will be recorded. Eligible subjects will be scheduled for Visit 2 in 7 days. 
10.3 Visit 2 (week 2)  
Any Adverse Experiences will be recorded. Subject diary for adverse experiences and 
dosing compliance will be reviewed. Concomitant medications will be reviewed; 
abbreviated physical examination will be performed, vital signs will be recorded, CGI-SF, 
IIEF15, and ASEX will be completed. Eligible subjects will be scheduled for Visit 3in 7 
days. 
10.4 Visit 3 (week 3)  
Any Adverse Experiences will be recorded. Subject diary for adverse experiences and 
dosing compliance will be reviewed. Concomitant medications will be reviewed; 
abbreviated physical examination will be performed, vital signs will be recorded, 
Urinalysis for illicit drug and electrocardiography will be recorded. Approximately 5ml(1 
teaspoon) of blood will be collected for liver function test: AST(GOT) and ALT(GPT). 
CGI-SF, IIEF15, and ASEX will be completed. Eligible subjects will be scheduled for 
Visit 4 in 7 days. 


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10.5 Visit 4 (week 4) 
Any Adverse Experiences will be recorded. Subject diary for adverse experiences and 
dosing compliance will be reviewed. Concomitant medications will be reviewed; 
abbreviated physical examination will be performed, vital signs will be recorded, CGI-SF, 
IIEF15, and ASEX will be completed. Eligible subjects will be scheduled for Visit 6 in 7 
days. 
10.6 Visit 5 (week 5) 
Any Adverse Experiences will be recorded. Subject diary for adverse experiences and 
dosing compliance will be reviewed. Concomitant medications will be reviewed; 
abbreviated physical examination will be performed, vital signs will be recorded, CGI-SF, 
IIEF15, and ASEX will be completed. Eligible subjects will be scheduled for Visit 6 in 7 
days. 
10.7 Visit 6 (week 6) (end of study drug) 
Any Adverse Experiences will be recorded. Subject diary for adverse experiences and 
dosing compliance will be reviewed. Concomitant medications will be reviewed; 
abbreviated physical examination will be performed, vital signs will be recorded, 
Urinalysis for illicit drug and electrocardiography will be recorded. Approximately 5ml(1 
teaspoon) of blood will be collected for liver function test: AST(GOT) and ALT(GPT). 
CGI-SF, IIEF15, and ASEX will be completed. CGI-SF, IIEF15, and ASEX will be 
completed.  
10.8 Early Withdrawal Visit 
Any Adverse Experiences will be recorded. Subject diary for adverse experiences and 
dosing compliance will be reviewed. Concomitant medications will be reviewed; 
abbreviated physical examination will be performed, vital signs will be recorded, 
Urinalysis for illicit drug and electrocardiography will be recorded. 
11 STATISTICAL PLAN 
11.1 Sample Size Determination 
For the hypothesis testing of this study, the significance level was set at 5%. The 
hypothesis involves comparison of 2 groups on the mean of a continuous outcome. Each 
group of 35 provides 90% power to detect an effect size of 0.5. 
11.2 Statistical Methods 
Data Screening and Cleaning: Principal investigator will perform the data analyses. Prior 
to performing analyses, standard data screening/cleaning procedures will be applied. 
These procedures will screen the data for data-entry errors, check for outliers, assess the 
extent and pattern of missing data, and check that appropriate assumptions of Normality 
are met whenever necessary. Because of the size of the sample, it is unlikely that the 
randomization will result in significant imbalance of the distributions of demographic or 
other variables across the treatment groups. However, the randomization will be checked 
by comparing the groups on relevant background variables. The comparisons will use 


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analyses of variance for continuous variables and log-linear models for discrete or ordinal 
responses. Variables on which the groups show significant differences may be included as 
covariates in later analyses.  
Linear Mixed Model: The analyses described below will involve the use of linear mixed 
model. These models extend the traditional repeated-measures framework in several ways. 
The main advantage is that it allows flexible regression modeling of patterns over time. It 
deals easily with measurements at irregular time points and automatically deals with 
missing data. It also allows a variety of structures for residual variations and correlations. 
In the present setting, the main explanatory variables will be medication group and time. 
Additional terms and random effects are included for each individual to model the 
correlation between observations on the same individual. In terms of missing data, they 
require that the data be missing at random, which is often reasonable. This means that the 
linear mixed model effectively assume that the missing data are similar to the observed 
data that do not drop out. In all analyses, the assumptions underlying the application of all 
the statistical methods that are used will be examined, principally through the use of 
standardized residuals, influence diagnostics, and graphical displays. 
Analyses of the Primary and Secondary Endpoints: The effect of Bupropion 
Hydrochloride Sustained-Release in improving the sexual dysfunction in the subjects is 
measured with CGI-SF at baseline, week 2, 4 and 6. The secondary outcomes are 
measured with IIEF15, its 5 domains and ASEX at baseline, week 2, 4 and 6. These 
repeated measurements will be analyzed using linear mixed-effects model. While these 
analyses are exploratory, they will provide useful information on differences in trends of 
reduction of depression and other outcomes between the Bupropion Hydrochloride 
Sustained-Release and placebo groups. 
11.3 Subject Population(s) for Analysis 
Efficacy analysis will be performed on ITT basis. Any subject randomized into the study, 
regardless of whether they received study drug will be included into the analyses. 
 
11.4 Data Management 
A computerized data entry and management system will be developed during the initial 
project months that will enter all study data. All data will be entered using data entry 
programs.  
 
12 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
12.1 Adverse Events 
Definitions: Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  


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• 
Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the protocol or consent form and the patient information sheets) 
• 
Related or possibly related to participation in the research (i.e. possibly related 
means there is a reasonable possibility that the incident experience, or outcome may have 
been caused by the procedures involved in the research) 
• 
Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries should 
be regarded as adverse events.  Abnormal results of diagnostic procedures are considered 
to be adverse events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
AE Severity 
Table 1: below should be used to grade severity.  It should be pointed out that the term 
“severe” is a measure of intensity and that a severe AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may be 
aware of the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 


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Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by stopping 
or reducing the dosage of the drug; and that is not explained by any other 
reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to the suspected 
drug; that is confirmed by stopping or reducing the dosage of the drug; and 
that is unlikely to be explained by the known characteristics of the subject’s 
clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to that suspected 
drug; but that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
study drug. 
12.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed. Important medical events are those that may not be 
immediately life threatening, but are clearly of major clinical significance.   They may 
jeopardize the subject, and may require intervention to prevent one of the other serious 
outcomes noted above.   
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the 
period from the initiation of any study procedures to the end of the study treatment follow-
up.  For this study, the study treatment follow-up is defined as 14 days following the last 
administration of study treatment.  


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Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as an 
adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At 
the last scheduled visit, the investigator should instruct each subject to report any 
subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study.  The investigator should notify the 
ethical committee of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this study.   
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of 
the following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further 
diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be documented 
as an adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or diagnostic 
and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 


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• Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events 
by specific questioning and, as appropriate, by examination.  Information on all adverse 
events should be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related signs, 
symptoms, and abnormal diagnostic procedures results should recorded in the source 
document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up to 
determine the final outcome.  Any serious adverse event that occurs after the study period 
and is considered to be possibly related to the study treatment or study participation 
should be recorded and reported immediately. 
Reporting of Serious Adverse Events and Unanticipated Problems 
The investigator and sub-investigators report all types of unanticipated problems, adverse 
events and serious adverse events to the ethical committee within 24 hours of the event. A 
Serious Adverse Event (SAE) form must be completed by the investigator and send to the 
EC within 24 hours. The investigator will keep a copy of this SAE form on file at the 
study site. 
 
Investigators must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum those 
events that must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 12.1).   
If the report is supplied as a narrative, the minimum necessary information to be provided 
at the time of the initial report includes: 
• Protocol number 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was discontinued 
• The reason why the event is classified as 
serious 
• Investigator assessment of the association 
between the event and study treatment 
 
Within the following 48 hours, the investigator must provide further information on the 
serious adverse event in the form of a written narrative. This should include a copy of the 
completed Serious Adverse Event form, and any other diagnostic information that will 


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assist the understanding of the event. Significant new information on ongoing serious 
adverse events should be provided promptly to the MEC, UMMC. 
Unblinding Procedures 
While the safety of the subject always comes first, it is important to consider if unblinding 
the study therapy is necessary to ensure a subject’s safety. If the SAE is confirmed due to 
the study therapy, the timeline of reporting is within 24 hours, however, in cases where 
unblinding was not associated with an SAE, the timeline of reporting is within 1 week. 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site. This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above, as well as the construction and 
implementation of a site data and safety-monitoring plan (see Section 10 Auditing, 
Monitoring and Inspecting). Medical monitoring will include a regular assessment of the 
number and type of serious adverse events. 
Protection of Subjects 
Complementing the safety measures noted above, additional procedures will be followed 
to protect the safety of the research subjects. Potential Subjects will be screened for 
medical illnesses that would preclude the use of methylphenidate. Specifically, these 
include known allergies to this agent. Subjects selected for the study will be evaluated 
daily while receiving study drug treatments. AEs will be monitored daily and a study 
physician will be available at all times to evaluate and treat adverse effects of the 
medication. On a daily basis, vital signs will be obtained. Significant AEs will result in 
exclusion from the study (see Clinical Trial Discontinuation Criteria). Subjects will be 
given a 24-hour emergency number they can call if necessary. The investigator or sub-
investigators will clinically follow all subjects who are discontinued due to serious AEs 
until the AE resolves and becomes completely stable, unless a referral to another 
physician (i.e. specialist) is clinically indicated or requested by the subject.  
   
13 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
13.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation:  
• 
Subject withdrawal of consent (or assent) 
• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best interest  
of the subject to discontinue study treatment 
• 
Protocol violation requiring discontinuation of study treatment 


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• 
Lost to follow-up 
• 
Sponsor request for early termination of study 
 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
13.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  As noted above, subjects who discontinue study 
treatment early, should have an early discontinuation visit. Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced.   
 
14 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
• 
Failure to meet inclusion/exclusion criteria 
• 
Use of a prohibited concomitant medication 
• 
non-compliance with study drug regimen 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation.  
 


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15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Authorities 
15.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents 
and data records include: hospital records, clinical and office charts, laboratory notes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, X-rays, subject files, and records kept at the pharmacy and at the laboratories 
involved in the clinical trial. 
15.3 Data Quality Control and Reporting 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  If a 
space on the CRF is left blank because the procedure was not done or the question was not 
asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All 
entries should be printed legibly in black ink.  If any entry error has been made, to correct 
such an error, draw a single straight line through the incorrect entry and enter the correct 
data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the 
clarification above the item, then initial and date it. 
15.4 Records Retention 
These medical notes and documents will be retained in the UMMC Medical Record 
Department.  
All study documents (patient files, signed informed consent forms, copies of CRFs, Study. 
16 STUDY MONITORING, AUDITING, AND INSPECTING 
16.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan in Attachment ___. The 
investigator will allocate adequate time for such monitoring activities. The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is 
given access to all the above noted study-related documents and study related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the 
monitoring visit. 
16.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the 
EC/IRB, government regulatory bodies, and University compliance and quality assurance 


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groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality 
assurance offices. 
17 ETHICAL CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Good Clinical 
Practice (International Conference on Harmonization guidelines), MEC, UMMC, NMRR 
research policies and procedures  
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet 
17.1 Informed Consent Form  
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study. See Attachment ___ for a copy of the Subject Informed 
Consent Form. This consent form will be submitted with the protocol for review and 
approval by the IRB/EC for the study. The formal consent of a subject, using the IRB/ED-
approved consent form, must be obtained before that subject is submitted to any study 
procedure. This consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent.  
The investigator or sub-investigators will obtain informed consent before any study 
procedures occur, explaining all procedures in detail in an individual session. The consent 
form and explanation will include; detailed information about methylphenidate, the 
rationale for why it is being studied, frequency of dosing, and length of treatment, 
potential side effects and risks, safeguards and emergency procedures. Information will 
also be provided about the psychosocial treatment, including the frequency and length of 
visits. The number and frequency of the research interviews and self-assessments will be 
described in details. Subjects will be assured that their participation is voluntary and that 
withdrawal from the study would not jeopardize current or future treatment. All subjects 
will be informed of potential risks and benefits involved in the study, including side 
effects of methylphenidate. Randomization will be explained to the subjects. 
18 STUDY FINANCES 
18.1 Funding Source 
Will apply for university grant 


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18.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by MEC, UMMC. 
19 PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided for the purposes of performing the study, 
will be published or passed on to any third party without the consent of the principle 
investigator. The principal Investigator will be responsible for publishing the primary 
results of this study. All subsequent publications will be at the discretion of the Principal 
Investigator 
 


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(1) At baseline: Montgomery-Åsberg Depression Rating Scale (MADRS, Malay version ), 
Mini International Neuropsychiatric Interview (M.I.N.I), Opiate Treatment Index (OTI) 
and World health organization Quality of Life-Brief Scale (WHOQoL-Brief, Malay 
version, Malay Version of the Golombok-Rust Inventory of Marital State (Mal-GRIMS), 
International Index of Erectile Function (IIEF), Clinical Global Impression Scale adapted 
for Sexual Function (CGI-SF), Arizona Sexual Experience Scale (ASEX). Then, IIEF, 
CGI-SF, ASEX at week 2, 4, and 6. 
(2) Blood test: Approximately 20 ml (4 teaspoons) of blood will be collected at visit 0 
(baseline) for Full blood count, Renal function test, Liver function test, Fasting blood 
sugar, total testosterone (TT), free testosterone (FT), estradiol (E2), luteinizing hormone 
(LH), and prolactin. Hepatitis B, C and HIV. Approximately 5ml(1 teaspoon) of blood 
will be collected during visit 3 and 6 for liver function test: AST(GOT) and ALT(GPT). 
(3) Urinalysis for illicit drug 
 
Screening  
test 
During treatment with the study drug 
 
Time 
baseline 
1 
week 
2 
week 
3 
week 
4 
week 
5 
week  
6 
week  
At 
withdrawal 
Visit 
Visit 0 
Visit1 Visit2 Visit3 Visit4 Visit5 Visit6  
Informed consent 
√ 
 
 
 
 
 
 
 
Prescription of study 
drug 
 
√ 
√ 
√ 
√ 
√ 
√ 
 
Treatment 
compliance 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Interview for 
assessment of sexual 
dysfunction(1) 
√ 
 
√ 
 
√ 
 
√ 
√ 
New symptoms that 
occur during 
treatment with the 
study drug 
 
√ 
√ 
√ 
√ 
√ 
√ 
√(until  14 
days) 
Body weight 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Blood 
pressure/pulse rate/ 
body temperature 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Blood test (2) 
20ml 
 
 
5ml 
 
 
5ml 
 
Urinalysis(3) 
√ 
√ 
 
√ 
 
 
√ 
 
Electrocardiography 
√ 
√ 
 
√ 
 
 
√ 
 


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20 REFERENCES: 
1. 
Laumann, E.O., A. Paik, and R.C. Rosen, Sexual dysfunction in the United States. 
JAMA: the journal of the American Medical Association, 1999. 281(6): p. 537-544. 
2. 
Macdonald, S., et al., Nithsdale Schizophrenia Surveys 24: sexual dysfunction 
Case—control study. The British Journal of Psychiatry, 2003. 182(1): p. 50-56. 
3. 
Rosen, R.C., Prevalence and risk factors of sexual dysfunction in men and women. 
Curr Psychiatry Rep, 2000. 2(3): p. 189-95. 
4. 
Grube, M. and H. Weigand-Tomiuk, Sexual dysfunctions in a group of psychiatric 
in-patients]. Psychiatrische Praxis, 2002. 29(4): p. 194. 
5. 
Oksuz, E. and S. Malhan, The prevalence of male sexual dysfunction and potential 
risk factors in Turkish men: a Web-based survey. International journal of impotence 
research, 2005. 17(6): p. 539-545. 
6. 
Mattick, R.P., et al., Methadone maintenance therapy versus no opioid replacement 
therapy for opioid dependence. Cochrane Database Syst Rev, 2009. 3. 
7. 
Yee, A., H.S. Loh, and C.G. Ng, The Prevalence of Sexual Dysfunction among 
Male Patients on Methadone and Buprenorphine Treatments: A Meta‐Analysis 
Study. The Journal of Sexual Medicine, 2014. 11(1): p. 22-32. 
8. 
Brown, R., et al., Methadone maintenance and male sexual dysfunction. Journal of 
addictive diseases, 2005. 24(2): p. 91-106. 
9. 
Hallinan, R., et al., Erectile dysfunction in men receiving methadone and 
buprenorphine maintenance treatment. The Journal of Sexual Medicine, 2008. 5(3): 
p. 684-692. 
10. 
La Pera, G., et al., Sexual dysfunction prior to first drug use among former drug 
addicts and its possible causal meaning on drug addiction: preliminary results. The 
journal of sexual medicine, 2008. 5(1): p. 164. 
11. 
Maremmani, I., The Principle and Practice of Methadone Treatment. 2010: 
Europad. 
12. 
Balon, R. and R.T. Segraves, Handbook of sexual dysfunction. 2005: CRC Press. 
13. 
Yee, A., et al., Clinical factors associated with sexual dysfunction among men in 
methadone maintenance treatment and buprenorphine maintenance treatment: a 
meta-analysis study. International journal of impotence research, 2014. 
14. 
Trajanovska¹, A.S., et al., Sexual dysfunction as a side effect of hyperprolactinemia 
in methadone maintenance therapy. Med Arh, 2013. 67(1): p. 48-50. 
15. 
Van Ree, J.M., et al., Endogenous opioids and reward. European journal of 
pharmacology, 2000. 405(1): p. 89-101. 
16. 
Dominguez, J.M. and E.M. Hull, Dopamine, the medial preoptic area, and male 
sexual behavior. Physiology & behavior, 2005. 86(3): p. 356-368. 
17. 
Gradin, V.B., et al., Abnormal Brain Activity During a Reward and Loss Task in 
Opiate-Dependent Patients Receiving Methadone Maintenance Therapy. 
Neuropsychopharmacology, 2013. 


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18. 
Argiolas, A. and M.R. Melis, Neuropeptides and central control of sexual 
behaviour from the past to the present: A review. Progress in neurobiology, 2013. 
108: p. 80-107. 
19. 
Tatari, F., et al., Bupropion in Methadone Induced Erectile Dysfunction. Life 
Science Journal, 2013. 10(9s). 
20. 
https://www.gsksource.com/gskprm/htdocs/documents/WELLBUTRIN-SR-PI-
MG.PDF. 
21  ATTACHMENTS 
 
• Sample Consent Form 
• Study Procedures Flowchart/Table 
• Patient information sheets 
• Medical Monitoring Plan 
• Descriptions of measuring scales 
• Laboratory tests normal cutoff values