Conditions: Cocaine Use Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 55
Healthy volunteers: no

Brief summary:
NS2359 attenuates the euphoria associated with cocaine use. In a manner parallel to cocaine, NS2359 blocks the reuptake of dopamine (DA), norepinephrine (NE), and serotonin (5HT) with nanomolar affinities at the 3 transporters. In primates NS2359 significantly attenuated cocaine self-administration. In several phase II clinical trials for major depressive disorder and adult attention deficit disorder, NS2359 did not cause euphoria. NS2359 exhibited no abuse potential in a human laboratory study comparing NS2359 with amphetamine. In a phase I human laboratory interaction study, NS2359 showed no toxicity after 20 or 40 mg of cocaine, but it attenuated the both the rewarding and cardiovascular effects of intravenous cocaine. On the basis of these promising studies, investigators propose a Phase II double-blind clinical trial of NS2359 in cocaine addiction (CA). The proposed trial will involve 100 CA subjects participating in an eight week trial, including a 1-week baseline and 8 weeks of NS2359 or placebo treatment. Four weeks after completing the medication phase, there will be one follow-up visit. Subjects will be randomly assigned to treatment with placebo or 2 mg NS2359 daily, with a possible decrease to 1 mg daily for adverse events. This dose range is selected on the basis of phase I and II evidence of tolerability and NS2359 plasma levels which were associated with blockade of cocaine reward. This project has the potential to identify the first effective pharmacotherapy for CA.

Detailed description:
In this phase II randomized double-blind, placebo-controlled trial, 40 persons will be randomized to NS2359 and 40 to placebo. The primary hypothesis is: more NS2359-treated subjects (compared to placebo-treated subjects) will achieve 3 consecutive weeks of cocaine abstinence, as measured by urine benzoylecgonine (BE) assay, during the last three weeks of the trial. The study is 9 weeks: one week of screening, followed by an 8-week double-blind, placebo-controlled trial. All subjects will receive weekly cognitive behavioral therapy (CBT) to encourage abstinence during their 3 times weekly clinic visits. Investigators expect \~ 20% dropout rate, based on our recent CA clinical trials (eg, Kampman et al, 2015 and 2013), so 80 randomized patients will yield \~ 64 study completers. There will be a 1 month start-up period, followed by 20 months of recruitment for the study. The 1 month start-up period will allow for training of staff, preparation of study capsules, placement of study advertisements, etc. Penn IRB approval has been obtained. There will be a 2-month termination period to allow the final patients to complete the study. Data cleaning, statistical analyses and preparation of reports will be done in the final two months. Based on recent cocaine pharmacotherapy trials conducted by our team, monthly enrollment of \~4 CA participants (respondents to flyers and advertisements) is feasible.

Recruitment will occur at the University of Pennsylvania's Treatment Research Center (TRC), led by Kyle Kampman, MD, and Wade Berrettini, MD, PhD, Professors of Psychiatry at Penn. At the TRC, CA patients are respondents to advertisements for free treatment of CA. The ethnicity is 90% African-American, 9 % European-American, 70% male, mean age 47 (+/- 12).

Arms:
arm 1: The initial dose of the NS2359 will be two mg once daily. Patients with difficult adverse events at the 2 mg dose will be allowed to reduce to 1 mg once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9. arm 2: Placebo pills matched to NS2359 pills will be given once daily. Patients with difficult adverse events at the 2 mg placebo will be allowed to reduce to 1 mg placebo once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9.

Interventions: intervention 1: NS2359 intervention 2: placebo
Intervention descriptions: intervention 1: NS2359 is a small molecule which inhibits the reuptake of dopamine, norepinephrine and serotonin with equal affinity. intervention 2: Placebo pills identical in appearance to the NS2359 will be provided

Protocol document:
Prot_SAP_000.pdf: 
 
 
 University of Pennsylvania 
 
 
 
A PHASE II, DOUBLE-BLIND, PLACEBO-CONTROLLED, TRIAL OF NS2359 FOR THE 
TREATMENT OF COCAINE DEPENDENCE 
 
Regulatory Sponsor: 
Kyle M. Kampman M.D. / Wade Berrettini M.D.  
Department of Psychiatry 
University of Pennsylvania Treatment Research Center 
3900 Chestnut Street 
Philadelphia, PA 19104 
215 222 3200 x 109 
 
Funding Sponsor: 
The DANA Foundation 
505 Fifth Avenue 6th Floor 
New York, New York 1007 
212 223 4040 
Study Product: 
NS2359 
Protocol Number: 
1.6 
IND Number: 
116053 
 
 
 
 
 
Date: 
7/2/2019 
Amended: 
 
Administrative 
Change: 
 
CONFIDENTIAL This document is confidential and the property of the University of 
Pennsylvania.  No part of it may be transmitted, reproduced, published, or used by other 
persons without prior written authorization from the study sponsor. 


 
 
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CONFIDENTIAL 
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Table of Contents 
STUDY SUMMARY ........................................................................................................................ 1 
1 
INTRODUCTION .................................................................................................................... 2 
1.1 
BACKGROUND ................................................................................................................... 2 
1.2 
INVESTIGATIONAL AGENT .................................................................................................. 4 
1.3 
DOSE RATIONALE AND RISK/BENEFITS………………………………………………………..7 
2 
STUDY OBJECTIVES ............................................................................................................ 8 
3 
STUDY DESIGN ................................................................................................................... 10 
3.1 
GENERAL DESIGN ........................................................................................................... 10 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................... 10 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................... 11 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................... 11 
4 
SUBJECT SELECTION AND WITHDRAWAL ......... ERROR! BOOKMARK NOT DEFINED. 
4.1 
INCLUSION CRITERIA ....................................................................................................... 12 
4.2 
EXCLUSION CRITERIA ................................................... ERROR! BOOKMARK NOT DEFINED. 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................ 13 
4.4.1 When and How to Withdraw Subjects ...................................................................... 13 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects ........................................... 13 
5 
STUDY DRUG ...................................................................................................................... 14 
5.1 
DESCRIPTION.................................................................................................................. 14 
5.2 
TREATMENT REGIMEN .................................................................................................... 14 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................ 14 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG .................................................... 15 
5.5 
SUBJECT COMPLIANCE MONITORING .............................................................................. 15 
5.6 
PRIOR AND CONCOMITANT THERAPY .............................................................................. 15 
5.7 
PACKAGING .................................................................................................................... 15 
5.8 
BLINDING OF STUDY DRUG ............................................................................................. 15 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ........................................................... 16 
5.9.1 Receipt of Drug Supplies .......................................................................................... 16 
5.9.2 Storage ...................................................................................................................... 16 
5.9.3 Dispensing of Study Drug ......................................................................................... 16 
5.9.4 Return or Destruction of Study Drug ........................................................................ 16 
6 
STUDY PROCEDURES ....................................................................................................... 17 
7 
STATISTICAL PLAN ............................................................................................................ 19 
7.1 
SAMPLE SIZE DETERMINATION ........................................................................................ 19 
7.2 
STATISTICAL METHODS ................................................................................................... 20 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ........................................................................ 22 
8 
SAFETY AND ADVERSE EVENTS ..................................................................................... 22 
8.1 
DEFINITIONS ................................................................................................................... 22 
8.2 
RECORDING OF ADVERSE EVENTS .................................................................................. 24 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS.................................................................... 24 
8.3.1 Study Sponsor Notification by Investigator .............................................................. 24 
8.3.2 EC/IRB Notification by Investigator .......................................................................... 25 
8.3.3 FDA Notification by Sponsor .................................................................................... 25 


 
 
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8.4 
UNBLINDING PROCEDURES ............................................................................................. 25 
8.5 
STOPPING RULES ........................................................................................................... 26 
8.6 
MEDICAL MONITORING .................................................................................................... 27 
8.6.1 Internal Data and Safety Monitoring Board .............................................................. 27 
8.6.2 Independent Data and Safety Monitoring Board ...................................................... 31 
9 
DATA HANDLING AND RECORD KEEPING ..................................................................... 31 
9.1 
CONFIDENTIALITY ........................................................................................................... 31 
9.2 
SOURCE DOCUMENTS ..................................................................................................... 31 
9.3 
CASE REPORT FORMS .................................................................................................... 32 
9.4 
RECORDS RETENTION .................................................................................................... 32 
10 STUDY MONITORING, AUDITING, AND INSPECTING .................................................... 32 
10.1 
STUDY MONITORING PLAN .............................................................................................. 32 
10.2 
AUDITING AND INSPECTING ............................................................................................. 32 
11 ETHICAL CONSIDERATIONS ............................................................................................ 33 
12 STUDY FINANCES .............................................................................................................. 33 
12.1 
FUNDING SOURCE .......................................................................................................... 33 
12.2 
CONFLICT OF INTEREST .................................................................................................. 33 
12.3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................. 33 
13 PUBLICATION PLAN .......................................................................................................... 34 
14 REFERENCES ..................................................................................................................... 34 
 


page 1 
 
 
Study Summary 
Title 
A Phase II, Double-Blind, Placebo-Controlled, Trial of NS2359 For The 
Treatment of Cocaine Use Disorder 
Short Title 
NS2359 for cocaine dependence 
Protocol Number 
NS2359 1.3   
Phase 
Phase 2 
Methodology 
Double-blind placebo-controlled parallel group clinical trial. 
Study Duration 
24 months 
Study Center(s) 
University of Pennsylvania 
Objectives 
Exploratory trial examining the efficacy and tolerability of NS2359 for 
the treatment of patients with cocaine use disorder 
Number of Subjects 
80 subjects 
Diagnosis and Main 
Inclusion Criteria 
Cocaine use disorder.  Men and women over 18 years of age. Subjects 
must have current DSM V diagnosis of cocaine use disorder. Subjects 
must be in good health and psychiatrically stable.  They must have no 
other substance use disorder except tobacco use disorder or cannabis 
use disorder. Comorbid alcohol use disorder will be accepted if alcohol 
use disorder is not severe enough to require a medical alcohol 
detoxification. 
Study Product, 
Dose, Route, 
Regimen 
NS2359 2 mg daily 
Duration of 
administration 
8 weeks of medication 
Reference therapy 
Placebo 
Statistical 
Methodology 
Cocaine use will be measured using three-times-weekly qualitative 
urine benzoylecgonine (BE) levels.  More NS2359-treated subjects 
(compared to placebo-treated subjects) will achieve 3 consecutive 
weeks of cocaine abstinence during the last three weeks of the 
medication trial, as measured by the Timeline Follow-Back method and 
qualitative urine benzoylecgonine (BE) levels  
 


 
 
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Structure of NS2359
1 
 Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 
and International Conference on Harmonization guidelines), applicable government regulations 
and Institutional research policies and procedures.  
1.1 Background 
The 2008 National Household Survey on Drug Abuse (SAMHSA) reported that 1.9 million 
Americans were regular cocaine users, making cocaine one of the most commonly abused illicit 
drugs in the US, with ~250,000 individuals in treatment at any one time (SAMSHA, 2008).  5-6% 
of recent cocaine users will develop cocaine dependence (CD) (O'Brien and Anthony, 2005). 
There is no FDA approved pharmacotherapy for CD.  CD standard treatment consists of 
individual and group psychotherapy and self-help groups, which do not provide substantial 
benefit for many patients (Kampman et al, 2001; Alterman et al, 1996; Caroll et al, 2004).  
Dropout rates in outpatient treatment programs are very high (Kampman et al, 2002). Among 
patients who complete treatment, relapse is common (McKay et al, 2010).  In other addictive 
disorders (eg, nicotine and opioid dependence), medications have been employed usefully to 
improve treatment outcomes. With these two addictions as models, investigators have searched 
for medications to treat CD (Kampman et al, 1996, 2000, 
2003 and 2006; Pettinati et al, 2008; Plebani et al, 2012). 
          Cocaine’s rewarding effect is mediated by inhibition 
of transporters for DA, NE and 5HT, a mechanism which is 
qualitatively similar to that of NS2359, a compound 
synthesized 
and 
characterized 
pharmacologically 
by 
NeuroSearch (Copenhagen). NS2359 (structure at right), 
unlike cocaine, has slow dissociation kinetics at all three 
transporters and a long half-life in humans (~ 7 days). Thus 
it has the potential to block the binding of cocaine to these 
transporters and the euphoria associated with cocaine.   
      The effect of NS2359 acute pretreatment (0.064 mg/kg to 2.05 mg/kg IM) on cocaine self-
administration was examined 
in 
four 
rhesus monkeys trained to lever press for 
cocaine (eg, 0.0032 mg/kg IV per lever 
press).   NS2359 potently and dose-
dependently inhibited responding for IV 
cocaine (ED50 = 0.45 mg/kg) in 3/4 rhesus 
monkeys (see figure). In a monkey given 2 
mg/kg, cocaine responding did not recover 
for 22 hours after the NS2359 dose. This 
dose does not block responding for food 
(data not shown).     
A 
cocaine-NS2359 
safety 
interaction study, was conducted with 24 
psychostimulant 
users. 
Participants 
received 20 mg IV cocaine 6 hours after placebo (n=6) or after acute pretreatment with a single 
oral dose of NS2359 (1.5, 3 or 6 mg, n = 6/dose). ~24 hours later, subjects received 40 mg 
cocaine IV. No evidence of toxicity was seen; NS2359 attenuated heart rate and blood pressure 
increases after 40 mg cocaine.  However, there was no overall significant effect of NS2359 on 
the cardiovascular or subjective responses to cocaine. While lower NS2359 doses had little 
NS2359 Blocks Cocaine Self-administration in Monkeys
Cocaine
Cocaine + 1 mg NS2359
Unit Dose Cocaine (mg/kg/inj)
Monkey C


 
 
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influence on subjective responses to cocaine, there is evidence that the 6 mg dose blocked 
cocaine’s effects.  Mean (+/- SD) maximal subjective ratings, from visual analog scales, suggest 
an NS2359 effect at the 6 mg dose (Appendix 4, Tables 21-30, pp 64-72). Absence of overall 
statistical significance is due to the lack of influence of cocaine subjective effects at the two 
lower NS2359 doses, the small sample sizes (n = 6) at each dose, and the large variances in 
subjective ratings.  Given the expected large variances in subjective ratings, the study was not 
powered adequately for this endpoint.   
cocaine 
dose  
NS2359 
dose  
any 
effect 
high 
good 
effect 
liking 
desire 
stimulated 
likely to 
use 
amount 
you would 
pay 
20 mg 
0 mg 
33 +/- 24 
27+/-20 
24 +/- 22 
26 +/- 27 
28+/- 28 
33 +/- 27 
27+/-33 
19 +/- 31 
20 mg 
6 mg 
7.2+/-8.8 
6.6+/11 
6.3+/-7.7 
4.4+/-8.2 
6.3+/-11 
7.4 +/-13 
7.2+/11 
5.8 +/- 3.8 
40 mg 
0 mg 
60 +/- 26 
53+/-28 
52 +/- 33 
52+/- 36 
50+/- 38 
48 +/- 30 
50+/-37 
33 +/- 37 
40 mg 
6 mg 
32 +/- 34 
28+/-27 
22 +/-20 
12 +/- 16 
18+/- 26 
28 +/- 33 
16+/-23 
13 +/- 9.3 
The 6 mg NS2359 dose (but not the lower doses) attenuated 40 mg cocaine-induced increases 
in heart rate (p = 0.0018) and systolic blood pressure (p = 0.024), with a trend to do so for 
diastolic blood pressure (p = 0.11, Table 8, p 46, Appendix 1, cocaine interaction study). This 
suggests that NS2359 might have a protective effect on the major source of morbidity and 
mortality in cocaine overdose (stroke and myocardial infarction) due to rapid rise in blood 
pressure. 
 
NS2359 was licensed to GlaxoSmithKline (GSK), where it (as GSK472375) was 
examined in phase 1 and 2 trials. At single oral doses of 9 mg, unacceptable levels of insomnia 
and impaired concentration were observed (Appendix 1, p 91), but a single 6 mg oral dose was 
moderately well tolerated (Appendix 1, p 91).  2 mg/day for 28 days was well-tolerated among 
healthy volunteers (Appendix 1, p91).   
 
GSK conducted several phase 2 clinical trials. NS2359 (at 0.5 mg/day) did not show 
efficacy in an adult attention deficit disorder (ADD) placebo-controlled study (Willens et al, 
2008).  Absence of efficacy probably was due to the low NS2359 dose of 0.5 mg/day. NS2359 
(at 1.5-2 mg/day) did not differentiate from placebo in two major depressive disorder (MDD) 
trials (Appendix 1, pp 104-114), in which the active comparators were superior to placebo and 
NS2359 (Learned et al, 2011).  The reasons for lack of efficacy are unclear.  In these trials, 
insomnia, loss of appetite and anxiety were common CNS adverse events. Insomnia, loss of 
appetite and anxiety may be particularly difficult for MDD patients to tolerate, as these adverse 
events are common depressive symptoms, and they could have led to the excess 
discontinuation rate among patients randomized to NS2359 (Appendix 1; Learned et al, 2011). 
However, the total adverse event reports were not greater for NS2359 than for the active 
comparators (Learned et al, 2011).  No serious adverse events were attributed to NS2359 in ~ 
500 persons exposed in the phase 1 and phase 2 studies (Appendix 1; Learned et al, 2011; 
Wilens et al, 2008). 
 
After the disappointing results in MDD and adult ADD, the NS2359 license reverted from 
GSK back to NeuroSearch, which is making the medication available to us for a phase two trial 
in CD (letter from Pierandrea Muglia, MD).  NeuroSearch has supported our application to the 
FDA for an IND for this trial, allowing us to cross-reference their existing IND.  NeuroSearch has 
supplied the NS2359 for purification and stability testing, while packaging will be done by the 
University 
of 
Pennsylvania 
Investigational 
Drug 
Service 
(www.med.upenn.edu/cores/investigational_drug_service.shtml) into 1.0 mg pills with matching 
placebo.     
 
1.2 Investigational Agents 
 


 
 
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NS2359 (from Investigators Brochure) 
 
NS2359 is a novel drug candidate that exhibits potent in vitro and in vivo inhibition of re-
uptake transporters for the neurotransmitters serotonin (5-HT), norepinephrine (NE) and 
dopamine (DA).  It was developed under the name NS2359 by NeuroSearch.  Therefore 
GlaxoSmithKline had in-licensed NS2359 (as GSK372475) and performed non clinical and 
clinical studies. This compound was investigated for its potential as an antidepressant agent 
and for the treatment for adults with attention deficit hyperactivity disorder. Currently, 
Neurosearch is planning to investigate the potential of NS2359 in the treatment of addiction.  
 
Nonclinical Pharmacology Studies 
In vitro and in vivo studies have clearly demonstrated NS2359 (also known as GSK372475) 
to potently and selectively inhibit the re-uptake of the 3 monoamines, serotonin, norepinephrine 
and dopamine, in the central nervous system.  Studies in rodents have shown low doses of 
NS2359 to increase the extracellular levels of these monoamines in the frontal cortex, 
hippocampus, striata and nucleus accumbens.  In addition, NS2359 increased cortical and 
hippocampal levels of acetylcholine. 
At similarly low doses, NS2359 enhanced learning and memory and did not induce anxiety 
or influence explorative open field behavior in the rat.  NS2359 was also active in mouse models 
of depression and showed a unique anti-Parkinson activity in the monkey.  NS2359 was active 
in the cocaine drug discrimination paradigm, attenuated experimental alcohol craving and 
demonstrated anti-nociceptive properties. 
High doses of NS2359 caused an increase in locomotor activity in rodents, and at still higher 
doses, induced typical dopaminergic stereotypic behavior. 
A series of cardiovascular safety studies conducted with NS2359 in dogs demonstrated 
dose-dependent increases in blood pressure.  In one study in conscious restrained dogs, 
NS2359 caused an increase in QTc interval; however, only one animal was outside the 
historical QTc interval range.  In another study in dogs fitted with atrial pacemakers, much 
higher plasma concentrations produced no effect on QT interval, when heart rate was 
controlled.  Similarly, 28 days administration in dogs did not affect any of the cardiovascular 
parameters measured, including QT interval.  NS2359 inhibited hERG currents at 37°C with an 
IC50 value of 1.4 μM (420 ng/mL).  NS2359 did not affect respiratory rates in the dog and did 
not affect gastrointestinal transport in the rat.  In a rat respiratory study, single oral doses of ≥4.8 
mg/kg NS2359 produced increases in total pulmonary ventilation. 
 
Nonclinical Pharmacokinetic Studies 
In the mouse, rat, rabbit, dog and monkey, NS2359 was shown to be well absorbed, with a 
moderate to high clearance.  NS2359 was highly distributed with variable half-lives in the rat, 
dog and monkey ranging between 1 and 24 hours. 
Systemic exposure to NS2359 typically increased in a supraproportional fashion following 
administration to rat and rabbit, whilst in mouse, minipig, dog and monkey, exposure increased 
in a generally proportional manner.  In the rat, systemic exposure was greater in females than 
males, whilst in the mouse, exposure tended to be greater in males than females.  In the other 
pre-clinical species, where assessed, no sex differences were observed.  There was evidence 
of accumulation upon repeat administration in the rat and dog.  Notable exposure to 
GSK459151 (the O-desmethyl metabolite) was observed in rat (exposure greater than to 
NS2359) and dog, and to a lesser degree in monkey and mouse. 
The distribution of drug-related material was widespread following oral and/or intravenous 
administration of [14C]NS2359 to rats (albino and pigmented).  By 35 days post dose, 
concentrations were below the limit of quantification in most tissues except in uveal tract/retina 
(suggesting some association with melanin), epididymes and testes.  Liver concentrations were 


 
 
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approximately 50-fold or greater than those in plasma in the rat, and there was also evidence of 
notable CNS penetration of drug-related material in the rat, mouse and hamster.  The plasma 
protein binding and the association of NS2359 with blood cells were moderate. 
NS2359 and GSK459151 were determined to have high and moderate passive membrane 
permeability, respectively, at pH 7.4 (which decreased notably at lower pH).  NS2359 and 
GSK459151 were shown to be inhibitors and substrates of human P glycoprotein.  Pgp was 
shown not to have a biologically important role in the absorption of NS2359 or to contribute to 
the distribution into the kidney or liver.  Pgp was shown to have a role in the efflux of NS2359 
from the brain and in its urinary elimination. 
Preliminary information in man indicates that the major metabolic routes of NS2359 are 
demethylation (to form GSK459151), hydroxylation, N-oxidation and glucuronidation.  This is 
generally consistent with the routes observed in nonclinical species (rat, mouse and hamster).  
However, in the minipig desmethylation to GSK459151 was only a minor route.  In rat liver, the 
major component present was GSK459151, although NS2359 was also seen.  Drug-related 
material in the brains of rats and mice was predominantly attributable to NS2359, although 
GSK459151 was also observed in rats. 
Following oral administration of [14C]NS2359 to rat, minipig, dog and monkey, urinary 
elimination was the major route of elimination in female rat, minipig and monkey, whereas in 
male rat and dog the fecal route predominated.  In the rat, the majority of the fecal elimination 
can be accounted for by biliary secretion. 
In vitro, NS2359 showed inhibition of CYP2C19, CYP2D6 and CYP3A4, but with no 
evidence for any metabolism-dependent inhibition of any of the activities investigated.  There 
was evidence of induction of CYP1A and CYP2B following repeat oral administration for 13 
weeks in the rat but not in the monkey. 
 
Toxicology Studies 
The maximum non-lethal single oral doses in the rat and mouse were 30.5 mg/kg and 6.4 
mg/kg, respectively.  At these doses, treatment-related effects were limited to behavioural signs 
(stereotypy) and reduced appetite with an associated decrease in weight gain, and were 
attributable to the pharmacological effects of NS2359. 
Similar findings were seen following repeated oral administration of NS2359 for up to 15 
weeks in minipigs, 13 weeks in rats and monkeys, and 28 days in dogs, and were reversible. 
Three episodes of convulsions were observed in two minipigs after 17, 27 and 29 weeks of 
treatment in a 52 weeks toxicity study, suspended after completion of the in life treatment. They 
have been considered isolated and not dose or exposure related.  
Target organ toxicity was not identified in any species tested.  The behavioural effects 
limited the maximum dose employed, and hence systemic exposure in all species. 
NS2359 had no effect on embryofetal development in either the rat or the rabbit.  Rat female 
fertility was also unaffected by NS2359.  Maternal toxicity in rats was comprised of hyperactivity 
and increased body weight and food consumption. 
NS2359 was considered not to be genotoxic.  Polyploidy highlights the potential for 
aneuploidy, but as both the mouse lymphoma assay and in vivo micronucleus assay detect 
aneuploidy, and all of these results were negative, this data is not considered to be biologically 
relevant. 
 
Clinical Studies 
The maximum acute dose level achieved within the Phase I single escalating-dose study in 
healthy volunteers was 9 mg [study 1253/127].  Although single doses of 6 mg and 9 mg were 
associated with a number of adverse events (AEs) including pronounced insomnia and impaired 
concentration, no clinically significant drug or dose-related findings on clinical laboratory 


 
 
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measures, electrocardiograms (ECGs) or vital signs were reported in Phase I single-dose 
studies [studies: 1253/127; SND101811; SND102340; SND110117; CA2359-002]. 
In the six Phase I repeat-dose studies conducted with NS2359, doses up to 2 mg/day for up 
to 28 days were evaluated and considered generally well tolerated [studies: DDS633554; 
GDRS-QGUY; PBR-022341; CA2359-003; SND103869; SND108813] .  
One serious adverse event (SAE) has been recorded in Phase I studies (exacerbation of 
cholelithiasis), which occurred in the SND103869 study.  The SAE was considered to be 
unrelated to the study drug by the investigator and the subject was not withdrawn from the 
study.   
Three studies in patient populations have also been completed. An 8-week ADHD study with 
0.5 mg NS2359 [study: NS2359-001], and two 10-week MDD studies with NS2359 flexible 
doses of 1.0 to 1.5 and 1.5 to 2.0 mg/day respectively [studies: SND103288; SND103285].  
The most frequently reported AE in these studies were insomnia, headache, fatigue, 
dizziness, palpitations, and constipation.  The majority of AEs were of mild or moderate  
intensity.   
No SAEs emerged in the 8-week ADHD study in which the dose was 0.5 mg/day (NS2359-
001). 
In the two 10-weeks MDD clinical efficacy studies (SND103285 and SND103288), a total 12 
SAEs were observed in NS2359 groups, including one death (completed suicide); 3 SAEs in the 
Paroxetine active comparator group (SND103288); and a total of 3 SAEs  in the Placebo groups 
(SND103285 and SND103288); no SAEs were observed in the Venlafaxine group 
(SND103285). Two of the 12 SAEs (i.e. completed suicide, and mania in the NS2359 group of 
study SND103288) were considered by the Investigator to be potentially related to the 
investigational product.  
 
Clinically significant elevations in some hepatic enzymes (e.g., AST and ALT) were recorded 
in one healthy volunteer Phase I study, but were considered unlikely to have been caused by 
NS2359.  A relatively modest, apparently dose-related, overall trend for NS2359-associated 
increases in mean blood pressure and/or heart rate was observed, and one subject (receiving 2 
mg for 3 days and then 1 mg per day for 25 days) had more notably elevated blood pressure 
and heart rate values (PBR-022341).  However, within the other Phase I studies, no vital signs 
were otherwise identified as clinically significant.  Increases in mean change from baseline in 
heart rate and sitting blood pressure were grater for NS2359 than observed for either placebo or 
active control groups in the MDD studies. A relationship between changes from Baseline in vital 
signs and median concentrations was shown by the exploratory PK/PD analysis only in the 
SND103288 study. 
In one repeat-dose phase I study (PBR-022341) and in the ADHD study and in the two MDD 
studies there was a trend towards decreasing weight in subjects receiving NS2359 when 
compared to placebo groups.   
 
Studies of the pharmacokinetics of NS2359 in man indicate that the absorption is fairly slow 
with Tmax ranging from 6 to 7 hours.  The elimination phase is also slow with a terminal 
elimination half-life of 8-10 days.  There is a high degree of accumulation of NS2359 observed 
with repeated dosing, in line with the long half-life of the compound.   The AUC0-∞ and Cmax 
appeared to increase in a dose-proportional manner. PK findings in the clinical efficacy studies 
(ADHD and MDD) indicated slightly lower exposure and higher variability as compared to 
studies in healty volunteers. 
 
Two imaging studies with NS2359 demonstrated excellent CNS penetration and dose-
dependent specific binding to brain dopamine and serotonin transporter sites in healthy male 


 
 
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subjects at well-tolerated doses. The plasma concentration/receptor occupancy data indicated 
equivalent potency across the monoaminergic transporters tested. 
 
The abuse liability of NS2359 was evaluated in experienced users of stimulant drugs in a 
randomized, double-blind, placebo controlled cross-over study, comparing NS2359 to placebo 
and to two active controls, pseudoephedrine and d-amphetamine (SND101811).  The overall 
pattern of pharmacodynamic responses demonstrated that NS2359 is unlike d-amphetamine 
and more like placebo. The results from this study indicate that the abuse potential of NS2359 is 
likely to be very low.   
 
The results of the clinical efficacy studies showed that there were no significant differences 
between NS2359 and placebo groups for any of the primary or secondary efficacy endpoints, for 
either ADHD or MDD. In the two MDD phase II studies, venlafaxine (study SND103285 or 
paroxetine (study SND103288) were the active comparators, in addition to a placebo arm. Total 
adverse events were not significantly greater for NS2359, compared to venlafaxine or 
paroxetine.  Voluntary withdrawal was 13% for NS2359, compared to 8% for placebo and 2% 
for venlafaxine. Physician withdrawal was 14% for NS2359 versus 14% for venlafaxine  and 
15% for NS2359 versus 6% for paroxetine. 
 
In summary, the available data from Phase I and II studies did not show compound safety 
and tolerability issues. The studies in MDD indicated a possible dose-dependent effect in 
increasing blood pressure and heart rate. Also a possible effect in lowering body weight has 
been detected in the MDD studies, with similar results  for the ADHD study. Efficacy data 
indicate that NS2359 does not warrant further study as treatment in MDD.  
Data from one human abuse liability study (SND101811) and a human cocaine interaction 
study (CA2359-002) indicate that NS2359 has low abuse potential and no significant effect on 
the PK of cocaine. These data allow clinical testing of NS2359 in addiction. 
  
1.3 Dose Rationale and Risk/Benefits 
 
The overriding principle for NS2359 dosing is that the daily dose will not exceed the 
maximum dose or duration in the phase II studies of major depressive disorder (Learned, et al, 
2012). The daily NS2359 doses of 1-2 mg/day will not exceed the maximum daily dose given in 
phase I and phase II studies, 2 mg/day, as detailed in Appendix 2, Investigators’ Brochure. This 
2 mg/day dose was well tolerated by normal volunteers in phase I for 28 days (see Appendix 2, 
Investigators Brochure, Study SND103869, p 76-77). Mean Cmax plasma level was 36 ng/ml in 
that phase I study (Table 18, p 77, Investigators’ Brochure, Appendix 2).  Further, in study 
SND103285 – MDD (p 79, in Appendix 2, Investigators’ Brochure) patients received 1.5 mg/day 
for 6 weeks (mean plasma NS2359 Cave = 16 ng/ml) or 2 mg/day for 6 weeks (mean Cave plasma 
NS2359 = 23 ng/ml; p 81, Table 21, Investigators’ Brochure, Appendix 2). In neither of these 
investigations was there a serious adverse event.    
 
Medications will be started at the beginning of week 2 and stopped at the end of week 9. 
At each clinic visit (Monday, Wednesday and Friday), patients will be asked to take the 
medication under the direct observation of staff. Subjects will take 2 mg of NS2359. Depending 
on tolerability, the dose may be reduced to 1 mg once daily. Thus, the dosing regimen chosen 
will not exceed the NS2359 exposure at 2 mg/day for the phase I and II trials in which there 
were no serious adverse events. Patients experiencing intolerable adverse events at the 2 
mg/day dose will be allowed to reduce the dose to 1 mg/day. This flexible dose strategy is 
designed to enhance patient retention while providing adequate exposure to NS2359 to 
attenuate the rewarding and cardio-vascular effects of cocaine.  


 
 
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Potential risks. The potential risks of this study include adverse reactions to NS2359, 
potential adverse interactions between NS2359 and cocaine, and the small risk incurred by 
venipuncture.  
 
 Risks associated with NS2359.   NS2359 has been shown to be safe and well 
tolerated in a number of Phase I and Phase II trials, including two relatively large trials for the 
treatment of depression and ADHD, involving 1200 subjects. These studies were characterized 
by NS2359 plasma levels similar to those proposed here.  The most common side effects of 
NS2359 noted in clinical trials include:  insomnia, weight loss, dizziness, headache, 
constipation, dry mouth, anxiety, increased heart rate and increased blood pressure.  The heart 
rate and blood pressure increases were small and not clinically significant.  There were no 
medication associated serious adverse events in any of the clinical trials conducted thus far. As 
described in Preliminary Studies in Research Strategy, a safety interaction trial of NS2359 and 
cocaine was conducted and no adverse interactions between NS2359 and cocaine were found 
(see Appendix I).  The preliminary data support the safety of NS2359 for this trial.  In the 
proposed trial, patients will be monitored closely (three times per week) to ensure that any 
adverse events will be identified and treated appropriately. Vital signs and weight will be 
monitored weekly by a nurse practitioner. 
 
Consent procedures.   All study procedures will be described in detail for the subjects 
by one of the project investigators in an individual consent session.  The consent form and 
session will include the following information: Detailed information about the study medication; 
that is, a description of the medication, rationale for why it is being studied, frequency of dosing 
and length of treatment, potential side effects, safeguards and emergency procedures. 
Information will also be provided about the psychosocial treatment, frequency of visits and 
length of treatment, safeguards and emergency procedures, etc. Collection of lab specimens 
(number of venipunctures and urine specimens required) will be reviewed.  Eligibility will be 
reviewed.  The number and frequency of the research interviews and self-assessments will be 
reviewed. 
 
In addition, subjects will be assured that their participation is voluntary and that 
withdrawal from the study does not jeopardize current or future treatment.  Patients will also be 
told that if at any time during the study the research team and the clinical treatment team feel 
that the patient needs more intensive, standard treatment, the patient will be referred to one of 
the available inpatient treatment programs in Philadelphia.  All subjects will be informed of 
potential risks and benefits involved in the study.  Potential medication side effects will be 
described to all subjects.  Patients will be informed that their participation in the treatment trial 
may be discontinued at any time because of serious medication side effects, their 
noncompliance with treatment, missing appointments or if continued participation is considered 
an endangerment to their welfare. 
 
At the end of the consent session, a quiz is given. Subjects scoring below 100% correct 
will receive additional instruction regarding the study and consent form.  Incorrect questions 
from the quiz will be administered again until all questions are answered correctly. All 
participants are provided with a hard copy of the consent form that includes the name and 
telephone numbers of the investigative team, and the Chair of Penn’s Institutional Review Board 
(IRB).  A 24-hour Emergency contact is provided in case of an adverse consequence or any 
other emergency.   
 
 


 
 
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Protection of Subjects.  Potential subjects will be screened for medical illnesses that 
would preclude the use of NS2359, eg, untreated hypertension and untreated cardiac disease 
detected by EKG and/or physical exam.  Subjects selected for the study will be monitored 
closely.  Adverse events will be monitored by a nurse practitioner at weekly visits.  Individuals 
with urine drug screen results indicating recent cocaine ingestion will be questioned closely 
about adverse events. At the conclusion of medications, an end of study physical will be 
completed and the baseline laboratory tests, including EKG, will be repeated.  Subjects will be 
given a 24-hour emergency number they can call if necessary. Adverse events: If the patient is 
discontinued in treatment due to a serious adverse event, the patient will be followed clinically 
by medical staff until the adverse experience resolves itself and becomes stable. 
   
Subjects taking other concomitant medications will be monitored closely for signs of 
toxicity. Subjects with a history of current severe psychiatric symptoms, impaired renal function 
or known liver disease, use of any investigational medication within the last 30 days, or AIDS or 
any other serious illness which may require hospitalization during the study, will be excluded.  
Pregnant females or women who refuse to use acceptable forms of birth control will be excluded 
from the study. Should a participant become pregnant while participating in the study, outcome 
data will be collected via self report and any medical charts made available. A pregnant partner 
authorization form will be signed so data may be collected from female subjects and female 
partners of male subjects who become pregnant while in the study.  
   
Venipuncture will be carried out with good aseptic technique by a nurse practitioner or 
physician.  Venipuncture sites will be monitored carefully for signs of infection. 
 
If a patient experiences an adverse event, appropriate evaluation and management will 
be undertaken.  This may include medical management, a reduction in study of medication, a 
temporary cessation of study drug, or early termination from the trial if necessary. 
   
HIV antibody testing will be available to all research patients on a voluntary basis.  Pre 
and post-test counseling is conducted for all subjects by the nurse practitioner.  Informed 
consent is signed and maintained in the patient’s clinical chart.  Subjects who have positive 
tests have access to supportive counseling by the nurse practitioner with psychiatric 
consultation available through Dr. Kampman and/or Dr. Berrettini.  Subjects have the option of 
medical follow-up through their personal physician or through referral to the Infectious Disease 
Clinic of The Hospital of the University of Pennsylvania. 
 
Confidentiality. No information about subjects will be disclosed to others without their 
prior written permission, except as stated in the informed consent, or if necessary to protect the 
rights or welfare of a subject in accordance with the law. Subject names or unique identifying 
information are never used in the publication of research data. Procedures designed to maintain 
confidentiality include: (1) formal training sessions for all research staff emphasizing the 
importance of confidentiality; (2) specific procedures developed to protect a patient’s 
confidentiality; and (3) formal mechanisms limiting access to information that can link data to 
individual patients.  Data forms that include identifying information are kept in locked cabinets.  
Only the unique identification (ID) number, assigned at the time of initial contact represents 
patients during data entry, data transfer, data analysis, or other file management procedures.  
To facilitate tracking, a password-protected computer file on a secure server is maintained 
containing the identity of patients, their ID numbers, and information about how they can be 
reached.  This file, however, contains no clinical data. All data are stored in a securely locked 
area accessible only to authorized research personnel.  The Principal Investigator (PI) is 
required to allow trial-related monitoring, audits, IRB review, and regulatory inspection by 
providing direct access to source documents.  The FDA, IRB, and other regulatory authorities 
will also have access to source documents.  We inform subjects of this access in the informed 
consent. Finally, HIPPA regulations are followed.  
 


 
 
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With respect to minimizing the discomfort that may result from the interview, research 
assistants are selected on the basis of their personal attributes and interpersonal skills as well 
as their substantive knowledge.  They are further trained and periodically observed to ensure 
that they are respectful and sensitive to the needs and feelings of the patients in all contacts.  
Furthermore, they are trained to recognize signs of significant stress or enervation in patients, 
and are instructed that they should gently terminate the interview and schedule the patient for 
another time or request assistance from a trained clinician. 
 
HIPPA compliance. Penn investigators support the appropriate privacy of all clinical 
and research data collected as part of any study. We follow NIH policy in the use and disclosure 
of protected health information in research in a manner that respects the subject’s privacy in 
accordance with the “Privacy Rule” promulgated under the Health Insurance Portability and 
Accountability Act (HIPPA) and other applicable laws.  All staff receive appropriate HIPPA 
training.  All subjects sign a HIPPA-authorization form, receive a copy of this form, and receive a 
notice of the site’s privacy practice.  HIPPA signed forms are retained in locked file cabinets with 
patients’ source documents. 
2 Study Objectives 
 
The primary objective of this single site trial is to evaluate the efficacy of NS2359 for the 
treatment of cocaine use disorder.  The study will be double-blind, and placebo-controlled.  The 
project proposes to randomize 80 treatment-seeking subjects with DSM-V diagnoses of cocaine 
use disorder to NS2359 or placebo. All subjects will receive weekly sessions of Medical 
Management (MM) and Cognitive Behavioral Therapy (CBT). We chose to use the MM from the 
NIAAA-funded COMBINE national study because of its distinctive procedures for maximizing 
medication adherence. We also plan to provide once weekly sessions of CBT as a psychosocial 
treatment in our exploratory trials because CBT has been shown to be effective for promoting 
treatment retention in prior medication trials for the treatment of cocaine dependence.  
Following the treatment trial, there will be one follow-up visit conducted with subjects at 12 
weeks after starting study medications (four weeks after completing the medication phase of the 
trial). 
3 Study Design  
3.1 General Design 
 
Study Design: The hypotheses in the proposed study will be tested with a 2-group 
design to assess the efficacy of NS2359 compared to placebo. We will follow NIAAA’s 
COMBINE Medical Management (MM) manual in weekly dispensing medications, safety checks 
and medication adherence. The psychosocial treatment will be Cognitive Behavioral Coping 
Skills Therapy (CBT). Subjects will be 80 men and women with current DSM-V diagnoses of 
cocaine use disorder who will be randomized to NS2359 or placebo (40 subjects per group). All 
subjects will receive weekly sessions of CBT. The study length for each subject is comprised of 
1-week of screening and baseline evaluations, an 8-week double-blind, placebo-controlled trial 
with CBT (medication phase), and one follow-up visit 4 weeks after end of medication phase. 
3.2 Primary Study Endpoints 
 


 
 
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Primary Hypothesis: More NS2359-treated subjects (compared to placebo-treated subjects) 
will achieve 3 consecutive weeks of cocaine abstinence during the last three weeks of the 
medication trial, as measured by the Timeline Follow-Back method and qualitative urine 
benzoylecgonine (BE) levels.   
 
3.3 Secondary Study Endpoints 
 
1. NS2359-treated subjects will have reduced craving for cocaine, compared to placebo-treated 
subjects, as measured by the Brief Substance Craving Scale.  
2. NS2359-treated subjects will have reduced cocaine withdrawal symptom severity, as 
measured by the Cocaine Selective Severity Assessment (CSSA).  
3. NS2359-treated subjects will have higher rates of cocaine abstinence at the final 
appointment, four weeks after the 8 weeks of medication treatment has been completed, as 
measured by self-report and by urine drug screen for BE levels. 
3.4 Primary Safety Endpoints 
 
NS2359 adverse events: NS2359 has been shown to be safe and well tolerated in a 
number of Phase I and Phase II trials, including two relatively large trials for the treatment of 
depression and ADHD, involving 1200 subjects. The most common side effects of NS2359 
noted in clinical trials include:  insomnia, weight loss, dizziness, headache, constipation, dry 
mouth, anxiety, increased heart rate and increased blood pressure.  The heart rate and blood 
pressure increases were small and not clinically significant.  There were no medication 
associated serious adverse events in any of the clinical trials conducted thus far. As described 
in Preliminary Studies in Research Strategy, a safety interaction trial of NS2359 and cocaine 
was conducted and no adverse interactions between NS2359 and cocaine were found (see 
Appendix I).  The preliminary data support the safety of NS2359 for this trial.  In the proposed 
trial, patients will be monitored closely (three times per week) to ensure that any adverse events 
will be identified and treated appropriately. Vital signs and weight will be monitored weekly by a 
nurse practitioner. 
Clinical deterioration and/or suicide risk management:  All of the investigators have 
had experience managing and referring subjects under these conditions.  The TRC follows 
standing emergency policy when managing clinical deterioration related to addiction or 
psychiatric symptomatology for all of our subjects.  At the weekly visit, subjects are evaluated 
for the presence or persistence of any symptoms indicative of clinical deterioration due to a 
rapidly increasing problem with cocaine use, alcohol use, and/or psychiatric symptoms, 
including suicidality.  Between visits, subjects are instructed to contact their treating physician or 
an authorized research staff member in the event that disturbing symptoms become evident. In 
all cases, these subjects are immediately evaluated, and if deemed appropriate, are referred to 
clinical treatment.  If possible, they will be maintained in the trial as long as it is deemed safe to 
do so. Also, any additional treatment is recorded for data analysis purposes.  At any time, 
subjects who are severely suicidal or at high risk of medical or physical harm will be immediately 
discontinued from the trial and appropriate medical treatment instituted.  All subjects who are 
discontinued from the trial are still encouraged to attend the follow-up visits. 
 
4. Subject Selection and Withdrawal 


 
 
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4.1 Inclusion Criteria 
1. Male and females, 18-70 years old.   
2. Meets DSM-5 criteria for current diagnosis of cocaine use disorder moderate or severe, as   
    determined by the  SCID -5 semi-structured interview.   
3. In the past 30 days, used no less than $100-worth of cocaine   
4. Speaks, understands, and prints in English.     
4.2  Exclusion Criteria 
1.  Meets DSM-5 criteria for a substance use disorder, moderate or severe on any substance 
other than cocaine, alcohol, marijuana or nicotine as determined by the SCID.  Subjects with 
comorbid alcohol use disorder will be accepted if their alcohol use disorder is not severe 
enough to require a medical alcohol detoxification.  
2.   Needs treatment with any psychoactive medications (with the exception of diphenhydramine 
or melatonin, if necessary, for sleep).  
3.  Meets current or lifetime DSM-5 criteria for schizophrenia or any psychotic disorder, or 
organic mental disorder.  
4.  Has another Axis I psychiatric disorder that in the opinion of the PI will interfere with 
completion of the study or place the patient at heightened risk through participation in the 
trial.  
5.  Has evidence of a history of significant hematological, pulmonary, endocrine, cardiovascular, 
renal or gastrointestinal disease such as AIDS, active hepatitis, significant hepatocellular 
injury as evidenced by elevated bilirubin levels (>1.3), or elevated levels (over 3.5x normal) 
of aspartate aminotransferase (AST), and serum alanine aminotransferase (ALT).  
6.  Use of an investigational medication in the 30 days prior to randomization.  
7.  History of hypersensitivity to NS2359.   
8.  Is female and tests positive on a pregnancy test, is contemplating pregnancy in the next 6 
months, is nursing, or is not using an effective contraceptive method (if relevant).  
9.  Has a self-reported gambling problem.  This exclusion criterion is required because of the 
fishbowl technique of contingency management. 
4.3 Subject Recruitment and Screening 
 
Screening, consent and subject eligibility.  After signing a screening consent, persons will be 
screened to verify that they meet all inclusion/exclusion criteria. A medical history, physical and 
laboratory examination will be conducted. The research clinician will offer eligible patients 
participation in the study. The study clinician will ensure that the patient understands the 
risks/potential benefits of the study prior to signing the consent form. 
 
Contacting Subjects: Subjects are informed during the informed consent process that contact 
information provided to the research staff may be used at a later date to contact them by phone 
or mail. Reasons for contact include but are not limited to: missed appointments, appointment 
reminders, requests for follow-up visits, notifications of medical testing results, or other clinical 
reasons. Subjects are instructed to notify study staff if they no longer wish to be contacted. 
 


 
 
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4.4. Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Clinical trial discontinuation criteria: All randomized subjects are included in the 
intent-to-treat analysis. After the completion of Week 9, or at the termination for patients who 
discontinue from the trial prematurely, we will conduct the following procedures: physical exam, 
vital signs and weight, electrocardiogram, monitor adverse events and concomitant medications, 
obtain blood samples for chemistry, CBC, liver function tests, obtain a urinalysis (and a 
pregnancy test for women), Clinical Global Impression and the Treatment Opinion Form. They 
will also be scheduled for an end-of trial visit (unless it falls within 2 weeks of the final 
evaluation), and the follow up visit.  Subjects will also be given appropriate treatment referrals.  
Subjects are not dropped from all study activity unless they request they not be contacted, or 
the subject cannot be located for assessment by the follow-up. Subjects will be informed at the 
consent session that medications may be discontinued (discretion of principal investigator and 
study doctor) due to: 1) Intolerable side effects; or 2) Extreme lab values with a repeat test. 
(AST or ALT levels greater than 5 times the upper limit of normal and bilirubin above 1.5 mg./dl). 
3) If the participant develops signs of cardiovascular instability (vital signs and clinical 
evaluation; pulse at rest > 100 or BP at rest >140/90 mm Hg for more than 2 weeks or 
SBP>160, DBP>110, sitting quietly HR>110 on any visit will result in immediate discontinuation 
of study medications). In these cases, the subjects may continue with the CBT part of the 
treatment.  Subjects will be informed at the consent session that he or she may be discontinued 
from all treatment due to: 1) Development or exacerbation of significant psychiatric or medical 
symptoms which necessitate inpatient admission or a more aggressive therapeutic intervention 
than provided by the protocol; these subjects would not be invited back to take study medication 
but will be followed for data collection and may remain eligible for psychosocial treatment; 
Psychiatric symptoms that would require inpatient treatment would include suicidal ideation 
acute psychosis or acute mania. 2) Emergence of another substance abuse problem which 
necessitates inpatient admission or a more aggressive treatment than provided by the protocol; 
subjects who are admitted for inpatient stabilization for alcohol and cocaine use may return for 
data collection and psychosocial treatment after discharge to complete the 11 week medication 
phase of the trial;  3) Clinical deterioration for any reason or a clinical status which necessitates 
inpatient admission; subjects may return for data collection and psychosocial treatment after 
discharge to complete the 9 week medication phase of the trial 4) Incarceration > 1 week; 
subjects may return for data collection and psychosocial treatment after discharge to complete 
the 11 week medication phase of the trial 5) subject behaviors compromise subject’s safety. The 
reason the subjects are discontinued from medication and/or the clinical trial and any referrals 
made are documented on the Final Evaluation Form in the subject’s casebooks. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
Standard procedures developed at the treatment sites are used to help locate missing 
subjects.  These include the identification and verification of home and work phone numbers, 
emergency contacts and locators.  Subjects who have missed an appointment are recontacted 
initially by phone, then by letter and finally by registered mail.  Emergency and other locators 
are used when subjects themselves cannot be contacted. Contacts are attempted at least two 
times a week for a minimum of two weeks then less frequently by mail.  Subjects are not 
considered lost to follow up until the entire study is completed and the database is ready to be 
closed. 
 


 
 
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5. Study Drug  
5.1 Description 
 
NS2359 is a novel drug candidate that exhibits potent in vitro and in vivo inhibition of re-
uptake transporters for the neurotransmitters serotonin (5-HT), norepinephrine (NE) and 
dopamine (DA). It was developed under the name, NS2359, by NeuroSearch (now Saniona).   
GlaxoSmithKline had in-licensed NS2359 (as GSK372475) and performed pre-clinical and 
clinical studies. This compound was investigated for its potential as an antidepressant agent 
and for the treatment for adults with attention deficit hyperactivity disorder. Saniona has 
provided us with the API  to investigate the potential of NS2359 in the treatment of cocaine 
addiction.  
Study medication has been supplied by Saniona. Study medication will be maintained and 
dispensed by the Investigational Drug Service of the Hospital of the University of 
Pennsylvania.   
5.2 Treatment Regimen 
Three visits weekly will be scheduled for dispensing medication, and treatment 
evaluation will be scheduled so that patients have three visits per week. Medications will be 
started at the beginning of week 2 and stopped at the end of week 9. At each clinic visit 
(Monday, Wednesday and Friday), patients will be asked to take the medication under the direct 
observation of staff. The initial dose of the medication during week 2 will be 2 mg orally on days 
1-7.  Patients with intolerable adverse events at the 2 mg/day dose will be allowed to reduce the 
dose to 1 mg/day. Subjects with intolerable adverse events at the 1 mg/day dose will be allowed 
to reduce the dose to 1 mg every other day.    
The Director of the Investigational Drug Service of the Hospital of the University of 
Pennsylvania will conduct the randomization using a computer-generated program of urn 
randomization, based on specified criteria that have been described below: 
5.3 Method for Assigning Subjects to Treatment Groups 
Urn Randomization. We plan to use urn randomization to stratify subjects across the two 
treatment conditions. We will stratify subjects on four baseline variables: 1) a co-morbid DSM-IV 
diagnosis of alcohol dependence; 2) gender; 3) high cocaine withdrawal symptom severity, as 
measured by a score above 22 on the Cocaine Selective Severity Assessment (CSSA, 
Kampman et al, 1998); 4) urine drug screen results on the day of randomization. Subjects with 
high CSSA scores and patients who enter a trial with cocaine positive urines often have poor 
outcomes during pharmacotherapy trials (Kampman et al, 2001, 2002).     
An off-site statistician will work with the research pharmacist at IDS in setting up the urn 
randomization sequences, and will ensure that the codes linking subject’s ID numbers to 
treatments are secure. IDS uses an electronic emergency-unmasking database that works off 
the PennKey and is accessible 24/7 from any computer with internet access.  Tables are 
uploaded by IDS and pocket cards are issued to investigators when access is granted.  The 
system only provides access for one subject at a time and all transactions are recorded. If a 
subject is prematurely discontinued from the trial, all attempts will be made to not break the 
blind. If an emergency necessitates that the blind be broken, only the pharmacist will have 
access to the blind to do so. He will be given the name of the staff members who have authority 
to request that the blind be broken. The IDS pharmacist can be reached 24 hours a day and can 
access a subject’s code rapidly. 


 
 
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5.4 Preparation and Administration of Study Drug 
Study medication will be prepared, stored and dispensed by the Research Pharmacist at 
Investigational Drug Services.   Ken Rockwell 215 349 8817. 
5.5 Subject Compliance Monitoring 
Medication adherence.  Adherence will be reinforced in several ways.  There will be observed 
medication ingestion at each clinic visit, three times weekly. In addition, an automated telephone 
reminder system, utilizing either voice or text, will be used to remind patients to attend 
scheduled appointments and take medication on days between clinic appointments.  Telephone 
voice reminders have been successfully used to enhance compliance in geriatric patients taking 
HIV medications and in patients taking asthma medications (Hayes et al., 2009; Strandbygaard 
et al, 2010, Pop-Eleches et al, 2011). Medication adherence will further be enhanced using 
weekly Medical Management (MM) sessions. 
5.6 Prior and Concomitant Therapy 
      Concomitant medications will be recorded for the time period of one month before the 
initial screening visit throughout the follow up phase.  
.   
Additional psychosocial therapies including self-help groups will be allowed during the 
randomized medication phase but will be measured using the Treatment Services Review 
(TSR).  
5.7 Packaging 
Study drug will be dispensed weekly in blister packs. Subjects will be instructed to bring 
their blister pack to each visit and dosing will be observed at each visit (three times weekly)  
5.8 Blinding of Study Drug 
 
Integrity of the blind.  All research and clinical staff will be blind to the medication status until 
the end of the study.  An off-site statistician will work with the research pharmacist in the urn 
randomization sequences, and will ensure that the codes linking subject’s ID numbers to 
treatments are secured. If a patient is prematurely discontinued from the trial, all attempts will be 
made to maintain the blind.  If an emergency necessitates that the blind be broken, study 
personnel who received access to the electronic unmasking database or the Penn pharmacist 
will have access to the blind. The Penn pharmacist will have the name(s) of the staff at all sites 
who have authority to request that the blind be broken.  The Penn pharmacist is “on call” 24 
hours a day. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
 
Study drug has been supplied by Saniona. It will be stored, and dispensed by the 
Research Pharmacy at the Hospital of the University of Pennsylvania consistent with regulations 
governing a Schedule II medication.  
 


 
 
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Upon receipt of the of the study treatment supplies, an inventory will be performed and a 
drug receipt log filled out and signed by the person accepting the shipment.  It is important that 
the designated study staff counts and verifies that the shipment contains all the items noted in 
the shipment inventory.  Any damaged or unusable study drug in a given shipment (active drug 
or comparator) will be documented in the study files.   
5.9.2 Storage 
Study medication will be stored at the Research Pharmacy at the Hospital of the 
University of Pennsylvania as a Schedule II medication.  
5.9.3 Dispensing of Study Drug 
After randomization, study drug will be dispensed to each subject according to his or her 
randomization number.  Medication will be dispensed on Mondays, Wednesdays and Fridays 
during clinic appointments by research staff who will observe ingestion.  Ingestion of drug by 
each patient will be recorded in the CRF by research staff who observed ingestion by that 
patient. A dispensing log will be maintained at the Research Pharmacy. Sufficient medication in 
blister packs will be given to each patient weekly.  Patients will be required to bring their blister 
packs to each clinic visit. 
Regular study drug reconciliation will be performed to document drug assigned, drug 
consumed, and drug remaining.  This reconciliation will be logged on the drug reconciliation 
form, and signed and dated by the study team. 
5.9.4 Return of Study Drug 
All unused study drug will be returned to the Research Pharmacy.  At the completion of 
the study, there will be a final reconciliation of drug obtained from the Research Pharmacy, drug 
consumed, and drug returned.  This reconciliation will be logged on the drug reconciliation form, 
signed and dated.  Any discrepancies noted will be investigated, resolved, and documented. 
Unused study drug will be destroyed in a manner consistent with regulations governing 
Schedule II medications. 
6  Study Procedures. 
 
Table 1. Schedule of Assessments 
Assessment 
Week 1 
Weeks 2-9 
End of Trial 
F/U 
Medical Exam and ECG ,CBC and blood chemistry Urinalysis (UA)  
Risk Assessment Battery 
1X 
 
1X 
 
Pregnancy Test (women),  
1X 
2X 
1X 
 
Structured clinical Interview for DSM 5  
1X 
 
 
 
Cocaine Selective Severity Assessment (CSSA) 
3X 
9X 
1X 
 
Columbia Suicide Severity Rating Scale 
1x 
1x 
1X 
x 
Vital Signs, Weight,  
3X 
24X 
1X 
1X 
Clinical Global Impression Scale (CGI) Treatment Services Review (TSR) 
,Concomitant Medications, Minnesota Cocaine Craving (MCC) scale, Urine 
Toxicology-other than cocaine 
1X 
9X 
1X 
1X 
Urinary BE,Breathalyzer (BAL),Timeline Follow back (TLFB), SAFTEE 
3X 
24X 
1X 
1X 
Addiction Severity Index (ASI),HAM A and D, Standard Form 36 
1X 
1X 
1X 
1X 
Pill Counts  
 
9X 
1X 
 
Treatment Opinion Form  
 
1X, week 5 
1X 
 
Medical Management  
1X 
9X 
1X 
 
Blood for NS2359 level 
 
1X, week 5 
1X 
 


 
 
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DESCRIPTION OF INSTRUMENTS (See Table 1 for timing) 
Measures to be used (See table below for timing) 
Addiction Severity Index  (ASI) (McLellan, 1992b). The ASI is a 45-minute interview which 
yields composite scores, ranging from 0 to 1, of problem severity over the past 30 days in 7 
areas: medical, employment, drug use, alcohol use, legal, family/social, and psychiatric.  The 
ASI will be used to characterize baseline demographic and drug use variables for each subject. 
The composite scores will be used as secondary outcome measures.  The ASI is administered 
on four occasions spaced throughout the trial. 
Clinical Global Impression Scale (CGI) (Guy, 1976). The CGI is a brief clinical rating of 
severity of illness (at time of interview) and global improvement (from admission) using a 7-point 
Likert scale.  The CGI is completed by the MM practitioner, and the subject to assess clinical 
progress, global improvement and to assess the severity of the subject’s illness at regular 
contacts over the course of the study.  The CGI is done at baseline, weekly during the 
medication phase of the trial, at the end of the medication phase of the trial and at follow up. 
Cocaine Selective Severity Assessment (CSSA) (Kampman, 1998). The CSSA is a 10-
minute, 18-item clinician-administered cocaine withdrawal scale developed at the TRC. The 
CSSA will be used to stratify subjects at the start of the trial and to measure cocaine withdrawal 
symptom severity during the trial.  The CSSA is administered at each visit during baseline and 
weekly during the medication phase of the trial. 
Columbia Suicide Severity Rating Scale (C-SSRS) (Chappell, 2012). This is a 5-item scale 
with additional questions that may be asked based on the participant’s responses to the core 
items. This questionnaire will assess both lifetime and recent suicidal ideation and behavior, 
including both passive and active thoughts/plans. It is extensively used across clinical practices, 
hospitals, research institutions and schools to address potential thoughts of suicide expressed 
by the client. This questionnaire will be administered at baseline, and once a week through  the 
trial and at follow-up. 
Hamilton Anxiety Rating Scale (Ham-A) (Hamilton, 1959). The Ham-A is a 15-minute, 14-
item, clinician-administered instrument that measures current anxiety and changes in anxiety 
symptoms. The Ham-A is administered at baseline, end of medication phase, and at follow up.   
Hamilton Depression Rating Scale (Ham-D) (Hamilton, 1967). The Ham-D is a 20-minute, 24-
item interview that measures the severity of depression and changes in depressive symptoms. 
The Ham-D is administered at baseline, end of medication phase and at follow up. 
Brief Substance Craving Scale (BSCS) (Somoza 1995).  The BSCS is a valid and reliable 
measure of cocaine craving.  The BSCS is administered at baseline, weekly during weeks 2-9 
and at follow up. 
Risk Assessment Battery (RAB) (Metzger, 1993). The RAB is a self-administered 
questionnaire designed for use with substance using populations.  It provides a rapid and 
confidential method of assessing needle use practices and sexual activity associated with HIV 
transmission.  The RAB is given at baseline and at week 9. 
Short Form-36 Health Status Questionnaire (SF-36) (Jenkinson, 1994). The SF-36 is a 36-
item self-report of the subject’s quality of life, and will be completed at baseline, end of 
medication phase and at follow up.  
Structured Clinical Interview for DSM- 5 (SCID) The SCID 5 is a 60-minute, semi-structured 
interview that yields current and lifetime DSM-IV Axis I diagnoses for the major psychiatric 
disorders including cocaine and alcohol dependence.  The SCID is administered once during 
week 1. 
Systematic Assessment for Treatment Emergent Effects (SAFTEE)  (Rabkin et al., 1992). 
Adverse events are queried and documented at each visit by the SAFTEE. This constitutes our 
primary measure of safety.   


 
 
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Timeline Follow-Back Interview (TLFB, Sobell, 1995). The TLFB is a 15-30 minute, semi-
structured interview that measures self reported cocaine use and other drug use. The TLFB will 
be administered at each visit. 
Treatment Opinion Form (TOF) The TOF questionnaire asks the MM clinician and subject 
whether they think the subject is receiving active medication or placebo.  It will be administered 
twice (mid- and end-trial). 
Treatment Services Review  (TSR) (McLellan, 1992a). The measure is given at baseline, 
weekly throughout the medication phase and at follow up, providing a record of non-study 
treatment services throughout the trial. 
Laboratory Measurements (in alphabetical order) 
Blood chemistry and CBC are obtained to assess for adverse events. Enzyme levels will be 
obtained once at baseline and at the beginning of week 7 and at the end of week 9.  
Pregnancy Testing Urine pregnancy tests will be obtained from all women at weeks 1, 5, 9, 
and end of study.  
Plasma NS2359 Level  A blood sample will be obtained at the end of week 5 (steady state for 
1mg/day) and at the end of week 9 (steady state for 1.5 mg/day).  Plasma NS2359 levels will be 
measured using a reverse phase high performance liquid chromatography/tandem mass 
spectrometry method (Appendix 3). All samples (n = 2 samples each for patients treated with 
NS2359) will be assayed in one batch in a commercial lab (www.aptuit.com) by the individual 
who developed the assay for GSK, Luca Ferrari, PhD (letter attached).  Values will be reported 
to Drs. Berrettini and Kampman, then entered into the database.  Because all patients will take 
medication under direct study staff observation three times weekly, it is not expected that any 
sample will have undetectable levels of NS2359, given its long half-life of ~ 7 days. Any 
samples with undetectable NS2359 will be re-assayed. Plasma levels will be used in data 
analysis (see below) as quantitative co-variates.   
Urine Drug Screen and Urine Benzoylecgonine (BE) Qualitative urine BE will be assessed 
three times weekly throughout the trial. Qualitative (emit) urine toxicology for other drugs 
(benzodiazepines, barbiturates, opiates, marijuana, and amphetamine) is done at baseline and 
weekly throughout the trial.  
 
Regular evaluation visits.  Subjects will have appointments with study staff three times weekly 
throughout the 8-week medication phase of the trial, Monday, Wednesday and Friday.  An 
automated telephone system will provide reminder calls and/or text messages to enhance 
attendance. Urine drug screens (UDS) for benzoylecgonine (BE) will be obtained at each visit, 
along with vital signs and weight, CSSA, adverse events (SAFTEE) and time line follow back 
(TLFB). Clinical Global Impression (CGI), the Minnesota Cocaine Craving Scale (MCCS), the 
Columbia Suicide Severity Rating Scale (CSSRS) and Treatment Services Review (TSR) will be 
obtained weekly. Other measures completed routinely but not weekly are as follows: Addiction 
Severity Index (ASI), Short Form 36 (SF36), Hamilton Anxiety Rating Scale (HAM-A), and a 
Hamilton Depression Rating Scale (HAM-D), the Risk Assessment Battery (RAB), and the 
Treatment Opinion Form (TOF) from the MM clinicians. A description and schedule of 
assessments is provided below.  Each patient will meet weekly with the MM clinician who will 
assess clinical status, dispense study medications and monitor adverse events and concomitant 
medications.   
 
After the completion of Week 9, or at the termination for patients who discontinue from 
the trial prematurely, we will conduct the following procedures: physical exam, vital signs and 
weight, electrocardiogram, monitor adverse events and concomitant medications, obtain blood 
samples for chemistry, CBC, liver function tests, obtain a urinalysis (and a pregnancy test for 
women), CGI, and the TOF. A safety follow up visit will be conducted one month after the 
completion of the medication phase at week 9. At this follow-up visit, a nurse practitioner will 


 
 
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collect the following: vital signs and weight, monitor adverse events and concomitant 
medications.  A research technician will conduct the following procedures: breathalyzer, ASI, 
TSR, PACS, MCCS, SF36, TLFB, and a UDS for BE and other drugs. 
 
Psychosocial Treatment. Subjects will participate in weekly manualized individual cognitive 
behavioral relapse prevention psychotherapy from week 2 through week 9. (Carroll, 1998). They 
will also receive weekly Medication Management (MM), an intervention developed as part of 
NIAAA’s Project COMBINE study, that provides advice and support from medical practitioners 
concomitantly with dispensing medications, safety checking and compliance (Pettinati et al., 
2004). The main goal of MM is to increase the likelihood that patients will reduce their cocaine 
use. The initial MM session is an hour; subsequent sessions are 15-30 minutes.  
7 Statistical Plan 
7.1 Sample Size Determination 
Power Analyses: We have one primary hypothesis and will test it at a 5% level of significance. 
Our principal interest is in the comparison of urine drug screen BE results between the placebo 
group and the NS2359 group during the final three weeks of the medication phase (weeks 7-9). 
To ensure an intent-to-treat comparison, we will test this in the context of a model that uses all 
data. Power will largely depend on the amount of data available for the final period, so we focus 
on that. Given our assumptions on dropout rate and missing data, about 60 people will yield a 
response for the final period, and 20 will be missing. For the case when missing data are 
regarded as indicative of use, then we have a full sample of 80 subjects. This yields 80% power 
for an odds ratio of 3.6 or larger (corresponding to a difference such as 30% versus 61%). If 
missing data are ignored, then we have 80% power for an odds ratio of 4.5. 
7.2 Statistical Methods 
Data Management.  Data will be gathered using Penn’s Center for the Study of Addiction's 
(CSA) direct-entry data system, and will be stored on the data management unit (DMU) 
network. Interview data and self-report data are entered directly onto computers at the research 
sites, by research technicians and study subjects respectively. Field validation (eg, no out of 
range or otherwise invalid responses will be accepted) and form validation (e.g. logically 
impossible responses to different questions will not be accepted) are built into this entry 
process. Data are transmitted (128-bit encrypted form) over the internet to the DMU servers. 
After online reviews, the data are archived on the servers. No identifying information is stored 
on the DMU servers. Certain DMU staff members have permission to modify the archived data. 
Audit logs record any modification to the original entry. Password protection allows members of 
the research team appropriate levels of data access.  
Data Analyses. Kevin Lynch, PhD, the CSA Statistician, and his staff will perform the data 
analyses.  Prior to analyses, standard data screening/cleaning procedures will be applied 53.  
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.  Due to sample size, it is unlikely that the randomization will result in 
significant imbalance of the distributions of demographic or other variables across treatment 
groups. Additional covariates will be considered for inclusion in the analyses, to improve the 
precision of estimation for the treatment effects.  Covariates describing levels of cocaine use 
prior to the study may be included.  Assumptions underlying the application of statistical 
methods will be examined, through use of standardized residuals, influence diagnostics, and 
graphical displays.  Primary Hypothesis: More subjects treated with active medication will 


 
 
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achieve 3 consecutive weeks of cocaine abstinence during the last three weeks of the 
medication trial compared to placebo-treated subjects Abstinence will be determined by self-
report using the TLFB method and urine BE levels. Cocaine use will be measured by three-
times-weekly urine BE levels, so the total urine BE data will be 24 binary indicators of cocaine 
use, accompanied by TLFB data. These data will be employed to assign a binary use/no-new-
use measure for each day of the treatment period. To explicitly address the primary hypothesis 
of abstinence during the final three weeks, we will model time as a four-level discrete variable, 
corresponding to weeks 2-4, 4-6, and 7-9, and will determine whether subjects show complete 
abstinence during those periods. This will yield a binary response for each subject for each of 
the three periods. We will use a generalized linear mixed effects model to estimate the effects of 
medication group and time on the log-odds of complete abstinence across the periods, and in 
particular during the last three weeks of the treatment phase.  The explanatory variables in 
these models will be a binary indicator of medication group, variables representing time effects, 
together with possible interaction terms. Possible interaction terms include gender and plasma 
NS2359 levels at week 5 and week 9. The group by time interactions will yield an estimate of 
the log odds of complete abstinence for the final three weeks, for the active medication group 
versus the placebo group, explicitly addressing the primary hypothesis. If we find that these 
interaction terms are not significant, then we will remove them from the model and compare the 
two groups across the entire 8-week treatment period.  
 
 
Secondary Hypotheses:   
Secondary Hypothesis 1: Subjects treated with the active medication will have reduced 
craving for cocaine, compared to placebo-treated subjects, as measured by the Brief Substance 
Craving Scale (BSCS) Scale. The BSCS scale will provide weekly measures of cocaine craving.  
The scale provides a six-category Likert response, and it is likely that we will collapse some 
adjacent categories prior to the analyses, and regard the responses as ordinal.  We will 
compare the two medication groups across the treatment weeks using mixed-effects models for 
ordinal responses 54. The fixed effects are the medication group, and time, together with 
possible interaction terms. The effect of time will be broken into linear, quadratic and, possibly, 
cubic, trends across the weekly time points. These analyses will be performed using PROC 
GLIMMIX in SAS.  
       
Secondary Hypothesis 2: Subjects treated with the active medication will have reduced 
cocaine withdrawal symptom severity, as measured by the Cocaine Selective Severity 
Assessment (CSSA). The CSSA provides weekly measures of the severity cocaine withdrawal, 
whose distribution is likely to be skewed towards higher values. Based on our experiences with 
these responses in other studies, we expect that a log transformation of these responses will 
yield approximately normally distributed responses. The hypothesis (that medication will 
decrease CSSA scores) will be tested using linear mixed effects models, following the same 
approach described for Hypothesis 2. These models will be fit using PROC MIXED in SAS, or 
PROC GLIMMIX if transformations fail to reduce skewness enough for the assumption of a 
Normal response to be valid..  
 
Secondary Hypothesis 3: subjects treated with the active medication will have higher 
rates of cocaine abstinence during the treatment period, and at the final appointment, four 
weeks after the 8 weeks of medication treatment has been completed, as measured by self-
report and by urine drug screen for BE levels. The analyses will use the same type of 
generalized linear mixed effects models as described for the Primary hypothesis above. In 
contrast to the earlier analyses, where the focus was on three-week periods, we will examine 
weekly time-periods, and will include the week 15 follow up as an additional time point.  
Missing Data and Nonadherence:  For the longitudinal analyses described above, 
premature discontinuation from treatment and occasional missing daily use indicators will lead 


 
 
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to incomplete data. The mixed effects models described above can make use of all available 
data provided by subjects, but the inferences drawn from them will be unaffected by the missing 
data only if the missing data can be regarded as ignorable, in the sense of Laird 55. To assess 
the sensitivity of our analyses to this assumption, we will use shared parameter models, which 
allow for correlated random effects underlying the cocaine use measurements and the pattern of 
dropout 56.  We will also use selection models to examine the effects of missing data 57,58. We 
will explicitly model the probability of premature discontinuation at a time point as a function of 
baseline characteristics and responses at previous time points, using a logistic regression 
model, and incorporate the predicted probabilities into a weighted analysis of the main 
hypotheses. We will do analyses in a range of assumptions and assess the sensitivity of results 
to them 58. We will use self-report of pill ingestion, and blood levels of NS2359 as measures of 
compliance with assigned medication regime. We will use the methods of Nagelkerke et al 59 
and Small et al 60, to obtain estimates of the intervention effect in a population compliant with 
treatment i.e. the Complier Average Causal Effect (CACE).  
Safety: The SAFTEE responses will be analyzed as a measure of safety.  Total number of 
adverse events, adverse events leading to discontinuation (in the judgment of the study 
physician), % of patients reporting at least one adverse event, clinical lab assessments, ECG, 
vital signs, BMI and evidence of clinical worsening (by urine drug screen results and TLFB 
results) will be considered in assessment of safety.  In a manner parallel to the analysis for 
therapeutic response, medication group, plasma NS2359 levels, gender, age and other clinical 
variables will be entered into a generalized linear mixed effects model to predict adverse events. 
Body weight is measured weekly, as NS2359 may cause weight loss is some individuals 6. 
7.3 Subject Population(s) for Analysis 
 
All-treated population:  Any subject randomized into the study that received at least one 
dose of study drug 
8. Safety and Adverse Events 
8.1 Definitions 
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 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any 
AE that is:  
• 
fatal 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
results in persistent or significant disability or incapacity 


 
 
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• 
a congenital anomaly or birth defect 
• 
an important medical event 
 
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.  For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered 
serious.  
 
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 30 days following the last 
administration of study treatment.  
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 
study sponsor 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.  
The sponsor should also be notified if the investigator should become aware of the 
development of cancer or of a congenital anomaly in a subsequently conceived offspring 
of a subject that has participated in 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 


 
 
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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 an 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. 
• 
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. 
8.2 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. 
8.3 Reporting of Serious Adverse Events 
8.3.1 Study Sponsor Notification by Investigator 
A serious adverse event must be reported to the study sponsor (Penn) by email 
or telephone within 72  hours of when the event is reported to any of the study staff.  A 
Serious Adverse Event (SAE) form must be completed by the investigator and faxed to 
the study sponsor within 72  hours.  The investigator will keep a copy of this SAE form 
on file at the study site.  Report serious adverse events by phone and facsimile to the 
study sponsor: 
 
Kyle M. Kampman, M.D. 
215 222 3200 x 109 
215 386 6770 fax 
 
kampman@upenn.edu 
 
At the time of the initial report, the following information should be provided: 
 


 
 
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• 
Study identifier 
• 
Study Center 
• 
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 assist the understanding of the event.  Significant new information on ongoing 
serious adverse events should be provided promptly to the study sponsor. 
8.3.2 EC/IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be 
submitted to the EC/IRB based on the IRBs current AE/SAE reporting requirements and 
timeline for reporting (e.g. 5 business days).  Copies of each report and documentation 
of EC/IRB notification and receipt will be kept in the study regulatory binder. 
8.3.3 FDA Notification by Sponsor 
The study sponsor (Penn) shall notify the FDA by telephone or by facsimile 
transmission of any unexpected fatal or life-threatening experience associated with the 
use of the drug as soon as possible based on the  FDAs current SAE reporting 
requirements and timeline for reporting (e.g. no later than 7 calendar days from the 
sponsor’s original receipt of the information). 
 
If a previous adverse event that was not initially deemed reportable is later found 
to fit the criteria for reporting, the study sponsor (Penn) will submit the adverse event in a 
written report to the FDA as soon as possible based on the  FDAs reporting 
requirements and timeline for reporting (e.g. but no later than 15 calendar days from the 
time the determination is made). 
8.4 Unblinding Procedures 
 
All research staff will be blind to the medication status until the end of the study.  An off-
site statistician will work with the research pharmacist at IDS in setting up the urn randomization 
sequences, and will ensure that the codes linking subject’s ID numbers to treatments are 
secure. IDS uses an electronic emergency-unmasking database that works off the PennKey and 
is accessible 24/7 from any computer with internet access.  Tables are uploaded by IDS and 
pocket cards are issued to investigators when access is granted.  The system only provides 
access for one subject at a time and all transactions are recorded. If a subject is prematurely 
discontinued from the trial, all attempts will be made to not break the blind.  If an emergency 
necessitates that the blind be broken, only the pharmacist or approved study personnel will 
have access to the blind to do so. He will be given the names of the staff members who have 
authority to request that the blind be broken (Dr. Kampman or the TRC Doctor-On-Call ).  The 
IDS pharmacist can be reached 24 hours a day by beeper and can access a subject’s code 
rapidly.  The CBT therapist and subject will be asked for their opinion twice (mid- and end-trial) 
about whether they think the subject is receiving NS2359 or placebo. 


 
 
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8.5 Stopping Rules  
Clinical trial discontinuation criteria: All randomized subjects are included in the 
intent-to-treat analysis. All subjects who prematurely discontinue treatment will be scheduled for 
a final evaluation, end-of trial visit (unless these two fall within 2 weeks of each other), and the 
follow up visit.  Subjects will also be given appropriate treatment referrals.  Subjects are not 
dropped from all study activity unless they request they not be contacted, or the subject cannot 
be located for assessment by the follow-up. Subjects will be informed at the consent session 
that medications may be discontinued due to: 1) Intolerable side effects; or 2) Extreme lab 
values with a repeat test. (AST or ALT levels greater than 5 times the upper limit of normal and 
bilirubin above 1.5 mg./dl) In these two cases, the subjects may continue with the CBT part of 
the treatment.  Subjects will be informed at the consent session that he or she may be 
discontinued from all treatment due to: 1) Development or exacerbation of significant psychiatric 
or medical symptoms which necessitate inpatient admission or a more aggressive therapeutic 
intervention than provided by the protocol; these subjects would not be invited back to take 
study medication but will be followed for data collection and may remain eligible for 
psychosocial treatment; 2) An emergence of another substance abuse problem which 
necessitates inpatient admission or a more aggressive treatment than provided by the protocol; 
subjects who are admitted for inpatient stabilization for alcohol and cocaine use may return for 
data collection and psychosocial treatment after discharge to complete the 8 week medication 
phase of the trial 3) Clinical deterioration for any reason or a clinical status which necessitates 
inpatient admission; subjects may return for data collection and psychosocial treatment after 
discharge to complete the 8 week medication phase of the trial 4) Incarceration > 1 week; 
subjects may return for data collection and psychosocial treatment after discharge to complete 
the 8 week medication phase of the trial 5) subject behaviors compromise subject’s safety.  6) 
signs of cardiovascular instability (vital signs and clinical evaluation; pulse at rest > 100 or BP at 
rest >140/90 mm Hg for more than 2 weeks or SBP>160, DBP>110, sitting quietly HR>110 on 
any visit will result in immediate discontinuation of study medications).  Subjects who 
experience elevated blood pressure as a result of exposure to study medications will be allowed 
to continue to participate in psychosocial treatment.  The reason the subjects are discontinued 
from medication and/or the clinical trial and any referrals made are documented on the Final 
Evaluation Form in the subject’s casebooks. 
 
Study Stopping Criteria: In addition to oversight by the University of Pennsylvania IRB 
and Office of Human Research , the trial will be conducted under the supervision of a Data 
Safety and Monitoring Board, as outlined below in section 8.6.1.  This independent board will 
review the study every 6 months. The DSMB is charged with monitoring the safety of 
participants and the quality of the data, as well as the appropriate termination of studies either 
when significant benefits or risks have been uncovered or when it appears that a clinical trial 
cannot be concluded successfully.  The DSMB will review all adverse events and will have 
access to unblinded data in order to determine the association between adverse events and 
study medication. If a pattern of significant adverse events is uncovered that suggests that the 
risks of continuing the trial outweigh the expected benefits of the trial then the DSMB will 
recommend that the study be stopped. 
8.6 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 


 
 
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and safety-monitoring plan (see section 9 Auditing, Monitoring and Inspecting).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
8.6.1 Internal Data and Safety Monitoring Board 
Purpose: The monitoring of a clinical trial is necessary to ensure the protection of the 
patient’s rights, the safety of the patients enrolled in the trial and the integrity and quality of 
the resulting data.  This monitoring plan details the source data verification of efficacy and 
safety parameters, the frequency of monitoring visits, regulatory document review and drug 
accountability/patient compliance.   
Protocol summary:  This trial is intended to explore the potential efficacy and 
tolerability of NS2359 for the treatment of cocaine dependent patients.  Patients admitted to 
this trial will be men and women with cocaine dependence.  Treatment will consist of 8 
weeks of NS2359 or placebo plus weekly individual cognitive behavioral relapse prevention 
therapy and medical management therapy. 
Monitor selection and training: One monitor will be assigned for this trial and will be 
responsible to complete the monitoring process. The monitor will be selected from one of 
the Study Coordinators working at the University of Pennsylvania Center for the Studies of 
Addictions.  A CV for the monitor will be obtained and updated bi-annually. The CV will be 
kept in the regulatory binder to document the qualifications of the monitor. Monitors will be 
trained by the Administrative Director of the TRC.  Monitors will meet with the 
Administrative director and review the protocol, CRF and the monitoring checklists to be 
completed by the monitor.  The monitoring process will be reviewed and approved by the 
University of Pennsylvania Office of Human Research. 
Study initiation visit: The Principal Investigator will be responsible for assuring through 
personal contact between the co-investigators, the monitor and the clinical staff that each 
clearly understands and accepts the obligations incurred in the undertaking of this clinical 
trial. 
The co-Principal Investigators (Drs. Kampman and Berrettini) and the assigned monitor 
will meet with the clinical staff (research nurses and study technician) to ensure that they 
understand and accept the following: the nature of the protocol and the requirements for an 
adequate and well-controlled study; the obligation to conduct the clinical investigation in 
accordance with 21 CFR Parts 312, 511, 812, 813 and any other applicable regulations; the 
obligation to obtain informed consent in accordance with 21 CFR Part 50; the obligation to 
obtain IRB review and approval of a clinical investigation before the investigation may be 
initiated and to ensure continuing review of the study by the IRB in accordance with 21 
CFR Part 56; and to keep the sponsor informed of such IRB approval and subsequent IRB 
actions concerning the study.  
Training will consist of an explanation of the protocol and review of the CRF.  In addition 
the duties of each member of the staff outlined in all applicable regulations will be reviewed.  
All questions will be answered. 
A report of the Study Initiation will be written by the monitor detailing the visit, specifically 
noting the information reviewed with the clinical staff and any questions generated during 
the training.  The report will be filed in the regulatory binder.  A copy of the Study Initiation 
Report will be sent to the Office of Human Research, University of Pennsylvania School of 
Medicine, Room 150 Anatomy-Chemistry Building, Philadelphia, PA 19104-6061.  
Monitoring Visits: Monitoring will be conducted in accordance with University of 
Pennsylvania Sponsor-Investigator Standard Operating Procedure PM 504.  Enrollment 
will be complete when 80 patients are randomized into the trial.   Approximately 4 
patients will be randomized per month.  Monitoring visits will be conducted periodically 


 
 
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throughout the study.  The first monitoring visit will occur no more than two weeks after 
the first patient is entered.  Subsequent monitoring visits will be conducted quarterly. 
Monitoring log: At the beginning of each monitoring visit, the monitor and any 
representative of the Sponsor participating in any aspect of monitoring the study is 
required to sign and date the monitoring log documenting the visit. 
Monitoring report:  All monitoring visits will be documented on the Monitor’s Report and 
Visit Checklist. The original report for each visit will be filed with in the regulatory binder 
and copies of the report will be sent to the Data Safety Monitoring Board (DSMB) and 
the Office of Human Research at the aforementioned address. 
Routine Monitoring Visits: 
Monitoring visits are conducted periodically throughout the study as described below.  
 
o Visit 1: Initiation Visit 
 
o Visit 2: Approximately 25% of subjects to be randomized have completed the trial and 
100% Source Document Verification for the first two randomized subjects 
 
o Visit 3: Approximately 50% of subjects to be randomized have completed the trial. 
 
o Visit 4:  Approximately 100% of subjects to be randomized have completed the trial. This 
visit serves as the closeout-monitoring visit. 
 
Study initiation visit: The Principal Investigator will be responsible for assuring through 
personal contact between the co-investigators, the monitor and the clinical staff that each clearly 
understands and accepts the obligations incurred in the undertaking of this clinical trial. 
The Principal Investigator and the assigned monitor will meet with the clinical staff (research 
nurses and study technician) to ensure that they understand and accept the following: the 
nature of the protocol and the requirements for an adequate and well-controlled study; the 
obligation to conduct the clinical investigation in accordance with 21 CFR Parts 312, 511, 812, 
813 and any other applicable regulations; the obligation to obtain informed consent in 
accordance with 21 CFR Part 50; the obligation to obtain IRB review and approval of a clinical 
investigation before the investigation may be initiated and to ensure continuing review of the 
study by the IRB in accordance with 21 CFR Part 56; and to keep the sponsor informed of such 
IRB approval and subsequent IRB actions concerning the study.  
Training will consist of an explanation of the protocol and review of the CRF.  In addition the 
duties of each member of the staff outlined in all applicable regulations will be reviewed.  All 
questions will be answered. 
A report of the Study Initiation will be written by the monitor detailing the visit, specifically noting 
the information reviewed with the clinical staff and any questions generated during the training.  
The report will be filed in the regulatory binder.  A copy of the Study Initiation Report will be sent 
to the Office of Human Research, University of Pennsylvania School of Medicine, Room 150 
Anatomy-Chemistry Building, Philadelphia, PA 19104-6061.  
 
Visits 2, 3 and 4: 
 
Regulatory binders and Case Report Forms 


 
 
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All regulatory documents are maintained in the Regulatory Binder. The monitor at monitoring 
visit 2, 3  and 4 will review the Regulatory Binder.  
==> 
The Compliance Assessment Checklist, developed by the University of Pennsylvania 
Office of Human Research, will be used for monitoring the Regulatory Binders.  This form is 
located on the OHR website.   
==> 
The monitor will also ensure that the CRFs are being completed and Final QA’d in a 
timely manner and that FMPro is up to date and complete. 
 
For all Randomized subjects the following will be reviewed: 
 
1) 
Screening consent  
==> 
 Source document verify (SDV) that consent is on file with signature, date, and proper 
version. 
2) 
Informed consent  
==> 
SDV that consent on file with signature, date, and proper version. 
3) 
Inclusion/Exclusion Criteria  
==> 
 SVD for completeness and accuracy. 
4) 
Severe Adverse Events (SAEs) 
==> 
Verify study specific reporting requirements were followed for reportable SAEs according 
to section 8.3 above and proper follow-up and resolution of SAE was documented. 
5) 
Adverse Events  
==> 
Verify an annual blinded report of all AEs was reviewed by study PI and M.D.  
==> 
Review all AEs collected during the study reported as severe were reported to 
appropriate agency and resolved. 
6) 
Drug accountability   
==> 
Verify all drug accountability form are complete for subjects finished the treatment phase 
of the study and medication is returned to pharmacy. 
7) 
Stopping Rules  
==> 
Verify documentation of Final Evaluation Form for subjects finished the treatment phase. 
8) 
Prohibited Concomitant Medication 
==> 
Verify restricted concomitant meds were not taken. 
9) 
Review gross clinical indicators for all subjects lost to follow-up during the treatment 
phase of the trial. 
==> 
Review of drug use captured on TLFB and UDS; 
==> 
Review of HAMS for high scores; 
==> 
Review of Clinical notes by the Director of Operations or his designee; 
==> 
Summary of relevant findings will be written by monitor and Director of Operations and 
included in the report. 
10) 
Review of key safety & efficacy data for those subjects discontinued due to AEs 
==> 
Specifically a thorough review of Clinical Notes by the Director of Operations or his 
designee.  Relevant findings will be summarized and included in the monitoring report. 
 


 
 
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Additional 100% Source Data Verification (SDV) for Randomized subjects with the DMU, 
Clinical Chart, and Case Report Form 
==> 
At the second visit the monitor will 100% SDV 1 subject among the first 25% of 
participants;  
==> 
At the third visit the monitor will 100% SDV 1 subject between 25% and 50% of 
participants randomized; 
==> 
At the fourth visit the monitor will 100% SDV 1 subject between 50% and 75% of 
participants randomized. 
 
If a greater than 10% error rate is noted during the data review, the monitor will source data 
verify 100% of the data on a larger sample at the following monitoring visit. 
 
Visit 4: Close-Out Visit:  
 
The monitor will conduct the Close-Out Visit at the time of the fifth monitoring visit. The monitor 
will complete the following activities at visit 5 in addition to the above items to close out the 
study: 
==> 
Ensure all data have been reviewed and collected; 
==> 
Ensure all outstanding queries are answered; 
==> 
Perform drug accountability and return any unused drug to the Penn Pharmacy; 
==> 
Review requirements for record retention with the investigator and the clinical staff; 
==> 
The Close-Out Visit Report, developed by the University of Pennsylvania Office of 
Research, will be used for monitoring the Regulatory Binders.  This form is located on the OHR 
website.   
 
Content of monitoring report;  
Monitoring visits can be documented on the Monitoring Visit Report, developed by the 
University of Pennsylvania Office of Human Research.  This form is located on the OHR 
website.  After each visit is complete the monitor and investigator will review the report. The 
original report for each visit will be filed in the Monitoring Binder maintained by the Regulatory 
Coordinator.  In addition to the Monitoring Visit Report, the monitor will write a letter to the PI 
addressing each component of the visit.  Queries will be given to the study staff to complete 
within 1 month of the report. 
 
8.6.2 Independent Data and Safety Monitoring Board 
 
A safety monitoring board has been established at the Center for the Studies of 
Addiction with the following purpose (according to NIDA guidelines): to assure that the safety of 
study subjects is protected while the scientific goals of the ongoing studies are being met. 
Specifically, the DSMB is charged with monitoring the safety of participants and the quality of 
the data, as well as the appropriate termination of studies either when significant benefits or 
risks have been uncovered or when it appears that a clinical trial cannot be concluded 
successfully. 
All board members will meet NIDA requirements regarding background and experience, 
and none will have ethical conflicts, including financial interest related to study outcome.  


 
 
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Individuals invited to serve on the board will disclose any potential conflicts in writing.  The 
board will meet every six months (unless more frequent meeting are deemed necessary) and 
will be chaired by David Oslin, M.D., a faculty member within the Department of Psychiatry at 
the University of Pennsylvania.  Other members of the board include Kevin Lynch, Ph.D. (senior 
statistician), and David Metzger, PhD., who are faculty members of the University of 
Pennsylvania School of Medicine, Department of Psychiatry.  When the current study is 
reviewed, Dr. Kampman will open the meeting with a report on the trial status, followed by a 
closed session under the direction of Dr. Oslin. Issues related to recruitment, subject safety and 
efficacy, whether the primary study question is being answered, conflict of interest, 
confidentiality, and ongoing study review (including AEs, SAEs, and regulatory issues) will be 
assessed.  Following each DSM Board meeting, Dr. Oslin will make recommendations to Dr. 
Kampman, and a final report (edited by all Board members) will be prepared and submitted to 
NIDA, the Penn IRB, and (if required) the FDA. 
In addition to semiannual reviews, at the occurrence of the second medication 
associated serious adverse event or after the first fatal medication associated adverse event the 
protocol will be reviewed by the DSMB the DSMB to consider modifications to the protocol or 
discontinuation.  
 
 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 
9.2 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, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 


 
 
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9.3 Case Report Forms 
Research 
data 
will 
be 
collected 
electronically 
on 
the 
internet 
at 
<https://dmu.trc.upenn.edu/dmumain>, a password-protected website run by the University of 
Pennsylvania’s Data Management Unit. Binders will also be kept for each participant. These will 
contain checklists for study assessments to be administered online, as well as source 
documents. 
9.4 Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 years 
after the last approval of a marketing application in their country and until there are no pending 
or contemplated marketing applications in their country or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period if required by an agreement with the sponsor.  
In such an instance, it is the responsibility of the sponsor to inform the investigator/institution as 
to when these documents no longer need to be retained.  
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan as noted above.  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. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, 
the sponsor, government regulatory bodies, and University compliance and quality assurance 
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. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.  The investigator should 
provide a list of EC/IRB members and their affiliate to the sponsor. 


 
 
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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 Attachments for a copy of the Subject Informed Consent Form.  
This consent form will be submitted with the protocol for review and approval by the EC/IRB for 
the study.  The formal consent of a subject, using the EC/IRB-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.  
12 Study Finances 
12.1 Funding Source 
 
This study is financed through a grant from the DANA Foundatio. Saniona has provided 
study drug. 
 
12.2 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 a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study 
sponsor prior to participation in this study.  All University of Pennsylvania investigators will follow 
the University conflict of interest policy. 
12.3 Subject Stipends or Payments 
Attendance and Adherence Contingencies. Contingency management (CM), where tangible 
reinforcement is provided in close temporal proximity to a subject performing a target behavior 
(e.g., on-time attendance, drug abstinence, medication compliance) is highly efficacious in 
engendering abstinence and other target behaviors among many patients engaged in substance 
abuse treatment.  During screening, participants will receive $30 total cash (two payments of 
$15 if screening is completed over two days, or three payments of $10 if screening 
assessments span three days). Participants will receive $25 cash for the follow up study visit at 
week 13. During the active phase, CM will be provided in the form of an opaque “fishbowl” with 
a high proportion of chips with little ($1) monetary value.  Subjects draw from the fishbowl upon 
completion of an objectively verified target behavior, and bonuses are often provided for 
continued performance.  Petry and colleagues have seen success with the fishbowl for 
attendance in prior studies, and our recently completed trial of varenicline for CA used a 
fishbowl for attendance and treatment visit compliance, resulting in attendance rates of 80% 42, 
as compared to the <60% attendance rates seen in many of our prior clinical trials. 
 
For each visit, subjects will provide a urine sample, take medication and complete 
assessment paperwork. Upon completion of all requirements for a given visit, patients will 
receive fishbowl draws for that visit. Draws will be available on an escalating schedule with a 
bonus contingency. Attendance at all three visits earns subjects bonus draws for that week.  


 
 
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Failure to attend a visit without prior approval or failure to complete all visit requirements results 
in no draws earned for that visit and results in loss of bonus draws for that week.  
      The fishbowl contains 500 chips, half (250) with no value that simply say “good job”, 219 of 
which have a value of $1, 30 of which have a value of $5, 2 have a value of $25, and 1 of which 
has a value of $50. Patient will earn five draws per visit, for week 2 (visits 4-6), with draws 
increasing by one each week. The weekly bonus draws will remain constant at 5 draws.  
Subjects who attend all required visits will have the opportunity to make 203 draws from the 
fishbowl, for maximum possible earnings of $800 during the trial.  Based on prior use of this 
fishbowl schedule, actual earnings based on the statistics of drawing chips with dollar value for 
each patient are expected to be approximately $400. Subjects will receive vouchers redeemable 
for gift cards from local merchants contingent on attendance at each visit and completing all 
required activities. Gift cards are used to avoid giving cash to CUD patients, as cash is often a 
trigger for drug craving and relapse. Patients will receive $5.00 for each medication pack they 
return for a total of up to $40 in cash. 
Financially compensation for travel Patients will receive 2 transit tokens at each visit totaling ; 
56 transit tokens valued at $112..  
 
13 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 by the sponsor for the purposes of performing the study, will 
be published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
 
 
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Berrettini WH, Persico A: D2 dopamine receptor gene polymorphisms and vulnerability to 
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Guy, W., ed. Assessment Manual for Psychopharmacology:  Publication ADM 76-338. 1976, US 
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Kampman, K.M., Volpicelli, J.  A caution against the use of fluoxetine and methylphenidate for 
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 Introduction to Amendment 1  
 
In this phase II 8 week randomized double-blind, placebo-controlled trial of NS2359 in 
cocaine use disorder, with a dose of 1.3 mg/day of the free base (2.0 mg of the tartrate 
monohydrate), interim blinded analysis of 40 persons (19 from group 1 and 21 from group 2) 
provided sufficient toxicology and self-report data to determine whether any of those weeks 
were cocaine use weeks, according to the same weekly-use definition described in the main 
protocol, 
(section 
3.2). For these 40, 
89% of group 1 and 
90% of group 2 had 
cocaine use in the 
final three weeks 
(Chi-square=0.01, 
p=0.92). There were 
no serious adverse 
events 
and 
this 
dose 
was 
well-
tolerated.  
 
We propose 
to continue the trial 
using 2.0 mg/day of 
the free base 
(equivalent to 2.7 
mg/day of the 
tartrate 
monohydrate). The 
rationale for 
continuing the trial 
at this higher dose is found in evidence for target engagement only at this higher dose, based 
on a brain-imaging study. At an oral dose of 1 mg/day free base, mean trough steady-state 
plasma values are approximately 12 ng/ml, and dopamine transporter occupancy is only 55%. 
At an oral dose of 2.0 mg/day free base, mean trough steady-state plasma values are 
approximately 30 ng/ml, and the extrapolated estimated dopamine transporter occupancy is 
~90%. A high degree of DA transporter occupancy is characteristic of compounds which block 
cocaine self-administration in primates (Lindsey et al, 2004).  
 
Study Design 
 
 
The overall design of the trial will remain the same except where specifically noted 
below. There will be no changes in subject selection, primary and secondary endpoints, subject 
selection and withdrawal.  There will be no changes to Section 8 of the protocol Safety and 
Adverse Events. There will be no changes to Sections 10, 11, 12, or 13. 
 
Study Medication 
 
 
3
SPECT Study of Human Striatal Dopamine Transporter 
Occupancy at 0.25, 0.50 and 1 mg Doses of NS2359.
low dose
mid dose
high dose
05
10
15
20
25
30
35
40
45
50
55
60
65
70
75
0.25 mg/day
Percent displacement V3"
from baseline
Days
Loading Dose
Maintenance Dose
1-7
1.5 mg on Days 1-2
0.25 mg on Days 3-7
8-14
1.5 mg on Days 8-9
0.5 mg on Days 10-14
15-21
2 mg on Days 15-17
1 mg on Days 18-21
~90% DA transporter occupancy is estimated for steady state 
plasma levels of 25-30 ng/ml at 2 mg/day by extrapolation.
0.5 mg/day
1.0 mg/day


 
 
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Capsules containing 2.7 mg of  NS2359 tartrate monohydrate will be manufactured 
using the techniques described  Section 5 of the main protocol and further described in the 
CMC of the IND 112053.  
 
Procedures 
 
 
In addition to the 55 of subjects already enrolled in the trial, an additional 36 subjects will 
be randomized to either 2.7 mg of NS2359 or identical placebo capsules in a ratio of 4:1. 
Twenty seven subjects will receive 2.7 mg and 9 subjects will receive placebo.  For these 36 
subjects all other study procedures will be identical to those described in the main protocol.  
 
 
Statistical Plan  
 
Sample Size Determination 
Power Analyses: For this renewal, we will combine the planned nine new placebo 
participants with the 21 already recruited, and compare their outcomes with those of the 
36 participants recruited into the high dose group. We have the same primary hypothesis 
as in the original study, namely that during the final three weeks of the medication phase 
(weeks 7-9), the high dose NS2359 group will have a lower rate of positive urine drug 
screen BE results than the placebo group. If we regard missing UDS tests as positive for 
use, then we will compare 36 to 30 participants, which yields 80% power for an odds ratio 
of 4.1 or larger (corresponding to a difference such as 30% versus 64%); if missing data 
are ignored, resulting in a 25% loss in sample size, then we have 80% power for an odds 
ratio of 5.2. 
Statistical Methods 
Data Management.  The data will be managed using Penn’s Center for the Study of 
Addiction's (CSA) direct-entry data system, and will be stored on the data management unit 
(DMU) network, as described in the original proposal.  
Data Analyses. The data analysis procedures will closely parallel those described in the 
original proposal. Dr. Kevin Lynch, PhD, the CSA Statistician, and his staff will perform the data 
analyses. The main change will be that we will combine the placebo and low dose NS2359 
participants from the current study with the additional placebo and high dose NS2359 
participants, yielding a three-group (placebo, low dose, high dose) trial. The primary comparison 
for the new proposal (high-dose versus placebo) will be tested using contrasts from the three-
group model. Apart from the change from a binary (placebo, low-dose) treatment factor to a 
three-level factor, the analytic approach for the primary and secondary analyses will exactly 
parallel that described in the original proposal. 
Missing Data and Nonadherence:  Same as original proposal 
Safety: Same as original proposal 
 
 
 
 
 


 
 
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Reference 
Lindsey KP, Wilcox KM, Votaw JR, Goodman MM, Plisson C, Carroll FI, Rice KC, Howell LL. 
Effectsof dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: 
relationship totransporter occupancy determined by positron emission tomography 
neuroimaging. J Pharmacol Exp Ther. 2004 309:959-69.