Clinical trial NCT03242928
Conditions: Cocaine-related Disorder
Keywords: Cocaine Use Disorder; cocaine dependence,AFQ056,adult, cocaine use,CUD, drug abuse, drug addiction,
Sponsor: Novartis Pharmaceuticals
Start date: 2017-12-04; Completion date: 2019-12-16
Enrollment: 68 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study assessed whether AFQ056 had a beneficial effect by reducing cocaine use in Cocaine Use Disorder (CUD) patients as assessed by Timeline Follow-Back cocaine self-report.

Detailed description:
This was a randomized, subject- and Investigator-blinded, parallel-group, placebo-controlled study in subjects with CUD. The study consisted of a 17-day screening period followed by a 12-day baseline, a 98-day outpatient treatment period (14-day up-titration dose regimen followed by 84-day maintenance dose), and an End of Study evaluation visit approximately 14 days after the last study drug administration. The total duration for each subject in the study was approximately 20 weeks including screening and baseline.

Arms: arm 1: Matching tablet of placebo taken orally BID arm 2: Mavoglurant was up titrated on a bid regimen followed by fixed-dose bid regimen: 50 mg bid from Day 1 to Day 7, 100 mg bid from Day 8 to Day 14, and then fixed-dose 200 mg bid for 84 days
Interventions: intervention 1: AFQ056 intervention 2: Placebo
Intervention descriptions: intervention 1: 50 mg and 100 mg tablets taken orally intervention 2: Matching placebo tablets taken orally BID

Protocol documents:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research
AFQ056
Clinical Trial Protocol CAFQ056X2201
A randomized, subject and investigator blinded, placebo-
controlled, parallel group study to investigate whether 
AFQ056 reduces cocaine use in patients diagnosed with 
Cocaine Use Disorder (CUD)
Document type:
Amended Protocol Version
EUDRACT number:
2017-000736-33
Version number:
v01 (Clean)
Clinical Trial Phase:
Phase II
Release date:
15-Nov-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. 
Note: The SOM does not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below. Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO & PS)
within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the SOM.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................11
Glossary of terms...............................................................................................................13
Amendment 1 (November 2017).......................................................................................15
Protocol summary..............................................................................................................17
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Nonclinical data.....................................................................................................20
1.2.1
Teratogenicity and reproductive toxicity data.......................................21
1.2.2
Summary of non-clinical pharmacokinetics and metabolism...............22
1.2.3
Nonclinical abuse and dependence potential ........................................23
1.3
Clinical data...........................................................................................................23
1.3.1
Human safety and tolerability data .......................................................23
1.3.2
Human pharmacokinetic data................................................................25
1.3.3
Human pharmacodynamics data ...........................................................27
1.4
Study purpose ........................................................................................................28
2
Objectives and endpoints...................................................................................................29
2.1
Primary objective(s)...............................................................................................29
2.2
Secondary objective(s)...........................................................................................29
2.3
Exploratory objective(s) ........................................................................................29
3
Investigational plan ...........................................................................................................30
3.1
Study design...........................................................................................................30
3.2
Rationale of study design.......................................................................................32
3.3
Rationale for dose/regimen, route of administration and duration of treatment....32
3.4
Rationale for choice of comparator .......................................................................34
3.5
Rationale for choice of background therapy..........................................................34
3.6
Purpose and timing of interim analyses/design adaptations..................................34
3.7
Risks and benefits..................................................................................................34
3.7.1
Blood sample volumes..........................................................................35
3.7.2
Risks associated with study procedures ................................................35


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4
Population..........................................................................................................................35
4.1
Inclusion criteria ....................................................................................................35
4.2
Exclusion criteria...................................................................................................36
5
Restrictions for Study Subjects .........................................................................................39
5.1
Contraception requirements...................................................................................39
5.2
Prohibited treatment...............................................................................................39
5.3
Dietary restrictions.................................................................................................40
5.4
Other restrictions ...................................................................................................40
6
Treatment...........................................................................................................................41
6.1
Study treatment......................................................................................................41
6.1.1
Investigational treatment and control drug(s) .......................................41
6.1.2
Additional study treatment....................................................................41
6.2
Treatment arms......................................................................................................41
6.3
Treatment assignment and randomization.............................................................41
6.4
Treatment blinding.................................................................................................42
6.5
Treating the subject................................................................................................44
6.6
Permitted dose adjustments and interruptions of study treatment.........................44
6.7
Emergency breaking of assigned treatment code ..................................................44
6.8
Treatment exposure and compliance .....................................................................45
6.9
Recommended treatment of adverse events ..........................................................45
6.10
Rescue medication.................................................................................................45
6.11
Concomitant treatment...........................................................................................45
7
Study completion and discontinuation ..............................................................................46
7.1
Study completion and post-study treatment ..........................................................46
7.2
Discontinuation of study treatment........................................................................46
7.3
Withdrawal of informed consent ...........................................................................48
7.4
Lost to follow-up ...................................................................................................48
7.5
Study stopping rules ..............................................................................................48
7.6
Early study termination by the sponsor .................................................................49
8
Procedures and assessments ..............................................................................................49
8.1
Assessment schedule .............................................................................................49
8.2
Informed consent procedures.................................................................................57
8.3
Subject screening...................................................................................................57
8.4
Subject demographics/other baseline characteristics.............................................58
8.5
Efficacy / Pharmacodynamics ...............................................................................58
8.5.1
Clinical Outcome Assessments (COAs) ...............................................58
8.6
Safety.....................................................................................................................60


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8.6.1
Physical examination ............................................................................60
8.6.2
Height and weight .................................................................................60
8.6.3
Laboratory evaluations..........................................................................60
8.6.4
Hematology...........................................................................................60
8.6.5
Clinical chemistry .................................................................................61
8.6.6
Urinalysis ..............................................................................................61
8.6.7
ECG evaluation.....................................................................................61
8.6.8
Pregnancy and assessment of fertility...................................................61
8.7
Pharmacokinetics...................................................................................................62
8.8
Other assessments..................................................................................................63
8.8.3
Positive Reinforcement (PR).................................................................63
8.9
Use of residual biological samples ........................................................................64
9
Safety monitoring..............................................................................................................64
9.1
Adverse events.......................................................................................................64
9.2
Serious adverse event reporting.............................................................................66
9.2.1
Definition of SAE .................................................................................66
9.2.2
SAE reporting........................................................................................67
9.3
Liver safety monitoring .........................................................................................68
9.4
Renal safety monitoring.........................................................................................69
9.5
Reporting of study treatment errors including misuse/abuse ................................69
9.6
Pregnancy reporting...............................................................................................70
9.7
Prospective suicidality assessment ........................................................................70
9.8
Early phase safety monitoring ...............................................................................71
10 Data review and database management.............................................................................71
10.1
Site monitoring ......................................................................................................71
10.2
Data collection.......................................................................................................72
10.3
Database management and quality control............................................................72
10.4
Data Monitoring Committee..................................................................................73
10.5
Adjudication Committee........................................................................................73
11 Data analysis......................................................................................................................73
11.1
Analysis sets ..........................................................................................................73
11.2
Subject demographics and other baseline characteristics......................................74
11.3
Treatments .............................................................................................................74
11.4
Analysis of the primary variable(s) .......................................................................74
11.4.1
Primary Variable(s)...............................................................................74
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11.4.2
Statistical model, hypothesis, and method of analysis..........................74
11.4.3
Handling of missing values/censoring/discontinuations.......................75
11.4.4
Sensitivity analyses ...............................................................................75
11.5
Analysis of secondary variable(s)..........................................................................75
11.5.1
Efficacy / Pharmacodynamics...............................................................75
11.5.2
Safety.....................................................................................................76
11.5.3
Pharmacokinetics ..................................................................................76
11.5.4
Pharmacokinetic / pharmacodynamics interactions..............................76
11.5.5
Other assessments .................................................................................77
11.6
Analysis of exploratory variables (if applicable)...................................................77
11.7
Sample size calculation..........................................................................................77
11.8
Power for analysis of key secondary variables......................................................79
11.9
Interim analyses.....................................................................................................79
12 Ethical considerations........................................................................................................79
12.1
Regulatory and ethical compliance........................................................................79
12.2
Responsibilities of the investigator and IRB/IEC..................................................79
12.3
Publication of study protocol and results...............................................................80
12.4
Quality Control and Quality Assurance.................................................................80
13 Protocol adherence ............................................................................................................80
13.1
Protocol Amendments ...........................................................................................80
14 References .........................................................................................................................82
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................83
16 Appendix 2: Specific Renal Alert Criteria and Actions....................................................85
17 Appendix 3: Drugs affecting CYP3A4..............................................................................87
List of tables
Table 6-1
Overview of study medication ..............................................................41
Table 6-2
Randomization assignment numbering.................................................42
Table 6-3
Blinding levels ......................................................................................43
Table 8-1
Assessment schedule.............................................................................50
Table 9-1
Guidance for capturing study treatment errors......................................69
Table 15-1
Liver Event Definitions.........................................................................83
Table 15-2
Actions required for Liver Events.........................................................83
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Table 15-3
Exclusion of underlying liver disease ...................................................84
Table 16-1
Specific Renal Alert Criteria and Actions.............................................85
Table 16-2
Follow-up of renal events......................................................................86
List of figures
Figure 3-1
Study Design .........................................................................................30
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List of abbreviations
AA
anonym alcoholic
ACR
albumin-creatinine ratio
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BE
Benzoylecgonine 
BID
twice a day
BMI
Body Mass Index
C-SSRS
Columbia Suicide Severity Rating Scale
CFR
U.S. Code of Federal Regulation
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
CNS
Central nervous system
CO2
carbon dioxide
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSF
Clinical Service Formulation
CUD
Cocaine Use Disorder
DMC
Data Monitoring Committee
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition.
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
eSource
Electronic Source
EtG
Ethyl Glucuronide 
FDA
Food and Drug Administration
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FXS
Fragile X Syndrome
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator's Brochure
i.v.
intravenous
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
lactate dehydrogenase
LFT
Liver function test
mAIMS
modified Abnormal Involuntary Movement Scale
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MTD
maximum tolerated dose
p.o.
oral
PA
posteroanterior
PCR
protein-creatinine ratio
PD
pharmacodynamic(s)
PD-LID
Parkinson’s disease - L-dopa induced dyskensia
PIP
pediatric investigation plan
PK
pharmacokinetic(s)
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PPND
pre- and post-natal development
PSD
Premature subject discontinuation
PT
prothrombin time
RBC
red blood cell(s)
RO
receptor occupation
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SOM
Site Operations Manual
SSRI
Selective serotonin reuptake inhibitors
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TLFB
Timeline Follow-Back
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
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Pharmacokinetic definitions and symbols
Ae0-t
Amount of drug (or defined metabolite) excreted into the urine from time zero 
to time 't' where t is a defined time point after administration [mass units or % 
of dose]
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to time 't' where t is a defined time point after administration [mass x 
time / volume]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to infinity [mass x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the time of the last quantifiable concentration [mass x time / 
volume]
AUCtau
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau [mass x time / volume]
AUCtau,ss
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau at steady state [mass x time / 
volume]
Cav,ss
The average steady state plasma (or serum or blood) concentration during 
multiple dosing
CL
The systemic (or total body) clearance from plasma (or serum or blood) 
following intravenous administration [volume / time]
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or 
blood) following extravascular administration [volume / time]
CLr
The renal clearance from plasma (or serum or blood) [volume / time]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Cmax,ss
The observed maximum plasma (or serum or blood) concentration following 
drug administration at steady state [mass / volume]
Cmin,ss
The lowest plasma (or serum or blood) concentration observed during a dosing 
interval at steady state [mass / volume]
F
Bioavailability of a compound. Fabs is the absolute bioavailability, i.e. the 
fraction (or percentage) of the administered extravascular dose systemically 
available. Frel is the relative bioavailability, i.e. the bioavailability relative to a 
reference
MRT
Mean residence time determined as AUMCinf/AUCinf following intravenous 
administration [time]
Racc
The accumulation ratio
T1/2
The terminal elimination half-life [time]


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T1/2,acc
The effective half-life based on drug accumulation at steady state [time]
Tmax
The time to reach the maximum concentration after drug administration [time]
Vss
The volume of distribution at steady state following intravenous administration 
[volume]
Vss/F
The apparent volume of distribution at steady state following extravascular 
administration [time]
Vz
The volume of distribution during the terminal elimination phase following 
intravenous administration [volume]
Vz/F
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [volume]


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) which 
is used as a comparator to the investigational drug being tested in the 
trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at the 
point of care.
Enrollment
Point/time of subject entry into the study at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated 
with a purpose (e.g. screening, randomization, treatment, follow-up) 
which applies across all arms of a study.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource combines source 
documents and case report forms (eCRFs) into one application, allowing 
for the real time collection of clinical trial information to sponsors and 
other oversight authorities, as appropriate.
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug,” 
"Investigational Medicinal Product," or “test substance”
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest


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Randomization 
number
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment
Run in Failure
A subject who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to subject’s medications 
or other intervention)
Screen Failure
A subject who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study treatment
Any drug or combination of drugs administered to the study participants 
as part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study related 
contact, and does not allow analysis of already obtained biologic material


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Protocol summary
Protocol number
CAFQ056X2201
Full Title
A randomized, subject and investigator blinded, placebo-controlled, parallel 
group study to investigate whether AFQ056 reduces cocaine use in patients 
diagnosed with Cocaine Use Disorder (CUD).
Brief title
Study to investigate whether AFQ056 reduces cocaine use in patients 
diagnosed with Cocaine Use Disorder (CUD).
Sponsor and 
Clinical Trial 
Phase
Novartis
Phase II
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
The main purpose of this study is to evaluate whether AFQ056 can have a 
beneficial effect by reducing cocaine use in Cocaine Use Disorder (CUD) 
patients as assessed by Timeline Follow-Back (TLFB) cocaine self-report 
(TLFB, Sobell and Sobell 1996). 
Primary 
Objective(s)

To evaluate treatment effect of 98-day AFQ056 administration in reducing
cocaine use.
Secondary 
Objectives

To assess the effects of 98-day AFQ056 administration versus placebo on:

other measures of cocaine use

alcohol use

To assess the safety and tolerability of multiple bid oral doses of AFQ056.

To evaluate the pharmacokinetics of AFQ056.
Study design
This is a randomized, subject and investigator blinded, parallel group, placebo-
controlled study.  The total duration for each patient in the study is up to 
approximately 20-weeks including periods of: screening, baseline, treatment, 
observational follow-up and end of study. The entire study is to be run in 
outpatient setting.
Population
Male and female subjects, 18 to 65 years of age (inclusive) diagnosed with 
Cocaine Use Disorder according to DSM 5 (Diagnostic and Statistical Manual 
of Mental Disorders, 5th Ed.).
Key Inclusion 
criteria

Understand the study procedures and provide written informed consent
before any assessment is performed.

Male and female subjects, 18 to 65 years of age (inclusive)  and diagnosed
with Cocaine Use Disorder according to DSM 5 (Diagnostic and Statistical
Manual of Mental Disorders, 5th Ed.).

Must use cocaine through snorting (intranasally) as primary route of
administration.

Recent cocaine use confirmed by positive urine screen for 1 or more
benzoylecgonine (BE).

Must be seeking treatment for cocaine dependence and have a desire to
reduce or cease cocaine use.
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Key Exclusion 
criteria

Has current diagnosis of Substance Use Disorder (according to the DSM 5)
on alcohol, cannabis or other stimulants, except cocaine.

Meets current or lifetime DSM 5 criteria for schizophrenia or any psychotic
disorder, or organic mental disorder.
Notes: Subjects diagnosed with other psychiatric disorders may be included
at the discretion of the PI provided that the concurrent treatment for the
comorbid psychiatric condition will not interfere with completion of the study
or place the patient at heightened risk through participation in the trial.

Have current treatment for Substance Use Disorder (e.g.: disulfiram,
acamprosate, methyl phenidate, modafinil, topiramate, immediate release
dexamfetamine,or baclofen).

Pregnant or nursing (lactating) women, where pregnancy is defined as the
state of a female after conception and until the termination of gestation,
confirmed by a positive hCG laboratory test

Have a history of any illness, condition, and use of medications that in the
opinion of the investigator or designee might confound the results of the
study or pose additional risk in administering the investigational agents to
the subject or preclude successful completion of the study

Current or/and previous treatment with concomitant medications that are
strong or moderate inducers/inhibitors of CYP3A4 (e.g., clarithromycin,
ketoconazole, ritonavir, etc.)

History of immunodeficiency diseases, including a positive HIV (ELISA and
Western blot) test result.

Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV).

Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the C-
SSRS, if this ideation occurred in the past 6 months, or “yes” on any item of
the Suicidal Behavior section, except for the “Non-Suicidal Self-Injurious
Behavior” (item also included in the Suicidal Behavior section), if this
behavior occurred in the past 2 years.

Controlled hypertension
Study treatment

AFQ056 50 mg bid for 7 days followed by AFQ056 100 mg bid for next 7
days and then fixed dose of 200 mg bid for 84 days.

Placebo - matched for 98 days.
Pharmacokinetic 
assessments

AFQ056 plasma concentrations (pre- and 3 h post-dose levels).
Key Efficacy/PD 
assessments

Proportion of cocaine use days delivered from TLFB cocaine self-report.

Cocaine Benzoylecgonine (BE) as delivered from urinalysis.

Alcohol consumption as delivered from TLFB alcohol self-report.
Key safety 
assessments
Vital 
signs, 
ECG 
parameters, 
clinical 
safety 
laboratory 
parameters 
(chemistry/hematology/urinalysis), (serious) adverse events reporting, suicidal 
ideation (Columbia Suicide Severity Rating Scale (C-SSRS).
Other 
assessments
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Data analysis
Primary variable: a Bayesian analysis will be conducted on the proportion of 
cocaine use days.
Key words
Cocaine Use Disorder; cocaine dependence
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1
Introduction
1.1
Background
Cocaine use in the United States is a significant public health concern, leading to loss of 
income, use of public services, and mortality. The results from the 2012 National Survey on 
Drug Use and Health (2013) shows that 1.6 million Americans aged 12 or older were current 
cocaine users (including crack cocaine), comprising 0.6% of the population. Despite this 
widespread use, there are currently no approved medications for the treatment of cocaine use 
disorder, therefore there is a high medical need.
AFQ056 (mavoglurant) is a structurally novel, subtype-selective, non-competitive antagonist 
at the mGlu5 receptors. It is an allosteric modulator, an emerging class of orally available 
small molecule therapeutic agents. Cocaine Use Disorder (CUD) is associated with 
dysregulated glutamate neurotransmission. Preclinical studies indicate that the modulation of 
glutamate signaling through the antagonism of the mGlu5 receptor can attenuate cocaine 
mediated drug induced behaviors such as drug seeking, self-administration and re-instatement 
(relapse) (Lee et al 2005).
AFQ056 has been demonstrated to be generally safe and well tolerated in several Phase I and 
II/III studies in Fragile X Syndrome (FXS); Levodopa-induced dyskinesia in Parkinson’s 
disease (PD-LID) and in Obsessive Compulsive Disorder (OCD). While the full development 
programs for FXS and PD-LID were discontinued due to lack of efficacy in these indications, 
the compound was found to have good tolerability and due to its mechanism of action, 
remains of high interest in other CNS disorders associated with excessive glutamatergic 
transmission.
The most relevant data for the present study are summarized in the sections below. For 
detailed information, please refer to the Investigator's Brochure.
1.2
Nonclinical data
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1.2.1
Teratogenicity and reproductive toxicity data
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1.2.2
Summary of non-clinical pharmacokinetics and metabolism
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1.2.3
Nonclinical abuse and dependence potential
1.3
Clinical data
1.3.1
Human safety and tolerability data
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1.3.1.1
Abuse and dependence potential – human data
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1.3.2
Human pharmacokinetic data
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1.3.3
Human pharmacodynamics data
Efficacy in patients with PD-LID
The efficacy of AFQ056 in PD patients with LID was assessed in six patient studies, five 
using the IR formulation and one (CAFQ056A2223) using the MR formulation. Efficacy on 
LIDs, as measured by the mAIMs, was shown in three of the six studies as summarized below. 
Studies with similar designs are grouped.
Proof of Concept studies (CAFQ056A2203 and CAFQ056A2206): In a pooled analysis of the 
efficacy data for these two PoC studies , reduction of LIDs was observed using the mAIMS, 
UPDRS-Part IV, and the activities of daily living using the Lang- Fahn Scale Activities of 
Daily Living Dyskinesia Scale (LFADLDS). The difference in mean change from baseline to 
day 16 for AFQ056 treated patients vs placebo was -5.4 points (improvement) on the mAIMs 
total score (Berg et al 2011).
Dose finding study (CAFQ056A2208): The primary efficacy objective in study 
CAFQ056A2208 was to compare the antidyskinetic effect of five fixed doses of AFQ056 (10, 
25, 50, 75, and 100 mg bid.) vs. placebo (Stocchi et al 2013). The primary analysis (mAIMS) 
showed statistical significance vs. placebo at the dose of AFQ056 100 mg bid. (p=0.007) and 
there was a trend for significant improvement in patients treated with AFQ056 at 25 mg bid. 
Analysis of the mAIMS by final actual dose of AFQ056 demonstrated a monotonic ascending 
dose-response relationship with highest change from baseline at the AFQ056 100 mg bid. 
dose. For the 100 mg bid dose, the adjusted change from baseline (standard error [SE]) was -
5.7 (0.75) points and difference vs placebo was -2.8; Secondary assessments: the overall F-
test for dyskinesia duration (item 32 of UPDRS part IV) was significant and pair-wise 
comparisons for dyskinesia duration were significant for the AFQ056 25 mg and 100 mg bid 
treatment groups vs. placebo. There were no statistically significant differences on any other 
secondary assessments including the Clinical Global Impression of Change (CGIC), Patient 
Global Impression of Change, patient diary or disability due to dyskinesia (26-Item Parkinson 
Disease Dyskinesia Scale).
Efficacy in patients with Fragile X Syndrome
Study CAFQ056A2204 was a placebo controlled crossover study evaluating AFQ056 150 
mg .i.d. (n=30). The primary efficacy variable (ABC-C) was assessed at Day 19. No 
beneficial effect of AFQ056 over placebo on ABC-C total score and sub scores was observed 
at Day 19.
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Study CAFQ056A2212 was a large double blind parallel group randomized controlled trial 
comparing three doses of AFQ056 (25, 50, and 100 mg bid.) to placebo in a total of 175 adult 
patients aged 18 to 45 years with FXS. The study population was stratified based on the extent 
of methylation of the FMR1 gene (methylation status). The primary objective was to assess 
the efficacy of the three doses of AFQ056 versus placebo in reducing the ABC-C Total score 
(using the FXS specific algorithm - ABC-CFX) after 12 weeks of treatment in FXS patients 
with FM FMR1 gene. The study was considered to have achieved its primary objective if at 
least one of the AFQ056 doses was statistically significantly better than placebo in FXS 
patients with FM FMR1 gene after adjustment for multiplicity. Of note, the baseline values of 
the efficacy variables were after 4 weeks of placebo run-in and an improvement in ABC-CFX 
is indicated by a lower post-baseline score. The LS mean changes from baseline were -11.4 
for the placebo group, -14.3 for the AFQ056 25 mg bid treatment group, +1.8 for the AFQ056 
50 mg bid treatment group, and -1.8 for the AFQ056 100 mg bid treatment group. Hence, the 
greatest improvement in ABC-CFX total score was seen in the AFQ056 25 mg bid treatment 
group. However, no statistical significance was reached in favor of any of the three AFQ056 
treatment groups over placebo at the significance level with multiplicity adjustment. Even 
though the p-value of comparing AFQ056 50 mg bid to placebo reached statistical 
significance in favor of placebo, the positive change in ABC-CFX total score for the 50 mg 
bid. AFQ056 treatment group was small and should not be viewed as worsening of symptoms, 
especially since the final score for the AFQ056 50 mg bid dose group was lower than the 
mean score at Screening.  
Study CAFQ056A2214 was a large double blind parallel group randomized controlled trial 
comparing three doses of AFQ056 (25, 50, and 100 mg bid.) to placebo in a total of 139 
adolescent patients with FXS, aged 12 to 17 years inclusive. The study population 
stratification and study methodology were similar to those in the adult study 
(CAFQ056A2212). In FM patients, the LS mean changes from baseline were –9.4 for the 
placebo group, -11.8 for the AFQ056 25 mg bid treatment group, -3.4 for the AFQ056 50 mg 
bid treatment group, and +8.6 for the AFQ056 100 mg bid treatment group. Hence, the 
greatest improvement in ABC-CFX total score was seen in the placebo group. In comparing 
the AFQ056 100 mg bid to placebo on change from baseline at Week 12 for the ABC-CFX 
total score, a statistically significant difference was observed at the significance level of 
multiplicity adjustment in the FM stratum (p=0.004). However, it was not in favor of AFQ056 
100 mg bid.
1.4
Study purpose
Background
Cocaine use has become the third most common reason (after opiate and cannabis use) for 
patients in Europe to enter drug abuse treatment. Currently, no pharmacological treatment of 
proven efficacy exists for cocaine addiction. AFQ056 is a mGlu5 receptor antagonist and has 
shown to reduce cocaine-seeking behavior in animal models. 
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Purpose
The main purpose of this study is to evaluate whether AFQ056 can have a beneficial effect by 
reducing cocaine use in Cocaine Use Disorder (CUD) patients as assessed by Timeline 
Follow-Back (TLFB) cocaine self-report (TLFB, Sobell and Sobell 1996), a validated and 
widely employed method in stimulant abuse trials.
2
Objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To evaluate treatment effect of 98-day
AFQ056 administration in reducing
cocaine use.

Proportion of cocaine use days by TLFB
cocaine self-report.
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the effects of 98-day AFQ056
administration versus placebo on:
a) other measures of cocaine use
b) alcohol use

a) Urinalysis (cocaine Benzoylecgonine
(BE)
b) TLFB alcohol self-report

To assess the safety and tolerability of
multiple bid oral doses of AFQ056.

Vital signs, ECG parameters, clinical
safety laboratory parameters
(chemistry/hematology/urinalysis),
(serious) adverse events reporting,
suicidal ideation (Columbia Suicide
Severity Rating Scale (C-SSRS).

To evaluate the pharmacokinetics of
AFQ056.

AFQ056 plasma concentrations (pre- and
post-dose levels).
2.3
Exploratory objective(s)
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3
Investigational plan
3.1
Study design
This is a randomized, subject and investigator blinded, parallel group, placebo-controlled 
study in approximately 60 patients with CUD. The study consists of: about 17-day screening 
period followed by a 12-day baseline; a 98-day out-patient treatment period (14-day up-
titration dose regimen followed by 84-day maintenance dose) and finally an end of study visit 
evaluation approximately 14-days after the last study drug administration. The total duration 
for each patient in the study is up to approximately 20-weeks including screening and baseline.  
The study design is summarized in Figure 3-1 below.
Figure 3-1
Study Design
Study visits: (days 1-113): study visits will be performed in an ambulatory setting of 
frequency twice per week. During these visits the urine samples will be collected for cocaine's 
metabolite benzoylecgonine (BE) and other illicit drug, as applicable, along with 
safety/efficacy assessments as specified in the Assessment schedule.
Screening (days -28 to -11): includes safety examinations and other clinical tests, determines 
patients' initial eligibility. Patients who meet the eligibility criteria at screening will be 
admitted to the baseline evaluation. For all examinations to be done at screening, refer to the 
Assessment schedule.
Baseline (days -13 to -1): includes, in addition to the safety evaluations, a patient's self-
assessment on various scales and questionnaires (see Section 8.5.1). During baseline, a history 
of self-reported cocaine use (TLFB) and two urine samples collected on two different days 
with second sample collected 3 days prior randomization must demonstrate the abstinence 
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from cocaine use. For all examinations to be done at baseline, refer to the 
Assessment schedule.
Treatment (days 1-98): following baseline, on Day 1, approximately 60 eligible patients will 
be randomly assigned in a 1:1 ratio to either AFQ056 or placebo

Group A - AFQ056: up-titration regimen for the first 2 weeks (14 days): 50 mg bid from
Day 1 to Day 7 , 100 mg bid from Day 8 to Day 14 , followed by dosing at 200 mg bid for
84-days

Group B: matching placebo.
Study drug: must be taken twice daily (bid) in the morning and evening (separated by 
approximately 12 hour intervals) with food. For all ambulatory morning visits that involve 
any study assessments or PK/urine sample collection, study medication will be self-
administered by patient at study center and supervised by study personnel. On these days, 
standard breakfast should be served at study center and consumed by the patient during 
his/her medication intake. 
During treatment period, patients will also undergo assessments with various scales and 
questionnaires, as well as safety assessments and pharmacokinetic sampling at pre- and 2 ± 1-
hour post dose per SoA. For a detailed outline of all study assessments and time points refer to 
the Assessment schedule.
Urine samples (days1-113): samples will be collected at study center twice per week, with at 
least 48 hours separating tests. The sample collection will be assayed quantitatively for the 
presence of cocaine's metabolite (benzoylecgonine (BE), as well as, other illicit drugs may be 
assayed. It is expected that a total of approximately 33 urine samples will be collected during 
study conduct: 28 samples from patients who remain in treatment for the 14 weeks (total of 4 
samples: weeks 1–2 of up-titrations); 24 samples in weeks 3–14 (maintenance dose); 4 
samples in weeks 15–16 (follow up) and finally 1 last sample at end of study visit. If a patient 
fails to attend the clinic or refuses to provide a sample on a scheduled testing day, samples 
will be considered positive unless an excused absence is granted (e.g.. illness, other personal 
reason). In cases of missed or refused samples, samples should be collected on the next day 
whenever possible.
Clinical support to ensure medication and protocol's adherence:

Positive Reinforcement (PR): on top of study treatment, all patients will receive weekly
at site the Positive Reinforcement (PR) with the focus on patients' adherence to the
medication and study procedures. Detailed description of PR techniques will be provided
to the participating sites in a separate document.

Medication compliance: 
patients will be at the study site at time of study drug
administration for the morning dose on PK collection days and on all other days that
involves urine sampling assessments. On these days study medication self-administration
will be supervised by study personnel. It is recommended to the site personnel to check
patient's mouth to ensure that the medication(s) has(ve) been swallowed. To monitor
medication adherence, patients will be provided with individual Medication Diary
(booklet) to record administration of study medication. Medication compliance will be
monitored by the Investigator and/or study personnel at least on a weekly basis using
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Diary self-reported data against the total number of tablets in the returned bottle or blister 
(depends on the packaging form). Adherence will be calculated as the total amount of 
tablets taken divided by the scheduled total amount to be taken during the treatment phase. 
If the Investigator feels it is appropriate, the patient may also be contacted during the out-
patient periods to confirm compliance.
3.2
Rationale of study design
The design of this trial has been selected to adequately assess the primary objective and 
follows the similar design of trials for substance use disorders (American Psychiatric 
Association (APA) Practice Guidelines, 2006). Furthermore, randomized subject and 
investigator blinded control design are considered as “validated method in stimulant abuse 
trials” and parallel treatment group design was selected due to the long duration of treatment.
The entire study treatment duration of 98 days will be conducted in an outpatient treatment 
setting, which is a commonly used setting in treatment of substance use disorders 
(UNODC-WHO, 2016) and appropriate for the purpose of this study. The outpatient setting in 
this study includes frequent visit schedule (twice/week) in conjunction with urine sample 
collection; weekly monitoring of medication and study assessment adherence and safety 
adverse event monitoring. As an outpatient setting may increase the likelihood of patients 
dropping out of treatment, weekly interventions of Positive Reinforcement techniques are 
introduced with the focus on patient's adherence to the protocol’s procedures and medication
compliance.
For primary objective, daily cocaine use will be determined using TLFB self-report, which is 
a ''gold standard'' for measurement of substance use (Robinson et al 2012). For secondary 
objective, cocaine use will be determined twice/week by urine drug screen
Frequency of urine sample collection was scheduled in accordance 
with the halflife of cocaine metabolites BE in urine (3-4 days). 
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The dose selected (200 mg bid with modified release formulation) for evaluation in this study 
has been chosen based on the safety, tolerability of dose, regimen and pharmacokinetic data 
from completed healthy volunteers and patient studies including modeling and simulation of 
PK and RO profiles. A total of 2159 study subjects have been enrolled in a total of 42 
completed human studies with AFQ056. Dosage of 200 mg bid have been shown to be safe 
and tolerable.
During clinical development, majority of the studies were conducted using immediate release 
(CSF, MF) capsule formulations for oral administration. Nevertheless, there were some 
challenges experienced with the immediate release formulation as most of the AFQ056-
mediated AEs (dizziness, insomnia, and headache) appear to be peak plasma concentration 
dependent. As a result, a modified release (MR) formulation of AFQ056 has been developed 
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with the goal of reducing peak plasma concentrations while maintaining optimal exposure (i.e. 
reducing Cmax/AUC ratio).
The maximum anticipated therapeutic dose levels of AFQ056 are 150 mg bid. (CSF 
formulation – immediate release), 100 mg bid. (MF- IR formulation) or 200 mg bid. (MR 
formulation).
In the proposed CUD study it is assumed that patients will have certain levels of cocaine when 
receiving AFQ056. Chronic cocaine administration has been reported to induce CYP3A4 in 
rodents (Pellinen et al 1996) and P-glycoprotein, an efflux transporter. AFQ056 is primarily 
eliminated via metabolism catalyzed by multiple CYP isoenzymes (incl. CYP1A1, 2C9, 2C19, 
3A4) and possibly by UGT isoenzymes. Thus one cannot rule out that the AFQ056 levels may 
be altered (lowered) in subjects with long term cocaine use. Thus lowering of AFQ056 levels 
may affect efficacy rather than posing a safety risk.
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Up-titration regimen: Data from three patients studies (CAFQ056A2203, CAFQ056A2206 
and AFQ056A2225) indicated that the up-titration period will allow patients to adapt towards 
any side effects and thus have a better chance of tolerating the target dose of 200 mg bid.. 
3.4
Rationale for choice of comparator
As there are currently no approved medications for the treatment of Cocaine Use Disorder, 
placebo is the only relevant comparator to be used in this study. . 
3.5
Rationale for choice of background therapy
Not applicable.
3.6
Purpose and timing of interim analyses/design adaptations
Due to the small sample size for this type of population, no IA planned for this trial. 
3.7
Risks and benefits
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring. Women of child bearing potential must be informed that taking the study 
treatment may involve unknown risks to the fetus if pregnancy were to occur during the study, 
and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the Section 4.2 (Exclusion Criteria). If there is any question that the 
subject will not reliably comply, they should not be entered or continue in the study.
Sexually active males must be informed of the requirement to wear a condom for the 
following reasons:

Prevent pregnancy in a female partner
AND

Prevent  delivery of investigational drug via seminal fluid to their partner as study
treatment may involve unknown risks to the fetus if pregnancy were to occur
Although, AFQ056 has been tested in more than 2000 subjects, and it has been shown to be 
safe and well tolerated it may be unknown risk associated to AFQ056.The most frequent side 
effects of the study medicine include: headache, dizziness, initial insomnia, feeling drunk and 
euphoric mood. In addition visual hallucinations have been reported after single intakes of 
high doses of the study drug (3 to 4 times of the highest dose used in this study) and in 
chronic smokers. The different studies performed in healthy volunteers and patients showed 
that AFQ056 is well tolerated also when given over a period of several weeks.
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3.7.1
Blood sample volumes
A maximum of up to 500 mL of blood is planned to be collected over a period of 14 weeks of 
treatment, from each subject as part of the study. Additional samples may be required for 
safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule (Section 8.1).
A summary blood log is provided in the Site Operations Manual. Instructions for all sample 
collection, processing, storage and shipment information is also available in the Bioanalytics 
Study Specifications (BSS) and Central Laboratory Manual.
3.7.2
Risks associated with study procedures
In this study the tests done at each visit are standard medical tests. The most unpleasant is 
often having blood samples taken. The risks of taking blood may include fainting, pain and/or 
bruising at the site of needle or canula insertion.  Rarely, a small blood clot or infection could 
occur that would require treatment. at the site of the needle puncture. The blood pressure cuff 
may also cause discomfort or bruising to the upper arm. There is also a chance for redness or 
irritation of the skin where the sticky electrode patches are placed during the heart tracing test 
(electrocardiogram).
4
Population
CUD patients
A total of approximately 60 patients, aged of 18-65 inclusive with a diagnosis of CUD who 
use cocaine through snorting (intranasally) will be enrolled in the study.
The investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria(s). No additional criteria should be applied by the investigator, in 
order that the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all eligibility criteria at screening 
and baseline. A relevant record (e.g. checklist) of the eligibility criteria must be stored with 
the source documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
4.1
Inclusion criteria
CUD patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Understand the study procedures and provide written informed consent before any
assessment is performed.
2. Male and female subjects, 18 to 65 years of age (inclusive) and diagnosed with Cocaine
Use Disorder according to DSM 5 (Diagnostic and Statistical Manual of Mental Disorders,
5th Ed.).
3. Must use cocaine through snorting (intranasally), as primary route of administration.
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4. Recent cocaine use confirmed by positive urine screen for 1 or more benzoylecgonine
(BE).
5. Must be seeking treatment for cocaine dependence and have a desire to reduce or cease
cocaine use as per goals assessed at baseline.
6. Must be abstinent from cocaine use for at least 3 days preceding 1st dosing (Day 1) as
assessed by self-report TLFB. The two urine drug screen samples at v2 and v3 must show
a decrease in BE level or both must be negative.
7. Must be in good health as determined by medical history, physical examination, at
screening.
8. At screening and baseline, vital signs (systolic and diastolic blood pressure and pulse rate)
must be within the acceptable ranges by the investigator considering the cocaine's
increasing effect on pulse rate in order for the subject to qualify. The investigator may be
guided to use the below ranges:

systolic blood pressure, 90-150 mmHg

diastolic blood pressure, 50-90 mmHg
Three readings are acceptable. At least the one of three readings must be within the
acceptable ranges.
9. Patients must be able to:

communicate well verbally with the Investigator and to understand written
instructions.

verbalize a willingness to complete all study procedures.

verbally acknowledge that she/he will be able to attend each scheduled visit, and that
she/he does not have any already scheduled events or activities that may substantially
interfere with study participation.
4.2
Exclusion criteria
CUD patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. History of hypersensitivity to any of the study treatments or excipients or to drugs of
similar chemical classes.
2. Has current diagnosis moderate or severe Substance Use Disorder (according to the DSM
5) on alcohol, cannabis, opioids or other stimulants, except cocaine.
3. Meets current or lifetime DSM 5 criteria for schizophrenia or any psychotic disorder or
organic mental disorder.
Notes: Subjects diagnosed with other psychiatric disorders may be included at the
discretion of the PI provided that the concurrent treatment for the comorbid psychiatric
condition will not interfere with completion of the study or place the patient at heightened
risk through participation in the trial.
4. Have current treatment for Substance Use Disorder (e.g.: disulfiram, acamprosate, methyl
phenidate, modafinil, topiramate, immediate release dexamfetamine, or baclofen).
5. Requires treatment with any psychoactive medications, including any anti-seizure
medications (with an exception of medications used for short-term treatment of insomnia)
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
SSRI’s are allowed if they have adequate stable dose for at least 1 month prior to
study treatment dosing
6. Use of other investigational drugs at the time of screening, or within 5 half-lives of
enrollment, or within 30 days, whichever is longer; or longer if required by local
regulations.
7. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test
8. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using effective methods* of contraception during
dosing and for 30 days after last dosing of study medication.
*Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject).  Note: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. Note:
In case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the
study, the vasectomized male partner must be the sole partner for that subject

Barrier methods of contraception: Condom or Occlusive cap (diaphragm
orcervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository;
Placement of an intrauterine device (IUD) or

intrauterine system (IUS)
Hormonal contraceptives that are injected or implanted or administered orally or 
transdermally cannot be considered as effective methods of contraception if taken with 
study medication.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of  vasomotor symptoms)
Note: In case the local requirement differs from the contraception methods listed above, 
local regulations would apply and it will be described in the ICF.
9. History of Porphyria.
10. History or presence of malignancy of any organ system, (other than localized basal cell
carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5
years, regardless of whether there is evidence of local recurrence or metastases
11. Have a history of any illness, condition, and use of medications that in the opinion of the
investigator or designee might confound the results of the study or pose additional risk in
administering the investigational agents to the subject or preclude successful completion
of the study
12. Any surgical or medical condition which might significantly alter the absorption,
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case of participation in the study. The Investigator must make this determination in 
consideration of the subject’s medical history and/or clinical or laboratory evidence of the 
following, at screening:

Clinical laboratory values (including AST, ALT, total bilirubin or creatinine)
considered as not clinically acceptable for CUD population, in the opinion of the
Investigator, at screening:

ALT, serum bilirubin must not exceed 2 x ULN

GGT, AST and alkaline phosphatase must not exceed 5 x ULN.
In the case where a safety laboratory assessment at screening is outside of the range 
specified above, the assessment may be repeated once prior to randomization. If the repeat 
value remains outside of the specified ranges, the subject is excluded from the study.
13. Current or/and previous treatment with concomitant medications that are strong or
moderate inducers/inhibitors of CYP3A4 (e.g., clarithromycin, ketoconazole, ritonavir,
etc.).
Note: Concomitant medications that are strong or moderate inducers/inhibitors of
CYP3A4 should have been stopped at least 5 half-lives prior to first dosing.
14. Concomitant use of agents known to prolong the QT interval unless these can be
permanently discontinued for the duration of study.
15. History or current diagnosis of ECG abnormalities,  at screening or baseline, indicating
significant risk of safety for subjects participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular
tachycardia, and clinically significant second or third degree AV block without a
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes

QTcF > 450 msec (males) ;  QTcF > 460 msec (females)
Note : sinus tachycardia, left axis deviation, and nonspecific ST or T wave changes are not
exclusionary
16. Known history or presence of cardiovascular or cerebrovascular disease such as: angina
pectoris, myocardial infarction, stroke, transient ischemic attack, peripheral vascular
disease.
17. History of immunodeficiency diseases, including a positive HIV (ELISA and Western
blot) test result.
18. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV).
19. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this
ideation occurred in the past 6 months, or “yes” on any item of the Suicidal Behavior
section, except for the “Non-Suicidal Self-Injurious Behavior” (item also included in the
Suicidal Behavior section), if this behavior occurred in the past 2 years.
20. Patient  cannot :

anticipate any significant problems with transportation arrangements or available time
to travel to the study site and have any plans to move within the next months to a
location which would make continued participation in the study impractical

be involved in any unresolved legal problems that could jeopardize continuation or
completion of the study


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21. Patients with controlled hypertension i.e. patient diagnosed for hypertension and taking
anti-hypertensive treatment must be excluded from this study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Restrictions for Study Subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
5.1
Contraception requirements
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirement outlined 
in the Section 4.2 (Exclusion Criteria). If there is any question that the subject will not reliably 
comply, they should not be entered or continue in the study.
5.2
Prohibited treatment
Use of the following treatments/therapies are NOT allowed during the study:

Cognitive Behavioral Therapy (CBT) or other similar interventional behavioral
therapy(ies). Group therapies and support groups (such as AA) are allowed, provided the
patients have been on such therapies for at least 3 months before screening, and therapies
are continuing during the conduct of the study.

Glutamatergic drugs due to potential mechanistic interactions with AFQ056

Moderate or strong inducers/inhibitors of CYP3A4 – potential for increased/decreased
metabolism of AFQ056 ( see Section 17)

Lithium– narrow therapeutic windows and not enough data regarding potential
interactions between AFQ056 and these compounds

Unstable treatment (unstable dose) with domperidone, antidepressants, and anxiolytics
(see below *) – multiple potential interactions confounding the safety of AFQ056,
especially when doses are adjusted

Typical or atypical neuroleptic agents – risk of malignant neuroleptic syndrome when
dopaminergic medication is adjusted

Any pharmacotherapy with a potentially effective drug for cocaine dependence (i.e.
disulfiram, acamprosate, methyl phenidate, modafinil, topiramate, immediaterelease
dexamfetamine, or baclofen) – potential for confounding the safety and/or efficacy of
AFQ056
Notes:
SSRI are not allowed unless patients are on stable dose regimen and this dose is maintained 
over Screening and Baseline and being maintained stable during the treatment period. 
Short-acting benzodiazepines used occasionally (e.g. against insomnia) are permitted 


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5.3
Dietary restrictions 

Cruciferous vegetable consumption (e.g. Brussel sprouts, broccoli, cabbage, cauliflower)
should be limited to 1-2 times per week (due to the potential interaction with CYP 450
enzymes (Nakajima et al 2001).

No grapefruit or grapefruit juice is to be consumed for 14 days prior to dosing until 7 days
following the last dose.

In order to avoid wide variations in urine volumes, patients should be encouraged to have
a fluid intake of approximately 240 mL every 4 hours during their waking hours, in
addition to the fluid taken with meals and medication.
Dosing regimen:
Study medication will be provided in bottles. Patients should take one tablet in the morning 
with solid food (i.e. breakfast/morning meal) and one tablet in the evening with solid food (i.e. 
dinner/evening meal). The morning and evening doses should be taken at approximately 12-
hour intervals. Study medication should be administered with a glass of water, and taken with 
a meal as described above. Patients should not chew the medication, but swallow it whole. 
Patients should avoid drinking grapefruit juice during the study.
Missed doses:

If a patient misses a dose of study medication for any reason, the patient should not make
up the missed dose with the next scheduled dose.

If a patient misses a dose and realizes it within 3 hours, he/she should take the missed
doses immediately; if a patient realizes it after 3 hours and more the doses is missed and a
patient should take the next planned doses.

The dosing regimen should be overseen by a caregiver, where appropriate, to ensure the
dosing regimen is correctly followed.
5.4
Other restrictions
Not applicable.


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6
Treatment
6.1
Study treatment
The investigational drug AFQ056 50mg, 100mg tablets and placebo will be prepared by 
Novartis and supplied to the Investigator as single blind patient specific medication pacs. 
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the SOM.
6.1.1
Investigational treatment and control drug(s)
Table 6-1
Overview of study medication
Study drug name
Formulation
mg per tablet
Packaging
Provided by
AFQ056 50mg
Tablet
50mg
Single blind patient specific kits
Novartis
AFQ056 100mg
Tablet
100mg
Single blind patient specific kits
Novartis
Placebo
Table
0mg
Single blind patient specific kits
Novartis
6.1.2
Additional study treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
6.2
Treatment arms
Subjects will be assigned to one of the following 2 treatment arms in a ratio of 1:1.

AFQ056 arm:: up-titration bid regimen followed by fixed-dose bid regimen (50 mg bid
from Day 1 to Day 7 followed by AFQ056 100 mg bid from Day 8 to Day 14, and then
fixed-dose 200 mg bid  for 84 days)

Placebo arm: matching placebo
6.3
Treatment assignment and randomization
Randomized treatment will be assigned to individual subjects by way of a randomization 
number, which will be in the range of 5101-5300. Randomization numbers will be assigned to 
the different centers in multiples of the block size, depending on the recruitment of each site. 
The Subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study.  For information on subject numbering, please see ‘Subject 
numbering’ section in the SOM.
Replacement randomization numbers will be in the range of 6101-6300. If a subject requires a 
replacement (for reasons other than safety or/and if the drop-out rate is higher than anticipated 
(20%higher), the replacement subject will be assigned a randomization number corresponding 
to the original subject (e.g. Subject 6103 would replace Subject 5103).  Any additional 
subjects enrolled will use sequential subject numbering.


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The table below details the general details of the numbering of the subjects once randomized 
to treatment:
Table 6-2
Randomization assignment numbering
Randomization numbers
Replacement randomization numbers
5101 – 5300
6101 – 6300
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A 
randomization list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of treatment 
arms to randomization numbers in the specified ratio.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of subjects
6.4
Treatment blinding
This is a subject and investigator-blinded study. Subjects and investigators will remain 
blinded to study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).
Drug product will be supplied as single blind patient specific kits, so an unblinded pharmacist 
who is independent of the study team will be required in order to maintain the blind. This 
unblinded pharmacist will receive treatment allocation cards from Drug Supply Management 
with the appropriate treatment allocation numbers. Appropriate measures must be taken by the 
unblinded pharmacist to ensure that the treatment assignments are concealed from the rest of 
the site staff.
Sponsor staff or delegate
The following unblinded sponsor roles are required for this study:

unblinded field monitor(s)

unblinded sample analysts  (PK, PD)
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors are not provided with a randomization list directly but will be 
unblinded through review of source documentation compiled by the unblinded pharmacist, 


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which details treatment allocation to individual subjects. The unblinded monitors will also be 
able to review the treatment allocation cards/randomization list provided to the unblinded 
pharmacist. The names of the unblinded monitor(s) are to be detailed in the Monitoring Plan.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-3. For example, unblinded summaries and 
unblinded individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis (e.g. 
) are allowed to access treatment assignment information for the purpose of conducting 
interim analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff (e.g. 
decision boards) as required for internal decision making on the study or the project at the
time of interim analyses while the study is ongoing.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
Table 6-3
Blinding levels
Role
Time or Event
Randomization list 
generated
Treatment 
allocation & 
dosing
Safety event (single 
subject unblinded)
Interim 
Analysis 
Subjects/Patients
B
B
UI
B
Site staff
B
B
UI
B
Unblinded site staff (see text 
for details) 
B
UI
UI
UI
Drug Supply and 
Randomization Office
UI
UI
UI
UI
Unblinded sponsor staff (see 
text for details)
B
B
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
UI
All other sponsor staff not 
identified above
B
B
UI
UI
B Remains blinded
UI Allowed to be unblinded on individual patient level
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6.5
Treating the subject
AFQ056 or placebo will be administered to the subject via oral route of administration.
On the first day of each up-titration dosing and on days that PK samples are scheduled, the 
subject will be required to not take the medication before the visit, as it will be administered 
by the site personnel. Study medication (AFQ056/placebo) will be administered to subjects 
with solid food (i.e. breakfast /morning meal) in the morning and in the evening (i.e. 
dinner/evening meal).
On other days where no visits are scheduled at site, study treatment administration will occur 
at home/outpatient basis See the SOM for further details.
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments and/or interruptions are not permitted.
6.7
Emergency breaking of assigned treatment code
Emergency unblinding must only be undertaken when it is essential to treat the subject safely 
and efficaciously. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. A complete set of emergency code break cards will be provided to the investigator 
site(s) and a complete set will be available at Novartis. All code break cards must be retained 
until the end of the study and returned to Novartis. They must be stored in a secure place but 
be accessible to the investigator 24 hours per day in case of emergency. The investigator will 
receive a blinded code break card for each subject, with the details of study treatment covered 
by a removable, scratch-off cover. In an emergency, the scratch-off cover can be removed to 
determine the treatment. The scratch-off covers are not to be removed for any reason other 
than an emergency. When the investigator removes the scratch-off cover he/she must note the 
date, time, and reason for removing it and retain this information with the case report form 
documentation. The unblinded treatment code must not be recorded on the CRF. The 
investigator must also immediately inform the study monitor that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the code break cards at any time in case of emergency.   The investigator will 
need to provide: 

protocol number

study drug name (if available)

subject number.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject.


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6.8
Treatment exposure and compliance
The investigator must promote compliance by instructing the subject to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the subject’s 
safety and the validity of the study. The subject must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the subject. This information should be captured in the 
source document at each visit. 
The subjects will also be instructed to bring back used packaging and unused medication at 
each visit for drug accountability checking. Subjects will be provided with individual 
Medication Diary (paper version)  to record each administration of study. This record will be 
checked regularly ( at least weekly) by site staff.
All study treatment dispensed and returned must be recorded in the Drug Accountability Log.
For the titration of the study medication, the investigator should provide clear instruction 
along with the dispensed medication in order to comply with the dosing titration schedule. 
Actual study medication intake by the subject (recorded during site administration or 
Medication Diary) and all titrated dose (up-titration to 200 mg bid) during the study must be 
recorded on the Dosage Administration Record CRF. 
6.9
Recommended treatment of adverse events
Patients in the study may develop symptoms that normally appear in CUD, however an 
increase in these symptoms is not expected. If during the study symptoms occur that are 
severe enough to interfere with the activities of daily living of the patients, they should be 
treated according to current clinical practice:
If patients develop adverse events such as hallucinations, agitation, delirium and/or confusion 
medical supervision should be implemented, and if severe enough to warrant pharmacological 
intervention then antipsychotic medication can be given, along with the discontinuation of 
study medication following the follow-up period, where possible.
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.10
Rescue medication
Rescue medication should be given according to clinical practice, and it should be 
documented
6.11
Concomitant treatment
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/ Significant non-drug therapies section of the 
CRF.


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Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.
All concomitant diseases and conditions will be treated in accordance with prevailing medical 
practice. 
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them.
Study completion is defined as when the last subject completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision.
All randomized and/or treated subjects will have a safety follow-up call conducted 14 days 
after last administration of study treatment. The information collected is kept as source 
documentation.  All SAEs reported during this time period must be reported as described in 
Section 9.2 and the Site Operations Manual.  Documentation of attempts to contact the subject 
should be recorded in the source documentation.
Continuing care should be provided by investigator and/or referring physician based on 
subject availability for follow-up. This care may include:

promote compliance for the visits schedule for urine samples collection

promote compliance for data entry in TLFB cocaine , as well as TLFB alcohol
7.2
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped 
earlier than the protocol planned duration. Discontinuation of study treatment can be decided 
by either the subject or the investigator.
Discontinuation of study treatment and patient withdrawal will be at the discretion of the 
Investigator, under the following circumstances:

Moderate and persistent (>24 hours) CNS related AEs, i.e.. behavioral effects and/or
neurological adverse effects, in the opinion of the Investigator as suspected to be related to
AFQ056 study medication

Missed > 6 consecutive visits

Missed > 7 consecutive doses of study medication during the fixed-dose treatment period
or a total of more than 14 cumulative doses at any time during the study

Use any of prohibited treatment
* If a liver or renal event occurs, follow guidelines outlined in Appendix 2 regarding
discontinuation of study treatment.
Study treatment must be discontinued under the following circumstances:


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
Subject/guardian decision - subjects may choose to discontinue study treatment for any
reason at any time.

The investigator believes that continuation would negatively impact the safety of the
subject or the risk/benefit ratio of trial participation.

Any protocol deviation that results in a significant risk to the subject’s safety.

Pregnancy (see Section 8.6 (Safety) and Section 9.6 (Pregnancy reporting).

Severe withdrawal syndrome or need for detoxification
For all discontinued patients, the follow-up period is to be followed, where possible.
Patients, who discontinue study treatment must NOT automatically be considered withdrawn 
from the study. Patients who discontinue study treatment before completing the study, and 
those who prematurely withdraw from the study for any reason, must be scheduled for a visit 
approximately 1 week after the last dose of study medication, at which time all of the 
assessments listed for the final visits
(End of Study visit) must be performed 
(see Assessment schedule). 
After study treatment discontinuation, at a minimum, the following data should be collected at 
clinic visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
If discontinuation of study treatment occurs, investigator must determine the primary reason 
for the subject’s premature discontinuation of study treatment and record this information on 
the Dosage Administration CRF
For patients who are lost to follow-up (e.g.. those patients whose status is unclear because 
they fail to appear for study visits without stating an intention to withdraw), the investigator 
must show "due diligence" by documenting in the source documents steps taken to contact the 
patient, e.g. dates of telephone calls, registered letters, etc.
If a patient needs to be hospitalized either temporarily or permanently during the course of 
this study, the sponsor needs to be notified by the investigator and the sponsor will make a 
decision whether the patient can remain in the study or needs to be discontinued.
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been broken inadvertently 
for any reason.


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7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent from the study is defined as when a subject:

Does not want to participate in the study anymore and

Does not want any further visits or assessments and

Does not want any further study related contacts and

Does not allow analysis of already obtained biologic material.
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject cannot be formally considered lost to follow-
up until his/her scheduled end of study visit would have occurred.
7.5
Study stopping rules
The study will be placed “on hold” if any of the following criteria are met, and no new 
patients will be randomized, pending a safety review, if:

at least 1 or more patients exhibits a life threatening or persisting/significant disabling
SAEs such as confusion, mood alteration, somnolence and/or psychosis, that are deemed
related to the study medication by the investigator, and confirmed to be on active
treatment when blind is broken for that patient

at least 3 and more patients exhibit at least one severe AE such as confusion, delirium,
mood alteration (euphoria or agitation) and/or psychosis (hallucinations or delusions)
which interfere with their activities of daily living, require medical intervention and
medical supervision, and are deemed related to the study medication by the investigator,
and confirmed to be on active treatment when blind is broken for that patient

The Sponsor considers that the number and/or severity of AEs, abnormal safety
monitoring tests or abnormal laboratory findings justify putting the study on hold.
Following the safety review, the study may continue, if the Investigator and Sponsor agree it 
is safe to proceed.


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7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, subjects 
must be seen as soon as possible and treated as a prematurely discontinued subject. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the subject’s interests. The investigator 
will be responsible for informing IRBs/IECs of the early termination of the trial.
8
Procedures and assessments
8.1
Assessment schedule
Subjects should be seen for all visits/assessments as outlined in the Assessment schedule or as 
close to the designated day/time as possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At 
this final visit, all dispensed investigational product should be reconciled, and the adverse 
event and concomitant medications recorded on the CRF.


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Table 8-1
Assessment schedule
Epoch
Screening
Treatment
Visit Name
Screening14
Baseline15
Up-Titration 50 mg 
bid (Days 1 to 7)
Up-Titration 100 mg 
bid (Days 8 to 14)
Treatment
Visit Numbers1
1
2
316
4
101
102
103
104
105
106 107 108
109
110 111 112 113 114
Days -28 to -
12
-14 to -
11
-13 to -
10
-3 to -1
1
4
±1
8
±1
11
±1
15
±1
18
±1
22
±1
25
±1
29
±1
32
±1
36
±1
39
±1
43
±1
46
±1
Time (post-dose)
-
-
-
-
-
-
-
-
0h
2h
±1
-
-
-
0h
2h
±1
-
-
-
-
-
Informed consent
X
Demography
X
Body Weight
X
Body Height
X
Body Temperature
X
X
X3
Blood Pressure and Pulse 
Rate
X
X
X3
Physical Examination
X
X
Medical history/current 
medical conditions
X
reduce / cease cocaine use 
17
X
Amount spent on cocaine
X
X
TLFB cocaine
X
TLFB alcohol
X
Urine drug screen 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis screen
S
Hematology
X
X
X
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Epoch
Screening
Treatment
Visit Name
Screening14
Baseline15
Up-Titration 50 mg 
bid (Days 1 to 7)
Up-Titration 100 mg 
bid (Days 8 to 14)
Treatment
Visit Numbers1
1
2
316
4
101
102
103
104
105
106 107 108
109
110 111 112 113 114
Days -28 to -
12
-14 to -
11
-13 to -
10
-3 to -1
1
4
±1
8
±1
11
±1
15
±1
18
±1
22
±1
25
±1
29
±1
32
±1
36
±1
39
±1
43
±1
46
±1
Time (post-dose)
-
-
-
-
-
-
-
-
0h
2h
±1
-
-
-
0h
2h
±1
-
-
-
-
-
Blood chemistry
X
X
X
Urinalysis
X
X
X
Pregnancy test4
X5
X6
X6
X6
X6
ECG evaluation7
X
X
X
X
X
X
HIV screen
S
Concomitant therapies8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug administration record
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medication patient diary 9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood collection11
X
X
X
X
Adverse Events12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study completion 
information
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Epoch
Treatment
Follow up
Visit Name
Treatment
Follow up
Visit Numbers1
115
116
117
118
119
120
121
122
123
124
125
126
127
128
199
201
202
203
Days
50
±1
53
±1
57
±1
60
±1
64
±1
67
±1
71
±1
74
±1
78
±1
81
±1
85
±1
88
±1
92
±1
95
±1
98
±1
99
±1
102
±1
106
±1
Time (post-dose)
-
-
0h
2h
±1
-
-
-
-
-
-
-
-
-
-
-
0h
2h
±1
-
-
-
Informed consent
Demography
Body Weight
Body Height
Body Temperature
X3
Blood Pressure and Pulse Rate
X3
Physical Examination
Medical history/current medical 
conditions
reduce / cease cocaine use 17
Amount spent on cocaine
X
X
TLFB cocaine
X
TLFB alcohol
X
Urine drug screen
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis screen
Hematology
X
X
Blood chemistry
X
X
Urinalysis
X
X
Pregnancy test4
X6
X6
X6
X6
ECG evaluation7
X
X
X
X
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Epoch
Treatment
Follow up
Visit Name
Treatment
Follow up
Visit Numbers1
115
116
117
118
119
120
121
122
123
124
125
126
127
128
199
201
202
203
Days
50
±1
53
±1
57
±1
60
±1
64
±1
67
±1
71
±1
74
±1
78
±1
81
±1
85
±1
88
±1
92
±1
95
±1
98
±1
99
±1
102
±1
106
±1
Time (post-dose)
-
-
0h
2h
±1
-
-
-
-
-
-
-
-
-
-
-
0h
2h
±1
-
-
-
HIV screen
Concomitant therapies8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug administration record
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medication patient diary 9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood collection11
X
X
X
X
Adverse Events12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study completion information
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Epoch
Follow up
Visit Name
Follow up
EOS
Visit Numbers1
204
299
Days
112
±1
113
±3
Time (post-dose)
-
-
Informed consent
Demography
Body Weight
X
Body Height
Body Temperature
X3
X3
Blood Pressure and Pulse Rate
X3
X3
Physical Examination
X
Medical history/current medical conditions
reduce / cease cocaine use 17
Amount spent on cocaine
X
TLFB cocaine
X
TLFB alcohol
X
Urine drug screen
X
X
Hepatitis screen
Hematology
X
Blood chemistry
X
Urinalysis
Pregnancy test4
X6
ECG evaluation7
X
HIV screen
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Epoch
Follow up
Visit Name
Follow up
EOS
Visit Numbers1
204
299
Days
112
±1
113
±3
Time (post-dose)
-
-
Concomitant therapies8
X
X
Drug administration record
Medication patient diary 9
C-SSRS10
X
X
PK blood collection11
Adverse Events12
X
X
Serious Adverse Events13
X
X
Study completion information
X
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1 Visit structure given for internal programming purpose only.
3 Assessment to be done once per week, during one of the visits when urine sample is collected.
4 Assessment for females patients only.
5 Serum pregnancy test
6 Urine pregnancy test
7 On PK days , assessment to be done after post dose PK sample
8 Record includes: Positive Reinforcement 
9 Medication compliance to be assessed at least once per week
10 Assessment to be done at every visit
11 Pk samples collected in the morning at predose and 2 ± 1 hours post-morning dose
12 AEs to be collected from signed ICF up to study completion visit (EOS)
13 SAEs to be collected from signed ICF up to 30 days following study completion visit (EOS) 
14 If considered appropriate by the investigator, screening assessments may be carried out on two separate days.
15 If considered appropriate by the investigator, baseline assessments may be carried out on two separate days.
16 Visit 3 should take place 1-3 days after visit 2.
17 Subjects should be asked about their goals to cease/reduce cocaine use. Guidance is provided in the SOM.
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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject’s representative gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible 
given his/her understanding. If the subject is capable of doing so, he/she must indicate assent 
by personally signing and dating the written informed consent document or a separate assent 
form.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICH E6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research.  The 
procedures set out in the main consent form concerning the storage, maintenance of privacy, 
and release of the data or specimens for the main study will also be adhered to for any future 
research. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any 
new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and then must be discussed with the subject.
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of Informed Consent Forms included 
in this study.
8.3
Subject screening
It is permissible to re-screen a subject if s/he fails the initial screening; however, each case 
must be discussed and agreed with the Sponsor on a case-by-case basis.
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Information on what data should be collected for screening failures is outlined in the Site 
Operations Manual.
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.  
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.5
Efficacy / Pharmacodynamics
Pharmacodynamics assessments are detailed below. For all completed scales/questionnaire 
described below, the Investigator will be required to review and examine responses which 
may indicate potential AEs or SAEs. The investigator should review not only the responses to 
the scale but also for any unsolicited comments written by the patient. If the occurrence of 
AEs or SAEs is confirmed, the physician should record the events as per instructions given in 
Section 9. Investigators should not encourage the subjects to change the responses reported on 
the scale.
Pharmacodynamics
samples will be collected at the timepoints defined in the 
Assessment schedule. Follow instructions outlined in the Site Operations Manual regarding 
sample collection, numbering, processing and shipment. In order to better define the PD 
profile, the timing of the sample collection may be altered based on emergent data. The 
number of samples/blood draws and total blood volume collected will not exceed those stated 
in the protocol.
8.5.1
Clinical Outcome Assessments (COAs)
Clinical Outcome Assessments such as Patient report Outcome and Observer reported 
Outcome are specific methods for assessment and recording are specified in the Site 
Operations Manual, with the Assessment schedule (Section 8.1) detailing when each 
assessment is to be performed. Safety assessments are specified below; methods for 
assessment and recording are specified in the Site Operations Manual, with the 
Assessment schedule (Section 8.1) detailing when each assessment is to be performed.
Patient Reported Outcome includes:

The TLFB cocaine:  is a cocaine assessment method that obtains estimates of daily
cocaine intake and has been evaluated with clinical and nonclinical populations. Using a
calendar, people provide retrospective estimates of their daily cocaine use over a specified
time period that can vary up to 12 months from the interview date. Several memory aids
can be used to enhance recall (e.g., calendar; key dates serve as anchors for reporting
cocaine use). The Cocaine TLFB has been shown to have good psychometric
characteristics with a variety of cocaine use groups, and can generate variables that
provide a wide range of information about an individual’s cocaine use (e.g., pattern,
variability, and magnitude of cocaine use). The method is recommended for use when
relatively precise estimates of cocaine use are necessary, especially when a complete


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picture of cocaine use days (i.e., high- and low-risk days) is needed (evaluating cocaine 
use pre-posttreatment). Clinically, the TLFB can be used to provide feedback about one’s 
cocaine consumption in an effort to increase a client’s motivation to change.

The TLFB alcohol: is a drinking assessment method that obtains estimates of daily
drinking and has been evaluated with clinical and nonclinical populations. Using a
calendar, people provide retrospective estimates of their daily drinking over a specified
time period that can vary up to 12 months from the interview date. Several memory aids
can be used to enhance recall (e.g., calendar; key dates serve as anchors for reporting
drinking; standard drink conversion). The Alcohol TLFB has been shown to have good
psychometric characteristics with a variety of drinker groups, and can generate variables
that provide a wide range of information about an individual’s drinking (e.g., pattern,
variability, and magnitude of drinking). The method is recommended for use when
relatively precise estimates of drinking are necessary, especially when a complete picture
of drinking days (i.e., high- and low-risk days) is needed (evaluating drinking pre-
posttreatment). Clinically, the TLFB can be used to provide feedback about one’s drinking
in an effort to increase a client’s motivation to change. Overall, the Alcohol TLFB method
provides a relatively accurate portrayal of drinking, and has both clinical and research
utility.

The C-SSRS: refer to Section 9.7
Observer Reported Outcome includes:
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8.5.1.1
Urine drug screen
Urine sample will be analyzed with primary objective for the presence of cocaine metabolite's 
Benzoylecgonine (BE) the main metabolite of cocaine present in urine. Urine specimen 
collection 
will 
take 
place 
in 
conjunction 
with 
regular 
clinic 
visits 
(see Assessment schedule for the visits).
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule (Section 8.1) detailing when each 
assessment is to be performed.
8.6.1
Physical examination
See Site Operations Manual for details. 
8.6.1.1
Vital signs

Body temperature

Blood pressure (BP)

Pulse
8.6.2
Height and weight

Height

Body weight

Body mass index (BMI) will be calculated as (Body weight (kg) / [Height (m)]2)
8.6.3
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should be contacted.
8.6.4
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differentials (e.g. 
neutrophils, basophils, eosinophils, monocytes, lymphocytes presented as % of total white 
blood cell count and as absolute concentrations), and platelet count will be measured. 
Coagulation testing including prothrombin time (PT) also reported as INR and activated 
partial thromboplastin time (aPTT) will be measured.


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8.6.5
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, total cholesterol,
chloride, creatinine, CK, γ-GT, glucose, LDH, inorganic phosphorus, lipase, amylase, 
magnesium, potassium, total protein, AST, ALT, sodium, triglycerides, urea and uric acid.If 
the total bilirubin concentration is increased above 1.5 times the upper limit of normal, direct 
and indirect reacting bilirubin should be differentiated.
8.6.6
Urinalysis
Dipstick measurements for protein, nitrite, specific gravity, pH, blood, and WBC/leukocytes 
will be performed. If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, 
the sample will be sent for microscopic analysis of WBC, RBC and casts, furthermore the 
protein-creatinine ratio (PCR) and the albumin-creatinine ratio (ACR) will also be measured.
8.6.7
ECG evaluation
Full details of all procedures relating to the ECG collection and reporting are contained in the 
Site Operations Manual.

PR interval, QRS duration, QT interval and heart rate, 
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
As applicable, QTcF and QTcB may be calculated in-house. Unless auto-calculated by the 
ECG machine, the investigator must calculate QTcF at the Screening and/or Baseline visit(s) 
(as applicable) to assess eligibility. See the Site Operations Manual for additional details.
Clinically significant abnormalities must be reported in the AE CRF.
8.6.8
Pregnancy and assessment of fertility
Pregnancy Testing
Pregnancy tests are required of all female subjects regardless of age or reported sterilization. 
The result of this test must be received before any female subject may be dosed. See the 
Assessment schedule (Section 8.1), for timing of the protocol required pregnancy testing; 
additional pregnancy testing may be performed to meet local requirements.  A positive urine 
pregnancy test requires immediate interruption of study treatment until serum β-hCG is 
performed and found to be negative.
Refer to Section 9.6 for details on Reporting Pregnancy.


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Assessments of Fertility
Refer to Section 4.2 for criteria to determine women that are not of child bearing potential.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source. Subsequent hormone level assessment to confirm the woman is not of child bearing 
potential must also be available as source documentation in the following cases:

surgical bilateral oophorectomy without a hysterectomy

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
subject, regardless of reported reproductive/menopausal status at Screening/Baseline
8.7
Pharmacokinetics
PK samples will be collected at the time points defined in the Assessment schedule
(Section 8.1). Follow instructions outlined in the Bioanalytics Study Specifications (BSS) and 
Central Laboratory Manual regarding sample collection, numbering, processing and shipment. 
See Section 8.9 regarding the potential use of residual samples.
PK samples post morning dose will be obtained and evaluated in all subjects, except the 
samples collected during treatment with placebo.
The PK blood collection log is provided in the Site Operations Manual.
Conventional PK parameters will not be calculated due to the limited sampling schedule. 
However, plasma concentrations will be listed and summary statistics for concentrations will 
be provided for plasma. The data will be part of the over-all Population PK model
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8.8
Other assessments
8.8.3
Positive Reinforcement (PR)
For each study visit patients will receive money compensation for travel expenses. In order to 
stimulate clinic attendance and to enable optimal monitoring of patients' medication 
adherence and health (including adverse events), patients will be remunerated for complying 
with study visits and standard requirements (urine submission, TLFB, medication diary, 
adverse events, and basic physical examination). In order to reinforce regular participation 
with study assessments a bonus will be provided each time patients attend two consecutive 
study visits. Finally, patients will receive additional remuneration for their time investment in 
case of ECG-evaluations and for extended study visits with additional questionnaires and/or 
PK-blood sampling. The maximum remuneration for patients complying with all study 
assessments. Given our experience with pharmacotherapy studies with cocaine dependent 
patients, we expect that patients, on average, will attend a maximum of 70-80% of all planned 
study visits. 
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In addition to positive reinforcement, participants will be stimulated at every planned visit and 
encouraged for attending appointments, as well as adherence to the protocol.
Positive Reinforcement will be made available for the sites as a separate document. 
8.9
Use of residual biological samples
9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
after providing written informed consent for participation in the study until the end of study 
visit. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an adverse event irrespective if a clinical event has occurred. See Section 9.5 for 
an overview of the reporting requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination finding, laboratory 
test finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and Appendix 2, respectively. 
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For all completed scales/questionnaire described below, the Investigator will be required to 
review and examine responses which may indicate potential AEs or SAEs. The investigator 
should review not only the responses to the scale but also for any unsolicited comments 
written by the subject. If the occurrence of AEs or SAEs is confirmed, the physician should 
record the events as per instructions given in Section 7. Investigators should not encourage the 
subjects to change the responses reported on the scale.
Adverse events should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:

AE severity grade (mild/moderate/severe):

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment

Yes or

No

No Relationship to study treatment or other investigational treatment or

Relationship to study treatment  or

Relationship to other investigational treatment or

Relationship to both study treatment and other investigational treatment or
indistinguishable

its duration (start and end dates) or if the event is ongoing an outcome of not
recovered/not resolved must be reported.

whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which seriousness
criteria have been met

action taken regarding investigational treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving,
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications.  Once an adverse event is detected, it must be followed 
until its resolution or until it is judged to be permanent, and assessment should be made at 
each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the investigational drug, the interventions required to treat it, and the outcome.


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The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
*Refer to the Site Operations Manual for data capture methodology regarding AE collection 
for subjects that fail screening.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition (that is unrelated to the 
indication under study  and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s general 
condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to European Medicines Agency (EMA) 
(2003) ICH-E2D Guideline).


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Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
subject or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to European Medicines Agency (EMA) 
(2003) ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO & PS) as per 
Section 9.2.2.
9.2.2
SAE reporting
Screen Failures
Note the following requirement for Screen Failures: SAEs occurring after the subject has 
provided informed consent until the time the subject is deemed a Screen Failure must be 
reported to Novartis. 
Randomized / Treated Subjects
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last administration of study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence as described below.
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Chief Medical Office 
and Patient Safety (CMO& PS) Department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue 
an Investigator Notification (IN) to inform all investigators involved in any study with the 


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same study treatment that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis.   Note:  SAEs must be reported to 
Novartis within 24 hours of the investigator learning of its occurrence/receiving follow-up 
information.
9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1-Appendix 1 for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2 - Appendix 1.

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm
elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory, with 
the results provided via the standard electronic transfer.  If results will not be available from 
the central laboratory within 24 hours, then the repeats can also be performed at a local 
laboratory to monitor the safety of the subject. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should 
have results reported on the unscheduled local laboratory CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated,
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study
treatment), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event
Thorough follow-up of the liver event should include

Repeating liver chemistry tests two or three times weekly. Testing should include ALT,
AST, ALP, PT/INR, and GGT. If total bilirubin is elevated > 2 x ULN, fractionation into
direct and indirect bilirubin is required. To rule out muscular origin of transaminase
elevations, CPK should be measured along with liver chemistry tests. Frequency of
retesting can decrease to once a week or less if abnormalities stabilize or the study drug
has been discontinued and the subject is asymptomatic. Retesting should be continued up
to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.


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
Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets.

Exclusion of underlying liver disease, as specified in Table 15-3.

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details. 
9.4
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Appendix 2.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details.
9.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF. Study treatment errors are only to be 
reported to Chief Medical Office and Patient Safety (CMO& PS) department if the treatment 
error is associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances 
of misuse or abuse must be reported to Novartis Chief Medical Office and Patient Safety 
(CMO& PS). As such, instances of misuse or abuse are also to be reported using the SAE 
form/CRF. Table 9-1 summarizes the reporting requirements.
Table 9-1
Guidance for capturing study treatment errors
Treatment error type
Document in Dose 
Administration (DAR) CRF 
Document in AE 
CRF
Complete SAE 
form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
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For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.6
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO& PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The study drug must be discontinued*, though the subject may stay in the study, if she wishes 
to do so. All assessments that are considered as a risk during pregnancy must not be 
performed. The subject may continue all other protocol assessments.
9.7
Prospective suicidality assessment
The Columbia-Suicide Severity Rating Scale (C-SSRS), is a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior. The C-SSRS must be administered at each 
visit, including unscheduled visits.
The C-SSRS, which uses a semi-structured interview to probe subject responses, will be 
administered by an individual who has received training and certification in its administration. 
At the first study visit, the “baseline/screening” version of the C-SSRS, will be administered. 
This version assesses Suicidal Ideation and Suicidal Behavior during the subject’s lifetime 
and during a predefined period. At subsequent visits, the “since last visit” version will be 
administered.
If, at any time after screening and/or baseline, the score is “yes” on item 4 or item 5 of the 
Suicidal Ideation section of the C-SSRS or “yes” on any item of the Suicidal Behavior section, 
the subject must be referred to a mental health care professional for further assessment and/or 
treatment. The decision on whether the study treatment should be discontinued is to be taken 
by the investigator in consultation with the mental health professional to whom the subject is 
referred.
In addition, all life-threatening events must be reported as SAEs. For example, if a subject 
answers “yes” to one of the questions in the Suicidal Behavior section, an SAE must be 
reported if the event was life-threatening. All events of “Non-Suicidal Self-Injurious 
Behavior” (question also included in the Suicidal Behavior section) should be reported as AEs 
and assigned the appropriate severity grade.
All SAEs relating to suicidal behavior must be reviewed by the Safety Management Team or 
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9.8
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the Sponsor and Investigator. Such 
evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (eCRFs) with the 
investigators and their staff. During the study Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The monitor will 
visit the site to check the completeness of subject records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and ensure that study drug is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the monitor during these visits.
Continuous remote monitoring of each site’s data may be performed by Novartis or CRO 
working on behalf of Novartis. Additionally, a central analytics organization may analyze data 
and identify risks & trends for site operational parameters, and provide reports to Novartis 
Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and the recording of data that will be 
used for all primary and safety variables. Additional checks of the consistency of the source 
data with the CRFs are performed according to the study-specific monitoring plan. No 
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10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the subject data for archiving at the 
investigational site.
Certain data may be captured via other source documentation (such as safety laboratory data 
report) and then transcribed, uploaded or transferred into the EDC system. This, and any 
additional data treated in this manner, will be source data verified by the study monitor per the 
monitoring plan and the location of source data (i.e., Source, paper or a local electronic 
system) will be documented prior to study start in the Data Handling Plan. 
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
vendor working on behalf of Novartis.
Remote monitoring of the original electronic source records will take place, however on-site 
monitoring inspections will continue to take place in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
adherence, to assess site operational capabilities, and to perform other monitoring activities 
that cannot be performed remotely.
The investigator must certify that the data entered into CRFs are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule (Section 8.1) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
CRO working on behalf of Novartis review the data entered into the CRFs by investigational 
staff for completeness and accuracy and instruct the site personnel to make any required 
corrections or additions. Queries are sent to the investigational site using an electronic data 
query. Designated investigator site staff is required to respond to the query and confirm or 
correct the data. If the electronic query system is not used, a paper Data Query Form will be 
faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to CRO 
working on behalf of Novartis who will make the correction to the database. The signed copy 
of the Data Query Form is kept at the investigator site.


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Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
management. 
10.4
Data Monitoring Committee
Not applicable.
10.5
Adjudication Committee
Not applicable.
11
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment received.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
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The PD analysis set will include all subjects with available PD data and no protocol 
deviations with relevant impact on PD data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject.
11.4
Analysis of the primary variable(s)
The primary objective is to evaluate the effect of AFQ056 in reducing cocaine use.
11.4.1
Primary Variable(s)
The primary variable is the proportion of cocaine use days during the treatment period (days 
1-98).
For each patient, the proportion of cocaine use days will be calculated by dividing the number 
of days of cocaine use during the treatment period, i.e. 98 days for completers and number of 
days between Day 1 and day of last dose in case of premature discontinuation of study 
treatment. It is considered as a continuous variable with a normal distribution. The cocaine 
consumption will be recorded daily (Yes/No) using the TLFB during the entire study. 
11.4.2
Statistical model, hypothesis, and method of analysis
A Bayesian analysis will be conducted on the proportion of cocaine use days
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11.4.3
Handling of missing values/censoring/discontinuations
In case of premature discontinuation of study treatment, the calculation of the primary 
variable will be done on the period with both TLFB data available and study treatment was 
taken. No missing data is expected between visits per the TLFB completion guidelines an 
investigator's checks at the visits.
For sensitivity analysis, the incomplete profiles will be included in longitudinal analyses.
11.4.4
Sensitivity analyses
Sensitivity analyses will be performed using other models if the distribution of the data is not 
deemed normal. 
Additionally, the profiles of consumption over time will be compared between treatment 
groups through analyses of longitudinal data (weekly use and monthly use) using linear mixed 
models for repeated measures or other models depending on th distribution.
Data visualization techniques will be used in order to detect potential patterns in the daily data 
obtained from the TLFB.
The missing data mechanism will be explored to check that the missing data due to dropouts 
are at least missing at random. 
11.5
Analysis of secondary variable(s)
The secondary objectives are to assess the effect of AFQ056 on other measures of cocaine use 
and on measures of alcohol use, to assess the safety and tolerability and to evaluate the PK of 
AFQ056.
11.5.1
Efficacy / Pharmacodynamics
11.5.1.1 Measure of cocaine in (BE) in urine
Two urine samples per week will provide a quantitative measure of cocaine's metabolite BE.
The proportions of positive urine samples over the treatment period will be compared between 
groups using a t-test.
The quantitative BE profiles over time will be explored using visualization techniques and 
compared between groups using models appropraite to the distribution of the data.
11.5.1.2 Measures of alcohol use
Alcohol consumption will be recorded by the patients using TLFB. The number of standard 
drinks will be recorded daily.
The proportion of days of alcohol consumption during the study treatment period will be 
compared between groups using an ANCOVA model with treatment as factor and past 
alcohol consumption as covariate.
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The longitudinal profiles (daily number of drinks, weekly and monthly mean number of 
drinks) will be explored.
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system.
Other safety evaluations
Columbia Suicide Severity Rating Scale (C-SSRS). The C-SSRS data will be listed by 
treatment group, subject and visit.
11.5.3
Pharmacokinetics
Analysis will be performed under PK analysis set.
AFQ056 plasma concentration data will be listed by treatment, subject, and visit/sampling 
time point. 
Conventional PK parameters will not be calculated due to the limited sampling schedule. 
However, plasma concentrations will be listed at pre-dose and 2±I hour sampling window 
post morning dose and summary statistics for concentrations will be provided for plasma. The 
data will be part of the over-all Population PK model. 
11.5.4
Pharmacokinetic / pharmacodynamics interactions
Not applicable.
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11.5.5
Other assessments
Not applicable.
11.6
Analysis of exploratory variables (if applicable)
11.7
Sample size calculation
A sample size of approximately 60 patients (30 patients on AFQ056 and 30 patients on 
placebo) was determined, assuming a SD of 32% (Nuijten et al 2016) for the proportion of 
cocaine use days. Patients who are withdrawn from the study for reasons other than safety 
may be replaced, if the drop-out rate is higher than anticipated (20 % higher).
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11.8
Power for analysis of key secondary variables
Not applicable.
11.9
Interim analyses
12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
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12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
12.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.
13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.


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Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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14
References
References are available upon request.
American Psychiatric Association (APA) (2006) Practice Guidelines Substance Use Disorder.
Berg D, Godau J, Trenkwalder C, et al (2011) AFQ056 treatment of levodopa-induced 
dyskinesias: results of 2 randomized controlled trials. Mov. Disord. 1243-50.
European Medicines Agency (EMA) (2003) ICH-E2D Guideline, CPMP/ICH/3945/03.
Lee J.LC, Di Ciano P, Thomas KL et al (2005) Disrupting reconsolidation of drug memories 
reduces cocaine-seeking behavior. 47:795–801.
Nakajima M, Yoshida R, Shimada N, et al (2001) Inhibition and inactivation of human 
cytochrome P450 isoforms by phenethyl isothiocyanate. 29:1110-3.
Nuijten M, Blanken P, van de Wetering B, et al (2016) Sustained-release dexamfetamine in 
the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a 
randomised, double-blind, placebo-controlled trial. www.thelancet.com Vol 387 May 28, 
2016.
Pellinen P, Stenbäck F, Kojo A, et al (1996) Regenerative changes in hepatic morphology and 
enhanced expression of CYP2B10 and CYP3A during daily administration of cocaine. 
Hepatology. 23(3):515–523.
Robinson SM, Sobell LC, Sobell MB, et al (2012) Reliability of the Timeline Followback for 
Cocaine, Cannabis, and Cigarette Use. doi: 10.1037/a0030992.
Sobell LC, Sobell MB (1996) Timeline FollowBack user’s guide: A calendar method for 
assessing alcohol and drug use.
Stocchi F, Rascol O, Destee A, et al (2013) AFQ056 in Parkinson patients with 
levodopainduced dyskinesia: 13-week, randomized, dose-finding study. Mov Disord. 28: 
1838-46.
The United Nations Office on Drugs and Crime (UNODC) (2016) UNODC-WHO 
International Standards for the Treatment of Drug Use Disorders.


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15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase 
in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤ 8 x ULN

3 x ULN < ALT/AST ≤ 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance*
ALT or AST elevation with coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 8 
× ULN

If confirmed, consider interruption or discontinuation 
of study drug

If elevation persists for more than 2 weeks, 
discontinue the study drug 

Establish causality

Complete CRFs per liver event guidance*
Isolated ALT or AST elevation > 3 to ≤ 5 
× ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; if 
>50% is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance*
Any AE potentially indicative of liver 
toxicity

Consider study treatment interruption or 
discontinuation

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance*
*Liver event guidance for CRF completion is available in the Site Operations Manual


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Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV RNA, 
IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV 
infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic 
steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic 
hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin 
deficiency

Alpha-1-antitrypsin


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16
Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
Criteria
Action required
Serum creatinine (sCr) increase 25 – 49% 
compared to baseline

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase > 50%

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 

Consider hospitalization and specialized 
treatment
Protein-creatinine or albumin-creatinine ratio 
increase ≥ 2-fold
or
new onset dipstick proteinuria ≥ 1+
or
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or ≥ 
3 mg/mmol;
or
Protein-creatinine ratio (PCR )≥ 150 mg/g or 
>15 mg/mmol

Consider causes and possible interventions

Assess serum albumin & serum protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
New onset glucosuria on urine dipstick (unless 
related to concomitant treatment, diabetes)
Assess & document:

Blood glucose (fasting)

Serum creatinine

Urine albumin-creatinine ratio
New hematuria on dipstick
Assess & document:

Urine sediment microscopy

Assess sCr and urine albumin-creatinine ratio

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed subject history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:

Blood pressure assessment (after 5 min rest, with an appropriate cuff size)

Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, 
dysuria, hematuria, dependent or periorbital edema


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
Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other potential 
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-2
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case Report Form 
(CRF) or via electronic data load. Review and record 
possible contributing factors to the renal event (co-
medications, other co-morbid conditions) and additional 
diagnostic procedures (MRI etc) in the CRF.

Urine dipstick and sediment 
microscopy

Blood pressure and body weight

Serum creatinine, electrolytes 
(sodium, potassium, phosphate, 
calcium), bicarbonate and uric acid

Urine output
Monitor subject regularly (frequency at investigator’s 
discretion) until:

Event resolution: (sCr within 10% of 
baseline or protein-creatinine ratio 
within 50% of baseline)
or

Event stabilization: sCr level with 
±10% variability over last 6 months 
or protein-creatinine ratio 
stabilization at a new level with 
±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very sensitive 
metric for integrated kidney function that requires excellent tubular function. A high urinary osmolality 
in the setting of an increase in sCr will point toward a “pre-renal” cause rather than tubular toxicity.


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17
Appendix 3: Drugs affecting CYP3A4
Drugs affecting CYP3A4
This appendix provides a specific list of drugs that should not be co-administered with 
AFQ056 because of their CYP3A4 inhibiting potency or CYP3A4 inducing potency.
Drugs inhibiting CYP3A4
This list is by no means exhaustive and medical judgment should always prevail. The clinical 
investigators must refer to the product information of any concomitant medication to ascertain 
any potential drug interactions. This list is adapted to the patient population and the exclusion 
criteria.
List of CYP3A4 inhibitors not to be co-administered with AFQ056 in study 
CAFQ056A2201
• Amiodarone
• Amprenavir
• Aprepitant
• Atazanavir
• Cimetidine
• Clarithromycin
• Diltiazem
• Erythromycin
• Fluconazole
• Fluoroquinolones (e.g. ciprofloxacin)
• Fluvoxamine
• Fosamprenavir
• Gestodene
• Grapefruit juice
• Indinavir
• Itraconazole
• Ketoconazole
• Mibefradil
• Nefazodone
• Nelfinavir
• Ritonavir


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• Saquinavir
• Telithromycin
• Verapamil
• Voriconazole
Drugs inducing CYP3A4:
• Barbiturates (e.g. primidone, phenobarbital)
• Carbamazepine
• Efavirenz
• Glucocorticoids (except for topical or inhalation use)
• Phenytoin
• Rifabutin
• Rifampin
• Rifapentin
• St. John’s Wort

SAP_000.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
AFQ056
CAFQ056X2201
A randomized, subject and investigator blinded, placebo-
controlled, parallel group study to investigate whether 
AFQ056 reduces cocaine use in patients diagnosed with 
Cocaine Use Disorder (CUD)
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Final Amendment 2
Release date:
07-Apr-2020
Number of pages:
18
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Scope of document ..................................................................................................6
1.2
Study reference documentation ...............................................................................6
1.3
Study objectives.......................................................................................................6
1.3.1
Primary objective ....................................................................................6
1.3.2
Secondary objectives...............................................................................6
1.3.3
Exploratory objectives ............................................................................6
1.4
Study design and treatment......................................................................................6
2
First interpretable results (FIR) ...........................................................................................7
3
Interim analyses...................................................................................................................7
4
Statistical methods: Analysis sets........................................................................................8
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................9
5.1
Variables..................................................................................................................9
5.2
Descriptive analyses ................................................................................................9
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................10
6.1
Primary objective...................................................................................................10
6.1.1
Variables ...............................................................................................10
6.1.2
Descriptive analyses..............................................................................10
6.1.3
Statistical model, assumptions and hypotheses.....................................10
6.2
Secondary objectives .............................................................................................12
6.2.1
Variables ...............................................................................................12
6.2.2
Descriptive analyses..............................................................................12
6.2.3
Statistical model, assumptions and hypotheses.....................................13
6.3
Exploratory objectives...........................................................................................14
6.3.1
Variables ...............................................................................................14
6.3.2
Descriptive analyses..............................................................................15
6.3.3
Statistical model, assumptions and hypotheses.....................................15
6.3.4
Graphical presentation of results...........................................................15
7
Statistical methods for safety and tolerability data............................................................15
7.1
Variables................................................................................................................15
7.2
Descriptive analyses ..............................................................................................16
7.3
Graphical presentation...........................................................................................17


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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CAFQ056X2201”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
This SAP has been developed using Clinical Trial Protocol version v01
dated 
15 November 2017.
1.3
Study objectives
1.3.1
Primary objective
To evaluate treatment effect of 98-day AFQ056 administration in reducing cocaine use.
1.3.2
Secondary objectives

To assess the effects of 98-day AFQ056 administration versus placebo on:
a)
other measures of cocaine use
b)
alcohol use

To assess the safety and tolerability of multiple bid oral doses of AFQ056.

To evaluate the pharmacokinetics of AFQ056.
1.3.3
Exploratory objectives
1.4
Study design and treatment
This is a randomized, subject and investigator blinded, parallel group, placebo-controlled study 
in approximately 60 patients with cocaine use disorder. The study consists of: about 17-day 
screening period followed by a 12-day baseline; a 98-day out-patient treatment period (14-day 
up-titration dose regimen followed by 84-day maintenance dose) and finally an end of study 
visit evaluation approximately 14-days after the last study drug administration. The total 
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duration for each patient in the study is up to approximately 20-weeks including screening and 
baseline. The study design is summarized in Figure 1.4-1 below.
Figure 1.4-1   Overall study scheme
Following baseline, on Day 1, approximately 60 eligible patients will be randomly assigned in 
a 1:1 ratio to either AFQ056 or placebo.

Group A – AFQ056: up-titration regimen for the first 2 weeks (14 days): 50 mg bid
from Day 1 to Day 7, 100 mg bid from Day 8 to Day 14, followed by dosing at
200 mg bid for 84-days.

Group B: matching placebo.
2
First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial.
3
Interim analyses 
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4
Statistical methods: Analysis sets
For subjects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
The randomized set will include all subjects randomized.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects with any available PD data, who received any study 
drug for at least 14 days in the treatment period and experienced no protocol deviations with 
relevant impact on PD data.
The Full analysis set (FAS) will include all subjects with any available PD data who received 
at least any study drug.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
TRT02
Subject was randomized but did not take any 
dose of study treatment
Subject will be counted in 
randomized set, but 
excluded from safety, PD 
and PK analysis sets
TRT05
Bad compliance to study treatment
Exclude subject from PD
and PK analysis sets
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
TRT02
Subject was randomized but did not take any 
dose of study treatment
Subject will be 
counted in randomized 
set, but excluded from 
safety, PD and PK 
analysis sets
TRT05
Bad compliance to study treatment
Exclude subject from 
PD and PK analysis 
sets
Subjects are excluded from PK and PD analysis in case of these 
PDs:
Exclude subject from PK 
and PD analysis sets


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Category
Deviation code
Text description of deviation
Data exclusion
TRT02
Subject was randomized but did not take any 
dose of study treatment
Subject will be 
counted in randomized 
set, but excluded from 
safety, PD and PK 
analysis sets
TRT05
Bad compliance to study treatment
Exclude subject from 
PD and PK analysis 
sets
Subjects are excluded from Safety analysis in case of these 
PDs: 
Exclude subject from Safety 
analysis set 
TRT02
Subject was randomized but did not take any 
dose of study treatment
Subject will be counted in 
randomized set, but 
excluded from safety, PD 
and PK analysis sets
Subjects are analyzed according to treatment actually received
TRT04
Wrong treatment arm medication given to the 
subject by mistake of pharmacist – not 
according to treatment randomized.
Subject will be 
analyzed according to 
treatment actually 
received (ie the other 
trt group than 
randomized)
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
Conventional PK parameters will not be calculated due to the limited sampling schedule.
5.2
Descriptive analyses
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6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
The primary objective is to evaluate the effect of AFQ056 in reducing cocaine use.
6.1.1
Variables 
The primary variable is the proportion of cocaine use days during the treatment period (day 1 
to last day of treatment).
For each subject, the proportion of cocaine use days will be calculated by dividing the number 
of days of cocaine use by the number of days during the treatment period, i.e. 98 days for 
completers and number of days between Day 1 and day of last dose in case of premature 
discontinuation of study treatment. For the weekly proportions, the full 7 days of data should 
be available for a subject. For monthly proportions, at least 7 days of data should be available. 
It is considered as a continuous variable with a normal distribution. The cocaine consumption 
will be recorded daily (Yes/No) using the timeline follow-back during the entire study.
The timeline follow-back cocaine is a cocaine assessment method that obtains estimates of daily 
cocaine intake and has been evaluated with clinical and nonclinical populations. Using a 
calendar, people provide retrospective estimates of their daily cocaine use over a specified time 
period that can vary up to 12 months from the interview data. 
6.1.2
Descriptive analyses
The cocaine daily consumption (Yes/No) will be listed by treatment, subject, and day. The 
overall proportion of cocaine use days, along with the monthly and weekly proportions will be 
listed by treatment and subject.
A descriptive summary table of the proportion of cocaine use days will be provided by treatment 
and week.  A similar table shall also be provided to summarize the proportion of cocaine use 
days by treatment and month (28 days was selected as a nominal length month, rather than 
actual calendar month). The overall proportion of cocaine use days will also be summarized.
6.1.3
Statistical model, assumptions and hypotheses
A Bayesian analysis will be conducted on the proportion of cocaine use days
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6.1.3.1
Model checking procedures
6.1.3.2
Sensitivity analyses
6.1.3.3
Supportive analyses
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6.1.3.4
Graphical presentation of results
6.2
Secondary objectives
The secondary objectives are to assess the effect of AFQ056 on other measures of cocaine use 
and on measures of alcohol use, to assess the safety and tolerability and to evaluate the 
pharmacokinetics of AFQ056.
6.2.1
Variables 
Two urine samples per week will provide a quantitative measure of cocaine’s metabolite
Benzoylecgonine.
Alcohol consumption will be recorded by the subjects using timeline follow-back. The number 
of drinks will be recorded daily. For the weekly consumption, the full 7 days of data should be 
available for a subject. For monthly consumptions, the full 28 days of data should be available.
The timeline follow-back alcohol is a drinking assessment method that obtains estimates of 
daily drinking and has been evaluated with clinical and nonclinical populations. Using a 
calendar, people provide retrospective estimates of their daily drinking over a specified time 
period that can vary up to 12 months from the interview data.
Abstinence last x weeks at end of treatment
Binary response variables based on abstinence will be calculated as follows:
A subject is considered abstinent the last x weeks of treatment if they completed the 14 weeks 
treatment period and were abstinent the last x weeks (with x=1 , 2, 3...., 14).
If a subject didn’t complete 14 weeks they will be considered as not abstinent.
6.2.2
Descriptive analyses
The log-transformed quantitative urine measurements of Benzoylecgonine will be summarized 
by treatment and visit / time and weekly. To obtain the weekly profiles, the BE measurements 
obtained by a subject during each week (aligned with the weekly profiles of TLFB) will be 
averaged. These data shall also be listed by subject, and time point.
Descriptive summary tables shall be provided to summarize the alcohol consumption by 
treatment and week, and by treatment and month. The alcohol daily consumption, weekly 
consumption and monthly consumption will be listed by subject and time point. If country is a 
significant effect in the model stated in section 6.2.3 then summary statistics will also be 
provided by country.
The amount spent on cocaine will be summarized by treatment and listed by subject and time 
point. The amount spent will be converted inEuros for the summary statistics, using the 
exchange rates recorded on 7th August 2019 from  XE currency converter website 
(https://www.xe.com/currencyconverter/convert).  The exchange rates are:
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US Dollar to Euro – 0.891
Swiss Franc to Euro – 0.916
Argentine Peso to Euro – 0.019
The number and % of subjects abstinent the last x weeks will be described both on the PD 
analysis set and FAS.
6.2.3
Statistical model, assumptions and hypotheses
6.2.3.1
Model checking procedures
6.2.3.2
Graphical presentation of results
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6.3
Exploratory objectives
6.3.1
Variables 
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6.3.2
Descriptive analyses
6.3.3
Statistical model, assumptions and hypotheses
6.3.4
Graphical presentation of results
7
Statistical methods for safety and tolerability data
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
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7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and patient.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment group and patient.
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all parameters 
in a subject with any abnormal values. Summary statistics will be provided by treatment and 
visit/time. Newly occurring liver enzyme abnormalities will be listed by treatment, subject and 
visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
incidence greater than X% and on <on-treatment/treatment emergent> serious adverse events 
and SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population.
If for a same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:


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
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
Other safety evaluations
The Columbia Suicide Severity Rating Scale data will be listed by treatment group, subject and 
visit.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
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