Clinical trial NCT03769896
Conditions: Parkinson Disease
Keywords: Parkinson´s Disease cannabinoids non-motor symptoms
Sponsor: Medical University Innsbruck
Start date: 2017-10-03; Completion date: 2019-07-15
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized placebo-controlled, double-blind, parallel-group, enriched enrollment randomized withdrawal study assessing the efficacy and safety of nabilone for non-motor symptoms in patients with Parkinson´s Disease. Nabilone is an analogue of tetrahydrocannabinol (THC), the psychoactive component of cannabis. Nabilone acts as a partial agonist on both Cannabinoid 1 (CB1) and Cannabinoid 2 (CB2) receptor in humans and therefore mimics the effect of THC but with more predictable side effects and less euphoria.

Part 1 is an open-label dose adjustment phase of the study. In eligible patients, a screening period is followed by an open-label nabilone dose optimization phase and a stable phase for at least 1 week. Treatment responders will be included in Part 2 of the study (randomized placebo-controlled, double-blind, parallel-grouped).

Part 2 is the placebo-controlled, double-blind, parallel-group randomized withdrawal phase of the study.

Detailed description:
This is a randomized placebo-controlled, double-blind, parallel-group, enriched enrollment randomized withdrawal study assessing the efficacy and safety of nabilone for non-motor symptoms in patients with Parkinson´s Disease. Nabilone is an analogue of tetrahydrocannabinol (THC), the psychoactive component of cannabis. Nabilone acts as a partial agonist on both Cannabinoid 1 (CB1) and Cannabinoid 2 (CB2) receptor in humans and therefore mimics the effect of THC but with more predictable side effects and less euphoria.

Part 1 is the open-label dose adjustment phase of the study. In Part 1, eligible subjects, who have signed the informed consent form at the screening visit, will receive open-label nabilone starting with a dosage of 0.25 mg in the evening. During dose titration and optimization, nabilone will be titrated in 0.25 mg increments (increase by 0.25 mg/ every one to four days) up to a maximum dose of 1 mg twice daily. Patients should be on a stable nabilone dose for at least 1 week afterwards until Baseline Visit (V 0).

Part 2 is the placebo-controlled, double-blind, parallel-group randomized withdrawal phase of the study. At Baseline Visit, treatment responders will be included in Part 2 of the study (randomized placebo-controlled, double-blind, parallel-grouped). Responders are randomized in a 1:1 ratio at Baseline Visit to receive either nabilone or matching placebo for 4 weeks + 2 days. The placebo-controlled, double-blind, randomized withdrawal phase will end with a clinic visit (Termination Visit V 1). Following this, the study medication will be tapered in all patients. During this period the patients will receive phone calls every other day. A Safety Telephone Call and a Safety Follow-Up Visit will be performed.

Arms: arm 1: Nabilone 0.25 mg arm 2: Placebo (corn starch)
Interventions: intervention 1: Nabilone 0.25 mg intervention 2: Placebo
Intervention descriptions: intervention 1: capsules, 0.25 mg up to 2 mg of nabilone taken orally on a daily basis intervention 2: capsule, corn starch, daily basis

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
 
 
Title 
Nabilone 
for 
non-motor 
symptoms 
in 
Parkinson’s disease: A Randomized Placebo-
controlled, 
double-blind, 
parallel-group, 
enriched enrolment randomized withdrawal 
Study  
Short Title 
The NMS-Nab study 
Protocol Version 
1.4 
Effective 
08th June 2018 
Phase 
IIa 
EudraCT No. 
2017-000192-86 
Original Date of Issue 
December 2016 
Investigational Medicinal Product: 
 
Nabilone:  
Synthetic cannabinoid nabilone, other 
components: Polyvinylpyrollidone (Povidone) 
co-precipitate and corn starch  
 
Placebo: corn starch 
Route and Dosage Form 
nabilone 0.25 - 1 mg or matching placebo, 
administered orally once or twice daily 
NCT Number 
NCT03769896 
 
 
 
 
 
 
 
 
 
 
C o n f i d e n t i a l   M a t e r i a l 
 
 
The information provided in this clinical investigation plan are strictly confidential and will be 
available for potential investigators, involved investigators and their study team only, as well 
as for the medical director of the conducting hospital, health authorities and ethics 
committees to review, verify or implement the clinical trial. Any publication or disclosure to a 
third party without prior written consent of the Sponsor is expressly prohibited. By signing the 
clinical investigation plan, the provisions of it are binding for all parties. 
 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 2/107 
General Information 
Sponsor of the Clinical Trial 
Medical University of Innsbruck 
Represented by:  
O.Univ.-Prof. Dr. Werner Poewe 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria 
E-Mail: mui-sponsor@i-med.ac.at 
Tel.: 0043-512-504-23850 
Fax: 0043-512-504-23852 
Coordinating Investigator of the Clinical 
Trial 
Prof. Dr. Seppi Klaus 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria 
E-Mail: Klaus.Seppi@tirol-kliniken.at 
Tel.: 0043-512-504-81498 
Fax: 0043-512-504-25819 
 
Author of the Clinical Investigation Plan 
Dr. Marina Peball 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria 
E-Mail: Marina.Peball@i-med.ac.at  
Tel.: 0043-512-504-82718 
Fax: 0043-512-504-25819 
Manufacturer of study medication 
AOP Orphan Pharmaceuticals AG 
Wilhelminenstraße 91/II 
1160 Wien 
Austria 
Tel.: 0043-1-503 72 44-37 
 
Responsible Contact Person for Drug 
Safety 
Prof. Dr. Prof. Hans-Guenther Knaus 
Medical University Innsbruck 
Department for Medical Genetics, Molecular 
and Clinical Pharmacology 
Peter-Mayr Strasse 1 
A-6020 Innsbruck, Austria 
Tel.: 0043-512-9003 70440 / 70441             
Fax: +43-512-9003 73440                      
E-mail: hans.g.knaus@i-med.ac.at  
 
 
Statistics will be performed by the Study Team. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 3/107 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 4/107 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 5/107 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 6/107 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 7/107 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 8/107 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 9/107 
Study Site and Members of the Study Team 
 
Study Site 
 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria 
 
 
Members of the Study Team  
 
Dr. Atbin Djamshidian-Tehrani 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria  
 
Dr. Marina Peball 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria  
 
Dr. Mario Werkmann 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria  
 
Dr. Beatrice Heim 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria  
 
Dr. Roberto De Marzi 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria  
 
Dr. Sweta Bajaj 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria  
 
Dr. Philipp Ellmerer 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 10/107 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria  
 
Dr. Federico Carbone 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria  
 
Dora Valent, M.Sc. 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria  
 
Katarzyna Wachowicz, PhD. 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria  
 
 
Richard Menegotto 
Medical University Innsbruck 
Department of Neurology 
Anichstraße 35 
6020 Innsbruck 
Austria 
 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 11/107 
Additional involved Persons and Institutions 
 
Laboratory 
Laboratory of the Hospital Innsbruck (ZIMCL) 
Head: Univ. Prof. Dr. Andrea Griesmacher 
Anichstraße 35 
6020 Innsbruck 
Austria 
 
Contactperson: 
Anna Kirchmayr 
E-Mail: anna.kirchmayr@tirol-kliniken.at  
Tel.: 0043-512 504-24081 
Fax: 043-512 504-24088 
Datamanagement 
and  
Monitoring 
OE Clinical Trial Center (OE CTC) 
Medical University of Innsbruck 
Head: Mag.(FH) Sabine Embacher-Aichhorn 
Anichstraße 29-31 
6020 Innsbruck 
Austria 
 
Contactperson: 
Mag.a (FH) Sabine Embacher-Aichhorn 
Tel.: 0043-512 9003-70085 
Fax: 0043-512 9003-73086 
eMail: sabine.embacher@i-med.ac.at  
 
 
 
 
 
ECG Evaluation 
 
Cardiologic Outpatient Department 
Head: Univ. Prof. Dr. Weiss Günter 
Anichstraße 35 
6020 Innsbruck 
Austria 
 
Contactperson: 
Stefanie Feiss 
E-Mail: Lki.me.kardio-ambulanz@tirol-kliniken.at  
Tel.: 0043-50 504-23268 
Fax: 043-50 504-23264 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 12/107 
Protocol Synopse 
Protocol Number: 
Version 1.4 
Eudract Number: 
2017-000192-86 
Study Title:  
Nabilone for non-motor symptoms in Parkinson’s disease: A 
Randomized 
Placebo-controlled, 
double-blind, 
parallel-group, 
enriched enrolment randomized withdrawal Study 
Number of Centers: 
One clinical site (Medical University of Innsbruck) 
Clinical Phase: 
IIa 
Treatment Duration: 
Planned start: June 2017 
Time of Recruitment:  6 months  
Titration phase: 2-28 days, 1 – 2 weeks on stable nabilone dose, 4 
weeks (+ 2 days) in double-blind parallel-group, enriched 
enrolment 
randomized 
withdrawal 
phase, 
dose 
tapering 
(individual) and Safety follow-up two weeks after discontinuation 
from study drug 
Planned end of the trial: December 2019 (LPLV) 
Study Population / 
Indication: 
Subjects with Parkinson’s disease (PD) 
Study Objective: 
To test the clinical effect of nabilone on non-motor symptoms 
(NMS) in subjects with PD  
Study Design: 
Placebo-controlled, 
double-blind, 
parallel-group, 
enriched 
enrolment randomized withdrawal study, in which a screening 
period is followed by an open-label nabilone dose optimization 
lasting up to 28 days and at least 1 week on a stable OL nabilone 
dose. (Part 1) 
 
Eligible subjects, who have signed the informed consent form at 
the screening visit, will receive open-label nabilone starting with a 
dosage of 0.25 mg at the evening. During dose titration and 
optimization, nabilone will be titrated in 0.25 mg increments 
(increase by 0.25 mg/ every one to four days) up to a maximum 
dose of 1 mg twice daily (dose increments: 1: 0.25 mg 0-0-1; 2:  
0.25 mg 1-0-1; 3: 0.25 mg 1-0-2; 4: 0.25 mg 2-0-2; 5: 0.25 mg 2-0-
3; 6: 0.25 mg 3-0-3; 7: 0.25 mg 3-0-4; 8: 0.25 mg 4-0-4). During 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 13/107 
titration phase regular two-daily phone calls with the study center 
will be performed. Dose tapering will be performed according to 
the investigator´s decision. This open-label titration phase will last 
up to 28 days and will end with a visit on-site (V – 1). Patients 
should be on a stable nabilone dose for at least 1 week afterwards 
until Baseline Visit (V 0). 
 
During optimization, doses will be adjusted upward in 0.25 mg one 
to four-daily increments until the patient  
• 
has reached a rating of “1” (i.e. very much improved) or “2” 
(i.e. much improved) on the 7-point Clinical Global 
Impression of Improvement (CGI-I; i.e. a 7 point scale that 
requires the clinician to assess how much the patient's 
illness has improved or worsened relative to a baseline 
with the following ratings: 1, very much improved; 2, much 
improved; 3, minimally improved; 4, no change; 5, 
minimally worse; 6, much worse; or 7, very much worse) 
[i.e. criterion 1]; or 
• 
experiences intolerable side effects believed to be related 
to study medication [i.e. criterion 2]; or  
• 
reaches the maximum permitted dosage of 1 mg twice 
daily [i.e. criterion 3].  
 
Patients who meet  
• 
criterion 1 will enter into the 1 weeks OL treatment period 
at that dose.  
• 
criterion 2 will proceed to the 1 week OL treatment period 
at the previous lower dose, providing they will meet the 
definition of a responder at that dose.  
• 
criterion 3 and were a responder will enter the study at 1 
mg twice daily.  
 
Patients are discontinued after dose optimization phase 
• 
if they meet criterion 2 but did not meet the responder 
definition at the previous dose,  
• 
if they meet criterion 2 at the initial dose of 0.25 mg once 
daily,  
• 
or if they meet criterion 3 but did not meet the definition of 
a responder. 
 
Responders are then randomized in a 1:1 ratio at Baseline Visit to 
receive either nabilone or matching placebo for 4 weeks + 2 days 
(Part 2). During the first week of the double-blind withdrawal 
phase regular phone calls will be held every other day. 
After 4 weeks of the placebo-controlled, double-blind, randomized 
withdrawal phase, patients will be invited to the clinic for a 
Termination Visit (V 1). Following this, nabilone will be tapered in 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 14/107 
all patients in 0.25 mg two-daily decrements. During this period 
the patients will receive phone calls every other day. A Safety 
Telephone Call and a Safety Follow-Up Visit will be executed 5 
days ± 2 days and 2 weeks + 2 days after the last intake of study 
drug. 
Assessments: 
Subjects will be evaluated at the clinic site by the investigator at 
the screening visit, at weeks -1 (end of optimization phase, start of 
open label nabilone at a fixed dose ranging between 0.25 mg once 
daily up to 1 mg twice daily), 0 (V 0, baseline of randomized 
withdrawal phase), 4 (termination visit/ V 1). A Safety Phone Call 
and a Safety Follow-Up Visit will be performed 5 days ± 2 days 
and 2 weeks + 2 days after the end of the last intake of nabilone, 
respectively. 
Study visits will include the following assessments: 
• 
Movement Disorder Society (MDS)-sponsored new version 
of the UPDRS (MDS-UPDRS) (all visits including 
screening) 
• 
Non-Motor Symptoms Scale (NMSS) (all visits except for V 
-1)  
• 
Hospital Anxiety and Depression Scale (HADS) (all visits 
except for V -1) 
• 
39-Item Parkinson's Disease Questionnaire (PDQ-39) (all 
visits except for V -1) 
• 
Montreal Cognitive Assessment Scale (MoCA) (all visits 
except for V -1) 
• 
Epworth Sleepiness Scale (ESS) (all visits except for V -1) 
• 
Visual Analog Scale (VAS) of Pain (all visits except for V -
1) 
• 
King's Parkinson's disease pain scale (KPPS) (all visits 
except for V -1) 
• 
Fatigue Severity Scale (FSS) (all visits except for V -1) 
• 
Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s Disease–Rating Scale (QUIP-RS) (all visits 
except for V -1) 
• 
Columbia Suicide Severity Rating scale (C-SSRS) (all 
visits) 
• 
CGI-I (V -1, V 0, V 1, and Safety Follow-Up Visit only) 
• 
Vital signs (all visits including screening) 
• 
Concomitant medications (all visits including screening) 
• 
Adverse Events (all visits including screening) 
• 
Physical examination (screening, V 0, V 1, and Safety 
Follow-Up Visit only) 
• 
Local ECG and Clinical Laboratory tests ((pre-)screening 
and V 1 only) 
• 
Measurement of Eye-Movements with a Tobii TX300 Eye-
Tracker (Screening Visit, Termination Visit) 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 15/107 
Subjects will undergo two-daily phone visits during the titration 
phase, the first week of the parallel-group, enriched enrolment 
randomized withdrawal study, and the tapering phase. These will 
include the following: 
• 
Concomitant medications use 
• 
Adverse Events 
• 
CGI-I 
• 
Hallucination 
item 
(1.2) 
of 
Movement 
Disorders Society – Unified Parkinson´s 
Disease Rating Scale (MDS-UPDRS) 
• 
Orthostatic hypotension (OH) item (1.12) of 
Movement 
Disorders 
Society 
– 
Unified 
Parkinson´s Disease Rating Scale (MDS-
UPDRS) 
• 
Day-time sleepiness item (1.8) of Movement 
Disorders Society – Unified Parkinson´s 
Disease Rating Scale (MDS-UPDRS)  
• 
Columbia Suicide Severity Rating scale (C-SSRS)  
 
Concomitant medications:  
Anti-parkinsonian treatment: 
All anti-parkinsonian medications will be permitted during the 
study. However, no changes to medications or dosage will be 
allowed during this trial. 
Number of subjects: 
48 Patients are planned to be included  
Inclusion/ Exclusion 
criteria: 
Subjects must meet all inclusion criteria in order to be eligible for 
the study: 
Inclusion criteria: 
1. age ≥30 years  
2. diagnosis of PD (de novo or on stable medication 
without disturbing motor fluctuations or dyskinesia) 
3. NMS with a score of ≥4 on MDS-UPDRS Part 1. One of 
the following domains have to be affected with a score 
≥2: 1.4 (anxious mood) or 1.9 (pain) 
4. On a stable regimen of anti-parkinson medications for 
at least 30 days prior to screening and willing to 
continue the same doses and regimens during study 
participation 
5. Any other current and allowed prescription/non-
prescription medications and/or nutritional supplements 
taken regularly must have been at a stable dose and 
regimen for at least 30 days prior to screening, and 
subject must be willing to continue the same doses and 
regimens during study participation 
6. Signed a current IRB-approved informed consent form 
7. Acceptable method of contraception  
 
Any of the following conditions will exclude the subject from 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 16/107 
entering the study: 
Exclusion criteria: 
1. Previous participation in any study with nabilone 
2. current use of cannabinoids or use within 30 days prior 
to screening  
3. current or recent (within 30 days prior to screening) 
participation in another study with an investigational 
medicinal product 
4. atypical or secondary parkinsonism 
5. presence of motor complications if, based on the 
investigator’s judgment, not adequately controlled (i.e. 
a score ≥2 on one of the items of the MDS-UPDRS 
Part IV at screening)  
6. Hoehn and Yahr stage ON > 3 
7. Evidence of disturbing impulse control disorder 
8. History of neurosurgical intervention for PD 
9. Presence 
of 
clinically 
significant 
symptomatic 
orthostatic hypotension at screening (MDS-UPDRS 
1.12 > 2) 
10. Use of prohibited medication listed in 7.4.2 
11. Laboratory values clinically significant out-of-range at 
screening or within 4 weeks prior to screening 
12. Known or diagnosed sinus tachycardia in ECG 
evaluation at screening or within 4 weeks prior to 
screening 
13. presence of an acute or chronic major psychiatric 
disorder (e.g., Major Depressive Disorder, psychosis) 
or symptom (e.g., hallucinations, agitation, paranoia) 
(MDS-UPDRS 1.2 and/or 1.3 > 2) 
14. recent suicidal attempt within the past five years or 
suicidal ideation within the past 6 months 
15. presence of dementia (MDS-UPDRS 1.1 > 2, MMSE of 
< 24 at screening) 
16. clinically significant or unstable medical or surgical 
condition that may preclude safe and complete study 
participation (based on the investigator’s judgment).   
17. moderate or severe hepatic or renal impairment. 
18. History of chronic alcohol or drug abuse within the last 
2 years 
19. women of child-bearing potential who do not practice 
an acceptable method of birth control [*Acceptable 
methods of birth control for women and men in this 
study are: surgical sterilization (e.g. tubal ligation for 
females), intrauterine devices that release hormones 
(hormone 
spiral), 
oral 
hormonal 
contraceptive, 
contraceptive patch, dermal hormonal contraception, 
vaginal hormonal contraception (NuvaRing®), implants 
that release progesterone (Implanon®), long-acting 
injectable 
contraceptive, 
partner’s 
vasectomy, 
a 
double-protection method, postmenopausal (> 2 year 
absence of vaginal bleeding).]  
20. Pregnant women, or women planning to become 
pregnant during the course of the study, or nursing 
women. 
21. Known hypersensitivity to any components of the IMP 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 17/107 
or excipients 
22. Patient is legally incapacitated or persons held in an 
institution by legal or official order 
23. Persons with any kind of dependency on the 
investigator or employed by the Sponsor or investigator 
Route and Dosage 
Form: 
nabilone 0.25 – 1 mg or matching placebo, administered orally 
once or twice daily 
Endpoints 
Primary efficacy endpoint:  
• 
Change from baseline to Week 4/Termination Visit in the 
MDS-UPDRS Part I (non-motor Experiences of daily living; 
nmEDL) 
 
Key Secondary efficacy endpoints: 
• 
Change from baseline to Week 4/Termination visit in the 
following assessments:   
• 
NMSS 
• 
total MDS-UPDRS (i.e. Part II + III + IV) 
• 
different domains of NMSS and MDS-UPDRS Part I 
• 
HADS 
• 
PDQ-39  
• 
MoCA 
• 
ESS, FSS 
• 
VAS of Pain  
• 
KPPS 
• 
QUIP-RS 
 
• 
CGI-I scale at termination visit  
 
 
Safety and tolerability endpoints: 
Safety and tolerability will be evaluated with reference to the 
following: 
• 
Tolerability 
• 
Number of subjects (%) who discontinue the study 
• 
Number of subjects (%) who discontinue the study due to 
AE 
• 
Safety Measures 
• 
Adverse Events (AE) 
• 
Clinical and laboratory assessments 
• 
Vital signs 
• 
ECG 
• 
Subjects compliance, prior and concomitant medication 
use 
• 
Hallucination 
item 
(1.2) 
of 
Movement 
Disorders Society – Unified Parkinson´s 
Disease Rating Scale (MDS-UPDRS) 
• 
Orthostatic hypotension (OH) item (1.12) of 
Movement 
Disorders 
Society 
– 
Unified 
Parkinson´s Disease Rating Scale (MDS-
UPDRS) 
• 
Day-time sleepiness item (1.8) of Movement 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 18/107 
Disorders Society – Unified Parkinson´s 
Disease Rating Scale (MDS-UPDRS)  
• 
C-SSRS 
 
Exploratory endpoints: 
• 
Change in reaction time, attention span, and 
concentrativeness as measured by the Eye-
tracking examination 
 
Statistical 
Considerations: 
Sample size calculation  
A total of 38 patients (19 patients per group) will provide 80% 
power at two-sided 5% significance level to detect a statistically 
significant difference in the change from baseline to Week 
4/Termination visit in MDS-UPDRS Part I score between nabilone 
and placebo assuming a true difference of 2.5 points. This sample 
size calculation assumes a standard deviation of the change from 
randomization to week 4 to be 2.4 points. (46) With a drop- out 
quote of 25 % we will include 48 patients in the trial.  
The sample size calculation was performed with the Program 
nQuery Advisor (Version 7). 
Importantly, although a sample size calculation is provided, this is 
an exploratory study evaluating different NMS domains. Therefore, 
corrections for multiple comparisons are not planned. 
 
Endpoints 
Results of the changes of all clinical scales in this trial will be 
shown in a descriptive way by median and interquartile range 
(quartile 1, quartile 3), separately for the nabilone and placebo of 
the clinical trial. Mean and standard deviation for the descriptive 
analysis of the two study arms will also be provided. P-values for 
the change of the results will be given. 
 
The primary and key secondary efficacy criteria refer to the 
double-blind placebo-controlled enriched enrolment randomized 
withdrawal phase of the study. The primary efficacy criterion will 
be measured as the change of the MDS-UPDRS Part I between 
baseline and week 4. The key secondary efficacy criteria will be 
measured as the change in the other assessments between 
baseline and week 4. Because an interpolation of data will not be 
performed in case of a drop-out, the primary analysis is a per-


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 19/107 
protocol analysis. All statistical tests will be performed with a two-
sided alpha risk of 0.05.  
For the study’s primary efficacy and key secondary efficacy 
analyses, mean changes from randomization to 4-week follow-up 
in the nabilone and placebo groups will be analyzed separately for 
the two groups by Wilcoxon matched-pairs test and then 
compared by Mann-Whitney U Test. (49) The data set for this 
analysis will include patients with measurements for the score at 
V0 and V1. 
Additionally, a sensitivity analysis will be performed for a primary 
efficacy or key secondary efficacy variable, if mean value of an 
efficacy variable should be different at randomization at a 2-sided 
10% level (using Mann-Whitney U tests). To estimate the 
treatment effect, we will then compare mean change from 
randomization to 4 weeks-follow-up in both treatment groups using 
analysis of covariance, with value at randomization as covariate 
and treatment group as main effect.  
Moreover, sensitivity to treatment will be assessed using effect 
sizes of the different outcome variables when using nabilone to 
treat non-motor symptoms in Parkinson´s disease.  
For 
CGI-I 
analyses, 
distributions 
of 
aggregated 
ratings 
(amelioration, aggravation) in the nabilone and placebo groups at 
4-week´s- Termination Visit will be compared by Fisher exact test. 
(49) 
The primary safety analysis will be performed with the safety data 
set. Distributions of AEs, SAEs, and SUSARs in the nabilone and 
placebo groups at week 4 will be compared by Fisher exact test. 
Additionally, a safety analysis will be performed on all events and 
tolerability issues, as well as the hallucination item, orthostatic 
hypotension item, the day-time sleepiness item of Part I of MDS-
UPDRS, and C-SSRS occurring through the overall course of the 
study and provided separately for the nabilone and placebo group. 
This will be a descriptive analysis reporting overall number, 
frequencies, and percentage of AEs, SAEs, and SUSARs in 
patients taking nabilone, patients withdrawn from the study, and 
patients withdrawn due to an AE. 
Separate summaries of AEs in regard of severity and relationship 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 20/107 
to the study drug, separate summaries of AEs leading to 
withdrawal from the study and separate summaries for SAEs will 
be provided. 
For the Eye-tracking analyses, mean changes from Screening 
Visit to the Termination Visit in the nabilone and placebo groups 
will be analyzed separately for the two groups by Wilcoxon 
matched-pairs test and then compared by Mann-Whitney U Test.  
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 21/107 
List of Abbreviations 
2-AG 
2-arachidonoyl glycerol 
ADR 
Adverse Drug Reaction 
AE 
An adverse event is “any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and 
which does not necessarily have to have a causal relationship with this 
treatment”. (47) 
AMG 
“Arzneimittelgesetz” = Medicines Act in Austria 
Anandamide  
Arachidonoyl ethanolamide 
BID 
“bis in die” (Latin), twice daily 
CA  
competent authority 
cAMP 
cyclic adenosine monophosphate 
CB1 receptor 
cannabinoid 1 receptor 
CB2 receptor 
cannabinoid 2 receptor 
CBD 
Cannabidiol 
CGI-I 
Clinical Global Impression – Global Improvement 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating scale  
Directive 2001/20/EC 
Directive 2001/20 der European Commission 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders 
DSUR 
Development Safety Update Report 
ECG 
electrocardiogram 
ECS 
endocannabinoid system 
ESS 
Epworth Sleepiness Scale 
ET 
Early Termination Visit 
EU  
European Union 
EudraCT  
European Clinical Trials Database 
FAAH 
fatty acid amide hydrolysis 
FSS 
Fatigue Severity Scale 
GCP 
Good Clinical Practice 
GPR55 
GTP-binding protein-coupled receptor 55 
HADS  
Hospital Anxiety and Depression Scale  
HEENT examination 
Examination of the head, eyes, ears, nose, throat 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 22/107 
IEC/IRB 
Independent ethics committee/ Institutional review board 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
ISF 
Investigator Site File 
KPPS 
King's Parkinson's disease pain scale  
LD/CD Treatment 
Levodopa / Carbidopa Treatment 
LID 
Levodopa-induced Dyskinesia  
LPLV 
Last Patient Last Visit 
MDS  
Movement Disorder Society  
mg  
Milligramme 
mm 
Millimetre 
MMSE 
Mini Mental State Examination 
MoCA 
Montreal Cognitive Assessment Scale 
MS 
Motor symptoms 
NMS 
Non-motor symptoms 
NMSS  
Non-Motor Symptoms Scale 
OFF state 
the phase with no response to medication and significant motor symptoms 
OH  
orthostatic hypotension 
OL 
open-label 
ON state  
period when the patient notices a benefit on MS from standard oral LD/CD 
treatment 
PD 
Parkinson´s disease 
PDQ-39 
39-Item Parkinson's Disease Questionnaire 
PPAR 
peroxisome proliferator-activated receptor  
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–
Rating Scale  
RBD 
REM Sleep Behavior Disorder 
RCT 
randomized controlled trials 
REM 
rapid eye movement 
RNA 
Ribonucleic acid 
SAE 
“A serious adverse event (experience) or reaction is any untoward medical 
occurrence that at any dose results in death, is life-threatening, requires 
inpatient hospitalisation or prolongation of existing hospitalisation, results in 
persistent or significant disability/incapacity, or is a congenital 
anomaly/birth defect”. (47) 
SOP  
Standard Operating Procedures 
SUSARs 
A SUSAR is an event that is believed to be causal to the to the  


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 23/107 
administration of the study drug and is severe and unexpected. 
TMF 
Trial Master File 
TC 
Telephone Call 
TC – S  
Safety Telephone Call 
TRPV1 
transient receptor potential vanilloid type 1 cation channel 
UPDRS 
Unified Parkinson Disease Rating Scale 
V  
Visit 
V – S 
Safety Follow-Up Visit 
VAS of Pain 
Visual Analog Scale of Pain 
Δ9-THC 
Δ9 – tetrahydrocannabinol 
 
 
 
 
 
 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 24/107 
 
Table of contents 
General Information ............................................................................................................... 2 
Clinical Study Signature Page, Amendment (1/2) ............ Fehler! Textmarke nicht definiert. 
Clinical Study Signature Page, Amendment (2/2) ............ Fehler! Textmarke nicht definiert. 
Study Site and Members of the Study Team ........................................................................ 8 
Additional involved Persons and Institutions ................................................................... 11 
Protocol Synopse ................................................................................................................. 12 
List of Abbreviations ............................................................................................................ 21 
1 
Background and Rationale ........................................................................................... 28 
1.1 
The endocannabinoid system ................................................................................................ 28 
1.2 
Non-motor symptoms in Parkinson´s Disease ................................................................. 30 
1.3 
Preclinical Research in Parkinson´s disease .................................................................... 32 
1.4 
Therapeutic potential of Cannabinoids in Parkinson´s Disease ................................ 32 
2 
Objectives and Endpoints ............................................................................................ 34 
2.1 
Objectives ...................................................................................................................................... 34 
2.1.1 
Primary Efficacy Objective .............................................................................................................. 34 
2.1.2 
Key Secondary Efficacy Objectives .............................................................................................. 34 
2.1.3 
Safety Objectives .................................................................................................................................. 34 
2.1.4 
Exploratory Objective ........................................................................................................................ 35 
2.2 
Efficacy Endpoints ...................................................................................................................... 35 
2.2.1 
Primary Efficacy Endpoint ............................................................................................................... 35 
2.2.2 
Key Secondary Efficacy Endpoints ............................................................................................... 35 
2.2.3 
Safety Endpoints .................................................................................................................................. 35 
2.2.4 
Exploratory Endpoints ...................................................................................................................... 35 
3 
Study Design ................................................................................................................. 36 
3.1 
Study Description ....................................................................................................................... 36 
3.1.1 
Study end: ............................................................................................................................................... 37 
3.1.2 
Visits .......................................................................................................................................................... 38 
3.1.3 
Study Duration Per Patient ............................................................................................................. 39 
3.1.4 
Planned Number of Patients ........................................................................................................... 39 
3.1.5 
Anticipated Regions and Countries ............................................................................................. 39 
3.2 
Schedule of Events ..................................................................................................................... 40 
3.3 
Schematic Diagram .................................................................................................................... 41 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 25/107 
4 
Study Population and Withdrawal of Patients ............................................................ 42 
4.1 
Inclusion Criteria ........................................................................................................................ 42 
4.2 
Exclusion Criteria ....................................................................................................................... 42 
4.3 
Discontinuation of the Study, Premature Termination ................................................. 43 
4.3.1 
Potential Criteria for Withdrawal from Study ........................................................................ 44 
4.3.2 
Definite Criteria for Withdrawal from Study ........................................................................... 44 
4.4 
Further treatment after end of treatment ......................................................................... 45 
4.5 
Closure of the Study ................................................................................................................... 45 
5 
Study Procedures (by Visits) ....................................................................................... 46 
5.1 
Screening Period ........................................................................................................................ 47 
5.1.1 
Recruitment and Informed Consent Process ........................................................................... 47 
5.1.2 
Screening Visit ...................................................................................................................................... 48 
5.1.3 
Dose Titration Phase .......................................................................................................................... 49 
5.1.4 
Visit -1 (week – 1) ............................................................................................................................... 50 
5.2 
Baseline Visit / V 0 and Randomization to Study Drug ................................................. 51 
5.2.1 
Baseline Visit / V 0 (week 0) .......................................................................................................... 51 
5.2.2 
Randomization ..................................................................................................................................... 52 
5.3 
Termination Visit / V 1 (week 4) .......................................................................................... 53 
5.4 
Safety Telephone Call (TC – S) and Safety Follow-Up Visit (V – S) .............................. 54 
5.5 
Early Termination Visit ............................................................................................................ 55 
5.6 
Unscheduled Visit / USV ........................................................................................................... 56 
5.7 
Telephone calls ........................................................................................................................... 57 
6 
Description of Assessments: Efficacy and Safety Variables .................................... 58 
6.1 
Assessments of Efficacy ............................................................................................................ 58 
6.2 
Safety Assessments .................................................................................................................... 61 
6.2.1 
Adverse Events, Serious Adverse Events, Adverse Drug Reaction, Suspected 
unexpected serious adverse reactions .......................................................................................................... 62 
6.2.2 
Description of other safety measures ......................................................................................... 62 
6.3 
Assessment of exploratory endpoint ................................................................................... 66 
7 
Study Treatments .......................................................................................................... 67 
7.1 
Details of Study Treatment ..................................................................................................... 67 
7.1.1 
Name and Description of Investigational Medicinal Product (IMP) and Comparator
 
67 
7.1.2 
Dosing Instructions ............................................................................................................................ 67 
7.1.3 
Packaging and Labelling ................................................................................................................... 68 
7.1.4 
Handling and Storage Requirements .......................................................................................... 68 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 26/107 
7.2 
Randomization and Blinding, Subject´s Compliance ...................................................... 69 
7.2.1 
Randomization and Numbering of Patients ............................................................................. 69 
7.2.2 
Procedures for Maintaining and Breaking the Treatment Blinding .............................. 69 
7.3 
Drug Accountability and Treatment Compliance ............................................................ 70 
7.3.1 
Procedures for Monitoring Patient Compliance .................................................................... 71 
7.4 
Prior and Concomitant Medications/Treatments ........................................................... 71 
7.4.1 
Allowed Anti-PD Medications/Treatments .............................................................................. 71 
7.4.2 
Prohibited Concomitant Medications/Treatments .............................................................. 72 
7.5 
Concomitant Non-Pharmacologic Therapies .................................................................... 72 
8 
Adverse Events ............................................................................................................. 73 
8.1 
Summary of known and possible Adverse Events of the IMP ...................................... 73 
8.2 
Definition of an Adverse Event (AE) .................................................................................... 74 
8.3 
Definition of a Serious Adverse Events (SAEs) ................................................................. 75 
8.4 
Adverse Drug Reaction (ADR) & Unexpected Adverse Drug Reaction ..................... 76 
8.5 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................................... 77 
8.6 
Pregnancy ..................................................................................................................................... 77 
8.7 
Overdose of Investigational Medicinal Product ............................................................... 78 
8.8 
Grading of Severity of Adverse Events ................................................................................ 78 
8.9 
Causality ........................................................................................................................................ 79 
8.10 Recording, Reporting, and Follow-Up Procedures .......................................................... 79 
8.10.1 
Procedures for Recording, Reporting, and Follow-Ups of Adverse Events ................ 80 
8.10.2 
Recording, Reporting, and Follow-Up Procedures for Serious Adverse Events and 
Suspected Unexpected Serious Adverse Reactions .................................................................................. 81 
8.11 Review and Annual report on Adverse Events, Serious Adverse Events and 
Suspected Unexpected Serious Adverse Reactions ..................................................................... 83 
9 
Documentation .............................................................................................................. 85 
9.1 
Data Recording (Case Report Form, CRF and Patient´s Record) ................................ 86 
9.2 
Trial Folders ................................................................................................................................. 87 
9.2.1 
Trial Master File (TMF) ..................................................................................................................... 87 
9.2.2 
Investigator Site File (ISF) ............................................................................................................... 88 
9.3 
Data Storage ................................................................................................................................. 88 
9.3.1 
Storage duties of the Sponsor ........................................................................................................ 88 
9.3.2 
Storage duties of the investigator ................................................................................................ 88 
10 
Data Management ...................................................................................................... 89 
11 
Protocol Deviations ................................................................................................... 89 
12 
Statistical Analysis .................................................................................................... 90 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 27/107 
12.1 Determination of Sample Size ................................................................................................ 90 
12.2 Study Populations: Datasets or Populations analyzed .................................................. 90 
12.3 Background and Demographic Characteristics ............................................................... 91 
12.4 Efficacy Variables and Analysis ............................................................................................. 91 
12.5 Safety Analysis ............................................................................................................................. 92 
12.6 Handling of Missing Data ......................................................................................................... 93 
13 
Quality Management .................................................................................................. 94 
13.1 Qualifications ............................................................................................................................... 94 
13.2 Monitoring .................................................................................................................................... 94 
13.3 Audits and Inspections ............................................................................................................. 95 
14 
Reporting .................................................................................................................... 96 
14.1 Annual Progress Reports ......................................................................................................... 96 
14.2 Final Study Report ..................................................................................................................... 96 
15 
Publication ................................................................................................................. 97 
16 
Amendments .............................................................................................................. 97 
17 
Ethical and Regulatory Aspects ............................................................................... 98 
17.1 Responsibilities of the Sponsor and the investigator .................................................... 98 
17.2 Approval and Consent ............................................................................................................... 99 
17.3 Patient Insurance .................................................................................................................... 101 
17.4 Data Protection and Confidentiality ................................................................................. 101 
17.5 Discontinuation of the Study by the Sponsor ................................................................. 102 
18 
References ............................................................................................................... 103 
19 
Index of Figures ....................................................................................................... 107 
20 
Index of Tables ......................................................................................................... 107 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 28/107 
1 
Background and Rationale 
1.1 The endocannabinoid system 
The endocannabinoid system (ECS) has become a center of attention for its 
(neuro)modulatory effects in the last 25 years and has become a potential target of drug 
therapy for a variety of illnesses. The ECS plays an important role in many physiological 
body functions and influences mood, motor control, cognition, eating behavior, and 
nociception. Therefore, indications like neuropathic pain, anorexia, and spasticity associated 
with multiple sclerosis or spinal trauma, as well as chemotherapy-induced emesis can now 
be treated with cannabinoids like nabilone, dronabinol, sativex, and epidiolex. [12,31,32] 
 
The two main cannabis species sativa and indica have been the ancestors of almost all 
strains that exist today and from which more than 60 pharmacologically active components 
derive. The main psychoactive compound of Cannabis sativa is Δ9 – tetrahydrocannabinol 
(Δ9-THC), which has a stronger euphoric potential than isolated components of Cannabis 
indica that have more sedative, analgesic, and antiemetic effects. [1,12] 
The ECS summarizes endogenous cannabinoids (endocannabinoids), cannabinoid receptors 
and their synthesis, and degradation enzymes. 
Endocannabinoids are endogenous lipids and ligands to cannabinoid receptors. 
Arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) have been the 
first discovered and therefore best known endogenous cannabinoids out of a large group of 
molecules binding to the endocannabinoid receptors. Endocannabinoids are not stored in 
vesicles like other neurotransmittors. They show a release on-demand into the extracellular 
space mainly through retrograde signaling after postsynaptic activation with the duty to 
decrease presynaptic neurotransmission. After their local and short-lasting task is fulfilled 
endocannabinoids are taken up by surrounding cells and degraded mainly by fatty acid 
amide hydrolysis (FAAH) for anandamide and by monoacylglycerol lipase for 2-AG.  
[2,12,32] 
The endocannabinoid receptors, named CB1 and CB2, are G-protein coupled, seven-
transmembrane domain receptors of the Gi and Go classes. Both are activated mainly by 
cannabinoids and their synthetic analogues, eicosanoids or aminoalkylindoles as well as by a 
large number of synthesized agonists, inverse agonists, antagonists and allosteric 
modulators. [1] Activation of these receptors inhibits adenylate cyclases and subsequently 
increases the intracellular amount of cyclic adenosine monophosphate (cAMP), resulting in 
alteration of the level of activity in voltage- dependent calcium channels and potassium 
channels and an activation of several mitogen-activated protein kinases. [3] 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 29/107 
The CB1 cannabinoid receptor is referred to as the „brain cannabinoid receptor“ due to its 
numerous occurrence in all brain structures. Particularly, the Cortex, Basal Ganglia, 
Hippocampus and Cerebellum present with a high density of CB1 receptor. Combining all its 
effects, the CB1 receptor aids in the control of cell survival, differentiation and proliferation, 
and several cell functions. Through retrograde activation the duration of synaptic activation, 
synaptic plasticity, and neurotransmitter release is influenced. [1,4,32] 
Moreover, non-neuronal cells of the brain, astrocytes in particular, express the CB1 receptor 
in a large amount and its activation through glutamate release leads to an activation of 
presynaptic metabotropic glutamate receptor. [5] 
The occurrence of the CB1 receptor is not limited to the brain, but also appears in the 
peripheral nervous system and other mammal tissues and organs, where it aids in 
maintaining homeostasis. [1] 
The CB2 receptor is of little homology to the CB1 receptor but shows similar ways of 
activation through Gi/o. It is expressed mostly in cells and organs playing a role in the body´s 
immune system where its activation reduces the liberation of pro-inflammatory response 
(cytokines, lymphoangiogenic factors). [6] CB2 receptors are also expressed in the 
gastrointestinal tract and in microglia and vascular cells of the brain as well as in the dorsal 
vagal motor nucleus, the nucleus ambiguous and the spinal trigeminal nucleus. CB2 receptor 
activation may contribute to affective behavior but its concrete role in the brain is not defined 
yet. In the gastrointestinal tract effects on food intake, gastrointestinal motility, gastric 
secretion and gastroprotection, cell proliferation, and intestinal inflammatory processes are 
discussed. [7] 
 
In 2003 the U.S. Health and Human Services granted U.S. Patent 6630507 which describes 
the use of components extracted from Cannabis sativa as useful in neuroprotective disorders 
like PD, Alzheimer´s disease, and HIV- induced dementia. [33] Neuroprotective potential of 
cannabinoids is believed to be due to receptor- induced but also – independent mechanisms 
and specific effects of several endocannabinoids and synthetic agents, like THC, CBD, 
cannabinol, CP55,940, and AM404 (an anandamide analog). [12] In preclinical experiments, 
cannabinoids have the ability to counteract reactive oxygen species and strengthen 
endogenous antioxidants and thereby prevent oxidative stress on neuronal cells by reducing 
microglial and proinflammatory activation through agonistic action of the CB2 receptor 
system as well as by reducing glutamatergic excitotoxicity. [34, 12] 
 
Moreover, there exist other receptors where several endocannabinoids like anandamide can 
bind to under certain circumstances, like the transient receptor potential vanilloid type 1 
(TRPV1) cation channel, the peroxisome proliferator-activated receptor (PPAR), the 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 30/107 
abnormal-CBD receptor and the GTP-binding protein-coupled receptor (GPR)55 that 
possibly influence the clinic of movement disorders. [1,12] 
 
Nabilone is an analogue of dronabinol (THC), the psychoactive component of cannabis, but 
it is not derived from the cannabis plant in contrast to dronabinol. Nabilone acts as a partial 
agonist on both CB1 and CB2 receptor in humans and therefore mimics the effect of THC but 
with more predictable side effects and less euphoria. In Austria, nabilone is licensed for the 
use as an antiemetic for chemotherapy-induced nausea and vomiting not responding to 
conventional antiemetic treatment. The FDA approved nabilone for treating anorexia and 
weight loss in patients with AIDS. Nabilone is widely used as an adjunct therapy for chronic 
pain management, although it is only officially approved for this use in Mexico. 
Nabilone is a racemate consisting of the (S,S) and the (R,R) isomers ("trans") with an 
average weight of 372.5408 Dalton. After oral administration it is rapidly absorbed via the 
gastrointestinal tract. The major excretory pathway is the biliary system. The half-life of 
nabilone amounts to 2 hours, with a half-life of its metabolites of around 35 hours. 
The chemical formula of nabilone is: C24H36O3. 
 
1.2 Non-motor symptoms in Parkinson´s Disease  
Parkinson´s Disease (PD) is a neurodegenerative disorder that occurs with a prevalence of 
1,6/1000 in both males and females equally in all geographical areas. It is less common in 
Asia than in Europe, Africa, North America, South America, or Australia and its prevalence is 
increasing with age (1% in 60 years old people, 3% at the age of 80 years). The mean age of 
onset is 55 years (17 – 80 years). 
Although PD is generally considered a paradigmatic movement disorder, it has long been 
recognized that the neuropathology underlying PD involves many brain areas that are not 
directly involved in motor control. [14,15] It is therefore not surprising that a majority, if not all, 
PD patients suffer from non-motor symptoms adding to the overall burden of parkinsonian 
morbidity. [16,17,18] In this trial, male and female PD patients without disturbing motor 
fluctuations or dyskinesia over the age of 30 years suffering from non-motor symptoms 
(measured on the basis of UPDRS Part I, including at least anxiety or pain) will be included. 
Non-motor symptoms in PD involve a multitude of functions including disorders of sleep-
wake cycle regulation, cognitive dysfunction, disorders of mood and affect, autonomic 
dysfunction as well as sensory symptoms and pain. They become increasingly prevalent and 
obvious over the course of the illness and are a major determinant of quality of life, 
progression of overall disability, and of nursing home placement in PD. [19] 
Common non-motor symptoms in late stage PD include hallucinations, dementia, and 
autonomic dysfunction including urinary incontinence, constipation, and symptomatic 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 31/107 
orthostatic hypotension. In PD patients who have had 20 years of disease duration, dementia 
occurs in 83%, hallucinosis in 74%, symptomatic OH in 48%, constipation requiring daily 
laxatives in 40% and urinary incontinence in 71%. [18]  
Moreover, certain non-motor symptoms such as constipation, olfactory loss, anxiety, 
depression, and RBD may antedate the onset of classical motor symptoms by years or even 
decades. [20,21,22,23,24,25,26] 
Unlike most motor features of PD, NMS often have limited treatment options or response. 
[13] Although common, there is a paucity of research concerning the diagnosis and treatment 
of non-motor symptoms in PD. Indeed, non-motor symptoms in PD are frequently missed or 
undeclared during routine consultations and well-performed large-scale RCTs for the 
treatment of the different non-motor symptoms in PD are lacking. [27,28] 
However, a variety of treatments are available, and for some patients, these treatments can 
effectively control or improve disability from non-motor symptoms, such as psychiatric 
symptoms, sleep disorders, autonomic dysfunction, and fatigue (see Table 1).  
Table 1: Drug classes for non-motor symptoms in PD 
NON-MOTOR SYMPTOMS 
DRUG CLASS (NAME) 
Disorders of sleep and wakefulness 
 
REM Sleep behavioural disorder 
Benzodiazepine (Clonazepam), hormons 
(Melatonin) 
Autonomic dysfunction 
 
Constipation 
Osmotic laxative (Polyethylene Glycol), 
Chloride channel activator (Lubiprostone) 
Gastrointestinal motility 
Peripheral dopamine antagonist 
(Domperidone) 
Orthostatic hypotension 
Peripheral dopamine antagonist 
(Domperidone), mineralcorticoid 
(Fludrocortisone), vasopressor (Midodrine), 
acetylcholineesterase inhibitor 
(Pyridostigmine), Norepinephrine prodrug 
(Droxidopa) 
Sialorrhoea 
Anticholinergic (Atropine drops, 
Glycopyrrolate), Neurotoxin (Botulinum toxin 
A, Botulinum toxin B) 
Cognitive impairment 
 
Dementia 
Acetylcholinesterase inhibitor (Rivastigmine) 
Psychiatric symptoms 
 
Depression 
Dopamine agonist (Pramipexole), serotonin 
reuptake inhibitor / serotonin and 
norepinephrine reuptake inhibitor 
(Citalopram, Escitalopram, Fluoxetine, 
Paroxetine, Sertraline, Venlafaxine extended 
release), Tricyclic antidepressant 
(Desipramine, Nortriptyline) 
Psychosis 
Atypical antipsychotic (Clozapine, 
Quetiapine), Acetylcholinesterase inhibitor 
(Rivastigmine) 
Other 
Fatigue (Stimulant Methylphenidate, 
Modafinil) 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 32/107 
 
1.3 Preclinical Research in Parkinson´s disease 
The endocannabinoid system (ECS) functions as a regulator of dopamine release and 
uptake. Inversely, changes of dopamine levels in the brain can alter the ECS. [9,10] To date 
the hypothesis is that endocannabinoids are a compensational mechanism to the loss of 
dopamine in patients with PD. [1,12]  A reduction of CB1 receptors has been shown in post 
mortem analyses of the caudate nucleus, anterior dorsal putamen and external segment of 
the globus pallidus in comparison to normal levels to the rest of the brain. This might be 
related to an overactive endocannabinoid system with increased CB1 receptor activity, 
messenger RNA levels and levels of endocannabinoids in the basal ganglia which has been 
described in animal models. It is believed that these findings play a role in motor symptoms 
of patients with PD and can be influenced by Levodopa therapy. [1,11,30] Moreover, 
neuroprotective properties of cannabinoids in preclinical experiments are gaining more and 
more attention for clinicians dealing with patients with movement disorders. These effects are 
mainly due to antioxidant mechanisms, microglial inhibition and modulation of cell-cell 
interaction of glia cells and neuronal cells in the basal ganglia. [1,11,30] 
Indeed, activated microglia have been found in lesions of neurodegeneration in the 
substantia nigra of deceased patients with PD in comparison to healthy person. Moreover, a 
decrease of microglial activation is the reason why CB2 receptor agonists have shown to 
reduce inflammation and degeneration of dopaminergic neurons in PD. [1,11,30] 
Interestingly, Barrero et. al discovered that polymorphisms in the cannabinoid receptor gene 
influence depressive mood in patients with PD. [35]  
 
1.4 Therapeutic 
potential 
of 
Cannabinoids 
in 
Parkinson´s Disease 
The endocannabinoid system takes part in building emotions, motor control, attention and 
concentration, the sensation of pain, and eating. [12,31,32] 
Evidence of effects of cannabinoids on symptoms in PD from clinical trials is scarce. Most of 
these trials are either small-sized with less than 20 patients included [12,40,42] or 
uncontrolled [12,36,37,38,39].  
Improvement of motor and non-motor symptoms in PD after intake of cannabinoids has been 
described in several uncontrolled observational studies with ameliorated rest tremor, 
bradykinesia, rigidity, and Levodopa-induced Dyskinesia (LID) as well as improved pain, 
psychosis, symptoms of RBD, and sleep-quality. These effects could not be reproduced by 
randomized controlled trial (RCTs), which were small-sized and used different cannabinoids. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 33/107 
Thus, while a randomized, double-blind, placebo-controlled crossover trial in 7 PD patients 
suggested improvement of Levodopa-induced Dyskinesia (LID) with the synthetic 
cannabinoid nabilone (0.03mg/kg nabilone per day) [42], another randomized, double-blind, 
placebo-controlled crossover trial in 19 PD patients found no effects on LID with an oral 
cannabis extract (40). Interestingly the same study did not show any effects on QoL (40), 
while another parallel-group randomized controlled trial (RCT) [43] in 21 PD patients treated 
with placebo, cannabidiol (CBD) 75 mg/day or CBD 300 mg/day reported improved QoL in 
patients using CBD 300 mg/day and placebo. The same study showed no difference in the 
mean total UPDRS scores of patients with placebo and CBD in different dose regimens. 
Overall, there is no conclusive evidence from RCT on the symptomatic treatment of motor 
symptoms in PD. [12,40, 43, 42] 
Cannabinoids were well tolerated in all of these trials. No serious adverse events were 
recorded. The most common side effects from the RCTs have been the feeling of dizziness 
in up to 10% of patients, mild hypotension in up to 90% of patients, deterioration or new-
onset change of perception (hallucinations, the feeling to be detached, confusion), and 
somnolence in up to 47% of patients. [40,42, 43] In one RCT two patients withdraw from the 
study due to vertigo and postural hypotension resulting from receiving nabilone but this was 
not consistent with other RCTs which included a greater sample size and documented no 
withdrawals due to side effects of cannabinoids. 
 
Due to the overall impact of NMS in PD and based on the influence of the endocannabinoid 
system on NMS in broad manner in PD, we decided to perform a proof of concept study to 
test nabilone for the treatment of NMS in PD. 
We hypothesize that because of the described effects of the endocannabinoid system, 
nabilone will improve non-motor symptoms in patients with PD. This therapy should be well 
tolerated by contrast to some of the drug classes used in standard medical care and can 
therefore be an ethically justified additional treatment option for symptoms not concerning 
motor control of PD. If the treatment shows to be effective, the use of nabilone in health care 
practice can be supported by the data from this study.  


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 34/107 
2 
Objectives and Endpoints 
2.1 Objectives 
2.1.1 Primary Efficacy Objective 
The primary efficacy objective of this study is to demonstrate the efficacy of nabilone 
concerning non-motor symptoms of patients with Parkinson´s disease, based on the change 
from baseline to Week 4/Termination visit in the MDS-UPDRS Part I. 
2.1.2 Key Secondary Efficacy Objectives  
The key secondary efficacy objectives of this study are to evaluate the effect of nabilone on 
motor symptoms of PD and on different domains of NMS by means of the change from 
baseline to Week 4/Termination visit in the following assessments:   
• 
Movement Disorders Society – Unified Parkinson´s Disease Rating Scale (MDS-
UPDRS (i.e. Part II, III + IV)) (including NMS and motor symptoms) 
• 
Non Motor Symptoms Scale (NMSS) 
• 
mood/anxiety domain of MDS-UPDRS Part I (items 1.3 and 1.4) 
• 
different other domains of NMSS and MDS-UPDRS part I 
• 
Hospital anxiety and depression scale (HADS) 
• 
Parkinson´s Disease Questionnaire – 39 (PDQ-39) 
• 
Montreal Cognitive Assessment (MoCA) 
• 
Epworth Sleepiness Scale (ESS) 
• 
Fatigue Severity Scale (FSS) 
• 
Visual Analog Scale (VAS) of Pain  
• 
King's Parkinson's disease pain scale (KPPS) 
• 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating 
Scale (QUIP-RS) 
 
Moreover, Clinical Global Impression – Global Improvement 
(CGI-I) scale at Termination 
Visit will be a key secondary efficacy objective. 
2.1.3 Safety Objectives  
The safety objectives of this study are to evaluate the safety and tolerability of nabilone in 
patients with PD with reference to the following: 
 
1. Tolerability 
§ Number of subjects (%) who discontinue the study 
§ Number of subjects (%) who discontinue the study due to AE 
 
2. Safety Measures 
§ Adverse Events (AE), Serious Adverse Events (SAEs) 
§ Clinical and laboratory assessments 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 35/107 
§ Vital signs including performance of active orthostatism (measurement of heart 
rate and blood pressure after 10 minutes of quiet rest in the supine position and 
at 1, 2, 3, 5, and 10 minutes of active standing) 
§ ECG 
§ Patient´s Compliance 
§ Prior and Concomitant Medication Use 
§ Hallucination item (1.2) of Movement Disorders Society – Unified Parkinson´s 
Disease Rating Scale (MDS-UPDRS) 
§ Orthostatic hypotension (OH) item (1.12) of Movement Disorders Society – 
Unified Parkinson´s Disease Rating Scale (MDS-UPDRS) 
§ Day-time sleepiness item (1.8) of Movement Disorders Society – Unified 
Parkinson´s Disease Rating Scale (MDS-UPDRS)  
§ Columbia Suicide Severity Rating scale (C-SSRS)  
 
2.1.4 Exploratory Objective 
The exploratory objective of this study will be an Eye-tracking evaluation in PD patients 
taking nabilone or placebo at the Screening and the Termination visit: 
• 
Change of the reaction time, attention span, and concentrativeness 
between Screening and Termination Visit as measured by the Eye-
tracking examination. 
 
2.2 Efficacy Endpoints  
2.2.1 Primary Efficacy Endpoint  
The primary efficacy endpoint will be measured as the change of the MDS-UPDRS Part I 
between baseline and week 4. 
2.2.2 Key Secondary Efficacy Endpoints  
The change in the other assessments listed above between baseline and week 4 will be the 
key secondary efficacy criteria, as well as the CGI-I at Termination Visit. 
2.2.3 Safety Endpoints 
The safety and tolerability of nabilone will be evaluated in this study using the measures 
described in 2.1.3. between Baseline and Week 4. 
2.2.4 Exploratory Endpoints 
The change of the reaction time, attention span, and concentrativeness between Screening 
and Termination Visit as measured by the Eye-tracking examination will be an exploratory 
endpoint. Because of potential of habituation of the Eye-tracking measurements, we will only 
these measures at Screening and Termination Visit.  


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 36/107 
3 
Study Design 
3.1 Study Description 
This is a mono-centric Phase IIa, placebo-controlled, double-blind, parallel-group, enriched 
enrolment randomized withdrawal study in patients with Parkinson´s disease includes a 
screening period, followed by an open-label nabilone dose optimization period (Phase 1) and 
a placebo-controlled, double-blind, parallel-group randomized withdrawal phase (Phase 2). 
 
After providing written informed consent, patients will undergo screening evaluations. 
Patients must meet all inclusion criteria and none of the exclusion criteria. Eligible subjects, 
who have signed the informed consent form, will receive open-label nabilone starting with a 
dosage of 0.25 mg in the evening after the Screening Visit. During dose titration period, 
nabilone will be titrated in 0.25 mg increments one- to four-daily until a maximum dosage of 1 
mg twice daily. Dose tapering will be performed according to the investigator´s decision. The 
dose increments will be hold as follows:  
1. 0.25mg 0-0-1;  
2. 0.25mg 1-0-1;  
3. 0.25mg 1-0-2;  
4. 0.25mg 2-0-2;  
5. 0.25mg 2-0-3;  
6. 0.25mg 3-0-3;  
7. 0.25mg 3-0-4;  
8. 0.25mg 4-0-4.  
Regular phone calls with the study center will be performed every other day during titration 
phase. These will include the following: 
1. Concomitant medications use, 2. Adverse Events, 3. CGI-I, 4. Hallucination item (1.2), 
Orthostatic hypotension (OH) item (1.12), Day-time sleepiness item (1.8) of MDS-
UPDRS 5. C-SSRS 
 
The open-label titration phase will last up to 28 days and ends with an on-site visit (V -1). 
Afterwards, patients should be on a stable nabilone dosage for at least 1 week before 
randomization. 
 
Dose adjustments during titration phase will be performed until the patient: 
1. has much (CGI-I Rating Scale: 2) or very much (CGI-I Rating Scale: 1) improved 
NMS on the 7-point Clinical Global Impression of Improvement Scale.  
2. experiences intolerable side effects believed to be related to the study medication or;  
3. reaches the maximum permitted dosage of 1 mg twice daily.  


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 37/107 
 
Criterion 1 defines responders. Patients who meet this criterion will enter into the 4-weeks 
treatment period at the last prescribed dose. Patients who meet criterion 2 will proceed to the 
4-weeks treatment period at the previous lower dose, providing they will meet the definition 
of a responder at that dose. Patients who meet criterion 3 and were responder will enter the 
study at 1 mg twice daily.  
 
Patients are discontinued after dose optimization phase if they meet criteria number 2 but did 
not meet the responder definition at the previous dose, if they meet criteria 2 at the initial 
dose of 0.25 mg once daily, or if they meet criteria 3 but did not meet the definition of a 
responder. 
 
After at least 1-week of stable nabilone dosage, responders are randomized in a 1:1 ratio at 
the Baseline Visit to receive either nabilone at the dosage reached during the titration phase 
or matching placebo for 4 weeks + 2 days (Part 2). During the first week of the double-blind 
placebo-controlled parallel-group enriched enrolment randomized withdrawal phase regular 
phone calls will be held every other day. During the open-label treatment period, dose 
adjustments can be performed if CGI-I deteriorates. In this case, patient will re-enter the 
titration phase of the trial.  
 
After having finished the parallel-group, enriched enrolment randomized withdrawal study, a 
termination visit will be held and nabilone will be tapered in the patients in 0.25 mg two-daily 
decrements. Phone calls will be held every other day during dose tapering phase. The 
patients will be asked for the use of concomitant medications, AEs, CGI-I, the items 1.2, 1.8, 
and 1.12 of MDS-UPDRS Part I, and the C-SSRS. A phone call for safety issues will be held 
after 5 days ± 2 days and a Safety Follow- Up Visit will be scheduled after 2 weeks + 2 days 
of discontinuation from study drug. (see 5.4) 
 
3.1.1 Study end:  
1) After having finished the parallel-group, enriched enrolment randomized withdrawal 
study, patients will be down-titrated from the study medication in 0.25 mg decrements 
every other day. During tapering two-daily phone calls will be held, asking for 
concomitant medications, AEs, CGI-I, the items 1.2, 1.8, and 1.12 of MDS-UPDRS 
Part I, and the C-SSRS. A safety call will be performed 5 days ± 2 days after having 
stopped study medication and a safety follow-up visit will be done 2 weeks + 2 days 
after having stopped study medication. (see 5.4) 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 38/107 
2) If the trial is stopped on behalf of the Sponsor or a regulatory authority or if patients 
withdraw from study medication due to personal or medical reasons during the course 
of the study, the patients will be advised to come to the hospital as soon as possible 
for an Early Termination Visit (see 5.5). A Safety Follow-Up Visit should be performed 
2 weeks + 2 days after the last intake of study medication (if the Early Termination 
Visit occurs not longer than 5 days after the discontinuation of the study medication). 
(for reasons for discontinuation and withdrawal see 4.3, for ET and Safety Follow-Up 
Visit see 5.4) 
 
3.1.2 Visits 
Subjects will be evaluated in the study center by the investigator at the screening visit, at the 
end of the open-label titration phase (i.e. V -1 / weeks -1), at the end of the open-label 7-day 
+ 7 days treatment period (i.e. V 0 / week 0; baseline of randomized withdrawal phase), and 
at the termination visit (V 1 / week 4). A Safety Telephone Call (TC – S) and Safety Follow- 
Up Visit (V - S) will be performed 5 days ± 2 days and 2 weeks + 2 days after the last intake 
of study drug. 
 
The following scales or questionnaires will be performed during all study visits: 
1. Movement Disorder Society (MDS) - sponsored new version of the UPDRS (MDS-
UPDRS) (all visits including screening) 
2. Non-Motor Symptoms Scale (NMSS) (all visits except for V -1)  
3. Hospital Anxiety and Depression Scale (HADS) (all visits except for V -1) 
4. 39-Item Parkinson's Disease Questionnaire (PDQ-39) (all visits except for V -1) 
5. Montreal Cognitive Assessment Scale (MoCA) (all visits except for V -1) 
6. Epworth Sleepiness Scale (ESS) (all visits except for V -1) 
7. Visual Analog Scale (VAS) of Pain (all visits except for V -1) 
8. King's Parkinson's disease pain scale (KPPS) (all visits except for V -1) 
9. Fatigue Severity Scale (FSS) (all visits except for V -1) 
10. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating 
Scale (QUIP-RS) (all visits except for V -1) 
11. Columbia Suicide Severity Rating scale (C-SSRS) (all visits) 
12. CGI-I (V -1, V 0, V 1, and Safety Follow-Up Visit only) 
13. Vital signs (all visits including screening) 
14. Concomitant medications (all visits including screening) 
15. Adverse Events (all visits including screening) 
16. Physical examination (screening, V 0, V 1, and Safety Follow-Up Visit only) 
17. Local ECG and Clinical Laboratory tests ((pre-)screening and V 1 only) 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 39/107 
18. Measurement of Eye-Movements with a Tobii TX300 Eye-Tracker (screening, 
termination visit) 
 
3.1.3 Study Duration Per Patient  
Recruitment will start after the ethical committee and regulatory authorities approve the study 
and all necessary documents are available and filed. Recruitment phase will last to the point 
when 48 patients are included in the trial.  
The study will begin with the screening visit. If patient is eligible for the study, patients will 
then enter in the open-label dose titration phase. This optimization phase will last from 2 up 
to 28 days for each patient and will include phone calls every other day and a visit at the end 
of the titration phase (week -1). Before entering the double-blinded withdrawal phase, 
patients have to stay for a minimum of one week on a stable dose of nabilone. After this 
week, the baseline visit of the double-blinded withdrawal phase will be performed. The 
double-blinded withdrawal phase will end with the termination visit. 
The total anticipated study duration for an individual patient starting from screening visit will 
be a minimum of 53 days / 7 weeks + 4 days (including safety follow-up visit) and a 
maximum of 104 days / 14 weeks + 6 days. The end of the study is defined as the date of the 
last visit of the last patient in the study (LPLV). 
3.1.4 Planned Number of Patients  
A total of 38 patients will provide 80% power at a 2-sided 5% significance level to detect a 
statistically significant difference in the change from randomization to Week 4 in MDS-
UPDRS Part I score between nabilone and placebo if the true difference is 2.5 points. In the 
absence of previous data, we empirically chose as clinically meaningful a 2.5 units change 
from randomization to the visit at 4 weeks (in Phase 2). This sample size calculation 
assumes a standard deviation of the change from randomization to week 4 to be 2.4 points. 
(46) Assuming a drop-out rate of 25%, we will include around 48 patients with Parkinson´s 
disease in this trial. 
Importantly, although a sample size calculation is provided, this is an exploratory study 
evaluating different NMS domains. Therefore, corrections for multiple comparisons are not 
planned. 
3.1.5 Anticipated Regions and Countries  
This study will be held at one clinical site (Medical University of Innsbruck). 
 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 40/107 
 
3.2 Schedule of Events  
Table 2: Nabilone for non-motor symptoms in Parkinson´s Disease 
STUDY 
PERIOD 
Screen- 
ing 
Dose Titration 
Period 
Randomized 
Withdrawal 
Period 
Dose Tapering 
Safety 
Follow-
Up  
Early 
Terminat
- 
ion  
STUDY 
WEEK, 
STUDY VISIT 
Week 0, 
Screen- 
ing 
Visit 
Tele-
phone 
calls 
 
Week -1, 
Visit -1 
Week 0, 
Baseline 
Visite 0 
Phone 
calls 
 
Week 4, 
Termination 
Visit, 
Visite 1 
Tele-
phone 
calls 
 
 
Safety 
Follow- 
Up Phone 
Call 
Safety 
Follow-Up 
Visit 
V - S 
Early 
Terminat- 
ion Visit 
ET 
Visit 
Descriptor 
SCR 
 
V - 1 
V 0 
 
V 1 
 
 
V - S 
ET 
 
Visit window 
(days) 
 
Day 0 
 
Every 
other 
day 
 
2 – 28 
days 
 
7 days + 7 
days 
 
Every 
other day 
in the 
first week 
 
4 weeks 
+ 2 days 
 
Every 
other day 
until IMP 
Stopp 
 
5 days ± 
2 days 
after IMP 
Stopp 
 
2 weeks + 
2 days 
after IMP 
Stopp 
As soon 
as 
possible 
after the 
last intake 
of IMP 
Written 
Informed 
consent 
 
X 
 
 
 
 
 
 
 
 
 
Randomiza-
tion 
 
 
 
X 
 
 
 
 
 
 
Vital signs
1 
X 
 
X 
X 
 
X 
 
 
X 
X 
Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con- 
comitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical and 
Neurol. Exam 
X 
 
 
X 
 
X 
 
 
X 
X 
12-lead ECG 
X 
(Or within 4 
weeks prior 
to SCR) 
 
 
 
 
X 
 
 
 
X 
Clin.Lab. 
Test
2, 
Urinalysis 
X 
(Or within 4 
weeks prior 
to SCR) 
 
 
 
 
X 
 
 
 
X 
MDS-UPDRS 
X 
Partly 
(Part I) 
X 
X 
Partly 
(Part I) 
X 
Partly 
(Part I) 
Partly 
(Part I) 
Partly 
(Part I) 
X 
NMSS 
X 
 
 
X 
 
X 
 
 
 
X 
HADS 
X 
 
 
X 
 
X 
 
 
 
X 
PDQ-39 
X 
 
 
X 
 
X 
 
 
 
X 
MoCA 
X 
 
 
X 
 
X 
 
 
 
X 
ESS 
X 
 
 
X 
 
X 
 
 
 
X 
VAS for Pain 
X 
 
 
X 
 
X 
 
 
 
X 
KPPS 
X 
 
 
X 
 
X 
 
 
 
X 
FSS 
X 
 
 
X 
 
X 
 
 
 
X 
CGI-I 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
MMSE 
(Inclusion Criterion) 
X 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QUIP-RS 
X 
 
 
X 
 
X 
 
 
 
X 
Eye-tracking 
X 
 
 
 
 
X 
 
 
 
X 
Dispense IMP 
X 
 
X 
X 
 
X 
 
 
 
 
Drug 
Account-
ability 
 
 
X 
X 
 
X 
 
 
X 
X 
1 Vital Signs include height (only at Screening Visit), weight, temperature, pulse rate and blood pressure after at least 10 
minutes of rest and at 1,3,5, and 10 minutes of active standing. 
2 Clinical Laboratory Test includes haematology and chemistry. Urinalysis and a urine pregnancy test for women of child-
bearing potential will be performed. 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 41/107 
3.3 Schematic Diagram  
 
 
Figure 1: Schematic Diagram for participants 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 42/107 
4 
Study Population and Withdrawal of Patients 
4.1 Inclusion Criteria  
In order to be eligible for the study subjects must meet all inclusion criteria: 
1. Age ≥30 years  
2. Diagnosis of PD: PD should be either de novo or on stable medication without 
disturbing motor fluctuations or dyskinesia. 
3. NMS with a score of ≥4 on MDS-UPDRS Part 1. One of the following domains have 
to be affected with a score ≥2: 1.4 (anxious mood) or 1.9 (pain) 
4. On a stable regimen of anti-parkinson medications for at least 30 days prior to 
screening and willing to continue the same doses and regimens during study 
participation 
5. Any other current and allowed prescription/non-prescription medications and/or 
nutritional supplements taken regularly must have been at a stable dose and regimen 
for at least 30 days prior to screening, and subject must be willing to continue the 
same doses and regimens during study participation 
6. Patient is informed and had enough time and opportunity to think about his/her 
participation in the study and has signed a current IRB-approved informed consent 
form 
7. Contraception 
a. Women of childbearing potential must use or attest an acceptable method* of 
contraception starting 4 weeks prior to study drug administration and for a 
minimum of 1 month after study completion.  
b. Men with a potentially fertile partner must be willing to use an acceptable 
method* of contraception for the duration of the study and for 3 months after 
study drug discontinuation or have had a vasectomy. 
 
*Acceptable methods of birth control for women and men in this study are:  
surgical sterilization (e.g. tubal ligation for females), intrauterine devices that release 
hormones (hormone spiral), oral hormonal contraceptive, contraceptive patch, dermal 
hormonal contraception, vaginal hormonal contraception (NuvaRing®), implants that release 
progesterone (Implanon®), long-acting injectable contraceptive, partner’s vasectomy, a 
double-protection method, postmenopausal (> 2 year absence of vaginal bleeding).  
This means that the following are not regarded as safe: condom plus spermicide, simple 
barrier methods (vaginal pessaries, condom, female condoms), copper spirals, the rhythm 
method, basal temperature method, and the withdrawal method (coitus interruptus). 
The regulations for contraception are derived from Guideline ICH E8 Chapter 3.2.2.1 
Selection of subjects together with ICH M3 Note 4. 
 
4.2 Exclusion Criteria  
Patients with any of the following characteristics will be excluded from entering the study: 
1. Patient previously participated in any study with nabilone. 
2. Current use of cannabinoids or use of cannabinoids within 30 days prior to screening. 
3. Patient is currently participating in or has participated in another study of 
investigational products within 30 days prior to screening. 
4. Patient has any form of secondary or atypical parkinsonism (e.g., drug-induced, post 
stroke). 
5. Patient presents with motor complications which are, based on the investigator’s 
judgment, not adequately controlled (i.e. a score ≥2 on one of the items of the MDS-
UPDRS Part IV at screening)  


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 43/107 
6. Hoehn and Yahr stage > 3 
7. Evidence of disturbing (i.e. requiring treatment) impulse control disorder in the 
participant. Can be resolved through a structural interview during screening period. 
8. History of neurosurgical intervention for PD 
9. presence of symptomatic orthostatic hypotension at screening (MDS-UPDRS 1.12 > 
2) 
10. Use of prohibited medication listed in 7.4.2 
11. Patients with laboratory values that are out-of-range at Screening (or within 4 weeks 
prior to Screening) and haven´t been reviewed and documented as not clinically 
significant by the investigator. Lab Tests can be repeated for confirmation. 
12. Patients with known or newly diagnosed sinus tachycardia in ECG evaluation at 
Screening or within 4 weeks prior to Screening. 
13. presence of an acute or chronic major psychiatric disorder (e.g., Major Depressive 
Disorder, psychosis) or symptom (e.g., hallucinations, agitation, paranoia) (MDS-
UPDRS 1.2 and/or 1.3 > 2) 
14. Patients who had a recent suicidal attempt (active, interrupted, aborted) within the 
past five years or report suicidal ideation within the past 6 months. 
15. presence of dementia (MDS-UPDRS 1.1 > 2, MMSE of <24 at the Screening visit) 
16. clinically significant or unstable medical or surgical condition at Screening or Baseline 
visit that may preclude safety and the completion of the study participation (based on 
the investigator’s judgment).   
17. Patients with moderate or severe hepatic or renal impairment. 
18. Patient has a history of chronic alcohol or drug abuse within the last 2 years. 
19. women of child-bearing potential who do not practice an acceptable method of birth 
control (See: acceptable methods of birth control at 4.1.) 
20. Pregnant women or women planning to become pregnant during the course of the 
study and nursing women. 
21. Patients who are knowingly hypersensitive to any of the components of the IMP or 
excipients. 
22. Patient is legally incapacitated or persons held in an institution by legal or official 
order 
23. Persons with any kind of dependency on the investigator or employed by the Sponsor 
or investigator 
 
4.3 Discontinuation of the Study, Premature Termination 
Subjects have the right to withdraw fully or partially from the study at any time and for any 
reason without prejudice to their future medical care by the physician or at the institution. 
Withdrawal of full consent for a study means that the subject does not wish to receive further 
investigational treatment and does not wish or is unable to continue further study 
participation. Subject data up to withdrawal of consent will be included in the subject’s study 
data, but no further information will be collected unless a separate consent has been given. 
Withdrawal of partial consent means that the subject does not wish to take the protocol-
specified product any longer but is still willing to collaborate in providing further data by 
continuing on study. 
The investigator has the right to discontinue a patient from IMP or withdraw a patient from 
the study at any time. The primary reason for withdrawal from the study should be 
documented.  Patients should be discontinued if they experience intolerable side effects 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 44/107 
believed to be related to the study drug and they will be terminated if they did not meet the 
responder criterion at the previous dose or the maximum permitted dose. 
If patient discontinues study participation for reasons unrelated to an adverse event, no 
additional patient will be enrolled to replace that subject. 
The Sponsor has the right to discontinue this trial at any time. The Sponsor will notify the 
investigator if the sponsor decides to stop the clinical trial.  
The Sponsor has the right to terminate the trial prematurely at any time. 
This might be if there are any relevant medical or ethical concerns, or if completing the trial is 
no longer practicable. If such action is taken, the reasons for terminating the trial must be 
documented in detail. All trial subjects still under treatment at the time of termination must 
undergo a final examination (Early Termination Visit as soon as possible and Safety Follow-
Up Visit 2 weeks + 2 days after the ET (if the ET is performed after 5 days after the last 
intake of study drug)) which must be documented. The principal investigator must be 
informed without delay if any investigator has ethical concerns about continuation of the trial. 
In case of discontinuation of the trial the IEC and competent regulatory authority must be 
informed within 15 days of early termination. 
 
4.3.1 Potential Criteria for Withdrawal from Study 
The investigator should inform the Medical Monitor if any of the following events occur that 
may lead to a discontinuation of the participation in the study: 
1. Noncompliance of the patient with the study procedures or medications. 
2. The patient doesn´t have a stable PD or changes his/her medication or receives 
neurosurgical intervention for PD. 
3. The patient presents with one or more clinically significant laboratory values that are 
not within normal limits or clinically significant abnormal findings on physical 
examination, or experiences AEs that are intolerable (as determined by the patient) or 
that endanger the safety of the patient based on the investigator´s judgement. 
4.3.2 Definite Criteria for Withdrawal from Study 
A definite withdrawal from the study must be operated if any of the following events occur: 
1. The patient withdraws his/ her consent willingly. 
2. Patient develops a psychiatric, medical or surgical condition that would interfere with 
his/ her participation. 
3. Patient shows abnormal laboratory values concerning hepatic and renal function as 
described in the exclusion criteria. 
4. Pregnancy of the patient during the study, as confirmed by a positive pregnancy test. 
5. Withdrawal of the patient is requested by the Sponsor or a regulatory agency. 
6. The Sponsor or a regulatory agency discontinues the study. Reasons for 
discontinuation may include, but are not limited to the following: 
• 
Patient enrolment is unsatisfactory 
• 
Administrative Reasons 
7. The Sponsor terminates the study prematurely. Premature termination of the trial will 
be considered if: 
• 
The risk-benefit balance for the trial subject changes markedly. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 45/107 
• 
It is no longer ethical to continue treatment with the IMP. 
• 
The Sponsor considers that the trial must be discontinued for safety reasons. 
• 
An interim analysis or results of other research show that one of the trial 
treatments is superior or inferior to another. 
• 
It is no longer practicable to complete the trial. 
8. Patient has performed an active suicide since the last visit or reports any suicidal 
behavior. In this case he/she should be referred to a hospital for Mental Health 
immediately. 
 
Should the trial be discontinued or should a subject request or decide to withdraw from the 
study, all efforts will be made to complete and report the observations as thoroughly as 
possible up to the end of withdrawal. 
Thus, if a discontinuation of or a withdrawal from the study occurs, all observations, 
evaluations as well as lab results and other test results should be documented. Moreover, a 
short description of the primary reason(s) for removing the patient must be recorded in the 
source documents and provided to the Sponsor. 
In case of a discontinuation of or a withdrawal from the study every effort should be made for 
attendance of an Early Termination (ET) Visit, which will be scheduled as soon as possible, 
followed by a Safety Follow-Up Visit after 2 weeks + 2 days of the ET (if the ET is performed 
after 5 days after the last intake of study drug) (see 5.4 and 5.5). Patients will not be followed 
for any reason after consent has been withdrawn, unless a separate consent has been given 
for further data collection. 
 
In case the withdrawal was due to an AE the patient should be followed up until he/she has 
recovered/ it has resolved, has reached a stable state, the investigator determines that it is 
no longer clinically significant, or the patient is lost to follow up. (see 8) 
 
4.4 Further treatment after end of treatment 
After the end of the study treatment, alternative methods for the therapy of disturbing non-
motor symptoms in PD can be prescribed to the patients as seen in Table 1: Drug classes for 
non-motor symptoms in PD, keeping in mind the patient´s tolerance. If the patient has shown 
benefit from the therapy with nabilone, a cannabinoid therapy could be prescribed on behalf 
of the investigator´s decision. 
 
4.5 Closure of the Study 
The clinical trial shall be deemed to end when the last patient absolved the planned last visit 
according to protocol. The completion of the study will be reported to the ethics committee as 
well as to the relevant authorities. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 46/107 
5 
Study Procedures (by Visits) 
An overview of the study procedures, including the time of events and assessments 
performed, may be found in 3.2 and 3.3. Details of scales used to evaluate efficacy and 
safety can be found in Section 6.1 and 6.2 and in the applicable appendices. A detailed 
description of study procedures by visit will be provided in this section.  
 
Eligible subjects who meet all inclusion criteria and none of the exclusion criteria at the 
Screening visit will be titrated to the optimal dose as described above which could last up to 
28 days (Part 1). During this phase regular phone calls will be held every other day. After 
reaching the optimal dose, the patients will stay on a stable nabilone dose for at least one 
week and will then visit the outpatient clinic for the Baseline visit. At Baseline, the participants 
will be randomized using a randomization list provided by the Statistics Department of the 
Medical University of Innsbruck and will begin Part 2 of the study. The first dose of IMP will 
be taken at home after the Baseline Visit. The participants will be evaluated after 4 weeks of 
double-blind placebo-controlled parallel-group enriched enrolment randomized withdrawal 
phase (termination visit). However, during the first week of the double-blind placebo-
controlled parallel-group enriched enrolment randomized withdrawal phase regular phone 
calls will be held every other day. A Safety Phone call will take place 5 days ± 2 days and a 
Safety Follow-Up visit will be performed 2 weeks + 2 days after the last intake of study 
medication. At visits after intake of medication, the patients will be requested to return the 
IMP kits (including all used, unused, and partially used medication) dispensed to them at the 
previous visit and to take their IMP in the morning before every visit. Furthermore, the 
patients should take their concomitant medication at home and at the clinic, if permitted, as 
normally scheduled. Safety evaluations will be performed as scheduled in the schedule of 
events table with examination of vital signs, AE, concomitant medication, the items 1.2, 1.8, 
and 1.12 of MDS-UPDRS Part I, and the C-SSRS operated at every visit and AE and 
concomitant medication, the items 1.2, 1.8, and 1.12 of MDS-UPDRS Part I, and the C-
SSRS at every phone call. In the event of Early Termination, patients will be asked to 
complete an Early Termination Visit as soon as possible and to return for a Safety Follow-Up 
Visit 2 weeks + 2 days after their last dose of IMP.  
Please refer to the Schedule of Events table and the Schematic diagram (in 3.2 for specific 
timing of assessments and Section 5.1, 5.2, 5.4, and 6  for a detailed description of timing 
and aim of study procedures and scales.  
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 47/107 
5.1 Screening Period 
5.1.1 Recruitment and Informed Consent Process 
Patients will be seen in the outpatient´s department on-site or at the neurologic wards. For 
interested patients a member of the qualified research team will explain the study purpose, 
goals, and requirements in an understandable way and an IRB/IEC-approved informed 
consent form will be handed to the patients considering participation for information. 
Relevant contact from the site including phone numbers will be given to the patient. Thus the 
patient can read, ask questions, and consult his/her family members if requested 
It is the responsibility of the principal investigator, or a subinvestigator delegated by the 
principal investigator to obtain written informed consent from each subject prior to 
participation in the trial, following adequate explanation of the aims, methods, anticipated 
benefits and potential hazards of the study. The person taking consent must be GCP trained, 
suitably qualified and experienced, and have been delegated this duty by the PI on the 
delegation log.  
The investigator or designee will explain the patients are under no obligation to enter the trial 
and that they can withdraw at any time during the trial, without having to give a reason. 
No clinical trial procedures will be conducted prior to taking consent from the participant. 
Consent will not denote enrolment into trial.  
If all questions are clarified and the patient has been given ample time to think about his/her 
participation, the informed consent will be obtained in accordance with ICH GCP by signing 
the informed consent form at a visit on-site before any trial-related procedures are 
completed. The signature from the investigator who conducted the informed consent 
discussion and the patient as well as the date will be provided and documented in the source 
documents. For patients who consent to participate in the study a copy of the signed ICF and 
other information available will be provided to them prior to participation. The original signed 
and dated ICF will be maintained at the investigator´s site. 
Any patient who is unable to demonstrate understanding of the information contained in the 
ICF won´t be allowed to participate in the study. The ICF and any other information provided 
to patients will be revised whenever important new information (e.g. safety information 
resulting in significant changes in the risk/benefit assessment) becomes available that is 
relevant to the consent and continued participation of a patient in the study. The revised ICF 
and information must receive IRB/IEC-approval prior to its use, and a copy of the IRB/IEC’s 
approval will be provided to the Sponsor. The patient will be informed of any new information 
via the revised ICF or information material by the investigator and his/her willingness to 
further participate in the study will be questioned. A signed and dated new ICF will be 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 48/107 
obtained and stored, and a copy will be given to the patient. This will as well be recorded in 
the source documents.  
After providing and documenting consent on the IRB/IEC-approved written ICF, patients will 
be assigned their patient screening number and proceed to the Screening Visit. 
 
5.1.2 Screening Visit 
All subjects must provide written informed consent before any study-specific assessments or 
procedures are performed. 
The following assessments will be performed during the Screening Visit and used to 
determine whether a patient is eligible for the study or not. Screening data will be reviewed 
prior to the baseline visit.  
Screening Assessments: 
1. Obtain written informed consent (see Section 5.1.1), sign and date, and provide a 
copy to the patient. 
2. Obtain demographics (see: 6.2.2) and medical history including any co-existing pre-
treatment AEs and allergies. 
3. Obtain neurological and PD history, including questions for disturbing (i.e. treatment 
required) impulse control disorders. 
4. Obtain complete medication history including anti-PD medications, record the start 
date and stop date (if applicable), as well as the indication 
5. Perform assessment of Vital signs: obtain weight, height, and temperature, obtain and 
record serial BP and pulse measurements after at least 10 minutes of supine rest and 
again after 1, 3, 5, and 10 minutes of active standing 
6. Perform brief physical and neurological examination (see: 6.2.2) 
7. Obtain 12-lead ECG and review (if not performed within 4 weeks prior to Screening) 
8. Withdraw blood for the following laboratory measurements and record the time and 
date: haematology, chemistry (if not performed within 4 weeks prior to Screening) 
9. Urine sample for urinalysis, including pregnancy test (for women of childbearing 
potential only) 
10. Administer the MDS-UPDRS Part I, II, III, and IV (record if patient is in ON or OFF 
state), and the Modified Hoehn and Yahr stage (document for entry criteria). 
11. Administer the following assessments:  
a. MMSE 
b. NMSS 
c. HADS 
d. PDQ-39 
e. MoCA 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 49/107 
f. 
ESS 
g. FSS 
h. VAS for Pain 
i. 
KPPS 
j. 
C-SSRS 
k. QUIP-RS 
l. 
Eye-tracking 
12. Review inclusion and exclusion criteria for eligibility 
 
If the patient does not meet eligibility criteria at the time of screening, e.g., if a laboratory 
result disqualifies the patient from participating in the study, the patient is considered a 
screen failure. Record the primary reason for screen failure in the source documents.  
Screen failures maybe eligible for rescreening to acceptable parameters. This will need to be 
discussed with the Sponsor or designee. 
Screening does not necessarily constitute enrolment of the subject. 
 
Pseudonymized information on the patient including date of screening visit, demographics, 
medical history, and neurological history (including Parkinson’s disease, UPDRS scores, 
modified Hoehn and Yahr staging, current treatment, and concomitant medications) will be 
reviewed for preliminary eligibility of the patient. If eligible, dose titration phase will begin. 
 
13. Dispense the IMP kits assigned by the Sponsor to the patient so that he/she has 
enough until the Week - 1 Visit.  
14. Record the dates the patient is instructed to take the study drug on the packaging of 
it. Record the following information in the source documents: patient number, 
assigned IMP kit number, date, and time the study drug was dispensed. 
15. Instruct the patient to bring his/her used, unused, and partially used IMP kits to the 
next visit and schedule this visit. 
16. Review the dosing instructions for the study drug with the patient and answer any 
questions. The patient will be instructed to take one tablet of the study drug by mouth 
two times daily starting in the evening after the Baseline Visit. The evening dose 
should be approximately 12 hours after the morning dose. Document that the patient 
understood the dosing instructions. 
 
5.1.3 Dose Titration Phase 
For patients who remain eligible, proceed with starting nabilone with a dosage of 0.25 mg in 
the evening and titrate in in one- to four-daily increments at a maximum dosage of 1 mg 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 50/107 
twice daily. Dose tapering will be performed according to the investigator´s decision. Dose 
increments will be held as follows:  
1. 0.25 mg 0-0-1; 2. 0.25 mg 1-0-1; 3. 0.25 mg 1-0-2; 4. 0.25 mg 2-0-2; 5. 0.25 mg 2-0-3; 6. 
0.25 mg 3-0-3; 7. 0.25 mg 3-0-4; 8. 0.25 mg 4-0-4.  
 
Regular phone calls with the study center will be performed every other day during titration 
phase. These will include questions for concomitant medication, AEs, and the assessment of 
the CGI-I. Moreover, the items 1.2, 1.8, and 1.12 of MDS UPDRS Part I, and the C-SSRS will 
be assessed. The duration of the open-label titration phase can range from 2 days up to 28 
days. 
 
Dose adjustments during titration phase will be performed until the patient: 
1. Criterion 1: has much (CGI-I Rating Scale: 2) or very much (CGI-I Rating Scale: 1) 
improved NMS on the 7-point Clinical Global Impression of Improvement Scale. 
This criterion defines responders. Patients who meet this criterion will enter into the 4-weeks 
treatment period at the last prescribed dose. 
2. Criterion 2: experiences intolerable side effects believed to be related to the study 
medication. 
Patients who meet criteria 2 will proceed to the 4-weeks treatment period at the previous 
lower dose, assuming they will meet the definition of a responder at that dose. 
3. Criterion 3: reaches the maximum permitted dosage of 1 mg twice daily.  
Patients who meet criteria 3 and were a responder will enter the study at 1 mg twice daily. 
 
Patients are discontinued if they meet criteria number 2 but did not meet the responder 
definition at the previous dose, if they meet criteria 2 at the initial dose of 0.25 mg once daily, 
or if they meet criteria 3 but did not meet the definition of a responder. 
 
5.1.4 Visit -1 (week – 1) 
Patients will have an on-site visit at the clinic after they meet the responder criterion at their 
“optimal dose”. The following assessments should be performed at this visit: 
1. Perform assessment of Vital signs: obtain weight and temperature, obtain and record 
serial BP and pulse measurements after at least 10 minutes of supine rest and again 
after 1, 3, 5, and 10 minutes of active standing 
2. Ask for AE occurring since the last visit. 
3. Interview on concomitant medication use since the last visit. 
4. Administer the MDS-UPDRS Part I, II, and IV (record if patient is in ON or OFF state), 
and the Modified Hoehn and Yahr stage (document with date and time). 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 51/107 
5. Administer the following assessments: 
a. CGI-I 
6. Collect all used, unused, and partially used study drug and record it in the source 
documents and Drug Accountability Section.  
7. Schedule the Baseline Visit, which must occur after at least 1 week of stable nabilone 
dosage (1 week + 7 days) from the date of the Visit -1. 
8. Instruct the patient to bring their medication to the baseline visit (including 
concomitant medication so that they are able to maintain their regular treatment 
schedule) 
9. Dispense the IMP kits assigned by the Sponsor to the patient so that he/she has 
enough until the Baseline Visit.  
10. Record the dates the patient is instructed to take the study drug on the packaging of 
it. Record the following information in the source documents: patient number, 
assigned IMP kit number, date, and time the study drug was dispensed. 
11. Review the dosing instructions for the study drug with the patient, answer any 
questions, and remind the patient to return all used, unused, and partially used study 
drugs at the next visit. The patient will be instructed to take one tablet of the study 
drug by mouth two times daily starting in the evening after the Baseline Visit. The 
evening dose should be approximately 12 hours after the morning dose. Document 
that the patient understood the dosing instructions. 
 
5.2 Baseline Visit / V 0 and Randomization to Study Drug 
Randomization will occur at Baseline (Visit 0), after the patient’s eligibility for the study has 
been confirmed and all pre-dosing Baseline procedures have been performed. Baseline Visit 
will take place 1 – 2 weeks after V -1. 
 
5.2.1 Baseline Visit / V 0 (week 0) 
At the beginning of the Baseline Visit the patient’s medical history and co-existing pre-
treatment AEs since the last assessment will be reviewed and continued eligibility for the 
study will be confirmed. The following assessments should be performed and documented 
with date and time at this visit: 
1. Perform assessment of Vital signs: obtain weight, temperature, obtain and record 
serial BP and pulse measurements after at least 10 minutes of supine rest and 
again after 1, 3, 5, and 10 minutes of active standing 
2. Ask for AE occurring since the last visit. 
3. Interview on concomitant medication use since the last visit. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 52/107 
4. Perform physical and neurological examination 
5. Administer the MDS-UPDRS Part I, II, III, and IV (record if patient is in ON or OFF 
state), and the Modified Hoehn and Yahr stage 
6. Administer the following assessments: 
a. NMSS 
b. HADS 
c. PDQ-39 
d. MoCA 
e. ESS 
f. 
FSS 
g. VAS for Pain 
h. KPPS 
i. 
CGI-I 
j. 
C-SSRS 
k. QUIP-RS 
7. Collect all used, unused, and partially used study drug and record it in the source 
documents and Drug Accountability Section.  
8. Schedule the Termination Visit / V 1, which must occur after 4 weeks + 2 days from 
the date of the Visit 0. 
9. Instruct the patient to bring their medication to the baseline visit (including 
concomitant medication so that they are able to maintain their regular treatment 
schedule) 
5.2.2 Randomization  
If the Sponsor confirms the patient to be eligible and after one week of stable nabilone 
dosage, responders are randomized in a 1:1 ratio to receive either nabilone at the dosage 
reached during the titration phase or matching placebo for 4 weeks.  
During the randomized withdrawal phase of the trial, dose adjustments can be performed if 
CGI-I deteriorates. In this case, patient will re-enter the titration phase of the trial.  
For randomization a randomization list provided by the Statistics Department of the Medical 
University of Innsbruck will be used to randomize the patients to the placebo or nabilone 
group. Information about the blinded medication kits to be used will be provided by the 
Sponsor or its designee to the investigator according to the randomization and the scheduled 
visits. (For further details see: 7.2) 
 
10. Dispense the double-blind IMP kit assigned by the Sponsor to the patient for this 
study visit.  
11. Record the dates the patient is instructed to take the study drug on the packaging 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 53/107 
of it. Record the following information in the source documents: patient number, 
assigned IMP kit number, date, and time the study drug was dispensed. 
12. Review the dosing instructions for the study drug with the patient, answer any 
questions, and remind the patient to return all used, unused, and partially used 
study drugs at the next visit. The patient will be instructed to take one tablet of the 
study drug by mouth two times daily starting in the evening after the Baseline Visit. 
The evening dose should be approximately 12 hours after the morning dose. 
Document that the patient understood the dosing instructions. 
13. Instruct the patient to inform the investigator if an AE or a change of concomitant 
Medication occurs during this period, if the patient runs out of IMP kit (e.g. due to 
damage), or if the patient´s condition worsens, and provide relevant contact details. 
 
The patient will leave the clinic with enough IMP for the next 4 weeks + 2 days and begin to 
take the assigned IMP (placebo or nabilone) in the evening after the baseline visit. 
 
During the first week of placebo-controlled, double-blind, parallel-group, enriched enrolment 
randomized withdrawal phase of the trial, the patients will receive phone calls every other 
day to ask for AEs, Concomitant Medication use, CGI-I, the items 1.2, 1.8, and 1.12 of MDS-
UPDRS Part I, and the C-SSRS. 
5.3 Termination Visit / V 1 (week 4) 
After 4 weeks of placebo-controlled, double-blind, parallel-group, enriched enrolment 
randomized withdrawal phase, the patient will return to the clinic to perform his/her 
termination Visit / V1. The time and date of the last dose of study drug will be documented. 
The following assessments should be performed and documented with date and time at this 
visit: 
1. Perform assessment of Vital signs: obtain weight, temperature, obtain and record 
serial BP and pulse measurements after at least 10 minutes of supine rest and again 
after 1, 3, 5, and 10 minutes of active standing 
2. Ask for AE occurring since the last visit. 
3. Interview on concomitant medication use since the last visit. 
4. Perform physical and neurological examination 
5. Obtain 12-lead ECG and review 
6. Obtain blood samples to perform the following laboratory measurements: 
haematology, chemistry, pregnancy test (for women of childbearing potential only) 
7. Urine sample for urinalysis, including pregnancy test (for women of childbearing 
potential only) 
8. Administer the MDS-UPDRS Part I, II, III, and IV (record if patient is in ON or OFF 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 54/107 
state), and the Modified Hoehn and Yahr stage 
9. Administer the following assessments: 
a. NMSS 
b. HADS 
c. PDQ-39 
d. MoCA 
e. ESS 
f. 
FSS 
g. VAS for Pain 
h. KPPS 
i. 
CGI-I 
j. 
C-SSRS 
k. QUIP-RS 
l. 
Eye-tracking 
10. Collect all used, unused, and partially used study drug and record it in the source 
documents and Drug Accountability Section.  
 
Nabilone will then be down-titrated in 0.25 mg decrements every other day until it is 
discontinued. During dose tapering phone calls will be held every other day to receive 
information on AEs, Concomitant Medication use, CGI-I, the items 1.2, 1.8, and 1.12 of MDS-
UPDRS Part I, and the C-SSRS will be executed. A phone call for safety issues will be held 
after 5 days ± 2 days and a Safety Follow- Up Visit will be scheduled after 2 weeks + 2 days 
of discontinuation from study drug. (see 5.4) 
The Safety Follow- Up Visit should therefore be scheduled with the patient and he/she 
should be reminded on the telephone calls. Relevant contact to the site should be updated if 
necessary if there are any questions or adverse events occurring until the Safety Telephone 
Call or Follow-Up Visit. 
 
5.4 Safety Telephone Call (TC – S) and Safety Follow-Up 
Visit (V – S) 
The Safety Telephone Call will be held after 5 days ± 2 days after stopping the study drug 
and will include the assessment of AE, concomitant medication, and the CGI-I. 
Questions for the following items and assessment of the following scale will be performed: 
§ Hallucination item (1.2) of Movement Disorders Society – Unified Parkinson´s 
Disease Rating Scale (MDS-UPDRS) 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 55/107 
§ Orthostatic hypotension (OH) item (1.12) of Movement Disorders Society – 
Unified Parkinson´s Disease Rating Scale (MDS-UPDRS) 
§ Day-time sleepiness item (1.8) of Movement Disorders Society – Unified 
Parkinson´s Disease Rating Scale (MDS-UPDRS)  
§ C-SSRS 
 
Documentation in the source document will include the time and date of the call as well as 
the results of the assessments.  
 
The Safety Follow-Up Visit will take place 2 weeks + 2 days after the withdrawal from study 
drug and will include the following assessments (documented with date and time in the 
source documents): 
1. Perform assessment of Vital signs: obtain weight, temperature, obtain and record 
serial BP and pulse measurements after at least 10 minutes of supine rest and again 
after 1, 3, 5, and 10 minutes of active standing 
2. Ask for AE occurring since the discontinuation of the study drug. 
3. Interview on concomitant medication use since the last intake of study medication. 
4. Perform physical and neurological examination 
5. Administer the MDS-UPDRS Part I and C-SSRS 
6. Collect all used, unused, and partially used study drug and record it in the source 
documents and Drug Accountability Section.  
 
5.5 Early Termination Visit 
If the patient has discontinued IMP, an early termination visit should be performed as soon 
as possible after the last dose of study drug and the Sponsor should be informed. The date 
of the last intake of study drug should be documented and a reason for withdrawal of the 
study drug if available. This visit will include the following assessments (documented with 
date and time in the source documents): 
1. Perform assessment of Vital signs: obtain weight, temperature, obtain and record 
serial BP and pulse measurements after at least 10 minutes of supine rest and again 
after 1, 3, 5, and 10 minutes of active standing 
2. Ask for AE occurring since the discontinuation of the study drug. 
3. Interview on concomitant medication use since the last intake of study medication. 
4. Perform physical and neurological examination 
5. Obtain 12-lead ECG and review 
6. Obtain blood samples to perform the following laboratory measurements: 
haematology, chemistry, pregnancy test (for women of childbearing potential only) 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 56/107 
7. Urine sample for urinalysis, including pregnancy test (for women of childbearing 
potential only) 
8. Administer the MDS-UPDRS Part I, II, III, and IV (record if patient is in ON or OFF 
state), and the Modified Hoehn and Yahr stage 
9. Administer the following assessments: 
a. NMSS 
b. HADS 
c. PDQ-39 
d. MoCA 
e. ESS 
f. 
FSS 
g. VAS for Pain 
h. KPPS 
i. 
CGI-I 
j. 
C-SSRS 
k. QUIP-RS 
l. 
Eye-tracking 
10. Collect all used, unused and partially used study drug kits and document in the 
source documents and Drug Accountability Section. 
A Safety Follow-Up Visit should be performed 2 weeks + 2 days after the last intake of study 
medication (if the Early Termination Visit occurs not longer than 5 days after the 
discontinuation of the study medication). 
5.6 Unscheduled Visit / USV 
An Unscheduled Visit is defined as any additional visit performed at any time between the 
Screening Visit and the Safety Follow-Up Visit. This visits can be held at the investigator’s 
discretion. An USV should at least contain questions and assessments for: 
1. AE occurring since the last visit. 
2. Concomitant medication use since the last visit. 
3. CGI – I 
4. C-SSRS 
5. Obtain and record the date and approximate time when the patient took the most 
recent dose of IMP. Collect all used, unused, and partially used study drug kits 
dispensed at the previous visit and document in the source documents and Drug 
Accountability Section. Assess compliance. Document any missed doses, lost tablets, 
and number of tablets taken 
The reason for the Unscheduled Visit should be provided and recorded in the source 
documents. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 57/107 
Additional assessments can be performed if necessary by the means of the investigator 
including a neurological and physical exam, laboratory tests and urinalysis, a pregnancy test, 
a 12-lead ECG, and the clinical scores used in the trial.  
In consultation with the Medical Monitor, discuss any other appropriate diagnostic tests 
required to evaluate AEs. 
 
5.7 Telephone calls  
Telephone calls will be performed according to the study protocol during dose titration 
phase(s), the first week of placebo-controlled, double-blind, parallel-group, enriched 
enrolment randomized withdrawal phase, and during dose tapering as summarized in 3.2 
(Schedule of Events). Telephone calls will be held every other day (1) during dose titration 
phase until optimal dose will be reached, (2) during the first week of the placebo-controlled, 
double-blind, parallel-group, enriched enrolment randomized withdrawal phase, and (3) 
during dose tapering until IMP is stopped. A Safety Telephone Call will be held 5 days ± 2 
days after discontinuation of study medication. During these telephone calls patients will be 
asked for any AEs, SAEs, and the CGI-I. Moreover, the hallucination item (1.2), the day-time 
sleepiness item (1.8), the OH item (1.12) of the MDS-UPDRS, and the C-SSRS will be 
applied.  
 
If the site is not able to reach a patient (or study partner) via telephone on the scheduled day 
and all attempts have been made and there is no other possibility to reach the patient and no 
reasonable explanation, the site is allowed to stop trying to connect to the patient. At least 3 
attempts have to be made. Attempts have to be documented as well as the decision to 
discontinue trying. The site has to attempt to reach the patient on the consecutive working 
day again. 
If a telephone call is scheduled on a Saturday, the patient should be reached on Friday. If a 
telephone call should be held on Sunday, the call will be scheduled on Monday. On bank 
holiday, the patient should be called the day before or after the day off. 
The patients will be provided with an emergency phone number available 24 hours to contact 
a member of the study team in case of emergencies. 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 58/107 
6 
Description of Assessments: Efficacy and Safety 
Variables 
6.1 Assessments of Efficacy  
The primary efficacy criterion will be measured as the change of the MDS-UPDRS Part I 
between baseline and week 4 / termination visit as determined by the investigator. The 
change is given in points in the scale. The subscale provides score values from 0 to 52 
points in which 0 means that all measured values appear normal and 52 points that all 
domains are severely impaired. 
Currently, the MDS-UPDRS Scale is the most common used scale in evaluation motor 
symptoms in patients with PD. The Movement Disorder Society (MDS)-sponsored new 
version of the UPDRS was published in 2003 with respect to the Task Force for Rating 
Scales´ proposed criticism of the original UPDRS concerning issues of weakness and 
ambiguities. (44) The scale consists of four components with each part addressing different 
domains of symptoms of PD and its therapy (Part I: Non-Motor Experiences of Daily living; 
Part II: Motor experiences of daily living; Part III: Motor Examination; Part IV: Motor 
Complications). Each section was written by appropriate members of the subcommittees, 
reviewed, and ratified by the subcommittee. Part I of the MDS-sponsored new version of the 
UPDRS consists of one part (Part IA) containing the observations of the investigator 
regarding behaviors based on information from patients and caregivers, and one part (Part 
IB) to be self-administered by the patient alone or with help of the caregiver without 
cooperation with the investigator. The rater can solely review this part to ensure that all items 
are rated and questions for understanding can be addressed to him/her. Part II is also based 
on the patient´s self-evaluation. Part III needs to be demonstrated or performed by the rater. 
Part IV consists of instructions for the investigator and the patients to combine clinical 
observations with information provided by the patient and it is executed by the rater. 
Only qualified and trained raters will administer the UPDRS subscales in accordance with 
requirements for background and experience in research settings. Trainings will be 
documented by providing a Certificate of Rater Approval. The UPDRS Scale will first be 
measured before the patient receives nabilone and in subsequent visits after the patient´s 
morning dose of nabilone. It will be documented if the patient is in an ON state (i.e. period 
when the patient notices a benefit on MS from standard oral LD/CD treatment) or in an OFF 
state (i.e. the phase with no response to medication and significant motor symptoms). 
The key secondary efficacy criteria will be measured as the change in the other clinical 
scales and questionnaires regarding motor symptoms and different domains of non-motor 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 59/107 
symptoms in Parkinson´s Disease between baseline and week 4. Therefore, the total MDS-
UPDRS Part I, II, III, and IV (total UPDRS: 50 items, Part I: 0 to 52 points, Part II: 0 – 52 
points, Part III: 0 – 132 points plus Hoehn and Yahr Scale 0 - 5 points, Part IV: 0-24 points), 
the Non Motor Symptoms Scale (4 domains, 15 items, points from 0 – 12x15 with the latter 
being severely impaired daily or always), the Hospital Anxiety and Depression Scale (14 
items, values from 0 – 42 points), the Parkinson´s Disease Questionnaire – 39 (8 domains, 
39 items), the Montreal Cognitive Assessment (8 items, score ranges from 0 – 30 points), the 
Epworth Sleepiness Scale (8 items, ranges from 0 – 24 points), the Fatigue Severity Scale (9 
items, 9 – 63 points), the Visual Analog Scale of Pain, the King´s Parkinson´s Disease Pain 
Scale (7 domains, 14 items, 0 – 168 points), and the Questionnaire for Impulsive-Compulsive 
Disorders in Parkinson’s Disease–Rating Scale (7 domains, 0 – 122 points) will be 
performed. The result of the Clinical Global Impression – Global Improvement scale (ratings 
from 1 to 7) at Visit V 1 will be used as a key secondary efficacy criterion. All presented 
scales are measured in points given above.  
 
The Non-Motor Symptoms Scale (NMSS) was developed by an international 
multidisciplinary PD-NMS group in order to create a comprehensive questionnaire to assess 
symptoms of PD that are not affecting movement. Symptoms included in the scale range 
from vertigo and other symptoms of orthostatic hypotension, falls, daytime sleepiness and 
subsequent loss of energy, sleep disturbances at night, restlessness in the legs to psychiatric 
and cognitive symptoms like apathy, loss of motivation and interest, nervousness, anxiety, 
worry, sadness, depression, mood swings, loss of joy in usual activities, and symptoms of 
delusion, hallucinations, and double vision. 
 
The Hospital Anxiety and Depression Scale was developed in 1983 from Ziegmond und 
Snaith which edited a longer version of the questionnaire and published this 14-items-long 
tool. The Scale aims to assess symptoms of anxiety and depression and was generated as a 
screening tool. 7 items address symptoms of anxiety and the other 7 items assess 
depression in patients. Therefore, a subscore for anxiety and depression can be generated. 
Questions regarding physical symptoms and intrusive items are not included to avoid 
confounding of the result by organic diseases. 
 
Parkinson´s Disease Questionnaire-39 
The PDQ-39 is the most widely used PD specific measure of health status and functional 
capacity. Its thirty-nine questions cover eight aspects of quality of life. The instrument was 
developed on the basis of interviews with people diagnosed with PD and it has been widely 
validated. The questions relate to mobility, activities of daily living, emotional well-being, 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 60/107 
social support, cognition, communication, and bodily discomfort. The patient is asked to rate 
each question regarding his/her PD symptoms over the past month.  
 
Montreal Cognitive Assessment Scale 
Nasreddine et. al created the MoCA in 1996 in Montreal, Quebec to asses symptoms of mild 
cognitive impairment. The test assesses several cognitive domains through its task for 
orientation to time and place (6 points), its learning task (five nouns) to assess short-term 
memory recall (5 points), a task to assess visuospatial / executive functions (task adapted 
from trail making B task, clock-drawing task, and drawing a three-dimensional cube, 5 
points), and a phonemic fluency task (1 point), and a two-item verbal abstraction task (2 
points). 
Cognitive function and working memory are evaluated using a sustained attention task 
(target detection using tapping,1 point), a serial number subtraction task (3 points), and a 
task where digits are repeated forwards and backwards (1 point each). Verbal skills are 
assessed by using a confrontation naming task with animals with low familiarity (lion, camel, 
rhinocerus, 3 points), by letting the patient repeat two sentences with complex syntax (2 
points), and the fluency task described above.  
 
Epworth Sleepiness Scale (ESS)  
Daytime sleepiness is assessed by the ESS, which is a short self-administered scale asking 
for the probability of dozing in eight different situations during the day. Answers can range 
from no chance of dozing to high chance of dozing in the following scenarios: sitting and 
reading, watching TV, sitting in a public space, being an assistant driver in a one-hour ride 
without a break, relaxing in the evening, sitting and talking to another person, sitting still after 
lunch without intake of alcohol and stopping the car at a traffic light. 
 
Visual Analog Scale (VAS) of Pain  
The VAS of Pain is a tool to measure pain by indicating a position along a continuous line 
between two end-points (0 - 100 mm). There is evidence that shows that the visual analogue 
scales as continuous scales have superior metrical characteristics than discrete scales and a 
wider range of statistical methods can be applied to its results. 
 
 
King's Parkinson's disease pain scale (KPPS)  
Chaudhuri et al. initially published the KPPS to be a reliable and valid scale to rate different 
types of pain in PD in 2015. (45) Its aim is to evaluate the global and bedside burden of pain 
and to characterize various phenotypes of pain in Parkinson Disease (PD) patients. 
The scale consists of seven domains including 14 items, with each item scored by severity 
(0-3) multiplied by frequency (0-4), resulting in a subscore of 0 to 12, with a total possible 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 61/107 
score range from 0 to 168. The KPPS provides questions for musculoskeletal pain, chronic 
pain, fluctuation-related pain, nocturnal pain, oro-facial pain, discolouration, oedema / 
swelling and radicular pain. 
The contact information for this questionnaire and the permission to use for this study was 
granted by: Mapi Research Trust, Lyon, France – Internet: https://eprovide.mapi-trust.org 
 
Fatigue Severity Scale (FSS)  
To evaluate the level and severity of fatigue of patients during the past week the FSS will be 
used in this study. It consists of nine statements with levels ranging from 0 to 7 points 
whereat a low value indicates a strong disagreement with the statement and a high value a 
strong approval of it. The scale pays attention to motivation, the impact of exercise on 
fatigue, the impact of fatigue on (physical) functioning, work, family or social life, and 
problems and disability arising from fatigue. 
 
Clinical Global Impression - Improvement (CGI-I) 
The CGI-I is used by the investigator to rate the patient´s total improvement based on a 1 to 
7 point weighted scale at which one point means “very much improved” and seven points 
indicate a status of being “very much worse”. If the scale has not been assessed, a zero 
score will be given. The rater should evaluate the improvement of the patient to his clinical 
judgment, whether or not the improvement is believed to be due to drug therapy. 
 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating 
Scale (QUIP-RS) 
The QUIP-RS is a measurement designed to support the diagnosis and to measure the 
severity of symptoms of impulse control disorders and related disorders in PD in the last four 
weeks. The QUIP-RS consists of 4 primary questions addressed to commonly reported 
thoughts, urges/desires, and behaviours associated with impulse control disorders each 
applied to 4 domains of impulse control disorders and 3 domains of related disorders. These 
4 domains are: compulsive gambling, buying, eating, and sexual behavior. The 3 domains of 
related disorders are medication use, punding, and hobbyism. Each question can have a 
score from 0 to 4 assessing the frequency of thoughts, urges, or behaviours. The scores for 
each impulse control disorder and related disease can range from 0 to 16 points, with a 
higher score indicating a greater severity of symptoms. The total QUIP-RS score for all ICDs 
and related disorders combined can have values from 0 to 112 points.  
© University of Pensylvannia 
 
6.2 Safety Assessments 
Tolerability will be described through the: 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 62/107 
§ Number of subjects (%) who discontinue the study 
§ Number of subjects (%) who discontinue the study due to AE 
 
Safety Measures include the following: 
§ Adverse Events (AE), Serious Adverse Events (SAEs), Suspected Unexpected 
Serious Adverse Reactions (SUSARs) 
§ Clinical and laboratory assessment 
§ Vital signs including performance of active orthostatism (measurement of heart 
rate and blood pressure after 10 minutes of quiet rest in the supine position and 
at 1, 2, 3, 5, and 10 minutes of active standing) 
§ ECG 
§ Patient´s Compliance 
§ Prior and Concomitant Medication Use 
§ Hallucination item (1.2) of Movement Disorders Society – Unified Parkinson´s 
Disease Rating Scale (MDS-UPDRS) 
§ Orthostatic hypotension (OH) item (1.12) of Movement Disorders Society – 
Unified Parkinson´s Disease Rating Scale (MDS-UPDRS) 
§ Day-time sleepiness item (1.8) of Movement Disorders Society – Unified 
Parkinson´s Disease Rating Scale (MDS-UPDRS)  
§ Columbia Suicide Severity Rating Scale (C-SSRS) 
 
6.2.1 Adverse Events, Serious Adverse Events, Adverse Drug 
Reaction, Suspected unexpected serious adverse reactions 
Safety assessment can be implemented by monitoring and recording of AEs including ADR, 
SAEs, and SUSARs. For a description of the terms, documentation, and reporting see 8 of 
this protocol. The patients should be questioned for adverse reactions at any visit and 
telephone call. This should be reported on the CRF and in the patient´s record. In case of an 
SAE or SUSAR, an immediate (within 24 hours) reporting to the Sponsor and the competent 
authorities is obligatory.  
 
6.2.2 Description of other safety measures 
Demographics 
At the Screening Visit, the patient will be asked for ethnicity, sex, age at examination, year 
and age of symptom onset, marital state, education (years), profession, family history (brief), 
and social history (brief). 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 63/107 
 
Physical and neurological examination  
A brief physical and neurological examination of the patient will be held at the Screening 
Visit, Baseline Visit, V 1, the Safety Follow-up Visit, and an Early Termination Visit (if 
applicable) of the patient and documented in the patient´s record. 
All physical examinations will be performed by trained medical personnel only, prior to IMP 
administration on dosing days. Any abnormal findings will be recorded as AEs. 
Physical examination must at least include assessment of the vigilance and orientation, 
general condition, nutritional condition, HEENT (head, eyes, ears, nose and throat), 
respiratory system, heart, abdomen, extremities, and visible skin and mucous membrane. 
Patients should be questioned for defecation and the act of urination. 
Neurological examination should include standard neurological assessment of vigilance, 
orientation, mental status (e.g. consciousness), meningism, cranial nerves, the motor system 
and sensory system of both upper and lower extremities, reflexes (including pathological 
reflexes), cerebellar signs, gait, tandem gait, and postural stability, as well as special tests for 
parkinsonism (e.g. finger tapping, toe tapping, facial expression, …). 
 
Laboratory assessments and Urinalysis   
 All laboratory assessments will be made at the central laboratory of the Medical University of 
Innsbruck to ensure the patient´s safety and for early detection of changes in the course of 
the clinical trial. All members of the study team that are authorized by the principal 
investigator will be allowed to obtain blood samples. In total 8.2 ml of blood will be withdrawn 
in 2 tubes at one visit. After withdrawal of blood, it will be sent to the central laboratory and 
processed via standard methods. Time and Date of Collection of Blood will be provided in the 
patient´s records. 
The results will be displayed in the clinical information system, printed, reviewed by the 
principal investigator or authorized medical personnel, signed, dated and filed in the patient´s 
chart. An interpretation by the principal investigator or authorized medical personnel 
(clinically significant (c.s.) or non-clinically significant (n.c.s)) will be provided.  
Urinalysis will be performed by authorized members of the study team using the Combur 10 
Test M (Roche®) and reviewed by the investigator or authorized medical personnel. Time 
and Date of Collection of Urine will be provided in the patient´s records. The results will be 
written down on the Test Result Pads which will be stored in the patient´s folder. Date and 
signature as well as an interpretation of the results by the principal investigator or authorized 
medical personnel (clinically significant (c.s.) or non-clinically significant (n.c.s)) will be 
provided. 
If an abnormal laboratory measurement or result at urinalysis will be detected, further 
measures and care will be performed to ensure the patient´s safety. The abnormal finding 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 64/107 
will be recorded and reported as an AE, SAE, or SUSAR if clinically significant. In the case of 
a serious adverse event or SUSAR, further participation of the patient in the trial will be 
discussed with the Medical Monitor. 
 
Laboratory assessments will include standard hematology, chemistry, and urinalysis as 
outline in the schedule of events table and will be performed using standard kits of 
outpatient´s department. The following laboratory parameters will be measured: 
Haematology: Leucocytes, Erythrocytes, Haematocrit, Haemoglobin, MCH, MCV, MCHC, 
Platelets 
Chemistry: AST, ALT, Troponin-I, CK-MB, Creatinine, GGT, Electrolytes, Total conjugated 
and unconjugated bilirubin 
Urinalysis: Leucocytes, Nitrite, Protein, Glucose, pH, Ketones, Urobilinogene, Bilirubin, 
Blood, Haemoglobin, Urine pregnancy test (females of childbearing potential, only)  
 
(RBC: red blood cell, WBC: white blood cell, MCV: mean corpuscular volume, MCH: mean 
corpuscular haemoglobin, MCHC: mean corpuscular haemoglobin concentration, ALP: 
alkaline phosphatase, ALT: alanine transaminase, AST: aspartate transaminase, BUN: blood 
urea nitrogen, CK-MB: creatine phosphokinase-MB, GGT: gamma-glutamyl transpeptidase, 
LDH: lactate dehydrogenase, pH: reverse logarithmic representation of relative hydrogen 
proton (H+) concentration) 
 
Vital signs  
Vital signs including the evaluation of weight, height (only at Screening Visit), temperature, 
and active orthostatism will be performed at all visits during the course of the study. The 
latter will be assessed by measuring the heart rate and blood pressure after 10 minutes of 
quiet rest in a supine position and at 1, 2, 3, 5, and 10 min after active standing. 
Blood pressure and pulse rate should be obtained in a quiet room at a comfortable 
temperature, with the patient’s arm unconstrained by clothing or other material, and with an 
appropriate cuff size. In this study, an automatic BP cuff (sphygmomanometer) with digital 
advert will be used. Patients with symptomatic orthostatic hypotension will be excluded from 
the study. 
 
Concomitant medications  
The patients will be asked for concomitant medication on every visit and telephone call and 
will be assessed in regard to permitted and prohibited concomitant medication. 
 
Twelve-lead Electrocardiogram (ECG) 
For ECG analysis the patient will be sent to the cardiologic outpatient´s department of the 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 65/107 
Medical University of Innsbruck at Screening (if not performed within 4 weeks prior to SCR), 
Visit V 1 and Early Termination Visit (if applicable) at which an ECG is required. The ECG 
will be reviewed by a cardiologist and displayed in the information system of the clinic. 
Members of the study team will print it, the investigator or a designee will review it, and the 
copy will be filed in the patient´s records. If an abnormal ECG will be detected, necessary 
procedures to ensure the safety of the patient will be performed and an AE, SAE, or SUSAR 
will be recorded and reported as described in 6.2. A standard 12-lead ECG will be performed 
in a supine position after at least 10 minutes of resting to minimize variability at the study 
visits outlined in the Schedule of Events table. ECGs for each patient should be obtained 
from the same machine whenever possible. Body position should be consistently maintained 
for each ECG evaluation to prevent changes in heart rate. Environmental distractions (e.g., 
television, radio, conversation) should be avoided during the pre-ECG resting period and 
during ECG recording. ECGs should be performed prior to any scheduled vital signs 
measurements and blood draws. 
For safety monitoring purposes, the investigator or designee must review, sign, and date all 
ECG tracings.  
The 12-lead ECG includes standard PR, QRS, QT, and QTc (heart-rate corrected QT) 
intervals as read by the machine. Fridericia’s correction (QTcF) must be used for correction 
of the QT interval. The recorded ECG will be used to determine eligibility at the Screening 
visit and to supervise the heart rhythm through the course of the study. Tachycardia is 
defined as a pulse rate above 100 bpm and by its characteristic changes in ECG waves. A 
QTcF interval under 430 ms for males and under a value of 450 ms for females is considered 
to be normal. Values above 450 ms for male patients and above 470 ms for female 
participants display a prolonged QTcF interval (FDA).  
 
Patient´s Compliance 
The patient´s compliance will be assessed by open questions from the investigator at every 
on-site visit and phone call. 
 
Hallucination item (1.2) of MDS-UPDRS 
Day-time sleepiness item (1.8) of MDS-UPDRS 
Orthostatic hypotension (OH) item (1.12) of MDS-UPDRS 
These items are part of the UPDRS Part I (Mental Activity, Behaviour, and 
Mood) and refer to delusions and hallucinations of all sensations and to the loss 
of insight of the patient, to day-time sleepiness and its frequency while reading 
or watching TV, while having a discussion or during the meal, and to the 
sensation of drowsiness and vertigo and its consequences, like falls during the 
last week. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 66/107 
The items are assessed to detect potential side effects that may occur due to 
drug treatment. The will be assessed at every clinical visit and during all phone 
calls and documented in the source documents. 
 
Columbia Suicide Severity Scale (C-SSRS) 
The C-SSRS was initially designed for suicidal assessment in one study, but 
has shown overall successful prediction of suicidal behaviour in adolescences 
and adults. It is the only screening tool to assess the full range of suicidal 
ideation and behaviour including criteria for the next steps (e.g. referral to a 
mental health professional). Suicidality in this study with this scale will be 
assessed by trained study personnel only (Posner et. al, 2011) on all visits and 
telephone calls as a measurement for safety. The scale consists of 4 
categories: suicidal ideation, intensity of suicidal ideation, suicidal behaviour, 
and actual/potential lethality which can be answered by Yes or No. At 
Screening Visit the questionnaire for the past 6 months will be used and for all 
other visits and phone calls the version “Since the last visit” will be 
administered. 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 
6.3 Assessment of exploratory endpoint 
§ Eye-tracking Examination (reaction time, attention span, concentrativeness) 
 
Eye-tracking: Measurement of eye-movements with the Tobii TX-300 
Eye-tracking provides a fast and non-invasive method for various examinations. In this study 
we will measure the reaction time using prosaccade and antisaccade tasks. Moreover, we 
will assess attention spans and the concentrativeness using a customized saccade task and 
a test involving task-switching. The examination will be performed at the Screening Visit and 
the Termination Visit (Week 4). Examinations will take place in a quiet room by trained 
personnel only. 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 67/107 
7 
Study Treatments 
7.1 Details of Study Treatment 
7.1.1 Name and Description of Investigational Medicinal Product 
(IMP) and Comparator 
Nabilone:  
Nabilone is a synthetic cannabinoid derivative. Canemes 0.25 mg capsules are an oral 
dosage form in white hard gelatine capsules. Each capsule contains 0.25 mg Nabilone as the 
active ingredient, in the form of a polyvinylpyrollidone (Povidone) co-precipitate and corn 
starch. Each PE bottle contains 28 capsules for a treatment period of approximately 1 month. 
 
Synthetic cannabinoid nabilone 
Other components: Polyvinylpyrollidone (Povidone) co-precipitate and corn starch  
Administration form: capsules 
Mode of administration: oral 
Dose: 0.25 – 2 mg per day 
Manufactured in 0.25 mg dosage strength 
Bottles of 28 capsules each 
For clinical trial use only, Usage as described in the protocol 
Stored at room temperature, 
Store pharmaceutical material out of the reach and sight of children 
Sponsor: Medical University of Innsbruck, Austria 
            Represented by O.Univ.-Prof. Dr. Werner Poewe 
 
Placebo: Matching Placebo capsules 
Placebo capsules to be used in the double-blind treatment phase are visually and physically 
indistinguishable from the active drug product and contain no active ingredient. They consist 
of corn starch. 
 
7.1.2 Dosing Instructions  
During titration phases nabilone will be started with a dosage of 0.25 mg in the evening orally 
and titrated by 0.25 mg increments every one- to four- daily. Dose adjustments should be 
performed as follows:   
First dose to be implemented: 0.25 mg orally in the evening once a day (0-0-1) 
Increase in one to four-day- steps, according to the investigator´s decision: 
2. 0.25 mg by mouth BID (1-0-1),  
3. 0.25 mg 1-0-2 orally,  
4. 0.25 mg 2-0-2 orally,  
5. 0.25 mg 2-0-3 by mouth,  
6. 0.25 mg 3-0-3 orally,  


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 68/107 
7. 0.25 mg 3-0-4 p.o.,  
8. 0.25 mg 4-0-4 orally 
 
A maximum of 1 mg twice a day should not be exceeded. Between morning dose an evening 
dose a time interval of 12 h should be meet. Preferably, tablets should be taken at the same 
time each day. In case a participant misses a dose, he/she will be instructed to take their 
next dose of nabilone at the normally scheduled time. 
The increment of dosage should take place until the patient has much (CGI- I Rating Scale: 
2) or very much (CGI-I Rating Scale: 1) improved, reached a maximum dose of 1 mg BID or 
experiences intolerable adverse events that are believed to be related to the study drug. 
 
In the double- blinded withdrawal phase of the study, the participants will receive nabilone 
0.25 mg – 1 mg BID or matching placebo, administered orally once or twice daily. During this 
phase the fixed dosage of the study drug should not be changed. If the patient deteriorates in 
his CGI-I, dose adjustments can be made and the patients restarts again at titration phase. 
 
7.1.3 Packaging and Labelling 
The IMP supplies for this study will be packaged according to current GMP guidelines and 
applicable national laws and regulations. For titration phase, IMP will be packaged 
in an open-label fashion and for the randomized withdrawal phase IMP will be packaged in a 
double- blind fashion. Packaging, labelling and distribution of IMP will be performed by the 
company Kwizda. 
7.1.4 Handling and Storage Requirements  
The investigators will be responsible for ensuring the correct storage and sufficient stocks of 
the IMP and comparative drug at the trial centers. The investigator bears the responsibility 
for the proper storage in a secure location at the site which means in a lockable cabinet with 
restricted access to the investigator(s) and authorized site staff. Personnel having access to 
the IMP will be listed on the Authorization and Delegation log in the Investigator Site File 
(ISF). The investigators will ensure that the IMP is only used according to this protocol and 
will only be dispensed to participants of the study. Dispensing will be performed by 
authorized members of the study team. The investigator will be responsible for the Drug 
Accountability log. Drug accountability will be recorded in the patient´s record as well. Drug 
accountability will be noted by a monitor during site visits and at the completion of the trial. 
Unused study drug from all sites will be sent to the company Kwizda for destruction after 
completion of the trial (LPLV). 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 69/107 
7.2 Randomization and Blinding, Subject´s Compliance 
7.2.1 Randomization and Numbering of Patients 
Responders according to the criteria, (see: Inclusion criteria 4.1.) are randomized in a 1:1 
ratio to receive either nabilone or matching placebo for 4 weeks. 
For randomization a generated list provided by the Statistics Department of the Medical 
University of Innsbruck will be used to distribute the patients to the placebo or nabilone 
group. The list will be kept at the Sponsor´s premises. 
Each patient will receive a unique number at the Screening visit to be identified throughout 
his/her participation in the study (in ascending order, starting with number 001 for the first 
patient). This number will be used in all communications between the investigator and the 
Sponsor for the specific patient. 
A patient only enters the trial, if he meets all inclusion and none of the exclusion criteria 
during the screening visit. After assuring eligibility of the patient, the Sponsor or its designee 
will use the randomization list to assign the participant to a treatment group and the 
medication to be used will be determined. The allocated kit number to the specific participant 
for each visit and information about the blinded medication kits to be used will be given to the 
investigator by the Sponsor or its designees according to the randomization and the 
scheduled visits.  
Therefore, the Sponsor or a designee needs to be provided with the randomization list and 
information on the medication that has been sent to the site. 
In case of a drop-out, no replacement will be recruited and the screening number will be 
assigned as before in an ascending order.  
 
7.2.2 Procedures for Maintaining and Breaking the Treatment 
Blinding 
 
Maintaining the Treatment Blinding: 
All members of the study team on-site will be blinded to the treatment group of the patients in 
the four weeks of randomized, double-blinded, parallel-group, enriched-enrolment 
randomized withdrawal phase of the trial. Treatment Blinding will be maintained by receiving 
nabilone or placebo labelled and packed in an equal looking fashion so that the study team 
cannot distinguish between the two treatment groups. Randomization will be performed 
according to a randomization list no member of the study team will see before the end of the 
trial. The Sponsor will have separate documentation concerning the randomization which will 
be kept in the Trial Master File and stored at a locked cabinet of the Sponsor. No data 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 70/107 
collected in the study should offer evidence of a participant’s assignment to a particular study 
arm. 
The patients will receive a screening number at the Screening Visit and will be randomized 
according to the randomization list. No patient will be informed about the assigned treatment 
group. Assignment will be documented by the Sponsor or its designee in the Trial Master File 
which will be stored securely at the Sponsor´s premises. 
 
 
Emergency Envelopes 
Emergency envelopes containing the patient´s name, number in the trial, the assigned 
treatment group, the dosage, and the start and presumably end of the intake of study 
medication will be provided in case of need. These emergency envelopes will be provided by 
the Sponsor or its designee and will be stored on-site separately from study documentation 
in a locked cabinet. In case of an emergency, a member of the study team is allowed to open 
the emergency envelope on behalf of the principal investigator. Authorized members will be 
displayed in the Delegation Log. Opening the emergency envelopes has to be documented 
in the patient´s records and the Sponsor or its designee has to be informed. 
 
Unblinding 
All patients are allowed to be unblinded after the end of the trial (official closure of the study) 
by providing the documentation to the authorized investigators on-site. Authorization will be 
shown in the Delegation Log. The documentation will be provided by the Sponsor´s or its 
designee. No patient is allowed to be unblinded before the end of the trial, except for 
emergencies. Premature treatment unblinding will be performed via the emergency 
envelopes by a member of the study team after consultation with the principal investigator in 
case of an “emergency”. An emergency can be any event that is serious and related to the 
treatment in the investigator´s discretion or an event for which knowledge of the treatment 
group is crucial (i.e. pregnancy). 
 
7.3 Drug Accountability and Treatment Compliance 
The receipt of medication and the condition of it as well as the loss or damage of medication 
will be recorded in the source documents and the company Kwizda will be informed. The 
dispensing and return of medication should be documented in the Drug Accountability 
Section and the patient´s record. Both this records and the medication supplies must be 
available to be reviewed by the study Sponsor or designee at any time requested. The 
investigator is responsible for appropriate storage of used, unused, and partially used study 
drug supplies on-site until they are returned for destruction on completion of the study 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 71/107 
(LPLV). 
Supplies of nabilone intended for this study should only be used for the purpose of the study 
and adhering to this protocol. It is prohibited to apply for any other purpose. The investigator 
is responsible that the use of the study drug is strictly in accordance with the study protocol. 
 
7.3.1 Procedures for Monitoring Patient Compliance  
In outpatient treatment procedures for the verification and documentation of the compliance 
will be as follows: 
• 
The patients only receive the amount of medication units at each visit that will be 
needed until the next visit. 
• 
The Investigator takes back the empty containers or non-used units. 
 
The patient must return all used, unused, and partially used study drug supplies at the 
planned visits in the study course. Drug accountability must be done in the presence of the 
participant. Thus discrepancies between the dosing regime and the patient´s compliance can 
be clarified directly. Drug Accountability must be recorded in the source documents and the 
Drug Accountability Log in the Investigator Site File. 
The end of treatment for the patient should be documented at the Termination visit (week 4). 
In case of persistent noncompliance of a patient (<80% to >120% of the assigned dose), the 
Sponsor or its designee will be informed to decide together with the investigator whether the 
patient should be discontinued or not. 
 
7.4 Prior and Concomitant Medications/Treatments  
7.4.1 Allowed Anti-PD Medications/Treatments  
All Anti-PD Medications are allowed in this study preconditioned the patient has a stable 
Parkinson´s disease and that the regimens of Anti-Parkinson´s medications, other current 
prescribed/non-prescribed medications or dietary supplements are stable for at least 30 days 
prior to screening and will be continued on the same doses and regimens. 
The addition of any new anti-PD medication or other prescribed / non-prescribed drugs are 
prohibited during the study as well as changes to frequency or intervals between doses.  
 
Participants will be advised to refrain from the use of any concomitant medication during their 
participation in the study without prior permission by the investigator. The use and the reason 
for the use of any additional medication will be recorded in source documents. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 72/107 
7.4.2 Prohibited Concomitant Medications/Treatments 
Nabilone has an addictive and CNS depressing effect if taken together with diazepam, Na-
Secobarbital, alcohol and codeine. 
 
Interactions between nabilone and the following medications have been observed. Therefore, 
these the intake of these drugs during the course of the clinical trial is prohibited for 
participants of this study. 
• 
amphetamine, cocaine, other sympathomimetics 
• 
atropine, scopolamine, antihistaminics, other anticholinergic substances 
• 
amitriptyline, amoxapine, desipramine, other tricyclic antidepressive drugs 
• 
barbiturates, benzodiazepines (except for clonazepam up to a maximum of 1.5 mg 
per d), lithium, opioids, buspirone, muscle relaxing agents, CNS depressing 
substances 
• 
disulfiram  
• 
fluoxetine  
• 
antipyrines  
• 
theophylline 
• 
naltrexone  
7.5 Concomitant Non-Pharmacologic Therapies  
All non-pharmacological therapies (physical therapy, exercise, yoga, ...) the patient performs 
to improve his/her parkinson symptoms can be continued during participation in the study. 
During the trial, however, such non-pharmacological therapies should not be started. All non-
pharmacological therapies will be documented in the source documents at the Screening 
Visit. The concomitant non-pharmacological therapies should be kept on the same levels 
during the study. 
 
 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 73/107 
8 
Adverse Events  
8.1 Summary of known and possible Adverse Events of 
the IMP 
Generally, nabilone is well tolerated.  
Common adverse reactions (>1/100 to <1/10) observed in patients are: 
• 
Somnolence 
• 
Vertigo 
• 
Euphoria 
• 
Ataxia 
• 
impaired vision 
• 
difficulties to concentrate 
• 
sleep disturbances 
• 
dysphoria 
• 
headache 
• 
hypotension 
• 
nausea 
• 
dry mouth  
 
Controlled trials with patients taking nabilone showed that at least one side effect occurred 
per subject. Most patients develop a tolerance in regard of adverse events concerning the 
CNS and therefore relaxation, somnolence and euphoria reside after some weeks. This 
effect is reversible.  
 
In therapeutic doses nabilone is a potential addictive drug. The potential to cause 
mental addiction is unknown and no patient has shown withdrawal symptoms in clinical trials. 
In conjunction with psychological stress, an overdose phenomenon of nabilone can appear 
at therapeutic doses. Symptoms due to overdosing nabilone have been described as 
enhanced psychomimetic and psychological side effects of the drug. In clinical trials a 
normalization of the mental state of the patient was reached after 72 hours of withdrawal of 
the drug without additional therapy. One should monitor vital signs due to the possible 
occurrence of hypertension, hypotonia, and tachycardia.  
No cases of patients taking doses above a level of 10mg daily have been described in 
clinical trials so far. Hereby, one would expect symptoms like hallucinations, anxiety, 
respiratory depression, and coma. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 74/107 
 
No adaption of dose needs to be done in the elderly. Nabilone should not be used in 
patients under the age of 18 years because it has not been studied in separate trials. The 
primary route of elimination of nabilone is biliary. Thus it should not be used in patients 
with severe impairment of liver function. No data in patients with impaired renal function 
have been collected, which is why it should be used with caution in these patients. 
 
Nabilone should not be used during pregnancy or lactation because of the lack of data 
in this cohort. In experiments with animals, no reproductive toxicity has been described. No 
studies on carcinogenesis have been performed. 
 
Minor risks of nabilone (>1/10.000 to <1/1.000) include: 
• 
Confusion 
• 
Disorientation 
• 
Hallucination 
• 
Psychosis 
• 
Depression 
• 
difficulties in coordination 
• 
tremor 
• 
loss of appetite 
• 
anxiety 
• 
depersonalisation 
• 
tachycardia 
• 
abdominal pain 
 
The IMP can cause alterations of physical and mental capabilities which are essential for 
tasks requiring high attention e.g. driving or operating machines. The study medication can 
be detected in the body after withdrawal (total half-life 35 hours) which could lead to 
misinterpretation in case of a control through regulatory authorities e.g. police. 
8.2 Definition of an Adverse Event (AE) 
An adverse event is “any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have 
a causal relationship with this treatment”. (47) 
An AE can therefore be any unfavourable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease which is considered to be 
clinically relevant by the physician and is temporally associated with the use of a medicinal 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 75/107 
(investigational) product, whether or not related to the study drug.  
Adverse events include: 
• 
Worsening or increase in frequency or intensity of a pre-existing disease or medical 
condition in an unexpected manner 
• 
Abnormal laboratory tests (clinically significant) 
Adverse events do not include: 
• 
Pre-planned interventions/hospitalizations 
• 
Medical or surgical procedures, e.g. surgery, endoscopy, tooth extraction, 
transfusion. However, the event leading to the procedure is an AE. If this event is 
serious, the procedure must be described in the SAE narrative. 
• 
Pre-existing disease or medical condition that does not worsen. 
• 
Overdose of either study drug or concomitant medication without any signs or 
symptoms. 
 
In order to ensure complete safety data collection, all AEs occurring during the study (i.e., 
after the signing of the ICF), including any post-treatment periods required by the protocol, 
must be recorded in source documents even if no investigational product was taken but 
specific study procedures were conducted. This includes all AEs not present prior to the 
Screening Visit and all AEs that occurred or worsened after the Screening Visit. Events that 
occur prior to giving informed consent are captured as medical history.  
Signs or symptoms of the disease for which the investigational product is being studied 
should be recorded as an AE if their frequency or intensity increases in a clinically significant 
manner or their nature changes unexpectedly as compared to the clinical course known to 
the investigator from the patient’s history, or the natural course of the disease.  
 
8.3 Definition of a Serious Adverse Events (SAEs) 
“A serious adverse event (experience) or reaction is any untoward medical occurrence that at 
any dose results in death, is life-threatening, requires inpatient hospitalisation or prolongation 
of existing hospitalisation, results in persistent or significant disability/incapacity, or is a 
congenital anomaly/birth defect”. (47) 
An adverse event is therefore considered serious by the definition by the International 
Conference on Harmonization (ICH) guidelines if it can be characterized by at least one of 
the following criteria:  
• 
Results in death 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 76/107 
• 
is life-threatening – defined as an event in which the subject was, in the judgment of 
the investigator, at risk of death at the time of the event; it does not refer to an event 
that hypothetically might have caused death if it had been more severe. 
• 
requires inpatient hospitalization or prolongs an existing hospitalization 
• 
causes persistent or significant disability or incapacity (i.e. a substantial disruption of 
a person’s ability to conduct normal life functions) 
• 
or is a congenital anomaly/birth defect (including that occurring in a fetus) 
• 
or requires medical or surgical intervention to prevent one of the above mentioned 
outcomes. (i.e. the development of drug dependency or drug abuse)  
 
Inpatient hospitalization is defined as an overnight stay in a hospital unit and/or emergency 
room that includes at least one night (midnight to 06:00 AM).  
The following is not considered as a SAE and should be reported as an AE only: 
• 
Treatment of an emergency or outpatient basis for an event not fulfilling the definition 
of seriousness given above and not resulting in hospitalization 
The following reasons for hospitalization are not considered as AEs or SAEs: 
• 
Standard monitoring of a pre-existing disease or medical condition that did not 
worsen, e.g. hospitalization for coronary angiography in a subject with stable angina 
pectoris 
• 
Elective treatment of a pre-existing disease or medical condition that did not worsen, 
e.g. hospitalization for chemotherapy for cancer, elective hip replacement for arthritis 
• 
Hospitalization for cosmetic elective surgery, social and/or convenience reasons 
 
A change in vital signs, diagnostic tests (e.g., an electrocardiogram), or laboratory test 
results may be an SAE if the change meets one of the above criteria. 
 
8.4 Adverse Drug Reaction (ADR) & Unexpected Adverse 
Drug Reaction 
An ADR is any noxious and unintended response to an IMP related to any dose with at least 
a reasonably possible causal relationship with the IMP. 
Unexpected ADR means the nature or severity of which is not consistent with the applicable 
product information available for the IMP. Expected ADRs are listed in the appropriate 
reference documents (e.g. Investigator’s Brochure). 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 77/107 
8.5 Suspected Unexpected Serious Adverse Reactions 
(SUSARs) 
A SUSAR is an event that is believed to be at least possible related to the administration of 
the study drug and is severe and unexpected. It therefore may illustrate a side effect of the 
drug. For clinical studies in which an IMP is used, the FDA defines an “unexpected” AE as an 
AE that has never been seen before, or is not consistent with the information about the 
drug´s risks in the relevant source documents (e.g. Investigator´s Brochure).  
8.6 Pregnancy  
In the event a patient becomes pregnant after the first intake of any IMP, the investigator and 
the Sponsor should be informed immediately. The patient should be withdrawn from the 
study as soon as pregnancy is known, and should immediately stop the intake of the IMP. If 
a pregnancy should be confirmed after informed consent has been obtained but prior to the 
initiation of the study drug, the patient must be excluded from the trial. The pregnancy must 
be followed up to determine outcome (including premature termination) and status of mother 
and child. Pregnancy complications (including spontaneous abortions) and elective 
terminations must be reported as an AE or SAE. Any SAE occurring in association with a 
pregnancy brought to the investigator’s attention after the subject has completed the study 
and considered by the investigator as possibly related to the IMP, must be promptly reported 
to the Sponsor. 
The participant should return for an Early Termination visit as soon as possible and should 
be followed by via a Safety Follow-Up Visit 14 days + 2 days after discontinuation of the 
study drug (if the ET is performed after 5 days after the last intake of study drug). The 
investigator must inform the patient of currently known potential risks for pregnancy outcome 
and available treatment alternatives. 
In case the partner of a male patient enrolled in the clinical study becomes pregnant, the 
Sponsor must be informed immediately by the investigator or designee and a decision of the 
further procedure will be made. 
The pregnancy will be documented in the source documents including the progression of the 
pregnancy and the eventual date of birth (if applicable) as well as the health of the mother 
and of the child. The health of the child must be followed for 30 days after birth for any 
significant medical issues.  
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion, or 
anomaly/birth defect of the child. Those SAEs must be reported to the Sponsor as described 
below.  
As the consent for the study does not cover the consent for the follow-up of the pregnancy, a 
separate consent has to be obtained. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 78/107 
8.7 Overdose of Investigational Medicinal Product  
If the patient has taken a dose beyond that prescribed in the protocol (including section on 
overdose) should be recorded in the source documents and in the Drug Accountability. 
These events are only considered to be AEs or SAE if there are associated clinical signs and 
symptoms or if the act of taking the excess medicine itself is an AE or SAE (e.g., suicide 
attempt). Any SAE or nonserious AE associated with excessive dosing must be followed as 
any other SAE or AE.  
 
8.8 Grading of Severity of Adverse Events 
The term “serious” in SAE refers to the outcome of a patient´s event that poses a threat to 
his/her life or functioning rather than to its intensity, which is described by the term “severity”. 
In the latter, the event itself may be of relatively minor medical significance (such as a severe 
headache). 
 
Intensity of all adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03 on a five-point scale (grade 1 to 5) and 
reported in detail in the patient´s records and CRF. 
Adverse events not listed in the CTCAE version 4.03 should be graded as follows: 
Table 4: CTC grading of Adverse Events 
CTC grade 
Equivalent to  
Definition 
Grade 1 
mild 
Discomfort noticed but no disruption of normal daily activity  
Grade 2 
moderate 
Discomfort sufficient to reduce or affect daily activity; no treatment 
or medical intervention is indicated although this could improve the 
overall wellbeing or symptoms of the patient.  
Grade 3 
severe 
Inability to work or perform normal daily activity; treatment or 
medical intervention is indicated in order to improve the overall 
wellbeing or symptoms; delaying the onset of treatment is not 
putting the survival of the patient at direct risk.  
Grade 4 
life-threatening 
/ disabling 
An immediate threat to life or leading to a permanent mental or 
physical condition that prevents work or performing normal daily 
activities; treatment or medical intervention is required in order to 
maintain survival.  
Grade 5 
death 
AE resulting in death  
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 79/107 
8.9 Causality 
The assessment of relationship of adverse events to the administration of IMP is a clinical 
decision based on all available information and considering all relevant factors such as (but 
not limited to) the underlying indication, coexisting diseases, concomitant medication, etc. at 
the time of the completion of the patient´s record and case report form of this visit. 
The term “related” refers to the ability of the study drug to cause the AE implicating a 
relationship in time and that the event would not have happened without the effort of the 
study drug. 
The question: “Is there a reasonable possibility that the study drug caused the event?”, 
should be asked. Answer YES (possibly, probably or definitely related) if one or more of the 
following criteria apply:  
• 
The event follows a reasonable temporal sequence from administration of study drug 
• 
The event could not be reasonably attributed to the known characteristics of the 
patient’s clinical state, environmental or toxic factors or other modes of therapy 
administered to the patient 
• 
The event follows a known pattern of response to study drug 
• 
The event disappears or decreases on cessation or reduction in dose of the study 
drug. (It should be noted that in some situations an AE will not disappear or decrease 
in intensity upon discontinuation of study drug despite other clear indications of 
relatedness). 
Otherwise answer NO (not related). 
 
Moreover, the relationship between the AE and the study drug can be described stepwise: 
• 
definitely related: an AE that follows a temporal relationship with implementing the 
study drug and a known response pattern to it and cannot be otherwise explained by 
the patient´s medical condition or concomitant medication 
• 
probably related: meets all criteria mentioned above and has to improve after de-
challenging the patient with the study drug. 
• 
possibly related: an AE that has a temporal relationship between administration of the 
study drug and its occurrence and is a known response pattern to the IMP but could 
also be explained by the patient´s medical history or treatment.  
• 
Unrelated: an AE without a relationship in time to study drug treatment and which is 
most likely explained by the patient´s medical condition or therapies. 
 
8.10 Recording, Reporting, and Follow-Up Procedures 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 80/107 
8.10.1 
Procedures for Recording, Reporting, and Follow-Ups of 
Adverse Events  
 
Recording and Reporting of Adverse Events 
The patient will be given the opportunity to report AEs spontaneously at every on-site visit 
and telephone call. Moreover, the rater will propose an open-ended, non-leading question to 
the participant to detect AEs. 
Documentation needs to be done in the patient´s medical record and in a special section for 
adverse events in the CRF where the following details must be entered: 
• 
Type of adverse event (diagnosis or syndrome; if not known signs or symptoms)  
• 
Start (date)  
• 
End (date)  
• 
Severity (mild, moderate, severe, life-threatening/disabling, death)  
• 
Serious (no / yes)  
• 
Unexpected (no / yes)  
• 
Outcome (resolved, ongoing, ongoing – improved, ongoing – worsening)  
• 
Action taken (none, study medication dose reduced, study medication interrupted, 
study 
medication 
discontinued, 
medication 
therapy, 
surgical 
procedure, 
hospitalization, other)  
• 
Relation to study drug (possibly, probably or definitely related or not related)  
 
The investigator should use syndromes or diagnosis of standard medical terminology to 
record adverse events, whenever possible. 
The Sponsor should be informed immediately by the investigator on-site, if an AE is thought 
to be at least probably related to the study drug treatment to discuss whether or not the 
administration of the IMP should be stopped. 
 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report such 
events to the Sponsor immediately; under no circumstances should reporting take place 
more than 24 hours after the investigator learns of the event. The following is a list of events 
that the investigator must report to the Sponsor within 24 hours after learning of the event, 
regardless of relationship to study drug:  
• 
Serious adverse events 
• 
Pregnancies 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 81/107 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e. no more than 24 hours after becoming aware of the information). 
New significant information includes the following:  
• 
New signs or symptoms or a change in the diagnosis.  
• 
Significant new diagnostic test results.  
• 
Change in causality based on new information.  
• 
Change in the event’s outcome, including recovery.  
• 
Additional narrative information on the clinical course of the event.  
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and IRB/EC. 
 
Follow Up of Adverse Events  
An AE will be followed until the patient has recovered/ it has resolved, has reached a stable 
state, the investigator determines that it is no longer clinically significant, or the patient is lost 
to follow up. The end of an AE should be documented in the CRF and the patient´s record. 
If an AE is still ongoing at the end of the study for a patient, follow up will be provided until 
resolution/stable level is achieved, or until it no longer is clinically significant by the 
judgement in the investigator, or until the patient is lost to follow up. In the latter the 
investigator has to take all possible actions in the discretion of his judgement to contact the 
patient and document a loss of follow-up in the source documents.  
In case of withdrawal from the study due to an AE, an Early Termination (ET) Visit will be 
scheduled as soon as possible followed by a Safety Follow-Up Visit after 2 weeks + 2 days 
of the ET (if the ET is performed after 5 days after the last intake of study drug). 
 
8.10.2 
Recording, Reporting, and Follow-Up Procedures for 
Serious Adverse Events and Suspected Unexpected Serious 
Adverse Reactions 
 
Reporting and Recording of Serious Adverse Events and Suspected Unexpected 
Serious Adverse Reactions 
Investigators will seek information on SAEs and SUSARs at each patient contact throughout 
the trial. As for all AEs, whether reported by the patient or noted by study personnel, SAEs 
and SUSARs will be recorded in the patient’s medical record and on the Adverse Event 
Section of the CRF.  


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 82/107 
In the event of a serious adverse event, the investigator has to use all supportive measures 
for best patient treatment. An SAE form must be completed by the investigator and reported 
no more than 24 hours after receiving notice of the event.  
The site must provide the Sponsor with a detailed description containing at least the 
symptoms and course of events, the actions taken, the medication given and if the dose of 
the study drug was changed. The following details should be available with the initial report:  
• 
Patient number 
• 
Patient: date of birth, ethnic origin 
• 
Name of investigator and investigating site 
• 
Period of administration 
• 
The suspected investigational medicinal product (IMP) 
• 
The adverse event assessed as serious 
• 
Concomitant disease and medication 
• 
Relevant medical history 
• 
Short description of the event and outcome 
• 
Description 
o Onset and if applicable, end  
o Therapeutic intervention  
o Causal relationship to each of the study drugs (for definition see: 8.2.1.) 
o Hospitalization or prolongation of hospitalization  
o Death, life-threatening, persistent or significant disability or incapacity  
 
This insight from the investigator is very important for the Sponsor to assess the safety of the 
IMP and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner.  
In case of a new development of the event, the initial report should be followed by the follow-
up report, indicating the outcome of the SAE. 
A copy of the reports will be provided to AOP Orphan Pharmaceuticals for safety records. 
 
SUSARs need to be reported and followed up in the same manner as SAEs. The Sponsor 
decides if the event needs to be classified as a SUSAR in discussion with the investigator. 
Therefore, detailed information about the event and the subsequent actions should be made 
available within 24 hours by the investigator and any relevant updates should be reported 
within 24 hours. SUSARs will be reported to the required regulatory authorities, 
investigators/institutions, and ethical committees in compliance with all reporting 
requirements according to local regulations and good clinical practice by the Sponsor and/or 
its designees. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 83/107 
 
After informed consent has been obtained but prior to initiation of the study drug, only SAEs 
considered to be related to a protocol-mandated intervention should be reported (e.g. SAEs 
related to invasive procedures such as withdrawal of blood).  
 
Follow Up of Serious Adverse Events and SUSARs 
For SAEs, SUSARs and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details and 
outcome information (e.g. from hospital discharge summaries, consultant reports, autopsy 
reports) in order to perform an independent medical assessment of the reported case.  
An SAE and SUSAR will be followed until it has resolved, has reached a stable state, the 
investigator determines that it is no longer clinically significant, or the patient is lost to follow 
up.  
If an SAE or SUSAR of a participant is still ongoing at the end of the study, follow up will be 
provided until resolution/ a stable level is achieved, or until the SAE or SUSAR is no longer 
clinically significant by the judgement in the investigator, or until the patient is lost to follow 
up. In the latter the investigator has to take all possible actions in the discretion of his 
judgement to contact the patient. A loss of follow-up should be documented in the source 
documents.  
In case the IMP was withdrawn due to an SAE or SUSAR, patients will be advised to come to 
the hospital as soon as possible for an Early Termination Visit (see 5.5). A Safety Follow-Up 
Visit should be performed 2 weeks + 2 days after the last intake of study medication (if the 
Early Termination Visit occurs not longer than 5 days after the discontinuation of the study 
medication). (see 5.4) The patient should be followed up until he/she has recovered/ it has 
resolved, has reached a stable state, the investigator determines that it is no longer clinically 
significant, or the patient is lost to follow up. 
 
8.11 Review and Annual report on Adverse Events, 
Serious Adverse Events and Suspected Unexpected 
Serious Adverse Reactions 
Data from this study will be reviewed periodically by the Sponsor or a designee to detect any 
safety concern(s) related to the study drug as early as possible so that the investigators, 
regulatory authorities, and IRB/IEC will be informed appropriately and as early as possible.  
SAEs will be reviewed ongoing and reconciliations will be performed in collaboration with the 
Sponsor of the study.  
If necessary, additional safety measurements can be implemented during the course of the 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 84/107 
study after approval by the local IRB/IEC and regulatory authorities. 
Once per year, the Sponsor or principal investigator will supply a report on the safety of trial 
subjects with all available relevant information concerning patient safety during the reference 
period to the competent supreme federal authority where the trial is being conducted. This 
report will also be supplied to the responsible ethics committee. 
The annual safety report will be compiled according to the corresponding ICH guideline E2F 
„Development Safety Update Report – DSUR“. 
The data lock point for the patient data to be included and analyzed is the day of the overall 
approval of the clinical trial. 
The Sponsor or principal investigator will supply the report within 60 days of one year after 
the reference date (data-lock point).  
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 85/107 
9 
Documentation 
The accomplishments of the study in agreement with the GCP-guidelines and the 
investigational plan as well as the accuracy of all data documented in the CRF are the 
responsibility of the Investigator. All collected data of this study have to be recorded on the 
CRF and/or the patient´s record by appropriate authorized persons. This also includes data 
of patients who dropped-out of the study. It has to be assured that all persons authorized for 
CRF entries can be identified. A list with signatures and identification codes of the persons 
must be archived in the ISF and TMF. Moreover, logs according to ICH E6 (e.g. 
Signature/Delegation/Screening/Drug Accountability log) will be implemented and maintained 
by the investigator. 
The investigator records the participation of a patient on a special identification list of patients 
(Screening Log). This list gives the possibility for a later identification of the patients and 
contains the patient number, full name, date of birth and the date of the enrolment into the 
study. The identification list of patients remains in the study center after the closure of the 
study. Additionally, the participation of the patient in this clinical study has to be recorded in 
the patient`s medical record. 
Each patient will receive a unique patient identification number. Data will be documented 
using this code for each patient that will also be used for communication with the Sponsor 
and other authorities. Only the Investigator and his/her designees will be able to connect the 
number and the patient´s name. Data collection must be completed for each subject which 
has signed an ICF and was administered study drug. 
Patient´s data will be stored on-site in a locker to which only the investigator and his/her 
designees have access. Personal patient information (such as name, date of birth etc.) is 
stored separately from the research data. 
For all work involving data collections of human information, electronic or otherwise, 
the study centre will adhere to the law as laid down in the European Regulation (EU) 
2016/679 (Regulation (EU) of the european parliament and of the council of 27 April 2016 on 
the protection of natural persons with regard to the processing of personal data and on the 
free movement of such data, and repealing Directive 95/46/EC (General Data Protection 
Regulation)) as well as national data protection law. These concern the protection of 
individuals with regard to the processing of personal data and on the free movement of such 
data. Adequate measures to ensure data protection, confidentiality will be duly taken into 
account by the Investigators and all parties involved in the study. 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 86/107 
9.1 Data Recording (Case Report Form, CRF and 
Patient´s Record) 
In this study, a Case Report Form (CRF) will be used for direct entry of the assessments of 
the scales used and for the telephone calls. Demographic data, medical history, neurological 
and PD history, medication history (including anti-parkinson´s disease medication), adverse 
events (including SAEs, SUSARs, ADRs), concomitant medication, the assessments of Vital 
Signs, and the neurological and physical examination will be provided at the Screening Visit 
in the CRF. The patient´s record will be used to document the date and identification of the 
visit, the investigator(s) conducting the visit, the process of Informed Consent (the description 
of the process of informed consent, the person conducting Informed Consent, the date, time, 
and version of ICF), the time and date of all the assessment of the clinical scales, the time 
and date of blood samples and urinalysis, the time and date of ECG analysis, protocol 
deviations (including actions), and the Drug Accountability (for returned and assigned kits). 
The results of blood samples, urinalysis and ECG will be kept in the patient´s file. 
 
The CRFs and the patient´s records are established to implement the Clinical Study Protocol, 
to facilitate subject observation and to record subject and IMP data during the clinical 
investigation according to the trial´s protocol. In this study, they exist as printed or written 
documents and are direct-entry CRFs.  
 
In the patient´s record and the CRFs, the following data should be documented: 
• 
the date and identification of the investigation, including the version number of the 
Clinical Study Protocol; 
• 
identification of the subject, date of enrolment, demographic data (at the Screening 
Visit); 
• 
identification of the IMP by lot number and kit number (if applicable); 
• 
medical diagnosis for which the subject is to be treated with the IMP to be 
investigated together with any concomitant illness (at the Screening Visit); 
• 
subject compliance information for concurrent procedures measures and for any 
emergency; 
• 
relevant previous medication and/or procedures (at the Screening Visit only); 
• 
subject baseline characteristics (at the Screening Visit only); 
• 
concomitant medication and/or procedures; 
• 
compliance with the inclusion/exclusion criteria; 
• 
dated clinical and non-clinical findings according to the Clinical Study Protocol; 
• 
procedural data; 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 87/107 
• 
subject assessment during the use of the IMP and follow-up with dates; 
• 
reported adverse events and adverse effects with dates; 
• 
date of the end of follow-up; 
• 
signature(s) of the clinical investigator(s) at the completion of follow-up 
 
Therefore, the CRF and the medical record of the patient will be a source document in this 
study.  
Only the use of ballpens is allowed for the entry in paper-based records. Corrections have to 
be made in a way, that the previous entries remain readable (the use of any instrument of 
correction is not allowed). Corrections have to be signed and dated by the authorised person, 
who made the corrections. Data, which are not available or were not collected, have to be 
clearly identifiable as such (NA). The reasons should be documented, if necessary. 
The investigator assures, that all data of patients are recorded immediately, readable, 
completed, and correct in the patient´s chart and in the CRFs. 
After the end of the study (end of the study defined as the last visit of the last patient) and 
after the verification regarding the plausibility and completeness by the Monitor, all 
documents and data relating to the study will be kept in an orderly manner by the investigator 
in a secure study file. Source data will be stored for 30 years (for medical records and other 
original data) after the end of the study (i.e. last visit of the last patient) according to local and 
national regulatories. It is the responsibility of the investigator to inform the Sponsor before 
study related documents will be destroyed. 
 
Monitors, auditors, and other authorized agents of the Sponsor or its designee, the EC/IRB 
approving the research, local law regulatory agents and appropriate authorities in conducting 
investigations for which the person´s medical history is necessary will be granted access to 
the study subject´s original medical records without violating the confidentiality of the subject 
to the extent permitted by the law and regulations. In any presentation of the results of this 
study or in publications, the subject´s identity will remain confidential. 
 
9.2 Trial Folders 
The trial folders should serve as gapless documentation. Individually or together they should 
allow the evaluation of the trial implementation as well as quality of data. 
9.2.1 Trial Master File (TMF) 
The paper-based TMF, established at the beginning of the trial and secured in a safe place, 
contains all essential documents that demonstrate that the trial is conducted in accordance 
with regulatory requirements and ICH GCP. All documents will be maintained and updated 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 88/107 
as appropriate throughout the trial. Previous versions of the documents must be retained in 
the TMF and will be clearly labelled as outdated. Previous versions will be relocated in a 
section for outdated documents. The TMF is archived at the end of the study for 15 years.  
 
9.2.2 Investigator Site File (ISF) 
The paper-based ISF, established at the beginning of the trial will be secured in a safe place 
(the file is provided to the site at the site initiation visit). It contains all essential documents 
maintained by the PI. All documents will be maintained and updated as appropriate 
throughout the trial. Previous versions of the documents must be retained in the ISF and will 
be clearly labelled as superseded-previous versions will be relocated in a section for 
outdated documents. Within each monitoring visit, the ISF will be checked for actuality and 
completeness in accordance to the formalities. After completion or discontinuation of the 
study this ISF has to be kept for 15 years. 
 
9.3 Data Storage 
9.3.1 Storage duties of the Sponsor 
The Sponsor has to keep all study-relevant documents of the clinical study after completion 
or discontinuation of the study for a minimum of 15 years. 
9.3.2 Storage duties of the investigator 
The Investigators have to keep all records and documents, which are related with the study 
or the allocation of investigational medicinal products (e.g. data entry form, consent form, list 
of the allocations of investigational medicinal products and further relevant documents), for a 
minimum of 15 years. Medical records and other source data (e.g. paper-based CRF) have 
to be kept for 30 years. 
 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 89/107 
10 Data Management 
Data are administered and processed by members of the study team with the support of the 
software Microsoft Word, Excel, and IBM SPSS Statistics. 
The evaluation of the data takes place by the programmed range-, validity- and consistence 
checks. In addition to that a manual/visual evaluation of the plausibility in accordance with 
the requirements of the GCP is performed. Queries may occur, which will be forwarded to the 
investigator by the Monitor of the study. By means of the queries the investigator has to 
evaluate and respond to the accrued discrepancies. After the record of all entries and 
clarification of all queries, the data based will be closed at the completion of the study. This 
performance has to be documented. 
 
11 Protocol Deviations 
All deviations to the study protocol have to be documented in the patient´s record with the 
explanation for variance. Deviations have to be announced to the Sponsor, who is 
responsible for their evaluation, within 24 hours after receipt of knowledge. The report should 
include the patient´s study code, sex, year of birth, a brief description of the event, the cause 
of it (if applicable), the time, the date, the duration of the event, and the corrective and 
preventive measurements performed. Protocol Deviations will be reported to the Sponsor to 
decide if the patient will be discontinued in the study or not. 
The Sponsor can terminate a trial during the course of it, whenever a reason for concern 
appears. The Sponsor or the investigator can discontinue a patient´s participation in the trial 
on their behalf (for criteria see 4.3). Reasons for termination of a trial or of a study participant 
have to be documented in the patient´s record or other source documents. In case of a 
security termination, the test person has to be further monitored. Deviations have to be 
analyzed whether changes of the clinical investigation plan or the closure of the study are 
necessary. If necessary, the ethics committee or the responsible authorities have to be 
informed.  
 
In case of a withdrawal from the study, the data will be included in the analysis up to the time 
of discontinuation.  
 
 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 90/107 
12 Statistical Analysis 
12.1 Determination of Sample Size 
This is a phase 2 randomized clinical trial that uses an enriched enrolment randomized 
withdrawal design to evaluate the effects of continuous nabilone therapy versus withdrawal 
to placebo in patients with PD suffering from NMS. This design has the advantage that the 
patient population enrolled is enriched by including only responders. (48) Moreover, 
exposure of patients to placebo during the withdrawal phase may be shorter than in a 
randomized treatment phase. 
The power calculation refers to the primary endpoint of the study, i.e. change of MDS-
UPDRS Part I score from randomization to Week 4 during the placebo-controlled, double-
blind, parallel-group randomized withdrawal phase (i.e. phase 2 of the study). A total of 38 
patients (19 in each group) will have 80% power to detect a probability of 0,231 that an 
observation in Group 1 is less than an observation in Group 2 using a Wilcoxon (Mann-
Whitney) rank-sum test with a 0,050 two-sided significance level. With this, a statistically 
significant difference in the change from randomization to Week 4 in MDS-UPDRS Part I 
score between nabilone and placebo will be detected if the true difference is 2.5 points. In 
the absence of previous data, we empirically chose as clinically meaningful a 2.5 units 
change from randomization to the visit at 4 weeks (in phase 2) This sample size calculation 
assumes a standard deviation of the change from randomization to week 4 to be 2.4 points. 
(46) Assuming a drop-out rate of 25%, we plan to include around 48 patients with 
Parkinson´s disease in this trial. The sample size calculation was performed with the 
Program nQuery Advisor (Version 7). 
Importantly, although a sample size calculation is provided, this is an exploratory study 
evaluating different NMS domains. Therefore, corrections for multiple comparisons are not 
planned. 
12.2 Study 
Populations: 
Datasets 
or 
Populations 
analyzed 
The primary analysis will be performed including all randomized subjects with scoring of 
MDS-UPDRS Part I at randomization and 4-week follow-up. The subjects will be grouped 
according to the randomized treatment group (nabilone or placebo) and all summaries and 
efficacy analysis will be based on the set. In case of a drop-out, no interpolation can be 
performed. Therefore, the primary analysis is a per-protocol analysis.   
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 91/107 
 
Safety and tolerability summaries will be based on a safety set which will include all patients 
receiving at least one dose of study medication during the randomized trial phase. The 
subjects will again be grouped by their assigned treatment group during the study. The safety 
set will be used for summaries of safety and tolerability. Additionally, summaries of baseline 
and demographic data will be produced out of the safety set. 
12.3 Background and Demographic Characteristics 
All baseline and demographic summaries will be produced for the data of patients gained at 
the Screening Visit. The data will be given for participants being randomized in V 0. 
 
The number and characteristics of patients in every safety set, the number and 
characteristics of patients assigned to a specific treatment group, the number of AEs, SAEs 
and SUSARs with description, the number of subjects with premature discontinuation from 
the study/or the study drug along with reasons for discontinuation will be provided. 
Furthermore, the number of screened subjects, the number of screening failures and reasons 
why they have been excluded will be given. 
 
A consort diagram will be provided. 
12.4 Efficacy Variables and Analysis 
This is a phase II randomized clinical trial that uses an enriched enrolment randomized 
withdrawal design to evaluate the effects of continuous nabilone therapy versus withdrawal 
to placebo in patients with PD suffering from NMS followed by an open-label treatment 
phase. The primary and key secondary efficacy criteria refer to the randomized, double-blind, 
placebo-controlled enriched enrolment randomized withdrawal phase of the study. Data 
analysis will be performed using IBM SPSS Statistics Software and Microsoft Excel. 
 
Results of the changes of all clinical scales in this trial will be shown in a descriptive way by 
median and interquartile range (quartile 1, quartile 3), separately for the nabilone and 
placebo of the clinical trial. Mean and standard deviation for the descriptive analysis of the 
two study arms will also be provided. P-values for the change of the results will be given. 
The primary efficacy criterion will be measured as the change of the MDS-UPDRS Part I 
between baseline (i.e. randomization) and week 4. The key secondary efficacy criteria will be 
measured as the change in the other clinical scales and questionnaires between baseline 
and week 4, except for the CGI-I measures, which will be singularly evaluated at week 4. 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 92/107 
Because an interpolation of data will not be performed in case of a drop-out, the primary 
analysis is a per-protocol analysis. 
 
For the study’s primary efficacy and key secondary efficacy analyses, mean changes from 
randomization to 4-week follow-up in the nabilone and placebo groups will be analyzed 
separately for the two groups by Wilcoxon matched-pairs test and then compared by Mann-
Whitney U test. (49) 
 
For all analyses, statistical significance will be set at the 2-sided 5% level. Additionally, a 
sensitivity analysis will be performed for a primary efficacy or key secondary efficacy 
variable, if mean value of an efficacy variable should be different at randomization at a 2-
sided 10% level (using Mann-Whitney U tests). To estimate the treatment effect, we will then 
compare mean change from randomization to 4 weeks-follow-up in both treatment groups 
using analysis of covariance, with value at randomization as covariate and treatment group 
as main effect.  
Moreover, sensitivity to treatment will be assessed using effect sizes of the different outcome 
variables when using nabilone to treat non-motor symptoms in Parkinson´s disease.  
For CGI analyses, distributions of aggregated ratings (amelioration, aggravation) in the 
nabilone and placebo groups at 4-week´s- Termination Visit will be compared by Fisher exact 
test. (49) 
All other analyses on the exploratory efficacy criteria will be performed with paired Wilcoxon 
signed-rank tests separately for the two treatment groups and compared by Mann-Whitney U 
tests. (49) 
 
12.5 Safety Analysis 
The primary safety analysis will be performed with the safety data set. Distributions of AEs, 
SAEs, and SUSARs in the nabilone and placebo groups at week 4 will be compared by 
Fisher exact test. Additionally, a safety analysis will be performed on all events as well as the 
hallucination item, orthostatic hypotension item and day-time sleepiness item of Part I of 
MDS-UPDRS occurring through the overall study. This will be a descriptive analysis reporting 
overall number and frequencies of the item´s points score, AEs, SAEs, and SUSARs in 
patients taking nabilone or placebo. Data will be presented separately for the nabilone and 
placebo group.  
Separate summaries of AEs in regard of severity and relationship to the study drug, separate 
summaries of AEs leading to withdrawal from the study and separate summaries for SAEs 
will be provided. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 93/107 
Tolerability measures will be provided in a descriptive analysis and will include the number of 
patients who discontinued from the study (%) and the number of patients who discontinued 
from the study due to an AE (%).  
Safety measures include vital signs including performance of active orthostatism, a 12- lead 
ECG, the hallucination item (1.2, 0 – 4 points) of MDS-UPDRS Part I, the orthostatic 
hypotension item (1.12, 0 – 4 points) of MDS-UPDRS Part I, the Daytime sleepiness item 
(1.8, 0 – 4 points) of MDS-UPDRS Part I, and the C-SSRS. All patients will therefore be 
questioned about the occurrence of an AE at each scheduled and unscheduled on-site visit 
or telephone visit. 
Vitals signs including performance of active orthostatism will be taken at any scheduled visit 
on-site. (see 7.2) In the latter the heart rate and blood pressure of the patient will be 
measured after 10 minutes of quiet resting in a supine position and at 1, 2, 3, 5, and 10 
minutes - time points of active standing. 
Clinical examination, ECG, and laboratory assessment including urinalysis and urine 
pregnancy test for women of childbearing potential will be executed at the Screening Visit 
(laboratory assessment and ECG if not performed within 4 weeks prior to Screening), the 
Baseline Visit (clinical examination only), the Termination Visit, an Early Termination Visit (if 
applicable), and the Safety Follow-Up Visit (except for ECG, laboratory testing and 
urinalysis). 
For the Eye-tracking analyses, mean changes from Screening Visit to the Termination Visit in 
the nabilone and placebo groups will be analyzed separately for the two groups by Wilcoxon 
matched-pairs test and then compared by Mann-Whitney U Test.  
 
12.6 Handling of Missing Data 
After withdrawal of study drug treatment, all patients will perform an ET visit. All withdrawals 
from the study or the study drug will be included in the safety analysis up to the time of 
discontinuation regardless of the duration of their participation. In case of a drop-out, no 
interpolation can be performed. Therefore, the primary analysis is a per-protocol analysis. 
 
 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 94/107 
13 Quality Management 
Training, monitoring and audits are performed for quality assurance reasons within this 
clinical study. Monitoring and auditing procedures developed or endorsed by the Sponsor will 
comply with ICH-GCP guidelines and local legal requirements to ensure acceptability of the 
study data and patient´s safety.  
 
13.1 Qualifications 
The Sponsor is responsible for selecting the investigator and Institution. Each investigator 
should be qualified by training and experience and should have adequate resources. Each 
individual involved in conducting a trial should be qualified by education, training and 
experience to perform his or her respective task(s) (see ICH GCP E6). 
To meet those objectives, every member of the study team must be GCP-trained. A 
Certificate of MDS-UPDRS Training, a C-SSRS Training Certificate, and experience in using 
the other scales (e.g. MMSE) must be provided by every investigator in the trial who intends 
to use these scales. The members of the study team must be trained on the trial´s protocol 
and the completion of the source data entry (CRF and patient´s record) by the principal 
investigator. This process has to be documented in the ISF. Authorization of a member of the 
study team to perform study related tasks have to be reported in the Delegation Log of the 
ISF. 
 
13.2 Monitoring 
A study monitor will perform source document verification at regular intervals in accordance 
with GCP and ICH guidelines. The objectives of the monitoring procedures are to ensure that 
the trial subject’s safety and rights as a study participant are respected, that accurate, valid 
and complete data are collected, used, and stored, and that the trial is conducted in 
accordance to the trial protocol, the principles of GCP and local legislation. 
All investigators agree that the monitor regularly visits the trial site. For monitoring, all study-
related documents must be given access to the monitor by the investigator for confirmation of 
data. Moreover, the investigators assure that the Monitor will receive appropriate support in 
their activities at the trial site, as agreed in separate contracts.  
The Informed Consent Form (ICF) includes a statement that the Monitor has the right – while 
observing the provisions of data protection legislation – to compare CRFs with the trial 
subject’s medical records (doctor’s notes, ECGs, laboratory printouts etc.).  


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 95/107 
A study specific monitoring plan will be established and the study will be monitored with the 
agreed plan. 
All representatives from regulatory authorities and the EC/IRB will be gained access to the 
study-related documents needed for their investigation. Protection of the patient´s personal 
data will be guaranteed to the extent possible. 
 
13.3 Audits and Inspections 
During the course of a study, a Quality Assurance audit or inspection can be performed by 
regulatory authorities, the ethics committees, or the Sponsor’s delegates. Therefore, the 
investigator has to grant direct access to all data and must provide support at all times. 
The aim of an audit is to verify the validity, accuracy and completeness of data, to establish 
the credibility of the clinical trial, and to check whether the trial subject’s rights and trial 
subject safety are being maintained. The Sponsor may assign these activities to persons 
otherwise not involved in the trial (Auditors). These persons are allowed access to all trial 
documentation (especially the trial protocol, CRFs, trial subject´s medical records, drug 
accountability documentation, and trial-related correspondence). 
After each external audit an audit-certificate by the Auditor has to be delivered to the 
investigator. This certificate has to be kept in the ISF to evidence the audit to the regulatory 
authorities in the case of an inspection by them. The audit-report is delivered to the Sponsor 
of the study. An audit-certificate will be attached to the final report at the end of the study. 
Additionally, according to the Austrian Medicines Law (AMG) audits and inspections by 
regulatory authorities may be performed. 
All persons conducting audits undertake to keep all trial subject data and other trial data 
confidential. 
 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 96/107 
14 Reporting 
14.1 Annual Progress Reports  
The Sponsor/investigator will submit a summary of the progress of the trial to the accredited 
EC and to the competent supreme federal authority (if applicable) once a year. Information 
will be provided on the date of inclusion of the first subject, numbers of subjects included and 
numbers of subjects that have completed the trial, data of safety of the trial subjects including 
serious adverse events/ serious adverse reactions, other problems, protocol deviations and 
amendments.  
The annual safety report will be compiled according to the corresponding ICH guideline E2F 
„Development Safety Update Report – DSUR“. 
The data lock point for the patient data to be included and analyzed is the day of the overall 
approval of the clinical trial. The Sponsor or principal investigator will supply the report within 
60 days of one year after the reference date (data-lock point).  
 
14.2 Final Study Report 
The end of the study is defined as the last visit of the last patient of the study (LPLV).  
On completion of the study, the EC/IRB, and the regulatory authorities will be notified that the 
study has ended. Within one year after the end of the study, the investigator/Sponsor will 
submit a final study report with the results of the study, including any publications/abstracts 
of the study, to the accredited EC/IRB.  
All information regarding this clinical study has to be kept in confidence. The statistical 
analysis and the integrated final study report will be prepared according to ICH E6 and 
finalized within 12 months after the last patient´s last visit (LPLV) took place. The final study 
report will be reviewed and signed by the Sponsor, the principal investigator and all further 
responsible persons. All information in that report is strictly confidential.  
The principal investigator will sign the final study report of the clinical trial. This confirms that 
the report describes implementation and results of the clinical trial by the best of his 
knowledge.  
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 97/107 
15 Publication 
The results of this study will be published according to the principles of publication policy. 
There are no arrangements on publication issues with subsiding parties.  
 
 
 
16 Amendments 
Amendments must be submitted to the appropriate regulatory authorities and ethical 
committees. Substantial amendments may be implemented only after approval of both 
parties has been obtained. Urgent amendments that are intended to eliminate an apparent 
immediate hazard to subjects may be implemented prior to receiving approval.  However, 
approval must be obtained as soon as possible after implementation. Therefore, the Sponsor 
or its designee must inform the regulatory authority and the EC about the new events, the 
measures taken and their plan for further action as soon as possible. The procedure should 
be held as follows: immediate telephone contact, followed by an e-mail or FAX notice, 
followed by a follow-up letter. 
 
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 98/107 
17 Ethical and Regulatory Aspects 
Ethical Conduct of the Study 
Ethics committee (EC) authorization for this study will be required. The project raises 
important issues of consent, confidentiality, data security, quality control, and national data 
protection legislation. To protect the information on each participating individual, protect 
privacy, and prevent misuse of data, all investigators and all parties involved in this study will 
adhere to national codes and rules for working with participant’s clinical data. Participants will 
be labeled in a coded fashion with unique identifiers. Data will be held secure and 
confidential and kept apart from personal identifiers. 
The project will be conducted in strict adherence to the Convention for the Protection of 
Human Rights and Fundamental Freedoms, and EU regulations on ethical issues including 
Regulation (EU) 2016/679  on the protection of individuals regarding the processing of 
personal data and the free movement of such data and the Directives 2001/20/EC, and 
2005/28/EC relating to implementation of good clinical practice in the conduct of clinical 
trials. 
Regulatory Requirements 
The present study will be conducted in compliance with Good Clinical Practices (ICH-E6: 
GCP recommended for adaptation on 1st of May 1996 by the ICH Steering Committee), the 
Declaration of Helsinki in its latest version concerning the conduct, evaluation and 
documentation of the study, the “Charter of Fundamental Rights” of the European Union 
(2000/C 364/01), the local laws and regulations and the applicable regulatory requirements.  
 
When conducting a clinical trial on drugs for use in humans in Austria the Medicines Act 
(“Arzneimittelgesetz”, AMG) has to be considered. This Act implemented the European 
Directives 2001/20/EC and 2005/28/EC into national law. In particular, section III (Clinical 
Trials) is relevant for the conduction of a clinical trial. 
 
17.1 Responsibilities of the Sponsor and the investigator 
The Sponsor of this clinical trial will assume responsibility for inducement and organization of 
the implementing trial according to the AMG. The procedures set out in this study protocol 
are designed to ensure that the Sponsor and the investigator abide the principles of ICH E6 
recommended for adaptation on 1st of May 1996 by the ICH Steering Committee and the 
Declaration of Helsinki concerning the conduct, evaluation and documentation of the study. 
The study will also be performed adhering the local legal conditions and requirements. Each 
investigator has to confirm this by signing the study protocol. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 99/107 
Responsibilities of the Sponsor:  
• 
Verification of the understanding of the Investigator´s Brochure or the described study 
medication 
• 
Verification of the understanding of treatment schedule 
• 
Ensuring for enough time and capacity for the implementation of this study 
• 
Correct collection and documentation of data, reporting 
• 
Provision of all data to the Sponsor, monitor or relevant authorities for audits or 
inspections 
• 
Assurance for the confidential handling of patient´s data and information 
The principal investigator accepts the responsibility for the implementation of this clinical trial 
at this study site according to the AMG.  
 
17.2 Approval and Consent 
Independent Ethics Committee or Institutional Review Board 
Before initiation of the study, the conduct of the study will be submitted to our local Ethics 
Committee (EC) / Institutional Review Board (IRB). Written approval of the study, the 
protocol, the Informed Consent Form (ICF), all questionnaires, and all other relevant study 
documentation must be obtained before the first patient will be screened and the study drug 
is released to the investigator. Any necessary extensions or renewals of EC/IRB approval 
must be obtained for changes to the study such as amendments to the protocol, the ICF or 
other study documentation. The written approval of the EC/IRB together with the approved 
ICF must be filed in the study files. 
The investigator will report promptly to the EC/IRB any new information that may 
adversely affect the safety of the participants or the conduct of the study. The investigator will 
submit written summaries of the study status to the EC/IRB as required. On completion of the 
study, the EC/IRB will be notified that the study has ended. End of the study is the time when 
the last visit of the last patient has been performed (LPLV). 
 
Regulatory Authorities 
All relevant study documentation will be submitted to the regulatory authorities according to 
local/national requirements, for review and approval before initiating the study.  
On behalf of the AMG in Austria, the Sponsor of the clinical trial submits the application to 
the competent ethics committee (EC) and the competent authority (CA). The CA reviews only 
the justification for and the relevance of the Clinical Trial. The EC acts as the “expert 
reviewer” for the CA and decides within 35 days, with only one “clockstop” possible to obtain 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 100/107 
supplementary information. If the EC vote is negative, the CA issues a legal document 
(“Bescheid”) prohibiting the clinical trial. 
On completion of the study (LPLV), the regulatory authorities will be notified of the end of the 
study. 
 
Informed Consent 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s) and must adhere to GCP. 
No subject will undergo any study related examination or activity in the responsibility of the 
investigator before he/she has given written informed consent to participate in the study. 
The investigator or designee explains orally and in writing manner the nature, the duration, 
the importance, the relevance, the purpose of the study, the consequences, and the action of 
the drug in such a manner that the patient and a study partner (if applicable) are aware of 
potential risks, inconveniences, and adverse events of the study and the study drug. It should 
also be straightened out that the subject is free to choose to take part in the study or to 
withdraw from participation without consequences for his/her further care. The patient should 
be given the opportunity to ask for clarification of any points he/she does not understand and, 
if necessary, ask for more information. At the end of the interview, the subject will be given 
ample time to consider his/her participation in the study. Subjects and the investigator will be 
required to sign and date the ICF. After signatures are obtained, the ICF will be kept and 
archived by the investigator in the investigator’s site file. A signed and dated copy of the 
Patient Information and Informed Consent Form will be provided to the patient.  
If new information becomes available that may be relevant to the subject’s willingness 
to continue participation in the study, a new ICF will be approved by the EC/IRB (and 
regulatory authorities, if required). The study subjects will be informed about this 
new information and re-consent will be obtained. 
 
Risks and Benefits   
Benefits: The patients participating in the study will receive specialized care and regular 
clinical monitoring. The results of this trial will be useful to evaluate the effect of nabilone on 
non-motor symptoms in PD. Moreover, management of NMS are an important area of unmet 
need in PD. Due to the overall impact of NMS in PD and based on the influence of the 
endocannabinoid system on NMS in broad manner in PD, we perform this trial of nabilone in 
PD patients. Hopefully, a symptomatic improvement of the patient´s clinical condition could 
be achieved. 
Risks: Disadvantages of participation could be the additional time spent in the hospital, the 
withdrawal of blood, currently unknown risks of the study drug therapy, or allergies to 
components of the IMP the patient is unaware at inclusion in the study. 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 101/107 
Patients will receive either nabilone or placebo. Treatment care in the study population will 
not be affected by the trial because nabilone will be used as an add-on therapy. 
Generally, nabilone is well tolerated. Common adverse reactions (>1/100 to <1/10) observed 
in patients are somnolence, vertigo, euphoria, ataxia, impaired vision, difficulties to 
concentrate, sleep disturbances, dysphoria, a headache, hypotonia, nausea, and a dry 
mouth. Controlled trials with patients taking nabilone showed that at least one side effect 
occurred per subject. Most patients develop a tolerance in regard of adverse events 
concerning the CNS and therefore somnolence and euphoria reside after some weeks. This 
effect is reversible. The potential to cause mental addiction is unknown and no patient has 
shown withdrawal symptoms in clinical trials.  
Minor risks of nabilone (>1/10.000 to <1/1.000) include confusion, disorientation, 
hallucination, psychosis, depression, difficulties in coordination, tremor, loss of appetite, 
anxiety, depersonalisation, tachycardia, and abdominal pain.  
All AEs will be rapidly detected by close clinical monitoring. In case of an AE the patient 
should be followed up until he/she has recovered/ it has resolved, has reached a stable 
state, the investigator determines that it is no longer clinically significant, or the patient is lost 
to follow up. Study treatment will be stopped in the discretion of the investigator and 
appropriate measurements, reporting, and visits on-site will be performed. 
These controlled risks must be balanced against the prospect of identifying a new 
therapeutic option for non-motor symptoms in PD. 
There are no known risks in relation to the Eye-tracking analysis. 
 
17.3 Patient Insurance 
During their participation in the clinical trial the patients will be insured as defined by legal 
requirements. The Sponsor is providing insurance in order to indemnify (legal and financial 
coverage) the investigator/trial center against claims arising from the study, except for claims 
that arise from malpractice and/or negligence. The compensation of the subject in the event 
of study-related injuries will comply with the applicable regulations. 
This insurance covers for damage to research subjects through injury or death caused by the 
study. The insurance applies to the damage that becomes apparent during the study. 
 
17.4 Data Protection and Confidentiality 
All local legal requirements regarding data protection will be adhered to. All study findings 
and documents will be regarded as confidential. The investigator and members of the 
research team must not disclose any information without prior written approval from the 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 102/107 
Sponsor. The pseudonymity of patients participating must be maintained. Throughout 
documentation and evaluation, the patients will be identified on CRFs and other documents 
by an ascending number according to their order of screening. Documents that identify the 
patient personally (e.g., the signed informed consent, patient identification list, patient´s 
record) must be maintained in confidence by the investigator. The patients will be informed in 
the ICF that all study findings will be stored in a locked cabinet and on computer and handled 
in strictest confidence. 
17.5 Discontinuation of the Study by the Sponsor 
The Sponsor or its representative is authorized to temporary hold or discontinue the study for 
any reason and at any time decided.  
The investigator/Sponsor will notify the accredited EC/IRB of the end of the study (LPLV). 
The Sponsor or its representative will notify the EC/IRB immediately of a temporary halt of 
the study, including the reason of such an action. In case the study is ended prematurely, the 
Sponsor or its designee will notify the accredited EC/IRB within 15 days, including the 
reasons for the premature termination.  
 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 103/107 
18 References 
1. Iannotti FA, Di Marzo V, Petrosino S, Endocannabinoids and endocannabinoid-
related mediators: Targets, metabolism and role in neurological disorders. Progress 
in lipid research, 2016. 62: p. 107-128 
2. Hui-Chen, Mackie K, An Introduction to the Endogenous Cannabinoid System. 
Biological Psychiatry, 2016. 79: p. 516-525 
3. Turu G, Hunyady L, Signal transduction of the CB1 cannabinoid receptor. J. Mo 
Endocrinol, 2010. 44: p. 75-85 
4. Di Marzo V, De Petrocellis L, Why do cannabinoid receptors have more than one 
endogenous ligand?. Philos Trans R Soc Lond Ser B Biol Sci, 2012. 367: p. 3216-
3228 
5. Stella N, Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and 
astrocytomas. Glia, 2010. 58: p. 1017-1030 
6. Matias I, Di Marzo V, Endocannabinoids and the control of energy balance. Trends 
Endocrinol Metab, 2007. 18: p.27-37 
7. Izzo AA, Cannabinoids and intestinal motility: welcome to CB2 receptors. Br J 
Pharmacol, 2004. 142: p. 1201-1202 
8. Pertwee RG, Receptors and channel targeted by synthetic cannabinoid receptor 
agonists. Curr Med Chem, 2010. 17: p. 1360-1381 
9. Melis M, Pistis M, Endocannabinoid signaling in midbrain dopamine neurons: more 
than physiology?. Curr. Neuropharmacol., 2007. 5: p. 268–277 
10. Maccarrone M, Gubellini P, Bari M, Picconi B, Battista N, Centonze D, et al., 
Levodopa treatment reverses endocannabinoid system abnormalities in experimental 
parkinsonism, J. Neurochem, 2003. 85: p. 1018–1025 
11. García C, Palomo-Garo C, García-Arencibia M, Ramos J, Pertwee R, Fernández-
Ruiz J, Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ-
THCV in animal models of Parkinson's disease. Br J Pharmacol, 2011. 163: p. 1495–
1506 
12. Kluger B, Triolo P, Jones W, Jankovic J, The Therapeutic Potential of Cannabinoids 
for Movement Disorders. Movement Disorders, 2015. 30, p. 313-327 
13. Kalia LV, Lang AE, Parkinson´s disease. The Lancet Neurology, 2015. 386(9996): 
p.896-912 
14. Braak H, de Vos RA, Bohl J, Del Tredici K, Gastric alpha-synuclein immunoreactive 
inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's 
disease-related brain pathology. Neurosci Lett., 2006. 396: p.67-72. Epub Dec 2005 
15. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E, Staging of 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 104/107 
brain pathology related to sporadic Parkinson's disease. Neurobiol Aging, 2003. 24: 
p.197-211 
16. Poewe W, The natural history of Parkinson's disease. J Neurol., 2006. 253 Suppl 7: 
VII2-6 
17. Hely MA, Morris JG, Reid WG, Trafficante R, Sydney Multicenter Study of 
Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years. Mov 
Disord., 2005. 20: p.190-199 
18. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG, The Sydney multicenter 
study of Parkinson's disease: the inevitability of dementia at 20 years. Mov Disord., 
2008. 23: p.837-44. doi: 10.1002/mds.21956 
19. Pfeiffer RF, Non-motor symptoms in Parkinson's disease. Parkinsonism Relat 
Disord., 2016. Suppl 1:S119-22. doi: 10.1016/j.parkreldis.2015.09.004. Epub 2015 
Sep 3 
20. Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, 
Blanchette PL, Popper JS, Ross GW, Frequency of bowel movements and the future 
risk of Parkinson's disease. Neurology, 2001, 57: p.456-462 
21. Savica R, Carlin JM, Grossardt BR, Bower JH, Ahlskog JE, Maraganore DM, 
Bharucha AE, Rocca WA, Medical records documentation of constipation preceding 
Parkinson disease: A case-control study.  Neurology, 2009, 73: p.1752-8. doi: 
10.1212/WNL.0b013e3181c34af5 
22. Mahlknecht P, Iranzo A, Högl B, Frauscher B, Müller C, Santamaría J, Tolosa E, 
Serradell M, Mitterling T, Gschliesser V, Goebel G, Brugger F, Scherfler C, Poewe W, 
Seppi K; Sleep Innsbruck Barcelona Group, Olfactory dysfunction predicts early 
transition to a Lewy body disease in idiopathic RBD. Neurology, 2015. 84: p.654-8. 
doi: 10.1212/WNL.0000000000001265. Epub 2015 Jan 21 
23. Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J, Masaki K, Launer L, White 
LR, Association of olfactory dysfunction with risk for future Parkinson's disease. Ann 
Neurol., 2008. 63: p.167-17 
24. Aarsland D, Marsh L, Schrag A, Neuropsychiatric symptoms in Parkinson's disease. 
Mov Disorders, 2009. 24: p.2175-86. doi: 10.1002/mds.22589 
25. Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, 
Schrag A. Meta-analysis of early nonmotor features and risk factors for Parkinson 
disease. Ann Neurol, 2012. 72:893-901. doi: 10.1002/ana.23687. Epub 2012 Oct 15 
26. Iranzo A, Tolosa E, Gelpi E, Molinuevo JL, Valldeoriola F, Serradell M, Sanchez-Valle 
R, Vilaseca I, Lomeña F, Vilas D, Lladó A, Gaig C, Santamaria J, Neurodegenerative 
disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep 
behaviour disorder: an observational cohort study. The Lancet Neurol, 2013. 12: 
p.443-53. doi: 10.1016/S1474-4422(13)70056-5. Epub 2013 Apr 3 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 105/107 
27. Seppi K, Weintraub D, Coelho M, Perez-Lloret S, Fox SH, Katzenschlager R, 
Hametner EM, Poewe W, Rascol O, Goetz CG, Sampaio C, The Movement Disorder 
Society Evidence-Based Medicine Review Update: Treatments for the non-motor 
symptoms of Parkinson's disease. Mov Disorder, 2011. 26 Suppl 3:S42-80. doi: 
10.1002/mds.23884. 
28. Schrag A, Sauerbier A, Chaudhuri KR, New clinical trials for nonmotor manifestations 
of 
Parkinson's 
disease. 
Mov 
Disorders, 
2015. 
30: 
p.1490-1504. 
doi: 
10.1002/mds.26415. 
29. Chaudhuri R K, Schapira A HV, Non-motor symptoms of Parkinson's disease: 
dopaminergic pathophysiology and treatment. The Lancet Neurology, 2009. 8: p. 464-
474 
30. Chaudhuri R K, Healy D G, Schapira A HV, Non-motor symptoms of Parkinson's 
disease: diagnosis and management. The Lancet Neurology, 2006. 5: p. 235-245 
31. Di Marzo V, Melck D, Bisogno T, De Petrocellis L, Endocannabinoids: endogenous 
cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci, 1998. 
21: p. 521-528 
32. Castillo PE, Younts TJ, Chavez AE, Hashimotodani Y, Endocannabinoid signaling 
and synaptic function. Neuron, 2012. 76: p.70.81 
33. Marinez-Orgado J, Fernandez-Lopez D, Lizasoain I, Romero J, The seek of 
neuroprotection: introducing cannabinoids. Recent Pat CNS Drug Discov, 2007. 2: p. 
131-139 
34. Sagredo O, Garcia-Arencibia M, de Lago E, Finetti S, Decio A, Fernandez-Ruiz J, 
Cannabinoids and neuroprotection in basal ganglia disorders. Mol Neurobiol, 2007. 
36: p. 82-91 
35. Barrero FJ, Ampuero I, Morales B, et al., Depression in Parkinson´s disease is 
related to a genetic polymorphism of the cannabinoid receptor gene (CNR1). 
Pharmacogenomics J, 2005. 5: p.135-141 
36. Zuardi AW, Crippa JA, Hallak JE, et al., Cannabidiol for the treatment of psychosis in 
Parkinson’s disease. J Psychopharmacol, 2009. 23: p. 979–983 
37. Venderova K, Ruzicka E, Vorisek V, Visnovsky P., Survey on cannabis use in 
Parkinson’s disease: subjective improvement of motor symptoms. Mov Disord, 2004. 
19: p.1102–1106 
38. Lotan I, Treves TA, Roditi Y, Djaldetti R., Cannabis (medical marijuana) treatment for 
motor and non-motor symptoms of Parkinson disease: an open-label observational 
study. Clin Neuropharmacol, 2014. 37: p.41–44.  
39. Chagas MH, Eckeli AL, Zuardi AW, Pena-Pereira MA, Sobreira-Neto MA, Sobreira 
ET, Camilo MR, Bergamaschi MM, Schenck CH, Hallak JE, Tumas V, Crippa JA, 
Cannabidiol can improve complex sleep-related behaviours associated with rapid eye 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 106/107 
movement sleep behaviour disorder in Parkinson’s disease patients: a case series. 
Journal of Clinical Pharmacy and Therapeutics, 2014. 39: p.564–566 
40. Carroll CB, Bain PG, Teare L, et al., Cannabis for dyskinesia in Parkinson disease: a 
randomized double-blind crossover study. Neurology, 2004. 63: p.1245–1250 
41. Mesnage V, Houeto JL, Bonnet AM, et al. Neurokinin B, neurotensin, and 
cannabinoid receptor antagonists and Parkinson disease. Clin Neuropharmacol, 
2004. 27: p.108–110 
42. Sieradzan KA, Fox SH, Hill M, Dick JP, Crossman AR, Brotchie JM, Cannabinoids 
reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology, 
2001. 57: p. 2108–2111  
43. Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, 
Dos Santos AC, Teixeira AL, Hallak JE, Crippa JA, Effects of cannabidiol in the 
treatment of patients with Parkinson’s disease: An exploratory double-blind trial. 
Journal of Psychopharmacology, 2014. 28: p.1088–1098 
44. Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease, 
The 
Unified 
Parkinson's 
Disease 
Rating 
Scale 
(UPDRS): 
status 
and 
recommendations. Mov Disord., 2003. 18: p.738-750 
45. Chaudhuri KR, Rizos A, Trenkwalder C, Rascol O, Pal S, Martino D, Carroll 
C, Paviour D, Falup-Pecurariu C, Kessel B, Silverdale M, Todorova A,  Sauerbier 
A, Odin P, Antonini A, Martinez-Martin P; EUROPAR and the IPMDS Non Motor PD 
Study Group, King's Parkinson's disease pain scale, the first scale for pain in PD: An 
international validation. Movement Disorders, 2015. 30: p.1623-1631, Epub 2015 Jun 
11. 
46. Poewe W, Hauser RA, Lang A, for the ADAGIO Investigators, Effects of Rasagiline 
on the Progression of Nonmotor Scores of the MDS-UPDRS. Movement Disorders,  
2015. 30: p.589-593 
47. ICH Expert Working Group, ICH Harmonised Tripartite Guideline, Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting E2A. European 
Medicines Agency. Step 5 Version, dated June 1995 
48. US Dept of Health and Human Services Food and Drug Administration. Guidance for 
industry: enrichment strategies for clinical trials to support approval of human drugs 
and biological products. Dec. 2012, 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM332181.pdf. Accessed October 09, 2016. 
49. Biaggioni I, Freeman R, Mathias CJ, Low P, Hewitt LA, Kaufmann H, on behalf of 
Droxidopa 302 Investigators, Randomized Withdrawal Study of Patients With 
Symptomatic Neurogenic Orthostatic Hypotension Responsive to Droxidopa. 
Hypertension, 2015. 65: p.101–107, Published online 2014 Dec 10, 


 
 
Clinical Study Protocol, the NMS-Nab Study, Version 1.4, 08/June/2018 
Page 107/107 
doi:  10.1161/HYPERTENSIONAHA.114.04035 
 
 
 
19 Index of Figures 
 
Figure 1: Schematic Diagram for participants ........................................................................ 41 
 
 
20 Index of Tables 
 
Table 1: Drug classes for non-motor Symptoms in PD .......................................................... 31 
Table 2: Nabilone for non-motor symptoms in Parkinson´s Disease ..................................... 40