Clinical trial NCT03368170
Conditions: Parkinson Disease
Keywords: Levodopa induced dyskinesia
Sponsor: Integrative Research Laboratories AB
Start date: 2018-04-12; Completion date: 2019-06-12
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Mesdopetam (IRL790) is an experimental small molecule compound with psychomotor stabilizing properties. The primary target is the dopamine D3 receptor, a target implicated in the generation of levodopa-induced dyskinesia, a side-effect frequently occurring with long-term levodopa treatment in patients with Parkinson's disease. In experimental animals mesdopetam potently reduced levodopa-induced involuntary movement without impairing the antiparkinsonian effect of levodopa.

The primary purpose of the trial is to investigate whether mesdopetam given as adjunctive treatment can reduce levodopa induced dyskinesia in patients with Parkinson's disease. The trial will also help to establish the most optimal dosing of the compound.

Detailed description:
METHODOLOGY:

This is a multicentre study where 74 patients with Parkinson's disease exhibiting levodopa induced dyskinesia will be randomised to receive study drug or placebo. Thirty seven patients will be randomised to mesdopetam and 37 patients to placebo (1:1 randomisation).

Patients will be screened for eligibility according to inclusion/exclusion criteria within four weeks of initiation of study treatment (Screening visit).

An outpatient study with the patients taking the study drug for four weeks at home. Mesdopetam will be taken twice daily (b.i.d.) as adjunctive treatment to the patients' regular and stable antiparkinsonian medication.

The first two weeks of treatment will allow for per patient titration of study medication to the highest tolerated predefined dose, after which patients will continue on this highest tolerated dose for an additional two weeks.

Changes in disease state and dyskinesia will be measured using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Unified Dyskinesia Rating Scale (UDysRS); furthermore, patients will administer two 24-hour diaries on run-in and on the fourth week of dosing to assess daily movements.

Pharmacokinetic (PK) samples will be collected for the determination of concentrations of mesdopetam and its metabolites IRL902 and IRL872 in plasma. They will be collected before and after IMP administration at two visits.

A Follow-up Visit will be performed for all patients five to eight days after last administration of IMP.

Arms: arm 1: Capsule 2.5 mg, oral administration arm 2: Identical capsule, oral administration
Interventions: intervention 1: Mesdopetam (IRL790)
Intervention descriptions: intervention 1: Mesdopetam (IRL790) capsule

Protocol documents:
Prot_000.pdf: 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 1 of 128 
 
 
 
 
CONFIDENTIAL 
 
A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PHASE IIA STUDY EVALUATING THE EFFICACY AND 
TOLERABILITY OF IRL790 IN PARKINSON’S DISEASE 
DYSKINESIA 
 
PROTOCOL 
Version: 
6 
Version date: 
14 January 2019 
Superseded version: 
Version 5, 24th July 2018 
Sponsor: 
Integrative 
Research 
Laboratories 
AB 
(IRLAB) 
Product: 
IRL790 (2.5mg hard HPMC capsules) 
Study Number(s): 
IRL790C003 
EudraCT number: 2017-003458-18 
 
NCT number: NCT03368170  
Integrative Research Laboratories AB (IRLAB) 
Arvid Wallgrens Backe 20 
413 46 Göteborg 
SWEDEN 
 
Phone: +46 (0) 707 60 16 91 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 2 of 128 
 
 
PROTOCOL APPROVAL PAGE 
This protocol has been read and approved by: 
Sponsor representative: 
 
Signature: 
 
Date: 
 
 
Chief Investigator: 
 
Signature: 
 
Date: 
 
 
The Clinical Trial 
Company: 
 
Signature: 
 
Date: 
 
 
Statistician: 
 
Signature: 
 
Date: 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 3 of 128 
 
 
INVESTIGATOR PROTOCOL APPROVAL PAGE 
A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PHASE IIA STUDY EVALUATING THE EFFICACY AND 
TOLERABILITY OF IRL790 IN PARKINSON’S DISEASE 
DYSKINESIA 
 
I, the undersigned, have read and understood the protocol and am aware of my responsibilities 
as an Investigator. I agree to conduct the study in accordance with this protocol and any 
subsequent amendments, the Declaration of Helsinki, ICH GCP guidelines, and the laws and 
regulations of the country in which the study is being conducted. 
Investigator Name: 
 
Investigator Title: 
 
Investigator Address: 
 
 
 
 
 
 
 
Investigator Signature: 
 
Date: 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 4 of 128 
 
 
AMENDMENT HISTORY 
Protocol Version 
Change 
Justification 
V6 14 January 2019 
Excl crit 9: Added definition 
of renal impairment 
7.3. Update of list of 
contraception methods 
regarded as highly effective 
according to CTFG 
recommendations 
Incl crit 4: Clarification that 
patients need >25% 
dyskinesia to score 2 or 
more 
4.1. Clarification the re-
screening is allowed 
Added to contact list that 
CTC Clinical Trial 
Consultants are also 
functioning as Swedish 
CRO 
Response to Swedish MPA 
 
Response to Swedish MPA 
 
 
Clarification 
 
Clarification 
 
New info 
V5 24 July 2018 
7.8. 
Follow Up (5-8 days 
after End of Treatment) 
The following procedures 
and assessments are to be 
carried out at Follow Up (4-
5 days after Visit 4) 
Changed to the following:  
The following procedures 
and assessments are to be 
carried out at Follow Up ( 5-
8 days after Visit 4): 
 
5.2 Non-permitted 
concomitant medications 
Table updated with the 
following: 
bupropion, paroxetine, 
quinidine, terbinafine 
 
 
 
 
Correction of typographical 
error 
 
 
 
 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 5 of 128 
 
 
Updated wording  
The list will be provided to 
the Investigator sites and 
maintained/updated 
throughout the study to 
provide information on 
clinical inhibitors for P450-
mediated metabolisms and 
clinical inhibitors for 
transporters. The list will be 
updated as new information 
becomes available and 
circulated to all sites. 
Wording amended to the 
following: 
The list will be provided to 
the Investigator sites and 
maintained/updated 
throughout the study to 
provide information on 
clinical inhibitors for P450-
mediated metabolisms and 
clinical inhibitors for 
transporters.  . Please note 
this is not an exhaustive the 
list will be updated as new 
information becomes 
available and circulated to 
all sites. 
Table updated to list correct 
CYP2D6 Strong Inhibitors 
 
V4 11 June 2018 
Section 8.1.1 ethnic origin 
changed to ethnicity and 
race 
8.1.5 resting 12 lead ECG- 
PQ changed to PR 
11.4 – ethnic origin changed 
to ethnicity and race 
Amendment history 
changed 
9. clarification that 
exclusion on hypotension 
and/or hepatic disease must 
be clinically significant 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 6 of 128 
 
 
Corrected spelling of 
disease as below: 
9. clarification that 
exclusion on hypotension 
and/or hepatic disease must 
be clinically significant 
Change of Statistician from 
Dave Fleet to Fredrik 
Hansson  
 
V3, 14 NOV 2017 
Addition of contact details 
for Statistics and Interactive 
Randomisation System 
Self-Evident 
V3, 14 NOV 2017 
Update to Abbreviations 
Self-Evident 
V3, 14 NOV 2017 
Section 1.1.Investigational 
agent 
Clarification that the study 
assesses IRL790 in 
treatment of Dyskinesia and 
not Psychosis 
Clarification 
V3, 14 NOV 2017 
Section 1.1.2. Efficacy 
Clarification of preclinical 
animal model 
Clarification 
V3, 14 NOV 2017 
Sections 1.3.1. Summary of 
risk management, 2.2. 
Secondary objectives, 3.1. 
Overall study design and 
plan description, 7.2.
 
Screening (-28 to -7 
days prior to 
randomisation), 7.6. Phone 
Call (Day 21 ± 2 days), 
8.2.2.6. (formerly 
Parkinson's KinetiGraph™ 
(PKG)) 24-hour patient 
diary, 11.7. 
Efficacy 
Endpoints,  
Replacement of actigraphic 
watch with 24 hour patient 
diaries 
The consistency across 
study sites cannot be 
guaranteed in the use of the 
actigraphic watch. 
Replaced with a 
standardised patient diary. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 7 of 128 
 
 
V3, 14 NOV 2017 
4.2. 
Inclusion criteria 
5. Clarification that rescue 
medication is allowed 
Addition of 
9. Able to complete 24-hour 
patient diaries 
 
Clarification 
 
 
Addition of diary 
V3, 14 NOV 2017 
4.3. 
Exclusion criteria 
6. Mini-Mental Status 
Examination score for 
exclusion reduced from 26 
to 24 
7. Hoehn & Yahr - 
Reference to MDS-UPDRS 
deleted 
7. Hoehn & Yahr – 
measurement in “off” phase 
deleted 
 
8. Timeframe for history of 
heart conditions added – 
within 5 years 
9. clarification that 
exclusion on hypotension 
and/or hepatic disease must 
be clinically significant 
10. clarification that patients 
with illusions or 
hallucinations with no loss 
of insight will be eligible 
11. Clarification that 
patients also enrolled in 
non-interventional clinical 
trials will be eligible. 
Removal of Current 
participation in another 
clinical trial 
 
The original level of 26 was 
considered too high and that 
patients with MMSE scores 
of 24 and above should be 
considered for inclusion 
Clarification 
 
Cannot measure when 
patient is “off” 
 
Clarification 
 
Clarification 
 
 
Clarification 
 
Clarification 
 
 
Removed in conjunction to 
update of criteria 11 
V3, 14 NOV 2017 
Section 6.4. 
Blinding and 
randomisation, 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 8 of 128 
 
 
8.2.2.5.1.Rush filming 
protocol 
Clarification that the 
investigator must ensure 
that Rush filming is 
performed with the patient 
in the “on” phase, during 
peak dose dyskinesia. 
Clarification 
V3, 14 NOV 2017 
Section 8.2.2.4.Unified 
Parkinson’s Disease Rating 
Scale (MDS-UPDRS) 
Definition of “ON” state 
added 
 
Clarification 
V3, 14 NOV 2017 
Synopsis & Schedule of 
assessments 
Updated to reflect 
amendments to main 
protocol text 
Self-Evident 
V2, 23 OCT 2017 
Section 6.4 Blinding and 
Randomisation 
Patient unblinding is also 
contained within the IRS 
system to allow the 
unblinding of patients for 
both Safety and Statistical 
purposes within the protocol 
via web or phone (per 
Sponsor outlined request). 
Amended to: 
Patient unblinding is also 
contained within the IRS 
system to allow the 
unblinding of patients for 
both Safety and Statistical 
purposes within the protocol 
via web or phone. If 
emergency unblinding is 
required this responsibility 
lies solely with the 
investigator, unblinding for 
other Safety and Statistical 
purposes will be managed 
Response to GNA dated 
18Oct17. 
 
 
 
 
 
 
 
Response to GNA dated 
18Oct17. 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 9 of 128 
 
 
per Sponsor outlined 
request. 
 
Inclusion Criteria 8 
Section 7.3 Visit 1 (Day 1) 
Addition: 
- 
Additional 
Requirements 
Subjects will be required to 
avoid exposure to direct 
sunlight from Visit 1 (day 1) 
until the follow-up visit (day 
28). 
 
V1, 20 SEPT 2017 
Initial 
N/A 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 10 of 128 
 
 
PROTOCOL SYNOPSIS 
TITLE: 
A randomised, double-blind, placebo-controlled, Phase IIa study evaluating the efficacy and 
tolerability of IRL790 in Parkinson’s disease dyskinesia. 
PROTOCOL NO: 
IRL790C003 
INVESTIGATOR STUDY SITES: 
This study will be conducted at approximately 15 study sites located in the United Kingdom. 
OBJECTIVES: 
Primary objective: 
To evaluate the efficacy of IRL790 in Parkinson’s disease dyskinesia. 
Secondary objectives: 
To evaluate the effects of IRL790 on core symptoms of Parkinson’s disease. 
To evaluate the pharmacokinetics, safety and tolerability of IRL790 in patients with Parkinson’s 
disease dyskinesia. 
METHODOLOGY: 
This is a multicentre study where 74 patients with Parkinson’s disease exhibiting levodopa 
induced dyskinesia will be randomised to receive study drug or placebo. Thirty seven patients 
will be randomised to IRL790 and 37 patients to placebo (1:1 randomisation). 
Patients will be screened for eligibility according to inclusion/exclusion criteria within four 
weeks of initiation of study treatment (Screening visit). 
 
This is an outpatient study with the patients taking the study drug for four weeks at home. 
IRL790 will be taken twice daily (b.i.d.) as adjunctive treatment to the patients’ regular and 
stable antiparkinsonian medication. 
The first two weeks of treatment will allow for per patient titration of study medication to the 
highest tolerated predefined dose, after which patients will continue on this highest tolerated 
dose for an additional two weeks. 
Changes in disease state and dyskinesia will be measured using the Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS) and Unified Dyskinesia Rating Scale (UDysRS); furthermore, 
patients will administer two 24-hour diaries on run-in and on the fourth week of dosing to assess 
daily movements. 
Pharmacokinetic (PK) samples will be collected for the determination of concentrations of 
IRL790 and its metabolites IRL902 and IRL872 in plasma. They will be collected before and 
after IMP administration at two visits. 
A Follow-up Visit will be performed for all patients five to eight days after last administration 
of IMP. 
NUMBER OF PATIENTS: 
Approximately 74 patients will be enrolled. Patients who are enrolled but not treated will be 
classed as Screen Failures and will be replaced. 
In the event that a patient withdraws from the study for any reason other than an adverse event 
or other safety concern, or is lost to follow-up within 30 days of treatment, a new patient will 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 11 of 128 
 
 
be enrolled to replace the withdrawn patient. The replacement will be managed through a 
centrally administered study wide randomisation list. The reason for the patient’s withdrawal 
from the study must be recorded. 
INCLUSION/EXCLUSION CRITERIA: 
Inclusion criteria 
1. Male or female ≥18 and ≤79 years of age. 
2. Signed a current Ethics Committee approved informed consent form. 
3. Parkinson's disease, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical 
Diagnostic Criteria. 
4. Waking day dyskinesia of >25% determined as a score of ≥2 as per Question 4.1 of the 
MDS-UPDRS. 
5. On a stable regimen of antiparkinson medications for at least 30 days prior to screening, 
including a levodopa preparation administered not less than three times daily and willing 
to continue the same doses and regimens during study participation. Rescue medication 
such as Madopar dispersable and Apomorphine injections are allowed. 
6. Taking a maximum of eight regular levodopa intakes per day, excluding bedtime and 
night time levodopa. 
7. 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 the patient must be willing to continue the same 
doses and regimens during study participation (this criterion does not apply to 
medications that are being taken pre-study only on an as-needed basis). 
8. Patient must be willing and able to avoid direct exposure to sunlight from day 1 to day 
28. 
9.  Able to complete at least one valid 24-hour patient diary at Visit 1. 
 
Exclusion criteria 
1. History of neurosurgical intervention related to Parkinson's disease (e.g. deep brain 
stimulation). 
2. Treatment with pump delivered antiparkinsonian therapy (i.e. subcutaneous 
apomorphine or levodopa/carbidopa intestinal infusion). 
3. History of seizures within two years prior to screening. 
4. History of stroke or transient ischemic attack (TIA) within two years prior to screening. 
5. History of cancer within five years prior to screening, with the following exceptions: 
adequately treated non-melanomatous skin cancers, localised bladder cancer, non-
metastatic prostate cancer or in situ cervical cancer. 
6. Presence of cognitive impairment, as evidenced by a Mini-Mental Status Examination 
(MMSE) score of less than 24 during screening. 
7. A Hoehn and Yahr stage of five. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 12 of 128 
 
 
8. Any history of a significant heart condition or cardiac arrhythmias within the past 5 
years, any repolarisation deficits or any other clinically significant abnormal ECG as 
judged by the Investigator 
9. Severe or ongoing unstable medical condition including a history of poorly controlled 
diabetes; obesity associated with metabolic syndrome; uncontrolled hypertension; 
cerebrovascular disease, or any form of clinically significant cardiac disease, clinically 
significant symptomatic orthostatic hypotension; clinically significant hepatic disease, 
renal failure or abnormal renal function (definition of abnormal renal function is 
creatinine clearance <45 ml/min (calculated according to the Cockcroft-Gault formula). 
10. Any history of a neurological other than Parkinson’s disease or a psychiatric disorder, 
including history of DSM IV diagnosed major depression or psychosis. Patients with 
illusions or hallucinations with no loss of insight will be eligible. Patients with mild 
depression who are well controlled on a stable dose of an antidepressant medication for 
at least 4 weeks before screening will be eligible. 
11. Enrolment in any other clinical study involving medication, medical devices or surgical 
procedures, current or within three months prior to screening visit, or previous 
participation in the present study. Patients enrolled in non-interventional clinical trials 
will be eligible. 
12. Drug and/or alcohol abuse. 
13. History of severe drug allergy or hypersensitivity. 
14. If female, is pregnant or lactating, or has a positive pregnancy test result pre-dose. 
15. Patients unwilling to use two forms of contraception (one of which being a barrier 
method see Section 7.3) 90 days for men and 30 days for women after last IMP dose 
16. Any planned major surgery within the duration of the study. 
17. Any other condition or symptoms preventing the patient from entering the study, 
according to the Investigator’s judgement. 
 
DOSE/ROUTE/REGIMEN: 
IRL790 will be given twice daily (b.i.d.) and given as adjunct treatment to the patients’ regular 
and stable antiparkinsonian medication. IMP treatment duration will be four weeks. 
IRL790 capsules, 2.5mg free base equivalent: White hard HPMC capsule, coni snap size 3, 
colour white containing IRL790 x ½ L-tartrate. 
Dosage: The starting dose will be three capsules (7.5mg) b.i.d. The dose will be titrated in 
intervals between two (5mg) to four capsules (10mg) b.i.d. 
 
REFERENCE TREATMENT: 
Placebo capsules: Placebo capsules: White hard HPMC capsule, coni snap size 3, colour white 
containing starch. Capsules are identical in appearance to active IMP. 
CRITERIA FOR EVALUATION: 
Efficacy assessments  


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 13 of 128 
 
 
• Primary Outcome Measure 
The primary evaluation endpoint is: 
• Change in the Unified Dyskinesia Rating Scale (UDysRS) total score from Baseline 
(Day 1) to Visit 4.  
 
• Secondary Outcome Measures 
The secondary evaluation endpoints are: 
• Change in Total Objective Score (III, IV) of the UDysRS from Baseline (Day 1) to Visit 
4. 
• Change in daily “OFF”-time as assessed with patient diaries from run-in to Visit 4. 
• Change in Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score of part 
III (motor), and sum score of Questions 4.1 and 4.2  (dyskinesia) in part IV from Baseline 
(Day 1) to Visit 4. 
 
• Exploratory outcome measures 
Additionally a number of exploratory end points will be assessed. The following items will be 
assessed: 
• Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part I (total score), part II 
(total score) and part IV (total score) from Baseline (Day 1) to Visit 4. 
• Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 1.2 (Hallucinations 
and Psychosis) from Baseline (Day 1) to Visit 4. 
• Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 1.6 (Features of 
dopamine dysregulation syndrome) from Baseline (Day 1) to Visit 4. 
• Clinician's Global Impression of Change in overall PD symptoms from Baseline (Day 1) 
to Visit 4. 
• Daily “ON”-time with troublesome dyskinesia as assessed with patient diaries from run-
in to Visit 4. 
• Daily  “ON”-time as assessed with patient diaries from run-in to Visit 4. 
 
Safety assessments  
• Frequency, seriousness and intensity of Adverse Events (AEs). 
• Physical examination. 
• Electrocardiogram (ECG) recordings. 
• Vital signs (blood pressure, heart rate). 
• Safety laboratory measurements. 
 
Pharmacokinetic (PK) assessments 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 14 of 128 
 
 
• After multiple doses: morning trough and Cmax 
• Dose proportionality after multiple doses based on morning trough and Cmax 
• P-Prolactin Pharmacokinetics 
 
STATISTICAL METHODS: 
A single analysis at the conclusion of the investigation is planned and there will be no interim 
analyses. 
 
All the efficacy safety (including laboratory safety) and pharmacokinetic data collected will be 
amalgamated into a single database with datasets constructed according to these categories.  
 
All data will be described and analysed according to Treatment group (IRL790, Placebo), day 
of assessment (Screening, Day 1 (Baseline), 7, 14, 21, 28, End of Treatment (Day 28 or last 
observation in the event of withdrawal), plus Follow-up (if appropriate)). However as this is a 
maximum tolerated dose (MTD) investigation where appropriate summaries according to Dose 
group may also be described (7.5mg b.i.d. upwards). Each data summary will be supported by 
individual patient listings. 
 
Power and Sample Size: 
Seventy Four (74) evaluable patients (37 per group) are sufficient to demonstrate an effect size 
of 0.67 between the active treatment and control (IRL790 vs Placebo) for the UDysRS primary 
endpoint with 80% power and type 1 error rate 0.05 (two tailed).  
 
Recruitment will continue until sufficient evaluable patients are available. 
 
Demographics and Baseline Characteristics: 
All basic information regarding the sample of patients recruited to represent the PD population 
with dyskinesia will be summarised. 
 
Analysis Sets 
Three analysis sets (or patient populations) will be evaluated: The Full Analysis Set (FAS), Per 
Protocol Set (PPS) and the Safety Set (SS). The FAS is considered of primary importance. 
 
Efficacy assessments 
The primary efficacy variable is the UDysRS total score.  
 
The secondary efficacy variables involve a subset of the UDysRS, the MDS-UPDRS rating 
scales and the daily “off” time as assessed with patient diaries. Similarly, the exploratory 
efficacy variables comprise a number of other subsections from the MDS-UPDRS and patient 
diaries. 
 
The Change from baseline (Screening) at Day 28 (Visit 4, Week 4) and End of Treatment (Day 
28 (Visit 4, Week 4 or earlier in the event of withdrawal) will be derived, summarised and 
analysed. The End of Treatment last assessment available is considered the primary time-point 
of interest and will be analysed as interval type data. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 15 of 128 
 
 
 
Each endpoint will be analysed using an Analysis Of Covariance (ANCOVA) model to 
compare the two treatment groups (IRL790 vs Placebo). The model will include Change from 
baseline as the dependent variable, Treatment group as a fixed factor and Baseline as the 
covariate term. Actual p-values and 95% confidence intervals for least square mean estimates 
of the treatment effects and differences from placebo will be presented. 
 
The CGI (an exploratory efficacy variable) however is categorical data which is ordinal in 
nature and will be analysed using the Van Elteren hypothesis test. 
 
Pharmacokinetic (PK) assessments 
PK variables measured in plasma are: IRL790 parent drug and two of its metabolites (IRL902 
(n-dealkylated) and IRL872 (acetylated)). In addition, the biomarker P-Prolactin is also 
measured. 
 
Samples are obtained pre-dose and 2h post dose (Cmax) on Day 1 and Day 28 and will be 
summarised as interval data. If appropriate, these will be presented overall for the IRL790 
treated group but also according to IRL dose. 
 
To assess the relationship between the treatment doses (7.5mg b.i.d. upwards) and drug plasma 
concentration a polynomial regression model to fit dose or log(dose) vs plasma concentration 
for each variable and sampling time will be used. However, this is dependent on the number of 
patients in each of the dose groups of this maximum tolerated dose (MTD) investigation. 
 
Safety assessments 
Safety evaluations include: Adverse events and Concomitant medications reporting, Complete 
physical examination, Vital signs, ECG (12 lead) and Clinical safety laboratory tests (clinical 
chemistry, haematology and coagulation). All will be presented as data summaries. No formal 
statistical analyses will be performed. 
 
Adverse events (Overall, By seriousness, By severity, By relationship) and Concomitant 
medications (Overall) recorded throughout the investigation will be reported following 
classification according to MedDRA (SOC/PT) and WHODD (ATC Level 2.4) dictionaries 
respectively.  
 
All other safety evaluations are performed at Screening, Day 28 (Visit 4 or at Withdrawal) and 
Follow-up (5-8 days after Visit 4) and will be summarised accordingly.  
 
Safety laboratory samples assayed at the local hospital will be presented as interval summaries 
according to Site. 
SAFETY 
 
Recruitment: 
The DSMB will convene after 20 and 40 patients have completed the Follow-Up visit (with 
adequate safety assessment data) for a formal safety review. 
 
Note that recruitment will continue throughout the 20 and 40 patient DSMB 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 16 of 128 
 
 
Data Safety Monitoring Board 
 
The DSMB will convene under the following circumstances: 
 
• The DSMB must meet once the 20th and 40th patient has completed the Follow-Up visit 
• The DSMB must meet as soon as there has been a SUSAR 
 
The DSMB has the right to recommend to the Sponsor that the study be suspended, terminated 
or lower doses be given, if considered appropriate. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 17 of 128 
 
 
STUDY SCHEDULE 
 
Screening 
Visit 1 
(Baseline) 
Visit 2 
Visit 3 
Phone call 
Visit 4 (EOT)1 
FU 
Treatment Period 
Follow-up 
Day 
-28- to -7 
1 
7 
14 
21 
28 
5-8 days after 
EOT 
Time window 
- 
- 
± 2 days 
± 2 
± 2 days 
-2 to 0 days 
 
Informed Consent 
X 
  
  
  
 
 
  
Demographics/Medical History 
X 
  
  
  
 
 
  
Inclusion/Exclusion Criteria 
X 
  
  
  
 
 
  
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
  
  
  
 
 
  
Weight 
X 
  
  
  
 
 
X 
Physical Examination  
X 
  
  
  
 
X 
X 
Vital Signs 
X 
 
 
 
 
X 
X 
12-lead ECG 
X2 
 
 
 
 
X 
X 
Haematology / Clinical Chemistry 
X 
  
  
  
 
X 
X 
Dipstick Urinalysis 
X 
 
 
 
 
X 
X 
Pregnancy Test 
X 
 
 
 
 
X 
 
PK sample3 
 
X 
 
 
 
X 
 
MMSE 
X 
 
 
 
 
 
 
Hoehn and Yahn scale 
X 
 
 
 
 
 
 
MDS-UPDRS 
X4 
X 
 
 
 
X 
 
UDysRS 
 
X 
 
 
 
X 
 
24-hour patient diary 
X 
 
 
 
X 
 
 
CGI-C 
 
 
 
 
 
X 
 
Treatment Emergent Adverse Events 
 
 
X 
X 
X 
X 
X 
Randomisation 
 
X 
 
 
 
 
 
Dispense Trial Medication 
 
X 
 
X 
 
 
 
Compliance 
 
 
X 
X 
X 
X 
 
Dose adjustment5 
 
 
X 
X 
 
 
 
Baseline events6 
X 
X 
 
 
 
 
 
 
1 All withdrawals have a final re-assessment if possible 
2 Triplicates separated by at least one minute 
3 Taken before and 2 hours after IMP administration 
4 Question 4.1 only 
5 Dose Adjustment if required 
6Medical events that occur between signing the ICF and first dose 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 18 of 128 
 
 
 
CONTACT NAMES AND ADDRESSES 
Sponsor: 
Integrative Research Laboratories AB (IRLAB) 
Address: 
Integrative Research Laboratories AB (IRLAB) 
Arvid Wallgreen backe 20, 
413 46 Göteborg, 
Sweden 
Contact details: 
Phone: +46 (0) 707 60 16 91 
E-mail: joakim.tedroff@irlab.se 
Personnel: 
Joakim Tedroff, MD, PhD, CMO 
 
 
CRO: 
The Clinical Trial Company Ltd 
Address: 
Mere View Barn, 
Park Lane, 
Pickmere, 
Knutsford, 
Cheshire, 
WA16 0LG 
United Kingdom 
Contact details: 
Tel: +44(0) 1565 733 772 
Fax: +44(0) 1565 732 958 
Personnel: 
Ewan Campbell – Director 
 
 
Pharmacovigilance 
Diamond Pharma Services 
Address: 
No. 4, East Wing, 
Gemini House, 
Flex Meadow, 
Harlow, Essex, 
CM19 5TJ, 
United Kingdom 
Telephone 
+44 (0) 8450 704336 
+44 (0)1279 441616 
Fax 
+44 (0)1279 418964 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 19 of 128 
 
 
Statistics  
and Swedish CRO 
CTC Clinical Trial Consultants AB 
 
Address: 
 
Dag Hammarskjölds väg 13, 752 37 Uppsala, Sweden 
E-mail: fredrik.hansson@ctc-ab.se 
Web: www.ctc-ab.se 
 
Telephone 
Phone: +46 (0) 721935501 
Skype: Fredrik.hansson@ctc-ab.se 
Personnel: 
Fredrik Hansson, Director Biometrics 
 
 
 
Interactive 
Randomisation System: 
Endpoint Clinical 
Address: 
55 Francisco Street, 
Suite 200, 
San Francisco, 
CA 94133 
Telephone 
+1 415 970  5548 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 20 of 128 
 
 
 
ABBREVIATIONS 
 
ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AIM 
Abnormal Involuntary Movements 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical classification system 
AUC 
Area under the concentration time curve 
b.i.d. 
Twice daily 
BMI 
Body Mass Index 
CA 
Competent Authority 
CGI-C 
Clinical Global Impression of Change 
CI 
Chief Investigator 
Cmax 
Maximum concentration 
CMH 
Cochran Mantel-Haenszel 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Clinical Research Organisation 
CSA 
Clinical Study Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ED50 
Median Effective Dose 
EOT 
End Of Treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FSH 
Follicle Stimulation Hormone 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 21 of 128 
 
 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
Hb 
Haemoglobin 
hERG 
Human Ether-à-go-go-Related Gene 
HPMC 
Hydroxypropyl Methylcellulose  
ICH 
International Council on Harmonisation 
ICF 
Informed Consent Form 
ID 
Identification/Identifier 
IMP 
Investigational Medicinal Product 
INR 
International Normalised Ratio 
IRL 
Integrative Research Laboratories 
IRS 
Interactive Randomisation System 
LDH 
Lactate dehydrogenase 
L-Dopa 
Levodopa 
LID 
L-Dopa Induced Dyskinesia 
MAD 
Multiple Ascending Dose 
MDS- UPDRS 
Movement Disorder Society – Unified Parkinson’s  
Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MMSE 
Mini–Mental State Examination 
MTD 
Maximum Tolerated Dose 
NMDA 
N-methyl-D-aspartate 
NOAEL 
No Observed Adverse Effect Levels 
6-OHDA 
6-hydroxydopamine 
PD 
Parkinson’s Disease 
PDP 
Parkinson’s Disease Psychosis 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PT 
Preferred Term 
PT 
Prothrombin time 
RBC 
Red Blood Cells 
REC 
Research Ethics Committee 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 22 of 128 
 
 
SAE 
Serious Adverse Event 
SAD 
Single Ascending Dose 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDV 
Source Data Verification 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
Apparent terminal half-life 
Tmax 
Time to maximum concentration 
T3 
Triiodothyronine 
T4 
Thyroxine 
TCTC 
The Clinical Trial Company 
TEAE 
Treatment Emergent AE 
TIA 
Transient ischaemic attack 
TMF 
Trial Master File 
TSH 
Thyroid-stimulating hormone 
UAE 
Unexpected Adverse Event 
UKPDS 
UK Parkinson's Disease Society  
UDysRS 
Unified Dyskinesia Rating Scale 
WBC 
White Blood Cells 
WHO 
World Health Organization 
WHODD 
World Health Organisation Drug dictionary 
Enrolled patient 
Patient who has signed the informed consent 
Screen failure 
Enrolled patient not included  
Included patient 
Patient randomised 
Withdrawn patient  
Patient randomised but not completed 
Completed patient 
Patient completed the study period, including follow-up 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 23 of 128 
 
 
TABLE OF CONTENTS 
 
1. 
BACKGROUND INFORMATION AND STUDY RATIONALE ............................. 28 
1.1. 
Investigational agent ............................................................................................... 28 
1.1.1. 
Mechanism of action .......................................................................................... 29 
1.1.2. 
Efficacy .............................................................................................................. 29 
1.2. 
Preclinical data ........................................................................................................ 29 
1.3. 
Risks / benefits ......................................................................................................... 30 
1.3.1. 
Summary of risk management ........................................................................... 30 
1.4. 
Dose rationale .......................................................................................................... 31 
1.5. 
Trial conduct ............................................................................................................ 31 
1.6. 
Population ................................................................................................................ 31 
1.7. 
Previous Clinical Studies ........................................................................................ 32 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 33 
2.1. 
Primary objective .................................................................................................... 33 
2.2. 
Secondary objectives ............................................................................................... 33 
3. 
STUDY DESIGN ............................................................................................................ 34 
3.1. 
Overall study design and plan description ............................................................ 34 
3.1.1. 
Study Schematic................................................................................................. 35 
3.2. 
Rationale for study design and dose selection ...................................................... 36 
3.3. 
Discussion of study design, including the choice of control groups .................... 36 
4. 
PATIENT SELECTION CRITERIA ........................................................................... 36 
4.1. 
Patient recruitment ................................................................................................. 36 
4.2. 
Inclusion criteria ..................................................................................................... 37 
4.3. 
Exclusion criteria..................................................................................................... 37 
4.4. 
Patient withdrawals................................................................................................. 38 
4.4.1. 
Replacements ..................................................................................................... 39 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 24 of 128 
 
 
5. 
CONCOMITANT MEDICATIONS ............................................................................. 39 
5.1. 
Permitted concomitant medications ...................................................................... 39 
5.2. 
Non-permitted concomitant medications .............................................................. 39 
6. 
TREATMENT(S)............................................................................................................ 41 
6.1. 
Appearance and content ......................................................................................... 41 
6.2. 
Dosage and administration ..................................................................................... 41 
6.3. 
Packaging and labelling .......................................................................................... 42 
6.4. 
Blinding and randomisation ................................................................................... 42 
6.5. 
Treatment compliance and accountability ............................................................ 44 
6.6. 
Drug storage............................................................................................................. 44 
7. 
STUDY PLAN ................................................................................................................. 44 
7.1. 
Continuous Assessments ......................................................................................... 44 
7.2. 
Screening (-28 to -7 days prior to randomisation) ............................................... 44 
7.3. 
Visit 1 (Day 1) .......................................................................................................... 45 
7.4. 
Visit 2 (Day 7 ± 2 days) ........................................................................................... 47 
7.5. 
Visit 3 (Day 14 ± 2 days) ......................................................................................... 47 
7.6. 
Phone Call (Day 21 ± 2 days).................................................................................. 47 
7.7. 
Visit 4 (End of Treatment, Day 28 -2 to 0 days) ................................................... 47 
7.8. 
Follow Up (5-8 days after End of Treatment) ...................................................... 48 
7.9. 
Early Termination Visit .......................................................................................... 48 
8. 
STUDY PROCEDURES / EVALUATIONS ................................................................ 48 
8.1. 
Clinical evaluations ................................................................................................. 48 
8.1.1. 
Demographics/Medical History ......................................................................... 48 
8.1.2. 
Height/Weight .................................................................................................... 48 
8.1.3. 
Physical Examination......................................................................................... 48 
8.1.4. 
Vital Signs .......................................................................................................... 49 
8.1.5. 
Resting 12-lead ECG ......................................................................................... 49 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 25 of 128 
 
 
8.2. 
Evaluations & Assessments .................................................................................... 49 
8.2.1. 
Clinical laboratory evaluations .......................................................................... 49 
8.2.2. 
Non-standard assays or procedures .................................................................... 50 
8.2.3. 
Specimen preparation, handling and shipping ................................................... 52 
9. 
ADVERSE EVENT REPORTING ............................................................................... 53 
9.1. 
Definitions ................................................................................................................ 53 
9.2. 
Expectedness ............................................................................................................ 54 
9.3. 
Intensity of adverse event ....................................................................................... 55 
9.4. 
Causality assessment ............................................................................................... 55 
9.5. 
Action taken regarding the study drug ................................................................. 56 
9.6. 
Outcome ................................................................................................................... 56 
9.7. 
Recording adverse events ....................................................................................... 56 
9.8. 
Serious Adverse Events ........................................................................................... 57 
9.9. 
Reporting of SUSARs.............................................................................................. 58 
10. DATA MANAGEMENT ................................................................................................ 58 
10.1. 
Trial Documentation and Trial Confidentiality ............................................... 58 
10.1.1. 
Trial Documentation, CRFs and Document Keeping .................................... 58 
10.1.2. 
Confidentiality of Trial Documents and Patient Records .............................. 59 
11. STATISTICAL METHODS .......................................................................................... 60 
11.1. 
General Considerations ....................................................................................... 60 
11.2. 
Sample Size/Power Calculation .......................................................................... 61 
11.3. 
Analysis Sets ......................................................................................................... 61 
11.4. 
Study Population.................................................................................................. 62 
11.5. 
Baseline Treatment Dose Group Comparability .............................................. 62 
11.6. 
Treatment Compliance........................................................................................ 62 
11.7. 
Efficacy Endpoints ............................................................................................... 62 
11.8. 
Pharmacokinetic Endpoints................................................................................ 64 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 26 of 128 
 
 
11.9. 
Efficacy Analyses ................................................................................................. 64 
11.10. 
Safety Analyses .................................................................................................... 65 
11.10.1. 
Adverse Events ............................................................................................... 65 
11.10.2. 
Concomitant Medications .............................................................................. 65 
11.10.3. 
Physical Examinations ................................................................................... 65 
11.10.4. 
Vital Signs ...................................................................................................... 65 
11.10.5. 
ECG (12-Lead) At Rest .................................................................................. 66 
11.10.6. 
Clinical Laboratory Tests ............................................................................... 66 
12. ETHICS COMMITTEE APPROVAL ......................................................................... 66 
13. REGULATORY REQUIREMENTS ............................................................................ 66 
14. INFORMED CONSENT ................................................................................................ 66 
15. DIRECT ACCESS TO SOURCE DOCUMENTATION / DATA ............................. 67 
16. STUDY MONITORING AND MANAGEMENT ....................................................... 67 
16.1. 
Training of study site personnel ......................................................................... 67 
16.2. 
Clinical Monitoring ............................................................................................. 67 
16.3. 
Source Data .......................................................................................................... 68 
16.4. 
Study agreements ................................................................................................. 68 
16.5. 
Study time table and end of study ...................................................................... 68 
17. QUALITY ASSURANCE .............................................................................................. 68 
18. INSURANCE .................................................................................................................. 69 
19. CONFIDENTIALITY .................................................................................................... 69 
20. PREMATURE TERMINATION OF THE STUDY ................................................... 69 
21. RECORD RETENTION ................................................................................................ 69 
22. PUBLICATION OF RESULTS .................................................................................... 69 
22.1. 
Clinical Study Report .......................................................................................... 69 
22.2. 
Annual safety report ............................................................................................ 70 
22.3. 
Confidentiality and ownership of study data .................................................... 70 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 27 of 128 
 
 
22.4. 
Publication ............................................................................................................ 70 
23. DATA SAFETY MONITORING BOARD (DSMB) ................................................... 70 
24. REFERENCES ............................................................................................................... 71 
25. APPENDICES ................................................................................................................. 73 
25.1. 
Appendix 1 Mini-Mental State Examination (MMSE) .................................... 73 
25.2. 
Appendix 2 Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) ......... 77 
25.3. 
Appendix 3 Unified Dyskinesia Rating Scale (UDysRS) ................................ 108 
25.4. 
Appendix 4 Clinical Global Impression of Change (CGI-C) ......................... 124 
25.5. 
Appendix 5 Declaration of Helsinki ................................................................. 126 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 28 of 128 
 
 
1. BACKGROUND INFORMATION AND STUDY RATIONALE 
Parkinson’s disease is a relatively common neurodegenerative disorder characterised by motor 
symptoms such as poorness and slowness of movement, tremors and loss of balance. 
Psychiatric symptoms such as anxiety and depression as well as other non-motor symptoms 
are also common. The disorder is associated with a markedly increased risk of developing 
dementia [1]. Treatments that restore dopamine deficits in the brain such as levodopa and 
dopamine agonists have been used since the 1970s to treat the motor symptoms in Parkinson’s 
disease. However, it has long been known that after a few years of initial motor normalisation, 
such drugs frequently cause adverse effects [2, 3]. Adverse effects on motor symptoms such as 
wearing-off, on-off and dyskinesias limit the usefulness of current approved drug treatments, 
prompting the use of device treatments such as deep brain stimulation and infusion pumps for 
patients in more advanced stages of disease. 
It is estimated that within five years of initiation of standard dopamine replacement therapy in 
Parkinson’s disease (PD), about 50% of patients (and after 10 years almost all patients) develop 
involuntary movements:- so called Levodopa Induced Dyskinesias (LIDs), in response to their 
medical treatment [4]. LIDs are often the key complication that limits further dose increases in 
dopaminergic therapy. 
There is increasing recognition that non-motor symptoms, such as Parkinson’s disease 
Psychosis (PDP) are burdensome to PD patients. Paranoid delusions result in patient distress 
and behavioural disturbance; visual or auditory hallucinations are more frequent. PD patients 
with cognitive impairment are prone to develop hallucinations, i.e. psychotic symptoms, in 
response to dopaminergic treatments [5]. In a systematic review of clinical populations the 
prevalence of hallucinations alone was between 21% and 46% [6]. 
The key pathophysiology of PD involves loss of dopaminergic and noradrenergic innervation. 
Other cortical, subcortical and autonomic pathologies contribute to the non-motor symptoms 
of the disorder [7]. It has been suggested that cortico-striatal dys-connectivity and plasticity are 
key drivers for both the core symptoms of PD as well as for the adverse effects emerging with 
long standing dopaminergic treatment [8] 
Because of the prevalence of dyskinesia and psychosis, and the limited options for effective 
treatment, developing new safe and effective therapies that treat LIDs, and/or PDP, without 
aggravating Parkinsonism addresses an unmet medical need in Parkinson’s disease. 
1.1. Investigational agent 
IRL790 was discovered in an in vivo systems pharmacology project and has been selected for 
development aimed as a treatment to reduce levodopa induced dyskinesia and psychosis in PD. 
Some specific desired properties of this compound are: 
• Efficacy in preclinical PD models of L-dopa induced motor dysfunction, such as 
reducing dyskinesia, while leaving locomotor activity intact. 
• Efficacy in preclinical models of disrupted cortical and striatal dopaminergic or 
glutamatergic transmission, such as counteracting N-methyl-D-aspartate (NMDA)-
antagonist induced hyperactivity demonstrating antipsychotic activity.  


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 29 of 128 
 
 
• Indications of strengthened cortico-striatal connectivity through neurochemical and 
transcriptional biomarkers of neurotransmission, related to monoaminergic, 
cholinergic and glutamatergic neurotransmitter pathways. 
• In normal animals, IRL790 has no effect on locomotor activity across a wide dose 
range. 
Two clinical indications, both of which are associated with dysfunctional cortico-striato-
thalamic connectivity, are considered for IRL790. The specific anti-dyskinetic and 
antipsychotic effects of IRL790 suggest its use in the treatment of L-Dopa Induced Dyskinesia 
(LID) and Parkinson’s Disease Psychosis (PDP) in PD. This trial is aimed at assessing IRL790 
as a treatment for LID. Its role as a treatment for PDP will be assessed in future trials. 
1.1.1. Mechanism of action 
IRL790, IRL790 x ½ L-tartrate, belongs to a new class of central nervous system (CNS) active 
agents called psychomotor stabilisers. These are compounds exerting antidyskinetic and 
antipsychotic effects via the brain monoaminergic systems without suppressing locomotor 
activity in normal un-pretreated rats. In vitro IRL790 acts as an antagonist of brain 
neuroreceptors belonging to the dopamine D2-type (D3 and D2) and the Sig-1 receptor (σ1) at 
sub-micromolar concentrations and serotonin family receptors (5-HT1a, 5-HT2) at micromolar 
concentrations. 
IRL790 at the same doses behaves as an antidyskinetic and antipsychotic leaving normal 
behaviour largely unaffected, combined with its neurochemical mode of action indicates a 
novel compound profile in PD with potential to alleviate LID and psychosis while sparing 
normal motor functions. 
1.1.2. Efficacy 
Behaviourally, IRL790 has the ability to normalise overt motor abnormalities induced by 
disruptions in both dopaminergic and glutamatergic neurotransmission in a dose dependent 
manner, hence directly addressing symptoms arising from aberrations in cortico-striatal 
communication. 
In an animal model of PD, the unilateral 6-hydroxy-dopamine lesioned rat model, IRL790 
significantly reduced L-Dopa induced dyskinesia but left the L-Dopa dependent motor 
activation intact. 
Furthermore, in a phase 1b study, patients with advanced PD experiencing levodopa induced 
dyskinesia were randomised to receive IRL790 or placebo as adjunct treatment for 28 days. 
Five patients treated with IRL790 reported transient mild worsening of parkinsonism during 
dose titration. Thirteen patients completed the study, nine patients on IRL790 and four patients 
on placebo. 
Patients with advanced Parkinson’s disease consistently tolerated IRL790. The adverse events 
reported in patients with advanced Parkinson’s disease were mitigated by dose adjustments and 
following dose titration, IRL790 seemed to reduce dyskinesia (assessed by UDysRS) without 
compromising motility. 
1.2. Preclinical data 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 30 of 128 
 
 
IRL790 has been shown to be negative in in vitro genotoxicity tests. Single and repeated oral 
administrations of IRL790 resulted in dose-related locomotor reductions and behavioural signs 
in rats and dogs. Following repeated administration for up to one month, microscopic changes 
were observed in the mammary gland, female reproductive organs, liver, adrenal glands, 
glandular stomach, pancreas and parotid glands in rats. In dogs, microscopic changes were 
noted in the small sized arteries of the alimentary tract, urinary bladder, gall bladder and lung. 
The CNS-related clinical signs in rats and dogs (tremor, decreased activity, abnormal gait and 
convulsion) and most of the histopathological findings in rats, such as changes in mammary 
gland and female reproductive organs, are considered to be a consequence of exaggerated 
pharmacology and/or compound-related perturbations of prolactin levels. Apart from findings 
related to exaggerated pharmacology (i.e. mild and transient clinical signs and slight 
histopathological changes in female mammary gland and vaginal epithelium), no treatment-
related findings were observed at 25 mg/kg/day in rats and 18 mg/kg/day in dogs. These doses 
were considered to be the No Observed Adverse Effect Levels (NOAELs) for the 1-month 
studies resulting in a mean Cmax of 10.8 µM and a mean AUC0-24h of 47.2 µM/h in rats and a 
mean Cmax of 8.9 µM and a mean AUC0-24h of 84 µM/h in dogs. IRL790 has low affinity for 
Human Ether-à-go-go-Related Gene (hERG) (IC50; 223.9 µM) and is therefore predicted to 
have low liability for QT prolongation. IRL790 was tested for excitability, automaticity, 
cardiac wavelength, TRIaD and proarrhythmia in the Hondeghem model using rabbit isolated 
hearts [9]. IRL790 was concluded to be safe in the dose range tested (0.5 to 45 µM). 
IRL790 was also evaluated for cardiovascular variables in a conscious beagle dog model 
following single twice daily (b.i.d) oral administrations. In this study, no physiologically 
relevant or statistically significant changes were observed in any of the variables investigated 
at any of the doses tested [10]. 
1.3. Risks / benefits 
Collectively, the data from nonclinical and clinical studies indicate that IRL790 is likely to 
have an acceptable safety profile. Possible adverse effects associated with IRL790 include mild 
and transient CNS associated adverse events (headache/loss of concentration/tremor/light 
headedness) and potential increases in plasma prolactin at higher dose levels. 
The doses to be used in this study have been selected based on the previous clinical study (see 
Section 1.7). A flexible dose titration using 2.5mg capsules with a starting dose of 7.5mg b.i.d. 
with a subsequent dose range from 5mg to 10mg b.i.d. will allow the physician to titrate an 
optimal dose for each individual patient, while retaining a pronounced margin of safety.  
Studies in humans have not identified any safety issues for the doses studied and the highest 
obtained plasma concentration of IRL790 in healthy volunteers was below the highest 
recommended level. To mitigate the risk for intolerability and AEs, the protocol allows for 
flexible dose titration and involves careful monitoring of the patients well-being.  
1.3.1. Summary of risk management 
The Principal Investigator at each research site will ascertain that adequate facilities and 
procedures are available to handle emergency situations should they occur during the study.  
During the treatment period the study patients will visit the clinic on Days 1, 7, 14 and 28 for 
monitoring of safety variables; PK sampling will occur on Days 1 & 28. A phone call will be 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 31 of 128 
 
 
made on Day 21 to collect information on any AEs or changes in concomitant medication (as 
well as instructing the user to complete two 24-hour diaries assessing daily motor function). 
Each study patient will be provided with a Patient Information Card with information about the 
study, the IMP, 24-hour diaries, patient study ID, name of the Investigator and an emergency 
number. 
Besides the risks related to the IMP as described above, study specific evaluations and sampling 
procedures like blood-pressure measurements using a blood pressure cuff and frequent blood-
sampling, can cause transient discomfort but the risk is deemed to be low and ethically 
justifiable.  
1.4. Dose rationale 
The pharmacological effects of IRL790 have been evaluated in a range of preclinical animal 
models. As to the suggested indication, levodopa induced dyskinesias in PD; the 6-OHDA AIM 
scoring rat model is most commonly suggested for use in pharmacological validation of anti-
dyskinetic efficacy of new therapies and is thus regarded to have predictive validity. Using this 
rodent lesion model, IRL790 has been studied in two independent tests, both in-house and by 
an external laboratory. IRL790 showed significant efficacy in reducing AIMs (active doses <10 
mg/kg s.c. with an ED50 of 3.7 mg/kg s.c.), without compromising beneficial effects of L-
DOPA. Taken together, a dose range of around 1-4 mg/kg in the rat (Cmax ≈ 0.5-2 µM, AUC ≈ 
0.,6 – 3 µM x h) covers effective doses up to and above the ED50s in the main preclinical in 
vivo pharmacological efficacy models. 
Integrating this data with in vitro affinity and functional assessments for the main molecular 
targets in the dopamine receptor family (dopamine D3 and D2 receptors) indicates that efficacy 
in patients with PD could be expected at Cmax levels below 0.5 µM in plasma. In such patients, 
the dosing of IRL790 is also likely to be personalised and hence flexible dosing will be explored 
in the initial clinical studies. A flexible dose titration ranging from 5mg b.i.d. up to a maximum 
10mg b.i.d. will allow the physician to titrate an optimal dose for each individual patient, while 
retaining a sufficient margin of safety. Given the plasma half-life of about 7 hours, sufficient 
coverage during the waking hours of the day is expected. 
To mitigate the risk for intolerability and AEs, the protocol allows for flexible dose titration 
and involves careful monitoring of the patients’ well-being. 
1.5. Trial conduct 
This study will be conducted in compliance with the protocol and according to Good Clinical 
Practice and applicable regulatory standards. No deviation from the protocol will be 
implemented without the prior review and approval of the ethics committee and regulatory 
authorities except where it may be necessary to eliminate an immediate hazard to a research 
subject. In such case, the deviation will be reported to the ethics committee and regulatory 
authorities as soon as possible. 
1.6. Population 
Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting 
more than one million people in the European Union (EU) and North America. It is estimated 
that within five years after initiation of standard dopamine replacement therapy, about 50% of 
patients with PD develop involuntary movements, so called levodopa (L-Dopa) induced 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 32 of 128 
 
 
dyskinesia (LID) in response to their medical treatment. LID is often the key complication that 
limits further dose increases in dopaminergic therapy. Moreover, treatment induced psychotic 
symptoms (Parkinson’s disease psychosis [PDP]) may also develop over time in a substantial 
proportion of patients. There are no approved treatments for such long term complications. 
IRL790 was discovered and developed in a project aimed at finding a treatment for LIDs and 
PDP in patients with PD treated with antiparkinsonian medications. Results from preclinical 
studies in experimental animals suggest that the compound could help to ameliorate such 
untoward effects without appreciably affecting the basic efficacy of antiparkinsonian 
medications. 
1.7. Previous Clinical Studies 
IRL790 has been investigated in two clinical studies, IRL790C001, a phase I randomised, 
double-blind, placebo-controlled, cross-over, single ascending dose (SAD) and multiple 
ascending dose (MAD) study in male healthy volunteers and IRL790C002, a phase 1b study 
of patients with advanced PD experiencing levodopa induced dyskinesia. 
In the SAD part of IRL790C001, subjects were divided into two cohorts. Within each cohort 
the subjects were randomised to one of four treatment sequences, which included three dose 
levels of IMP. One of the dose levels was repeated once, taken with a standardised meal, all 
other doses were taken without food. In each of the six administered dose levels (5, 15, 40, 80, 
120mg IRL790), six subjects received active drug and two subjects received matching placebo. 
In the MAD part of this study, twenty-three subjects were treated with IMP. In the first cohort, 
nine subjects received IRL790, 40 mg/day for 10 consecutive days and three subjects received 
matching placebo. In the second cohort, nine subjects received IRL790, 80 mg/day for 10 
consecutive days and three subjects received matching placebo. 
Overall, IRL790 was well tolerated when given to healthy male subjects at single doses up to 
120 mg and at multiple doses of 80mg per day for 10 days. The maximum tolerated dose was 
set to 120mg as a single dose and the maximal dose for multiple dosing was set to 80mg per 
day. Most of the treatment emergent (74%) AEs were of grade 1 intensity while 26% were of 
grade 2 intensity. The majority of AEs (48%) reported were considered as not related to study 
treatment while 11% were possibly related and 41% probably related. Overall treatment 
emergent AEs were mild, transient and possibly CNS related. 
In agreement with preclinical findings, the pharmacokinetic evaluation in humans showed 
dose-linear kinetics with rapid absorption (average Tmax ≈1 h) and log-linear decline with a 
plasma half-life around 7h. Urine recovery data confirmed elimination from plasma occurred 
by a combination of renal excretion (fractional excretion around 35%) and metabolic 
degradation. 
In the phase 1b study, patients with advanced PD experiencing levodopa induced dyskinesia 
were randomised to receive IRL790 or placebo (3:1 randomisation) as adjunct treatment for 28 
days. During the first two weeks of treatment, dosing was gradually increased until signs of 
intolerability occurred after which dose adjustments were made. Following this titration period 
the dosing was kept stable for the remaining two weeks. Fifteen patients were randomised to 
treatment, 11 to IRL790 and four to placebo. Generally, adverse events were of mild intensity 
and transient after dose adjustments. Ten patients in the IRL790 treated group and four patients 
in the placebo group reported at least one related adverse event. Nervous system disorder was 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 33 of 128 
 
 
the most common adverse event (31% of all reported adverse events). Five patients treated with 
IRL790 reported transient worsening of parkinsonism during dose titration, an adverse effect 
which was mitigated by dose reduction. Thirteen patients completed the study, nine patients on 
IRL790 and four patients on placebo. Two patients treated with IRL790 discontinued treatment 
due to adverse events.  
Patients with advanced Parkinson’s disease consistently tolerated IRL790. The adverse events 
reported in patients with advanced Parkinson’s disease were mitigated by dose adjustments and 
following dose titration, IRL790 seemed to reduce dyskinesia (assessed by Unified Dyskinesia 
Rating Scale UDysRS) without compromising motility. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Primary objective 
The primary objective of the study is to evaluate the effects of IRL790 on levodopa induced 
dyskinesia in patients with Parkinson’s disease. 
The primary evaluation endpoint is: 
• Change in the Unified Dyskinesia Rating Scale (UDysRS) total score from Baseline 
(Day 1) to Visit 4 (Day 28 End of Treatment or earlier in the event of withdrawal). 
2.2. Secondary objectives 
The secondary objectives of the study are: 
• To evaluate the effects of adjunctive treatment with IRL790 on levodopa induced 
dyskinesia assessed with the total objective score (part III + IV) in the Unified 
Dyskinesia Rating Scale (UDysRS), as compared to placebo. 
• To evaluate the effects of adjunctive treatment with IRL790 on symptoms of PD 
assessed with Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III 
(motor)), and sum of Questions 4.1 and 4.2 (dyskinesia)  in part IV as compared to 
placebo. 
• To evaluate the effects of adjunctive treatment with IRL790 on the daily motor “OFF” 
time as assessed by patient completed 24-hour diaries, as compared to placebo. 
Secondary endpoints 
The secondary evaluation endpoints are: 
• 
Change in Total Objective Score (III, IV) of the UDysRS from Baseline (Day 1) to 
Visit 4 (Day 28). 
• 
Change in total daily “OFF” time as assessed by patient completed 24-hour diaries, 
from run-in to Visit 4 (Day 28). 
• 
Change in Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score of 
part III (motor), and sum score of Questions 4.1 and 4.2 (dyskinesia) in part IV to 
Visit 4 (Day 28). 
 
Exploratory endpoints 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 34 of 128 
 
 
Additionally a number of exploratory end points will be assessed. The following items will be 
assessed: 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part I (total score), part 
II (total score) and part IV (total score) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 1.2 
(Hallucinations and Psychosis) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 1.6 (Features 
of dopamine dysregulation syndrome) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
Clinician's Global Impression of Change in overall PD symptoms from Baseline 
(Day 1) to Visit 4 (Day 28). 
• 
Change in ”ON” time with troublesome dyskinesia as assessed by patient 
completed 24-hour diaries, from run-in to Visit 4 (Day 28). 
• 
Change in ”ON” time as assessed by patient completed 24-hour diaries, from run-
in to Visit 4 (Day 28). 
3. STUDY DESIGN 
3.1. Overall study design and plan description 
This is a multi-centre, randomised, double-blind, placebo-controlled trial with the primary 
objective to evaluate the efficacy of 28 days treatment with IRL790 in patients with PD 
experiencing LID.  
Consenting patients will be screened for eligibility according to study-specific 
inclusion/exclusion criteria (see Sections 4.2 and 4.3) within 7-28 days before start of IMP 
administration (Screening Visit).  
At the Screening visit patients will be instructed and trained to complete two 24-hour diaries 
for assessment of daily motor function and to bring the completed diaries to the clinic at Visit 
1. Patients completing at least one valid diary will be eligible for inclusion.  
Following baseline assessments at Visit 1 (Day 1) patients will be randomised to receive 
IRL790 or placebo (1:1 randomisation). The treatment allocation will be double-blinded, i.e. it 
will not be disclosed to the patients, the site staff or the Sponsor (see Section 6.4). Study 
medication will be dispensed and the first capsules of IMP will be administered in the clinic. 
The patient will be instructed to take the second daily dose in the afternoon of the same day as 
the study visit. 
During the treatment period, Visits 2-4 will be performed on Days 7, 14 and 28 and a follow-
up phone call on Day 21. Dose adjustments of IRL790 will be made as described in Section 
6.2. 
During the telephone follow-up call on Day 21, the patient will be asked to complete two 24-
hour diaries for assessment of daily motor function and bring the completed diaries to the clinic 
at Visit 4 on Day 28. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 35 of 128 
 
 
On Day 28 (Visit 4) the morning IMP dose will be administered at the clinic. ECG will be 
assessed two hours after IMP administration. Blood samples for PK analysis will be collected 
pre-dose and two hours post dose.  
The MDS-UPDRS part 3 will be assessed with the patient in the “on state”7 on Day 1 (Visit 1) 
and Day 28 (Visit 4 End of Treatment or earlier in the event of withdrawal). 
To assess dyskinesia, the UDysRS will be administered on Day 1 (Visit 1) and Day 28 (Visit 
4 End of Treatment or earlier in the event of withdrawal). The physician rated part III will be 
assessed with the patients in the “on” state. Patients will be filmed using the “Rush filming 
protocol” (see Appendix 25.3) in the “on” state. The film sequences will be transferred to a 
blinded Central Rater for assessment and the results from this rating will subsequently be 
included in the CRF. 
A follow-up visit will take place 5-8 days after the last IMP dose. 
Unscheduled visits will be performed as needed during the study and should be documented in 
the appropriate section of the CRF. 
Each assessment is further described in Section 7. 
3.1.1. Study Schematic 
Randomisation 
 
7 “On-Dyskinesia” refers to the choreic and dystonic movements described to the patient as “jerking or twisting 
movements that occur when your medicine is working.” 
“Off-Dystonia” should be described to the patient as “spasms or cramps that can be painful and occur when your 
Parkinson’s disease medications are not taken or are not working. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 36 of 128 
 
 
Patient Path 
 
 
3.2. Rationale for study design and dose selection 
The pharmacological effects of IRL790 have been evaluated in a range of preclinical animal 
models. Integrating the preclinical in vivo data and in vitro assessments for the main molecular 
target, the dopamine D3 receptor, indicates that efficacy in patients with PD could be expected 
at doses below 500 nM in plasma. 
The Phase 1b study of IRL790 in advanced Parkinson’s disease indicated that efficacy could 
be achieved at such plasma concentrations with retained tolerability and safety and where the 
biomarker prolactin, indicating target engagement, was moderately elevated. 
Given the variability in tolerability of IRL790 in PD patients, the dosing of IRL790 will 
continue to be personalised and hence flexible dosing will be explored in this study. A flexible 
dose titration range of 5-10 mg b.i.d. will allow the physician to titrate an optimal dose for each 
individual patient, while retaining a large margin of safety. Given the plasma half-life of about 
7 hours, sufficient coverage during the waking hours of the day is expected. 
 
To mitigate the risk for intolerability and AEs, the protocol allows for flexible dose titration 
and involves careful monitoring of the patients’ well-being. 
 
3.3. Discussion of study design, including the choice of control groups 
The study has a parallel group design, which is deemed more appropriate than a cross-over 
considering the aetiology of the illness. Patients will be randomised, in equal proportions, to 
placebo or the active dose regimen. 
Bias is controlled through a placebo group. 
4. PATIENT SELECTION CRITERIA 
4.1. Patient recruitment 
Patients will be recruited from the population of outpatients at the study sites. Patients may 
also be recruited by other methods such as clinic lists, research registers, and patients learning 
about the study from websites or other sources or from a local research event. Potentially 
eligible patients interested in taking part of the study may therefore be referred from other sites. 
The Investigator will keep records of all patients screened and included. The reason for screen 
failure should be stated for all patients screened but not included. The reason for withdrawal 
should be stated for all patients included but not completed.  


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 37 of 128 
 
 
Seventy Four (74) evaluable patients are required. 
Patients who screen fail can be re-screened once depending on the reason for screen fail and as 
judged by the Investigator. The patient will then receive a new screening number. 
4.2. Inclusion criteria 
For inclusion in the study, patients must fulfil all the following criteria:  
1. Male or female ≥18 and ≤79 years of age. 
2. Signed a current Ethics Committee approved informed consent form. 
3. Parkinson's disease, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical 
Diagnostic Criteria. 
4. Waking day dyskinesia of >25% determined as a score of ≥2 as per Question 4.1 of the 
MDS-UPDRS. 
5. On a stable regimen of antiparkinson medications for at least 30 days prior to screening, 
including a levodopa preparation administered not less than three times daily and 
willing to continue the same doses and regimens during study participation. Rescue 
medication such as Madopar dispersable and Apomorphine injections are allowed. 
6. Taking a maximum of eight regular levodopa intakes per day, excluding bedtime and 
night time levodopa. 
7. 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 the patient must be willing to continue the 
same doses and regimens during study participation (this criterion does not apply to 
medications that are being taken pre-study only on an as-needed basis). 
8. Patient must be willing and able to avoid direct exposure to sunlight from day 1 to day 
28. 
9. Able to complete at least one valid 24-hour patient diary at Visit 1. 
 
4.3. Exclusion criteria 
Patients must not enter the study if any of the following exclusion criteria are fulfilled: 
 
1. History of neurosurgical intervention related to Parkinson's disease (e.g. deep brain 
stimulation). 
2. Treatment with pump delivered antiparkinsonian therapy (i.e. subcutaneous 
apomorphine or levodopa/carbidopa intestinal infusion). 
3. History of seizures within two years prior to screening. 
4. History of stroke or transient ischemic attack (TIA) within two years prior to screening. 
5. History of cancer within five years prior to screening, with the following exceptions: 
adequately treated non-melanomatous skin cancers, localised bladder cancer, non-
metastatic prostate cancer or in situ cervical cancer. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 38 of 128 
 
 
6. Presence of cognitive impairment, as evidenced by a Mini-Mental Status Examination 
(MMSE) score of less than 24 during screening. 
7. A Hoehn and Yahr stage of five. 
8. Any history of a significant heart condition or cardiac arrhythmias within the past 5 
years, any repolarisation deficits or any other clinically significant abnormal ECG as 
judged by the Investigator 
9. Severe or ongoing unstable medical condition including a history of poorly controlled 
diabetes; obesity associated with metabolic syndrome; uncontrolled hypertension; 
cerebrovascular disease, or any form of clinically significant cardiac disease, clinically 
significant symptomatic orthostatic hypotension; clinically significant hepatic disease, 
renal failure or abnormal renal function (definition of abnormal renal function is 
creatinine clearance <45 ml/min (calculated according to the Cockcroft-Gault formula). 
10. Any history of a neurological other than Parkinson’s disease or a psychiatric disorder, 
including history of DSM IV diagnosed major depression or psychosis. Patients with 
illusions or hallucinations with no loss of insight will be eligible. Patients with mild 
depression who are well controlled on a stable dose of an antidepressant medication for 
at least 4 weeks before screening will be eligible.  
11. Enrolment in any other clinical study involving medication, medical devices or surgical 
procedures, current or within three months prior to screening visit, or previous 
participation in the present study. Patients enrolled in non-interventional clinical trials 
will be eligible. 
12. Drug and/or alcohol abuse. 
13. History of severe drug allergy or hypersensitivity. 
14. If female, is pregnant or lactating, or has a positive pregnancy test result pre-dose. 
15. Patients unwilling to use two forms of contraception (one of which being a barrier 
method see Section 7.3) 90 days for men and 30 days for women after last IMP dose 
16. Any planned major surgery within the duration of the study. 
17. Any other condition or symptoms preventing the patient from entering the study, 
according to the Investigator’s judgement. 
 
4.4. Patient withdrawals 
In all circumstances, patients will be made aware of the rights to refuse participation in a 
clinical trial and are entitled to freely withdraw their consent, without giving reasons. Patients 
will be assured that the withdrawal from the trial will not cause prejudice, will not result in any 
determinant and will not affect treatment. In addition, refusal to give consent or withdrawal of 
consent to participate in research will not lead to any liability or discrimination against the 
person concerned. 
The Investigator has the right to withdraw patients from the study in the event of: 
• Use of any non-permitted concomitant medication 
• Non-compliance with the protocol and/or lack of willingness or commitment to co-
operate in all phases of the study 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 39 of 128 
 
 
• Protocol deviation 
• Pregnancy after entry into study 
• An adverse event which is considered intolerable by the patient 
• Intercurrent illness that necessitates pharmacological treatment with a drug which 
interacts in any way with the test treatment 
• Development of an exclusion criterion 
• Treatment failure 
 
Should a patient decide to withdraw for other reason, all effort will be made to complete and 
report observations as thoroughly as possible. A complete final evaluation at the time of 
withdrawal will be performed with an explanation of the exact reason why the patient is 
withdrawing from the study. 
The Investigator is responsible for the optimal individual treatment of the patient. 
The Investigator must fill in the “Study termination” section of the CRF explaining all reasons 
for withdrawal.  
After a patient withdraws from a trial, the Investigator remains responsible for reporting SAEs 
considered causally related to the study drug. In addition, the Investigator must ensure 
appropriate treatment and follow-up of each adverse event ongoing at the time of the patient’s 
discontinuation. 
In the event that a patient withdraws from the study for any reason other than an adverse event 
or other safety concern or is lost to follow-up within 30 days of treatment, the Principal 
Investigator may enrol a new patient to replace the withdrawn patient. The reason for the 
patient’s withdrawal from the study must be recorded. 
4.4.1. Replacements 
In the event that a patient withdraws from the study for any reason other than an adverse event 
or other safety concern, or is lost to follow-up within 30 days of treatment, a new patient will 
be enrolled to replace the withdrawn patient. The replacement will be managed through a 
centrally administered study wide randomisation list. The reason for the patient’s withdrawal 
from the study must be recorded. 
5. CONCOMITANT MEDICATIONS 
5.1. Permitted concomitant medications 
Patients included in the study will be on stable anti-Parkinson treatment for at least 30 days 
prior to inclusion and during the study. 
Other medications considered necessary for the patient’s safety and well-being may be given 
at the discretion of the Investigator. 
5.2. Non-permitted concomitant medications 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 40 of 128 
 
 
All concomitant therapy used during and within four weeks prior to the study period must be 
recorded in the CRF. No other drug under investigation may be used concomitantly with the 
study medication. 
Concomitant medications that are strong inhibitors of CYP2D6 should be avoided. As the 
elimination pathways of IRL790 regarding other CYP enzymes are unknown (except for 
CYP2A6, CYP2D6 and CYP3A4), there may be a risk of significant exposure increase when 
medications that are strong enzyme and transporter inhibitors are used together with IRL790. 
Strong inhibitors of these enzymes and transporters, including grapefruit juice, should be 
avoided throughout the study. 
 
Examples of clinical inhibitors for P450-mediated metabolisms and clinical inhibitors for 
transporters8 
Isoenzyme 
(cytochrome P450) 
Strong Inhibitors 
Moderate Inhibitors 
CYP1A2 
ciprofloxacin, enoxacin, 
fluvoxamine, zafirlukast 
methoxsalen, mexiletine, oral 
contraceptives 
CYP2B6 
- 
- 
CYP2C8 
clopidogrel, gemfibrozil 
deferasirox, teriflunomide 
CYP2C9 
- 
amiodarone, felbamate, fluconazole, 
miconazole, piperine 
CYP2C19 
fluconazole, fluoxetine, 
fluvoxamine, ticlopidine 
- 
CYP2D6 
bupropion, fluoxetine, 
paroxetine, quinidine, 
terbinafine 
cimetidine, cinacalcet, duloxetine, 
fluvoxamine, mirabegron 
Transporter 
Inhibitor 
P-gp 
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, 
lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, 
ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, 
verapamil 
BCRP 
curcumin, cyclosporine A, eltrombopag 
 
8 The list will be provided to the Investigator sites and maintained/updated throughout the study to provide 
information on clinical inhibitors for P450-mediated metabolisms and clinical inhibitors for transporters. Please 
note this is not an exhaustive and will be updated as new information becomes available and circulated to all sites. 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 41 of 128 
 
 
OAT1B1, 
OATP1B3 
atazanavir and ritonavir, clarithromycin, cyclosporine, erythromycin, 
gemfibrozil, lopinavir and ritonavir, rifampin (single dose), simeprevir 
OAT1, OAT3 
p-aminohippuric acid (PAH), probenecid, teriflunomide 
MATE1, MATE2-
K 
cimetidine, dolutegravir, isavuconazole, ranolazine, trimethoprim, 
vandetanib 
 
6. TREATMENT(S) 
6.1. Appearance and content 
IRL790 capsules, 2.5mg free base equivalent: White hard HPMC capsule, coni snap size 3, 
colour white containing IRL790 x ½ L-tartrate. 
Placebo capsules: White hard HPMC capsule, coni snap size 3, colour white containing starch. 
6.2. Dosage and administration 
The IMP (2-4 capsules) will be swallowed together with 200 mL of tap water in the morning 
and in the afternoon approximately 8 hours apart of each administration day, except for Day 
28 when the last dose will be taken in the morning at the clinic visit after trough PK sampling. 
Titration Phase 
The starting dose of IRL790 will be 7.5 mg (three capsules) b.i.d (Visit 1, Day 1). 
Formal dose adjustments can be made at the discretion of the treating physician according to 
the following: 
Visit 
Adjustment 
Visit 2 (Day 7) 
The dose can be increased to 10mg b.i.d., 
maintained at 7.5mg b.i.d. or decreased to 
5mg b.i.d 
Visit 3 (Day 14) 
The dose can be adjusted to 5 mg, 7.5mg or 
10mg b.i.d. (2-4 capsules b.i.d.) 
Note: Dose de-escalation/re-escalation is 
permitted at Visit 3 but is only in a 2.5mg (1 
capsule) step.9 
 
The reasoning for dose adjustment must be recorded in the CRF. 
 
9 i.e. Dose re-escalation from 5mg to 10mg b.i.d. or de-escalation from 10mg to 5mg b.i.d. is not permitted 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 42 of 128 
 
 
Unscheduled dose de-escalation can be made between Visit 1 and Visit 3 only in the case of 
intolerance; unscheduled dose escalation is not permitted. 
Fixed Dose Phase 
The fixed IRL790 dose for the remaining 14 days of treatment will be determined on Day 14 
(Visit 3) for each patient. 
Unscheduled dose de-escalation can be made between Visit 3 and Visit 4 only in the case of 
intolerance. 
There will be no treatment with IRL790 available after end of study participation. 
6.3. Packaging and labelling 
Finished product of IMP (active drug and placebo) will be packed and labelled by PCI, United 
Kingdom. 
Labels will comply with applicable Good Manufacturing Practice (GMP) requirements 
(EudraLex Volume 4, Good manufacturing practices, ANNEX 13, Manufacture of 
Investigational Medicinal Products). 
Containers will be packed with sufficient IMP for the study treatment period and labelled with 
the appropriate information required, before release and shipment. 
6.4. Blinding and randomisation 
This is a double-blind study, thus, the study patients and the site personnel who are making the 
study assessments will be blinded to the study treatments of IRL790 and Placebo (capsules of 
IRL790 and placebo will be of identical appearance.). 
Treatment allocation (1:1 randomisation) will be performed via a web-based IVRS and based 
on the randomisation list generated by Endpoint Clinical. 
Interactive Randomisation System (IRS): 
The Interactive Response System (IRS) will manage the randomisation and IMP inventory 
supply chain. IRS will deliver the IMP at the correct time for both new and existing patients. 
IRS will also support the dosing schedules and is used to track patient activities in real time 
throughout study visits. Real-time web reports and alerts platform (email, fax, SMS) give 
access to compliance feedback for continuous transparency of the study’s progress. Patient 
unblinding is also contained within the IRS system to allow the unblinding of patients for both 
Safety and Statistical purposes within the protocol via web or phone. If emergency unblinding 
is required this responsibility lies solely with the investigator, unblinding for other Safety and 
Statistical purposes will be managed per Sponsor outlined request. Unblinding access can be 
controlled within the IRS by role type allowing only the appropriate role to unblind the 
appropriate patient. 
 
Prolactin Results 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 43 of 128 
 
 
It is expected that Prolactin levels will be raised in participants randomised to IRL790. It should 
be noted that this elevation in Prolactin is not expected to be clinically significant (i.e. will not 
exceed the upper limit of normal) but is potentially detectable when comparing Visit 4 results 
to screening. 
There is no risk to the analysis of endpoints by unblinding as the Visit 4 safety test results 
(including Prolactin level) will only be available several hours after performing the UDysRS 
and other rating tests. 
No ratings can be performed after safety test results are received. 
Rush Filming Protocol 
To control variance, Parts III & IV of the UDysRS will be recorded using the Rush Filming 
Protocol and assessed by a Central Rater. The films will be recorded digitally with the patient 
in “on” state and each assigned a randomisation number ensuring that the Central Rater is 
blinded as to which films were recorded at Visit 1 (Pretreatment) and Visit 4 (End of 
Treatment). The investigator must ensure that the filming is performed with the patient in the 
“on” phase, during peak dose dyskinesia.  
Pharmacokinetic Samples 
The laboratory analysing the PK samples will have access to the randomisation list; only 
samples taken from patients in the active arm of the study will be analysed. Results of PK 
analysis will not be linked to patient number until the database is locked. 
Breaking the Blind 
IRL790 and Placebo (capsules of identical appearance.) will be dispensed in identical 
containers according to a blinded randomisation scheme. Study patients, Investigators, study 
staff and the Sponsor will remain blinded to the randomisation scheme until the blind is 
formally broken for all patients. For this to occur all patients must have completed the study 
and the study database must be locked. 
Prior to database lock, a treatment assignment may be unblinded only when knowledge of the 
treatment received is necessary for interpreting a serious adverse event, or essential for the 
medical management of the patient, or to provide critical safety information about a drug that 
could have implications for the ongoing conduct of the trial. Blinding codes must only be 
broken in emergency situations for reasons of patient safety.  
Investigators will receive a confidential code to access the IRS system that will enable them to 
selectively break the code for an individual patient. When the blinding code is broken, the 
reason must be fully documented and entered on the case report form (CRF). 
If a patient’s treatment assignment is unblinded, the Medical Monitor will be notified of the 
unblinding incident and the following information will be provided by the PI: date, time, 
patient’s trial identification (number and initials), and the reason for unblinding. The patient 
will be withdrawn. 
The identity and responsibility of those individuals at the study site who gain access to the 
unblinded treatment assignment must be documented.  It is mandatory that all personnel who 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 44 of 128 
 
 
are involved in the unblinding, and who have access to the unblinded treatment assignment, 
maintain the confidentiality of the information and do not divulge the treatment assignment. 
 
6.5. Treatment compliance and accountability 
Treatment compliance will be recorded at each visit during the treatment period. Unused 
medication and empty containers will be returned to the study site at Visit 4 (Day 28 End of 
Treatment or earlier in the event of withdrawal). 
6.6. Drug storage 
The IMP should be stored at room temperature (not to exceed 30oC).  
Any unused study medication will be returned to the Sponsor or the Hospital Pharmacy for 
destruction. Empty containers will be destroyed at the study site. The Monitor will perform 
final IMP accountability reconciliation at the study end to verify that all unused IMP is 
adequately destroyed/returned and documented. 
7. STUDY PLAN 
7.1. Continuous Assessments 
The following assessments will be carried out on a continuous basis and as events arise: 
• Adverse Events 
• Concomitant Medication 
• Medication Compliance 
 
7.2. Screening (-28 to -7 days prior to randomisation) 
The following assessments will be performed and documented in all patients consented to the 
study to assess whether a patient meets eligibility criteria: 
• Informed Consent (prior to any non-standard of care screening procedures being 
initiated) 
• Demographics/Medical History  
• Inclusion/Exclusion Criteria (screen failures to be recorded) 
• Pregnancy Test 
• Concomitant Medications 
• Height  
• Weight  
• Physical Examination 
• Vital Signs 
• 12-lead ECG  
• Haematology/Clinical Chemistry 
• Dipstick Urinalysis 
• MDS-UPDRS question 4.1 
• MMSE 
• Hoehn and Yahr score  


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 45 of 128 
 
 
• Baseline events 
• 24-hour patient diaries – Patients, after receiving training on diary completion, will be 
instructed to complete 24-hour diaries for assessment of daily motor function on two 
days in the weeks before Visit 1 and bring the completed diaries to the clinic. (see 
section 8.2.2.6) 
 
- 
GP Letter 
The patient’s GP will be informed of the patient’s entry in to the clinical trial.  
 
7.3. Visit 1 (Day 1) 
Eligible patients will be randomised to either trial drug (IRL790) or placebo.  
The following procedures and assessments are to be carried out at Visit 1 (Day 1): 
• Concomitant Medications 
• PK sample 
• MDS-UPDRS 
• UDysRS 
• Baseline Events 
• Randomisation 
• Dispense and Administer Trial Medication – starting dose 7.5mg (3 capsules b.i.d) 
 
- 
Patient Information Card 
All study patients enrolled will be provided with a Patient Information Card to be carried 
throughout the study. The card will include the following information: 
 
• That the carrier is participating in a clinical study 
• Patient study ID 
• That the carrier is potentially treated with IMP 
• The name and telephone number of the Investigator 
• Name and address of the Sponsor 
 
- 
Contraceptive Requirements: 
The patient must be reminded to use two forms of contraception (one of which being a barrier 
method) for three months (90 days) for men and four weeks (30 days) for women. 
 
Male patients 
 
Male patients must use acceptable methods of contraception if the male patient’s partner could 
become pregnant from the time of the first administration study medication until three months 
following administration of the last dose of study medication. The acceptable methods of 
contraception are as follows:  
• 
Surgical sterilisation (vasectomy with documentation of azoospermia) and a barrier 
method (condom or occlusive cap (diaphragm or cervical/vault caps) used with 
spermicidal foam/gel/film/cream/suppository) 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 46 of 128 
 
 
• 
The female partner uses oral contraceptives (combination oestrogen/ progesterone 
pills), injectable progesterone or subdermal implants and a barrier method (condom 
or occlusive cap (diaphragm or cervical/vault caps) used with spermicidal 
foam/gel/film/cream/suppository) 
• 
The female partner has undergone documented tubal ligation (female sterilisation). 
In addition, a barrier method (condom or occlusive cap (diaphragm or cervical/vault 
caps) used with spermicidal foam/gel/film/cream/suppository) must be used 
• 
The female partner has undergone documented placement of an intrauterine device 
(IUD) or intrauterine system (IUS) and the use of a barrier method (condom or 
occlusive cap (diaphragm or cervical/vault caps) used with spermicidal 
foam/gel/film/cream/suppository) 
• 
True abstinence when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
 
Male patients are expected to use a condom and contraceptive methods with a failure rate of < 
1% to prevent pregnancy and drug exposure to a partner and refrain from donating sperm from 
the date of dosing until three months after last dosing of IMP. 
 
Note: 
Male patients whose female partner(s) is (are) pregnant must use a condom from the time of 
the first administration of treatment or study medication until three months (90 days) following 
administration of the last treatment or dose of study medication. 
 
Female patients 
 
Female patients of childbearing potential must use medically acceptable methods of 
contraception from the time of the first administration of treatment or study medication until 
four weeks following administration of the last treatment or dose of study medication. 
Acceptable methods include:  
• A documented placement of an IUD or IUS and the use of a barrier method (condom 
or occlusive cap (diaphragm or cervical/vault caps) used with spermicidal 
foam/gel/film/cream/suppository). 
• Documented tubal ligation (female sterilisation). In addition, a barrier method (condom 
or occlusive cap (diaphragm or cervical/vault caps) used with spermicidal 
foam/gel/film/cream/suppository) should also be used; 
• Oral contraceptives (combination oestrogen/progesterone containing pills), injectable 
progesterone or subdermal implants and the use of a barrier method (condom or 
occlusive cap (diaphragm or cervical/vault caps) used with spermicidal 
foam/gel/film/cream/suppository). 
• True abstinence when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
 
- 
Additional Requirements 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 47 of 128 
 
 
Subjects will be required to avoid exposure to direct sunlight from Visit 1 (day 1) until the 
follow-up visit (day 28). 
 
7.4. Visit 2 (Day 7 ± 2 days) 
The following procedures and assessments are to be carried out at Visit 2 (Day 7 ± 2 days): 
• Concomitant Medications 
• Treatment Emergent Adverse Events 
• Compliance 
• Dose Adjustment (See Section 6.2) 
 
7.5. Visit 3 (Day 14 ± 2 days) 
The following procedures and assessments are to be carried out at Visit 3 (Day 14 ± 2 days): 
• Concomitant Medications 
• Treatment Emergent Adverse Events 
• Dispense Trial Medication 
• Compliance 
• Dose Adjustment (See Section 6.2) 
 
7.6. Phone Call (Day 21 ± 2 days) 
The following assessments are to be carried out at via phone call on Day 21 ± 2 days: 
• Concomitant Medications 
• Treatment Emergent Adverse Events 
• Compliance 
• 24-hour patient diaries - Patients will be instructed to complete 24-hour diaries for 
assessment of daily motor function on two days in the week before Visit 4 and bring 
the completed diaries to the clinic. 
 
7.7. Visit 4 (End of Treatment, Day 28 -2 to 0 days) 
The following procedures and assessments are to be carried out at Visit 4 (Day 28 -2 to 0 days): 
• Concomitant Medications 
• Physical Examination 
• Vital Signs 
• 12-lead ECG 
• Haematology/Clinical Chemistry 
• Dipstick Urinalysis 
• Pregnancy Test 
• PK sample 
• MDS-UPDRS 
• UDysRS 
• CGI-C 
• Treatment Emergent Adverse Events 
• Compliance 
 
NOTE: Withdrawn patients will undergo Visit 4 assessments 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 48 of 128 
 
 
 
7.8. Follow Up (5-8 days after End of Treatment) 
The following procedures and assessments are to be carried out at Follow Up (5-8 days after 
Visit 4): 
• Concomitant Medication 
• Weight 
• Physical Examination 
• Vital Signs 
• 12-lead ECG 
• Haematology/Clinical Chemistry 
• Dipstick Urinalysis 
• Treatment Emergent Adverse Events 
 
7.9. Early Termination Visit 
Patients have the right to withdraw from the trial at any time and for any reason. If a patient 
refuses to be seen for further visits the assessments at Visit 4 (End of Treatment) should be 
performed at the time they have indicated that they will not attend for further visits, assuming 
they are available and consent to this. 
8. STUDY PROCEDURES / EVALUATIONS 
Signed informed consent must be obtained before any screening procedures are initiated. The 
informed consent procedure is further described in Section 14. 
8.1. Clinical evaluations 
8.1.1. Demographics/Medical History 
The following demographic data will be recorded: gender, age, ethnicity and race. 
Medical/surgical history will be obtained by interview in order to verify that the eligibility 
criteria are met. 
Diagnosis of Parkinson’s disease must have been made as per the UK Parkinson’s Disease 
Society Brain Bank Clinical Diagnostic Criteria 
The duration of the patients’ Parkinson’s disease will be assessed by the following endpoints: 
• Years from diagnosis 
• Years from symptom onset 
8.1.2. Height/Weight 
Weight and height will be measured without shoes. Body mass index will be calculated from 
the height and weight recorded and rounded to the nearest whole number. 
8.1.3. Physical Examination 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 49 of 128 
 
 
A complete physical examination will include assessments of the head, eyes, ears, nose, throat, 
skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes 
and extremities. 
8.1.4. Vital Signs 
Heart rate, systolic and diastolic blood pressure will be measured in the supine position after 
five minutes of rest. 
8.1.5. Resting 12-lead ECG 
Single 12-lead ECGs will be recorded in a supine position after five minutes of rest. PR, QRS, 
QT, and QTcF intervals will be recorded. The time of the ECG recordings must be noted in the 
CRF. 
8.2. Evaluations & Assessments 
8.2.1. Clinical laboratory evaluations 
The anticipated volume of blood samples collected during the study from each patient will not 
exceed 250 mL per patient. 
Any remains from the safety laboratory samples will be disposed of after analyses. 
Blood samples for analysis of clinical chemistry, haematology and coagulation variables will 
be collected at Screening, Visit 4 (Day 28 End of Treatment or earlier in the event of 
withdrawal) and Follow-Up and sent to the certified laboratory at each local hospital and 
analysed by routine analytical methods. Urine analysis will be performed at clinic using dip 
sticks. 
The following safety laboratory variables will be assessed: 
 
Clinical Chemistry 
Haematology 
Alanine aminotransferase (ALT) 
Basophils 
Alkaline phosphatase (ALP) 
Eosinophils 
Amylase 
Haematocrit 
Aspartate aminotransferase (AST) 
Haemoglobin (Hb) 
Calcium 
Lymphocytes 
Albumin 
Monocytes 
Total bilirubin 
Neutrophils 
Creatinine 
Platelet count 
Creatinine kinase 
Red blood cell (RBC) count 
Lactate dehydrogenase (LDH) 
White blood cell (WBC) count with 
differential count 
Random Glucose 
Total cholesterol 
Coagulation 
Magnesium 
Phosphate 
Prothrombin time (PT) or International 
Normalised Ratio (INR) 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 50 of 128 
 
 
Potassium 
Urinalysis (dip stick) 
Prolactin 
Glucose 
Sodium 
Hb/erythrocytes 
Thyroid-stimulating hormone (TSH) 
Nitrite 
Triiodothyronine (Free T3)  
Protein 
Thyroxine (T4) 
 
Triglycerides 
 
Urea nitrogen 
 
Follicle Stimulating Hormone (FSH) 
 
Estradiol 
 
NOTE:  Sample collection to be carried out prior to dosing at Visit 4 
 
Estradiol is only required for Post-menopausal participants only. 
 
8.2.2. Non-standard assays or procedures 
8.2.2.1. 
Pharmacokinetic samples 
Venous blood samples (approximately 5mL) for the determination of concentrations of IRL790 
and its metabolites IRL902 (n-dealkylated) and IRL872 (acetylated) in plasma will be collected 
before and two hours (for trough and Cmax) after IMP administration at the specified time-points 
(Visits 1 & 4). The date and time of collection of each sample will be recorded in the CRF. 
Samples will be collected, handled, labelled stored and shipped as detailed in the laboratory 
manual. 
Samples for determination of concentrations of IRL790 and its metabolites in plasma will be 
analysed by the Swedish National Veterinary Institute, by means of a validated LC-MS/MS 
method. The details of the analytical method used will be described in a separate bioanalytical 
report. 
8.2.2.2. 
Mini-Mental State Examination (MMSE)  
The MMSE will be administered at screening. (See Appendix 1 Mini-Mental State 
Examination (MMSE)) 
 
 
 
 
8.2.2.3. 
Hoehn and Yahr scale 
The Hoehn and Yahr scale is a five point scale for describing how the symptoms of Parkinson's 
disease progress: 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 51 of 128 
 
 
Stage 
Hoehn and Yahr Scale 
0 
Asymptomatic 
1 
Unilateral involvement only 
2 
Bilateral involvement with impairment of 
balance 
3 
Mild to moderate involvement; some 
postural instability but physically 
independent; needs assistance to recover 
from pull test 
4 
Severe disability; still able to walk or stand 
unassisted 
5 
Wheelchair bound or bedridden unless aided 
 
8.2.2.4. 
Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 
The MDS-UPDRS part 1-4 will be administered at Visit 1(Baseline, Day 1) and Visit 4 (Day 
28 End of Treatment or earlier in the event of withdrawal). The MDS-UPDRS part III should 
be administered with the patient in “on” state. (See Appendix 2 Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS)). The “on” state is defined when the patient is at his/her best 
mobility, usually 1-2 hours post levodopa. The rater should make sure that the defined “on” 
state is in agreement with the patient’s perception of best mobility. Preferably, the same rater 
should complete MDS-UPDRS III at baseline and end of treatment visits. 
8.2.2.5. 
Unified Dyskinesia Rating Scale (UDysRS) 
The UDysRS will be administered at Visit 1(Baseline, Day 1) and Visit 4 (Day 28 End of 
Treatment or earlier in the event of withdrawal). The physician rated part (part III and IV) will 
be assessed by filming the patient 1-2 hours after levodopa in the “on” state. The Rush filming 
protocol will be employed and the films will be sent for subsequent rating performed by a 
blinded Centralised Rater. (See Appendix 3 Unified Dyskinesia Rating Scale (UDysRS)) 
8.2.2.5.1. 
Rush filming protocol 
The Rush filming protocol will be used to assess severity, distribution and functional 
impairment of dyskinesia. The investigator  must ensure that the filming is performed with the 
patient in best “on”, usually 1-2 hours post levodopa, during peak dose dyskinesia. The 
following situations will be captured while filming the patient: 
1. Communication: Instruct patient to look at evaluator (or camera) and describe a 
picture (the Cookie Thief Drawing).  
2. Drinking from a cup: Instruct the patient to pick up a 4 oz cup filled to within 1 cm of 
brim with water with the dominant hand and bringing it to lips, drink contents and 
replace cup on table. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 52 of 128 
 
 
3. Dressing: Instruct the patient to put on a lab coat and do up three buttons, undo the 
buttons and take the coat off. [Allow up to 60 seconds].  
4. Ambulation: Instruct the patient to rise from a chair, walk 15 feet, return and sit back 
down in the chair.  
8.2.2.6. 
24-hour patient diary 
Patient diaries have gained wide acceptance as endpoints for clinical development of 
therapeutics aiming to reduce treatment-related motor complications [18]. Motor fluctuations 
are associated with compromise in activities of daily living and health-related quality of life. 
For this clinical trial patients will record their 24-hours motor function in 30-minute intervals, 
beginning at midnight. For each 30-minute interval the patient will rate the state he or she has 
been in for the past 30 minutes; Off, On or On with troublesome dyskinesia. The patient will 
also denote the time when he or she has been asleep. 
- 
For this trial, patient training to improve accuracy and compliance is essential. Patients will 
be instructed and trained on how to complete the diary at the Screening visit (training 
detailed in the Study Operations Manual). The investigator must ensure that each patient 
understands how and when to fill in the diaries before leaving the clinic. Patients that have 
not been able to complete at least one valid diary at Visit 1 will not be included. Patients 
not completing at least one valid diary on Visit 1 may be rescheduled for Visit 1 following 
additional diary completion training.  The 24-hour diaries will be captured on two days at 
run-in at the patient’s choosing and at two days of Week 4 of treatment at the patients 
choosing. 
- 
For each of the two periods (run-in and week 4 of treatment) the Investigator will register 
the following data in the appropriate sections of the CRF: 
o The total daily time for the two diaries the patients spent in “OFF”, “ON” and “ON 
with troublesome dyskinesia”. 
- 
A patient diary will be regarded as valid if less than four of the 30-minute intervals have 
missing data for the waking part of the day (missing sleep assessments will be ignored). 
- 
If one of the two diaries is regarded invalid due to missing data or for any other reason the 
time spent in OFF”, “ON” and “ON with troublesome dyskinesia” derived from the valid 
diary should be registered in the CRF. If none of the two diaries are valid at Visit 4, missing 
data should be recorded in the CRF. 
8.2.2.7. 
Clinical Global Impression of Change (CGI-C) 
The CGI-C will be administered at the Visit 4 (Day 28 End of Treatment or earlier in the event 
of withdrawal). The Investigator will rate on a 7-grade scale how, in their judgment, the 
patients´ global clinical condition has changed from baseline. (See Appendix 4 Clinical Global 
Impression of Change (CGI-C)) 
8.2.3. Specimen preparation, handling and shipping 
8.2.3.1. 
Instructions for specimen preparation, handling and storage 
The samples for analysis of PK variables will be stored at -20°C or below until analysed. The 
samples will be disposed of after the clinical study report has been finalised. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 53 of 128 
 
 
If a patient withdraws consent to the use of biological samples donated, the samples will be 
disposed of/destroyed, if not already analysed and documented.  
The Principal Investigator will ensure that:  
• 
Patient withdrawal of informed consent is notified immediately to Sponsor. 
• 
Biological samples from the patient, if stored at the research clinic prior to 
shipment, are immediately identified, disposed of/destroyed and the action is 
documented. 
The Sponsor must ensure that laboratories holding samples are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed or returned to the research 
clinic and the action is documented. 
Specimen preparation, handling, storage and shipment will be detailed in the study operations 
manual. 
9. ADVERSE EVENT REPORTING 
9.1. Definitions 
Adverse Event (AE) 
Untoward medical occurrence in a patient administered a pharmaceutical product and that does 
not necessarily have a causal relationship with this treatment.  
An adverse event can therefore be any unfavourable and unintended sign (including laboratory 
abnormal finding), system or disease temporally associated with the use of the medicinal 
product, whether or not considered as related to the investigational medicinal product. 
A baseline event is any AE in a clinical study patient that occurs after the participant has signed 
the Informed Consent Form (ICF) up until the first administration of IMP. 
A treatment emergent AE (TEAE) is any AE not present prior to the initiation of IMP 
administration or any event already present that worsens in either intensity or frequency 
following exposure to the IMP. 
Adverse Drug Reaction (ADR) 
Untoward and unintended responses to an investigational medicinal product related to any dose 
administered. 
All adverse events judged by either the reporting Investigator or the Sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression “reasonable causal relationship” means to convey in general that there are facts or 
evidence meant to suggest a causal relationship. 
Serious Adverse Event (SAE) 
Untoward medical occurrence or effect that at any dose falls in one or more of the following 
categories: 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 54 of 128 
 
 
• Results in death 
• Is life-threatening 
• Requires hospitalisation or prolongation of existing inpatients’ hospitalisation.  
Hospitalisation refers to a situation whereby an AE is associated with unplanned 
overnight admission into hospital.  
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
Is a medically significant adverse event 
Planned hospitalisations or surgical interventions for a condition that existed before the patient 
signed the ICF and that did not change in intensity are not SAEs. 
Unexpected Adverse Event (UAE) 
When the nature or severity of an AE or SAE is not expected based on the information provided 
in the IB, it is considered to be an unexpected AE or SAE. The Sponsor or designee is 
responsible for determining the expectedness of an AE. 
Suspected Unexpected Serious Adverse Reactions (SUSARs)  
SUSARs are AEs that are suspected to be related to the IMP (i.e. AEs assessed as possibly, 
probably or definitely related according to Section 9.4) and are both unexpected and serious. 
The Sponsor or designee is responsible for determining whether a reported SAE meets the 
definition of a SUSAR. 
9.2. Expectedness 
An expected adverse reaction is an adverse reaction, the nature or severity of which is 
consistent with the applicable product information (see Investigator’s Brochure), otherwise it 
is considered unexpected. 
Based on non-clinical safety data in experimental animals as well as on Phase 1 data in healthy 
male volunteers and in patients with advanced Parkinson’s disease, adverse events are likely 
to predominantly be CNS related. Adverse reactions in patients with advanced Parkinson’s 
disease are listed below: 
Potential AEs associated with IRL790 treatment 
Nervous system 
Cardiac 
General disorders and 
administration site 
condition 
Musculoskeletal and 
connective tissue 
disorders 
Parkinsonism 
Postural dizziness 
Lethargy 
Muscular weakness 
Tremor 
Dyspnoea 
Fatigue 
 
Muscular rigidity 
 
Oedema 
 
Insomnia 
 
 
 
Somnolence 
 
 
 
Headache 
 
 
 
Slurred thinking 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 55 of 128 
 
 
Dissociation 
 
 
 
Balance disorder 
 
 
 
Dizziness 
 
 
 
Concentration 
difficulties 
 
 
 
 
9.3. Intensity of adverse event 
The grading of the severity of AEs will follow the Common Terminology Criteria for Adverse 
Events (CTCAE) v4.03 [14]. Grade refers to the severity of the AE. The CTCAE displays 
Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this 
general guideline. 
The Investigator must assess the severity of an AE using the following definitions, and record 
it on the Adverse Event Form in the CRF: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; 
limiting self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self- care ADL refer to bathing, dressing and undressing, feeding self, using the toilet taking 
medications, and not bedridden. 
 
9.4. Causality assessment 
The Investigator must assess the causal relationship between a treatment emergent adverse 
event and the IMP using the definitions below and record it on the Adverse Event Form in the 
CRF as well as on the Serious Adverse Event Report Form, if applicable: 
• Probable – the AE has a strong temporal relationship to the IMP or recurs on re-
challenge, and another aetiology is unlikely or significantly less likely 
• Possible – the AE has a suggestive temporal relationship to the IMP, and an alternative 
aetiology is equally or less likely 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 56 of 128 
 
 
• Not related – the AE has no temporal relationship to the IMP or is due to 
underlying/concurrent illness or effect of another drug (that is, there is no causal 
relationship between the IMP and the AE) 
 
An AE is considered causally related to the use of the IMP when the causality assessment is 
probable or possible. 
For baseline events, a causality assessment is not relevant. 
9.5. Action taken regarding the study drug 
The action taken regarding study drug must be described by selecting one of the following: 
• Permanently discontinued 
• Stopped temporarily 
• Dose reduced 
• Dose increased 
• No action taken 
• Unknown/not applicable 
9.6. Outcome 
The Investigator must assess the outcome of an AE using the definitions below and record it 
on the Adverse Event Form in the CRF: 
• Recovered – the patient has recovered completely, and no symptoms remain 
• Recovering – the patient’s condition is improving, but symptoms still remain 
• Recovered with sequelae – the patient has recovered, but some symptoms remain (for 
example, the patient had a stroke and is functioning normally, but has some motor 
impairment) 
• Not recovered – the patient’s condition has not improved and the symptoms are 
unchanged (for example, an atrial fibrillation has become chronic) 
• Death 
9.7. Recording adverse events 
AEs (including baseline events) identified using any of the following methods will be 
recorded: 
AEs spontaneously reported by the patient 
AEs observed by the Investigator or medical personnel 
AEs elicited based on non-leading questions from the Investigator or medical personnel 
Collection of baseline events starts after the patient signs the ICF and continues until the first 
administration of IMP. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 57 of 128 
 
 
TEAE collection starts with administration of the IMP and continues until the last follow-up 
assessment. Any AE with start date on the day of first IMP administration must be recorded 
with start time. 
At the Follow-up Visit, information on new AEs or SAEs, if any, and stop dates for AEs 
recorded and on-going during the dosing period must be recorded. 
AEs (including baseline events) must be recorded on an Adverse Event Form in the CRF. The 
Investigator must provide information on the AE, preferably with a diagnosis or at least with 
signs and symptoms; start and stop dates, start and stop time; intensity; causal relationship to 
IMP; action taken, and outcome. 
If the AE is serious, this must be indicated on the Adverse Event Form in the CRF. Furthermore, 
the Investigator must fill out the Serious Adverse Event Report Form and report the SAE to 
Diamond Pharma Services as described in Section 9.8. 
AEs, including out-of-range clinically significant safety laboratory values, must be recorded 
individually, except when considered manifestations of the same medical condition or disease 
state; in such cases, they must be recorded under a single diagnosis. 
If the severity/intensity of an AE increases a new Adverse Event Form must be completed in 
the CRF. 
Patients with AEs occurring during the study must be treated according to clinical practice at 
the discretion of the Investigator. 
AEs must be followed up until resolution or the follow-up assessment, whichever comes first. 
At the Follow-up Visit, information on new AEs, if any, and stop dates for previously reported 
AEs must be recorded. 
It is the responsibility of the Investigator to follow up on all SAEs until the patient has 
recovered, stabilised, or recovered with sequelae and to report to the Sponsor all relevant new 
information using the same procedures and timelines as those for the initial report. Relevant 
information includes discharge summaries, autopsy reports, and medical consultation. 
SAEs spontaneously reported by a patient to the Investigator within 30 days after the last 
follow-up assessment must be handled in the same manner as SAEs occurring during the study. 
These SAEs will be reported to the Sponsor. 
9.8. Serious Adverse Events  
All SAEs must be reported to the CI, CRO and Sponsor immediately and within 24 hours of 
awareness, regardless of causal relationship. An SAE form must be filled in by a member of 
the research team and kept in the TMF. 
All SAEs occurring until the end of the trial must be reported by fax and/or email immediately 
by the Investigator or designated assistant is made aware of the event and by full report as soon 
as possible thereafter. 
All SAEs must be emailed or faxed to Diamond Pharma Services: 
Email: PVServices@diamondpharmaservices.com  
Fax number: +44 (0)1279 418 964 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 58 of 128 
 
 
 
Where the Investigator requires advice regarding the handling of Serious Adverse Events, the 
contact in case of emergency is: 
Diamond Pharma Services Emergency 24 hour phone number: +44 (0)1279 441 616 
Pregnancies occurring during the study must be reported immediately by fax using the SAE 
Form. 
IRL and Diamond Pharma Services will keep the Investigator and DSMB (Section 23) 
informed of all SAEs reported to them for the product under investigation, from anywhere in 
the world, for the duration of the trial at a frequency appropriate to the trial.  
In addition, any new safety information that would adversely affect the safety of patients or the 
conduct of the trial will be reported by IRL to the CAs, RECs, DSMB and Investigators. If the 
trial is to be suspended as a result of a SUSAR, or due to any urgent safety measure taken, the 
CA and REC will be notified as soon as possible and within three days of the decision.  
IRL will submit Safety Reports to the CAs and RECs annually or more frequently if so 
requested. 
9.9. Reporting of SUSARs 
Diamond Pharma Services will report SUSARs occurring in the trial to the CA and to the 
relevant Research Ethics Committees (REC(s)) in line with the applicable regulatory 
requirements and to the DSMB as outlined in Section 23. 
10. DATA MANAGEMENT 
Data will be recorded on a CRF by the Investigator (or designee). The database, data entry and 
electronic checks will be developed using a Clinical Database Management System. 
Computerised data cleaning checks will be used in addition to manual review to check for 
discrepancies and to ensure consistency and completeness of the data.  An electronic audit trail 
system will be used to track all data changes in the database. 
Data clarification queries will be generated electronically in order to clarify any issues which 
arise regarding the data entered into the CRF and database. 
A 100% quality control check of the data entry will be performed on a randomly selected 
sample of the CRFs. 
Medical history findings and adverse events will be coded using the MedDRA dictionary; 
medications will be coded using the World Health Organisation Drug dictionary. 
10.1. Trial Documentation and Trial Confidentiality 
10.1.1. Trial Documentation, CRFs and Document Keeping 
The Investigator must generate and maintain adequate records (patient medical records, Case 
Report Forms, source documents) to enable the conduct of this trial to be fully documented. 
Each patient enrolled into the trial must have a CRF completed and the CRF must be reviewed 
and signed off by the Investigator. This applies to those patients who failed to complete the 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 59 of 128 
 
 
trial (even during the pre-randomisation period). CRFs are to be completed either at the time 
of the patient’s visit or as soon as possible after the visit so that they always reflect the latest 
observations on the patients participating in the study. The Investigator must verify that all data 
entries in the CRFs are accurate and correct. The nature and location of all source documents 
will be identified to ensure that all sources of original data required to complete the CRF are 
known to the investigational staff and are accessible for verification by the clinical monitor. If 
electronic records are maintained, the method of verification must be discussed with the 
investigational staff. A source data verification log will be prepared by the CRO. This will 
describe the proportion of CRF data that will be verified by the monitor against the patients’ 
medical records and source data.  
The Sponsor recommends that the author of an entry in the source documents be identifiable. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded on the CRF are consistent with the original source data. 
If data are recorded directly into the CRF, there should be, at a minimum, an entry in the 
medical record that each of the assessments was performed; who performed it and the date it 
was done. 
The CRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data. All entries, corrections, and alterations are to be made by the responsible 
Investigator or an authorised member of the investigational staff. 
Data clarification and query resolution will be conducted on an ongoing basis by the monitor 
and the contract data management company. The Sponsor will have overall responsibility for 
the data. 
The Principal Investigator must be aware of their responsibility to retain patient identification 
codes in line with regulatory requirements after completion or discontinuation of the trial. If a 
patient ceases treatment prematurely, then the reason must be noted in the CRF. If a patient 
ceases treatment because of an adverse event, reasonable efforts must be made to clearly 
document the outcome. 
The Principal Investigator will allow authorised Sponsor personnel, auditors and regulatory 
authorities direct access to the patients’ medical records.  
Copies of protocols, CRF page/printouts, originals of test results, reports, drug dispensing logs, 
correspondence, records of informed consent or other documents pertaining to the conduct of 
the trial must be kept on file by the Investigator in line with regulatory requirements or for the 
period of time specified by local law for the preservation of hospital patient documents, 
whichever is the longer. No trial documents should be destroyed without prior written 
agreement between Sponsor and the Investigator. Where storage at the centre is limited, the 
Sponsor may make arrangement for documents to be stored at an independent data archiving 
facility on behalf of the Principal Investigator. Should the Investigator wish to assign the trial 
records to another party, or move them to another location, the clinical trial monitor must be 
consulted.  
10.1.2. Confidentiality of Trial Documents and Patient Records 
The Investigator must ensure the patients’ anonymity is maintained. On CRFs or other 
documents submitted to TCTC/the Sponsor/third party contractor, patients must NOT be 
identified by their names but by an identification code (usually their trial number). The 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 60 of 128 
 
 
Investigator will be responsible for maintaining a separate log of patients’ codes, names and 
unique identifiers. This log will be maintained as required by applicable regulatory 
requirements. Documents not for submission to TCTC/the Sponsor/third party contractor, e.g. 
patients’ written consent forms, must be maintained by the Investigator in strict confidence. 
11. 
 STATISTICAL METHODS 
Statistical methods are outlined, however a Statistical Analysis Plan (SAP) will be produced 
between finalisation of the CRF and database lock. This will include detailed descriptions of 
all statistical methodology utilised, planned analyses (with any ‘sensitivity’ analyses), 
together with master table and listing shells and outline figures for reporting. 
 
11.1. General Considerations 
A single analysis at the conclusion of the investigation is planned and there will be no interim 
analyses (other than data safety reviews) that may impact on the experiment wide type 1 error 
rate. 
 
All data will be described and analysed according to Treatment group (IRL790, Placebo), 
Day of assessment (Screening, Day 1 (Baseline), 7, 14, 21, 28, End of Treatment (Day 28 or 
last observation in the event of withdrawal), plus Follow-up (if appropriate)). However as this 
is a maximum tolerated dose (MTD) investigation where appropriate summaries according to 
dose group may also be described. 
 
All interval (quantitative continuous) data will be presented as means, standard deviation, 
minimum, maximum, median, lower quartile and upper quartile as well as number of 
observations for both Actual values and Change from baseline data. All Categorical 
(qualitative binary, ordinal) data will be presented in contingency tables as frequencies and 
percentages with the denominator the total number of patients available from the relevant 
analysis set. 
 
Statistical methods applied will be appropriate to the nature and distribution of the data. A 
(two-sided10) significance level of 5% (<0.05) will be implemented throughout and in view to 
the stage of development of the drug no statistical adjustment for ‘multiplicity’ of analysis 
testing performed is planned. Graphical displays will be used to support the findings 
wherever possible. All will use two-sided 95% confidence intervals to allow estimation of the 
minimum likely effect size, which will be useful when moving the development programme 
forward to Phase III. 
 
The null hypothesis assumed throughout is that there is no difference between the Active 
treatment and the Control for any comparison performed (IRL790 vs Placebo). The 
alternative hypothesis is that there is in fact a difference and this may be in either direction in 
favour of active or the control. 
 
All data derivations, manipulations and reporting procedures will use SAS v9.4 in a Windows 
10 operating system environment. All data summaries will be supported by data listings with 
individual patient details.  
 
10 A two tailed type 1 error rate allows satisfaction of a routinely accepted bilateral alternative hypothesis. Strong 
evidence would be required to justify that the treatment could not adversely affect outcome. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 61 of 128 
 
 
 
11.2. Sample Size/Power Calculation 
Seventy Four (74) evaluable patients (37 per group) are sufficient to demonstrate an effect 
size of 0.67 between the active treatment and control (IRL790 vs Placebo) for the UDysRS 
primary endpoint with 80% power and type 1 error rate 0.05 (two tailed).  
 
As the drop-out rate is unknown at the outset recruitment will continue across the 15 sites 
until the total evaluable number of patients required is obtained. 
 
The effect size used is derived from the mean difference between the active and control 
groups (at the end of the treatment period) standardised according to the pooled 'between' 
group standard deviation. Estimates for these were obtained from published literature (Table 
1). 
 
Table 1: Sources For Effect Size 
Reference 
Mean Difference  
(A-P) (Diff) (n per group) 
After X Weeks Treatment  
 
Pooled Standard 
Deviation 
Effect 
Size11 
Goetz (2013)[15] 
31-23 (14) (30 per group) 
4wks Actual values 
~12 
0.58 
Pahwa (2017)[16] 
16 - 8 (8) (60 per group) 
12wks Change from baseline 
~12.3 (SE:1.6) 
0.6512 
Pahwa (2015)[17] 
16.7 - 6.7 (10) (20 per group) 
8wks Change from baseline 
~13 (SE: 3) 
0.7713 
 
11.3. Analysis Sets 
Three analysis sets (or patient populations) will be evaluated: The Full Analysis Set (FAS), 
Per Protocol Set (PPS) and the Safety Set (SS). 
 
The Full Analysis Set (FAS) will consist of all randomised and treated patients who receive 
one or more doses and who provide post baseline data whether or not they fully comply with 
the requirements of the protocol. However, given the stage of development patients will be 
analysed according to the treatment they actually receive in the event of randomisation errors 
and not according to the scheduled treatment assignment. 
 
The Per Protocol Set (PPS) will consist of patients from the FAS but exclude those with 
major protocol violations. A list of all relevant situations which constitute major protocol 
violations and constitute reasons for exclusion from the PPS will be described in the SAP.  
 
Patients who are to be included in and excluded from the PPS will be identified and listed 
following a Blind Data Review performed prior to the conclusion of the clinical investigation, 
database lock and unblinding. 
 
11 NB: Smaller effect size = larger sample size required to detect difference 
12 n per group approx 37 with 80% power 
13 n per group approx 28 with 80% power 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 62 of 128 
 
 
 
Statistical analyses for the primary and secondary endpoints will be performed using both the 
FAS and PPS. Although the FAS is considered of primary importance, the PPS will enable 
evaluation of the sensitivity and robustness of the estimates of the magnitude of the treatment 
effect 
 
All other evaluations will involve the FAS population (i.e.: Demographic and baseline 
characteristics, Exploratory investigations, Pharmacokinetics). 
 
The Safety Set (SS) will consist of all patients who receive at least one dose of study drug. 
All safety and tolerability evaluations will be based on this analysis set. Again patients who 
receive the wrong treatment according to the randomisation schedule will be analysed 
according to the treatment actually received. 
 
The SS population will be applied to all safety and tolerability assessments and analyses. 
 
11.4. Study Population 
All basic information regarding the sample of patients recruited to represent the PD 
population with dyskinesia will be summarised. This will include all assessments performed 
prior to the start of treatment (Screening) including Demographics (Gender, Age, Ethnicity 
and Race), Medical history, Diagnosis of PD, Duration of PD, Height, Weight, BMI, MMSE, 
Hoehn and Yahn Scale score and Prior medications. Each will be described overall and 
according to treatment group. 
  
11.5. Baseline Treatment Dose Group Comparability 
No formal statistical comparisons of the treatment groups at Screening or Baseline (Visit 1, 
Day 1) will be performed as this serves only to assess the randomisation process. 
 
11.6. Treatment Compliance 
At the conclusion of treatment period an assessment of compliance with the required dosing 
schedule will be performed and summarised by treatment group (((total tablets taken - total 
prescribed)/total prescribed)*100%). 
 
11.7. Efficacy Endpoints 
The primary efficacy variable is the UDysRS total score.  
 
This rating scale has two primary sections:  Historical [Part 1 (On-Dyskinesia) and Part 2 
(Off-Dystonia)], Objective [Part 3 (Impairment) and Part 4 (Disability)]. The Historical part 
has 15 items and the Objective part 11 items with each item having 0-4 ratings, where 0 = 
normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The subtotals for both the 
Historical and Objective parts are summed to give an overall score. 
 
The secondary efficacy variables involve a subset of the UDysRS, the MDS-UPDRS and the 
24-hour patient diaries (Table 2). 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 63 of 128 
 
 
The MDS-UPDRS has four parts with; (Part 1) nonmotor experiences of daily living (13 
items), (Part 2) motor experiences of daily living (13 items), (Part 3) motor examination (18 
items), and (Part 4) motor complications (six items). Each subscale has 0-4 ratings, where 0 = 
normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. 
 
Therefore in all efficacy evaluations the higher scores indicate worse symptoms. 
 
Table 2: Secondary Endpoints: 
 
 
The exploratory efficacy variables comprise a number of additional subsections of the MDS-
UPDRS and 24-hour patient diaries (Table 3).  
 
Table 3: Exploratory Endpoints: 
 
 
All the endpoints are measured at Screening and at Visit 4 (or earlier in the event of 
withdrawal) or during the intervening period for the 24-hour patient diaries.  
 
The Change from baseline (Screening) at Day 28 (Visit 4, Day 28) and End of Treatment (Day 
28 (Visit 4, Day 28 or earlier in the event of withdrawal)) for each patient will be derived for 
each endpoint and each endpoint summarised descriptively (according to Treatment group and 
Day of assessment (Screening, Day 28, End of Treatment). The End of Treatment last 
assessment available will be analysed as Interval data.  
Scale  
Component 
Attribute 
UDysRS 
Total Objective Score (III, IV) 
Total score 
MDS-UPDRS 
Part III (Motor) 
Part Score 
 
Part IV Questions 4.1 and 4.2 
Sum score 
24-hour 
patient 
diaries 
OFF time 
Total daily 
hours 
Scale  
Component 
Attribute 
MDS-UPDRS 
Part I  
Total score 
 
Part II  
Total score 
 
Part IV  
Total score 
 
Question 1.2  
(Hallucinations and Psychosis) 
Score 
 
Question 1.6  
(Features of dopamine dysregulation 
syndrome) 
Score 
24-hour 
patient 
diaries 
ON time 
Total daily 
hours  
 
ON 
time 
with 
troublesome 
dyskinesia 
Total daily 
hours  


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 64 of 128 
 
 
11.8. Pharmacokinetic Endpoints 
PK variables measured in plasma include: IRL790 parent drug and two of its metabolites 
(IRL902 (n-dealkylated) and IRL872 (acetylated)). In addition, biomarker P-Prolactin is also 
measured. 
 
Samples obtained pre-dose and 2h post dose (Cmax) on Day 1 and Day 28 will be summarised 
as interval data (using number (n), arithmetic mean, standard deviation (SD), minimum and 
maximum value, geometric mean and coefficient of variation (CV%)). If appropriate these 
will be presented overall for the IRL790 treated group but also according to IRL dose. 
 
In order to potentially assess the pharmacokinetic relationship between the treatment doses 
(7.5mg b.i.d. upwards) parent drug and metabolite assays obtained pre-dose and 2h post dose 
(Cmax) on Day 1 and Day 28 each will be analysed separately. 
 
This analysis will involve application of a polynomial regression model to fit dose or 
log(dose) vs drug plasma concentration with subsequent evaluation of the significance of the 
curve fit. However as this is a maximum tolerated dose (MTD) investigation the number of 
patients in each group is not known in advance. The analysis is therefore dependent on the 
resulting group sizes. 
 
11.9. Efficacy Analyses 
All Primary, Secondary and Exploratory endpoints (except CGI)  can be considered 
quantitative continuous data (Interval in type). As such the Change from baseline at  and at 
End of Treatment (Visit 4, Day 28 or earlier in the event of withdrawal) will be derived for 
each patient and analysed using an Analysis Of Covariance (ANCOVA) model to compare 
the two treatment groups (IRL790 vs Placebo). 
 
The ANCOVA analysis will allow estimation of the size of treatment effects as well as 
magnitude of differences between the active treatment and control (IRL790 - Placebo). The 
dependent variable will be the Change from baseline value and Treatment group the 
explanatory (independent) variable and fixed factor. A baseline covariate term will be 
included to ensure minimum variance unbiased estimation.  
 
In view of the small sample size and relatively large number of sites there are insufficient 
degrees of freedom to include Site as a factor in the model. 
 
Model assumptions will be investigated and a suitable data transformation or non-parametric 
equivalent model substituted if appropriate. 
 
Actual p-values and 95% confidence intervals for least square mean estimates of the 
treatment effects and differences from placebo will be presented for these models. 
 
The CGI exploratory endpoint is the only other type of data collected. This qualitative and 
ordinal categorical variable will be analysed using the Van Elteren non parametric hypothesis 
test (equivalent to Cochran Mantel-Haenszel test with modified ridits (CMH-row mean 
scores differ). Statistical significance (p-values) for differences between the two Treatment 
groups (IRL790, Placebo) will be reported together with the actual response proportions. 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 65 of 128 
 
 
11.10. Safety Analyses 
Safety evaluations include: Adverse events and Concomitant medications reporting, 
Complete physical examination, Vital signs, ECG (12 lead) at rest and Clinical safety 
laboratory tests (clinical chemistry, haematology and coagulation).  
 
Adverse events and concomitant medications are recorded throughout the investigational 
period with the rest performed at Screening, Day 28 (Visit 4 or at Withdrawal) and Follow-up 
(5-8 days after Visit 4).  
 
All safety laboratory samples are assayed at the local hospital. 
 
All safety evaluations will be presented as Interval or Categorical data summaries (as 
appropriate) according to Treatment group and Day of assessment (if appropriate) for the 
Safety population. No formal statistical analyses will be performed. 
 
11.10.1. 
Adverse Events 
All AEs will be summarised according to TEAE or Baseline Event following classification of 
the verbatim terms according to the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. The number and percentage of patients for all classified events will be presented 
according to System organ class (SOC) and Preferred term (PT) by treatment group and 
overall.  
 
Separate summaries will be presented for all AEs by event frequency of occurrence and also 
for all AEs according to Seriousness, Severity and Relationship. 
 
If appropriate separate summaries according to IRL790 maximum tolerated dose received 
may be used to support the findings.  
 
11.10.2. 
Concomitant Medications 
Concomitant medication will be summarised by Anatomical Therapeutic Chemical (ATC) 
code levels 2 and 4 using the World Health Organisation Drug dictionary (WHODD) with the 
number and percentage of patients by treatment group and overall. 
 
11.10.3. 
Physical Examinations 
Physical examination results will be categorically summarised as the number and percentage 
of patients according to body type, treatment group and assessment day.  
 
In addition, Weight additionally measured at Follow up following Screening will be 
summarised with descriptive statistics for Actual values and Change from Screening by 
treatment group. 
 
11.10.4. 
Vital Signs 
For blood pressure and pulse rate, descriptive statistics of Actual values and Change from 
Screening will be used to summarise by treatment group and assessment day. Categorically 
classified (Normal/Abnormal) results will also be summarised.  
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 66 of 128 
 
 
11.10.5. 
ECG (12-Lead) At Rest 
ECG variables will be summarised according to Actual values and Change from Screening 
using descriptive statistics and will be presented by treatment group and assessment visit. 
Categorically classified (Normal/Abnormal) results will also be summarised.  
 
11.10.6. 
Clinical Laboratory Tests 
All haematology, clinical chemistry and coagulation laboratory tests will be summarised 
using descriptive statistics for Actual values and Change from Screening and presented by 
treatment group and assessment day for each Hospital site separately (due to assays 
performed locally).  
 
Additionally the local laboratory normal ranges will be used to classify the results as: High, 
Normal or Low and categorical summaries presented overall according to treatment group 
and assessment visit. Pooling across all sites is possible here due to the categorical 
classification. 
 
12. 
ETHICS COMMITTEE APPROVAL 
The study proposal will be submitted to the Ethics Committee in accordance with the national 
requirements. 
The REC shall give its opinion in writing before the clinical trial commences. The Investigator 
should provide written reports to the REC annually or more frequently if requested on any 
changes significantly affecting the conduct of the trial and / or increasing risk to the patients. 
13. 
 REGULATORY REQUIREMENTS 
The study will be authorised by Medicines and Healthcare products Regulatory Agency 
(MHRA). 
Enrolment of patients will not commence until approval has been received from both the Ethics 
Committee(s) and Competent Authority. 
The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical 
Practice (GCP) and all other national requirements. 
14. 
INFORMED CONSENT 
It is the responsibility of the Investigator or an authorised associate to give each potential study 
patient adequate verbal and written information before any study specific assessments are 
performed. 
The information will include the objectives and the procedures of the study as well as any risks 
or inconvenience involved. It will be emphasised that participation in the study is voluntary 
and that the patient may withdraw from participation at any time and for any reason, without 
any prejudice. All patients will be given the opportunity to ask questions about the study and 
will be given sufficient time to consider participation before signing the ICF. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 67 of 128 
 
 
Before performing any study-related procedures the ICF must be signed and personally dated 
by the patient and by the Investigator. A copy of the Patient Information including the signed 
ICF will be provided to the patient. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation and in the CRF. The Patient Information sheet and the signed ICF should 
be filed by the Investigator for possible future audits and/or inspections.  
The final approved version of the Patient Information and ICF must not be changed without 
approval from the Sponsor and the applicable EC.  
15. 
DIRECT ACCESS TO SOURCE DOCUMENTATION / DATA 
The Investigator must permit trial-related monitoring, audits, Ethics Committee review or 
regulatory inspection, providing direct access to source data/documents. 
16. 
STUDY MONITORING AND MANAGEMENT 
16.1. Training of study site personnel 
Before enrolment of the first study patient a Sponsor representative or delegate will perform a 
Study Initiation Visit at the study site. The requirements of the Clinical Study Protocol and 
related documents will be reviewed and discussed and the investigational staff will be trained 
in any study specific procedures and system(s) utilised. 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are 
fully informed of all relevant aspects of the study and have a detailed knowledge of and training 
in the procedures that are to be executed by them. Any new information of relevance to the 
performance of this study must be forwarded to the staff involved in a timely manner. 
The Investigator will keep a list of all personnel involved in the study together with their 
function and study related duties delegated. A Curriculum Vitae will be available for all staff 
delegated study-specific duties. 
16.2. Clinical Monitoring 
The study site will be periodically monitored at times agreed on by the Investigator and the 
Monitor. At the time of each monitoring visit, the function of the Monitor is to:  
− provide information and support to the investigational team. 
− confirm that facilities and resources remain acceptable. 
− confirm that the investigational team is adhering to the Clinical Study Protocol, 
applicable SOPs, guidelines, manuals and regulatory requirements.  
− verify that data are being accurately and timely recorded in the CRFs and that IMP 
accountability checks are being performed. 
− verify that data in the CRF are consistent with the clinical records (SDV).  
− verify that the correct informed consent procedure has been adhered to for participating 
patients. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 68 of 128 
 
 
− ensure that withdrawal of informed consent to the use of the patient’s biological 
samples will be reported and biological samples are identified and disposed/destroyed 
accordingly, and that this action is documented and reported to the patient. 
− verify that AEs are recorded and reported in a timely manner and according to the 
Clinical Study Protocol. 
When the study has been completed, all queries have been resolved and the database has been 
locked, the Monitor will perform a close-out visit at the study site. 
 
16.3. Source Data 
The primary source documents for this study will be the patient’s medical records and all rating 
scale CRFs and worksheets used to directly record assessment scores for MMSE, MDS-
UPDRS, UDysRS and CGI-C throughout the study. If separate research records are maintained 
by the investigator(s) both the medical record and the research records should be 
monitored/audited for the purpose of the study. 
A separate source data agreement will be generated at the study site before start of enrolment, 
specifying the location of the source of derived information appearing in the CRF. This 
document must be signed by the Principal Investigator and the Monitor to confirm agreement 
before start of recruitment. 
The Investigator should guarantee access to source documents to the Monitor, Competent 
Authorities and the ECs, as required. 
16.4. Study agreements 
The Principal Investigator must comply with all the terms, conditions, and obligations of the 
Clinical Study Agreement (CSA) for this study. 
Agreements between Sponsor and the study sites must be in place before any study-related 
procedures can take place, or patients be enrolled. 
16.5. Study time table and end of study 
The end of the clinical part of the study is defined as the last visit of the last patient participating 
in the study. 
The study is expected to start in Quarter 4, 2017 and to be completed by Quarter 2, 2018.  
17. 
QUALITY ASSURANCE 
Authorised representatives of Sponsor, Competent Authority or EC may perform audits or 
inspections at the study site, including Source Data Verification (SDV). The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities 
and documents, to determine whether these activities were conducted and data were recorded, 
analysed, and accurately reported according to the Clinical Study Protocol, ICH-GCP 
guidelines and any applicable regulatory requirements. The Investigator will contact the 
Sponsor immediately if contacted by a Competent Authority about an inspection at the study 
site. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 69 of 128 
 
 
18. 
INSURANCE 
Appropriate insurance cover has been secured in favour of patients participating in clinical 
trials. The cover is provided to the patient on terms and conditions of the clinical trial insurance. 
Insurance cover exists for health damages as a result of measures carried out in connection with 
the clinical trial. 
19. 
CONFIDENTIALITY 
All study documents are provided by the Sponsor in confidence to the Investigator and 
appointed staff. No study material may be disclosed to any party not directly involved in the 
study without written permission from the Sponsor.  
The Investigator must assure that patient’s anonymity will be provided. The Investigator will 
keep a separate list with at least the initials, the patient’s study number, names, addresses and 
telephone numbers. The Investigator will maintain this for as long as requested by the Sponsor. 
Details of access to the patients’ data, conforming to the requirements of EU Directive 
95/46/EC, will be fully described within the patient information sheet. The consequence of the 
patients’ withdrawal of consent with regards to the use of data will also be described. 
20. 
PREMATURE TERMINATION OF THE STUDY 
The Sponsor reserves the right to discontinue the study at any time, but intends only to exercise 
this right for valid scientific or administrative reasons. 
After such a decision, the Investigator must inform all participating patients and perform 
relevant assessments, preferably according to the scheme for the final assessments. All 
delivered and unused IMP and other study materials must be returned and all CRFs completed 
as far as possible. 
21. 
RECORD RETENTION 
After completion of the study, all documents and data relating to the study will be kept in an 
orderly manner by the Investigator in a secure study file. 
Essential documents must be retained for at least two years after the final marketing approval 
in an ICH region or until two years have elapsed since the formal interruption of the clinical 
development of the product under study. 
It is the responsibility of the Sponsor to inform the Investigator of when these documents can 
be destroyed. The Investigator must contact the Sponsor before destroying any trial-related 
documentation. In addition, all patients’ medical records and other source documentation will 
be kept for the maximum time permitted by the institution. 
22. 
PUBLICATION OF RESULTS 
22.1. Clinical Study Report  
A summary report must be submitted to the Competent Authority and EC within 12 months of 
completion of the study. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 70 of 128 
 
 
A Clinical Study Report, in compliance with ICH E3; Structure and content of Clinical Study 
Reports, describing the conduct of the study, the statistical analysis performed and the results 
obtained, will be prepared. The report will be reviewed and approved by, as a minimum, the 
Chief Investigator, Statistician and the Sponsor. 
22.2. Annual safety report 
If the study duration exceeds one year, the Sponsor must submit an annual safety report to the 
Competent Authority and to the REC. The report shall summarise all SAEs and contain an 
update of the risk-benefit evaluation if there has been any change since the approval of the 
clinical study. 
22.3. Confidentiality and ownership of study data 
Any confidential information relating to the IMP or the study, including any data and results 
from the study will be the exclusive property of the Sponsor. The Investigator and any other 
persons involved in the study will protect the confidentiality of this proprietary information 
belonging to the Sponsor. 
22.4. Publication 
The Sponsor is entitled to publish and/or present any results at scientific meetings, and to 
submit clinical trial data to national and international Regulatory Authorities. The Sponsor 
reserves the right to use such data for commercial purposes. 
The results from this study will be submitted for publication only at the discretion of the 
Sponsor. 
23. 
DATA SAFETY MONITORING BOARD (DSMB) 
A committee will be set-up to monitor safety throughout the trial period. The committee will 
comprise a group of independent experts and will include a chairperson, a neurologist 
experienced in Parkinson’s disease and a statistician all of whom will be independent of the 
Sponsor and will not be involved in the conduct of the trial. 
A charter describing how the DSMB works and how it communicates with other study 
participants (e.g. steering committee) will be prepared. 
The DSMB will review unblinded study information which will include: 
• List of any protocol violations 
• Numbers of patient withdrawals/reason for withdrawal 
• Adverse/serious adverse events 
• Laboratory data 
 
Following review of the safety data, the committee will prepare written reports which will be 
forwarded to the Sponsor advising of any recommendations regarding modifications, 
continuation or termination of the study. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 71 of 128 
 
 
Where changes in the study conduct are recommended to the Sponsor, sufficient (blinded) 
information will be provided to allow the Sponsor to decide whether and how to implement 
these recommendations. 
DSMB Meetings: 
 
The DSMB will convene after 20 and 40 patients have completed the Follow-Up visit (with 
adequate safety assessment data) for a formal safety review. 
 
The assessment will provide three possible outcomes: 
1. Proceed as planned 
2. Proceed after substantial modification of the protocol 
3. Discontinue the study 
 
Recruitment will continue throughout the 20 and 40 patient DSMB 
 
 
24. 
REFERENCES 
1. Hwang, K. S., M. K. Beyer, A. E. Green, C. Chung, P. M. Thompson, C. Janvin, J. P. 
Larsen, D. Aarsland and L. G. Apostolova (2013). "Mapping cortical atrophy in 
Parkinson's disease patients with dementia." J Parkinsons Dis 3(1): 69-76. 
2. Yoritaka, A., Y. Shimo, M. Takanashi, J. Fukae, T. Hatano, T. Nakahara, N. 
Miyamato, T. Urabe, H. Mori and N. Hattori (2013). "Motor and non-motor 
symptoms of 1453 patients with Parkinson's disease: prevalence and risks." 
Parkinsonism Relat Disord 19(8): 725-731. 
3. Bastide, M. F., Meissner, W. G., Picconi, B., Fasano, S., Fernagut, P. O., Feyder, M., 
& Bézard, E. (2015). Pathophysiology of L-dopa-induced motor and non-motor 
complications in Parkinson's disease. Progress in neurobiology. 132, 96 -168. 
4. Manson, A., P. Stirpe and A. Schrag (2012). "Levodopa-induced-dyskinesias clinical 
features, incidence, risk factors, management and impact on quality of life." J 
Parkinsons Dis 2(3): 189-198. 
5. Zhu, K., J. J. van Hilten, H. Putter and J. Marinus (2013). "Risk factors for 
hallucinations in Parkinson's disease: results from a large prospective cohort study." 
Mov Disord 28(6): 755-762. 
6. Friedman, J. H. (2013). "Parkinson disease psychosis: Update." Behav Neurol 27(4): 
469-477. 
7. Samii, A., J. G. Nutt and B. R. Ransom (2004). "Parkinson's disease." Lancet 
363(9423): 1783-1793. 
8. Picconi, B., G. Piccoli and P. Calabresi (2012). "Synaptic dysfunction in Parkinson's 
disease." Adv Exp Med Biol 970: 553-572. 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 72 of 128 
 
 
9. Hondeghem, L. M. and P. Hoffmann (2003). "Blinded test in isolated female rabbit 
heart reliably identifies action potential duration prolongation and proarrhythmic 
drugs: importance of triangulation, reverse use dependence, and instability." J 
Cardiovasc Pharmacol 41(1): 14-24. 
10. Investigator’s Brochure IRL790. Edition 1.3, 4th September 2017. 
11. Shulman et al. Disability Rating Scales in Parkinson’s Disease: Critique and 
Recommendations. 
12. Griffiths RI, et al. Automated assessment of bradykinesia and dyskinesia in 
Parkinson's disease. Journal of Parkinson's disease. 2012;2(1):47-55. Epub 
2012/01/01. 
13. Horne MK, McGregor S, Bergquist F. An objective fluctuation score for Parkinson's 
disease. PLoS One. 2015;10(4):e0124522. Epub2015/05/01. 
14. National Cancer Institute, Cancer Therapy Evaluation Program. Common terminology 
criteria for adverse events, CTCAE v4.03, 2010 
15. Goetz CG 2013 Which Dyskinesia Scale Best Detects Treatment Response? Mov 
Disord. 2013 Mar;28(3):341-6.  
16. Rajesh Pahwa 2017: ADS-5102 (Amantadine) Extended-Release Capsules for 
Levodopa-Induced Dyskinesia in Parkinson Disease (EASE LID Study) JAMA 
Neurol. 2017;74(8):941-949 
17. Rajesh Pahwa 2015: "Amantadine Extended Release for Levodopa-Induced 
Dyskinesia in Parkinson’s Disease (EASED Study)" Movement Disorders, Vol. 30, 
No. 6, 2015 
18. Papapetropoulos SS. Patient diaries as a clinical endpoint in Parkinson's disease 
clinical trials. CNS Neurosci Ther. 2012;18:380-7 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 73 of 128 
 
 
 
25. 
APPENDICES 
25.1. Appendix 1 Mini-Mental State Examination (MMSE) 
Localised Versions of the Rating scales will be used 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 74 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 75 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 76 of 128 
 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 77 of 128 
 
 
25.2. Appendix 2 Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 
Localised Versions of the Rating scales will be used 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 78 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 79 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 80 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 81 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 82 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 83 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 84 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 85 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 86 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 87 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 88 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 89 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 90 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 91 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 92 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 93 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 94 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 95 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 96 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 97 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 98 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 99 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 100 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 101 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 102 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 103 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 104 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 105 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 106 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 107 of 128 
 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 108 of 128 
 
 
25.3. Appendix 3 Unified Dyskinesia Rating Scale (UDysRS) 
Localised Versions of the Rating scales will be used 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 109 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 110 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 111 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 112 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 113 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 114 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 115 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 116 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 117 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 118 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 119 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 120 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 121 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 122 of 128 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 123 of 128 
 
 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 124 of 128 
 
 
 
25.4. Appendix 4 Clinical Global Impression of Change (CGI-C) 
Localised Versions of the Rating scales will be used 
 
 
 
Clinical Global Impression of Change Rating 
 
 
Clinical Impression of Change from Baseline: 
 
 Marked improvement 
 Moderate improvement 
 Minimal improvement 
 No change 
 Minimal worsening 
 Moderate worsening 
 Marked worsening 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 125 of 128 
 
 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 126 of 128 
 
 
25.5. Appendix 5 Declaration of Helsinki 
Recommendations Guiding Medical Physicians in Biomedical Research Involving 
Human Volunteers 
Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964 amended by the 
29th World Medical Assembly, Tokyo, Japan, October 1975 and the 35th World Medical 
Assembly, Venice, Italy, October 1983 and revised 41st World Medical Assembly Hong 
Kong, 1989 and by the 48th World Medical Assembly, South Africa, October 1996  
Introduction 
It is the mission of the physician to safeguard the health of the people. His or her knowledge 
and conscience are dedicated to the fulfilment of this mission. 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration", and the International Code of 
Medical Ethics declares that, "A physician shall act only in the patient's interest when providing 
medical care which might have the effect of weakening the physical and mental condition of 
the patient".  
The purpose of biomedical research involving human volunteers must be to improve 
diagnostic, therapeutic and prophylactic procedures and the understanding of the aetiology and 
pathogenesis of disease. 
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve 
hazards. This applies especially to biomedical research. 
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human volunteers. 
In the field of biomedical research a fundamental distinction must be recognised between 
medical research in which the aim is essentially diagnostic or therapeutic for a patient, and 
medical research, the essential object of which is purely scientific and without implying direct 
diagnostic or therapeutic value to the person volunteered to the research. 
Special caution must be exercised in the conduct of research which may affect the environment, 
and the welfare of animals used for research must be respected. 
Because it is essential that the results of laboratory experiments be applied to human beings to 
further scientific knowledge and to help suffering humanity, the World Medical Association 
has prepared the following recommendations as a guide to every physician in biomedical 
research involving human volunteers. They should be kept under review in the future. 
It must be stressed that the standards as drafted are only a guide to physicians all over the world. 
Physicians are not relieved from criminal, civil and ethical responsibilities under the laws of 
their own countries. 
 
I Basic Principles 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 127 of 128 
 
 
Biomedical research involving human volunteers must conform to generally accepted scientific 
principles and should be based on adequately performed laboratory and animal experimentation 
and on a thorough knowledge of the scientific literature.  
The design and performance of each experimental procedure involving human volunteers 
should be clearly formulated in an experimental protocol which should be transmitted for 
consideration, comment and guidance to a specially appointed committee independent of the 
Investigator and the Sponsor provided that this independent committee is in conformity with 
the laws and regulations of the country in which the research experiment is performed.  
Biomedical research on human volunteers should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility 
for the human volunteer must always rest with a medically qualified person and never rest on 
the volunteer of the research, even though the volunteer has given his or her consent.  
Biomedical research involving human volunteers cannot legitimately be carried out unless the 
importance of the objective is in proportion to the inherent risk to the volunteer.  
Every biomedical research project involving human volunteers should be preceded by careful 
assessment of predictable risks in comparison with foreseeable benefits to the volunteer or to 
others. Concern for the interest of the volunteer must always prevail over the interests of 
science and society.  
The right of the research volunteer to safeguard his or her integrity must always be respected. 
Every precaution should be taken to respect the privacy of the volunteer and to minimise the 
impact of the study on the volunteer's physical and mental integrity and on the personality of 
the volunteer.  
Physicians should abstain from engaging in research projects involving human volunteers 
unless they are satisfied that the hazards involved are believed to be predictable. Physicians 
should cease any investigation if the hazards are found to outweigh the potential benefits.  
In publication of the results of his or her research, the physician is obliged to preserve the 
accuracy of the results. Reports on experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication.  
In any research on human beings, each potential volunteer must be adequately informed of the 
aims, methods, anticipated benefits and potential hazards of the study and the discomfort it 
may entail. He or she should be informed that he or she is at liberty to abstain from participation 
in the study and that he or she is free to withdraw his or her consent to participation at any time. 
The physician should then obtain the volunteer's freely-given informed consent, preferably in 
writing.  
When obtaining informed consent for the research project the physician should be particularly 
cautious if the volunteer is in a dependent relationship to him or her or may consent under 
duress. In that case the informed consent should be obtained by a physician who is not engaged 
in the investigation and who is completely independent of this official relationship.  
In the case of legal incompetence, informed consent should be obtained from the legal guardian 
in accordance with national legislation. Where physical or mental incapacity makes it 


Integrative Research Laboratories AB (IRLAB)  
IRL790C003 
Confidential 
Protocol: IRL790C003 
Version: 6 
Date: 14 Jan 2019 
Page 128 of 128 
 
 
impossible to obtain informed consent, or when the volunteer is a minor, permission from the 
responsible relative replaces that of the volunteer in accordance with national legislation.  
Whenever the minor child is in fact able to give consent, the minor's consent must be obtained 
in addition to the consent of the minor's legal guardian.  
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that the principles enunciated in the present Declaration are complied with.  
II  Medical Research Combined With Professional Care (CLINICAL RESEARCH) 
In the treatment of the sick person, the physician must be free to use a new diagnostic and 
therapeutic measure, if in his or her judgement it offers hope of saving life, re-establishing 
health or alleviating suffering.  
The potential benefits, hazards and discomfort of a new method should be weighed against the 
advantages of the best current diagnostic and therapeutic methods.  
In any medical study, every patient - including those of a control group, if any - should be 
assured of the best proven diagnostic and therapeutic method. This does not exclude the use of 
inert placebo in studies where no proven diagnostic or therapeutic method exists.  
The refusal of the patient to participate in a study must never interfere with the physician-
patient relationship.  
If the physician considers it essential not to obtain informed consent, the specific reasons for 
this proposal should be stated in the experimental protocol for transmission to the independent 
committee.  
The physician can combine medical research with professional care, the objective being the 
acquisition of new medical knowledge, only to the extent that medical research is justified by 
its potential diagnostic or therapeutic value for the patient  
III Non-Therapeutic Biomedical Research Involving Human Volunteers (NON-
CLINICAL BIOMEDICAL RESEARCH) 
In the purely scientific application of medical research carried out on a human being, it is the 
duty of the physician to remain the protector of the life and health of that person on whom 
biomedical research is being carried out. 
The volunteer should be volunteers - either healthy persons or patients for whom the 
experimental design is not related to the patient's illness.  
The Investigator or the investigating team should discontinue the research if in his/her or their 
judgement it may, if continued, be harmful to the individual.  
In research on man, the interest of science and society should never take precedence over 
considerations related to the well-being of the volunteer. 

SAP_001.pdf: 
Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 1 (23) 
 
 
 
 
 
 
CONFIDENTIAL 
Statistical Analysis Plan (SAP) 
___________________________________________________________ 
 
Sponsor: 
Integrative Research Laboratories AB 
Study code: 
IRL790C003 
Study title: 
A RANDOMISED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PHASE IIA STUDY 
EVALUATING THE EFFICACY AND 
TOLERABILITY OF IRL790 IN PARKINSON’S 
DISEASE DYSKINESIA 
Date: 
04JUL2018 – Draft 1 
15MAY2019 – Draft 2 
20MAY2019 – Final 
13JUN2019 – Final V02 
 
 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 2 (23) 
TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS ...................................................................................................................... 4 
2 
INTRODUCTION ........................................................................................................................................ 5 
3 
CLINICAL STUDY DETAILS .................................................................................................................... 5 
3.1 
Clinical Study Objectives.......................................................................................................... 5 
3.1.1 
Primary objective ............................................................................................................. 5 
3.1.2 
Primary endpoint ............................................................................................................. 5 
3.1.3 
Secondary objectives ....................................................................................................... 5 
3.1.4 
Secondary endpoints ....................................................................................................... 5 
3.1.5 
Exploratory endpoints ..................................................................................................... 6 
3.2 
Clinical Study Design ................................................................................................................ 6 
3.3 
Number of Subjects ................................................................................................................. 7 
3.4 
Methods of Assigning Subject to IMP ..................................................................................... 7 
4 
STATISTICAL AND ANALYTICAL PLANS........................................................................................... 7 
4.1 
Sample Size Justification .......................................................................................................... 7 
4.2 
Definition of Analysis Sets ....................................................................................................... 8 
4.2.1 
Full Analysis Set ............................................................................................................... 8 
4.2.2 
Per Protocol Analysis Set ................................................................................................. 8 
4.2.3 
Safety Analysis Set ........................................................................................................... 8 
4.2.4 
Use of analysis set ........................................................................................................... 8 
4.3 
Definition of Baseline .............................................................................................................. 9 
4.4 
Summary Statistics .................................................................................................................. 9 
4.5 
Significance Level..................................................................................................................... 9 
4.6 
Multiple Comparisons/Multiplicity ......................................................................................... 9 
4.7 
Handling of Drop-outs, Missing Data and Outliers .................................................................. 9 
4.8 
Adjustment for Covariates ...................................................................................................... 9 
4.9 
Multicenter Studies ................................................................................................................. 9 
4.10 
Examination of Subgroups....................................................................................................... 9 
4.11 
Blind Review ............................................................................................................................ 9 
5 
SUBJECTS .................................................................................................................................................... 9 
5.1 
Subject Disposition .................................................................................................................. 9 
5.2 
Baseline Characteristics and Demographics .......................................................................... 10 
6 
TREATMENT INFORMATION AND EXTENT OF EXPOSURE .................................................... 10 
6.1 
Compliance ............................................................................................................................ 10 
6.2 
Prior and Concomitant Medications ..................................................................................... 10 
7 
STATISTICAL METHODOLOGY ......................................................................................................... 10 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 3 (23) 
7.1 
Primary endpoint ................................................................................................................... 10 
7.1.1 
Definition ....................................................................................................................... 10 
7.1.2 
Analyses ......................................................................................................................... 10 
7.1.3 
Presentation .................................................................................................................. 11 
7.2 
Secondary Endpoints ............................................................................................................. 11 
7.2.1 
Definitions ..................................................................................................................... 11 
7.2.2 
Analyses ......................................................................................................................... 11 
7.2.3 
Presentation .................................................................................................................. 12 
7.3 
Exploratory Endpoints ........................................................................................................... 12 
7.3.1 
Definitions ..................................................................................................................... 12 
7.3.2 
Analyses ......................................................................................................................... 12 
7.3.3 
Presentation .................................................................................................................. 13 
7.4 
PK Endpoints .......................................................................................................................... 13 
7.4.1 
Definitions ..................................................................................................................... 13 
7.4.2 
Analyses ......................................................................................................................... 13 
7.4.3 
Presentation .................................................................................................................. 13 
7.5 
Safety Endpoints .................................................................................................................... 13 
7.5.1 
Physical Examinations ................................................................................................... 13 
7.5.2 
Vital signs ....................................................................................................................... 13 
7.5.3 
ECG (12-Lead) At Rest .................................................................................................... 14 
7.5.4 
Safety laboratory ........................................................................................................... 14 
7.5.5 
Adverse events .............................................................................................................. 14 
7.6 
Discontinuation ..................................................................................................................... 14 
7.7 
Interim Analysis ..................................................................................................................... 14 
8 
CHANGES FROM THE CSP ................................................................................................................... 14 
9 
STATISTICAL DELIVERABLES ........................................................................................................... 14 
10 
SOFTWARE ......................................................................................................................................... 15 
11 
APPROVAL .......................................................................................................................................... 16 
12 
APPENDIX ........................................................................................................................................... 17 
12.1 
Generic tables ........................................................................................................................ 17 
12.2 
AE tables ................................................................................................................................ 20 
 
 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 4 (23) 
1 
LIST OF ABBREVIATIONS 
AE – Adverse Event 
ATC – Anatomical-Therapeutic-Chemical 
CF – Clean File  
CRF – Case Report Form 
CSP – Clinical study protocol 
FAS – Full Analysis Set 
MedDRA – Medical Dictionary for Regulatory Affairs 
PPS – Per Protocol Set 
SAE – Serious Adverse Event 
SAP – Statistical Analysis Plan 
SAS – Statistical Analysis System 
SD – Standard Deviation 
 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 5 (23) 
 
 
2 
INTRODUCTION 
This Statistical Analysis Plan (SAP) gives details regarding the statistical analyses and data 
presentation outlined in the final Clinical study protocol (CSP) for the study 
IRL790C003_Protocol_V36_14Nov1714Jan2019. Any changes from the final CSP are given in 
Section 8. 
 
3 
CLINICAL STUDY DETAILS 
3.1 Clinical Study Objectives 
3.1.1 
Primary objective 
The primary objective of the study is to evaluate the effects of IRL790 on levodopa induced 
dyskinesia in patients with Parkinson’s disease. 
3.1.2 
Primary endpoint 
Change in the Unified Dyskinesia Rating Scale (UDysRS) total score from Baseline (Day 1) to Visit 
4 (Day 28 End of Treatment or earlier in the event of withdrawal). 
3.1.3 
Secondary objectives 
The secondary objectives of the study are: 
1. To evaluate the effects of adjunctive treatment with IRL790 on levodopa induced 
dyskinesia assessed with the total objective score (part III + IV) in the Unified Dyskinesia 
Rating Scale (UDysRS), as compared to placebo. 
2. To evaluate the effects of adjunctive treatment with IRL790 on symptoms of PD assessed 
with Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part II + III (motor aspects of 
experiences of daily living (M-EDL + motor examination (ME)), and sum of Questions 4.1 
and 4.2 (dyskinesia) in part IV (motor complications) as compared to placebo. 
3. To evaluate the effects of adjunctive treatment with IRL790 on the daily motor “OFF” 
time as assessed by patient completed 24-hour diaries, as compared to placebo 
 
3.1.4 
Secondary endpoints 
• 
Change in Total Objective Score (III, IV) of the UDysRS from Baseline (Day 1) to Visit 4 
(Day 28). 
• 
Change in total daily “OFF” time as assessed by patient completed 24-hour diaries, from 
run-in to Visit 4 (Day 28). 
• 
Change in Unified Parkinson's Disease Rating Scale (MDS-UPDRS) sum score of part II+ III 
(M-EDL+ ME)).  
• 
Change in sum score of Questions 4.1 and 4.2 (dyskinesia) in MDS-UPDRS part IV to Visit 
4 (Day 28). 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 6 (23) 
3.1.5 
Exploratory endpoints 
Additionally, a number of exploratory end points will be assessed. The following items will be 
assessed: 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part I (total score), part II (total 
score), part III (total score) and part IV (total score) from Baseline (Day 1) to Visit 4 (Day 
28). 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 1.2 (Hallucinations and 
Psychosis) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 1.6 (Features of 
dopamine dysregulation syndrome) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
Change in sum score of Questions 4.3, 4.4 and 4.5 (motor fluctuations) in MDS-UPDRS 
part IV to Visit 4 (Day 28). 
• 
Change in sum score of Questions 3.15 and 3.16 (postural and kinetic tremor of the 
hands) in MDS-UPDRS part III to Visit 4 (Day 28). 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 4.3 (Time spent in the 
off state) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 4.6 (Painful off state 
dystonia) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
UDysRS part 1 (Historical on-dyskinesia) 
• 
UDysRS part 2 (Historical off-dystonia) 
• 
UDysRS part 1+2 (Historical dyskinesia) 
• 
Change in ”ON” time with troublesome dyskinesia as assessed by patient completed 24-
hour diaries, from run-in to Visit 4 (Day 28). 
• 
Change in ”ON” time as assessed by patient completed 24-hour diaries, from run-in to 
Visit 4 (Day 28). 
• 
Change in Sleep time as assessed by patient completed 24-hour diaries, from run-in to 
Visit 4 (Day 28). 
 
3.2 Clinical Study Design 
 
This is a multi-centre, randomised, double-blind, placebo-controlled trial with the primary 
objective to evaluate the efficacy of 28 days’ treatment with IRL790 in patients with PD 
experiencing LID.  
Consenting patients will be screened for eligibility according to study-specific inclusion/exclusion 
criteria (see protocol sections 4.2 and 4.3) within 7-28 days before start of IMP administration 
(Screening Visit).  
At the Screening visit patients will be instructed and trained to complete two 24-hour diaries for 
assessment of daily motor function and to bring the completed diaries to the clinic at Visit 1. 
Patients completing at least one valid diary will be eligible for inclusion.  
Following baseline assessments at Visit 1 (Day 1) patients will be randomised to receive IRL790 
or placebo (1:1 randomisation). The treatment allocation will be double-blinded, i.e. it will not 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 7 (23) 
be disclosed to the patients, the site staff or the Sponsor (see protocol Section 6.4). Study 
medication will be dispensed and the first capsules of IMP will be administered in the clinic. The 
patient will be instructed to take the second daily dose in the afternoon of the same day as the 
study visit. 
During the treatment period, Visits 2-4 will be performed on Days 7, 14 and 28 and a follow-up 
phone call on Day 21. Dose adjustments of IRL790 will be made as described in protocol Section 
Error! Reference source not found.. 
During the telephone follow-up call on Day 21, the patient will be asked to complete two 24-
hour diaries for assessment of daily motor function and bring the completed diaries to the clinic 
at Visit 4 on Day 28.  
On Day 28 (Visit 4) the morning IMP dose will be administered at the clinic. ECG will be assessed 
two hours after IMP administration. Blood samples for PK analysis will be collected pre-dose and 
two hours post dose.  
The MDS-UPDRS part 3 will be assessed with the patient in the “on state” on Day 1 (Visit 1) and 
Day 28 (Visit 4 End of Treatment or earlier in the event of withdrawal). 
To assess dyskinesia, the UDysRS will be administered on Day 1 (Visit 1) and Day 28 (Visit 4 End 
of Treatment or earlier in the event of withdrawal). The physician rated part III will be assessed 
with the patients in the “on” state. Patients will be filmed using the “Rush filming protocol” (see 
protocol Appendix Error! Reference source not found.) in the “on” state. The film sequences 
will be transferred to a blinded Central Rater for assessment and the results from this rating will 
subsequently be included in the CRF. 
A follow-up visit will take place 5-8 days after the last IMP dose. 
Unscheduled visits will be performed as needed during the study and should be documented in 
the appropriate section of the CRF. 
3.3 Number of Subjects 
A total number of 74 patients will be required.  
3.4 Methods of Assigning Subject to IMP 
This is a double-blind study, thus, the study patients and the site personnel who are making the 
study assessments will be blinded to the study treatments of IRL790 and Placebo (capsules of 
IRL790 and placebo will be of identical appearance.). 
Treatment allocation (1:1 randomisation) will be performed via a web-based IVRS and based on 
the randomisation list generated by Endpoint Clinical 
4 
STATISTICAL AND ANALYTICAL PLANS 
4.1 Sample Size Justification 
Seventy-Four (74) patients (37 per group) are sufficient to demonstrate an effect size of 0.67 
between the active treatment and control (IRL790 vs Placebo) for the UDysRS primary endpoint 
with 80% power and type 1 error rate 0.05 (two tailed).  
 
The effect size used is derived from the mean difference between the active and control groups 
(at the end of the treatment period) standardised according to the pooled 'between' group 
standard deviation. Estimates for these were obtained from published literature (Table 1). 
Table 1: Sources For Effect Size 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 8 (23) 
Reference 
Mean Difference  
(A-P) (Diff) (n per group) After X 
Weeks Treatment  
 
Pooled Standard 
Deviation 
Effect Size1 
Goetz (2013)  
31-23 (14) (30 per group) 
4wks Actual values 
~12 
0.58 
Pahwa (2017)  
16 - 8 (8) (60 per group) 
12wks Change from baseline 
~12.3 (SE:1.6) 
0.652 
Pahwa (2015)  
16.7 - 6.7 (10) (20 per group) 
8wks Change from baseline 
~13 (SE: 3) 
0.773 
4.2 Definition of Analysis Sets 
4.2.1 
Full Analysis Set  
The Full Analysis Set (FAS) will consist of all randomised and treated patients who receive one or 
more doses and who provide post baseline data whether or not they fully comply with the 
requirements of the protocol. However, given the stage of development patients will be 
analysed according to the treatment they actually receive in the event of randomisation errors 
and not according to the scheduled treatment assignment. 
4.2.2 
Per Protocol Analysis Set 
The Per Protocol Set (PPS) will consist of patients from the FAS but exclude those with major 
protocol violations. All protocol deviations will be reviewed prior to database lock and situations 
which constitute major protocol violations and constitute reasons for exclusion from the PPS will 
be defined and documented in the clean file report.   
4.2.3 
Safety Analysis Set 
The Safety Set (SS) will consist of all patients who receive at least one dose of study drug. All 
safety and tolerability evaluations will be based on this analysis set. Again, patients who receive 
the wrong treatment according to the randomisation schedule will be analysed according to the 
treatment actually received. 
The SS population will be applied to all safety and tolerability assessments and analyses. 
4.2.4 
Use of analysis set 
Patients who are to be included in and excluded from the PPS will be identified and listed 
following a Blind Data Review performed prior to the conclusion of the clinical investigation, 
database lock and unblinding. 
Statistical analyses for the primary and secondary endpoints will be performed using both the 
FAS and PPS. Although the FAS is considered of primary importance, the PPS will enable 
evaluation of the sensitivity and robustness of the estimates of the magnitude of the treatment 
effect 
All other evaluations will involve the FAS population (i.e.: Demographic and baseline 
characteristics, Exploratory investigations, Pharmacokinetics). 
 
1 NB: Smaller effect size = larger sample size required to detect difference 
2 n per group approx 37 with 80% power 
3 n per group approx 28 with 80% power 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 9 (23) 
4.3 Definition of Baseline 
Baseline measurement is defined as the latest measurement prior to first dose of IMP. 
4.4 Summary Statistics 
In general, all data collected will be presented with summary statistics and given in patient data 
listings. Summary statistics will include at least number of patients, mean, standard deviation, 
median, minimum and maximum for continuous data and frequency and percentage for 
categorical data. Tables with summary statistics will be divided by treatment group and dose 
group and visit where applicable. Patient data listings will be sorted by treatment, subject and 
timing of assessments. 
4.5 Significance Level 
A significance level of 5% will be applied. 
4.6 Multiple Comparisons/Multiplicity 
No adjustments for multiplicity will be performed. All statistically significant results must be 
judged by study physician in order to declare clinical relevance. 
4.7 Handling of Drop-outs, Missing Data and Outliers  
Outliers will be included in summary tables and listings and will not be handled separately in any 
analyses.  
In the event of missing data for the any of the endpoints at baseline will as the primary analysis 
the baseline value be set to missing, and as a sensitivity analysis will the mean value of all 
patients be imputed as baseline value. 
In the event of missing data at Visit 4 (last efficacy visit) for any of the endpoints will as the 
primary analysis the Visit 4 value be kept as missing and as a sensitivity analysis will the baseline 
value be imputed as Visit 4 value. 
No imputation of individual questions will be performed. 
4.8 Adjustment for Covariates 
Only baseline measurement will be used as covariate for the absolute change analysis. 
4.9 Multicenter Studies 
No adjustment or analyses for site will be applied. 
4.10 Examination of Subgroups 
Subjects randomized to IRL790 treatment will be analysed by final dosing (and compared to 
placebo as one group and within IRL790) according to the following: 
1. Subjects prescribed 5mg b.i.d (or a lower dose) 
2. Subjects prescribed 7.5mg b.i.d. or a higher dose 
4.11 Blind Review 
Not applicable. 
5 
SUBJECTS 
5.1 Subject Disposition 
The number of subjects that entered the study, withdrawn subjects, completed subjects and the 
number of subjects at each visit will be summarized by treatment. 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 10 (23) 
5.2 Baseline Characteristics and Demographics 
This will include all assessments performed prior to the start of treatment (Screening) including 
Demographics (Gender, Age, Ethnic Origin), Medical history, Diagnosis of PD, Duration of PD, 
Height, Weight, BMI, MMSE, Hoehn and Yahn Scale score and Prior medications. Each will be 
described overall and according to treatment group. 
 
6 
TREATMENT INFORMATION AND EXTENT OF EXPOSURE 
6.1 Compliance 
At the conclusion of treatment period an assessment of compliance with the required dosing 
schedule will be performed and summarised by treatment group (((total tablets taken - total 
prescribed)/total prescribed)*100%). 
6.2 Prior and Concomitant Medications 
Concomitant medication will be summarised by Anatomical Therapeutic Chemical (ATC) code 
levels 2 and 4 using the World Health Organisation Drug dictionary (WHODD) with the number 
and percentage of patients by treatment group and overall 
 
7 
STATISTICAL METHODOLOGY 
All parameters will be presented by treatment and visit using summary statistics. Additional 
statistical analyses are specified below. 
7.1 Primary endpoint  
7.1.1 
Definition 
The primary efficacy variable is the UDysRS total score. The change from baseline will be defined 
as absolute change. 
 
This rating scale has two primary sections:  Historical [Part 1 (On-Dyskinesia) and Part 2 (Off-
Dystonia)], Objective [Part 3 (Impairment) and Part 4 (Disability)]. The Historical part has 15 
items and the Objective part 11 items with each item having 0-4 ratings, where 0 = normal, 1 = 
slight, 2 = mild, 3 = moderate, and 4 = severe. The subtotals for both the Historical and Objective 
parts are summed to give an overall score. 
7.1.2 
Analyses 
The Primary endpoint can be considered quantitative continuous data (Interval in type). As such 
the Change from baseline to End of Treatment (Visit 4, Day 28 or earlier in the event of 
withdrawal) will be derived for each patient and analysed using an Analysis of Covariance 
(ANCOVA) model to compare the two treatment groups (IRL790 vs Placebo). 
The ANCOVA analysis will allow estimation of the size of treatment effects as well as magnitude 
of differences between the active treatment and control (IRL790 - Placebo). The dependent 
variable will be the Change from baseline value and Treatment group the explanatory 
(independent) variable and fixed factor. A baseline covariate term will be included to ensure 
minimum variance unbiased estimation  
Model assumptions will be investigated, and a suitable data transformation or non-parametric 
equivalent model substituted if appropriate. 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 11 (23) 
Actual p-values and 95% confidence intervals for least square mean estimates of the treatment 
effects (including differences between active treatment and placebo) will be presented for these 
models. 
7.1.3 
Presentation 
The summary statistics, including least squares mean estimates, 95% confidence interval and p-
values will be presented using SAS output delivered in Word format. 
 
7.2 Secondary Endpoints 
7.2.1 
Definitions 
• 
Relative Change in UDysRS total score, calculated from baseline. 
• 
Change in Total Objective Score (III, IV) of the UDysRS from Baseline (Day 1) to Visit 4 
(Day 28). 
• 
Change in total daily “OFF” time as assessed by patient completed 24-hour diaries, from 
run-in to Visit 4 (Day 28). 
• 
Change in Unified Parkinson's Disease Rating Scale (MDS-UPDRS) sum score of parts II+ 
III (M-EDL+ ME)).  
• 
Change in sum score of Questions 4.1 and 4.2 (dyskinesia) in MDS-UPDRS part IV to Visit 
4 (Day 28). 
 
 
 
7.2.2 
Analyses  
The change from baseline will be defined as both absolute and percent change. 
All Secondary endpoints can be considered quantitative continuous data (Interval in type). As 
such the Change from baseline to End of Treatment (Visit 4, Day 28 or earlier in the event of 
withdrawal) will be derived for each patient and analysed using an Analysis of Covariance 
(ANCOVA) model to compare the two treatment groups (IRL790 vs Placebo). 
The ANCOVA analysis will allow estimation of the size of treatment effects as well as magnitude 
of differences between the active treatment and control (IRL790 - Placebo). The dependent 
variable will be the Change from baseline value and Treatment group the explanatory 
(independent) variable and fixed factor. A baseline covariate term will be included to ensure 
minimum variance unbiased estimation. 
Model assumptions will be investigated, and a suitable data transformation or non-parametric 
equivalent model substituted if appropriate. 
Actual p-values and 95% confidence intervals for least square mean estimates of the treatment 
effects (including differences between active treatment and placebo) will be presented for these 
models. 
Scale  
Component 
Attribute 
UDysRS 
Total Objective Score (III, IV) 
Total score 
MDS-UPDRS 
Part II+III (M-EDL +ME) 
Sum score 
 
Part IV Questions 4.1 and 4.2 
Sum score 
24-hour patient diaries OFF time 
Total daily hours 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 12 (23) 
7.2.3 
Presentation 
The summary statistics, 95% confidence interval and p-values will be presented using SAS output 
delivered in Word format. 
 
7.3 Exploratory Endpoints 
7.3.1 
Definitions 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part I (total score), part II (total 
score), part III (total score) and part IV (total score) from Baseline (Day 1) to Visit 4 (Day 
28). 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 1.2 (Hallucinations and 
Psychosis) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 1.6 (Features of 
dopamine dysregulation syndrome) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
Change in sum score of Questions 4.3, 4.4 and 4.5 (motor fluctuations) in MDS-UPDRS 
part IV to Visit 4 (Day 28). 
• 
Change in sum score of Questions 3.15 and 3.16 (postural and kinetic tremor of the 
hands) in MDS-UPDRS part III to Visit 4 (Day 28). 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 4.3 (Time spent in the 
off state) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Question 4.6 (Painful off state 
dystonia) from Baseline (Day 1) to Visit 4 (Day 28). 
• 
Clinician's Global Impression of Change in overall PD symptoms at Visit 4 (Day 28). 
• 
Change in ”ON” time with troublesome dyskinesia as assessed by patient completed 24-
hour diaries, from run-in to Visit 4 (Day 28). 
• 
Change in ”ON” time as assessed by patient completed 24-hour diaries, from run-in to 
Visit 4 (Day 28). 
• 
Change in Sleep time as assessed by patient completed 24-hour diaries, from run-in to 
Visit 4 (Day 28). 
The change from baseline will be defined as both absolute and percent change. 
7.3.2 
Analyses  
The Exploratory endpoints (except CGI) can be considered quantitative continuous data (Interval 
in type). As such the Change from baseline to End of Treatment (Visit 4, Day 28 or earlier in the 
event of withdrawal) will be derived for each patient and analysed using an Analysis Of 
Covariance (ANCOVA) model to compare the two treatment groups (IRL790 vs Placebo). 
The ANCOVA analysis will allow estimation of the size of treatment effects as well as magnitude 
of differences between the active treatment and control (IRL790 - Placebo). The dependent 
variable will be the Change from baseline value and Treatment group the explanatory 
(independent) variable and fixed factor. A baseline covariate term will be included to ensure 
minimum variance unbiased estimation. 
Model assumptions will be investigated, and a suitable data transformation or non-parametric 
equivalent model substituted if appropriate. 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 13 (23) 
Actual p-values and 95% confidence intervals for least square mean estimates of the treatment 
effects (including differences between active treatment and placebo) will be presented for these 
models. 
The CGI will be analysed using Chi-square test without continuity correction. 
 
7.3.3 
Presentation 
The summary statistics, 95% confidence interval and p-values will be presented using SAS output 
delivered in Word format. 
 
7.4 PK Endpoints 
Plasma concentrations of IRL790 and its metabolites IRL872 and IRL 902 in samples obtained 
pre-dose and 2h post dose (Cmax) on Day 1 and Day 28 will be summarized, as interval data 
(using number (n), arithmetic mean, standard deviation (SD), minimum and maximum value, 
median, geometric mean and coefficient of variation (CV%)) by Day and time-point. If 
appropriate these will be presented overall for the IRL790 treated group but also according to 
IRL dose. 
 
7.4.1 
Definitions 
All absolute and percent change in plasma concentration will be calculated as 2 hour value – 
pre-dose value. 
7.4.2 
Analyses  
The absolute and percent change will be analyzed using Wilcoxon Rank Sum test. 
7.4.3 
Presentation 
The summary statistics will be presented using SAS output delivered in Word format. 
 
7.5 Safety Endpoints 
7.5.1 
Physical Examinations 
Physical examination results will be categorically summarised as the number and percentage of 
patients according to treatment group and assessment day.  
7.5.2 
Vital signs 
For blood pressure and pulse rate, Actual values and Change from Screening will be summarized 
with descriptive statistics, by treatment group and assessment day. Categorically classified 
(Normal/Abnormal) results will also be summarized. 
In addition, Weight measured at Follow up following Screening will be summarised with 
descriptive statistics for Actual values and Change from Screening by treatment group. 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 14 (23) 
7.5.3 
ECG (12-Lead) At Rest 
ECG variables will be summarised according to Actual values and Change from Screening using 
summary statistics and will be presented by treatment group and assessment visit. Categorically 
classified (Normal/Abnormal) results will also be summarised. 
7.5.4 
Safety laboratory 
All haematology, clinical chemistry and coagulation laboratory tests will be summarised using 
listings for Actual values and Change from Screening and presented by treatment group and 
assessment day for each Hospital site separately (due to assays performed locally).  
Additionally, the local laboratory normal ranges will be used to classify the results as: High, 
Normal or Low and categorical summaries presented overall according to treatment group and 
assessment visit. Pooling across all sites is possible here due to the categorical classification. 
7.5.5 
Adverse events 
All AEs will be summarised according to TEAE or Baseline Event following classification of the 
verbatim terms according to the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. The number and percentage of patients for all classified events will be presented 
according to System organ class (SOC) and Preferred term (PT) by treatment group and overall.  
Separate summaries will be presented for all AEs by event frequency of occurrence and also for 
all AEs according to Seriousness, Severity and Relationship. 
If appropriate separate summaries according to IRL790 maximum tolerated dose received may 
be used to support the findings. 
 
7.6 Discontinuation 
Patients who discontinue from IMP treatment will be tabulated. The reason for discontinuation 
will be given. For discontinuation due to AE, the AEs will be given. 
 
7.7 Interim Analysis 
Not applicable. 
 
8 
CHANGES FROM THE CSP 
Clinician's Global Impression of Change in overall PD symptoms is assessed at Visit 4 (Day 28) 
only, and there is hence no comparison from baseline (Day 1) to Visit 4 (Day 28) as stated in the 
Clinical Study Protocol.. 
Change in total score of MDS-UPDRS part II+III has been included as a secondary endpoint. 
Change in total score of MDS-UPDRS part II, and change in total score of UPDRS part III, have 
been added as exploratory endpoints. 
 
9 
STATISTICAL DELIVERABLES 
The following documents will be delivered: 
• 
SAP 
• 
Statistical analyses, summary tables and listings 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 15 (23) 
 
10 SOFTWARE 
All statistical analyses will be performed using SAS Version 9.4 (SAS institute, Cary, NC). 
 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 16 (23) 
11 APPROVAL 
 
Issued by: 
 
 
______________________________  
_____________________ 
Fredrik Hansson, Director Biometrics 
 
Date (dd-Mmm-yyyy) 
CTC Representative 
 
 
Approved by: 
 
 
______________________________  
_____________________ 
 
 
 
 
Date (dd-Mmm-yyyy) 
Sponsor Representative 
 
 
 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 17 (23) 
12 Appendix 
12.1 Generic tables 
 
Table 12.1-1 Generic table for categorical data 
 
XXXX 
XXX 
Category of Question 
Assessment 
Visit Name 
Result 
 
XXX 
YYY 
Visit 8 Day 29 2. MUCH IMPROVED 
0 
1(17%)/6 
3. MINIMALLY IMPROVED 
5(22%)/23 
1(17%)/6 
4. NO CHANGE 
11(48%)/23 4(67%)/6 
5. MINIMAL WORSENING 
4(17%)/23 
0 
6. MODERATE WORSENING 
3(13%)/23 
0 
 
 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 18 (23) 
Table 12.1-2 Generic table for continuous data measured at one occasion 
 
 
XXXXX(
N=25) 
XXXXXX 
(N=7) 
Total 
(N=32) 
Age (years) 
n/nmiss 
25/0 
7/0 
32/0 
Mean (SD) 
71.8 
(3.89) 
72.7 
(5.59) 
72 
(4.23) 
 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 19 (23) 
Table 12.1-3 Generic table for continuous data measured at several occasions 
 
XXX 
XXX 
Category of Question 
Subcategory for Question 
Assessment 
Result Category 
Visit Name 
 
A 
C 
C 
Measured value 
Visit 2 Day 1 
N 
23 
6 
Mean (SD) 
5.7 (1.7) 
5.8 (2.4) 
Median (Min, Max) 
5.0 (3, 10) 
6.5 (3, 9) 
95% CI 
5.0;6.5 
3.3;8.4 
Visit 7 Day 28 
N 
23 
6 
Mean (SD) 
5.2 (2.1) 
5.0 (3.0) 
Median (Min, Max) 
5.0 (2, 9) 
5.0 (2, 9) 
95% CI 
4.3;6.1 
1.8;8.2 
Absolute change 
from pre-dose 
baseline 
Visit 7 Day 28 
N 
23 
6 
Mean (SD) 
-0.6 (2.0) 
-0.8 (1.6) 
Median (Min, Max) 
-1.0 (-5, 4) 
0.0 (-4, 0) 
95% CI 
-1.4;0.3 
-2.5;0.8 
Within group p-value 
0.1835 
0.5000 
Relative change 
from pre-dose 
baseline (%) 
Visit 7 Day 28 
N 
23 
6 
Mean (SD) 
-5.5 (42.8) 
-16.7 (28.0) 
Median (Min, Max) 
-10.0 (-71, 
100) 
0.0 (-67, 0) 
95% CI 
-24.0;13.0 
-46.0;12.7 
Within group p-value 
0.2498 
0.5000 
 
 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 20 (23) 
12.2  AE tables 
 
TABLE 14.3.1.1 OVERVIEW OF ADVERSE EVENTS, FAS 
 
 
XXXX 
N=31 
XXXX 
N=32 
Total 
N=32 
 
n(%) 
m 
n(%) 
m 
n(%) 
m 
Any AE 
12(39%) 
17 
10(31%) 
16 
16(50%) 33 
Any SAE 
0 
0 
0 
0 
0 
0 
Any AE leading to withdrawal 
0 
0 
0 
0 
0 
0 
Any AE leading to death 
0 
0 
0 
0 
0 
0 
Causality 
 
 
 
 
 
 
      Not Related 
8(26%) 
9 
5(16%) 
8 
9(28%) 
17 
      Possibly Related 
7(23%) 
7 
5(16%) 
7 
10(31%) 14 
      Probably Related 
1(3%) 
1 
1(3%) 
1 
2(6%) 
2 
Severity 
 
 
 
 
 
 
      Mild 
9(29%) 
11 
8(25%) 
9 
13(41%) 20 
      Moderate 
5(16%) 
6 
6(19%) 
7 
9(28%) 
13 
 
 
n, number of subjects; m, number of events 
Percentages are based on the number of subjects in the full analysis set 
XXXXXX.rtf AE: Overview of AEs, SAS program: ae_summary_tables.sas. Run by: XXXXXXX 
 
 
 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 21 (23) 
TABLE 14.3.1.2 ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND PREFERRED TERM, FAS 
 
 
XXXXXXX 
N=31 
XXXXXXX 
N=32 
Total 
N=32 
System organ class 
      Preferred term 
n(%) 
m 
n(%) 
m 
n(%) 
m 
Nervous system disorders 
8(26%) 
9 
7(22%) 
8 
11(34%) 17 
      Headache 
5(16%) 
6 
6(19%) 
7 
8(25%) 
13 
      Paraesthesia 
1(3%) 
1 
1(3%) 
1 
1(3%) 
2 
      Presyncope 
2(6%) 
2 
0 
0 
2(6%) 
2 
Gastrointestinal disorders 
2(6%) 
2 
3(9%) 
3 
4(13%) 
5 
      Nausea 
2(6%) 
2 
2(6%) 
2 
3(9%) 
4 
      Paraesthesia oral 
0 
0 
1(3%) 
1 
1(3%) 
1 
General disorders and administration site conditions 
1(3%) 
1 
2(6%) 
2 
3(9%) 
3 
      Fatigue 
1(3%) 
1 
2(6%) 
2 
3(9%) 
3 
Infections and infestations 
2(6%) 
2 
1(3%) 
1 
3(9%) 
3 
      Nasopharyngitis 
2(6%) 
2 
1(3%) 
1 
3(9%) 
3 
Respiratory, thoracic and mediastinal disorders 
2(6%) 
2 
1(3%) 
1 
2(6%) 
3 
      Oropharyngeal pain 
1(3%) 
1 
0 
0 
1(3%) 
1 
      Rhinitis allergic 
1(3%) 
1 
1(3%) 
1 
1(3%) 
2 
Musculoskeletal and connective tissue disorders 
0 
0 
1(3%) 
1 
1(3%) 
1 
      Back pain 
0 
0 
1(3%) 
1 
1(3%) 
1 
Reproductive system and breast disorders 
1(3%) 
1 
0 
0 
1(3%) 
1 
      Dysmenorrhoea 
1(3%) 
1 
0 
0 
1(3%) 
1 
 
 
 
 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 22 (23) 
TABLE 14.3.1.3 ADVERSE EVENTS: NUMBER OBSERVED AND RATE, WITH PATIENT IDENTIFICATIONS, FAS 
 
 
Mild 
--- 
NR 
Mild 
--- 
Related 
Moderate 
--- 
NR 
Moderate 
--- 
Related 
Total 
--- 
NR 
Total 
--- 
Related 
Total 
--- 
R+NR 
XXXXXXX (N=32) 
Gastrointestinal disorders 
Nausea 
1 (3%) 
 
106 ** 
1 (3%) 
 
108 
 
 
1 (3%) 
1 (3%) 
2 (6%) 
 
 
Paraesthesia oral 
1 (3%) 
 
127 
 
 
 
1 (3%) 
 
1 (3%) 
 
General disorders and administration site conditions 
Fatigue 
 
1 (3%) 
 
122 
 
1 (3%) 
 
126 
 
2 (6%) 
2 (6%) 
 
Infections and infestations 
Nasopharyngitis 
1 (3%) 
 
103 
 
 
 
1 (3%) 
 
1 (3%) 
 
Musculoskeletal and connective tissue disorders 
Back pain 
 
 
1 (3%) 
 
103 
 
1 (3%) 
 
1 (3%) 
 
Nervous system disorders 
Headache 
1 (3%) 
 
124 
2 (6%) 
 
127 
132 
2 (6%) 
 
106 
125 
1 (3%) 
 
122 
3 (9%) 
3 (9%) 
6 (19%) 
 
 
Paraesthesia 
 
1 (3%) 
 
121 
 
 
 
1 (3%) 
1 (3%) 
 
Respiratory, thoracic and mediastinal disorders 
Rhinitis allergic 
 
 
1 (3%) 
 
127 
 
1 (3%) 
 
1 (3%) 
XXXXXXXX (N=31) 
Gastrointestinal disorders 
Nausea 
 
2 (6%) 
 
106 
124 
 
 
 
2 (6%) 
2 (6%) 
 
General disorders and administration site conditions 
Fatigue 
 
 
 
1 (3%) 
 
125 
 
1 (3%) 
1 (3%) 


Protocol Number:  IRL790C003 
CTC Project Code: 190_14_2018 
 
Statistical Analysis Plan version 1.0, Final 13JUN2019 V02 
 23 (23) 
 
Mild 
--- 
NR 
Mild 
--- 
Related 
Moderate 
--- 
NR 
Moderate 
--- 
Related 
Total 
--- 
NR 
Total 
--- 
Related 
Total 
--- 
R+NR 
 
Infections and infestations 
Nasopharyngitis 
2 (6%) 
 
116 
125 
 
 
 
2 (6%) 
 
2 (6%) 
 
Nervous system disorders 
Headache 
2 (6%) 
 
124 
130 
2 (6%) 
 
104 
127 
1 (3%) 
 
106 
 
3 (10%) 2 (6%) 
5 (16%) 
 
 
Paraesthesia 
 
1 (3%) 
 
121 
 
 
 
1 (3%) 
1 (3%) 
 
 
Presyncope 
 
 
 
2 (6%) 
 
115 
123 
 
2 (6%) 
2 (6%) 
 
Reproductive system and breast disorders 
Dysmenorrhoea 
 
 
1 (3%) 
 
114 
 
1 (3%) 
 
1 (3%) 
 
Respiratory, thoracic and mediastinal disorders 
Oropharyngeal pain 1 (3%) 
 
126 
 
 
 
1 (3%) 
 
1 (3%) 
 
 
Rhinitis allergic 
1 (3%) 
 
127 
 
 
 
1 (3%) 
 
1 (3%) 
**: Subject randomization number 
AEs judged as 'Possibly Related' or 'Problably Related' are grouped as 'Related'. 
XXXXXX.rtf AE: Number observed and rate, with patient identifications, FAS, SAS program: ae_tabulations.sas. Run by: XXXXX