Clinical trial NCT04435431
Conditions: Parkinson Disease
Sponsor: Integrative Research Laboratories AB
Start date: 2020-10-29; Completion date: 2022-12-09
Enrollment: 155 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2b study investigating the efficacy and safety of mesdopetam as adjunct therapy on daily ON-time without troublesome dyskinesia in patients with Parkinson disease. Mesdopetam is taken for 84 days.

Detailed description:
At the screening visit consenting patients will be screened for eligibility according to study specific inclusion/exclusion criteria within 8 weeks before start of Investigational Medicinal Product (IMP) administration. A diary concordance training will be performed and following the screening visit the patient will be asked to self-administer three 24-hour home diaries and to bring the completed diaries to the baseline visit for assessment prior randomization.

At the baseline visit, patients will be randomized to receive one of three doses of mesdopetam (dose 1, dose 2 and dose 3) or placebo b.i.d.

During the first week a dose run-in phase will take place, where all patients allocated to mesdopetam will receive a run-in dose of mesdopetam twice daily and patients allocated to placebo will receive placebo twice daily. At Visit 2, patients will receive mesdopetam dose 1, dose 2 or dose 3 or placebo b.i.d., as randomized and continue the same dose for the rest of the treatment period until end of treatment (EOT). Dose reductions are restricted and the dose can only be reduced once. Dose reductions are permitted from visit 2 (day 9) until visit 3 (day 28), where after the dose should be kept stable until EOT.

The treatment allocation will be double-blind, i.e. it will not be disclosed to the patients, the site staff or the Sponsor.

During the treatment period, changes in disease state and ON phase dyskinesia will be assessed using the Movement Disorder Society revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the modified Unified Dyskinesia Rating Scale (UDysRS), i.e. parts 1, 3 and 4, and Clinician's Global Impression of Severity (CGI-S). Furthermore, patients will self-administer three 24-hour home diaries prior to visit 3 (week 4), visit 4 (week 8) and visit 5 (week 12) to assess daily motor function.

Blood samples for pharmacokinetic (PK) analysis will be collected at visit 4 (week 8) and visit 5 (week 12).

Visit 6 (follow-up) will be performed for all patients, including any patients that discontinue the IMP early, 5-8 days after last administration of IMP.

Arms: arm 1: Mesdopetam capsule (mg), dose 1, 1 capsule b.i.d. for 84 days. arm 2: Mesdopetam capsule (mg), dose 2, 1 capsule b.i.d. for 84 days. arm 3: Mesdopetam capsule (mg), dose 3, 1 capsule b.i.d. for 84 days. arm 4: Placebo capsule, 1 capsule b.i.d. for 84 days
Interventions: intervention 1: Mesdopetam intervention 2: Placebo
Intervention descriptions: intervention 1: Oral use intervention 2: Oral use

Protocol documents:
Prot_000.pdf: 
Confidential 
Protocol: IRL790C005 
Version: 5.0 
Date: 5 Mar 2021 
Page 1 of 74 
 
 
 
CONFIDENTIAL 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PHASE IIB STUDY EVALUATING THE EFFICACY OF 
MESDOPETAM ON DAILY ON-TIME WITHOUT TROUBLESOME 
DYSKINESIA IN PATIENTS WITH PARKINSON’S DISEASE 
 
PROTOCOL 
 
Version: 
5.0  
Version date: 
5 March 2021 
Superseded version: 
1.1 (29 May 2020) 
Sponsor: 
Integrative Research Laboratories Sweden 
AB (IRLAB) 
Product: 
Mesdopetam (IRL790) (2.5 mg, 5 mg and 
7.5 mg hard HPMC capsules) 
Study Number(s): 
IRL790C005 
EudraCT number: 2020-002010-41 
 
Integrative Research Laboratories Sweden AB (IRLAB) 
Arvid Wallgrens Backe 20 
413 46 Göteborg 
SWEDEN 
 
Phone: +46 (0) 707 60 16 91 
 


Integrative Research Laboratories Sweden AB (IRLAB)  
IRL790C005 
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Protocol: IRL790C005 
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PROTOCOL APPROVAL PAGE 
This protocol has been read and approved by: 
Sponsor representative, 
Joakim Tedroff (Chief 
Medical Officer, CMO): 
 
Signature: 
 
Date: 
 
 
Sponsor representative, 
Maria Jalmelid (Chief of 
Clinical Operations): 
 
 
Signature: 
 
Date: 
 
 
CRO Worldwide Clinical 
Trials representative, 
Aimie Nunn (Statistician): 
 
 
Signature: 
 
Date: 
 


Integrative Research Laboratories Sweden AB (IRLAB)  
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INVESTIGATOR PROTOCOL APPROVAL PAGE 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PHASE IIB STUDY EVALUATING THE EFFICACY OF 
MESDOPETAM ON DAILY ON-TIME WITHOUT TROUBLESOME 
DYSKINESIA IN PATIENTS WITH PARKINSON’S DISEASE  
 
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 (ICH E6 (R2)) 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: 
 
 
 
 
 
 
 
 
 
 


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Date: 5 Mar 2021 
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AMENDMENT HISTORY 
Protocol version 
Change 
Justification 
V 1.1 29 May 2020 
Initial version 
Not applicable 
V 2.0 France 21 Oct 2020 
(Local version for France) 
Added U-hCG test at visit 3 and visit 
4. Impacted sections: Schedule of 
study and study procedures, section 
10.8, 10.10 and 11.2.1. 
Response to French ANSM 
comments, dated 12 Oct 2020 
Corrected the Sponsor name by adding 
“Sweden”. Impacted section: Header, 
front page and contact name and 
address page. 
In line with protocol 
administrative letter change #1, 
dated 14 Aug 2020 
Changed one of the Sponsor’s 
protocol signees. Impacted section: 
Protocol approval page. 
Administrative change 
V 2.1 France 24 Nov 2020 
(Local version for France) 
Clarifying details added to exclusion 
criterion 11. Impacted sections: 
Protocol synopsis and Section 7.3. 
Response to the French Central 
Ethics Committee - Request for 
supplementary information issued 
on 07 Nov 2020 
V 3.0 Poland 05 Nov 2020 
(Local version for Poland) 
Added U-hCG test at visit 3 and visit 
4. Impacted sections: Schedule of 
study and study procedures, section 
10.8, 10.10 and 11.2.1. 
Response to Polish MOH 
comments, dated 28 Oct 2020 
 
Corrected the Sponsor name by adding 
“Sweden”. Impacted section: Header, 
front page and contact name and 
address page. 
In line with protocol 
administrative letter change #1, 
dated 14 Aug 2020 
Changed one of the Sponsor’s 
protocol signees. Impacted section: 
Protocol approval page. 
Administrative change 
V 4.0 Italy 24 Nov 2020 
(Local version for Italy) 
Added definition of woman of 
childbearing potential and/or 
postmenopausal woman according to 
CTFG Guideline Recommendations 
related to contraception and pregnancy 
testing in clinical trials, Version 1.1, 
dated 21/09/2020. Impacted section: 
8.1. 
Response to Italian AIFA 
comments, dated 12 Nov 2020 
 
 
 
Added U-hCG test at visit 3 and visit 
4. Impacted sections: Schedule of 
study and study procedures, section 
10.8, 10.10 and 11.2.1. 
According to CTFG Guideline 
Recommendations related to 
contraception and pregnancy 
testing in clinical trials, Version 
1.1, dated 21/09/2020. 
Corrected the Sponsor name by adding 
“Sweden”. Impacted section: Header, 
In line with protocol 
administrative letter change #1, 
dated 14 Aug 2020 


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Date: 5 Mar 2021 
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front page and contact name and 
address page. 
Changed one of the Sponsor’s 
protocol signees. Impacted section: 
Protocol approval page. 
Administrative change 
V 5.0 5 March 2021 
Corrected the Sponsor name by adding 
“Sweden”. Impacted section: Header, 
front page and contact name and 
address page. 
In line with protocol 
administrative letter change #1, 
dated 14 Aug 2020. Added to 
local versions (France, Poland, 
Italy) – now implemented 
globally. 
Changed one of the Sponsor’s 
protocol signees. Impacted section: 
Protocol approval page. 
Administrative change. Added to 
local versions (France, Poland, 
Italy) – now implemented 
globally. 
Added U-hCG test at visit 3 and visit 
4. Impacted sections: Schedule of 
study and study procedures, section 
10.8, 10.10 and 11.2.1. 
Added to local versions (France, 
Poland, Italy) in response to local 
requirements – now implemented 
globally. 
Clarifying details added to exclusion 
criterion 11. Impacted sections: 
Protocol synopsis and Section 7.3. 
Added to local version (France) 
in response to local requirements 
– now implemented globally. 
Added definition of woman of 
childbearing potential and/or 
postmenopausal woman according to 
CTFG Guideline Recommendations 
related to contraception and pregnancy 
testing in clinical trials, Version 1.1, 
dated 21/09/2020. Impacted section: 
8.1. 
Added to local version (Italy) in 
response to local requirements – 
now implemented globally. 
Addition of safety parameters (vital 
signs, haematology/clinical chemistry 
incl prolactin, dipstick urinalysis and 
ECG) at Visit 1 (Baseline) if 29 days 
or more between the Screening visit 
and Visit 1 (Baseline). Impacted 
sections: Schedule of study and study 
procedures, section 10.4 and 11.2.1.   
Added to ensure baseline safety 
assessments in association to 
initiation of study treatment. 
Clarification that the three 24-hour 
home diaries can be completed during 
three consecutive days or any 
combination of days during the week 
prior V1, V3, V4 and V5. Impacted 
sections: Schedule of study and study 
procedures. 
Clarification 
Pregnancy form to be used for 
reporting of pregnancy, not SAE form. 
Impacted section: 12.9. 
Correction 


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Correction of Stage 2 Hoehn and Yahr 
description. Impacted section: 11.1.2.  
Correction 
Revision of approximate number of 
sites participating in the study 
(increased from 28 to 35). Impacted 
section: Protocol synopsis. 
Update based on new information 
Minor updates (typos, clarifications) 
for consistency throughout the 
document. 
Corrections/clarifications 
 
 


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1. PROTOCOL SYNOPSIS  
Study title: 
A randomized, double-blind, placebo-controlled, Phase IIb study evaluating the efficacy of 
mesdopetam on daily ON-time without troublesome dyskinesia in patients with Parkinson’s 
disease (PD). 
Study Code: 
IRL790C005 
EudraCT No: 
2020-002010-41 
Study period: 
Estimated date of first patient enrolled: Sep 2020 
Estimated date of last patient completed: Jan 2022 
Phase of development: 
Phase IIb 
Study design: 
This will be a randomized, double-blind, placebo-controlled multi-centre study.  
Number of patients planned: 
A total number of 140 patients (35 per group) will be randomized to the study. The Sponsor will 
evaluate the actual dropout rate after 70 randomized patients have completed Visit 3 (Week 4) 
and can, if the dropout rate at this point is higher than expected, decide to increase the sample 
size to a total of maximum 154 randomized patients (+10%). 
Investigator study sites: 
This study will be conducted at approximately 35 study sites in approximately 6 countries. 
Objectives: 
Primary objective: 
• To evaluate the effectiveness of adjunctive treatment with mesdopetam dosed at 2.5 mg, 
5 mg or 7.5 mg b.i.d. (permitting a single 2.5 mg dose reduction to a minimum dose of 
2.5 mg, up to Day 28) compared to placebo in patients with PD exhibiting troublesome ON-
phase dyskinesia.  
Secondary objectives:  
• To establish the dose response relationship with 3 dose levels of mesdopetam. 
• To evaluate the effects of mesdopetam on severity of ON-phase dyskinesia and motor 
symptoms of PD. 
• To evaluate the effects of mesdopetam on the daily hours spent in different motor states.  
• To evaluate the safety and tolerability of mesdopetam given twice daily during 
84 consecutive days.  
• To evaluate trough and 2-hour post dose plasma concentrations of mesdopetam and its two 
main metabolites, IRL902 (N-dealkylated) and IRL872 (acetylated). 
Exploratory objectives: 
• To assess overall PD symptoms.  
• To assess cognitive function.   


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Efficacy Endpoints 
Primary efficacy endpoint 
Change in average daily hours of ON-time without troublesome dyskinesia with mesdopetam 
compared to placebo as assessed with 24-hour patient home diaries from baseline to end of 
treatment (EOT) (Visit 5, Week 12). 
Secondary efficacy endpoints 
• Change from baseline in average daily hours of ON-time without troublesome dyskinesia 
for each individual dose level (2.5 mg, 5 mg, 7.5 mg b.i.d.), as well as all active doses 
grouped compared to placebo.   
• Change from baseline in mean score or average daily hours with mesdopetam compared to 
placebo for the following measures: 
o ON-phase dyskinesia assessed with the sum score of the modified UDysRS (parts 1, 
3 and 4). 
o Disability associated with ON-phase dyskinesia assessed with the sum score of parts 
1b and 4 of the UDysRS. 
o ON-phase dyskinesia assessed by MDS-UPDRS part 4 questions 4.1 (Time spent 
with dyskinesias) and 4.2 (Functional impact of dyskinesias). 
o Motor symptoms of PD assessed with MDS-UPDRS total score of part 2 (M-EDL). 
o Daily OFF-time, daily ON-time with troublesome dyskinesia and daily total ON-time 
(defined as the sum of ON-time with and without troublesome dyskinesia).  
o CGI-S of ON-phase dyskinesia.   
Exploratory endpoints 
• Change from baseline with mesdopetam compared to placebo in:  
o CGI-S of overall PD symptoms.   
o Total MMSE score.   
Safety endpoints 
• Frequency and nature of Adverse Events (AEs), laboratory results, vital signs, physical 
examinations, Columbia-Suicide Severity Rating Scale (C-SSRS) and 12-lead 
electrocardiograms (ECG) at each visit from baseline to follow-up. 
Pharmacokinetic endpoints 
• Plasma concentrations of mesdopetam and its two main metabolites at pre-dose and 2 hours 
post-dose at 8 and 12 weeks of treatment. 
Diagnosis and main eligibility criteria: 
Male and female patients 30-79 years of age with PD according to the specified inclusion and 
exclusion criteria will be recruited. 


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Inclusion & Exclusion criteria: 
For inclusion in the study, patients must fulfil all the following criteria: 
1. Male or female ≥30 and ≤79 years of age at the time of screening. 
2. Signed a current Ethics Committee approved informed consent form (ICF). 
3. PD, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic 
Criteria. 
4. Minimal amount of 2 hours of levodopa-induced daily “ON-time with troublesome 
dyskinesia” during waking hours. 
5. Functional impact of dyskinesias determined as a score of ≥2 as per Question 4.2 of the 
MDS-UPDRS. 
6. On a stable regimen of antiparkinson medications for at least 30 days prior to first home 
diary completion which must include a levodopa preparation administered 3-8 times/day 
(excluding nighttime levodopa), and willing to continue the same doses and regimens 
during study participation. Rescue medications such as Madopar dispersable and 
Apomorphine injections are allowed if prescribed PRN prior to study entry. 
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 first home diary completion 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. Able to complete 24-hour patient home diaries of which two valid diaries must be 
presented at Visit 1. 
Patients must not enter the study if any of the following exclusion criteria are fulfilled: 
1. History of neurosurgical intervention related to PD (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, localized bladder cancer, 
non-metastatic prostate cancer or in situ cervical cancer. 
6. Presence of cognitive impairment, as evidenced by a Mini-Mental State Examination 
(MMSE) score of less than 24 during screening. 
7. A Hoehn and Yahr stage of 5. 
8. Ongoing treatment with amantadine at time of screening or within 6 weeks prior first 
home diary completion. 
9. Treatment with Inbrija (levodopa inhalation powder) at time of screening or within 4 
weeks prior first home diary completion. 


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10. 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. 
11. 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 (a fall and/or a discomfort); clinically 
significant hepatic disease, severe renal impairment, i.e. creatinine clearance <30 
mL/min (stage IV or V). 
12. Any history of a neurological disorder other than PD or a psychiatric disorder, including 
history of Diagnostic and Statistical Manual of Mental Disorders (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. 
13. 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. 
14. Drug and/or alcohol abuse. 
15. History of severe drug allergy or hypersensitivity. 
16. If female, is pregnant or lactating, or has a positive pregnancy test result pre-dose. 
17. Patients unwilling to use two forms of contraception (one of which being a barrier 
method (see Section 8.1) during the treatment period and 90 days for men and 30 days 
for women after last IMP dose. 
18. Any planned major surgery within the duration of the study. 
19. Any other condition or symptoms preventing the patient from entering the study, 
according to the Investigator’s judgement. 
Methodology: 
This is a multicentre study where 140 patients with PD exhibiting ON-phase dyskinesia will be 
randomized to receive Investigational Medicinal Product (IMP) or placebo, respectively.  
At the screening visit consenting patients will be screened for eligibility according to study 
specific inclusion/exclusion criteria within 8 weeks before start of Investigational Medicinal 
Product (IMP) administration. A diary concordance training will be performed, either during the 
screening visit or during a separate scheduled visit prior start of the baseline diary completion 
period.  
Following the screening visit and the diary concordance training, the patient will be asked to 
self-administer three 24-hour home diaries and to bring the completed diaries to the baseline 
visit (Visit 1, Day 1), for assessment prior to randomization.  
At the baseline visit (Visit 1, Day 1), patients will be randomized 1:1:1:1 to receive one of three 
doses of mesdopetam (2.5 mg, 5 mg or 7.5 mg) or placebo b.i.d.  
During the first week (Day 1 evening dose to Day 9 morning dose) a run-in phase with either 
5 mg mesdopetam or placebo b.i.d. will take place, during which all patients allocated to 


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mesdopetam will receive 5 mg mesdopetam b.i.d. and patients allocated to placebo will receive 
placebo b.i.d. At Visit 2 (Day 9), patients will receive mesdopetam 2.5 mg, 5 mg or 7.5 mg or 
placebo b.i.d., as randomized.    
Patients will continue the same dose for the rest of the treatment period until EOT (Visit 5, 
Week 12, Day 84). Dose reductions will only be allowed if the patient manifests increased 
parkinsonism and/or a consistent increase in motor OFF-time. The dose can only be reduced 
once (and only by 2.5 mg b.i.d.). Dose reductions are permitted from Visit 2 until Visit 3 (i.e. 
Day 9 - Day 28 ±4 days), where after the dose should be kept stable until EOT (Visit 5, Week 12, 
Day 84).  
The treatment allocation will be double-blind, i.e. it will not be disclosed to the patients, the site 
staff or the Sponsor. Starting on Day 1, the IMP will be self-administered by the patient at home 
for 12 consecutive weeks: two oral daily doses (approximately 8 hours apart) as adjunct 
treatment to the patients’ regular and stable antiparkinsonian medication.  
During the treatment period at Visits 3-5, changes in disease state and ON-phase dyskinesia will 
be assessed using the MDS-UPDRS, the modified UDysRS (i.e. parts 1, 3 and 4), and Clinician’s 
Global Impression of Severity (CGI-S). Furthermore, patients will self-administer three 24-hour 
home diaries prior to Visit 3 (Week 4), Visit 4 (Week 8) and Visit 5 (Week 12) to assess daily 
motor function. 
Blood samples for pharmacokinetic (PK) analysis will be collected within 15 min pre-dose 
(trough) and approximately 2 hours (± 15 min) post dose on Visit 4 (Week 8) and Visit 5 
(Week 12). PK data collected at 2 hours post dose will be used as an estimate of the maximum 
concentration (Cmax). 
Visit 6 (follow-up) will be performed for all patients, including any patients that discontinue the 
IMP early, 5-8 days after last administration of IMP. 
IMP dosage and mode of administration:  
Mesdopetam capsules: 2.5 mg, 5 mg and 7.5 mg free base equivalent: White hard 
Hydroxypropyl Methylcellulose (HPMC) capsule, coni snap size 3, colour white containing 
mesdopetam x ½ L-tartrate for oral administration. 
Placebo capsules: White hard HPMC capsule, coni snap size 3, colour white containing starch 
for oral administration. Capsules are identical in appearance to active IMP. 
Mesdopetam 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 84 consecutive 
days. The starting dose will be 5 mg b.i.d. (mesdopetam or placebo) during the dose run-in 
period (one week) and thereafter mesdopetam 2.5 mg, 5 mg or 7.5 mg or placebo b.i.d as 
randomized. The minimum dose is 2.5 mg b.i.d. and the maximum dose is 7.5 mg b.i.d. 
 
 


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Duration of each patients’ involvement in the study: 
Patients will be screened for eligibility up to 8 weeks prior start of IMP treatment at Day 1. IMP 
treatment will last for twelve weeks. A follow-up visit will be performed approximately 1 week 
after the last IMP dose. 
Efficacy assessments  
• 24-hour patient home diary 
• Modified UDysRS (i.e. parts 1, 3 and 4) 
• MDS-UPDRS  
• Clinical Global Impression of Severity (CGI-S) Rating 
• MMSE 
Safety assessments  
• Frequency, seriousness and intensity of AEs  
• Physical examination 
• 12-lead ECG recordings 
• Vital signs (blood pressure (BP) and heart rate) 
• Clinical laboratory measurements 
• Columbia-suicide severity rating scale (C-SSRS) 
PK assessments 
• After multiple doses: morning trough and Cmax 
• Dose proportionality after multiple doses based on morning trough and Cmax 
Statistical methods: 
A single analysis at the conclusion of the investigation is planned and there will be no interim 
analyses.  
Power and sample size: 
140 patients (35 per group), are enough to demonstrate a treatment difference of 3 hours, pooled 
standard deviation 3.5, between a single dose level of active treatment and control (i.e. 2.5 mg, 
5 mg or 7.5 mg mesdopetam vs placebo b.i.d.) for the primary endpoint with 92% power and 
type 1 error rate 0.05 (two tailed). The sample size calculation is based on an expected dropout 
rate of 10%. The Sponsor will evaluate the actual dropout rate after 70 randomized patients have 
completed Visit 3 (Week 4) and can, if the dropout rate in the study is higher than expected, 
decide to increase the sample size to a total of maximum 154 randomized patients (+10%).   
Randomization will be performed via a web-based Interactive Response System (IRS), using a 
dynamic balancing (minimization) algorithm. Randomization will be stratified by the average 
daily hours spent in ON-time with troublesome dyskinesia (<6 hours and ≥6 hours) at baseline.  
 
 
 
 


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Demographics and baseline characteristics: 
All demographic information and baseline characteristics relating to patients with PD 
exhibiting ON-phase dyskinesia will be summarized to describe the population of patients 
recruited to the study.   
Efficacy analyses 
The primary efficacy analysis will be conducted on the Full Analysis Set (FAS), defined as all 
randomized subjects who have received at least 1 dose of IMP and have at least 1 post baseline 
assessment.  
The primary efficacy assessment is the change in average daily hours of ON-time without 
troublesome dyskinesia with mesdopetam compared to placebo as assessed with 24-hour 
patient home diaries from baseline to EOT (Visit 5, Week 12). This will be analyzed using a 
mixed model repeated measures (MMRM) analysis that includes changes from baseline to 
Visit 3 (Week 4), Visit 4 (Week 8) through to EOT (Visit 5, Week 12). The model will include 
randomized treatment, visit (Visits 3, 4 and 5 (EOT)), and treatment by visit interaction as 
explanatory variables. Treatment, visit and treatment by visit interaction will be fixed effects 
in the model. Baseline value for average daily hours of ON-time without troublesome 
dyskinesia will be included as a continuous covariate along with the baseline stratification 
factor of daily hours spent in ON-time with troublesome dyskinesia (<6 hours and ≥-6 hours).   
Model assumptions will be examined and alternative analyses (e.g. analysis after data 
transformation or non-parametric analysis) may be performed as appropriate. 
The main comparison will be a contrast between treatment groups at EOT (Visit 5, Week 12).  
Estimates for each individual dose level, as well as all active doses grouped vs. placebo will be 
obtained from the model. Least squares means, 95% confidence intervals, and p-values of the 
treatment comparisons along with basic arithmetic summary statistics (mean, median, standard 
deviation, min and max) will be provided.    
Sensitivity analyses will be performed for the Primary efficacy endpoint to assess the 
robustness of the observed result. In the first instance, the Primary analysis will be repeated for 
all subjects without a major protocol deviation, followed by analysis by treatment received 
following Visit 3 (Week 4, Day 28) to EOT. An alternative analysis using Analysis of 
covariance (ANCOVA) may also be performed. Methods to assess the impact of missing data 
(including last observation carried forward or multiple imputation) may also be applied where 
appropriate.   
Key secondary efficacy assessments include the change in score of subsets of the UDysRS 
(parts 1+3+4 and parts 1+4) as well the MDS-UPDRS part 2 total score, the daily hours of 
OFF-time, the daily hours of ON-time with troublesome dyskinesia and the change in score of 
questions 4.1 and 4.2 of the MDS-UPDRS.   
Change from baseline (Visit 1, Day 1) through EOT (Visit 5, Week 12) will be derived, 
summarized and analyzed. EOT (Visit 5, Week 12) is considered the primary time-point of 
interest. 
All secondary and exploratory efficacy endpoints (including CGI-S data) will be analyzed per 
the Primary efficacy endpoint. Summary statistics (mean, median, standard deviation, min and 
max), least squares means, 95% confidence intervals, and p-values of the treatment 
comparisons will be provided for descriptive purposes.  
 


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PK analyses 
PK variables measured in plasma are: Plasma concentrations of mesdopetam parent drug and 
two of its metabolites (IRL902 (N-dealkylated) and IRL872 (acetylated)).  
Samples are obtained pre-dose (trough) and 2 hours post dose (Cmax) on Visit 4 (Week 8) and 
EOT (Visit 5, Week 12) and results will be summarised by timepoint, visit, and mesdopetam 
dose level.  
If appropriate, the PK relationship between the treatment doses and plasma exposure (trough 
concentrations and Cmax) of mesdopetam and its metabolites will be assessed using a power 
model. 
Safety analyses 
Safety evaluations include AE and concomitant medication reporting, complete physical 
examination, vital signs, 12-lead ECG, C-SSRS and clinical safety laboratory tests (serum 
chemistry, haematology, urinalysis and coagulation). All will be presented as data summaries. 
No formal statistical analyses will be performed. 
AEs (overall, by seriousness, by severity, by relationship) and concomitant medications 
(overall) recorded throughout the investigation will be reported following classification 
according to Medical dictionary for Regulatory Activities (MedDRA) System Organ Class 
(SOC) and Preferred Term (PT) and World Health Organisation Drug dictionary (WHODD) 
Anatomical Therapeutic Chemical (ATC) Classification System respectively.  
All other safety evaluations performed at screening and Visits 1-6 (EOS/EW) will be 
summarized accordingly.  
Unscheduled safety laboratory samples assayed at the local hospital will be listed according to 
Site. 
 
 
 
 
 
 
 
 
 
 


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Schedule of study and study procedures  
Visit 
Screening 
 
Phone 
calls 
 
Visit 1 
(Baseline) 
Visit 2 
 
Phone 
call 
 
Phone 
calls 
Visit 3 
 
Phone 
calls 
Visit 4 
 
 
Phone 
calls 
 
 
Visit 5 
(EOT) 
 
 
Visit 6 
(EOS/EW)
1 
Baseline 
diary period 
Dose run-in 
Treatment period 
Follow up 
Day 
-56 to -10 
-9 to -1 
Day 1 
9 
14 
21 
28 
 
56 
 
84 
5-8 days 
after EOT  
Week 
 
 
 
Week 1 
2 
 
3 
4 
7 
 
8 
11 
12 
Time window 
- 
-2 
- 
+ 2 days 
± 2 
days 
± 2 
days2 
± 4 days 
-2 
± 4 days 
-2 
-2 to 0 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
X3 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
Hoehn and Yahn scale 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs (incl supine/standing BP) 
X 
 
X5 
 
 
 
X 
 
X 
 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
X 
X 
12-lead ECG 
X4 
 
X5 
 
 
 
 
 
X 
 
X 
X 
Haematology / Clinical Chemistry 
X 
 
X5 
 
 
 
 
 
X 
 
X 
X 
CYP2D6 genotyping 
 
 
 
 
 
 
 
 
X 
 
 
 
Dipstick Urinalysis 
X 
 
X5 
 
 
 
 
 
X 
 
X 
X 
Pregnancy Test6/6a 
X6 
 
X6 
 
 
 
X6a 
 
X6a 
 
X6 
 
MDS-UPDRS 
X7 
 
X 
 
 
 
X8 
 
X 
 
X 
 
24-hour patient home diary training 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
1 Safety follow-up visit to be performed (if possible) for early IMP discontinuations (5-8 days after last dose of IMP) 
2 Site to call the patient the working day before the first 24-hour diary completion period, as a reminder, and the working day after the last 24-hour diary completion period to encourage compliance. 
3 CYP2D6 genetic informed consent must be signed prior CYP2D6 blood sample testing. Note: the CYP2D6 testing is optional 
4 Triplicates separated by at least one minute 
5 If 29 days or more between the Screening visit and Visit 1 (Baseline), safety parameters (Vital Signs, single ECG, Haematology/Clin Chem and Urinalysis) are included also at Visit 1 (Baseline). 
6 Serum hCG; Only applicable for women with childbearing potential (as defined in section 8.1) 
6a Urine hCG; Only applicable for women with childbearing potential (as defined in section 8.1) 
7 Part 4 question 4.2 
8 Part 2 (M-EDL) and part 4 questions 4.1 and 4.2 
9 Diary concordance training (takes approx. 2.5 hours). Could be done either at the screening visit or during a separate scheduled visit after receipt of the screening lab results and prior start of the baseline diary completion 
period. 


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Visit 
Screening 
 
Phone 
calls 
 
Visit 1 
(Baseline) 
Visit 2 
 
Phone 
call 
 
Phone 
calls 
Visit 3 
 
Phone 
calls 
Visit 4 
 
 
Phone 
calls 
 
 
Visit 5 
(EOT) 
 
 
Visit 6 
(EOS/EW)
1 
Baseline 
diary period 
Dose run-in 
Treatment period 
Follow up 
Day 
-56 to -10 
-9 to -1 
Day 1 
9 
14 
21 
28 
 
56 
 
84 
5-8 days 
after EOT  
Week 
 
 
 
Week 1 
2 
 
3 
4 
7 
 
8 
11 
12 
Time window 
- 
-2 
- 
+ 2 days 
± 2 
days 
± 2 
days2 
± 4 days 
-2 
± 4 days 
-2 
-2 to 0 
days 
24-hour patient home diaries hand 
out/collection 
X10 
 
 
X10 11  
 
 
 
X10 11 
 
X10 11 
 
X11 
 
24-hour patient home diary entry12 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Patient motor function review 
 
 
 
 
 
 
X 
 
 
 
 
 
Modified UDysRS 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
MMSE 
X 
 
 
 
 
 
 
 
 
 
X 
 
CGI-S 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
C-SSRS 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Adverse Event (AE) 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X  
X 
X 
Serious Adverse Event (SAE) 
collection/reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization13 
 
 
X 
 
 
 
 
 
 
 
 
 
PK sample14 
 
 
 
 
 
 
 
 
X 
 
X 
 
Dispense IMP 
 
 
X 
X 
 
 
X 
 
 
 
 
 
Collect empty bottles of IMP 
 
 
 
X 
 
 
X15 
 
X 
 
X 
 
Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
10 Three empty diaries handed out 
11 Three completed diaries collected 
12 Three 24-hour home diaries to be completed during separate days during the week (can be three consecutive days or any combination of days during the week) prior V1, V3, V4 and V5 (i.e. in total 12 diaries during 
the study). Set dates for the patient complete diaries to be agreed in advance. Clinic to call the patient the working day before the first 24-hour diary completion period, as a reminder, and the working day after the last 
24-hour diary completion period to encourage compliance. 
13 First dose to be taken in the evening at day 1  
14 Taken within 15 min pre-dose and approx. 2 hours (± 15 min) after morning dose of IMP 
15 Only collect the bottle if dose is reduced  


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CONTACT NAME AND ADDRESS 
Sponsor: 
Integrative Research Laboratories Sweden AB (IRLAB) 
Address: 
Integrative Research Laboratories Sweden 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, Chief Medical Officer (CMO) 
 
 
 
 
 
 
 
 
 


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2. ABBREVIATIONS 
ADL  
 
 
Activities of Daily Living 
ADR  
 
 
Adverse Drug Reaction 
AE 
 
 
 
Adverse Event 
AIM 
 
 
 
Abnormal Involuntary Movements 
ANCOVA 
 
 
Analysis of covariance 
ATC  
 
 
Anatomic Therapeutic Chemical classification system 
AUC  
 
 
Area under the concentration time curve 
b.i.d.  
 
 
Twice daily 
BMI 
 
 
 
Body Mass Index 
BP 
 
 
 
Blood Pressure 
CA 
 
 
 
Competent Authority 
CGI-S  
 
 
Clinical Global Impression of Severity 
Cmax 
 
 
 
Maximum concentration 
CMO  
 
 
Chief Medical Officer 
CNS  
 
 
Central Nervous System 
CRF 
 
 
 
Case Report Form 
CRO  
 
 
Clinical Research Organisation 
C-SSRS 
 
 
Columbia-Suicide Severity Rating Scale  
CYP  
 
 
Cytochromes 
DSM  
 
 
Diagnostic and Statistical Manual of Mental Disorders (DSM) 
ECG  
 
 
Electrocardiogram 
ED50  
 
 
Median Effective Dose 
EOS 
 
 
 
End of study 
EOT 
 
 
 
End of treatment 
EW 
 
 
 
Early withdrawal 
FAS 
 
 
 
Full Analysis Set 
ICH GCP (R2) 
International Conference on Harmonisation Good Clinical 
Practice (Revision 2) 
Hb 
Haemoglobin 
HPMC 
Hydroxypropyl Methylcellulose 
ICH 
International Conference on Harmonisation 
ICF 
 
 
 
Informed Consent Form 
IEC 
 
 
 
Independent Ethics Committee 
IMP 
 
 
 
Investigational Medicinal Product 
IRB 
 
 
 
Institutional Review Board 
IRL 
 
 
 
Integrative Research Laboratories 
IUD 
 
 
 
Intrauterine Device 
IUS 
 
 
 
Intrauterine System 
LID 
 
 
 
Levodopa-Induced Dyskinesia 
MAD  
 
 
Multiple Ascending Dose 
MDS-UPDRS  
 
Movement Disorder Society – Unified Parkinson’s  
Disease Rating Scale 
MedDRA 
 
 
Medical Dictionary for Regulatory Activities 
MMSE 
 
 
Mini–Mental State Examination 
NTEAE 
 
 
Non-Treatment Emergent Adverse Event 
PD 
 
 
 
Parkinson’s Disease 
PDP 
 
 
 
Parkinson’s Disease Psychosis 
PK 
 
 
 
Pharmacokinetic 


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PPS 
 
 
 
Per Protocol Set 
PT 
 
 
 
Preferred Term 
SAE 
 
 
 
Serious Adverse Event 
SAD  
 
 
Single Ascending Dose 
SAP 
 
 
 
Statistical Analysis Plan 
SDV  
 
 
Source Data Verification 
SOC  
 
 
System Organ Class 
SS 
 
 
 
Safety Set 
SUSAR 
 
 
Suspected Unexpected Serious Adverse Reaction 
Tmax 
 
 
 
Time to maximum concentration 
TEAE  
 
 
Treatment Emergent Adverse Event 
UAE  
 
 
Unexpected Adverse Event 
UKPDS  
 
 
UK Parkinson's Disease Society 
UDysRS 
 
 
Unified Dyskinesia Rating Scale 
WHODD 
 
 
World Health Organisation Drug dictionary 
 
 
Enrolled/screened patient:  
Patient who has signed the informed consent 
Screening failure:  
 
Enrolled patient not included 
Included patient:  
 
Patient randomized 
Withdrawn patient:   
Patient randomized but not completed 
Completed patient:  
 
Patient completed the study period, including follow-up 
 
 


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3. TABLE OF CONTENTS 
 
1. 
PROTOCOL SYNOPSIS ................................................................................................. 7 
2. 
ABBREVIATIONS ......................................................................................................... 18 
3. 
TABLE OF CONTENTS ............................................................................................... 20 
4. 
BACKGROUND INFORMATION AND STUDY RATIONALE ............................. 23 
4.1. 
Investigational agent............................................................................................ 23 
4.1.1. 
Mechanism of action .......................................................................................... 24 
4.1.2. 
Efficacy .............................................................................................................. 24 
4.1.3. 
Preclinical data ................................................................................................... 24 
4.2. 
Risks / benefits ..................................................................................................... 25 
4.2.1. 
Summary of risk management ........................................................................... 26 
4.3. 
Dose rationale ....................................................................................................... 26 
4.4. 
Trial conduct ........................................................................................................ 27 
4.5. 
Population............................................................................................................. 27 
4.6. 
Previous clinical studies ...................................................................................... 28 
5. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 29 
5.1. 
Primary objective and endpoint ......................................................................... 29 
5.2. 
Secondary and exploratory objectives and endpoints ...................................... 30 
6. 
STUDY DESIGN ............................................................................................................ 31 
6.1. 
Overall study design and plan description ........................................................ 31 
6.1.1. 
Study Schematic................................................................................................. 32 
6.2. 
Rationale for study design and dose selection ................................................... 33 
6.3. 
Discussion of study design, including the choice of control groups ................ 33 
7. 
PATIENT SELECTION CRITERIA ........................................................................... 33 
7.1. 
Patient recruitment .............................................................................................. 33 
7.2. 
Inclusion criteria .................................................................................................. 34 
7.3. 
Exclusion criteria ................................................................................................. 34 
7.4. 
Patient withdrawal and early IMP discontinuation ......................................... 35 
7.4.1. 
Replacements ..................................................................................................... 36 
8. 
RESTRICTIONS DURING THE STUDY ................................................................... 36 
8.1. 
General restrictions ............................................................................................. 36 
8.2. 
Concomitant medication ..................................................................................... 38 
9. 
TREATMENT(S)............................................................................................................ 39 
9.1. 
Appearance and content ..................................................................................... 39 
9.2. 
Dosage and administration ................................................................................. 39 
9.3. 
Packaging and labelling ...................................................................................... 42 
9.4. 
Blinding and randomization ............................................................................... 42 
9.5. 
Treatment compliance and accountability ........................................................ 43 
9.6. 
Drug storage ......................................................................................................... 44 
10. STUDY PLAN ................................................................................................................. 44 
10.1. 
Continuous Assessments ..................................................................................... 44 
10.2. 
Screening (-56 to -10 days prior to randomization).......................................... 44 
10.3. 
Phone calls (-9 to -1 days prior to randomization) ........................................... 45 
10.4. 
Visit 1 (Baseline, Day 1) ...................................................................................... 45 
10.5. 
Visit 2 (Day 9 + 2 days) ........................................................................................ 46 
10.6. 
Phone call (Day 14 ± 2 days) ............................................................................... 46 
10.7. 
Phone calls (Week 3, Day 21 ± 2 days) ............................................................... 46 
10.8. 
Visit 3 (Day 28 ± 4 days) ...................................................................................... 46 
10.9. 
Phone calls (Week 7)............................................................................................ 47 


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10.10. 
Visit 4 (Day 56 ± 4 days) ...................................................................................... 47 
10.11. 
Phone calls (Week 11).......................................................................................... 47 
10.12. 
Visit 5 (End-of-Treatment, Day 84, -2 to 0 days) .............................................. 48 
10.13. 
Visit 6 (Follow Up 5-8 days after End-of-Treatment) ...................................... 48 
10.14. 
Early Termination Visits..................................................................................... 48 
11. STUDY PROCEDURES / EVALUATIONS ................................................................ 49 
11.1. 
Clinical evaluations.............................................................................................. 49 
11.1.1. Demographics/Medical History ......................................................................... 49 
11.1.2. Hoehn and Yahr scale ........................................................................................ 49 
11.1.3. Height/Weight .................................................................................................... 49 
11.1.4. Physical Examination......................................................................................... 49 
11.1.5. Vital Signs .......................................................................................................... 50 
11.1.6. Resting 12-lead ECG ......................................................................................... 50 
11.2. 
Evaluations & assessments ................................................................................. 50 
11.2.1. Clinical laboratory evaluations .......................................................................... 50 
11.2.2. Columbia Suicide Severity Rating Scale (C-SSRS) .......................................... 51 
11.2.3. Assessments related to the primary endpoint..................................................... 51 
11.2.4. Assessments related to the secondary and other endpoints ............................... 53 
11.2.5. Specimen preparation, handling and shipping ................................................... 54 
12. ADVERSE EVENT REPORTING ............................................................................... 55 
12.1. 
Method of detecting AEs and SAEs ................................................................... 55 
12.2. 
Definitions............................................................................................................. 55 
12.3. 
Expectedness ........................................................................................................ 56 
12.4. 
Intensity of adverse event.................................................................................... 57 
12.5. 
Causality assessment ........................................................................................... 57 
12.6. 
Action taken regarding the IMP ........................................................................ 58 
12.7. 
Outcome ................................................................................................................ 58 
12.8. 
Recording adverse events .................................................................................... 58 
12.9. 
Serious adverse Events ........................................................................................ 59 
12.10. 
Reporting of SUSARs .......................................................................................... 60 
13. DATA MANAGEMENT ................................................................................................ 60 
13.1. 
Trial documentation and trial confidentiality................................................... 60 
13.1.1. Trial documentation, CRFs and document keeping ........................................... 60 
13.1.2. Confidentiality of trial documents and patient records ...................................... 61 
14. STATISTICAL METHODS .......................................................................................... 61 
14.1. 
General considerations ........................................................................................ 62 
14.2. 
Sample size/power calculation ............................................................................ 62 
14.3. 
Analysis sets.......................................................................................................... 63 
14.3.1. Safety analysis set .............................................................................................. 63 
14.3.2. Full analysis set .................................................................................................. 63 
14.3.3. Per protocol analysis set..................................................................................... 63 
14.4. 
Study population .................................................................................................. 63 
14.5. 
Baseline treatment dose group comparability .................................................. 63 
14.6. 
Treatment compliance ......................................................................................... 63 
14.7. 
Efficacy endpoints................................................................................................ 64 
14.8. 
Pharmacokinetic endpoints ................................................................................ 65 
14.9. 
Efficacy analyses .................................................................................................. 65 
14.9.1. Primary analyses ................................................................................................ 66 
14.9.2. Sensitivity analyses ............................................................................................ 66 
14.9.3. Handling of dropouts and missing observations ................................................ 66 


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14.9.4. Multiplicity ........................................................................................................ 66 
14.9.1. Secondary analyses ............................................................................................ 67 
14.10. 
Safety Analyses .................................................................................................... 67 
14.10.1. Extent of exposure ............................................................................................. 67 
14.10.2. Adverse events ................................................................................................... 67 
14.10.3. Concomitant medications................................................................................... 67 
14.10.4. Physical examinations ........................................................................................ 68 
14.10.5. Vital signs .......................................................................................................... 68 
14.10.6. ECG (12-Lead) at rest ........................................................................................ 68 
14.10.7. Clinical laboratory tests ..................................................................................... 68 
15. INDEPENDENT ETHICS COMMITTEE APPROVAL ........................................... 68 
16. REGULATORY REQUIREMENTS ............................................................................ 68 
17. INFORMED CONSENT ................................................................................................ 69 
18. DIRECT ACCESS TO SOURCE DOCUMENTATION / DATA ............................. 69 
19. STUDY MONITORING AND MANAGEMENT ....................................................... 69 
19.1. 
Training of study site personnel ......................................................................... 69 
19.2. 
Clinical monitoring .............................................................................................. 70 
19.3. 
Source data ........................................................................................................... 70 
19.4. 
Study agreements ................................................................................................. 70 
19.5. 
Study timetable and end of study ....................................................................... 71 
20. QUALITY ASSURANCE .............................................................................................. 71 
21. INSURANCE .................................................................................................................. 71 
22. CONFIDENTIALITY .................................................................................................... 71 
23. PREMATURE TERMINATION OF THE STUDY ................................................... 71 
24. RECORD RETENTION ................................................................................................ 72 
25. PUBLICATION OF RESULTS .................................................................................... 72 
25.1. 
Clinical study report ............................................................................................ 72 
25.2. 
Annual safety report ............................................................................................ 72 
25.3. 
Confidentiality and ownership of study data .................................................... 72 
25.4. 
Publication ............................................................................................................ 72 
26. REFERENCES ............................................................................................................... 73 
 
 
 
 
List of Tables 
Table 1: Examples of clinical inhibitors of CYP2D6- and CYP1A2-mediated metabolism ... 39 
Table 2: Treatment period – dosing phases ............................................................................. 40 
Table 3: Dose decrease guidance ............................................................................................. 40 
Table 4: Potential AEs associated with mesdopetam treatment .............................................. 56 
Table 5: Key secondary endpoints ........................................................................................... 64 
Table 6: Other endpoints .......................................................................................................... 64 
 
 
 


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4. BACKGROUND INFORMATION AND STUDY RATIONALE 
Parkinson’s disease (PD) is a relatively common neurodegenerative disorder characterized 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 [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 PD. 
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 
PD, about 50% of patients (and after 10 years almost all patients) develop involuntary 
movements appearing when the patient is in ON-phase, so called LIDs. [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]. 
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 PD. 
4.1. Investigational agent 
Mesdopetam was discovered in an in vivo systems pharmacology project and has been selected 
for development aimed as a treatment to reduce LID and psychosis in PD. 
Some specific desired properties of this compound are: 
• Efficacy in preclinical PD models of levodopa-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.  
• Indications of strengthened cortico-striatal connectivity through neurochemical and 
transcriptional biomarkers of neurotransmission, related to monoaminergic, 
cholinergic and glutamatergic neurotransmitter pathways. 
• In normal animals, mesdopetam 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 mesdopetam. The specific 
antidyskinetic and antipsychotic effects of mesdopetam suggest its use in the treatment of LID 


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and psychosis (PDP) in PD. This trial is aimed at assessing mesdopetam as a treatment for LID. 
Its role as a treatment for PDP will be assessed in future trials. 
4.1.1. Mechanism of action 
Mesdopetam 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’s monoaminergic systems without suppressing locomotor activity in 
normal un-pretreated rats. In vitro mesdopetam 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. 
Mesdopetam at the same doses behaves as an antidyskinetic and antipsychotic agent, leaving 
normal behaviour largely unaffected; combined with its neurochemical mode of action, 
mesdopetam indicates a novel compound profile in PD with potential to alleviate LID and 
psychosis while sparing normal motor functions. 
4.1.2. Efficacy  
Behaviourally, mesdopetam can 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, mesdopetam 
significantly reduced LID but left the levodopa-dependent motor activation intact. 
Furthermore, in a Phase 1b and a Phase 2a study, patients with advanced PD experiencing LID 
were randomized to receive mesdopetam or placebo as adjunct treatment for 28 days. In the 
Phase 1b study, 13 patients completed the study, with 9 patients on mesdopetam and 4 patients 
on placebo. In the Phase 2a study, 72 patients completed the study, with 37 patients on 
mesdopetam and 35 patients on placebo. For both studies, mesdopetam was safe and well 
tolerated following individual dose adjustments. It was also shown that the adjunct treatment 
of mesdopetam to otherwise stable antiparkinsonian medication reduced ON-phase dyskinesia 
without compromising general mobility. 
4.1.3.  Preclinical data 
The safety of mesdopetam has been evaluated in a standard battery of non-clinical studies, 
including in vitro and in vivo genotoxicity tests, repeat oral dose toxicity studies of up to 
13 weeks duration in rats and dogs, male fertility assessment in rats, and safety pharmacology 
studies on the cardiovascular, central nervous and respiratory systems. Mesdopetam is not 
genotoxic. Histopathological findings in the rat were either a probable effect on dopamine 
modulation of prolactin levels (effects on mammary gland, prostate gland, female reproductive 
organs and adrenal gland), related to metabolizing enzymes (liver finding) or a high-dose 
phenomena (stomach lesions and increased apoptosis in pancreas and parotids, 1-month study), 
all of which were partially or fully reversible. The principal clinical signs seen in the rat safety 
studies were Cmax-related and attributable to the pharmacological action of mesdopetam. The 
main dose limiting events were tremors, hypoactivity, hunched posture, abnormal or unsteady 
gait and reduced food consumption and body weight gain. The clinical signs recorded in the 
dog toxicity studies were of a similar nature to those in the rat, i.e. locomotor/postural and 
behavioural signs. In dogs, histopathological findings were seen only in the high-dose group in 


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the 1-month study (40 mg/kg/day). These were arteritis/periarteritis in small arteries mainly in 
the alimentary tract in one female (which had been preterminally sacrificed due to 
convulsions), and capillary dilation associated with an increased thickness of the alveolar walls 
in one male. These findings are considered to be adverse until their nature has been clarified. 
In the 3-month dog study, histopathological changes were only noted in the adrenal gland, and 
considered to be of adaptive nature and non-adverse. In the 1-month study in rat the NOAEL 
was considered to be 25 mg/kg/day (corresponding to mean Cmax of 10.8 µM; mean AUC0-24h 
of 47.2 µM•h). The NOAEL for microscopic findings is considered to be 55 mg/kg/day 
(corresponding to mean Cmax of 19 µM; mean AUC0-8h of 106 µM•h), while for the 3-month 
study the NOAEL was considered to be 55 mg/kg/day (including microscopic finding, 
corresponding to mean Cmax of 27.4 µM; mean AUC0-24h of 204 µM•h).  
In the 1- and 3-months studies in dog the NOAEL was considered to be 18 mg/kg/day 
(corresponding to mean Cmax of 8.9/10.6 µM and mean AUC0-24h of 84 /87.6 µM•h, for the 
1-month/3-month studies, respectively). 
Mesdopetam 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. Mesdopetam 
was tested for excitability, automaticity, cardiac wavelength, TRIaD and proarrhythmia in the 
Hondeghem model using rabbit isolated hearts [7]. Mesdopetam was concluded to be safe in 
the dose range tested (0.5 to 45 µM). 
Mesdopetam had no effects on cardiovascular parameters in dogs. No potential adverse effects 
were identified in the core battery safety pharmacology studies. Mesdopetam did not modify 
mating behavior, gonadal function and reproductive capacity of male rats. 
The phototoxicity potential of mesdopetam is assessed to be low, and the risk for phototoxic 
reactions is considered to be minimal in the planned clinical study. 
The major metabolites IRL902 and IRL872 are not considered to be pharmacologically active. 
The contribution of IRL902 and IRL872 to the overall assessment of general toxicity of 
mesdopetam has been investigated, by the presence of these metabolites in the 1- and 3-month 
studies in rats (IRL902 and IRL872) and dogs (IRL902) at significantly greater plasma 
concentrations (Cmax, AUC) than those occurring in humans (MAD study). Hence, the in vivo 
toxicity of IRL902 and IRL872 has been adequately characterized, and it is considered that 
these metabolites have been qualified in the pivotal toxicity studies in rats and dogs. The 
IRL902 and IRL872 metabolites are considered to be of no genotoxic concern in the proposed 
clinical study based on negative results in standard Ames test and in vitro micronucleus assays 
[8]. 
4.2. Risks / benefits  
Collectively, the data from nonclinical and clinical studies indicate that mesdopetam is likely 
to have an acceptable safety profile. Studies in humans have not identified any safety issues for 
the doses studied and the highest obtained plasma concentration of mesdopetam in healthy 
volunteers was below the highest recommended level. Possible adverse effects associated with 
mesdopetam include mild increase in parkinsonism and potential increases in plasma prolactin 
at higher dose levels.  
The dose levels to be used in this study have been selected based on analysis of previous clinical 
studies (see Section 4.6). A dose run-in phase for one week with a starting dose of 5 mg b.i.d. 


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and a subsequent dose allocation to three dose levels of mesdopetam (i.e. 2.5 mg, 5 mg or 
7.5 mg) b.i.d. or placebo b.i.d. is expected to retain a pronounced margin of safety. To mitigate 
the risk for intolerability, a one-step dose reduction is allowed but only once and only due to 
increased parkinsonism and/or consistent increase in motor OFF-time. There will be a careful 
monitoring of the patient's well-being including regular collection of Adverse Events (AEs). 
4.2.1. 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 (baseline), 9, 28, 
56 and 84 for monitoring of safety variables. PK sampling will occur on Days 56 and 84. Phone 
calls will be made between Screening and Visit 1 and on Weeks 2, 3, 7 and 11 to collect 
information on any AEs and changes in concomitant medication, as well as instructing the user 
to complete three 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 
patient home diaries, patient study identification, 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 BP cuff and frequent blood-sampling, 
can cause transient discomfort but the risk is deemed to be low and ethically justifiable.  
The Sponsor acknowledges the impact of global pandemic of COVID-19 on any health system 
and broader society, and the impact it may have on this clinical study and study participants. 
Extraordinary measures may need to be implemented and study adjusted due, among others, to 
study participants being in self-isolation/quarantine, limited access to public places (including 
hospitals) due to the risk of spreading infection, and health care professionals being committed 
to critical tasks. 
These challenges could have an impact on the conduct of the study such as the completion of 
study assessments, completion of study visits and the provision of the IMP. The ability to 
confirm eligibility and to conduct key safety assessments and study evaluations is of particular 
importance.  
If needed, actions will be proportionate and based on benefit-risk considerations, on 
contingency provisions taken nationally and locally by the authorities, with priority given to 
the impact on the health and safety of the study participant. Necessary actions may be that for 
example Visit 2 (Day 9) is performed as a home visit or a phone visit with the new bottle of 
IMP sent to the patient via a courier or importer as per local regulatory requirement, or that in 
case of dose reduction (i.e. allowed between Day 9 - Day 28) the new bottle of IMP could be 
sent to the patient via a courier or importer as per local regulatory requirements. The possibility 
to access source documents during remote monitoring could be considered necessary, but need 
to be regulated as per local requirements (or temporary national emergency measures). 
4.3. Dose rationale 
The pharmacological effects of mesdopetam have been evaluated in a range of preclinical 
animal models. As to the suggested indication, LID in PD, the 6-hydroxydopamine (6-OHDA) 
Abnormal Involuntary Movements (AIM) scoring rat model is most commonly suggested for 


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use in pharmacological validation of anti-dyskinetic efficacy of new therapies and is thus 
regarded to have predictive validity. Using this rodent lesion model, mesdopetam has been 
studied in two independent tests, both in-house and by an external laboratory. Mesdopetam 
showed significant efficacy in reducing AIMs (active doses <10 mg/kg s.c. with a Median 
Effective Dose (ED50) of 3.7 mg/kg s.c.), without compromising beneficial effects of 
levodopa. 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 mesdopetam is also likely to be personalized. Flexible dosing has been explored 
in two of the clinical studies (phase 1b and phase 2a). In this study (phase 2b) a dose-response 
analysis will be performed to evaluate three dose levels of mesdopetam (i.e. 2.5 mg, 5 mg and 
7.5 mg b.i.d.). The dose-response analysis will give knowledge of the relationship among dose, 
drug-concentration in blood and clinical response (effectiveness & safety).  
The dose levels to be used in this study have been selected based on previous clinical studies 
(see Section 4.6) where data indicates that clinically relevant efficacy may be achieved at the 
dose levels selected. The most commonly reported adverse event in patients randomized to 
mesdopetam in the phase 2a study was increased parkinsonism (during titration phase), and the 
finding of a possible dose dependent increase in OFF-time strongly suggest that lower doses 
than 10 mg b.i.d. should be explored in this forthcoming study. The finding of a strong trend 
towards improved general motor function in patients allocated to 7.5 mg b.i.d. or lower indicate 
that the efficacy of mesdopetam may extend beyond that of reducing peak dose dyskinesia. 
The treatment starts with a one-week dose run-in period where all patients are randomized to a 
starting dose of 5 mg mesdopetam or placebo (twice daily). Thereafter the patients are allocated 
to one of three doses of mesdopetam or placebo. Given the plasma half-life of about 7 hours, 
enough coverage during the waking hours of the day is expected. 
4.4. Trial conduct 
This study will be conducted in compliance with the protocol and according to International 
Conference on Harmonisation Good Clinical Practice Revision 2 (ICH GCP (R2)) 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. 
4.5. Population 
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 ON-phase involuntary movements, so called 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 may also develop over time in a 
substantial proportion of patients. There are few options for the treatment and prevention of 
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Mesdopetam was discovered and developed in a project aimed at finding a treatment for LID 
and psychosis 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 affecting the basic efficacy of antiparkinsonian medications. 
4.6. Previous clinical studies 
Mesdopetam has been investigated in the following three clinical studies: 
− IRL790C001, a randomized, double-blind, placebo-controlled, phase 1 single 
ascending dose (SAD) and multiple ascending dose (MAD) study in male healthy 
volunteers. 
− IRL790C002, a randomized, double-blind, placebo-controlled, phase 1b study 
evaluating the safety and tolerability of mesdopetam in patients with PD experiencing 
LID.   
− IRL790C003, a randomized, double-blind, placebo-controlled phase 2a study 
evaluating the efficacy and tolerability of mesdopetam in patients with PD experiencing 
LID. 
IRL790C001 (Phase 1) 
In the SAD part of IRL790C001, 16 subjects were divided into two cohorts. Within each cohort 
the subjects were randomized to one of four treatment sequences, which included three dose 
levels of IMP. One of the dose levels was repeated once, taken with a standardized meal, all 
other doses were taken without food. In each of the six administered dose levels (5, 15, 40, 80, 
120 mg mesdopetam), six subjects received active drug and two subjects received matching 
placebo. 
In the MAD part of this study, 23 subjects were treated with IMP. In the first cohort, 9 subjects 
received mesdopetam, 40 mg/day for 10 consecutive days and 3 subjects received matching 
placebo. In the second cohort, 9 subjects received mesdopetam, 80 mg/day for 10 consecutive 
days and 3 subjects received matching placebo. 
Overall, mesdopetam was well tolerated when given to healthy male subjects at single doses 
up to 120 mg and at multiple doses of 80 mg per day for 10 days. The maximum tolerated dose 
was set to 120 mg as a single dose and the maximal dose for multiple dosing was set to 80 mg 
per day. Most of the Treatment Emergent Adverse Events (TEAEs) (74%) were of grade 1 
intensity while 26% were of grade 2 intensity. Most AEs (48%) reported were considered as 
not related to study treatment while 11% were possibly related and 41% probably related. 
Overall TEAEs were mild, transient and possibly CNS related. 
In agreement with preclinical findings, the PK 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. 


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IRL790C002 (Phase 1b) 
In the Phase 1b study (IRL790C002), 15 patients with advanced PD experiencing LID were 
randomized to receive mesdopetam or placebo (3:1 randomization) 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 (15) patients were randomized to treatment, 11 to mesdopetam and 4 to placebo. 
Generally, AEs were of mild intensity and transient after dose adjustments. Ten (10) patients 
in the mesdopetam treated group and 4 patients in the placebo group reported at least one 
related AE. Nervous system disorder was the most common AE (31% of all reported AEs). 
Five patients treated with mesdopetam reported transient worsening of parkinsonism during 
dose titration, an adverse effect which was mitigated by dose reduction. Thirteen (13) patients 
completed the study, 9 patients on mesdopetam and 4 patients on placebo. Two (2) patients 
treated with mesdopetam discontinued treatment due to AEs.  
IRL790C003 (Phase 2a) 
In the Phase 2a study (IRL790C003), 75 patients with advanced PD experiencing LID were 
randomized to receive mesdopetam or placebo as adjunct treatment for 28 days, 39 to 
mesdopetam and 36 to placebo. 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, the dosing was kept stable for the remaining two weeks. 
Generally, AEs were of mild intensity and transient after dose adjustments. Parkinsonism was 
the most common AE. Nine  patients in the mesdopetam treated group reported parkinsonism 
during titration only and 2 patients in the mesdopetam treated group reported parkinsonism 
during steady state. 72 patients completed the study, with 37 patients on mesdopetam and 35 
patients on placebo. 3 patients discontinued treatment in advance due to AEs (two on 
mesdopetam and one on placebo).  
Vital signs, laboratory measurements and cardiovascular functions were unaffected by 
mesdopetam treatment.  
At EOT the number of daily hours spent in ON-phase with troublesome dyskinesia was 
significantly reduced for mesdopetam treated patients as compared to placebo. General 
mobility was unaltered by the treatment, there were no evidence for changes in time spent in 
OFF-state or in the total score of MDS-UPDRS parts 2 or 3. 
The clinical studies show that, following individualized dose adjustment, mesdopetam is well 
tolerated in patients with advanced PD and seem to act to reduce dyskinesia without 
compromising general motility. 
5. STUDY OBJECTIVES AND ENDPOINTS 
5.1. Primary objective and endpoint 
Primary objective: 
• To evaluate the effectiveness of adjunctive treatment with mesdopetam dosed at 
2.5 mg, 5 mg or 7.5 mg b.i.d. (permitting a single 2.5 mg dose reduction to a minimum 


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dose of 2.5 mg, up to Day 28) compared to placebo in patients with PD exhibiting 
troublesome ON-phase dyskinesia.  
Primary endpoint: 
• Change in average daily hours of ON-time without troublesome dyskinesia with 
mesdopetam compared to placebo as assessed with 24-hour patient home diaries from 
baseline to end of treatment (EOT) (Visit 5, Week 12). 
 
5.2. Secondary and exploratory objectives and endpoints 
Secondary objectives: 
• To establish the dose response relationship with 3 dose levels of mesdopetam. 
• To evaluate the effects of mesdopetam on severity of ON-phase dyskinesia and motor 
symptoms of PD. 
• To evaluate the effects of mesdopetam on the daily hours spent in different motor states. 
• To evaluate the safety and tolerability of mesdopetam given twice daily during 
84 consecutive days.  
• To evaluate trough and 2-hour post dose plasma concentrations of mesdopetam and its 
two main metabolites (IRL902 (N-dealkylated) and IRL872 (acetylated)). 
Exploratory objectives: 
• To assess overall PD symptoms.  
• To assess cognitive function.   
Secondary endpoints: 
• Change from baseline in average daily hours of ON-time without troublesome 
dyskinesia for each individual dose level (2.5 mg, 5 mg, 7.5 mg b.i.d.), as well as all 
active doses grouped compared to placebo.   
• Change from baseline in mean score or average daily hours with mesdopetam compared 
to placebo for the following measures: 
o ON-phase dyskinesia assessed with the sum score of the modified UDysRS (parts 
1, 3 and 4). 
o Disability associated with ON-phase dyskinesia assessed with the sum score of 
parts 1b and 4 of the UDysRS. 
o ON-phase dyskinesia assessed by MDS-UPDRS part 4 questions 4.1 (Time spent 
with dyskinesias) and 4.2 (Functional impact of dyskinesias). 
o Motor symptoms of PD assessed with MDS-UPDRS total score of part 2 (M-EDL). 
o Daily OFF-time, daily ON-time with troublesome dyskinesia and daily total 
ON-time (defined as the sum of ON-time with and without troublesome dyskinesia).  
o CGI-S of ON-phase dyskinesia.   
 


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Exploratory endpoints: 
• Change from baseline with mesdopetam compared to placebo in:  
o CGI-S of overall PD symptoms.   
o Total MMSE score.   
 
Safety endpoints: 
• Frequency and nature of AEs, laboratory results, vital signs, physical examinations, 
C-SSRS and 12-lead electrocardiograms (ECG) at each visit from baseline to follow-up. 
Pharmacokinetic endpoints: 
• Plasma concentrations of mesdopetam and its two main metabolites at pre-dose and 2 hours 
post-dose at 8 and 12 weeks of treatment 
 
6. STUDY DESIGN 
6.1. Overall study design and plan description 
This is a multi-centre, randomized, double-blind, placebo-controlled study with the primary 
objective to evaluate the efficacy of 84 days’ treatment with mesdopetam on ON-time without 
troublesome dyskinesia in patients with PD.  
At the screening visit, consenting patients will be screened for eligibility according to study-
specific inclusion/exclusion criteria (see Sections 7.2 and 7.3) within 10-56 days before start 
of IMP administration. Diary concordance training will be performed, either during the 
screening visit or in the period prior to first diary completion. Patients will be instructed to self-
administer three 24-hour home diaries (before Baseline, Visit 1) for assessment of daily motor 
function and to bring the completed diaries to the clinic at the next visit (Baseline, Visit 1). 
Screen failed patients will not complete any diaries. To be eligible for randomization the patient 
should have completed at least two valid 24-hour home diaries. 
Following baseline assessments, patients will be randomized 1:1:1:1 to receive one of three 
doses of mesdopetam (2.5 mg, 5 mg or 7.5 mg) or placebo b.i.d. During the first week (Day 1 
evening dose to Day 9 morning dose) a dose run-in phase will take place, during which all 
patients allocated to mesdopetam will receive mesdopetam 5 mg b.i.d. and patients allocated 
to placebo will receive placebo b.i.d.  
 
At Visit 2 (Day 9), patients will be dispensed mesdopetam 2.5 mg, 5 mg or 7.5 mg or placebo 
b.i.d., as randomized. The patients will continue the same dose for the rest of the treatment 
period until EOT (Day 84). Dose reductions will only be allowed if the patient manifest 
increased parkinsonism and/or consistent increase in motor OFF-time. The dose can only be 
reduced once (and only by 2.5 mg b.i.d.) (see Table 3). Dose reduction is only permitted from 
Visit 2 (Day 9) until Visit 3 (Day 28 ±4 days), where after the dosing should be kept stable 
until the EOT visit (Day 84). 
 
The treatment allocation will be double-blind, i.e. it will not be disclosed to the patients, the 
site staff or the Sponsor. Starting on Day 1 the IMP will be self-administered by the patient at 
home for 12 consecutive weeks; two oral daily doses (approximately 8 hours apart) as adjunct 
treatment to the patients’ regular and stable antiparkinsonian medication.  


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During the treatment period at Visits 3-5, changes in disease state and ON-phase dyskinesia 
will be assessed using the MDS-UPDRS, the modified UDysRS (i.e. parts 1, 3 and 4) 
standardized for levodopa intake and time of the day and Clinician’s Global Impression of 
Severity (CGI-S). The MDS-UPDRS part 2 will be assessed at all clinical visits. Part 3 will be 
assessed with the patient in ON at Visit 1 and Visits 4 and 5. 
Furthermore, patients will self-administer three 24-hour home diaries prior to Visit 3 (Week 4), 
Visit 4 (Week 8) and Visit 5 (Week 12) to assess daily motor function. Dates for the patient to 
complete home diaries will be agreed in advance. The clinic will call the patient the working 
day before the first scheduled 24-hour home diary completion period, as a reminder, and the 
working day after the last 24-hour home diary completion period to encourage compliance. 
Patients must bring all three diaries to the clinic at each visit. 
 
At Visit 4 and Visit 5, the morning IMP dose will be administered at the clinic. Blood samples 
for PK analysis will be collected within 15 min pre-dose and approximately two hours 
(± 15 min) post dose.  
Various parts of the safety assessments will be performed at all visits. The morning dose at 
Day 84 (Visit 5, EOT) will be the last dose of IMP. 
 
Visit 6 (follow-up) will be performed for all patients, including any patients that discontinue 
the IMP early, 5-8 days after last administration of IMP.  
 
Unscheduled visits will be performed as needed during the study and should be documented in 
the appropriate section of the Case report form (CRF). 
Each assessment is further described in Section 10. 
6.1.1. Study Schematic 
Patient path - primary endpoint 
  
 
 
 


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6.2. Rationale for study design and dose selection 
The pharmacological effects of mesdopetam 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 producing 100-200 nM in plasma concentration. 
 
Individualized dosing has been explored in two previous clinical studies (phase 1b and 
phase 2a). In this phase 2b study a dose-response analysis will be performed to evaluate three 
dose levels of mesdopetam (i.e. 2.5 mg, 5 mg and 7.5 mg b.i.d.). The dose-response analysis 
will give knowledge of the relationship among dose, drug-concentration in blood and clinical 
response (effectiveness & safety). The dose levels to be used in this study have been selected 
based on previous clinical studies (see Section 4.6) where data indicates that clinically relevant 
efficacy may be achieved at the dose levels selected. The most commonly reported AE in 
patients randomized to mesdopetam in the phase 2a study was increased parkinsonism (during 
titration phase), and the finding of a possible dose dependent increase in OFF time strongly 
suggest that lower doses than 10 mg b.i.d. should be explored in this forthcoming study. The 
finding of a strong trend towards improved general motor function in patients allocated to 7.5 
mg b.i.d. or lower indicate that the efficacy of mesdopetam may extend beyond that of reducing 
ON-phase dyskinesia. 
6.3. 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. The study will be double blind and placebo controlled. 
Patients will be randomized, in equal proportions, to placebo or to one of the three doses 
(2.5 mg, 5 mg or 7.5 mg b.i.d.) of the active dose regimen (mesdopetam), to permit analyses 
of the dose response relationship. For patients to adjust to the new medication, IMP treatment 
will start with a run-in period of one week. During this initial week, patients randomized to 
mesdopetam will receive 5 mg b.i.d. and patients randomized to placebo will receive placebo 
b.i.d. Results from previous clinical studies show that 5 mg b.i.d. is well tolerated by a vast 
majority of patients. Following the initial one-week run-in, patients randomized to mesdopetam 
will continue with their assigned dose (2.5 mg, 5 mg, or 7.5 mg b.i.d.) and patients randomized 
to placebo will continue with placebo. 
7. PATIENT SELECTION CRITERIA 
7.1. 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 early 
termination/withdrawal should be stated for all patients included but not completed.  
140 randomized patients are required for this study. 


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7.2. Inclusion criteria  
For inclusion in the study, patients must fulfil all the following criteria:  
1. Male or female ≥30 and ≤79 years of age at the time of screening. 
2. Signed a current Ethics Committee approved informed consent form. 
3. PD, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic 
Criteria. 
4. Minimal amount of 2 hours of levodopa-induced daily “ON-time with troublesome 
dyskinesia” during waking hours. 
5. Functional impact of dyskinesias determined as a score of ≥2 as per Question 4.2 of the 
MDS- UPDRS. 
6. On a stable regimen of antiparkinson medications for at least 30 days prior to first home 
diary completion, which must include  a levodopa preparation administered 3-8 
times/day (excluding nighttime levodopa) and willing to continue the same doses and 
regimens during study participation. Rescue medications such as Madopar dispersable 
and Apomorphine injections are allowed if prescribed PRN prior to study entry. 
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 first home diary completion 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. Able to complete 24-hour patient home diaries of which two valid diaries must be 
presented at Visit 1. 
7.3. Exclusion criteria 
Patients must not enter the study if any of the following exclusion criteria are fulfilled: 
1. History of neurosurgical intervention related to PD (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, localized bladder cancer, non-
metastatic prostate cancer or in situ cervical cancer. 
6. Presence of cognitive impairment, as evidenced by a Mini-Mental State Examination 
(MMSE) score of less than 24 during screening. 
7. A Hoehn and Yahr stage of 5. 
8. Ongoing treatment with amantadine at time of screening or within 6 weeks prior first 
home diary completion. 
9. Treatment with Inbrija (levodopa inhalation powder) at time of screening or within 4 
weeks prior home first diary completion. 


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10. 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. 
11. 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 (a fall and/or a discomfort); clinically 
significant hepatic disease, severe renal impairment, i.e. creatinine clearance <30 
mL/min (stage IV or V). 
12. Any history of a neurological disorder other than PD 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. 
13. 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. 
14. Drug and/or alcohol abuse. 
15. History of severe drug allergy or hypersensitivity. 
16. If female, is pregnant or lactating, or has a positive pregnancy test result pre-dose. 
17. Patients unwilling to use two forms of contraception (one of which being a barrier 
method see Section 8.1) during the treatment period and 90 days for men and 30 days 
for women after last IMP dose. 
18. Any planned major surgery within the duration of the study. 
19. Any other condition or symptoms preventing the patient from entering the study, 
according to the Investigator’s judgement. 
7.4. Patient withdrawal and early IMP discontinuation 
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 
discrimination, 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 and discontinue the IMP 
early 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 
• Protocol deviation 
• Pregnancy after entry into study 


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• Any AE 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 
If a patient discontinues the IMP early for any reason, if possible, a safety follow-up visit 
(according to Visit 6) should be scheduled within 5-8 days after the last intake of the IMP. The 
Investigator must complete the “Study termination” section of the CRF explaining all reasons 
for withdrawal.  
After a patient withdraws from the study, the Investigator remains responsible for reporting 
SAEs considered causally related to the IMP. In addition, the Investigator must ensure 
appropriate treatment and follow-up of each AE ongoing at the time of the patient’s 
discontinuation. 
The Investigator is responsible for the optimal individual treatment of the patient. 
7.4.1. Replacements 
Patients who are screened but not randomized will be classed as Screen Failures. The Sponsor 
will evaluate the actual dropout rate after 70 randomized patients have completed Visit 3 
(Week 4) and can, if the dropout rate at this point is higher than expected, decide to increase 
the sample size to a total of maximum 154 randomized patients (+10%). 
Patients who fail screening can be re-screened once, depending on the reason for screen failure 
and as judged by the Investigator. The patient acceptable for re-screening will then receive a 
new screening number. 
8. RESTRICTIONS DURING THE STUDY 
8.1. General restrictions 
Contraception Requirements: 
 
The patient must be reminded to use two forms of contraception (one of which being a barrier 
method) for six months (180 days) for men and four months (120 days) for women from the 
time of the first administration of IMP. 
 
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 of IMP until three months following 
administration of the last dose of IMP. Male patients must also refrain from donating sperm 
from the time of first administration of IMP until three months after last dosing of IMP. 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) 
• 
The female partner uses oral contraceptives (combination oestrogen/ progesterone 
pills), injectable progesterone or subdermal implants and a barrier method (condom 


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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 
 
Note: 
Male patients whose female partner(s) is (are) pregnant must use a condom from the time of 
the first administration of treatment or IMP until three months (90 days) following 
administration of the last treatment or dose of IMP. 
Female patients 
Female patients of childbearing potential must use medically acceptable methods of 
contraception from the time of the first administration of treatment or IMP until four weeks 
following administration of the last treatment or dose of IMP. A woman is considered of 
childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. A post-menopausal state is defined as no menses 
for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. However, in the absence 
of 12 months of amenorrhea, a single FSH measurement is insufficient. 
 
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. 
 
 
 


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Blood donation:  
The patients must not donate blood or plasma during the study conduct or until three months 
after the final medical examination at the follow-up visit. 
8.2. Concomitant medication 
Permitted concomitant medication: 
Patients included in the study must be on stable antiparkinsonian medications for at least 30 
days prior to first 24-hour patient home diary completion and during the study. Rescue 
medications such as Madopar dispersable and intermittent Apomorphine injections are allowed 
if prescribed PRN prior to study entry. Other medications considered necessary for the patient’s 
safety and well-being may be given at the discretion of the Investigator.  
All concomitant therapy used within the four weeks prior to the screening period and during 
the study must be recorded on the CRF. 
Non-permitted concomitant medication: 
Inbrija (levodopa inhalation powder) is not allowed as a rescue medication during the study. 
No other drug under investigation may be used concomitantly with the IMP.  
Treatment with amantadine is not allowed within 6 weeks before completion of the first 
24-hour patient home diary and during the study. 
Available in vitro data indicate that CYP2D6 and CYP1A2 are the main enzymes involved in 
the metabolism of mesdopetam. However, the exact contribution from each of these two 
enzymes in the elimination is not known, and there may be a risk for significant increase of 
exposure when mesdopetam is used together with a combination of medications being strong 
inhibitors of CYP2D6 and CYP1A2 (see Table 1). Therefore, a combination of such inhibitors, 
i.e. a CYP1A2 strong inhibitor and a CYP2D6 strong inhibitor concurrently, should be avoided 
throughout the study. A CYP2D6 genotyping testing will be performed at Visit 4 (Day 56). 
Mesdopetam and its two main plasma metabolites M1 (IRL902) and M2 (IRL872) have been 
shown in vitro to not be inhibitors of the main drug metabolizing CYP450 enzymes to a 
significant degree. Restrictions on concomitant medications being CYP450 substrates are 
therefore not considered necessary during the study. 
Mesdopetam and metabolite M2 (IRL872) are also not inhibitors or substrates to a significant 
extent to main drug membrane transporters. Restrictions on concomitant medications being 
substrates or inhibitors of drug transporters are not considered necessary during the study. 
 
 
 


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Table 1: Examples of clinical inhibitors of CYP2D6- and CYP1A2-mediated 
metabolism 
Isoenzyme 
(cytochrome P450) 
Strong Inhibitors 
A combination of a CYP1A2 
inhibitor and a CYP2D6 inhibitor is 
not permitted during the study. 
CYP1A2 
ciprofloxacin, enoxacin, 
fluvoxamine, zafirlukast 
CYP2D6 
bupropion, fluoxetine, 
paroxetine, quinidine, 
terbinafine 
 
9. TREATMENT(S) 
9.1. Appearance and content 
Mesdopetam capsules, 2.5 mg, 5 mg and 7.5 mg free base equivalent: White hard HPMC 
capsule, coni snap size 3, colour white containing mesdopetam x ½ L-tartrate. 
Placebo capsules: White hard HPMC capsule, coni snap size 3, colour white containing starch. 
9.2. Dosage and administration 
The IMP (1 capsule b.i.d.) will be swallowed together with 200 mL of water in the morning 
and in the afternoon approximately 8 hours apart on each administration day, except for Day 56 
and Day 84 when the dose will be taken in the morning at the clinic visit after trough PK 
sampling. 
Dose run-in phase and treatment phase 
Treatment allocation throughout the run-in and treatment dosing periods will be managed 
through the Interactive Response System (IRS) system. During the 9-day run-in phase, the IRS 
system will ensure all patients allocated to active dose regimen will receive 5 mg mesdopetam 
b.i.d, followed by the randomized dose at Visit 2 (Day 9). Patients allocated to placebo will 
receive placebo during the first week run-in and then continue placebo during the whole 
treatment period. Any dose reduction will also be managed through the IRS system to ensure 
that blinding is maintained.  
If a patient experiences increased parkinsonism and/or consistent increase in motor OFF-
time, during the treatment period from Visit 2 up to Visit 3 (i.e. Day 9 – Day 28 ±4 days), the 
dosing can be reduced by 2.5 mg b.i.d. A dose reduction is allowed at only one occasion. A 
review of motor function will be performed at Visit 3. 
The following tables give additional information on the two dose phases (Table 2) and the dose 
decrease guidance (Table 3). 


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Table 2: Treatment period – dosing phases  
Dose phase 
Details 
Dose run-in phase: 
Randomization Day 1. First dose taken Day 
1 (evening dose) and last dose taken Day 9 
(morning dose). 
All patients randomized to mesdopetam will 
receive 5 mg b.i.d. All patients randomized 
to placebo will receive placebo b.i.d.   
 
Dosing following Visit 2: 
First dose taken Day 9 (evening dose) and 
last dose taken Day 84 (morning dose/at the 
clinic due to PK sampling) 
All patients randomized to mesdopetam will 
receive mesdopetam 2.5 mg, 5 mg or 7.5 mg 
b.i.d., 
as 
randomized. 
All 
patients 
randomized to placebo will continue with 
placebo b.i.d. 
 
Table 3: Dose decrease guidance 
Treatment period 
Dose decrease guidance 
Applicable for treatment from Visit 2 
(Day 9) until Visit 3 (Day 28 ±4 days): 
Decision to reduce the dosing is only allowed 
from Visit 2 (Day 9) until Visit 3 (Day 28 ± 
4 days), and dose reduction is only allowed 
once. 
 
A dose reduction is only allowed if the 
patient 
experiences 
an 
increase 
in 
parkinsonism and/or a consistent increase in 
motor OFF-time. Increased parkinsonism is 
manifested 
as 
consistent 
increase 
in 
disability associated with parkinsonian 
symptoms (i.e. bradykinesia, tremor and/or 
rigidity).  
The following steps are permitted if the dose 
is decided to be reduced: 
 
Patients allocated to 7.5 mg b.i.d. → dose is 
reduced to 5 mg b.i.d. 
 
Patients allocated to 5 mg b.i.d. → dose is 
reduced to 2.5 mg b.i.d. 
 
Patients allocated to 2.5 mg b.i.d. → dose is 
maintained (i.e. 2.5 mg b.i.d.).  
Patients allocated to placebo b.i.d. → 
placebo b.i.d. is maintained. 


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If parkinsonism is still increased following 
this dose reduction, the patient and 
Investigator need to decide if the patient 
could continue with the same dose in the 
study (since the dose cannot be reduced 
further) or if the patient have to withdraw the 
IMP and the study. 
Dose reduction will be managed through the 
IRS system. 
Patient motor function review performed at 
Visit 3 (Day 28 ±4 days) 
 
This review is based on the 24-hour patient 
home diaries completed in the week prior to 
Visit 3 and the MDS-UPDRS part II 
assessment completed during site Visit 3. 
Diaries and MDS-UPDRS data are reviewed 
and compared to baseline.  
If there is a clinically relevant increase in 
OFF-time, the Investigator must determine if 
the increase has been consistent over time 
and if it is predominantly related to 
non-motor or motor OFF-time (according to 
the 
Investigator’s 
clinical 
judgement). 
Evaluation of results from MDS-UPDRS 
part 2 (M-EDL) should be weighted in the 
decision. 
Adherence 
to 
prescribed 
antiparkinsonian medications should also be 
reviewed.  
Should a consistent increase in motor 
OFF-time, and/or a clinically significant 
worsening of mobility due to parkinsonism 
be assessed as likely due to the IMP, the 
dosing should be reduced by 2.5 mg b.i.d. at 
this visit. If the patient has already had a dose 
reduction prior to Visit 3, the dose cannot be 
reduced further at this visit, and the 
Investigator must determine whether the 
patient can continue in the study (i.e. 
continue in the study with the same dose). 
Other AEs not relating to the core symptoms 
of parkinsonism (such as, fatigue, headache, 
dystonia and other) do not qualify for dose 
reduction. 
The reason for any dose adjustments must be recorded in the CRF. There will be no treatment 
with mesdopetam available after end of study participation. 
 


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9.3. Packaging and labelling 
Finished product of IMP (active drug and placebo) will be packed and labelled by Catalent 
Pharma Solutions. 
Labels will comply with applicable Good Manufacturing Practice (GMP) requirements 
(EudraLex Volume 4, Good manufacturing practices, ANNEX 13, Manufacture of 
Investigational Medicinal Products) and applicable local regulatory guidelines. Labels will be 
translated into local languages. 
Containers will be packed with enough IMP for the study treatment period and labelled with 
the appropriate information required before release and shipment. 
9.4. Blinding and randomization 
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 mesdopetam and placebo (capsules 
of mesdopetam and placebo will be of identical appearance.) 
At the baseline visit (Visit 1, Day 1) patients will be randomized 1:1:1:1 to receive one of three 
doses of mesdopetam (2.5 mg, 5 mg or 7.5 mg) or placebo b.i.d.  
During the first week (Day 1 evening dose to Day 9 morning dose) a run-in phase with either 
5 mg mesdopetam or placebo b.i.d. will take place, during which all patients allocated to 
mesdopetam will receive 5 mg mesdopetam b.i.d. and patients allocated to placebo will receive 
placebo b.i.d. At Visit 2 (Day 9), patients will receive mesdopetam 2.5 mg, 5 mg or 7.5 mg or 
placebo b.i.d., as randomized.    
Randomization will be performed via a web-based Interactive Response System (IRS), using a 
dynamic balancing (minimization) algorithm. Randomization will be stratified by average 
(based on at least two valid home diaries) of <6 daily hours or ≥6 hours of daily ON-time with 
troublesome dyskinesia at baseline. 
During the one-week run-in phase, the IRS system will ensure all patients allocated to 
mesdopetam treatment will receive 5 mg mesdopetam b.i.d, followed by the randomized dose 
during the treatment period. Patients allocated to placebo will receive placebo during the first 
week run-in and then continue placebo during the whole treatment period. Any dose reduction 
will also be managed through the IRS system to ensure that blinding is maintained. 
Interactive Randomization System (IRS): 
The IRS will manage the randomization, stratification 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 will be used to track patient activities in real time throughout study 
visits. Real-time web reports and alerts platform (such as email and fax) give access to 
compliance feedback for continuous transparency of study progress. Patient unblinding is also 
contained within the IRS system to allow the unblinding of patients for safety purposes within 
the protocol via web or phone. If emergency unblinding is required, this responsibility lies 
solely with the Investigator. Unblinding for other safety 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. 


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Prolactin Results 
Minor increases in prolactin levels may be present in participants randomized to mesdopetam. 
It should be noted that this elevation in prolactin is not expected to be clinically significant but 
could be potentially detectable if comparing Visit 5 (EOT) results to screening. For this reason, 
prolactin is not included in the safety lab measurements at Visit 4 and laboratory analysis 
results for the prolactin value at Visit 5 will be blank (i.e. not revealed to the Investigator).  
PK Samples 
The laboratory analysing the PK samples will have access to the randomization list; only 
samples taken from patients in the active group of the study will be analyzed. Results of PK 
analysis will not be linked to patient number until the database is locked. 
Breaking the Blind 
Mesdopetam and placebo (capsules of identical appearance.) will be dispensed in identical 
containers according to a blinded randomization scheme. Study patients, Investigators, study 
staff and the Sponsor will remain blinded to the randomization 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 an SAE, 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 have access to the IRS system with the permissions 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 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 
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. 
9.5. Treatment compliance and accountability 
Patients will be instructed to bring the IMP to the study site at each applicable visit and 
treatment compliance will be checked. If a subject shows significant non-compliance (<80% 
compliance) between any two scheduled visits, Medical Monitor should be contacted for 
further assessment. In the event that a subject is permanently unable to return study drug to 
the site (i.e. drug is lost, destroyed, or discarded), the subject testimony is to be used in 
determining compliance.  
 


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Unused medication and empty containers will be returned to the study site at each applicable 
visit. The investigators will maintain a Drug dispensing log detailing the dates and quantities 
of IMP received, dispensed to and used by each patient as well as IMP returned or destroyed 
at the end of the study. Any discrepancies between dispensed and returned IMP must be 
explained and documented. Products deliberately and/or accidentally destroyed by the 
investigator/pharmacy/Catalent or the patient must be accounted for. 
9.6. Drug storage 
The IMP should be stored at room temperature (not to exceed +30oC/+86oF).  
Any unused IMP will be returned to Catalent or the Hospital Pharmacy for destruction. The 
Monitor will perform final IMP accountability reconciliation at the study end to verify that all 
unused IMP is adequately destroyed/returned and documented. 
10. STUDY PLAN  
10.1. Continuous Assessments 
The following assessments will be carried out on a continuous basis and as events arise: 
• AEs including SAEs 
• Concomitant Medications 
• IMP compliance 
 
10.2. Screening (-56 to -10 days prior to randomization) 
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) 
• Hoehn and Yahr scale  
• Concomitant Medications 
• Height  
• Weight  
• Vital Signs (including supine/standing BP) 
• Physical Examination 
• 12-lead ECG (triplicates separated by at least one minute) 
• Haematology/Serum Chemistry/Coagulation  
• Dipstick Urinalysis 
• Serum Pregnancy Test (if applicable) 
• MDS-UPDRS question 4.2 
• 24-hour patient home diary completion training (minimum 2.5 hours). Could be done 
either at the screening visit or during a separate scheduled visit after receipt of the 
screening lab results and prior start of the baseline home diary completion period. An 
approved 24-hour diary trainer must perform the diary concordance session and the 
patient must achieve at least 75% overall diary concordance including at least one OFF 
interval (see section 11.2.3.1). 


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• Three 24-hour patient home diaries are handed out. Patients will be instructed to 
complete 24-hour home diaries for assessment of daily motor function on three days in 
the week before Visit 1 and bring the completed diaries to the clinic (see section 
11.2.3.1. Set dates for the patients to fill in the diaries to be decided. 
• MMSE 
• AEs/SAEs 
- 
General Practitioner Letter 
If appropriate, the patient’s General Practitioner will be informed of the patient’s entry into the 
clinical trial. 
 
10.3. Phone calls (-9 to -1 days prior to randomization) 
Several phone calls will take place during the baseline diary completion period to remind the 
patient about the 24-hour home diary completion. 
• Three 24-hour patient home diaries to be completed during the week (-9 to -1 days) 
prior Visit 1. Clinic to call the patient the working day before the first 24-hour diary 
completion period, as a reminder, and the working day after the last 24-hour diary 
completion period to encourage compliance. Screen failed patients will not complete 
any diaries. 
• Concomitant Medications 
• AEs/SAEs 
 
10.4. Visit 1 (Baseline, Day 1) 
Inclusion and Exclusion criteria will be re-assessed. Eligible patients will be randomized to 
either trial drug (mesdopetam) or placebo.  
The following procedures and assessments will be carried out at Visit 1: 
• Inclusion/Exclusion criteria 
• Concomitant Medications 
• Vital Signs (including supine/standing BP)*  
• 12-lead ECG (single assessment)* 
• Haematology/Serum Chemistry/Coagulation* 
• Dipstick Urinalysis* 
• Serum Pregnancy test (if applicable) 
• MDS-UPDRS (all parts) 
• Modified UDysRS (part 1, 3 and 4) 
• Three completed 24-hour patient home diaries collected and assessed for eligibility 
• Three empty 24-hour patient home diaries handed out 
• CGI-S 
• C-SSRS 
• AEs/SAEs 
• Randomization. Managed through IRS system. 
• Dispense IMP. First dose of IMP to be taken in the evening at Day 1. 
  
*  If 29 days or more between Screening Visit and Visit 1 (Baseline) 
 
 
- 
Patient Information Card 


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All study patients randomized 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 
 
10.5. Visit 2 (Day 9 + 2 days) 
The following procedures and assessments are to be carried out at Visit 2: 
• Allocation of randomized dose of mesdopetam/placebo. Managed through IRS system. 
• Dispense and collect empty bottle of IMP 
• Concomitant Medications 
• AEs/SAEs 
• IMP compliance 
 
10.6. Phone call (Day 14 ± 2 days) 
The purpose of the phone call is to check the general status of the patient. The following 
procedures and assessments are to be carried out during the phone call: 
• Concomitant Medications 
• AEs/SAEs 
• IMP compliance 
 
10.7. Phone calls (Week 3, Day 21 ± 2 days) 
Several phone calls will take place during Week 3 to remind patients about the 24-hour patient 
home diaries completion and to check the general status of the patient. 
• Three 24-hour patient home diaries to be completed during the week prior Visit 3. 
Clinic to call the patient the working day before the first 24-hour diary completion 
period, as a reminder, and the working day after the last 24-hour diary completion 
period to encourage compliance.  
• Concomitant Medications 
• AEs/SAEs 
• IMP compliance 
 
10.8. Visit 3 (Day 28 ± 4 days) 
The following procedures and assessments are to be carried out at Visit 3: 
• Concomitant Medications 
• Vital signs (including supine/standing BP) 
• Urine pregnancy test (if applicable) 
• MDS-UPDRS part 2 (M-EDL) and part 4 questions 4.1 and 4.2 
• Modified UDysRS (part 1, 3 and 4) 
• Three 24-hour patient home diaries collected 
• Three empty 24-hour patient home diaries handed out 


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• Patient motor function review (see Table 3) 
• CGI-S 
• C-SSRS 
• AEs/SAEs 
• Dispense IMP  
• IMP compliance 
 
10.9.  Phone calls (Week 7) 
Several phone calls will take place during Week 7 to remind about the 24-hour patient home 
diary completion and to check the general status of the patient. 
• Three 24-hour patient home diaries to be completed during the week prior Visit 4. 
Clinic to call the patient the working day before the first 24-hour diary completion 
period, as a reminder, and the working day after the last 24-hour diary completion 
period to encourage compliance. 
• Concomitant Medications 
• AEs/SAEs 
• IMP compliance 
 
10.10. Visit 4 (Day 56 ± 4 days) 
The following procedures and assessments are to be carried out at Visit 4: 
• Concomitant Medications 
• Vital signs (including supine/standing BP) 
• 12-lead ECG  
• Haematology/ Serum Chemistry (prolactin should not be included) /Coagulation 
• CYP2D6 genetic testing. Note: A genetic ICF must be signed prior testing. 
• Dipstick Urinalysis 
• Urine pregnancy test (if applicable) 
• MDS-UPDRS (all parts) 
• Modified UDysRS (part 1, 3 and 4) 
• Three 24-hour patient home diaries collected 
• Three empty 24-hour patient home diaries handed out 
• CGI-S 
• C-SSRS 
• PK sample 15 min pre-dose and approximately two hours (± 15 min) post dose. Patient 
need to bring the IMP morning dose to the site. 
• AEs/SAEs 
• Collect empty bottle of IMP 
• IMP compliance 
 
10.11. Phone calls (Week 11) 
Several phone calls will take place during Week 11 to remind about the 24-hour patient home 
diary completion and to check the general status of the patient. 
• Three 24-hour patient home diaries to be completed during the week prior Visit 5. 
Clinic to call the patient the working day before the first 24-hour diary completion 


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period, as a reminder, and the working day after the last 24-hour diary completion 
period to encourage compliance.  
• Concomitant Medications 
• AEs/SAEs 
• IMP compliance 
 
10.12. Visit 5 (End-of-Treatment, Day 84, -2 to 0 days) 
The following procedures and assessments are to be carried out at Visit 5: 
• Concomitant Medications 
• Vital signs (including supine/standing BP) 
• Physical Examination 
• 12-lead ECG  
• Haematology/Serum Chemistry (including prolactin) /Coagulation 
• Dipstick Urinalysis 
• Serum Pregnancy test (if applicable) 
• MDS-UPDRS (all parts) 
• Modified UDysRS (parts 1, 3 and 4) 
• Three 24-hour patient home diaries collected 
• CGI-S 
• C-SSRS 
• PK sample 15 min pre-dose and approximately two hours (± 15 min) post dose 
• MMSE 
• AEs/SAEs 
• IMP compliance 
• Collect empty bottle of IMP 
 
10.13. Visit 6 (Follow Up 5-8 days after End-of-Treatment) 
The following procedures and assessments are to be carried out at Follow Up: 
• Concomitant Medication 
• Weight 
• Vital Signs (including supine/standing BP) 
• Physical Examination 
• 12-lead ECG 
• Haematology/Serum Chemistry (including prolactin)/Coagulation 
• Dipstick Urinalysis 
• AEs/SAEs 
 
NOTE: Patients that discontinue IMP early for any reason should if possible, undergo Visit 6 
assessments 5-8 days after the last dose of IMP. 
 
10.14. Early Termination Visits 
Patients have the right to withdraw from the trial at any time and for any reason. If a patient 
discontinues the IMP early, a safety follow-up visit (according to follow-up, Visit 6) should if 
possible be scheduled within 5-8 days after the last intake of the IMP.  


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11. STUDY PROCEDURES / EVALUATIONS 
Signed informed consent must be obtained before any screening procedures are initiated. The 
informed consent procedure is further described in Section 17. 
11.1. Clinical evaluations 
11.1.1. Demographics/Medical History 
The following demographic data will be recorded: gender, age, ethnicity and race. 
Medical/surgical history including smoking will be obtained by interview in order to verify 
that the eligibility criteria are met. 
Diagnosis of PD must have been made as per the UKPDS Brain Bank Clinical Diagnostic 
Criteria. 
The duration of the patients’ PD will be assessed by the following endpoints: 
• Years from diagnosis 
• Years from symptom onset 
 
11.1.2. Hoehn and Yahr scale 
The Hoehn and Yahr scale is a five point scale for describing the severity of Parkinson's 
disease. The scale will be administered at screening and a Hoehn and Yahr stage of 5 is a study 
exclusion criterion. 
Stage 
Hoehn and Yahr Scale 
0 
Asymptomatic 
1 
Unilateral involvement only 
2 
Bilateral involvement without 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 
 
11.1.3. Height/Weight 
Weight and height will be measured without shoes. Body mass index (BMI) will be calculated 
from the height and weight recorded and rounded to the nearest whole number. 
 
11.1.4. Physical Examination 
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. 


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11.1.5. Vital Signs 
Pulse and systolic/diastolic BP will be measured in supine position after five minutes of rest 
and then after 1 minute and 3 minutes in standing position, without sitting in between. Any 
symptomatic orthostatic reaction will be noted in the CRF (no/yes). 
11.1.6. Resting 12-lead ECG 
12-lead ECGs will be recorded in a supine position after five minutes of rest. PR, QRS, QT, 
and QTcF intervals will be recorded. Three ECGs will be recorded at screening visit, separated 
by at least one minute. Single ECG for all other visits. The time of the ECG recordings must 
be noted in the CRF. 
11.2. Evaluations & assessments 
11.2.1. Clinical laboratory evaluations 
The anticipated volume of blood samples collected during the study from each patient will not 
exceed 250 mL in total per patient. 
Any remaining laboratory samples will be disposed of after analyses. 
Blood samples for analysis of serum chemistry, haematology and coagulation parameters will 
be collected at screening, Visit 1 (if 29 days or more between the Screening Visit and Visit 
1), Visit 4, 5 and 6 and sent to the certified Central laboratory for analysis. Screening 
laboratory test results will be taken into consideration for assessing subject’s eligibility. Urine 
analysis will be performed at the 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 
International Normalized Ratio (INR) 
Potassium 
Urinalysis (dip stick) 
Prolactin* 
Glucose 
Sodium 
Hb/erythrocytes 
Thyroid-stimulating hormone (TSH) 
Nitrite 


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Triiodothyronine (Free T3)  
Thyroxine (T4) 
Triglycerides 
Protein 
U-hCG*** 
 
Urea nitrogen 
human Chorionic Gonadotropin (hCG)** 
CYP2D6 genetic testing**** 
 
 
NOTE: *Prolactin at screening, Visit 1 (if lab sampling is applicable), Visit 5 and Visit 6  
             **hCG is only required for women with childbearing potential (as defined in section 8.1). S-hCG at 
Screening, Baseline and Visit 5 (if applicable) 
***U-hCG is only required for women with childbearing potential (as defined in section 8.1). U-hCG at Visit 
3 and Visit 4 (if applicable) 
             ****CYP2D6 genetic test at Visit 4 (optional testing). Signed genetic informed consent required. 
 
 
 
11.2.2. Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be assessed by trained study personnel using the C-SSRS [9]. 
The C-SSRS is a standardized suicidality rating system conducted by a certified rater. The 
interview measures presence of suicidality and consists of 4 categories: suicidal ideation, 
intensity of ideation, suicidal behaviour, and actual/potential lethality. This scale will be used 
for baseline as well as to assess for the occurrence of any suicidal ideation and/or behaviour 
during the study. 
 
11.2.3. Assessments related to the primary endpoint 
 24-hour patient home diary 
Home diaries have gained wide acceptance as endpoints for clinical development of 
therapeutics aiming to reduce treatment-related motor complications [10]. Motor fluctuations 
and dyskinesia are associated with compromise in activities of daily living (ADL) 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 (without troublesome 
dyskinesia) or ON with troublesome dyskinesia. The patient will also denote the time when he 
or she has been asleep. 
It has been demonstrated that OFF-time and ON-time with troublesome dyskinesia are 
generally considered by patients to be “bad time” with regard to motor function, whereas 
ON-time without troublesome dyskinesia are generally considered to be “good ON-time” [11]. 
In general, an “OFF” time reduction or “good ON-time” increase of 1 hour may be considered 
clinically significant and has been used as an assumption in power calculations in clinical trials 
[10]. Therefore, it can be assumed that shift towards more “good ON-time” of a minimum of 
1-hour daily represents a clinically meaningful effect, considering the total time spent in the 
daily ON state (ON with and without troublesome dyskinesia) is not negatively affected by the 
treatment. 
For this trial, patient diary concordance training to improve accuracy and compliance is 
essential. Patients will be instructed and trained on how to complete the home diary at the 
screening visit or during a separate scheduled visit after receipt of the screening lab results and 


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prior start of the baseline diary completion period. The Investigator must ensure that each 
patient understands how and when to complete diaries before leaving the clinic.  
The patient will receive instruction on how to complete the 24-hour home diary, including the 
definitions of ON and OFF. The definitions of ON and OFF will be reviewed, including ON 
time according to dyskinesia categories “without troublesome dyskinesia” and “with 
troublesome dyskinesia”, with emphasis on the need for the patient to be consistent in their use 
of the definitions when rating their status in the 24-hour home diary during the study.  
When instructions appear to have been understood by the patient, a diary concordance session 
will be initiated during which the patient and the diary trainer/rater will concurrently complete 
separate training diaries for at least 4 consecutive half-hour intervals (minimum 2 hours). 
During the diary concordance session, the patient must experience both ON and OFF. The 
2-hour session may be extended, as needed, so that the patient experiences OFF. If the patient 
is OFF at the beginning of the diary concordance session, they may be administered their next 
dose of levodopa-containing medication in order to experience ON.  
When the session is completed, the diary trainer/rater will review and assess the patient’s diary 
concordance with the trainer/rater. The patient is required to reach at least 75% overall diary 
concordance with the trainer/rater including at least one OFF interval. If the concordance 
criteria are not achieved, the trainer/rater will schedule a second diary training and diary 
concordance session within the 8-week screening period and prior start of the baseline diary 
completion period, unless the patient declines further participation.  
Following successful completion of the 24-hour home diary training and diary concordance 
session, patients will be required to complete 24-hour home diaries on three prespecified days 
(24-hour periods starting at midnight) prior the baseline visit (Visit 1).  
Patients that have not been able to complete at least two valid diaries at baseline (Visit 1) will 
not be included. Patients not completing at least two valid diaries at Visit 1 may be rescheduled 
for Visit 1 following additional diary completion training. For diaries completed prior to 
Visits 3-5, one valid diary is required for each visit for data to be captured. It is important that 
the Investigator take all possible measure for patients to complete all three of the weekly 
diaries. 
The 24-hour home diaries will be captured on three days during one week at the baseline diary 
completion period (prior to Visit 1) and Weeks 3, 7, and 11 (i.e. the week’s prior Visits 3, 4 
and 5). Set dates for the patient to complete diaries are to be agreed in advance. The clinic will 
call the patient the working day before the first 24-hour registration period, as a reminder, and 
the working day after the last 24-hour registration period to check for diary completion. 
At Visit 1, 3, 4 and 5, the Investigator (or designee) will register the data from all valid diaries 
in the appropriate sections of the CRF. 
A valid diary will not have ≥2 hours of invalid data entries (i.e. ≥4 invalid entries) over a given 
24-hour period. An invalid diary entry is defined as more than one entry recorded in each half-
hour interval, an unreadable entry, or the absence of an entry in each half-hour interval. The 
average diary information from 3 valid diaries (if available) for each visit will be used to 
calculate diary-based efficacy endpoints. If there are only 2 valid diaries for a visit, then the 
average information from the 2 valid diaries will be used. If only one diary is valid, information 


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from the single valid diary will be used. If no valid diaries are available for a patient visit, then 
the diary information is considered missing.  
 
11.2.4. Assessments related to the secondary and other endpoints 
 Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 
The MDS-UPDRS parts 1-4 will be administered at Visit 1, Visit 4 and Visit 5 (Day 84, EOT). 
Additionally, MDS-UPDRS part 4 (question 4.2) will be administered at screening and part 2 
(M-EDL) and part 4 (questions 4.1 and 4.2) will be administered at Visit 3. The MDS-UPDRS 
part 3 should be administered with the patient in ON-phase. The ON-phase 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-phase agrees with the patient’s perception of best mobility. Preferably, the 
same rater should complete MDS-UPDRS part 3 at Visit 1 (baseline), Visit 4 and Visit 5 (EOT).  
 
 Modified Unified Dyskinesia Rating Scale (UDysRS) 
Assessment of ON-phase dyskinesia will be administered according to the modified UDysRS, 
(i.e. parts 1, 3 and 4) at Visit 1, 3, 4 and 5 (Day 84 EOT) to assess impairment and disability 
of ON-phase dyskinesia. Rating of patient ON-dyskinesia will be performed in the ON-phase 
at so called peak dose dyskinesia following a regular levodopa dose at a similar time of day 
(± 1 hour), preferably before noon. The timing of the preceding levodopa intake and the 
subsequent assessment must be noted in the CRF. Likewise, it is important that morning dose 
of IMP is taken at the same time in the morning for these visits. The timing of morning intake 
of the IMP should be noted in the CRF.   
Dyskinesia assessment should be administered by a specialist physician (or specialist nurse) 
with previous experience using the scale in movement disorders and who has received 
appropriate training.  
The objective evaluation of dyskinesia impairment and disability will be captured while 
observing the patient in the following situations and scoring performed according to rating 
scale instructions [12]: 
1. Communication: Instruct patient to look at evaluator 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. 
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.  
 Clinical Global Impression of Severity (CGI-S)   
Two different assessments of the CGI-S will be administered at Visits 1 and Visits 3-5.  
The first CGI-S assessment is related to the patient’s physical functioning related to PD. The 
Investigator will rate, considering his or her total clinical experience with the PD population, 


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the severity of the patient’s disease, based on a 1-7 point weighted scale ranging from “normal”, 
not at all ill” (1) to “among the most extremely ill patients” (7).  
The second CGI-S assessment is related to the patient’s ON-phase dyskinesia. The Investigator 
will rate, considering his or her total clinical experience with the PD population, the severity 
of the patient’s ON-phase dyskinesia, based on a 1-7 point weighted scale ranging from 
“normal”, not at all ill” (1) to “among the most extremely ill patients” (7).  
 Mini-Mental State Examination (MMSE) 
The MMSE will be administered at screening and at Visit 5 (EOT).  
 Pharmacokinetic samples 
Venous blood samples (approximately 5 mL) for the determination of concentrations of 
mesdopetam and its metabolites IRL902 (N-dealkylated) and IRL872 (acetylated) in plasma 
will be collected 15 minutes before and two hours (for trough and Cmax) after IMP 
administration at the specified time-points (Visits 4 and 5). 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 mesdopetam and its metabolites in plasma will 
be analyzed 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. 
11.2.5. Specimen preparation, handling and shipping 
 Instructions for specimen preparation, handling and storage 
The samples for analysis of PK variables will be stored at -20°C or below until analyzed. The 
samples will be disposed of after the clinical study report has been finalized. 
Any remaining laboratory samples will be disposed of after analyses. 
If a patient withdraws consent to the use of biological samples donated, the samples will be 
disposed of/destroyed, if not already analyzed 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. 


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Specimen preparation, handling, storage and shipment will be detailed in the Laboratory 
Manual. 
12. ADVERSE EVENT REPORTING 
12.1. Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ending and non-
leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrence. Appropriate questions include: 
- 
“How are you feeling?” 
- 
“Have you had any (other) medical problem since your last visit /contact?” 
- 
“Have you taken any new medicines other than that are provided for this study since 
your last visit/contact?” 
12.2. 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 AE 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 IMP. 
Adverse Drug Reaction (ADR) 
Untoward and unintended responses to an IMP related to any dose administered. 
All AEs 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: 
• 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 
 


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Other important medical events that may not be immediately life-threatening or result in death 
or hospitalization but, when based on appropriate medical judgment, may jeopardize the 
subject or may require intervention to prevent one of the outcomes in the definition of SAE 
listed above. Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in such situations. 
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 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 12.5) and are both unexpected and serious. 
The Sponsor or designee is responsible for determining whether a reported SAE meets the 
definition of a SUSAR. 
 
12.3. Expectedness  
An expected adverse reaction is an adverse reaction, the nature or severity of which is 
consistent with the applicable product information (Investigator’s Brochure [8]), 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 PD (Phase 2a), AEs are likely to predominantly 
be CNS related. Adverse reactions in patients with advanced PD are listed below: 
Table 4: Potential AEs associated with mesdopetam 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 
 
 
 
Dissociation 
 
 
 
Balance disorder 
 
 
 
Dizziness 
 
 
 


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Nervous system 
Cardiac 
General disorders and 
administration site 
condition 
Musculoskeletal and 
connective tissue 
disorders 
Concentration 
difficulties 
 
 
 
Gait freezing 
 
 
 
Fall 
 
 
 
 
12.4. Intensity of adverse event 
The grading of the severity of AEs will follow the Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0 [13]. 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 AE 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. 
12.5. Causality assessment 
The Investigator must assess the causal relationship between an AE and the IMP using the 
definitions below and record it on the AE Form in the CRF as well as on the SAE 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 
• 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) 
 


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An AE is considered causally related to the use of the IMP when the causality assessment is 
probable or possible. 
12.6. Action taken regarding the IMP 
The action taken regarding IMP must be described by selecting one of the following: 
• Permanently discontinued 
• Stopped temporarily 
• Dose reduced 
• No action taken 
• Unknown/not applicable 
 
12.7. Outcome 
The Investigator must assess the outcome of an AE using the definitions below and record it 
on the AE 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 
12.8. Recording adverse events 
AEs 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 AEs starts after the patient signs the ICF 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 must be followed up 
until resolution or the follow-up assessment, whichever comes first. 
AEs must be recorded on an AE 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 


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dates, start and stop times (only applicable for AEs with start date on the day of first IMP 
administration); intensity; causal relationship to IMP; action taken, and outcome. 
If the AE is serious, this must be indicated on the AE Form in the CRF. Furthermore, the 
Investigator must fill out the SAE Report Form and report the SAE to Worldwide Clinical 
Trials as described in Section 12.9. 
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 AE 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. 
It is the responsibility of the Investigator to follow up on all SAEs until the patient has 
recovered, stabilized, 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. 
The SAE reporting period starts at the time of the signature of the ICF until 30 days after the 
last follow-up visit. 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. 
12.9. Serious adverse Events  
All SAEs must be reported to the Clinical Research Organisation (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 Trial Master File (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 Worldwide Clinical Trials: 
Email: drugsafety@worldwide.com 
Fax number: Fax US: 1-866 387 5539, Fax ROW: +44 208 043 4813 
Pregnancies occurring during the study must be reported immediately by email or fax using the 
Pregnancy Form. 
The Sponsor and Worldwide Clinical Trials will keep the Investigator informed of all SUSARs 
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, IECs/IRBs 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 
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The Sponsor will submit Safety Reports to the CAs and IEC/IRBs annually or more frequently 
if so requested. 
12.10. Reporting of SUSARs 
Worldwide Clinical Trials will report SUSARs occurring in the trial to the CA and to the 
relevant Independent Ethics Committees (IEC(s))/Institutional Review Boards (IRB(s)) in line 
with the applicable regulatory requirements. 
13. 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. 
Computerized 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. 
Quality control check of the data entry will be performed on the CRFs. 
Medical history findings and AEs will be coded using the MedDRA dictionary; medications 
will be coded using the World Health Organisation Drug dictionary. 
 
13.1. Trial documentation and trial confidentiality 
13.1.1. Trial documentation, CRFs and document keeping 
The Investigator must generate and maintain adequate records (patient medical records, CRFs, 
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 trial (even 
during the pre-randomization period). CRFs are to be completed either at the time of the 
patient’s visit or as soon as possible after the visit (no later than 72 hours) 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 (SDV) 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 author of an entry in the source documents must 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. The possibility to access 
source documents during remote monitoring, is regulated as per local requirements. 


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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. Source documents will be created and maintained in accordance with ALCOA-C 
(Attributable, Legible, Contemporaneous, Original, Accurate, Complete) criteria that is the 
standard for data integrity. 
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 authorized 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 AE, reasonable efforts must be made to clearly document the 
outcome. 
The Principal Investigator will allow authorized 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.  
13.1.2. Confidentiality of trial documents and patient records 
The Investigator must ensure the patients’ anonymity is maintained. On CRFs or other 
documents submitted to the CRO/the Sponsor/third party contractor, patients must NOT be 
identified by their names but by an identification code (usually their trial number). The 
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 the CRO /the Sponsor/third party contractor, 
e.g. patients’ written consent forms, must be maintained by the Investigator in strict confidence. 
14. 
 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 utilized, planned analyses (with any sensitivity analyses), together 
with master table and listing shells and outline figures for reporting. 


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14.1. General considerations 
A single analysis at the conclusion of the investigation is planned and there will be no interim 
analyses. 
All data will be described and analyzed according to allocated treatment group (mesdopetam 
2.5 mg, 5 mg, 7.5 mg and placebo b.i.d.), and visit. In addition, PK data will also be described 
and analyzed according to time-point, as appropriate (pre and post dose). Each data summary 
will be supported by individual patient listings. 
All quantitative, continuous data will be summarized by the number of non-missing 
observations, mean, median, standard deviation, and minimum and maximum for both actual 
values and, for all data except PK assessments, change from baseline data. All categorical 
(qualitative binary, ordinal) data will be summarized by presenting the frequency and percent. 
Percentages will be based on the number of non-missing observations or the patient population 
unless otherwise specified. For each variable, all categories will be shown. Zero frequencies 
(but not the percent) within a category will be presented. 
Statistical methods applied will be appropriate to the nature and distribution of the data. A 
(two-sided) 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 (mesdopetam 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.  
Baseline will be defined as the last non-missing assessment (either scheduled, unscheduled or 
repeat) that is completed prior to dosing. Baseline average daily time spent for each patient will 
be calculated by taking the arithmetic mean of daily time spent in each state from the three 24-
hour patient home diaries completed before the baseline visit.   
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.   
14.2. Sample size/power calculation 
140 patients (35 per group), are enough to demonstrate a treatment difference of 3 hours, pooled 
standard deviation 3.5, between a single dose level of active treatment and control (i.e. 2.5 mg, 
5 mg or 7.5 mg mesdopetam vs placebo b.i.d.) for the primary endpoint with 92% power and 
type 1 error rate 0.05 (two tailed). The sample size calculation is based on an expected dropout 
rate of 10%. The Sponsor will evaluate the actual dropout rate after 70 randomized patients 
have completed Visit 3 (week 4) and can, if the dropout rate in the study is higher than expected, 
decide to increase the sample size to a total of maximum 154 randomized patients (+10%). 
 


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14.3. Analysis sets 
14.3.1. Safety analysis set 
The Safety Analysis Set (SS) will include all randomized patients who received at least 1 dose 
of IMP. All safety and tolerability evaluations will be presented by the treatment received for 
the SS population.   
14.3.2. Full analysis set 
The Full Analysis Set (FAS) will include all randomized patients who received at least 1 dose 
of IMP and who provided at least one post baseline assessment. All efficacy analyses will be 
presented by allocated treatment for patients in the FAS population.      
14.3.3. Per protocol analysis set 
The Per Protocol Analysis Set (PPS) will consist of patients from the FAS but exclude those 
with major protocol violations. Situations which constitute a major protocol violation may 
include (but are not limited to) those subjects who:  
• Did not satisfy all of the inclusion/exclusion criteria  
• Any subjects with treatment administration errors 
• Any subjects taking inadmissible concomitant medication 
 
Patients who are to be included in and excluded from the PPS will be identified and listed 
following a Blind Data Review (BDR) performed prior to the conclusion of the clinical 
investigation, database lock and unblinding. Any deviation considered to have a serious impact 
on the efficacy results will lead to the relevant subject being excluded from the PPS. 
14.4. Study population 
All basic information regarding the sample of patients recruited to represent the PD population 
with dyskinesia will be summarized. This will include all assessments performed prior to the 
start of treatment (screening) including demographics (gender, age, ethnicity and race), medical 
history (including smoking), 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.  
14.5. 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 randomization process. 
14.6. Treatment compliance 
At the conclusion of treatment period an assessment of compliance with the required dosing 
schedule will be performed and summarized by treatment group. Compliance (%) will be 
calculated by the following: ((total prescribed - total returned)/total prescribed*100%). 
 


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14.7. Efficacy endpoints 
The primary efficacy variable is the 24-hour patient home diaries, total daily hours of ON-time 
without troublesome dyskinesia. Improvement is defined as an increase in the daily hours spent 
in this motor state.  
The 24-hours motor function is recorded in 30-minute intervals, beginning at midnight. For 
each 30-minute interval the patient will rate the state he or she has predominantly 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.  
The secondary efficacy variables involve a subset of the UDysRS, MDS-UPDRS and the 
24-hour patient home diaries (Table 5). 
UDysRS has two primary sections: Historical and Objective Part. In this study the Part 1 of the 
Historical part will be administered and the part 2 will be omitted. 
The full Objective part will be administered: [Part 3 (Impairment) and Part 4 (Disability)] 
including 11 items with each item having 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 
3 = moderate, and 4 = severe. The subtotals of the Objective parts are summed to give an 
overall score. 
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 secondary efficacy rating scales used, a higher score indicates worse 
symptoms. 
Table 5: Key secondary endpoints 
Table 6: Other endpoints 
Scale  
Component 
Attribute 
CGI-S (ON-phase 
dyskinesia) 
Clinicians assessment 
7-point scale 
CGI-S (Parkinson’s 
disease severity) 
Clinicians assessment 
7-point scale 
24-hour patient home 
diaries 
ON-time (with and without troublesome 
dyskinesia) 
Total daily hours 
Scale  
Component 
Attribute 
UDysRS 
Sum score (parts 1, 3 + 4) 
Sum score 
UDysRS 
Sum score (parts 1b and 4) 
Sum score 
MDS-UPDRS 
Part 4 Question 4.2 
Score 
 
Part 2 (M-EDL) 
Total score 
24-hour patient home diaries 
OFF-time 
Total daily hours 
24-hour patient home diaries 
ON-time with troublesome dyskinesia 
Total daily hours 


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MDS-UPDRS 
Part 3 (Motor Examination) 
Total score 
MDS-UPDRS 
Part 1 (Non-Motor Aspects of Experiences 
of Daily Living (nM-EDL) 
Total Score 
MDS-UPDRS 
Part 4 (Motor Complications) 
Total score 
MDS-UPDRS 
2.13 (Freezing) + 3.11 (Freezing of gait) 
sum score 
Sum score 
MDS-UPDRS 
Question 1.6 (Features of dopamine 
dysregulation syndrome) 
Single item score 
MMSE 
Clinicians assessment 
Total score 
 
All the outcome measures are measured at Baseline and at Visit 5 or during the intervening 
period for the 24-hour patient home diaries. In addition, UPDRS Part IV Question 4.1 and 4.2, 
UDysRS, CGI-S, and 24-hour patient home diaries (during the intervening period) are 
measured at Visit 3 and Visit 4. 
The change from Baseline to EOT (Visit 5, Day 84) for each patient will be derived for each 
endpoint and each endpoint summarized descriptively (according to treatment group and day 
of assessment (Baseline, EOT). The EOT/last assessment available will be analyzed as Interval 
data. For assessments performed at Visit 3 and Visit 4, the change from Baseline to Visit 3 and 
Visit 4 for each patient will also be derived.  
14.8. Pharmacokinetic endpoints 
PK variables measured in plasma include: mesdopetam parent drug and two of its metabolites, 
IRL902 (N-dealkylated) and IRL872 (acetylated).  
Samples obtained pre-dose and 2 hour post dose (as an estimate of Cmax) on Day 56 and Day 84 
will be summarized by timepoint, visit, and mesdopetam dose level using descriptive statistics: 
number (n), arithmetic mean, standard deviation, minimum, median, maximum, geometric 
mean, and coefficient of variation (CV%).  
If appropriate, the PK relationship between the treatment doses and plasma exposure (based on 
trough concentrations and Cmax) of mesdopetam and its metabolites will be assessed using a 
power model. 
Details of the PK analysis will be included in the SAP. 
14.9. Efficacy analyses 
All efficacy analyses will be performed by allocated treatment group for patients in the FAS.    
MMRM analysis will allow estimation of the size of treatment effects as well as magnitude of 
differences between the active treatment and control (mesdopetam 2.5 mg, 5 mg, 7.5 mg vs 
placebo).  
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. 


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Model assumptions will be investigated, and a suitable data transformation or non-parametric 
equivalent model substituted if appropriate. 
14.9.1. Primary analyses 
Per protocol, patients will be required to complete three 24-hour patient home diaries prior to 
Baseline (Visit 1), and Visits 3, 4 and 5 (EOT). Average daily ON-time without troublesome 
dyskinesia will be calculated by taking the arithmetic mean of daily ON-time without 
troublesome dyskinesia reported in each individual diary at each visit. Change from Baseline 
will be calculated by subtracting the mean values at each visit (Visits 3, 4 and 5 (EOT)) from 
the Baseline mean value for each individual patient.   
The primary endpoint will be analyzed using a mixed model repeated measures (MMRM) 
analysis that includes all average daily ON-time without troublesome dyskinesia changes from 
baseline to Week 4 (Visit 3) through to Week 12 (Visit 5/EOT) for all patients in the FAS. The 
model will include randomized treatment, visit (Visits 3, 4 and 5/EOT), and treatment by visit 
interaction as explanatory, fixed effect variables. Baseline value for average daily hours of ON-
time without troublesome dyskinesia will be included as a continuous covariate along with the 
baseline stratification factor of daily hours spent in ON-time with troublesome dyskinesia (<6 
hours and ≥6 hours).   
The treatment by visit interaction will remain in the model regardless of significance. The 
patient effect will be assumed to be random and an unstructured covariance structure will be 
assumed for within patient variation.  
The main comparison will be a contrast between treatment groups at EOT (Visit 5, Week 12). 
Estimates for each individual dose level, as well as all active doses grouped vs. placebo will be 
obtained from the model. Least squares means, 95% confidence intervals, and p-values of the 
treatment comparisons along with basic arithmetic summary statistics (mean, median, standard 
deviation, min and max) will be provided.    
14.9.2. Sensitivity analyses 
Sensitivity analyses will be performed for the Primary efficacy endpoint to assess the 
robustness of the observed result. In the first instance, the Primary analysis will be repeated for 
all subjects without a major protocol deviation, followed by analysis by treatment received 
following Visit 3 (Week 4, Day 28) to EOT. An alternative analysis using ANCOVA may also 
be performed.   
14.9.3. Handling of dropouts and missing observations 
Methods to assess the impact of missing data (including last observation carried forward or 
multiple imputation [14]) may also be applied where appropriate. Full details will be given in 
the study Statistical Analysis Plan (SAP).  
 
14.9.4. Multiplicity 
Multiple dose levels have been included in the study design to evaluate the dose response 
relationship of mesdopetam with the hypothesis that the 7.5 mg b.i.d. dose will be the most 
efficacious of the dose levels studied.   


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In order to control the overall Type I error rate at 5% for the Primary efficacy analysis, a fixed 
sequence testing procedure will be applied. Each test will be performed at 5% in decreasing 
dose sequence (mesdopetam 7.5 mg b.i.d, 5 mg b.i.d and 2.5 mg b.i.d vs placebo), until a null 
hypothesis cannot be rejected, after which the remaining null hypotheses also cannot be 
rejected.  
In view of the stage of development of the drug, no statistical adjustments for multiplicity of 
analysis testing are planned. The clinical relevance of any significant result will be discussed.   
14.9.1. Secondary analyses  
All secondary and exploratory efficacy endpoints (including CGI-S data) will be analyzed per 
the Primary efficacy endpoint for all patients in the FAS. Summary statistics (mean, median, 
standard deviation, min and max), least squares means, 95% confidence intervals, and 
p-values of the treatment comparisons will be provided for descriptive purposes.  
Where appropriate, alternative methods suited to the distribution of data may be applied. Full 
details will be provided in the SAP.   
14.10. Safety Analyses 
Safety evaluations include AEs and concomitant medications reporting, complete physical 
examination, vital signs, 12-lead ECG (at rest), C-SSRS rating and clinical safety laboratory 
tests (clinical chemistry, haematology, urinalysis and coagulation). All will be presented as 
data summaries. No formal statistical analyses will be performed. 
AEs and concomitant medications are recorded throughout the investigational period with the 
rest performed at screening, Visits 3, 4 and 5 and Visit 6 (follow-up) 5-8 days after last 
administration of IMP).  
All safety and tolerability evaluations will be presented by the treatment received for the SS 
population.  
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. 
14.10.1. 
Extent of exposure 
Duration of exposure will be calculated as the last date of dosing minus first day of dosing plus 
1 and summarized by treatment group. No adjustment will be made for breaks in therapy.   
14.10.2. 
Adverse events 
All AEs will be summarized according to TEAE or NTEAEs following classification of the 
verbatim terms according to the MedDRA dictionary, as presented in section 12. 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 (see section 12). 
14.10.3. 
Concomitant medications 


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Concomitant medication will be summarized by Anatomic Therapeutic Chemical (ATC) 
classification system levels 2 and 4 using the World Health Organisation Drug dictionary 
(WHODD) with the number and percentage of patients by treatment group and overall. 
14.10.4. 
Physical examinations 
Physical examination results will be summarized as the number and percentage of patients by 
body system, treatment group and assessment day.  
In addition, body weight measured at the follow up visit will be summarized with descriptive 
statistics for actual values and change from baseline by treatment group. 
14.10.5. 
Vital signs 
For BP and pulse rate, descriptive statistics of actual values and change from baseline will be 
summarized 
by 
treatment 
group 
and 
assessment 
day. 
Categorically 
classified 
(Normal/Abnormal) results will also be summarized.  
14.10.6. 
ECG (12-Lead) at rest 
ECG findings will be summarized according to actual values and change from baseline using 
descriptive statistics and will be presented by treatment group and assessment visit. Overall 
interpretation findings (Normal, Abnormal (NCS), Abnormal CS) will also be summarized.  
14.10.7. 
Clinical laboratory tests 
All haematology, clinical chemistry and coagulation laboratory tests run at the central 
laboratory will be summarized using descriptive statistics for actual values and change from 
baseline and presented by treatment group and assessment day.  
Results will be classified as below, within, or above normal range, based on ranges supplied 
by the central laboratory used. Shift tables for baseline and follow-up measurements will be 
presented by treatment group and assessment visit. 
Results from dipstick urinalysis will be summarized as reported on the CRF.   
Unscheduled safety laboratory samples assayed at the local hospital will be listed according to 
site. 
15. 
INDEPENDENT ETHICS COMMITTEE APPROVAL  
The study proposal will be submitted to the IEC/IRB in accordance with the national 
requirements. 
The IEC/IRB shall give its opinion in writing before the clinical trial commences. The 
Investigator should provide written reports to the IEC/IRB annually or more frequently if 
requested on any changes significantly affecting the conduct of the trial and / or increasing risk 
to the patients. 
16. 
 REGULATORY REQUIREMENTS 
The Sponsor is responsible for submission of study documents to the applicable National 
Competent Authorities according to local regulatory requirements. 


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National approval must be obtained in writing from National Competent Authority before the 
first study patient can be recruited in a country. 
Enrolment of patients will not commence until approval has been received from both the 
IECs/IRBs and Competent Authorities. 
The study will be conducted in accordance with the Declaration of Helsinki, ICH GCP (ICH 
E6 (R2) and all other national requirements. 
17. 
INFORMED CONSENT 
It is the responsibility of the Investigator or an authorized 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 emphasized 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. 
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 IEC/IRB.  
18. 
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. 
19. 
STUDY MONITORING AND MANAGEMENT 
19.1. 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) utilized. 
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. 


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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. 
19.2. Clinical monitoring 
The study site will be periodically monitored at times agreed on by the Investigator and the 
Monitor based on the risk-based monitoring plan. 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 Standard Operating Procedures (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. 
− 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. 
19.3. 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 24-hour patient home 
diary, MMSE, MDS-UPDRS, UDysRS, CGI-C and C-SSRS 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 IECs/IRBs, as required. 
 
19.4. Study agreements 
The Principal Investigator must comply with all the terms, conditions, and obligations of the 
Clinical Study Agreement (CSA) for this study. 


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Agreements between Sponsor and the study sites must be in place before any study-related 
procedures can take place, or patients be enrolled. 
19.5. Study timetable 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 3, 2020 and to be completed by Quarter 1, 2022.  
20. 
QUALITY ASSURANCE 
Authorized representatives of Sponsor, Competent Authority (CA) or IEC/IRB may perform 
audits or inspections at the study site, including 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, analyzed, and 
accurately reported according to the Clinical Study Protocol, ICH GCP (ICH E6 (R2) 
guidelines and any applicable regulatory requirements. The Investigator will contact the 
Sponsor immediately if contacted by a CA about an inspection at the study site. 
21. 
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. 
22. 
CONFIDENTIALITY 
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 Investigators and any other 
persons involved in the study will protect the confidentiality of this proprietary information 
belonging to 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 the General Data 
Protection Regulation (GDPR) 2016/679 and other applicable regulations 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. 
 
 
23. 
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. 


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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. 
24. 
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. 
25. 
PUBLICATION OF RESULTS 
25.1. Clinical study report  
Sponsor will post clinical trial results in the EudraCT and ClinicalTrials.gov database within 
the required timeline. 
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 
Statistician and the Sponsor. 
25.2. Annual safety report 
The Sponsor will submit an annual safety report to the CA and to the IEC/IRB. 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. 
25.3. 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. 
 
25.4. 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. 


Integrative Research Laboratories Sweden AB (IRLAB)  
IRL790C005 
Confidential 
Protocol: IRL790C005 
Version: 5.0 
Date: 5 Mar 2021 
Page 73 of 74 
 
 
The results from this study will be submitted for publication only at the discretion of the 
Sponsor. 
 
26. 
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. 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. 
8. Investigator’s Brochure mesdopetam 
9. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. 
(2011). The Columbia-Suicide Severity Rating Scale: initial validity and internal 
consistency findings from three multisite studies with adolescents and adults. Am J 
Psychiatry. 168:1266-77. 
10. Papapetropoulos SS. Patient diaries as a clinical endpoint in Parkinson's disease 
clinical trials. CNS Neurosci Ther. 2012;18:380-7 
11. Hauser RA, Friedlander J, Zesiewicz TA, et al. A home diary to assess functional 
status in patients with Parkinson’s disease with motor fluctuations and dyskinesia. 
Clin Neuropharmacol 2000;23:75–81 
12. Goetz CG, Nutt JG, Stebbins GT. The Unified Dyskinesia Rating Scale: presentation 
and clinimetric profile. Mov Disord. 2008; 23:2398–2403 


Integrative Research Laboratories Sweden AB (IRLAB)  
IRL790C005 
Confidential 
Protocol: IRL790C005 
Version: 5.0 
Date: 5 Mar 2021 
Page 74 of 74 
 
 
13. National Cancer Institute, Cancer Therapy Evaluation Program. Common terminology 
criteria for adverse events, CTCAE v5.0, 2017 
14. Rubin DB (1987). Multiple Imputation for Nonresponse in Surveys. New York, NY: 
J. Wiley & Sons, Inc. 

SAP_001.pdf: 
Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 1 of 49 
 
 
Statistical Analysis Plan 
A Randomized, Double-Blind, Placebo-Controlled Phase IIb Study 
Evaluating the Efficacy of Mesdopetam on Daily ON-Time Without 
Troublesome Dyskinesia in Patients with Parkinson’s Disease 
Protocol Number: IRL790C005 
Protocol Version: 5.0, dated 05 March 2021 
 
SAP Version 1.0 
SAP Issue Date: 18 NOV 2022 
SAP Author: Jack Hu, MS,  
Niccolò Bassani, PhD 
 
Previous SAP Versions 
Not Applicable 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 2 of 49 
SAP Amendments Before Database Lock 
Version  Issue Date 
Section 
Revision / Addition 
Rationale 
 
Not Applicable 
 
 
 
 
 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 3 of 49 
Table of Contents 
LIST OF ABBREVIATIONS .................................................................................... 6 
1 
INTRODUCTION ............................................................................................... 8 
2 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 8 
2.1 
Primary Objective ........................................................................................................... 8 
2.2 
Secondary Objectives...................................................................................................... 9 
2.3 
Exploratory Objectives ................................................................................................... 9 
3 
ENDPOINTS ....................................................................................................... 9 
3.1 
Primary Efficacy Endpoint ............................................................................................. 9 
3.2 
Key Secondary Efficacy Endpoints ................................................................................ 9 
3.3 
Other Key Secondary Efficacy Endpoints .................................................................... 10 
3.4 
Other Secondary Efficacy Endpoints ............................................................................ 10 
3.5 
Exploratory Efficacy Endpoints .................................................................................... 10 
3.6 
Safety Endpoints ........................................................................................................... 11 
3.7 
Pharmacokinetic Endpoints .......................................................................................... 11 
4 
SAMPLE SIZE ..................................................................................................11 
5 
RANDOMIZATION .........................................................................................12 
6 
PLANNED ANALYSES ...................................................................................12 
6.1 
Analysis Sets ................................................................................................................. 13 
6.1.1 
Safety Analysis Set ................................................................................................. 13 
6.1.2 
Full Analysis Set ..................................................................................................... 13 
6.1.3 
Per Protocol Set....................................................................................................... 13 
6.1.4 
Pharmacokinetic Analysis Set................................................................................. 13 
6.2 
Derived Data ................................................................................................................. 14 
6.2.1 
Race......................................................................................................................... 14 
6.2.2 
Baseline ................................................................................................................... 14 
6.2.3 
Early Withdrawal Assessments............................................................................... 14 
6.2.4 
Duration / Study Day / Time ................................................................................... 14 
6.2.5 
Conventions for Missing and Partial Dates ............................................................ 15 
6.2.6 
Missing Last Dates of Study Drug Dosing ............................................................. 16 
6.2.7 
Inexact Values ......................................................................................................... 16 
6.2.8 
Electrocardiogram Data .......................................................................................... 16 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 4 of 49 
6.2.9 
Vital Signs ............................................................................................................... 17 
6.2.10 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................... 17 
6.2.11 
Unscheduled Visits ................................................................................................. 18 
6.2.12 
24-Hour Patient Home Diary .................................................................................. 18 
6.2.13 
Modified Unified Dyskinesia Rating Scale (UDysRS) .......................................... 19 
6.2.14 
Movement Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS) 19 
6.2.15 
Definition of a Responder ....................................................................................... 20 
6.2.16 
Definition of Adjusted Dose Group ........................................................................ 20 
6.3 
Conventions .................................................................................................................. 20 
6.3.1 
Medical Coding ....................................................................................................... 20 
6.3.2 
Data Handling ......................................................................................................... 21 
6.3.3 
Validation Methods ................................................................................................. 21 
6.3.4 
Summary Statistics.................................................................................................. 21 
6.3.5 
Decimal Places ........................................................................................................ 22 
6.3.6 
Data Displays .......................................................................................................... 22 
6.4 
Patient Disposition ........................................................................................................ 23 
6.5 
Protocol Deviations ....................................................................................................... 23 
6.6 
Baseline Comparability ................................................................................................. 24 
6.7 
CYP Genotyping ........................................................................................................... 25 
6.8 
Medical History ............................................................................................................ 25 
6.9 
Prior and Concomitant Medications ............................................................................. 25 
6.10 
Exposure to Study Drug ................................................................................................ 26 
6.11 
Treatment Compliance .................................................................................................. 27 
6.12 
Primary Efficacy Analyses ........................................................................................... 27 
6.12.1 
Estimand ................................................................................................................. 27 
6.12.2 
Primary Endpoint .................................................................................................... 28 
6.12.3 
Primary Analysis ..................................................................................................... 28 
6.12.4 
Sensitivity Analyses ................................................................................................ 30 
6.12.5 
Supportive Analyses ............................................................................................... 33 
6.13 
Secondary Efficacy Analyses ....................................................................................... 34 
6.13.1 
Key Secondary Analyses ........................................................................................ 34 
6.13.2 
Other Key Secondary Analyses .............................................................................. 35 
6.13.3 
Other Secondary Analyses ...................................................................................... 36 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 5 of 49 
6.13.4 
Motor Examination, MDS-UPDRS - Part 3 Total Score ........................................ 38 
6.14 
Exploratory Efficacy Analyses ..................................................................................... 38 
6.14.1 
Overall PD Symptoms, Clinician’s Global Impression of Severity ....................... 38 
6.14.2 
Cognitive Function, Mini-Mental State Examination ............................................. 39 
6.14.3 
Improvement in Daily ON-time, Responder Analysis ............................................ 39 
6.14.4 
MDS-UPDRS: Part 1, and Part 4 Total Scores ....................................................... 39 
6.14.5 
Freezing and Freezing of Gait, MDS-UPDRS: Question 2.13 + Question 3.11 .... 40 
6.15 
Multiplicity ................................................................................................................... 40 
6.16 
Pharmacokinetic Analyses ............................................................................................ 41 
6.17 
Safety Analyses ............................................................................................................. 42 
6.17.1 
Adverse Events ....................................................................................................... 42 
6.17.2 
Laboratory Data ...................................................................................................... 44 
6.17.3 
Vital Signs ............................................................................................................... 44 
6.17.4 
Electrocardiogram Data .......................................................................................... 45 
6.17.5 
Physical Examination.............................................................................................. 45 
6.17.6 
C-SSRS ................................................................................................................... 46 
6.17.7 
Features of Dopamine Dysregulation Syndrome, MDS-UPDRS Question 1.6...... 46 
6.17.8 
Pregnancy ................................................................................................................ 46 
7 
INTERIM ANALYSIS ......................................................................................46 
8 
DATA SAFETY MONITORING BOARD ANALYSIS .................................46 
9 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................47 
10 REFERENCES ..................................................................................................49 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 6 of 49 
LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Events 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
b.i.d. 
Twice a Day 
BDR 
Blind Data Review 
BLQ 
Below the Limit of Quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CGI-S 
Clinician’s Global Impression of Severity 
CI 
Confidence Intervals 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV% 
Coefficient of Variation (%) 
ECG 
Electrocardiograms 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FWER 
Family Wise Error Rate 
IMP 
Investigational Medicinal Product 
IP 
Independent Programming 
IRS 
Interactive Response System 
LID 
Levodopa-Induced Dyskinesia 
LS 
Least Squares 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MDS-UPDRS 
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary of Regulated Activities 
M-EDL 
Motor Aspects of Experiences of Daily Living 
MMRM 
Mixed Model For Repeated Measures 
MMSE 
Mini-Mental State Examination 
MNAR 
Missing Not at Random 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 7 of 49 
Abbreviation 
Description 
NTEAE 
Non-Treatment-Emergent Adverse Event 
PD 
Parkinson’s Disease 
PDev 
Protocol Deviations 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SI 
Système International 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
WHO Drug 
World Health Organization Drug Dictionary 
 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 8 of 49 
1 INTRODUCTION 
This document details the planned statistical analyses for Integrative Research Laboratories 
Sweden AB, protocol “IRL790C005” study titled “A Randomized, Double-Blind, Placebo-
Controlled Phase IIb Study Evaluating the Efficacy of Mesdopetam on Daily ON-Time Without 
Troublesome Dyskinesia in Patients with Parkinson’s Disease”.  The proposed analyses are based 
on the contents of protocol Version 5.0, dated 05 March 2021.   
This is a multi-centre, randomized, double-blind, placebo-controlled study with the primary 
objective to evaluate the efficacy of 84 days’ treatment with mesdopetam compared to placebo in 
patients with Parkinson’s Disease (PD) exhibiting ON-phase dyskinesia.  
The study comprises a screening period of up to 8 weeks, followed by a 12-week treatment period.  
A follow-up visit will be performed approximately 1 week after the last Investigational Medicinal 
Product (IMP) dose.  
Patients will be randomized to receive one of three doses of mesdopetam (2.5 mg, 5 mg, or 7.5 mg) 
or placebo b.i.d. For patients to adjust to the new medication, a run-in phase with either 5 mg 
mesdopetam or placebo b.i.d. will take place during the first week (Day 1 evening dose to Day 9 
morning dose).  
A dose reduction is permitted if the patient manifests increased parkinsonism and/or a consistent 
increase in motor OFF-time. The dose can only be reduced once (and only by 2.5 mg b.i.d.). Dose 
reductions are permitted from Visit 2 until Visit 3 (i.e., Day 9 - Day 28), after which the reduced 
dose should be kept stable until end of treatment (EOT) period (Visit 5, Week 12). 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Primary Objective 
• To evaluate the effectiveness of adjunctive treatment with mesdopetam dosed at 2.5 mg, 
5 mg, or 7.5 mg b.i.d. (permitting a single 2.5 mg dose reduction to a minimum dose of 
2.5 mg, up to Day 28) compared to placebo in patients with PD exhibiting troublesome 
ON-phase dyskinesia.  


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 9 of 49 
2.2 Secondary Objectives 
• To establish the dose response relationship with 3 dose levels of mesdopetam.  
• To evaluate the effects of mesdopetam on severity of ON-phase dyskinesia and motor 
symptoms of PD. 
• To evaluate the effects of mesdopetam on the daily hours spent in different motor states. 
• To evaluate the safety and tolerability of mesdopetam given twice daily during 84 
consecutive days. 
• To evaluate trough and 2-hour post dose plasma concentrations of mesdopetam and its two 
main metabolites (IRL902 (N-dealkylated) and IRL872 (acetylated)).  
2.3 Exploratory Objectives 
• To assess overall PD symptoms.  
• To assess cognitive function. 
3 ENDPOINTS 
3.1 Primary Efficacy Endpoint 
• Change in average daily hours of ON-time without troublesome dyskinesia with 
mesdopetam compared to placebo as assessed with 24-hour patient home diaries from 
baseline to end of treatment (EOT) (Visit 5, Week 12).  
3.2 Key Secondary Efficacy Endpoints 
• Change from baseline with mesdopetam compared to placebo in ON-phase dyskinesia 
assessed by MDS-UPDRS part 4 question 4.2 (Functional impact of dyskinesias).  
• Change from baseline with mesdopetam compared to placebo in disability associated with 
ON-phase dyskinesia assessed with the sum score of parts 1b and 4 of the UDysRS.  


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 10 of 49 
3.3 Other Key Secondary Efficacy Endpoints 
• Change from baseline with mesdopetam compared to placebo in motor symptoms of PD 
assessed with MDS-UPDRS total score of part 2 (M-EDL).  
• Change from baseline with mesdopetam compared to placebo in average daily OFF-time. 
3.4 Other Secondary Efficacy Endpoints 
• Change from baseline in average daily hours spent in each motor state (ON-time without 
troublesome dyskinesia, ON-time with troublesome dyskinesia, OFF, and asleep) for each 
individual dose level (2.5 mg, 5 mg, 7.5 mg b.i.d.). 
• Change from baseline with mesdopetam compared to placebo in ON-phase dyskinesia 
assessed with the sum score of the modified UDysRS (parts 1, 3 and 4). 
• Change from baseline with mesdopetam compared to placebo in ON-phase dyskinesia 
assessed by MDS-UPDRS part 4 question 4.1 (Time spent with dyskinesias).  
• Change from baseline with mesdopetam compared to placebo in average daily total ON-
time (defined as the sum of ON-time with and without troublesome dyskinesia). 
• Change from baseline with mesdopetam compared to placebo in Clinician’s Global 
Impression of Severity (CGI-S) of ON-phase dyskinesia. 
• Change from baseline with mesdopetam compared to placebo in the total score for the 
MDS-UPDRS Part 3, Motor Examination.  
3.5 Exploratory Efficacy Endpoints 
• Change from baseline with mesdopetam compared to placebo in CGI-S of overall PD 
symptoms. 
• Change from baseline with mesdopetam compared to placebo in Total MMSE score. 
• Change from baseline with mesdopetam compared to placebo in the total scores for 
component parts of the MDS-UPDRS (Part 1, and Part 4).   


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 11 of 49 
• Change from baseline with mesdopetam compared to placebo in freezing and freezing of 
gait, assessed by MDS-UPDRS: Question 2.13 + Question 3.11. 
3.6 Safety Endpoints 
• Frequency and nature of adverse events (AEs), laboratory results, vital signs, physical 
examinations, Columbia-Suicide Severity Rating Scale (C-SSRS) and 12-lead 
electrocardiograms (ECG) at each visit from baseline to follow-up.  
• Change from baseline with mesdopetam compared to placebo in features of dopamine 
dysregulation syndrome assessed by MDS-UPDRS Question 1.6.  
3.7 Pharmacokinetic Endpoints 
• Plasma concentrations of mesdopetam and its two main metabolites at pre-dose and 2 hours 
post-dose at 8 and 12 weeks of treatment.   
4 SAMPLE SIZE 
Analysis of the Phase IIa study Efficacy and Tolerability of IRL790 in 74 PD patients with 
levodopa-induced dyskinesia (LID) on stable antiparkinsonian medication (NCT03368170) 
suggested that daily ON-time with troublesome dyskinesia decreased to an observed difference of 
approximately 1.6 hours (p=0.0274) among treated patients (n=39) versus placebo (n=36). Dose-
response analysis suggested a dose dependent effect with an observed difference vs. placebo 
around 4.6 h at the 7.5 mg dose. A pooled standard deviation of 3.2-3.3 hours was observed among 
the doses studied. This observed data provided the assumptions for the sample size calculation.   
140 randomized patients (35 per group) are thought to be enough to demonstrate a treatment 
difference of 3 hours with pooled standard deviation 3.5, between a single dose level of active 
treatment and control (i.e., 2.5 mg, 5 mg, or 7.5 mg mesdopetam vs placebo b.i.d.) for the primary 
endpoint with 92% power using a hierarchical testing strategy, with key secondary endpoints tested 
using a truncated Hochberg procedure with truncation parameter γ equal to 0.7 for the 7.5 and then 
the 5 mg doses and a standard Hochberg procedure for the 2.5 mg dose to maintain control of the 
family wise error rate (FWER) at the nominal 0.05 level.  


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 12 of 49 
The sample size calculation was based on an expected dropout rate of 10%, i.e., assuming 31 
patients per group will provide evaluable data on the primary endpoint at Week 12. The actual 
dropout rate was evaluated by the Sponsor after 70 randomized patients had completed Visit 3 
(Week 4) and due to a higher-than-expected dropout rate, it was decided to increase the sample 
size to 154 (+10%) randomized patients as permitted by the protocol.  
5 RANDOMIZATION 
At the baseline visit (Visit 1, Day 1) patients will be randomized 1:1:1:1 to receive one of three 
doses of mesdopetam (2.5 mg, 5 mg, or 7.5 mg) or placebo b.i.d. based on the randomization 
schedule prepared by the unblinded statistician.   
During the first week (Day 1 evening dose to Day 9 morning dose) a run-in phase with either 5 mg 
mesdopetam or placebo b.i.d. will take place, during which all patients allocated to mesdopetam 
will receive 5 mg mesdopetam b.i.d. and patients allocated to placebo will receive placebo b.i.d. 
The purpose of the run-in period with 5 mg b.i.d. is to allow for a one-week dose titration for 
patients randomized to 7.5 mg b.i.d.  In a previous Phase 2a study most patients tolerated 5 mg 
b.i.d. At Visit 2 (Day 9), patients will receive mesdopetam 2.5 mg, 5 mg or 7.5 mg or placebo 
b.i.d., as randomized.   
Randomization will be performed via a web-based Interactive Response System (IRS), using a 
dynamic balancing (minimization) algorithm. Randomization will be stratified by average (based 
on at least two valid home diaries) of <6 daily hours and ≥6 hours of daily ON-time with 
troublesome dyskinesia at baseline.   
During the one-week run-in phase, the IRS will ensure all patients allocated to mesdopetam 
treatment will receive 5 mg mesdopetam b.i.d., followed by the randomized dose during the 
treatment period. Patients allocated to placebo will receive placebo during the first week run-in 
and then continue placebo during the whole treatment period. Any dose reduction will also be 
managed through the IRS to ensure that blinding is maintained.  
6 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be definitive and the final 
Clinical Study Report (CSR) may contain additional tables or statistical tests if warranted by the 
data obtained. The justification for any such additional analyses will be fully documented in the 
final CSR. 


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6.1 Analysis Sets 
6.1.1 Safety Analysis Set 
The Safety Analysis Set (SAS) will include all randomized patients who received at least 1 dose 
of IMP. All safety and tolerability evaluations will be presented by the treatment received for the 
SAS.   
6.1.2 Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized patients who received at least 1 dose of 
IMP and who provided at least one valid post baseline diary. All efficacy analyses will be presented 
by randomized treatment for patients in the FAS.  
6.1.3 Per Protocol Set 
The Per Protocol Set (PPS) will consist of patients from the FAS without protocol deviations that 
impact the efficacy assessment. Situations which impact the efficacy assessment may include (but 
are not limited to) those patients who:  
• Did not satisfy all of the inclusion/exclusion criteria 
• Any patients with treatment administration errors 
• Any patients taking inadmissible concomitant medications 
Patients who are to be included or excluded from the PPS will be identified and listed following a 
Blind Data Review (BDR) performed prior to the conclusion of the clinical investigation, database 
lock and unblinding. Any deviation considered to have a serious impact on the efficacy results will 
lead to the relevant patient being excluded from the PPS.  Any patient exclusions from PPS will 
be documented in a patient evaluability document before database lock.  
6.1.4 Pharmacokinetic Analysis Set 
The Pharmacokinetic (PK) Analysis Set will include all randomized patients who received at 
least 1 dose of IMP and who have at least one evaluable PK concentration data. 


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6.1.4.1 CYP Genotype Subset 
The CYP Genotype Subset will be a subset of the PK Analysis Set including patients who 
consented to genotyping with respect to CYP2D6 and who received a genotype classification 
result.   
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 Race 
Where more than one race category has been selected for a patient, these race categories will be 
combined into a single category labelled “Multiple Race” in the summary tables. The listings will 
reflect the original selected categories.  
6.2.2 Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) before 
the patient receives the first dose of study drug.  
6.2.3 Early Withdrawal Assessments 
Early withdrawal assessments will be summarized as a separate visit and will be mapped to an 
expected visit window as follows: 
• During the run-in period 
• Post run-in and prior to visit 3 
• At visit 3 or post visit 3   
6.2.4 Duration / Study Day / Time  
Study day will be calculated as the number of days from first dose of study drug.  
• date of event – date of first dose of study drug + 1, for events on or after first dose  
• date of event – date of first dose of study drug, for events before first dose  


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6.2.5 Conventions for Missing and Partial Dates 
All rules explained below for partial / missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual patient listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules). 
Missing and partial start and stop dates will be imputed to identify treatment-emergent AEs and 
concomitant medications as follows. 
Partial or missing stop date will be imputed as follows: 
• If the stop date is completely missing and the event has resolved, or the patient has stopped 
taking the concomitant medication, the stop date will be imputed as the date of the patient’s 
last clinic visit in the study. 
• If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the patient’s last clinic visit in the study if in the same year. 
• If the month and year are known, the stop date will be imputed as the last day of that month 
unless the stop date corresponds to the same month as the patient’s last clinic visit in which 
case the date of patient’s last clinic visit in the study will be used instead. 
Missing start date will be imputed as follows: 
• If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  
• If the stop date occurs before the start of study drug, the start date of the event / concomitant 
medication will be imputed as the patient’s screening date or the stop date of the event / 
concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) 
• If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date will 
be imputed as the date of the first dose of study drug. If the year is different from the year 
of first dosing “01-Jan” will be used. 
• If the stop date occurs before the start of study drug, the start date of the event / concomitant 
medication will be imputed as the “01-Jan” of the same year. 
Partial start date (month and year present, but day missing) 


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Page 16 of 49 
• If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month and 
year unless this partial start date is in same month as the first dose of study drug in which 
case the date of first dose of study drug will be used.  
• If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
If the start time is missing it will be imputed only in the case where the start date of the concomitant 
medication / event corresponds to the date of the first dose of study drug. The time will be imputed 
as the same time as the first dose of study drug. In all other cases the time will not be imputed. 
6.2.6 Missing Last Dates of Study Drug Dosing 
If the date of last dose of study drug is completely missing, then the date of last dose of study drug 
will be taken for analysis purposes as the date when the patient would have run out of study drug 
assuming full compliance from the date the study drug was last dispensed, or the date of patient’s 
last clinic visit in the study or early termination or death whichever the earlier. 
If only the month and year of the last dose was recorded, then the date of last dosing will be taken 
for analysis purposes as the date the patient would have run out of study drug assuming full 
compliance from the date the study drug was last dispensed, the last day of the month of the 
recorded last dose or the date of patient’s last clinic visit in the study or early termination or death 
whichever the earlier. 
6.2.7 Inexact Values 
In the case where a variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will be taken 
for analysis purposes.  
6.2.8 Electrocardiogram Data 
For electrocardiogram (ECG) data recorded on continuous scales, if more than one value is 
recorded at a time point, the mean value (taken from the non-missing values) rounded to the integer 
will be presented. For overall interpretation, if more than one value is recorded, the most severe 
(worst case) of the respective readings will be taken.  


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6.2.9 Vital Signs 
For blood pressure and pulse rate, the orthostatic changes will be calculated as standing minus 
supine readings.  Patients meeting the following criteria will be identified:  
• Patients with > 20 mmHg reduction (standing minus supine) in systolic blood pressure at 
1 minute or 3 minutes of standing.  
• Patients with > 10 mmHg reduction (standing minus supine) in diastolic blood pressure at 
1 minute or 3 minutes of standing.  
6.2.10 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The following outcomes are C-SSRS categories and have binary responses (yes / no). The 
categories have been re-ordered from the actual scale to facilitate the definition of composite 
endpoints: 
Category 1  
Wish to be Dead 
Category 2  
Non-specific Active Suicidal Thoughts 
Category 3  
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 
Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 
Active Suicidal Ideation with Specific Plan and Intent 
Category 6 
Preparatory Acts or Behaviour 
Category 7  
Aborted Attempt 
Category 8 
Interrupted Attempt 
Category 9 
Actual Attempt (non-fatal) 
Category 10 
Completed Suicide 
Suicidal Ideation since baseline – A “yes” answer at any time during double blind treatment to any 
one of the 5 suicidal ideation questions (categories 1-5) on the C-SSRS. 
Suicidal Behaviour since baseline – A “yes” answer at any time during double blind treatment to 
any one of the 5 suicidal behaviour questions (categories 6-10) on the C-SSRS. 
There will be no imputation of missing data for C-SSRS. 


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Page 18 of 49 
6.2.11 Unscheduled Visits 
Only scheduled post-baseline assessments will be summarized and tabulated. Post-baseline repeat 
or unscheduled assessments will not be tabulated but will be included in listings of individual 
patient data.   
6.2.12 24-Hour Patient Home Diary 
Patients will complete the 24-hour home diary on 3 separate days during the week preceding a 
visit.  Patients will record their motor function in 30-minute intervals over 24-hours, beginning at 
midnight.  For each 30-minute interval, the patient will rate the motor state he or she has been in 
for the past 30 minutes.  Diary data will then be transcribed to the CRF by the clinic staff (ON 
without troublesome dyskinesia, ON with troublesome dyskinesia, OFF, Asleep, Missing entry, 
Invalid entry).  
6.2.12.1 Motor States 
Variables will be obtained from the diary data as follows: 
• ON-Time without troublesome dyskinesia 
• ON-Time with troublesome dyskinesia 
• Total ON-Time (ON-Time with and without troublesome dyskinesia) 
• OFF-Time 
• Asleep 
• Missing (or invalid) entry (missing + invalid) 
‘ON’ time is also referred to as ‘good ON time’ and is considered equivalent to ‘ON time without 
troublesome dyskinesia’.   
6.2.12.2 Identification of a Valid Diary 
A valid diary will not have ≥ 2 hours of invalid data entries (i.e., ≥4 invalid entries) over a given 
24-hour period. An invalid diary entry is defined as one having either more than one entry recorded 
in each half-hour interval, an unreadable entry, or the absence of an entry in a half-hour interval. 
The average diary information from 3 valid diaries (if available) for each visit will be used to 
calculate diary-based efficacy endpoints. If there are only 2 valid diaries for a visit, then the 


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Page 19 of 49 
average information from the 2 valid diaries will be used. If only one diary is valid, information 
from the single valid diary will be used. If no valid diaries are available for a patient visit, then the 
diary information is considered missing.  
Therefore, a Valid diary = diary where Missing + Invalid < 4 intervals.  Diaries where Missing + 
Invalid  ≥ 4 intervals will be excluded from the analysis.   
6.2.12.3 Total Daily Hours in Each Motor State 
Total daily hours for each motor state will be calculated as follows,    
Total daily hours = Number of 30-minute intervals with corresponding motor state / 2 
6.2.13 Modified Unified Dyskinesia Rating Scale (UDysRS) 
The modified Unified Dyskinesia Rating Scale (UDysRS) consists of two primary sections, 
Historical and Objective. For this study, Part 1 (On-Dyskinesia) of the Historical section will be 
administered, and Part 2 (Off-Dystonia) will be omitted. The Objective section consists of Part 3 
(Impairment) and Part 4 (Disability) including a total of 11 items, each rated 0-4, where 0 = normal, 
1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The subtotals of the Objective parts are summed 
to give an overall score. 
For efficacy analyses, the scores from the following parts will be analysed: 
• Parts 1, 3, and 4 (sum score) 
• Parts 1b and 4 (sum score) 
6.2.14 Movement Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS) 
The Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 
consists of four parts:  
• Part 1, non-motor aspects of experiences of daily living [nM-EDL] (13 items) 
• Part 2, motor aspects of experiences of daily living [M-EDL] (13 items) 
• Part 3, motor examination (18 items) 
• Part 4, motor complications (6 items) 
Each item is rated 0-4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.  


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Page 20 of 49 
For efficacy analyses, the scores from the following parts will be analysed: 
• Part 1 nM-EDL (13 items) (total score) 
• Part 2 M-EDL (13 items) (total score) 
• Part 3 Motor Examination (18 items) (total score) 
• Part 4 Motor Complications (6 items) (total score) 
• Question 1.6 Features of Dopamine Dysregulation Syndrome (1 item) (score) 
• Questions 2.13 Freezing + Question 3.11 Freezing of Gait (2 items) (sum score) 
• Question 4.1 Time Spent with Dyskinesias (1 item) (score). 
• Question 4.2 Functional Impact of Dyskinesias (1 item) (score) 
6.2.15 Definition of a Responder 
Patients who achieve any improvement (that is, at least 1 hour increase) in average daily ON-time 
without troublesome dyskinesia at Week 12 will be considered ‘responders’ and ‘non-responders’ 
(less than 1 hour increase) otherwise. Patients with missing data at Week 12, or who withdrew 
prior to Week 12 will be classified as non-responders.   
6.2.16 Definition of Adjusted Dose Group 
To account for patients who have a permitted dose reduction and remain stable thereafter, adjusted 
dose groups will be defined.  Patients randomly allocated to mesdopetam and who had a permitted 
dose reduction of 2.5 mg recorded at Visit 3, will be counted in the treatment group one dose lower 
than their randomized treatment.  Patients randomly allocated to placebo but who had a dose 
reduction will remain in the placebo group.   
6.3 Conventions 
6.3.1 Medical Coding 
Adverse events and medical history will be coded using the Medical Dictionary of Regulated 
Activities (MedDRA) Version 24.1 (or higher). Conditions will be assigned to a System organ 
class (SOC) and preferred term (PT) based on the Investigator-reported verbatim term.  
Any medications taken (other than study drug) will be coded using the World Health Organization 
Drug Dictionary (WHO Drug) September 2021 Version (or higher).  Medications (both prior and 


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Page 21 of 49 
concomitant) will be assigned to an Anatomical Therapeutic Chemical (ATC) Level 4 drug 
classification and Preferred Name based on the medication name reported on the eCRF.  
6.3.2 Data Handling 
All clinical data programming will be performed using SAS® statistical software package 
(Statistical Analysis System, Version 9.4 or higher)1 and based on Clinical Data Interchange 
Standards Consortium (CDISC) data standards.   
6.3.3 Validation Methods 
All programming of datasets and outputs will be validated by fully independent double 
programming of values and manual review of format compared to the SAP and agreed shell 
template.   Figures will be validated by manual review of format and visual inspection of graphical 
display compared to tabulated data.  Independent programming (IP) by a Statistician (Stat IP) will 
be performed for all statistical analyses. 
6.3.4 Summary Statistics 
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, and minimum and maximum.  
Plasma concentration data will be summarized by number of non-missing observations (n), number 
of observations with concentrations below the limit of quantification (BLQ), arithmetic mean 
(mean), geometric mean, standard deviation (SD), median, minimum (min), maximum (max), and 
coefficient of variation (CV%). Concentrations that are BLQ will be set to zero for summary 
statistics. BLQ concentrations will be retained as BLQ in listings.  
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the patient population unless otherwise 
specified. For each variable, all categories will be shown, including a category for missing where 
appropriate. Zero frequencies (but not the percent) within a category will be presented.  
Incidences of adverse events, medical history and concomitant medications will be reported at the 
patient level. Patients can only be counted once within each PT and SOC under the highest severity 
and most related.  Percentages will be calculated using the number of patients in the treatment 
group for the SAS. AE and medical history event tabulations will be presented by SOC and PT in 


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Page 22 of 49 
descending overall frequency of incidence and then alphabetically for ties.  Medications will be 
tabulated by ATC level 4 and preferred name in alphabetical order.   
6.3.5 Decimal Places 
Decimal places for derived data described in Section 6.2 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated value is ≥ 100; 1 decimal place will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement. 
Two decimal places will be displayed for the calculation of average daily hours in each motor 
state. 
For summary statistics, n will be reported as a whole number. Means, medians, and percentiles 
will be displayed to one more decimal place than the data, dispersion statistics (e.g., standard 
deviation) will have two more decimal places, and the minimum and maximum will be displayed 
to the same number of decimal places as reported in the raw data. Percentages will be displayed 
with one decimal place. P-values will be quoted to 3 decimal places. P-values < 0.001 will be 
presented as p<0.001 unless otherwise specified. Plasma concentration data will be reported to 3 
significant figures.  
All data presented in the individual patient listings will be as recorded on the eCRF.  
6.3.6 Data Displays 
All observed data and change from baseline to scheduled post-baseline visits will be summarized 
unless otherwise specified.  All collected data will be listed.  
All clinical data tabulations, figures and listings will be generated as individual Rich Text Format 
(.rtf) files using SAS® (Version 9.4 or higher)1. Data summaries and graphical analyses will be 
reported within Section 14 of the CSR and individual patient data listings within Appendix 16.2 
of the CSR.  
Patient disposition, baseline characteristics, demographic, compliance, concomitant medication, 
and adverse event data will be presented by treatment group and overall.  All other data will be 
presented by treatment group only.   
Treatment group labels will be displayed as follows:  


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Page 23 of 49 
Mesdopetam 
2.5 mg b.i.d. 
(N=XX) 
Mesdopetam 
5 mg b.i.d. 
(N=XX) 
Mesdopetam 
7.5 mg b.i.d. 
(N=XX) 
All 
Mesdopetam 
(N=XX) 
Placebo 
b.i.d. 
(N=XX) 
Listings will be sorted in the following order: treatment group, patient, visit, and parameter, unless 
otherwise stated. All collected data will be listed.   
6.4 Patient Disposition 
Patient disposition will be summarized by randomized treatment group and overall, as follows:  
• The number of patients entering the study. 
• The number of patients completing the study 
• The number of patients with early termination and the reasons for early termination. 
• The number of patients who were screened, who were re-screened, and who failed 
screening, with the reason for screen failure (for re-screened patients, the most recent 
reason for screen failure will be taken).  
• The number of patients in each analysis set. 
• The number of patients excluded from the PPS and the reason for exclusion.  
• The number of patients in each analysis set by country. 
• The number of patients attending each visit. 
• The number of patients with missed or remote visits due to COVID-19.   
By-patient listings of all disposition data will be presented for all enrolled patients as follows: 
• Study completion or early termination and reason for early termination. 
• Randomization details including randomization stratum. 
• Screening, re-screening and reason for screen failure. 
• Inclusion in analysis sets.  
• Missed or remote visits due to COVID-19. 
6.5 Protocol Deviations 
All reported protocol deviations (PDev) will be summarized by treatment group, PDev category 
and PDev classification (Major and Minor).  PDevs related to COVID-19 will also be summarized 


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Page 24 of 49 
separately.  All reported PDevs will be listed, and a separate listing of PDevs related to COVID-
19 will be provided.  
6.6 Baseline Comparability 
Comparability of treatment groups with respect to patient demographics and baseline 
characteristics will be assessed in a descriptive manner.  
Demographic and baseline characteristic summaries will be presented by treatment group and 
overall, based on the randomized treatment group for the FAS and the SAS.  If these sets are equal, 
only the FAS will be presented.  All collected data will be listed.  Summaries will be presented for 
the following variables: 
Demographic Data 
• Age at Screening (years) 
• Age by category (< 65 years and ≥ 65 years) 
• Gender 
• Fertility status (female only) 
• Ethnicity 
• Race (where more than one race is selected the patient will be presented under the ‘Multiple 
races’ category in the summary but each selected race will be identified in the listing).  
Baseline Characteristics 
• Weight at Screening (kg) 
• Height at Screening (cm) 
• BMI at Screening (kg/m2) 
Clinical Characteristics 
• Hoehn and Yahr Scale 
• Years from PD diagnosis at baseline and will be calculated as follows: Years from PD 
Diagnosis at Baseline = (Day 1 – Start Date of PD from the medical history) / 365.25. If 
the start date of PD is partial, then only year portion will be used for calculation and will 
follow Section 6.3.5 for rounding of decimals 
• Average levodopa dose based on evaluable reported usage (in mg) taken on or after first 
dose of study drug    


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• ON-time (hours) with troublesome dyskinesia 
• Randomisation strata (<6 hours or ≥6 hours of ON-time with troublesome dyskinesia) 
• MDS-UPDRS question 4.2 score (functional impact of dyskinesias) 
• MMSE at Baseline 
• Physical examination by body system at baseline 
6.7 CYP Genotyping 
The number and percent of patients consenting to CYP2D6 genetic testing as well as the number 
and percent of patients within each genotype category (poor, intermediate, normal, and ultrarapid 
metabolizer) will be summarized by treatment group and overall, for the PK set. Consent date, 
blood sample collection data and all reported genotyping data will be listed separately for patients 
consenting to CYP2D6 genetic testing.  
6.8 Medical History 
Separate tabulations of prior and ongoing conditions at screening will be presented by treatment 
group and overall, for the SAS. Prior conditions are those with a stop date prior to screening and 
conditions are ongoing otherwise. Tabulations will be presented by SOC and PT in descending 
frequency of incidence in the pooled mesdopetam arm and then alphabetically for ties. All reported 
medical history will be listed.  
6.9 Prior and Concomitant Medications 
Prior medications are defined as any medications starting and stopping prior to date of first dose 
of study drug. Concomitant medications are defined as medications taken on or after the date of 
first dose of study drug.  
Prior and concomitant medications will be presented alphabetically by ATC Level 2 classification 
followed by ATC level 4 classification and Preferred Name for each treatment group in the SAS.  
A separate tabulation will also be provided for all medications reported under ATC Level 1 = 
Nervous System, Level 2 = Anti-Parkinson Drugs.  Medications will be presented by ATC Level 3 
and Preferred Name by treatment group and overall.  


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Average levodopa dose will also be obtained from the medication log. The first reported levodopa 
dose taken on or after first dose of study drug will be summarized per treatment group alongside 
clinical characteristics.    
All reported medications will be listed. Medication logs will also be reviewed by the Sponsor and 
any non-permitted medications will be identified and listed separately.   
6.10 Exposure to Study Drug 
Exposure to study drug will be calculated as follows from the date of last dosing minus the first 
day of dosing + 1. The exposure calculation will not take into account breaks in therapy.  
Exposure to each dose level will be calculated as follows:  
Exposure 
Calculation 
Exposure to 5 mg during run-in 
period (all patients) 
Dispensing Date (Visit 2, Day 9) – Date of First Dose + 1 
Exposure to randomized dose if the 
patient did not have a dose 
reduction 
Date of Last Dose – Dispensing Date (Visit 2, Day 9) + 1 
 
 
Exposure to randomized dose if the 
patient had a dose reduction  
First dispensing date where dose is different to randomized 
dose – Dispensing Date (Visit 2, Day 9) + 1 
Exposure to adjusted dose if the 
patient had a dose reduction 
Date of Last Dose – First dispensing date where dose is 
different to randomized dose + 1 
 
(programming checks should be made to ensure the 
adjusted dose was also dispensed at Visit 3, Day 28) 
In the rare case that a kit was dispensed containing the wrong dose then those records will be 
excluded from calculations.  
Extent of exposure (number of days of exposure to study drug) will be presented by each treatment 
group and combined based on the randomized treatment. A separate tabulation will also be 
provided to present the exposure during the run-in period and the period after receiving the 
randomized dose.    
All reported data will also be listed. 


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6.11 Treatment Compliance 
Treatment compliance will be calculated as follows:  
• Compliance (%) = (Actual number of doses taken / Expected number of doses) *100 
The actual number of doses = Sum of quantity dosed across all records.  
The expected number of doses is obtained as follows:     
• If the last dose is a morning dose: [(End of treatment (Visit 5) date – Date of first dose – 
1) * 2] + 2 
• If the last dose is an evening dose: [(End of treatment (Visit 5) date – Date of first dose – 
1) * 2] + 3 
The expected number of doses is obtained by first calculating the number of full days on study 
treatment and multiplying by 2 doses per full day per protocol. Then one dose is added for the Day 
1 evening dose and either one dose is added if the last dose was a morning dose, or two doses are 
added if the last dose was an evening dose. 
Compliance (%) will be summarized by treatment group, combined treatment groups, and overall 
based on the actual treatment received for the SAS and will be presented following the decimal 
convention in Section 6.3.5.  The number and percent of patients with compliance <80% will also 
be provided by treatment group, combined treatment groups, and overall.  
All drug accountability data will be listed as recorded on the eCRF.  
6.12 Primary Efficacy Analyses 
All applicable statistical tests will be performed at a local significance level consistent with an 
overall FWER of 5% and the multiple testing strategy described in Section 0.  All comparisons 
between treatments will be reported with 95% confidence intervals (CI) for the difference. All 
efficacy analyses will be performed by randomized treatment group and adjusted dose group for 
patients in the FAS, as well as all active doses grouped compared to placebo.   
6.12.1 Estimand 
The main study estimand will follow the ‘treatment policy’ strategy to estimate the treatment effect 
of mesdopetam (2.5 mg, 5 mg, or 7.5 mg b.i.d.) compared to placebo b.i.d. (treatment) on the 


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change from baseline to Week 12 (population-level summary) in average daily ON-time (hours) 
(variable) in patients with Parkinson’s Disease exhibiting ON-phase dyskinesia, as defined by the 
inclusion/exclusion criteria (population) regardless of missing motor diary data, any permitted 
dose reduction, use of amantadine (if any), or discontinuation for any reason.  
6.12.2 Primary Endpoint 
The primary endpoint is the change from baseline to Week 12 in average daily hours of ON-time 
without troublesome dyskinesia with mesdopetam compared to placebo as assessed with 24-hour 
patient home diaries.    
The hypothesis that will be tested is as follows: 
𝐻0 = 𝜇𝑚𝑒𝑠𝑑𝑜𝑝𝑒𝑡𝑎𝑚−𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜= 0 
versus 
𝐻1 = 𝜇𝑚𝑒𝑠𝑑𝑜𝑝𝑒𝑡𝑎𝑚−𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜≠0 
 
Where 𝜇𝑚𝑒𝑠𝑑𝑜𝑝𝑒𝑡𝑎𝑚 denotes the mean change from baseline to Week 12 in the mesdopetam 
treatment group (2.5 mg b.i.d., 5 mg b.i.d., or 7.5 mg b.i.d.), and  𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜 denotes the mean 
change from baseline to Week 12 in the placebo group.  
The null hypothesis is that there is no difference between mesdopetam and placebo for the primary 
efficacy endpoint and the alternative hypothesis is that there is a difference between mesdopetam 
and placebo for the primary efficacy endpoint.  
6.12.3 Primary Analysis 
The number and percent of patients with valid diaries will be tabulated by treatment group and 
visit and a listing of diary completion will be provided. Descriptive statistics for the actual values 
by visit (including baseline) and change from baseline to each post-baseline visit (Visits 3, 4 and 
5/EOT) in average daily ON-time without troublesome dyskinesia (hours) will be presented.   
Change from baseline in average daily ON-time without troublesome dyskinesia (hours) will be 
analysed using a mixed model for repeated measures (MMRM) for all patients in the FAS. Change 
from baseline to Week 12 is the timepoint of interest for this analysis.  Any missing data is assumed 
to be missing at random (MAR) for this analysis.  
The model will include randomized treatment (2.5 mg, 5.0 mg, 7.5 mg, or placebo b.i.d.), visit, 
country, and treatment by visit interaction as explanatory, fixed effect variables. Country will be 


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Page 29 of 49 
weighted by the number of patients participating from each county. Baseline value for average 
daily hours of ON time without troublesome dyskinesia will be included as a continuous covariate 
along with the randomisation stratification factor of daily hours spent in ON-time with troublesome 
dyskinesia (<6 hours, ≥6 hours).  
An unstructured covariance matrix will be assumed for within-patient correlation over time. If the 
model fails to converge, the first approach for which the model converges among the following 
will be used: banded Toeplitz (TOEP), compound symmetry (CS) and variance component (VC).  
The LS mean estimate, corresponding SE, and 95% CI for the change from baseline at each post-
baseline visit will be obtained from the model and presented for each treatment group. The 
estimated treatment difference for each dose level compared to placebo and the combined dose 
levels compared to placebo, the corresponding SE, and p-value will also be presented by visit.  
A line plot showing the LS mean (±95% CI) change from baseline at each visit for each treatment 
group will also be provided.  
The following is the sample SAS code that will be used for this analysis: 
PROC MIXED DATA= analysis (where = (avisitn ne 0));  
    ODS OUTPUT LSMeans=LSMeans Diffs=Diffs LSMEstimates=Estimates; 
    CLASS USUBJID STRATF TRT01PN AVISITN COUNTRY;  
    MODEL CHG = BASE STRATF TRT01PN AVISITN COUNTRY TRT01PN*AVISITN / DDFM=KR 
s;  
    REPEATED AVISITN / SUBJECT=USUBJID TYPE=UN;  
    LSMEANS TRT01PN*AVISITN / CL DIFF OM;  
 
    LSMESTIMATE TRT01PN*AVISITN 'Difference at Week 4' 1 0 0 1 0 0 1 0 0 -3 0 
0 divisor = 3 / CL e OM;  
    LSMESTIMATE TRT01PN*AVISITN 'Combined at Week 4' 1 0 0 1 0 0 1 0 0 0 0 0 
divisor = 3 / CL e OM; 
    LSMESTIMATE TRT01PN*AVISITN 'Placebo at Week 4' 0 0 0 0 0 0 0 0 0 3 0 0 
divisor = 3 / CL e OM;  
 
    LSMESTIMATE TRT01PN*AVISITN 'Difference at Week 8' 0 1 0 0 1 0 0 1 0 0 -3 
0 divisor = 3 / CL e OM;  
    LSMESTIMATE TRT01PN*AVISITN 'Combined at Week 8' 0 1 0 0 1 0 0 1 0 0 0 0 
divisor = 3 / CL e OM; 
    LSMESTIMATE TRT01PN*AVISITN 'Placebo at Week 8' 0 0 0 0 0 0 0 0 0 0 3 0 
divisor = 3 / CL e OM;  
 
    LSMESTIMATE TRT01PN*AVISITN 'Difference at Week 12' 0 0 1 0 0 1 0 0 1 0 0 
-3 divisor = 3 / CL e OM;  


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    LSMESTIMATE TRT01PN*AVISITN 'Combined at Week 12' 0 0 1 0 0 1 0 0 1 0 0 0 
divisor = 3 / CL e OM; 
    LSMESTIMATE TRT01PN*AVISITN 'Placebo at Week 12' 0 0 0 0 0 0 0 0 0 0 0 3 
divisor = 3 / CL e OM;  
RUN; 
Where USUBJID = Subject Number; TRT01PN = Planned Treatment Group Number; AVISITN = Visit 
Number; BASE = Baseline Value; CHG = Change from Baseline Value; COUNTRY = Country; 
STRATF = Stratification Factor.  
6.12.4 Sensitivity Analyses 
6.12.4.1 Pattern-Mixture Model 
To assess the robustness of the results to deviations from the MAR assumption in the primary 
analysis, a sensitivity analysis will be conducted such that non-monotone missing data is imputed 
under the MAR assumption while the monotone missing data is imputed under the missing not at 
random (MNAR) assumption (i.e., that missingness is also dependent on the unobserved variable 
values).  
This analysis will therefore provide a stress test of the MAR assumption in the primary analysis 
and will provide a conservative estimate of the treatment effect.  
The pattern-mixture modeling will be implemented by first turning the non-monotone missing data 
pattern into a monotone missing pattern under the MAR assumption using the Markov Chain  
Monte Carlo (MCMC) method in SAS’ PROC MI with the IMPUTE = MONOTONE and  the 
PRIOR = JEFFREYS options to specify a non-informative prior for the imputation process. Then 
the MONOTONE statement along with the MNAR statement with option MODEL in SAS’ PROC 
MI will be utilized to implement the MNAR assumptions and control-based pattern imputation2,3. 
The inference of this sensitivity analysis will be based on the combined estimates using the 
standard multiple imputation technique via Rubin’s4 rules.  
Missing data will be imputed using a pattern-mixture model approach that uses a control-based 
pattern imputation. With this approach, patients who discontinued from active treatment groups 
will be assumed to follow a similar outcome trajectory as patients from the placebo (control) group, 
and patients who discontinued from placebo (control) group are modeled as completers within 
their own group (MAR within control group). That is, the imputation model for the missing 
observations in the active treatment groups is constructed not from the observed data in the active 
treatment groups, but rather from the observed data in the placebo group. This model is also the 


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Page 31 of 49 
imputation model that will be used to impute missing observations in the placebo group. The 
missing values for each variable will be imputed based on a model simulated from the posterior 
predictive distribution of the conditional regression model fitted on the imputed variable using 
only the observations from the placebo group.  
This will be implemented by utilizing the MONOTONE REG statement and MNAR statement 
with option MODEL of SAS’ PROC MI with options nimpute = 20 and seed = 32641726. 
The following is the sample SAS code that will be used to implement the control-based pattern 
mixture imputation: 
PROC MI DATA=DATAIN OUT=DATAIN_MONO SEED=32641726 NIMPUTE=1;  
BY TRT01PN; 
VAR BASE ONHOURS3-ONHOURS5;  
MCMC CHAIN=MULTIPLE IMPUTE=MONOTONE PRIOR = JEFFREYS;  
RUN;  
PROC MI DATA= DATAIN_MONO SEED=32641726 NIMPUTE=20  
OUT=DATA_IMPUTED;  
CLASS TRT01PN STRATF;  
MONOTONE REG(BASE ONHOURS3-ONHOURS5);  
MNAR MODEL(ONHOURS3-ONHOURS5 / MODELOBS=(TRT01P='Placebo'));  
VAR STRATF BASE ONHOURS3-ONHOURS5;  
RUN; 
Once the missing diary data has been imputed for all visits, the change from baseline at each visit 
will be calculated and consequently will be analysed using the same MMRM model employed in 
the primary analysis for each iteration of the imputed dataset.  
Then the results are to be summarized using PROC MIANALYZE, where the treatment group 
LS means and their differences between treatments will be combined across all 20 imputed 
datasets:  
PROC SORT DATA= LSMEANS; BY TRT01PN AVISITN _IMPUTATION_; RUN; 
PROC MIANALYZE DATA= LSMEANS; 
MODELEFFECTS ESTIMATE; 
STDERR STDERR; 
ODS OUTPUT PARAMETERESTIMATES= LSMEANS_COMB; 
BY TRT01PN AVISITN; 
RUN; 


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PROC SORT DATA= DIFFS; BY TRT01PN; RUN; 
PROC MIANALYZE DATA= DIFFS(WHERE=(AVISITN=_AVISITN)); 
MODELEFFECTS ESTIMATE; 
STDERR STDERR; 
ODS OUTPUT PARAMETERESTIMATES= DIFFS_COMB; 
BY TRT01PN AVISITN; 
RUN; 
LS means, SEs, and 95% CIs for each treatment group based on the imputed data will be presented 
at each week as well as the estimate of treatment difference, SE, and p-value at each week with 
Week 12 as the primary timepoint of interest.  
6.12.4.2 Tipping Point Analysis 
If the primary efficacy analysis significantly favours mesdopetam, a tipping-point sensitivity 
analysis for the primary efficacy endpoint will be conducted on the significant dose groups to 
investigate how severe the departure from the MAR assumption must be to overturn the conclusion 
from the primary analysis. In this analysis, the assumption will be that missing data in the active 
treatment groups follows a MNAR pattern.  
A tipping-point approach will be used such that the trajectories of the patients in the active 
treatment groups after early termination from study are assumed to be worse than placebo by a 
fixed amount (ẟ). Missing values will first be imputed using a MAR approach and then the value 
of ẟ will be deducted from all imputed values occurring after early termination for patients in the 
active treatment groups only.  The value of ẟ will be applied in increments of 0.5 hours (i.e., 0.5h, 
1h, 1.5h, 2h) up to the point at which the treatment difference at Visit 5 (Week 12) is no longer 
statistically significant at the local level (see Section 0). This analysis provides a measure of the 
degree by which the patients in the active treatment groups who discontinued early would need to 
be worse, compared to patients with similar trajectories up to the point of discontinuation in the 
same treatment arm, at each post-discontinuation visit for the null hypothesis of no treatment 
difference to no longer be rejected. 
6.12.4.3 Modified stratification factor 
The analysis of the primary endpoint will be repeated using the modified stratification factor in 
the mixed model for repeated measures (MMRM) on the randomised dose group.  


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6.12.5 Supportive Analyses 
6.12.5.1 Per Protocol Analysis 
The per protocol analysis will follow the same analysis method as the primary analysis, with the 
exception that the analysis will be based on the PPS.   
6.12.5.2 ANCOVA Analysis 
An analysis of covariance (ANCOVA) will also be performed using the FAS. The ANCOVA 
model will be adjusted for the following covariates: randomized treatment, baseline value for 
average daily hours of ON time without troublesome dyskinesia (continuous covariate), as well as 
randomisation stratification factor for daily hours spent in ON-time with troublesome dyskinesia 
(<6 hours, ≥6 hours).  The dependent variable is the change from baseline in average daily ON-
time (hours) at Week 12.  Missing observations will not be imputed.   
The LS means, SEs, and 95% CIs will be provided for each treatment group, as well as treatment 
difference estimates, SEs, and p-values for each dose level and combined dose groups compared 
to placebo.  
The following is the sample SAS code that will be used to implement this analysis: 
PROC MIXED DATA= DATAIN;  
CLASS TRT01PN STRATF;  
MODEL CHG_WEEK12 = TRT01PN BASE STRATF / SOLUTION;  
LSMEANS TRT01PN / CL DIFF OM; 
LSESTIMATE TRT01PN “Difference at Week 12” 1 1 1 -3 / CL e OM; 
LSESTIMATE TRT01PN “Combined at Week 12” 1 1 1 0 / CL e OM; 
RUN; 
Where TRT01PN = Planned Treatment Group Number; BASE = Baseline Value; CHG_WEEK12 = 
Change from Baseline at Week 12; STRATF = Stratification Factor. 
6.12.5.3 Impact of Permitted Dose Reduction   
The impact of permitted dose reductions on the primary analysis will be explored.   
The change from baseline in average daily ON-time without troublesome dyskinesia (hours) by 
visit will be analysed and reported (including line plots) using the same MMRM approach as for 


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the primary analysis, except the adjusted dose groups will be used as the treatment factor and 
pooled dose will be excluded from tabulations.   
LS means, SE, and 95% CI for the change from baseline by treatment group as well as the 
estimated treatment difference, SE, and p-value for each dose level compared to placebo, will be 
reported, and compared to the primary analysis at Week 12.   
6.12.5.4 Impact of Amantadine Usage 
The number and percent of patients taking amantadine treatment during the study (if any) will be 
presented alongside concomitant medications. If amantadine usage is reported among >5% of 
patients, the impact of amantadine usage on the primary analysis will be explored.  Any diary data 
collected after commencing amantadine treatment will be discarded and the primary analysis will 
be repeated for all patients in the FAS, excluding any values obtained after initiation of 
amantadine.  
6.13 Secondary Efficacy Analyses 
All secondary efficacy analyses will be performed on the FAS for all dose levels of mesdopetam 
(2.5 mg b.i.d., 5.0 mg b.i.d., 7.5 mg b.i.d., and pooled) and placebo.   
6.13.1 Key Secondary Analyses 
6.13.1.1 Functional Impact of Dyskinesia, MDS-UPDRS Question 4.2 
Change from baseline with mesdopetam compared to placebo in ON-phase dyskinesia will be 
assessed by MDS-UPDRS part 4 question 4.2 (Functional impact of dyskinesias).  
MDS-UPDRS Question 4.2 will be completed at all in-person visits up to end of treatment. A shift 
table for the change from baseline in number and percent of patients rated in each score category 
(0 to 4) will be presented by treatment group and visit. Percentages will be based on the number 
of patients with non-missing score at baseline and post-baseline for the relevant visit. Descriptive 
statistics for the score as a continuous measure for observed values and change from baseline to 
each post-baseline visit will also be provided.   
Change from baseline with mesdopetam compared to placebo in MDS-UPDRS Question 4.2 score 
will be analysed as a continuous variable using a MMRM, conducted in the same manner as for 
the primary analysis, and reported (including model estimates and line plot) as described in 


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Section 6.12.3. The analysis will be repeated using the modified stratification factor in the MMRM 
on the randomised dose group. 
6.13.1.2 Disability Associated with ON-Phase Dyskinesia, UDysRS Parts 1b and 4 Sum Score 
Change from baseline with mesdopetam compared to placebo in disability associated with ON-
phase dyskinesia will be assessed with the sum score of parts 1b and 4 of the UDysRS.  
Descriptive statistics for the sum score of parts 1b and 4 and change from baseline by visit will be 
provided by treatment group. Change from baseline in the sum score of parts 1b and 4 will be 
analysed and reported (including line plots) in the same manner as for the primary analysis, as 
described in Section 6.12.3. The analysis will be repeated using the modified stratification factor 
in the MMRM on the randomised dose group. 
6.13.2 Other Key Secondary Analyses 
6.13.2.1 Average Daily OFF-Time (Hours) 
Any observed changes in the average daily time spent in the OFF-state with mesdopetam compared 
to placebo will be evaluated.  The change from baseline in average daily OFF-time (hours) by visit 
will be analysed and reported using the same MMRM approach as for the primary analysis, with 
Week 12 as the timepoint of interest.   
The endpoint of interest will be the upper and lower bounds of the 95% CI for estimated difference 
in LS mean of OFF-time (hours) for mesdopetam dose levels compared to placebo.  As the study 
is not powered to detect equivalence of mesdopetam treatment compared to placebo, the 95% CI 
will be provided for discussion only and no inference will be made.  
6.13.2.2 Motor Symptoms of PD, MDS-UPDRS Part 2 (M-EDL) Total Score 
Change from baseline with mesdopetam compared to placebo in motor symptoms of PD will be 
assessed with the total score obtained from Part 2 of the MDS-UPDRS (M-EDL).   
Descriptive statistics for the M-EDL total score (0 to 52) and change from baseline by visit will be 
provided by treatment group. Change from baseline in M-EDL total score will be analysed and 
reported (including line plots) in the same manner as for the primary analysis, as described in 
Section 6.12.3.  


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6.13.3 Other Secondary Analyses 
6.13.3.1 ON-Phase Dyskinesia, Modified UDysRS Parts 1, 3 and 4 Sum Score 
Change from baseline with mesdopetam compared to placebo in ON-phase dyskinesia will be 
assessed with the sum score of the modified UDysRS (parts 1, 3 and 4). 
Descriptive statistics for the sum score of parts 1, 3 and 4 and change from baseline by visit will 
be provided by treatment group. Change from baseline in parts 1, 3 and 4 sum score will be 
analysed and reported (including line plots) in the same manner as for the primary analysis, as 
described in Section 6.12.3.  
6.13.3.2 Time Spent with Dyskinesias, MDS-UPDRS Question 4.1 
Change from baseline with mesdopetam compared to placebo in ON-phase dyskinesia will be 
assessed by MDS-UPDRS Question 4.1 (Time spent with dyskinesias).  
MDS-UPDRS Question 4.1 will be completed at all in-person visits up to end of treatment. A shift 
table for the change from baseline in number and percent of patients rated in each score category 
(0 to 4) will be presented by treatment group and visit. Percentages will be based on the number 
of patients with non-missing score at baseline and post-baseline for the relevant visit. Descriptive 
statistics for the score as a continuous measure for observed values and change from baseline to 
each post-baseline visit will also be provided.   
Change from baseline with mesdopetam compared to placebo in MDS-UPDRS Question 4.1 score 
will be analysed as a continuous variable using a MMRM, conducted in the same manner as for 
the primary analysis, and reported (including model estimates and line plot) as described in 
Section 6.12.3.  
6.13.3.3 Analysis of All Active Doses Pooled Compared to Placebo 
All active doses will be pooled into one mesdopetam dose group and will be analysed compared 
to placebo alongside the individual doses for each of the primary, secondary, and exploratory 
analyses.  


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6.13.3.4 Dose Response Relationship with 3 Dose Levels of Mesdopetam 
The dose response relationship will be explored by first considering the significance of the 
treatment effect in the primary model and then by visually assessing the relationship using line 
plots of LS mean (±95% CI) over time. If a significant effect is observed, a Jonckheere-Terpstra 
(JT) trend test may be performed using the contrast statement in PROC GLM to construct a T trend 
statistic to test a one-side hypothesis for increasing trend. If a normal distribution of values is not 
observed, a non-parametric approach may be pursued.  However, if a significant treatment effect 
is not observed, or there is a significant departure from a linear trend between doses, a test for 
trend will not be performed.   
6.13.3.5 Average Daily Hours Spent in Different Motor States 
Descriptive statistics for the average daily hours and change from baseline by visit will be provided 
for each motor state (ON-time without troublesome dyskinesia, ON-time with troublesome 
dyskinesia, OFF-time, and asleep). Additionally, average daily total ON-time (defined as the sum 
of ON-time with and without troublesome dyskinesia) will be summarized. Change from baseline 
in average daily hours for each motor state will be analysed and reported in the same manner as 
for the primary analysis, as described in Section 6.12.3.  
Boxplots showing the distribution of values (minimum value, first quartile, median, third quartile 
and maximum value) for each motor state will be presented by treatment group and visit.  If the 
presence of outliers affects the interpretation of the distribution, boxplots showing 1.5* 
interquartile range (IQR) may be shown.   
A line chart showing the change from baseline in mean (±SD) hours spent in each motor state 
(ON-time without troublesome dyskinesia, ON-time with troublesome dyskinesia, OFF-time) will 
be presented by treatment group and visit (one panel per visit).  A separate line chart will also be 
presented as above, showing the change in daily total ON-time (defined as the sum of ON-time 
with and without troublesome dyskinesia) versus the change in daily OFF-time.   
A stacked bar chart will be produced showing the mean percentage of time spent in each motor 
state during the day (ON-time without troublesome dyskinesia, ON-time with troublesome 
dyskinesia, OFF-time, or asleep) by treatment group and visit (one panel per visit).  


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6.13.3.6 ON-Phase Dyskinesia, Clinician’s Global Impression of Severity 
Severity of the patient’s ON-phase dyskinesia will be rated by the investigator, considering his or 
her total clinical experience with the PD population, using the CGI-S scale.  Severity will be rated 
based on a 1–7-point weighted scale ranging from “normal”, not at all ill” (1) to “among the most 
extremely ill patients” (7).  
CGI-S of ON-phase dyskinesia will be completed at all in-person visits up to end of treatment, 
including baseline. A shift table for the change from baseline in number and percent of patients 
rated in each score category (1 to 7) will be presented by treatment group and visit. Percentages 
will be based on the number of patients with non-missing score at baseline and post-baseline for 
the relevant visit. Descriptive statistics for the score as a continuous measure for observed values 
and change from baseline to each post-baseline visit will also be provided.   
Change from baseline with mesdopetam compared to placebo in CGI-S of ON-phase dyskinesia 
will be analysed as a continuous variable using a MMRM, conducted in the same manner as for 
the primary analysis, and reported (including model estimates and line plot) as described in 
Section 6.12.3.  
6.13.4 Motor Examination, MDS-UPDRS - Part 3 Total Score  
MDS-UPDRS Part 3 total score, will be summarized by treatment group and visit. Change from 
baseline will be summarised, analysed, and reported (including model estimates and line plot) in 
the same manner as for the primary analysis, as described in Section 6.12.3.  
6.14 Exploratory Efficacy Analyses 
All exploratory efficacy analyses will be performed on the FAS for all dose levels of mesdopetam 
(2.5 mg b.i.d., 5.0 mg b.i.d., 7.5 mg b.i.d., and pooled) and placebo.   
6.14.1 Overall PD Symptoms, Clinician’s Global Impression of Severity 
Severity of the patient’s PD will be rated by the investigator, considering his or her total clinical 
experience with the PD population, using the CGI-S scale. CGI-S of the patient’s overall PD 
symptoms will be completed at all in-person visits up to end of treatment, including baseline.  
Actual scores and changes in scores will be summarized, analysed, and reported by visit and 
treatment group as described in Section 6.13.3.6.  


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6.14.2 Cognitive Function, Mini-Mental State Examination 
Descriptive statistics for the MMSE total score at each visit (Baseline, Visit 5 (Week 12)) and the 
change from baseline will be provided per treatment group.    
Change from baseline to Week 12 with mesdopetam compared to placebo in the MMSE total score 
will be analysed using an ANCOVA. The model will include randomized treatment as a factor, 
and the baseline value for average daily ON time without troublesome dyskinesia (hours) as a 
continuous covariate.  The LS mean estimate, SE, and 95% CI, for each treatment group as well 
as the estimated treatment difference for each dose level compared to placebo, corresponding SE 
and p-value will be obtained from the model.   
6.14.3 Improvement in Daily ON-time, Responder Analysis 
The number and percent of responders (at least 1h improvement in average daily ON-time) versus 
non-responders at Week 12 will be tabulated by treatment group.  
Each dose level will be compared to placebo using a Cochran-Mantel-Haenszel (CMH) test. The 
risk difference for each dose level compared to placebo, corresponding 95% CI and p-value for 
the CMH statistic will be provided.  
The following is the sample SAS code that will be used for this analysis: 
PROC FREQ DATA=DATAIN; 
TABLES TRT01PN*RESP / RISKDIFF CMH; 
ODS OUTPUT RISKDIFFCOL2 = RISK CMH = CMH_PVAL; 
RUN; 
Where TRT01PN = Planned Treatment Group Number; RESP = Responder (0/1). 
6.14.4 MDS-UPDRS: Part 1, and Part 4 Total Scores  
MDS-UPDRS Part 1 total score, and Part 4 total score will be summarized separately by treatment 
group and visit. Change from baseline for each part total score will be summarised, analysed, and 
reported (including model estimates and line plot) in the same manner as for the primary analysis, 
as described in Section 6.12.3. 


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6.14.5 Freezing and Freezing of Gait, MDS-UPDRS: Question 2.13 + Question 3.11  
MDS-UPDRS Question 2.13 + Question 3.11 sum score and change from baseline by visit will be 
provided by treatment group. Change from baseline in question 2.13 + question 3.11 sum score 
will be analysed and reported (including model estimates and line plot) in the same manner as for 
the primary analysis, as described in Section 6.12.3. 
6.15 Multiplicity 
Multiple dose levels have been included in the study design to evaluate the dose-response 
relationship of mesdopetam with the hypothesis that the 7.5 mg b.i.d. dose will be the most 
efficacious of the dose levels studied.  
Two key secondary endpoints (change from baseline in ON-phase dyskinesia assessed by MDS-
UPDRS Question 4.2 and change from baseline in disability associated with ON-phase dyskinesia 
assessed with the sum score of UDysRS parts 1b and 4) will also be evaluated and thus a strategy 
for controlling the overall error rate whilst maintaining the planned study power is required. 
To such aim, a hierarchical testing strategy will be used whereby first the 7.5 mg b.i.d. will be 
tested at a 5% level on the primary endpoint, and should the test be significant, the 2 key secondary 
endpoints will be tested for the 7.5 mg b.i.d. dose using a truncated Hochberg procedure with a 
truncation parameter 𝛾 =  0.7. This procedure works as follows for 𝑛 =  2 tests: 
1) p-values are sorted in ascending order as p1 and p2;  
2) The largest p-value, p2, is compared against the modified critical value c2 below:  
𝑐2 = [
𝛾
𝑛−𝑖+ 1 + 1 −𝛾
𝑛
] 𝛼= [𝛾+ 1 −𝛾
2
] 𝛼= [0.7 + 0.3
2 ] 0.05 = 0.0425 
(where 𝑛 =  2 and 𝑖 =  2) 
3) If p2 ≤ c2 then all key secondary hypotheses are rejected, otherwise the hypothesis 
associated with p2 is retained and the other p-value, p1, is compared against the critical 
value c1, which can be obtained from the formula in 2) by replacing 𝑖 with 1, leading to a 
critical value of 0.025;  
4) If p1 ≤ c1 then the associated hypothesis is rejected, otherwise all hypotheses are retained 
and no more testing of primary or key secondary hypotheses for the lower doses is 
performed. 


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If at least one hypothesis is rejected in the above steps, then the primary endpoint is tested for the 
5 mg b.i.d. dose at an alpha level that depends on how many hypotheses were rejected in the 
truncated Hochberg procedure and the truncation parameter γ.  
To derive the amount of alpha level to carry over to the next level of testing, we account for how 
many hypotheses were rejected:  
a) If all or none were rejected, then we carry over, respectively, 0.05 (full 𝛼) or 0 (no 𝛼);  
b) If only one hypothesis were rejected, the amount of alpha to carry forward is given by: 
((1 −𝛾)|𝐼|𝛼) 𝑛 
⁄
= ((1 −0.7)|1|0.05) 2 
⁄
= 0.0075 
Testing of the primary endpoint for the 5 mg b.i.d. dose is then conducted at the specified alpha-
level and then, depending on the significance of this test, another truncated Hochberg procedure 
with the same truncation parameter is conducted for the key secondary endpoints, using the same 
alpha level carried over to test for the primary endpoint at 5 mg b.i.d. to derive the critical values 
for the testing using the same formulas shown above.  
Once the truncated procedure has been conducted, the same approach to derive the amount of alpha 
that can be carried forward to the testing of the primary endpoint for the lower dose is then 
followed. Once this testing is complete, if the primary endpoint is significant at the pre-specified 
alpha level, the key secondary endpoints are tested using a standard Hochberg procedure, which is 
conducted similarly to its truncated version but with 𝑐1  and 𝑐2  being equal to 𝛼/2 and 𝛼, 
respectively (where 𝛼 is the significance level at which the primary endpoint was tested for the 2.5 
mg b.i.d. dose).  
An ordered tabulation of the endpoints tested, p-values observed, alpha-level tested against and 
acceptance or otherwise of the null hypothesis at each stage will be presented.   
6.16 Pharmacokinetic Analyses 
Plasma concentrations of mesdopetam and its two main metabolites (IRL902 [N-dealkylated] and 
IRL872 [acetylated]) will be obtained pre-dose and 2 hours post-dose (as an estimate of Cmax) at 
Visit 4 (Week 8) and Visit 5 (Week 12).   


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Concentration data will be summarized by analyte, adjusted dose level, and visit at each scheduled 
sample time (nominal time) for the PK analysis set, using descriptive statistics. Line plots will also 
be provided showing mean (SD) by dose level and visit for each analyte.  
In addition, concentration data will be summarized by genotype (poor, intermediate, normal, and 
ultrarapid metabolizer), adjusted dose level, and visit at each scheduled sample time (nominal 
time) using descriptive statistics and line plots for the CYP Genotype Subset.  
All concentration data will be listed.  
6.17 Safety Analyses 
Safety analyses will be presented by actual treatment group as well as adjusted dose group for all 
patients in the SAS.  
6.17.1 Adverse Events 
Adverse events will be collected from the time of informed consent and continues through the last 
follow-up assessment in the study.  
A treatment emergent adverse event (TEAE) is defined as: 
• Any AE that has an onset on or after the first dose of study drug through the last follow-up 
assessment in the study. 
• Any pre-existing AE that has worsened in severity on or after the first dose of study drug 
through the last follow-up assessment in the study.  
A treatment-related AE is defined as an AE relationship to study drug classified by the Investigator 
as ‘possible’, or ‘probable’. If an AE has missing relationship, ‘probable’ will be assumed for 
analysis purposes. 
Severity of the AE will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) grading system (Version 5.0): Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), 
Grade 4 (Life-Threatening), Grade 5 (Fatal).  Grade 3 (Severe) will be assumed for an AE with 
missing grade. 
An overall summary table of AE incidence (number and percent of patients) and number of events, 
will be presented by treatment group and overall, for the following categories: 
• Any Reported TEAE 


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• Treatment-Related TEAEs 
• Serious TEAEs 
• Serious Treatment-Related TEAEs 
• TEAEs Leading to Reduction in Dose of Study Drug 
• TEAEs Leading to Interruption of Study Drug 
• TEAEs Leading to Withdrawal of Study Drug 
• TEAEs Leading to Early Withdrawal from Study 
• TEAEs Leading to Death 
Summaries of TEAE incidence and number of events by SOC and PT will be presented by 
treatment group and overall, for the following:   
• TEAEs 
• Treatment-related TEAEs 
• Serious TEAEs 
• Serious Treatment-Related TEAEs 
• TEAEs by Maximum Grade, (incidence only) 
• Treatment-Related TEAEs by Maximum Grade, (incidence only) 
• TEAEs by Strongest Relationship, (incidence only) 
• Treatment-Related TEAEs by Strongest Relationship, (incidence only) 
The following listings of AEs will be presented in Section 14.3.2 of the CSR:   
• Serious AEs 
• TEAEs Leading to Interruption of Study Drug 
• TEAEs Leading to Withdrawal of Study Drug 
• TEAEs Leading to Early Termination from Study 
• Deaths 
TEAE tabulations will be presented by SOC and PT in descending frequency of AE incidence in 
the pooled mesdopetam arm and then alphabetically for ties.  
All reported AEs will be listed in Appendix 16.2.7 of the CSR with separate listings for TEAE and 
non-treatment-emergent AEs (NTEAE).  
Overall ongoing TEAEs will be summarized by month 1, 2, and 3. Additionally, TEAEs that occur 
in >5% of all participants will be summarized by month 1, 2, and 3.  


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6.17.2 Laboratory Data 
Blood samples for analysis of serum chemistry, haematology and coagulation parameters will be 
collected at screening, Visit 1 (if 29 days or more between Screening and Visit 1), Visit 4, 5 and 6 
and sent to the certified central laboratory for analysis. Urine analysis will be performed at the 
clinic using dip sticks. Descriptive statistics for observed values and change from baseline will be 
presented by treatment group and visit for each continuous haematology, serum chemistry 
(including thyroid panel), and coagulation parameter. A shift table for the change from baseline in 
dipstick urinalysis (Normal, Abnormal NCS, Abnormal CS) will also be provided.   
Each continuous measurement will be classified as below, within, or above normal range, based 
on ranges supplied by the laboratory used. Shift tables in relation to the normal range from baseline 
to each follow-up visit will be presented.  
Summaries and listings will be presented using the Système International (SI) unit for each 
parameter as received from the analytical laboratory. 
A listing of any clinically significant laboratory measurements recorded throughout the study will 
be presented.  All collected laboratory data will be listed. Any unscheduled samples analysed at 
local hospital laboratories will be listed separately with references ranges as provided by the 
analytical laboratory.  
6.17.3 Vital Signs 
Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment group and visit:  
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Pulse rate (bpm) 
• Body weight (kg) 
Both standing and supine values, as well as orthostatic changes (standing – supine) will be 
presented for blood pressure and pulse rate.  Measurements taken either seated or prone will be 
considered taken supine. The number and percentage of patients with either >20 mmHg reduction 
in systolic blood pressure after standing, or >10 mmHg reduction in diastolic blood pressure after 
standing, or both will be summarized.  All vital sign data will be listed.   


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6.17.4 Electrocardiogram Data 
Descriptive statistics for observed values and changes from baseline in the following ECG 
variables will be presented by treatment group and visit:  
• Heart rate (bpm) 
• PR interval (ms) 
• QRS duration (ms) 
• QT interval (ms) 
• QTc interval (ms) 
• QTcB interval (ms) [Bazett’s formula] 
• QTcF interval (ms) [Fridericia’s formula] 
• RR interval (ms) 
Shift tables in relation to the overall interpretation i.e., Normal, Abnormal NCS (Not Clinically 
Significant), and Abnormal CS (Clinically Significant) from baseline to each follow-up visit will 
be presented.  
Any QTcF or QTcB Interval (ms) result meeting the following criteria will be identified as an 
electrocardiogram abnormality and a separate tabulation by treatment group will be provided:   
• Interval at Baseline of >450 msec and ≤ 480 msec 
• Interval at Baseline of >480 msec and ≤ 500 msec 
• Interval at Baseline of >500 msec 
• Post-Baseline value of >450 msec and ≤ 480 msec 
• Post-Baseline value of >480 msec and ≤ 500 msec 
• Post-Baseline value of >500 msec 
• Post-Baseline increase of >30 msec and ≤ 60 msec 
• Post-Baseline increase of >60 msec 
All ECG data, including details of any abnormalities, will be listed. 
6.17.5 Physical Examination 
Shift tables for the observed change in status of each of the body systems, (Normal, Abnormal 
NCS, and Abnormal CS) from baseline to each follow-up visit will be tabulated by treatment 
group.  All data, including details of clinically significant findings will be listed.  


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6.17.6 C-SSRS 
C-SSRS outcomes (Suicidal Ideation and Suicidal Behaviour) since baseline will be tabulated by 
treatment group and overall, by visit. A shift table for the change in number and percent of patients 
in each category (No Suicidal Ideation or Behaviour, Suicidal Ideation, Suicidal Behaviour) from 
baseline to each visit will be presented. Patients with both Suicidal Ideation and Suicidal Behaviour 
will be included in the Suicidal Behaviour category.  
All reported data will be listed.   
6.17.7 Features of Dopamine Dysregulation Syndrome, MDS-UPDRS Question 1.6 
MDS-UPDRS Question 1.6 will be completed at all in-person visits, (excluding Day 9 and Day 
28) up to end of treatment. A shift table for the change from baseline in number and percent of 
patients rated in each score category (0 to 4) will be presented by treatment group and visit. 
Percentages will be based on the number of patients with non-missing score at baseline and post-
baseline for the relevant visit. Descriptive statistics for the score as a continuous measure for 
observed values and change from baseline to each post-baseline visit will be provided and the 
number and percent of patients with a worsening post-baseline score of 2 or more points will also 
be presented. 
6.17.8 Pregnancy 
Pregnancy testing will be performed at Screening, Visit 1, Visit 3, Visit 4, and Visit 5 for women 
of childbearing potential. Patient counts within each category (positive/negative test result) will be 
summarized by visit. All pregnancy testing data will be listed. Any reported pregnancies and 
details of the condition of neonate(s) will be provided as separate listings.  
7 INTERIM ANALYSIS 
No interim analyses are planned for this study.  
8 DATA SAFETY MONITORING BOARD ANALYSIS 
No data safety monitoring board (DSMB) analyses are planned for this study. 
 
 


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IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 47 of 49 
9 CHANGES TO PLANNED PROTOCOL ANALYSIS 
1. The primary efficacy analysis will be adjusted for country and weighted by the number of 
subjects participating from each country to account for any observed imbalances in 
recruitment across countries.  
2. Analyses will be conducted for individual active dose and pooled doses. 
3. Secondary and exploratory endpoints have been itemized separately compared to the 
protocol for clarity.   
4. Key Secondary Efficacy Endpoints were defined: 
- Change from baseline with mesdopetam compared to placebo in ON-phase 
dyskinesia assessed by MDS-UPDRS part 4 question 4.2 (Functional impact of 
dyskinesias).  
- Change from baseline with mesdopetam compared to placebo in disability 
associated with ON-phase dyskinesia assessed with the sum score of parts 1b and 
4 of the UDysRS.  
5. Other Key Secondary Efficacy Endpoints were defined:  
- Change from baseline with mesdopetam compared to placebo in motor symptoms 
of PD assessed with MDS-UPDRS total score of part 2 (M-EDL).  
- Change from baseline with mesdopetam compared to placebo in average daily 
OFF-time. 
6. Exploratory endpoint added to reflect protocol section 14.7. Efficacy endpoints, Table 6 
Other endpoints: 
- Change from baseline with mesdopetam compared to placebo in the total scores for 
each component part of the MDS-UPDRS (Part 1, Part 3, and Part 4).   
- Change from baseline with mesdopetam compared to placebo in freezing and 
freezing of gait, assessed by MDS-UPDRS: Question 2.13 + Question 3.11. 
7. Safety endpoint added to reflect protocol section 14.7. Efficacy endpoints, Table 6 Other 
endpoints:  
- Change from baseline with mesdopetam compared to placebo in features of 
dopamine dysregulation syndrome assessed by MDS-UPDRS Question 1.6.  
8. Improvement in Daily ON-time, Responder Analysis 
9. PK Analysis Set was defined.  
10. CYP Genotype Subset was defined.  
11. Multiplicity strategy was refined to address Key Secondary Endpoints. 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 48 of 49 
12. Exposure calculation was redefined.  
13. Compliance calculated was redefined 
14. Analysis of the primary and key secondary endpoints will be repeated using the modified 
stratification factor. 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Integrative Research Laboratories Sweden AB 
Protocol Number: 
IRL790C005 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 49 of 49 
10 REFERENCES 
1. SAS Institute Inc., Cary, NC, 27513, USA 
2. Yuan, Y. (2014). Sensitivity Analysis in Multiple Imputation for Missing Data.  
SAS Global Forum 2014 Conference. Retrieved from: 
http://support.sas.com/resources/papers/proceedings14/SAS270-2014.pdf 
3. Li, L. (2019). SAS® V9. 4 MNAR statement for multiple imputations for missing not at 
random in longitudinal clinical trials. PharmaSUG 2019 Conference. Retrieved from 
https://www.pharmasug.org/proceedings/2019/ST/PharmaSUG-2019-ST-103.pdf 
4. Rubin, D. B. (1976), “Inference and Missing Data,”Biometrika, 63, 581–592.  
5. Multiple Testing Problems in Pharmaceutical Statistics, edited by Dmitrienko A, Tamhane 
AC and Bretz F. Printed 2009 by Chapman and Hall/CRC.