A Phase IIa, Randomized, Double Blind, Placebo Controlled, Single Ascending Dose, Safety and Pharmacokinetic/Pharmacodynamic Study of INP103 (POD L-dopa) Administered in the Presence of DCI to L-dopa Responsive Parkinson's Disease Patients
Phase: PHASE2
Conditions: Parkinson's Disease
Sponsor: Impel Pharmaceuticals

 
 
INP103 
INP103-201 Clinical Study Protocol 
 
Impel NeuroPharma 
V5.0– 20190201 
CONFIDENTIAL 
Page 1 of 90 
 
 
Impel NeuroPharma, Inc. 
201 Elliott Ave West, Suite 260 
Seattle, Washington 98119 
United States 
 
 
A Phase IIa, Randomized, Double Blind, Placebo Controlled, Single Dose, Safety 
and Pharmacokinetic/Pharmacodynamic Study of INP103 (POD L-dopa) 
Administered in the Presence of Decarboxylase Inhibitor to L-dopa Responsive 
Parkinson’s Disease Patients 
Short Title: Therapeutic potential for intranasal levodopa in Parkinson’s Disease – 
OFF Reversal (THOR 201) 
 
Protocol Number INP103-201 
 
 
Development Phase: Phase IIa 
Document Version: 5.0 
Amendment 04 
01 February 2019 
 
 
Property of Impel NeuroPharma – Confidential 
May not be used, divulged, published or otherwise disclosed without the consent of 
Impel 
 

 
 
INP103 
INP103-201 Clinical Study Protocol 
 
Impel NeuroPharma 
V5.0– 20190201 
CONFIDENTIAL 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................ 2 
TABLE OF TABLES ................................................................................................... 6 
LIST OF ABBREVIATIONS ...................................................................................... 7 
PROTOCOL AUTHORISATION ............................................................................. 9 
DECLARATION OF INVESTIGATORS ............................................................... 10 
FACILITIES AND PERSONNEL ........................................................................... 11 
STUDY SYNOPSIS ................................................................................................... 13 
STUDY SCHEDULE ................................................................................................ 26 
1. 
BACKGROUND AND INTRODUCTION ........................................ 31 
1.1. 
Introduction ........................................................................................... 31 
1.2. 
Summary of Non-Clinical and Clinical Studies ............................... 32 
1.2.1. 
Non-Clinical Studies............................................................................. 32 
1.2.2. 
Clinical Studies ...................................................................................... 35 
1.3. 
Summary of Potential Risks and Benefits ......................................... 35 
1.4. 
Dosage and Treatment Periods ........................................................... 36 
1.5. 
Study Population .................................................................................. 36 
1.6. 
Ethical Principles................................................................................... 37 
2. 
OBJECTIVES .......................................................................................... 38 
2.1. 
Primary Objectives ............................................................................... 38 
2.2. 
Secondary Objectives ........................................................................... 38 
3. 
STUDY DESIGN.................................................................................... 39 
3.1. 
Primary Endpoints................................................................................ 42 
3.2. 
Secondary Endpoints ........................................................................... 42 
4. 
STUDY POPULATION ........................................................................ 43 
4.1. 
Description of Numbers....................................................................... 43 
4.2. 
Inclusion Criteria .................................................................................. 43 
4.3. 
Exclusion Criteria .................................................................................. 44 
4.4. 
Contraceptive Requirements ............................................................... 45 
4.5. 
Concomitant Medication ..................................................................... 45 
4.6. 
Diet, Activity and Other Restrictions ................................................. 45 

 
 
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4.7. 
Meal Schedule ....................................................................................... 46 
5. 
STUDY MEDICATION ........................................................................ 47 
5.1. 
Investigational Product Identification ............................................... 47 
5.1.1. 
Placebo .................................................................................................... 47 
5.2. 
Randomization ...................................................................................... 47 
5.3. 
Blinding .................................................................................................. 48 
5.4. 
Dosage and Treatment ......................................................................... 48 
5.4.1. 
Study Supplies ....................................................................................... 48 
5.4.2. 
Storage, Dispensing and Investigational Product Accountability . 48 
6. 
STUDY PROCEDURES ........................................................................ 50 
6.1. 
Medical History ..................................................................................... 50 
6.2. 
Demographics ....................................................................................... 50 
6.3. 
Body Weight and Height/ Body Mass Index .................................... 50 
6.4. 
Safety Assessments ............................................................................... 50 
6.4.1. 
Nasal Inspection .................................................................................... 51 
6.4.2. 
Overall Dyskinesia Assessment .......................................................... 51 
6.4.3. 
Physical Examination ........................................................................... 51 
6.4.4. 
Mini Mental Status Examination (MMSE) ........................................ 51 
6.4.5. 
Vital Signs .............................................................................................. 52 
6.4.6. 
Electrocardiogram Monitoring ........................................................... 52 
6.4.7. 
Laboratory Investigations .................................................................... 52 
6.4.8. 
MDS-UPDRS .......................................................................................... 53 
6.4.9. 
Subject Questionnaire........................................................................... 53 
6.5. 
Pharmacokinetic Assessments ............................................................ 53 
6.5.1. 
Sampling and Processing ..................................................................... 53 
6.5.2. 
Analytical Methods .............................................................................. 54 
6.6. 
Pharmacodynamic Assessments ........................................................ 54 
6.6.1. 
MDS-UPDRS .......................................................................................... 54 
6.6.2. 
Assessment of ON ................................................................................ 54 
7. 
STUDY SCHEDULE ............................................................................. 55 
7.1. 
Screening (Up to 21 Days Prior to Visit 3 Dosing) (Visit 1) ............ 55 

 
 
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7.2. 
Admission to Clinic (Day prior to Visit 2 and Visit 3) .................... 55 
7.3. 
Evaluation of Dopamine Responsiveness (Screening [Visit 2]) ..... 56 
7.4. 
Dosing and Admission to Clinic (Day 0) (Visit 3) ............................ 56 
7.4.1. 
Before Dosing ........................................................................................ 56 
7.4.2. 
Dosing (Visit 3) ...................................................................................... 58 
7.4.3. 
After Dosing .......................................................................................... 58 
7.5. 
Follow-Up/End of Study (Day 7 + 2 days) ........................................ 59 
8. 
ADVERSE EVENTS .............................................................................. 60 
8.1. 
Safety Monitoring Committee ............................................................ 60 
8.2. 
Definition of an Adverse Event .......................................................... 60 
8.2.1. 
Severity of an Adverse Event .............................................................. 61 
8.2.2. 
Causal Relationship of an Adverse Event ......................................... 62 
8.2.3. 
Action Taken with Study Medications .............................................. 62 
8.2.4. 
Outcome ................................................................................................. 62 
8.3. 
Definition of a Serious Adverse Event ............................................... 63 
8.3.1. 
Notification of a Serious Adverse Event ........................................... 63 
8.4. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events and Serious Adverse Events ...... 64 
8.5. 
Documenting Adverse Events ............................................................ 64 
8.6. 
Regulatory Authorities ........................................................................ 65 
8.7. 
Follow-Up of Adverse Events and Serious Adverse Events .......... 65 
8.8. 
Pregnancy............................................................................................... 65 
9. 
STUDY COMPLETION AND DISCONTINUATION ..................... 67 
9.1. 
Subject Withdrawal .............................................................................. 67 
9.2. 
Subject Replacement ............................................................................. 67 
10. 
TERMINATION OR SUSPENSION OF THE STUDY ..................... 68 
11. 
STUDY MONITORING AND DATA MANAGEMENT ................ 69 
11.1. 
Study Monitoring .................................................................................. 69 
11.2. 
Access to the Study ............................................................................... 69 
11.3. 
Source Document and Data Verification ........................................... 69 
11.4. 
Data Management ................................................................................. 70 

 
 
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12. 
STATISTICAL ANALYSES ................................................................. 71 
12.1. 
Sample Size Calculation ....................................................................... 71 
12.2. 
Analysis Populations ............................................................................ 71 
12.3. 
Safety Analysis ...................................................................................... 72 
12.4. 
Pharmacokinetic Analysis ................................................................... 73 
12.5. 
Pharmacodynamic Analysis ................................................................ 73 
12.6. 
Pharmacokinetic/Pharmacodynamic relationship ........................... 74 
13. 
REGULATORY REQUIREMENTS ..................................................... 75 
13.1. 
Regulatory Approvals .......................................................................... 75 
13.2. 
Human Research Ethics Committee (HREC) Approval ................. 75 
13.3. 
Subject Informed Consent ................................................................... 75 
13.4. 
Data Protection ...................................................................................... 76 
14. 
ADMINISTRATIVE PROCEDURES .................................................. 77 
14.1. 
Liability/Indemnity/Insurance ............................................................ 77 
14.2. 
Recording of Data and Retention of Records ................................... 77 
14.3. 
Publication of Results ........................................................................... 77 
14.4. 
Disclosure and Confidentiality ........................................................... 78 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .................. 79 
15.1. 
Compliance with Good Clinical Practice........................................... 79 
15.2. 
Archiving and Regulatory Inspection ............................................... 79 
16. 
CLINICAL STUDY REPORT .............................................................. 80 
17. 
SPONSOR AND INVESTIGATOR OBLIGATIONS ........................ 81 
17.1. 
Protocol Amendments ......................................................................... 81 
17.2. 
Protocol Deviations .............................................................................. 81 
18. 
REFERENCES ........................................................................................ 83 
APPENDIX 1: BLOOD BIOCHEMISTRY PARAMETERS ................................. 84 
APPENDIX 2: HAEMATOLOGY PARAMETERS .............................................. 85 
APPENDIX 3: URINARY ANALYSIS PARAMETERS ...................................... 86 
APPENDIX 4: MDS-UPDRS ................................................................................... 87 
APPENDIX 5: PROHIBITED CONCOMITANT MEDICATIONS ................... 88 
APPENDIX 6: SUBJECT QUESTIONNAIRE ....................................................... 89 

 
 
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TABLE OF TABLES 
Table 1: 
Study Schedule ...................................................................................... 26 
 
 
 

 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AUC 
Area Under the Curve 
ANCOVA Analysis of Covariance 
BMI 
Body Mass Index 
cGMP 
Current Good Manufacturing Practices 
CNS 
Clinical Network Services 
eCRF 
Case Report Forms 
Cmax 
Maximum plasma concentration 
COMT 
Catechol-O-Methyl Transferase 
CRO 
Contract Research Organization 
CSH 
Heterogeneous Compound Symmetry 
CSR 
Clinical Study Report 
CTN 
Clinical Trial Notification 
DA 
Dopamine Agonist 
DCI 
Decarboxylase Inhibitor 
EC 
Ethics Committee 
FSH 
Follicle-Stimulating Hormone 
H&Y 
Hoehn & Yahr 
HREC 
Human Research Ethics Committee 
IB 
Investigator Brochure 
ICH GCP 
International Conference on Harmonisation Note for Guidance on Good 
Clinical Practice 
INP103 
Impel’s drug-device combination product (L-dopa delivered by the I231 
POD Device. Also referred to as POD L-dopa) 
ITT 
Intention-to-Treat 
L-dopa 
Levodopa 
LLN 
Lower Limit of Normal 
LS 
Least Square 
MAOB-I 
Monoamine Oxidase B Inhibitor 
MDS-
UPDRS 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities  
MMRM 
Mixed Model for Repeated Measures 
MMSE 
Mini Mental State Examination  
NHMRC 
National Health and Medical Research Council 
PI 
Principal Investigator 
PD 
PDyn 
Parkinson’s Disease 
Pharmacodynamic 
PK 
Pharmacokinetic 
POD 
Precision Olfactory Delivery 
PPP 
Pharmaceutical Packaging Professionals 

 
 
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SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedures 
t½ 
Apparent Terminal Half-Life  
TEAE 
Treatment-Emergent AE 
TGA 
Australian Therapeutic Goods Administration 
Tmax 
Time to maximum plasma concentration 
TOEPH 
Heterogeneous Toeplitz Structure  
ULN 
Upper Limit of Normal 
w 
Weight 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 

 
 
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INP103-201 Clinical Study Protocol 
 
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PROTOCOL AUTHORISATION 
Title: 
A Phase IIa, Randomized, Double Blind, Placebo Controlled, Single 
Dose, Safety and Pharmacokinetic/Pharmacodynamic Study of 
INP103 (POD L-dopa) Administered in the Presence of 
Decarboxylase Inhibitor to L-dopa Responsive Parkinson’s Disease 
Patients  
Short Title: 
Therapeutic potential for intranasal levodopa in Parkinson’s Disease 
– OFF Reversal (THOR 201) 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational 
product, as well as with the moral, ethical, and scientific principles governing 
clinical research as set out in the current Declaration of Helsinki and the guidelines 
on Good Clinical Practice. 
 
 
 
 
 
 
 
 
 
 
 
 
Dr Stephen Shrewsbury, Sponsor’s Medical Monitor & 
Chief Medical Officer, Impel NeuroPharma 
 
Date 
 
 
 
	


 
 
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DECLARATION OF INVESTIGATORS 
Title: 
A Phase IIa, Randomized, Double Blind, Placebo Controlled, Single 
Dose, Safety and Pharmacokinetic/Pharmacodynamic Study of 
INP103 (POD L-dopa) Administered in the Presence of 
Decarboxylase Inhibitor to L-dopa Responsive Parkinson’s Disease 
Patients  
Short Title: 
Therapeutic potential for intranasal levodopa in Parkinson’s Disease 
– OFF Reversal (THOR 201) 
All documentation for this study that is supplied to me and that has not been 
previously published will be kept in the strictest confidence. This documentation 
includes this study protocol, Investigator's Brochure(s) (IB), Case Report Forms 
(eCRFs), and scientific data not in the public domain. 
The study will not be commenced without the prior written approval of a properly 
constituted Human Research Ethics Committee (HREC). No changes will be made to 
the study protocol without the prior written approval of the Sponsor and the Ethics 
Committee (EC), except where necessary to avert an immediate hazard to the 
subjects. 
I have read the protocol and agree that the study will be conducted in compliance 
with the protocol and in accordance with the principles of the current version of the 
Declaration of Helsinki (Ethical Principles for Medical Research Involving Human 
Subjects), and with the National Health and Medical Research Council (NHMRC) 
National Statement on Ethical Conduct in Human Research (2007, incorporating all 
updates as at May 2015). The study will be conducted in accordance with the Notes 
for Guidance on Good Clinical Practice (CPMP/ICH/135/95), as adopted by the 
Australian Therapeutic Goods Administration (2000). 
I acknowledge that I am responsible for the overall study conduct. I agree to 
personally conduct or supervise the described clinical study. I agree to ensure that 
all associates, colleagues and employees assisting in the conduct of the study at my 
site are informed about their obligations. Mechanisms are in place to ensure that site 
staff receive the appropriate information throughout the study. 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator Name  
 
Site 
 
Signature 
 
Date 
 

 
 
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FACILITIES AND PERSONNEL 
Sponsor Medical Monitor: 
Dr Stephen B. Shrewsbury MD 
Chief Medical Officer & Medical Monitor 
Impel NeuroPharma 
201 Elliott Ave W, Suite 260 
Seattle, 
WA  98119, United States 
+1 (415) 250-1169 
sshrewsbury@impelnp.com 
Protocol Advisory Board: 
Alexander Lehn MD, FRACP 
 
Mater Misericordiae Ltd 
Level 3, Aubigny Place,  
Raymond Terrace 
South Brisbane,  
QLD, 4101, Australia 
John O’Sullivan MB, BS, MD, FRACP 
 
Q-Pharm Pty. Ltd 
Level 5 CBCRC  300C Herston Rd,  
Herston, 
QLD 4006, Australia 
Terry O’Brien MB, BS, MD, FRACP, FRCPE, FAHMS, 
FAES 
 
Alfred Hospital Commercial Rd,  
Melbourne, 
VIC 3004, Australia 
Dr Rick Stell  
 
Perron Institute 
Ground Floor, RR Block,  
QEII Medical Centre,  
8 Verdun Street, Nedlands, WA, 6009 
 
CRO Medical Monitor/ 
Pharmacovigilance: 
Dr John D Gillies MB, ChB, FRCPC, FAAP, FRACP 
Medical Monitor 
Clinical Network Services (CNS) Ltd 
Level 2, 381 MacArthur Avenue 
Hamilton 
QLD, 4007, Australia 
+64 21 664 484 
Clinical Laboratory Facilities: 
Sydpath. St Vincent’s Pathology 
Level 6 Xavier Building 
St. Vincent’s Hospital 
Darlinghurst, 
NSW 2010, Australia 

 
 
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Bioanalytical Laboratory Facilities:  
AIT Bioscience 
7840 Innovation Boulevard 
Indianapolis,  
IN 46278, United States 
Project Management: 
Clinical Network Services (CNS) Pty Ltd 
Level 2, 381 MacArthur Avenue 
Hamilton 
QLD, 4007, Australia 
 
Biostatistical Analysis, Data Management 
and Monitoring: 
Clinical Network Services (CNS) Pty Ltd 
Level 2, 381 MacArthur Avenue 
Hamilton 
QLD, 4007, Australia 
 
 
 

 
 
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STUDY SYNOPSIS 
Protocol Title: 
A Phase IIa, Randomized, Double Blind, Placebo Controlled, 
Single Dose, Safety and Pharmacokinetic/ Pharmacodynamic 
Study of INP103 (POD L-dopa) Administered in the 
Presence of Decarboxylase Inhibitor to L-dopa Responsive 
Parkinson’s Disease Patients (THOR 201) 
Protocol Number: 
INP103-201 
Sponsor: 
Impel NeuroPharma 
201 Elliott Ave W, Suite 260 
Seattle, Washington 98119 
United States 
Australian Sponsor: 
Clinical Network Services (CNS)  
CRO: 
Clinical Network Services (CNS)  
Study Phase: 
Phase IIa 
Study Objective(s): 
Primary Objective: 
To compare the safety and tolerability of intranasal single 
doses of INP103 in the presence of decarboxylase inhibitor 
(DCI) to that of placebo in patients with Parkinson’s Disease 
(PD) during an OFF episode. 
Secondary Objectives: 
1. To characterize the pharmacokinetics (PK) of single 
doses of INP103  
2. To explore the effect of single doses of INP103 
versus placebo on motor function 
3. To explore the PK/PDyn relationship of single doses 
of INP103 and motor function 
Study Design: 
This is a Phase IIa randomized, double-blind, placebo 
controlled, single dose study to compare the safety, 
tolerability and PK/PDyn of intranasal L-dopa following 
administration of INP103 in the presence of L-dopa 
decarboxylase inhibitor (DCI) during an OFF episode. 
Screening Assessment 
Subjects will attend two pre-dosing visits: an initial 
Screening visit up to Day -21 (Visit 1), and a second 
screening visit (Visit 2), which may be repeated, between 
Day -20 and Day -1 (the day prior to Visit 3) during which 
dopaminergic responsiveness will be confirmed (see 
Screening Procedures below). 

 
 
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Randomization and Dosing 
Subjects will be instructed not to take their usual PD 
medication from 22:00 pm on Day -1 (the day prior to 
dosing).  
Subjects who arrive at the study site on Day 0 (or who were 
domiciled overnight) and are determined by the investigator 
to be in an ON state up to the scheduled time of dosing will 
not be dosed and will be excluded from further study 
participation. 
Subjects will be enrolled into one of four dose treatment 
cohorts with at least 8 subjects per cohort. All subjects in 
Cohorts 1, 2 and 3 will receive oral DCI, benserazide 
hydrochloride, 25 mg at 60 ± 5 minutes before dosing with 
INP103 or placebo. Subjects in Cohort 4 will receive the DCI 
as carbidopa at 1/10th the dose of, and with, L-dopa via the 
POD device. At the discretion of the Sponsor, depending on 
rate of recruitment, cohort 4 may be over enrolled with a 
total of up to 12 subjects using the 3:1 randomization 
scheme. On Day 0 (Visit 3), subjects in each cohort will be 
randomized to receive treatments as follows: 
Cohort 
Treatment (Study Drug) 
1 
INP103 35 mg L-dopa (n=6); Placebo (n=2) 
2 
INP103 70 mg L-dopa (n=6); Placebo (n=2) 
3 
INP103 140 mg L-dopa (n=6); Placebo (n=2) 
4 
 INP103 70 mg L-dopa/7.0 mg carbidopa (n=6, 
maximum 9); Placebo (n=2, maximum 3)  
Cohorts will be enrolled and dosed in sequence. Escalation 
to the next higher dose cohort (Cohorts 1 to 2 and 2 to 3) may 
only commence after review and approval of safety data by a 
Safety Monitoring Committee (SMC). Interim analysis of 
data will be conducted upon completion of Cohort 1 and 2 
study procedures, at the discretion of the Sponsor, 
depending on rate of recruitment. In this scenario, Cohort 1 
and 2 data will be soft-locked, patients may be unblinded 
and tables, listings, and figures of collected data will be 
produced. Unblinding of Cohort 1 and 2 data will not 
jeopardise blinding of any enrolled Cohort 3 or 4 subjects at 
the time of the interim analysis. 
Follow-up 
Subjects will be monitored for 7 days after administration of 
INP103 or placebo. All subjects will be observed as in-
patients for at least 240 minutes post-dosing. Follow-up 

 
 
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evaluations will occur 7 days after dosing. The SMC will 
have 7–14 days between dosing of Cohorts 1 and 2 and again 
between 2 and 3 to review safety data compiled by the site 
and contract research organization (CRO). 
Outcome Measures: 
Primary Endpoints: 
Safety and tolerability, including the assessment of physical 
examinations (including nasal inspection), 
electrocardiograms (ECGs), vital signs (including supine and 
standing blood pressure, all other vital signs supine only), 
clinical laboratory results, and adverse events (AEs; 
specifically, overall dyskinesia assessments over the 
immediate 240 minutes following dosing and over 7 days of 
follow-up.  
Secondary Endpoints: 
1. PK profile of L-dopa for 120 minutes following 
dosing with INP103 (AUC0-2h, Cmax and Tmax). 
2. Motor function, evaluated as: 
x 
Change from baseline to 30 minutes post-dose in 
MDS-UPDRS Part III score (primary motor 
function endpoint) 
x 
Change from baseline to 15, 30, 45, 60, 90 and 
120 minutes post-dose for C1, C2, C3 and change 
from baseline to 30, 60, 90, 120 minutes for C4, in 
MDS-UPDRS Part III score 
x 
Cumulative proportion of responders by post-
dose time point (15, 30, 45, 60, 90 and 120 
minutes for C1, C2, C3 and change from baseline 
to 30, 60, 90, 120 minutes for C4,), where 
response is defined as an improvement of 30% in 
MDS-UPDRS Part III score from baseline. 
x 
Time to response, where response is defined as 
an improvement of 30% in MDS-UPDRS Part III 
score from baseline  
x 
Duration of response, where response is defined 
as an improvement 30% in MDS-UPDRS Part III 
score from baseline 
x 
Area Under the Curve (AUC) of changes in 
MDS-UPDRS Part III scores from pre-dose at 15, 
30, 45, 60, 90 and 120 minutes for C1, C2, C3 and 
change from baseline to 30, 60, 90, 120 minutes 
for C4, 
x 
Maximum response in MDS-UPDRS Part III 
scores from pre-dose to 15, 30, 45, 60, 90 and 

 
 
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120 minutes for C1, C2, C3 and change from 
baseline to 30, 60, 90, 120 minutes for C4, 
x 
Subjective time to ON, as evaluated by the 
Investigator and by subject self-assessment 
3. The PK/PDyn relationship of single doses of INP103 
and motor function 
Investigational Products and 
Administration: 
INP103 is a drug-device combination product containing a 
drug component, L-dopa, and device component, the I231 
Precision Olfactory Delivery (POD) device. In Cohorts 1, 2, 
and 3, L-dopa will be administered intranasally in single 
doses of one (35 mg), two (70 mg) or four (140 mg) puffs of 
INP103, 60 minutes after oral benserazide hydrochloride 25 
mg. 
In Cohort 4 the INP103 formulation will contain L-
dopa:carbidopa in a 10:1 ratio (70 mg L-dopa and 7.0 mg 
carbidopa (2 capsules)). Dosing will take place once OFF 
episode is confirmed and will not include predosing with 
oral benserazide. 
Placebo is an inert, visually similar product without L-dopa 
or carbidopa (microcrystalline cellulose). 
Planned Subjects: 
At least 32 L-dopa responsive PD patients will be enrolled 
and randomized; 4 cohorts with at least 8 patients per cohort. 
At the discretion of the Sponsor, depending on rate of 
recruitment, cohort 4 may be over enrolled with a total of up 
to 12 subjects using the 3:1 randomization scheme. Subjects 
will not be replaced once dosed. Randomized subjects who 
have not been dosed may be replaced. 
Subjects may only be dosed in ONE cohort. 
Subject Selection Criteria: 
Inclusion Criteria: 
1. Adult males and females, 40 to 80 years of age 
(inclusive) at the time of Screening (Visit 1) 
2. Diagnosed with Idiopathic PD (by UK Brain Bank 
Criteria) with Modified Hoehn & Yahr (H&Y) 
Stage I-III during an ON period at Visit 1 
3. Subjects who are prone to (and recognize) OFF 
episodes (when their usual PD medication has worn 
off) 
4. Shown to be responsive to L-dopa medication (≥ 30% 
improvement in MDS-UPDRS Part III Motor 
Examination score) as assessed during the Screening 
period (Visit 2) 

 
 
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5. On a stable dose of L-dopa containing medication 
for at least 2 weeks prior to Visit 1 (up to 
1200 mg/day) with no single dose exceeding 250 mg. 
All other anti-PD medication (e.g. dopamine 
agonists [DAs], monoamine oxidase-B inhibitor 
(MAOB-I) or catechol-O-methyl transferase (COMT) 
inhibitors ARE allowed if the subject has been on a 
stable dose for at least 30 days prior to Visit 1. 
6. Willing to omit their (usual) PD drugs (e.g. usual 
regular anti-PD medication including any L-dopa 
containing medication, DAs and/or COMT inhibitors 
and any required anti-OFF treatment) from 22:00 pm 
the evening prior to study dosing until 120 minutes 
post study treatment dosing. 
Cohorts 1, 2 and 3 ONLY WILL take oral 
benserazide 25 mg on arrival at the research site (at 
60 ± 5 minutes before dosing with INP103 or 
placebo).  
Cohort 4 will omit oral benserazide and subjects 
may be dosed once OFF episode has been confirmed 
and all baseline assessments have been completed. 
7. If female and of childbearing potential must agree to 
use adequate contraception (see Section 4.4) during 
the study 
8. Able and willing to attend the necessary visits at the 
study centre 
9. Willing to provide voluntary written informed 
consent signed prior to entry into the study 
Exclusion Criteria: 
1. Severe dyskinesia (defined as per MDS-UPDRS) 
during a ‘normal day’ that would significantly 
interfere with the subject’s ability to perform study 
assessments 
2. In receipt of L-dopa containing medication at 
> 1200 mg/day 
3. History of significant psychotic episode(s) within the 
previous 12 months in the opinion of the 
Investigator, or currently receiving anti-psychotic 
medication at a moderate dose (quetiapine 
>50 mg/day, risperidone >1 mg/day or olanzapine 
>2.5 mg/day) 
4. Mini Mental State Examination (MMSE) ≤ 25 as 
documented within the previous 36 months or as 
assessed by Investigator during Screening 

 
 
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5. History of suicidal ideation or attempted suicide 
within previous 12 months 
6. Narrow-angle glaucoma 
7. Presence of skin lesions that, in the opinion of the 
Investigator, may be cancerous 
8. Females who are pregnant, planning a pregnancy or 
lactating  
9. Subjects with any underlying physical condition 
that, in the opinion of the Investigator, would make 
it unlikely that the subject will comply with or be 
able to complete the study requirements 
10. Use of any medication likely to interact with 
benserazide, carbidopa or INP103 (see Appendix 5) 
11. Laboratory test abnormalities at Screening (Visit 1) 
deemed clinically significant by the Investigator.  
12. History or presence of alcoholism or drug abuse 
within the 2 years prior to INP103 or placebo dosing 
13. Administration of an investigational product in 
another trial within 30 days or 5 half-lives 
(whichever is longer) prior to INP103 or placebo 
dosing 
14. Significant nasal congestion, physical blockage in 
either nostril, or significantly deviated nasal septum 
as evaluated by the PI or other suitably trained 
healthcare professional 
15. Subjects who have previously shown 
hypersensitivity to L-dopa or benserazide (for 
Cohorts 1, 2 and 3), or L-dopa or carbidopa (for 
Cohort 4) or any of their excipients 
 
 

 
 
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Treatment Groups: 
Subjects will receive one of the following treatments: 
All subjects in Cohorts 1, 2 and 3 will receive oral 
benserazide hydrochloride (benserazide) 25 mg at 
60 ± 5 minutes prior to INP103 or placebo dosing and time 
recorded. Cohorts 1, 2 and 3 will comprise eight subjects 
total; six subjects in receipt of INP103 (L-dopa via I231 POD 
Device) and two subjects placebo (via I231 POD Device).  
Cohort 4 will NOT receive oral benserazide. Cohort 4 will 
comprise of eight subjects; six subjects in receipt of INP103 
(L-dopa with carbidopa via I231 POD Device) and two 
subjects placebo (via I231 POD Device). At the discretion of 
the Sponsor, depending on rate of recruitment, cohort 4 may 
be over enrolled with a total of up to 12 subjects using the 3:1 
randomization scheme. 
Cohort 1 (INP103 35 mg L-dopa total or placebo as one spray 
to one nostril): Each subject in this cohort will receive one 
dose of INP103 or placebo delivered by one actuation of the 
device.  
Cohort 2 (INP103 70 mg L-dopa total or placebo as one spray 
to each nostril): Each subject in this cohort will receive one 
dose of INP103 or placebo delivered by two actuations of the 
device.  
Cohort 3 (INP103 140 mg L-dopa total or placebo as two 
sprays to each nostril): Each subject in this cohort will receive 
one dose of INP103 or placebo delivered by four actuations 
of the device.  
Cohort 4 (INP103 70 mg L-dopa/7.0 mg carbidopa total or 
placebo as one spray to each nostril): Each subject in this 
cohort will receive one dose of INP103 or placebo delivered 
by two actuations of the device, one to each nostril.  
At 120 minutes post study dosing, subjects should take their 
usual anti-OFF medication (e.g. Madopar rapid) if they have 
not returned to ON, and their usual morning dose of PD 
medications (e.g. their regular Madopar® or Sinemet® 
morning dose). Subjects will remain under observation for 
another 120 minutes before they can be allowed to leave 
(health status permitting). 
Escalation to Cohorts 2 and 3 may only commence after 
review and approval of safety data by a SMC (see Study 
Design, above) of Cohorts 1 and 2 respectively. There will be 
no SMC meeting between Cohorts 3 and 4 if there are no 
safety concerns raised by the SMC meetings occurring after 
Cohorts 1 and 2, since the dose of L-dopa and DCI in Cohort 
4 is less than Cohort 3. However, all usual safety monitoring 
will remain in place. 

 
 
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Screening Procedures: 
Screening assessments must be completed within 3 weeks of 
randomization into the study and will require two clinic 
visits to complete. At the first Screening visit (Visit 1, up to 
Day -21) subjects will be required to sign a consent form, 
after which the following initial Screening assessments will 
be conducted: 
x 
Review of medication and medical history 
x 
Review of inclusion and exclusion criteria 
x 
Measurement of height and weight 
x 
Recording demographic information 
x 
Full physical examination, including full MDS-
UPDRS (I to IV). 
x 
12-Lead ECG 
x 
Vital signs (blood pressure – both supine and 
standing; supine only heart rate, respiration rate 
and oral temperature) 
x 
Clinical laboratory testing (non-fasting 
haematology, serum chemistry and urinalysis)  
x 
Serum pregnancy test (in women of childbearing 
potential only [WOCBP]) 
x 
Follicle-Stimulating Hormone (FSH; in 
postmenopausal women only) 
The second Screening visit (Visit 2) is required to complete 
the Screening assessment for dopamine response. Subjects 
must return to the clinic between Day -20 and Day 0 (Visit 3). 
Subjects must discontinue their usual anti-PD medication 
from 22:00 the previous evening (i.e. Day -10 if attending 
Visit 2 on Day -9) and their usual morning (i.e. Day -9 if 
attending Visit 2 on Day -9) L-dopa dose (50–250 mg e.g. in 
Madopar® or Sinemet®) in order to have their OFF state 
confirmed and characterized.  
A full MDS-UPDRS (see Appendix 4) will be conducted 
upon arrival and used as the baseline result, after which the 
subject will then be allowed to receive their usual L-dopa-
containing medication (which may be combined with a 
decarboxylase inhibitor [DCI], if part of the subject’s usual 
PD treatment). The MDS-UPDRS III (motor examination) 
only assessment will be repeated at 15, 30, 45, 60, 90 and 
120 minutes post-dose thereafter for C1, C2, C3, and at 30, 60, 
90, and 120 minutes for C4, and time to ON assessed by 
physician and by subject self-assessment. 

 
 
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Subjects showing at least a 30% improvement in MDS-
UPDRS Part III score during Visit 2 will be deemed 
dopamine responsive and will be eligible to be randomized. 
The Visit 2 assessment may be repeated during the 20 day 
window for Visit 2 if the subject usually responds well 
(subjectively) to their usual dopaminergic OFF medication, 
but does not achieve at least a 30% improvement at their 
initial Visit 2 assessment. 
Randomization Procedure: 
At least thirty-two (32) (maximum 36) subjects will be 
randomized. All subjects in Cohorts 1, 2 and 3 will receive 
oral benserazide hydrochloride 25 mg 60 ± 5 minutes before 
study drug.  
Subjects in Cohort 4 will not receive the oral benserazide and 
may be dosed once OFF episode has been confirmed and all 
baseline assessments have been completed.  
Treatment assignment will be randomized 3:1 in each of 4 
dose cohorts of at least eight subjects total per cohort (Cohort 
4 may be allowed to enrol 12 subjects depending on rate of 
enrolment):  
x 
INP103 (n=6) (Cohorts 1, 2 and 3) or INP103 with 
carbidopa (n=6, max 9) (Cohort 4) 
x 
Placebo (n=2, or Cohort 4, n=2, max 3) 
 
 

 
 
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Study Assessments: 
Clinical: 
Medical history, AEs, concomitant medication use, height 
and weight, physical examination (including nasal 
inspection), periodic vital signs (blood pressure - both supine 
and standing; supine only heart rate, respiratory rate and 
temperature) and 12-lead ECGs. 
Laboratory: 
x 
Haematology  
x 
Serum chemistry 
x 
Urinalysis 
Pregnancy test for WOCBP:  A serum β-human chorionic 
gonadotropin (βHCG) will be performed at Screening 
(Visit 1) and a urine pregnancy test will be performed in 
clinic before dosing on Day 0 (Visit 3). 
FSH for postmenopausal women: A serum FSH test will be 
performed at Screening (Visit 1). 
Pharmacokinetics: 
Blood sampling for PK parameter calculation 
Pharmacodynamics: 
x 
MDS-UPDRS Full 
x 
MDS-UPDRS III 
x 
Time to ON as assessed by the physician and by 
subject self-assessment 
Safety and Tolerability 
Assessments: 
Specific assessments to evaluate treatment safety include the 
following: overall dyskinesia assessment, nasal inspection 
(as part of physical examinations), the frequency and type of 
AEs, concomitant medications (including any short acting 
anti-OFF medication, permissible only at/after 120 minutes 
post dosing on dosing days alongside the subject’s delayed 
usual anti-PD morning dose), clinical laboratory testing, 
12-lead ECGs and vital signs (to include supine and standing 
blood pressure, all other vital signs supine only). 
All treated subjects will be observed for 240 minutes post 
dose and will undergo follow-up evaluations (by 
appropriately trained/qualified staff) at Day 7.  
Pharmacokinetic Assessments: 
PK blood samples will be collected from an indwelling 
cannula positioned so that it does not interfere with arm 
movements within 15 minutes prior to dosing and at 4, 9, 14,  
29, 44, 59, 89 and 119 minutes after dosing (with INP103 or 
placebo). 

 
 
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Pharmacodynamics Assessments: 
A full MDS-UPDRS score will be conducted at the start of all 
visits. MDS-UPDRS III scoring and assessment of time to ON 
by the physician/subject will occur after usual ON 
medication taken at Visit 2, and following dosing at Visit 3 as 
shown in the Study Schedule.  
Statistical Analysis: 
At least thirty-two (32) subjects are considered sufficient for 
assessment of safety and tolerability of SADs of INP103. 
Furthermore, with 8 subjects per cohort, the study has 80% 
power to detect a difference in improvement of 13 points 
compared to placebo from pre-dose in MDS-UPDRS Part III 
scores within each dose level, assuming a standard deviation 
of 11 points. 
Safety Population: All subjects who receive any amount of 
INP103 or placebo will be included in the Safety Population. 
A pooled placebo group (of subjects from each of the five 
cohorts) will be used for comparisons. The data will be 
analysed according to the treatment actually received. 
PK Population: All subjects who receive any amount of 
INP103 or placebo and have sufficient samples collected for 
non-compartmental analysis of L-dopa will be included in 
the PK Population. The data will be analysed according to 
the treatment received.  
Intention-to-Treat (ITT) Population: All randomized 
subjects who have pre-dose and at least one post-dose 
assessment of motor function will be included in the ITT 
Population. A pooled placebo group (of subjects from each 
of the five cohorts) will be used for comparisons. The data 
will be analysed according to the randomized treatment 
group. 
Safety and Tolerability: 
Continuous safety data will be summarised with descriptive 
statistics (arithmetic mean, SD, median, minimum, and 
maximum) by treatment. Categorical safety data will be 
summarised with frequency counts and percentages by 
treatment. 
AEs will be coded using the most current Medical Dictionary 
for Regulatory Activities (MedDRA®) available at CNS. A 
by-subject AE data listing, including verbatim term, 
preferred term, system organ class, treatment, severity, and 
relationship to INP103 or placebo, will be provided. The 
number of subjects experiencing treatment emergent AEs 
(TEAEs) and number of individual TEAEs will be 
summarized by treatment, system organ class and preferred 
term. TEAEs will also be summarized by seriousness, 

 
 
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severity, relationship to INP103 or placebo and the time of 
onset relative to dosing. 
Dyskinesia assessment, nasal inspection, laboratory 
evaluations, vital signs assessments (including supine and 
standing blood pressure, all other vital signs supine only) 
and ECG parameters will be summarized by treatment and 
collection time point. A summary of change-from-baseline at 
each time-point by treatment will be presented. In addition, 
the proportion of subjects experiencing orthostatic 
hypotension or abnormal ECGs will be summarized by 
treatment group. 
Proportion of subjects with abnormal physical examination 
findings will be summarized by treatment group. 
Prior and concomitant medications will be listed by subject 
and coded using the most current World Health 
Organization (WHO) drug dictionary and summarized by 
therapeutic class (Level 4 for anti-PD medications and Level 
2 for other medications) and preferred name. 
Medical history will be listed by subject. 
Pharmacokinetics: 
L-dopa concentrations will be summarized with descriptive 
statistics (arithmetic and geometric mean, SD, median, 
minimum, and maximum) by treatment group and time 
point. In addition, PK parameters (AUC0-0.5h, AUC0-1h AUC0-
2h, Cmax, Tmax) will be summarized with descriptive statistics 
by treatment group. 
Pharmacodynamics: 
Changes from baseline at Visit 3 in MDS-UPDRS Part III 
scores will be estimated using a Mixed Model for Repeated 
Measures (MMRM) with treatment group (INP103 35 mg L-
dopa, INP103 70 mg L-dopa, INP103 140 mg L-dopa,,  
INP103 70 mg/7.0 mg L-dopa: carbidopa , or placebo), time 
point (15, 30, 45, 60, 90 or 120 minutes in C1, C2, C3, and at 
30, 60, 90, or 120 minutes in C4) and the interaction between 
treatment group and time point as fixed factors. The pre-
dose score will be included as a covariate. The focus will be 
in the estimation of changes within each treatment group. 
The cumulative proportion of responders will be 
summarized descriptively by treatment group and time 
point. The endpoint related to time of response and time to 
ON will be evaluated with Kaplan-Meier methods. The 
duration of response will be summarized by treatment 
group. The AUC and individual maximum response from 
pre-dose to 15, 30, 45, 60, 90 and 120 minutes in C1, C2, C3, 
and at 30, 60, 90, or 120 minutes in C4 will be analysed with 

 
 
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an Analysis of Covariance (ANCOVA) model with treatment 
group as a fixed factor and pre-dose MDS-UPDRS Part III 
score as a covariate.  
Pharmacokinetic/Pharmacodynamics relationship: 
The analyses required to investigate the PK/PDyn 
relationship of INP103 will be defined in the Statistical 
Analysis Plan (SAP) which will be completed before the 
database is locked. 
Study Duration: 
Up to 28 days per subject from Screening (Visit 1) to follow-
up (Visit 4) 
 

 
 
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STUDY SCHEDULE 
Table 1:  Study Schedule 
Visit 
1 
2 
3 
4 
Day 
Up to -21 
Up to -20 
to -1 
-1 
0 
7 
Window 
N/A 
N/A 
N/A 
See Footnotes (and Section 7.4.3) 
± 10 mins 
± 2 daysa 
Time (min) 
 
 
 
Pre-dose 
0 
5 
10 
15 
30 
45 
60 
90 
120 
240 
 
Visit  
Screening 
Dopamine 
response 
Treatment 
Follow-
up 
Domiciled b 
 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Discharged 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
MMSEm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of Eligibility 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs d 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
12-lead ECG d 
X 
 
 
X 
 
 
 
 
 
 
 
 
Xd 
 
X 

 
 
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Visit 
1 
2 
3 
4 
Day 
Up to -21 
Up to -20 
to -1 
-1 
0 
7 
Window 
N/A 
N/A 
N/A 
See Footnotes (and Section 7.4.3) 
± 10 mins 
± 2 daysa 
Time (min) 
 
 
 
Pre-dose 
0 
5 
10 
15 
30 
45 
60 
90 
120 
240 
 
Visit  
Screening 
Dopamine 
response 
Treatment 
Follow-
up 
Physical Examination e 
X 
 
 
X 
 
 
 
 
 
 
 
 
Xe 
 
X 
Laboratory assessments 
(haem/serum chemistry) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis (dipstick and 
microscopy if abnormal) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Serum Pregnancy Test 
(WOCBP only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
(WOCBP only) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
FSH (Post-menopausal 
women only 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COHORTS 1, 2 & 3 
ONLY: 
Administration of 
benserazide 25 mg 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
INP103/placebo 
Administration g 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Pre-treatment 
(INP103/placebo) AEs 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Visit 
1 
2 
3 
4 
Day 
Up to -21 
Up to -20 
to -1 
-1 
0 
7 
Window 
N/A 
N/A 
N/A 
See Footnotes (and Section 7.4.3) 
± 10 mins 
± 2 daysa 
Time (min) 
 
 
 
Pre-dose 
0 
5 
10 
15 
30 
45 
60 
90 
120 
240 
 
Visit  
Screening 
Dopamine 
response 
Treatment 
Follow-
up 
AEs  
 
 
 
 
CONTINUOUS 
Rate dyskinesias 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
Nasal examination  
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Evaluation of ON/OFF 
(Investigator and self-
assessment) 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Rescue OFF Tx allowed  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Usual morning anti-PD 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
MDS-UPDRS Fullh 
X 
Xh 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
MDS-UPDRS (III) motor 
(Cohorts 1 through 3)  
 
Xi 
 
 
 
 
 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
 
 
MDS-UPDRS (III) motor 
(Cohort 4)  
 
Xi 
 
 
 
 
 
 
Xj 
 
Xj 
Xj 
Xj 
 
 
Prior and Concomitant 
Medications 
X 
 
 
X 
 
CONTINUOUS 
Subject Questionnaire k 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Light Breakfast Offered  
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Visit 
1 
2 
3 
4 
Day 
Up to -21 
Up to -20 
to -1 
-1 
0 
7 
Window 
N/A 
N/A 
N/A 
See Footnotes (and Section 7.4.3) 
± 10 mins 
± 2 daysa 
Time (min) 
 
 
 
Pre-dose 
0 
5 
10 
15 
30 
45 
60 
90 
120 
240 
 
Visit  
Screening 
Dopamine 
response 
Treatment 
Follow-
up 
PK Blood Collection l 
(Cohorts 1 through 3) 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
PK Blood Collection l 
(Cohort 4)  
Collected 1 minute prior 
to timepoint 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a A +4 day window may be permitted in exceptional circumstances. 
 b Prior to V2 and/or V3, subjects may attend the unit the previous evening and be domiciled overnight to allow early morning confirmation of their OFF state and facilitate 
scheduling of pre and post dosing procedures. Subjects not attending the unit the previous evening will arrive on Day 0. 
c Randomization may be performed on the day of dosing (Day 0) or the evening before (Day -1) for subjects being housed overnight prior to dosing. 
d  Subjects should be rested in a recumbent position for ≥ 3 minutes prior to recording of ECGs. Subjects should be supine for at least 3 minutes prior to determination of 
supine vital signs (including blood pressure), after which they should stand and have only standing blood pressure measured immediately. Staff should be on hand to 
support subjects if required. ECGs and vital signs should be assessed after UPDRS assessment and PK blood draws. Sites may follow their usual sequence of procedures for 
recording vital signs and ECG where they occur together. The window allotted for vital signs will be +15 minutes at the 30 and 60 minute post-dose timepoints. The vital 
signs and ECG collection at 120 minutes may occur up to 180 minutes. Due to variability in assessment length, assessments collected out of window, with the exception of 
PK samples and UPDRS, will not be considered deviations.  
e Complete physical examinations (including nasal examination) should be conducted at Screening, Day 0 (pre-dose only) and end of study visits. A directed physical 
examination will be conducted at 120 minutes post-dose at Visit 3 only and may occur up to 180 minutes. 
f 60 ±5 minutes pre-INP103 or placebo administration in Cohorts 1, 2 and 3 only. 
g Subjects will be randomized to INP103 (35, 70 or 140 mg; n=6 to each dose) or placebo (n=2) in each of Cohorts 1, 2 and 3 and to INP103 with carbidopa (70 mg L-dopa/7.0 
mg carbidopa; n=6) or placebo (n=2) in Cohorts 4. At the discretion of the Sponsor, depending on rate of recruitment, cohort 4 may be over enrolled with a total of up to 12 
subjects using the 3:1 randomization scheme. In Cohort 4, dosing may commence as soon as OFF state has been confirmed and all baseline assessments have been 
completed and will not include oral benserazide. 

 
 
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h Full MDS-UPDRS (Parts I-IV) will be assessed on arrival at clinic for dopaminergic responsiveness assessment at Visit 2 during Screening. Subjects will omit their usual anti 
PD therapy from 22:00 the previous evening and should arrive at the clinic in an OFF state. 
i Once a full MDS-UPDRS assessment has been undertaken, subjects will take their usual ‘ON’ medication and repeat only the MDS-UPDRS Part III (motor) assessment at 
+15, +30, +45, +60, +90 and +120 minutes for C1, C2, C3, and +30, +60, +90, and +120 for C4. Subjects demonstrating a 30% improvement in MDS-UPDRS Part III (motor 
assessment) within the 120 min will be deemed dopamine responsive and will be eligible for randomization. 
j MDS-UPDRS Part III is assessed after PK blood draws and actual time will be recorded (time from dosing to START of assessment).  
k Subject Questionnaire may be administered from 120 minutes up to 180 minutes to allow other study assessments to occur first.  
l Baseline PK samples will be taken within 15 minutes prior to dosing. For Cohorts 1-3; the time window for blood sample collection is ± 5 minutes for the samples through 
120 minutes. Actual time samples taken will be used for PK analysis. PK blood draws will occur AS SOON AFTER MDS-UPDRS Part III assessments as possible (even if 
outside of the ± 5 minute window) and time noted. FOR COHORT 4 ONLY: PK sample collection will occur 1 minute prior to the timepoint (samples will be collected at 4, 
9, 14, 29, 44, 59, 89, and 119 minutes post-dose). For Cohort 4; the window for blood sample collection is up to +1 minute for timepoints 5 minutes up through 30 minutes 
and ±2 minutes for timepoints 45 minutes through 120. PK blood draws will occur IMMEDIATELY PRIOR TO MDS-UPDRS Part III assessments as possible (even if outside 
of the time window) and time noted. 
m Only required if no documented history of an MMSE within 36 months prior to Screening. 
n A light breakfast should be offered to the patient 30 minutes prior to dosing; see section 4.7. 
 
 

 
 
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1. 
BACKGROUND AND INTRODUCTION 
1.1. 
Introduction 
The purpose of this study is to evaluate the INP103 drug-device combination 
product specifically as it pertains to the intranasal administration of L-dopa 
(levodopa; L-3,4-dihydroxyphenylalanine) to the upper nasal cavity using the I231 
Precision Olfactory Delivery (POD) device. L-dopa is the immediate metabolic 
precursor to the neurotransmitter dopamine; following crossing of the blood brain 
barrier, in a healthy brain, exogenous L-dopa is rapidly converted to dopamine. 
Dopamine itself cannot cross the blood brain barrier. Levodopa is given in 
combination with a decarboxylase inhibitor (DCI), which is either benserazide (in the 
brand Madopar®) or carbidopa (in Sinemet®) to ensure the L-dopa is not 
metabolized in the periphery before it can cross into the brain. INP103 is an 
experimental nasal L-dopa product. In Cohorts 1, 2, and 3 of this study, the DCI 
benserazide will be delivered orally 60 minutes before intranasal dosing with 
INP103. In Cohort 4, the INP103 formulation will contain the DCI, carbidopa, in a 
w:w ratio of 10:1 (L-dopa:carbidopa, the lowest ratio for oral co-administration) and 
will not require pre-treatment with an oral DCI. Neither DCI has any 
pharmacological activity other than to inhibit dopa decarboxylase. Cohort 4 will 
receive the same dose of L-dopa as in Cohort 2 and lower DCI levels than the orally 
administered benserazide. 
PD is a degenerative disorder of the central nervous system characterised by 
involuntary muscle movements (dyskinesias, including tremors), rigidity, slowness 
of movement and potential cognitive impairment. Motor symptoms are linked with 
depleted dopamine in the basal ganglia. As such, the first line of therapy in the 
management of PD is administration of L-dopa, which was first investigated in 
1961 (1).  
Use of L-dopa is long established, but a number of limitations persist, namely:  
x Penetration of L-dopa into the brain is limited by the presence of L-dopa 
decarboxylase and monoamine oxidase within the capillary endothelial 
cells. Together these form an enzymatic blood-brain barrier that limits 
passage of L-dopa into the brain.  
x Systemic L-dopa that does not pass the blood brain barrier causes side 
effects in the peripheral nervous system requiring co-administration of a 
L-amino acid decarboxylase inhibitor (DCI; typically, benserazide or 
carbidopa in combination with L-dopa).  
x Lastly, a progressive decline in L-dopa responsiveness occurs that leads to 
switches between mobility and immobility (ON and OFF periods, 
respectively) in L-dopa-treated patients. These ON/OFF oscillations have 

 
 
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been reported in at least 50% of PD patients who have been receiving 
L-dopa for 5–10 years and constitute a major cause of disability in 
advanced PD.  
Impel’s INP103 drug-device combination product is designed to deliver drugs (in 
this case L-dopa with or without DCI) to the upper nasal cavity. This region of the 
nasal cavity has many advantages for drug delivery. Administering drugs to the 
upper nasal cavity may reduce the overall variability and improve bioavailability by 
minimizing the amount of drug that drips out of the nose or runs into the posterior 
pharynx after nasal administration. In addition, the upper nasal cavity is highly 
vascularized for rapid drug absorption into the plasma. The upper nasal cavity is the 
only region of the body that has direct connections to the central nervous system via 
the olfactory and trigeminal nerve routes (2). Therefore, administration of central 
nervous system drugs to this region of the nasal cavity may lead to direct uptake 
into the brain. All of these factors make the upper nasal cavity a desirable route of 
administration for central nervous system-targeted drugs.  
Impel has been developing both an INP103 levodopa-only formulation that would 
need to be administered in the presence of an oral DCI, and a variation of the INP103 
formulation containing carbidopa to obviate the need for an oral DCI to be 
administered 60 minutes before dosing. Both DCIs to be used in this study are 
approved for use in Australia. 
INP103 is anticipated to rapidly deliver L-dopa, the dopamine precursor, to the 
brain via the vasculature and potentially the direct nose-to-brain pathway, thereby 
permitting rapid and efficient resolution of OFF periods in subjects in receipt of oral 
L-dopa. The present study is a proof of concept investigation of the INP103 drug-
device combination product incorporating the nasal delivery of L-dopa (with or 
without carbidopa) by the I231 POD Device. 
1.2. 
Summary of Non-Clinical and Clinical Studies 
1.2.1. 
Non-Clinical Studies 
Oral L-dopa has been extensively used in the treatment of PD and is supported by a 
literature evidence base. A review of literature is provided in the Investigator’s 
Brochure. In addition, Impel NeuroPharma has performed the following studies: 
x Six studies in the cynomolgus monkey examined the PK of powder 
L-dopa formulations, including two studies testing L-dopa formulations 
containing carbidopa, using a non-human primate version of the clinical 
POD Device (nhpPOD). The dose of L-dopa per nasal surface area varied 
from approximately 0.5 to 1.2 mg/cm2, similar to the local nasal 
concentrations estimated to be achieved clinically (0.4375–0.875 mg/cm2) 
following doses of 35–140 mg L-dopa to the nose. No clinical observations 
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 Study 1: Following intranasal administration of unmodified crystalline 
L-dopa (of particle size D50 = 50 μm) in the absence of benserazide, 
dose-dependent PK was shown (10-40 mg dose range). The Cmax 
following 40 mg L-dopa administration was 150 ng/mL, and the Tmax 
was delayed, showing an average of ≥75 minutes. A smaller particle 
size (20-40 μm) crystalline L-dopa material was also tested and 
indicated a higher exposure compared to an equivalent dose of an 
unmodified L-dopa formulation.  
 Study 2: The PK of intranasal L-dopa in combination with oral 
benserazide was explored (4 x 5mg administered over 24hr predose), 
demonstrating similar PK across four L-dopa formulations containing 
crystalline particle size sifted L-dopa (20-40 μm), spray dried L-dopa 
only (particle size D50 10-30 μm), spray dried L-dopa with sodium 
chloride (L-dopa:NaCl) and spray dried L-dopa with sodium chloride 
and HPMC (L-dopa:HPMC:NaCl). Cmax concentrations of >900 ng/mL 
were achieved following a dose of 20 mg (10 mg/nostril) of each 
formulation, which is above the threshold necessary for efficacy of OFF 
episode treatment. Cmax was approximately 10-fold higher in the 
presence of benserazide. Median Tmax was 45 to 60 minutes, an 
improvement over the Tmax observed in the absence of benserazide.  
 Study 3: A third study in the monkey explored the PK of intranasal 
L-dopa in a further five spray dried formulations in combination with 
oral benserazide (see below). All formulations achieved similar or up 
to 1.7-fold greater total exposure (AUC) and up to 2.3-fold increased 
Cmax compared to spray dried formulations tested in the second PK 
study. Median Tmax (53–105 minutes) for Groups 1, 2, 3 and 5 was 
similar or greater than Tmax in the second study. Tmax for Group 4 was 
significantly faster (median 30 minutes, with all four monkeys 
achieving >400 ng/mL L-dopa within 7 minutes of dosing). Since the 
product is intended to achieve plasma concentrations of L-dopa 
(>400 ng/mL) sufficient to rapidly switch a patient from OFF to ON, the 
maltoside-containing formulation was selected for testing in the 
proposed clinical study.     
Group 1: L-dopa:NaCl:HPMC:DSPC (68:2:16:14)  
Group 2: L-dopa:NaCl:HPMC:DSPC (68:2:23:7) 
Group 3: L-dopa:NaCl:HPMC:DSPC (68:2:23:7, minor manufacturing change 
compared to Group 2) 
Group 4: L-dopa:NaCl:HPMC:Maltoside (68:2:23:7) 
Groups 1 to 4 received pre-treatment with benserazide at -24, -16, -8 hours and -45 
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Group 5: L-dopa:NaCl:benserazide:HPMC:DSPC (68:2:7:16:7), pre-treated with 
benserazide at -24, -16 and -8 hours 
 Study 4: A fourth study determined PK of intranasal L-dopa in five 
spray dried formulations with a reduced concentration of maltoside 
(1% w/w) in combination with oral benserazide. All formulations 
contained 68% L-dopa and 2% NaCl; three formulations included 
29% w/w HPMC and 1% w/w maltoside (prepared by small 
modifications of the spray drying process) and two formulations 
contained 29.9% w/w HPMC with 0.1%  w/w maltoside or 29.5% 
HPMC with 0.5% w/w maltoside. Each group (N=4) received four oral 
5 mg benserazide pre-treatments at -24, -16, -8 and -0.75 hours before 
L-dopa formulation delivery by the nhpPOD Device. All formulations 
tested achieved similar AUC and Cmax levels compared to the third 
monkey PK study. Compared to the formulation in the third monkey 
PK study containing 7% maltoside, median Tmax was slightly delayed 
(<2.3-fold, range 37.5-68 minutes across all groups compared to 
30 minutes). However, while Tmax was slightly delayed, individual 
plasma levels following the Group 3 formulation (29% HPMC with 1% 
maltoside) increased rapidly and more consistently to achieve levels 
>400 ng/mL L-dopa within 15 minutes. This formulation was selected 
for GMP manufacture and for inclusion in the proposed clinical study. 
 Study 5: A PK and safety study of the nasal administration of L-dopa 
powder formulation containing carbidopa (Study 2037-017, N=20), in 
the absence of an orally administered DCI, demonstrated plasma 
exposures similar to the above referenced monkey PK studies (2037-
003, 2037-004, 2037-006, 2037-007) where formulations of levodopa 
were nasally administered after administration of an oral DCI 
(benserazide). Maximum plasma concentration (Cmax) of 560 ng/mL -
1,608 ng/ml were achieved following 20 mg L-dopa administration 
with median Tmax between 38-68 minutes. The group receiving a 
formula the same as the formula to be used in Cohorts 4-5 (BG54-126; 
levodopa: carbidopa: HPMC: maltoside:NaCl (68: 6.8: 22.2: 1: 2) 
resulted in an AUC of 149,941 r 22,112 ng*min/ml, a Cmax of 1,608 r 198 
pg/ml, and a Tmax of 53 minutes. These values are similar to the 
levodopa alone formulation administered in the above reference 
monkey study 2037-007 in which a formula representative of that being 
used in Cohorts 1-3 of the clinical study resulted in an AUC of 92,404 r 
18,094 ng*min/ml, a Cmax of 1,310 r 413 pg/ml, and a Tmax of 53 minutes. 
- 
Study 6: A PK and safety study in monkey (Study 2037-019, N=20) was 
conducted to explore the PK of nasal administration of L-dopa with the 
DCI carbidopa present in the formulation, in a ratio of either 1:4, 1:10, 
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safety and plasma exposure of different ratios of carbidopa in the 
formulation. This study resulted in similar plasma exposures to the 
previous study (2037-017) with Cmax values between 899 – 1,167 
ng*min/ml and Tmax between 45 – 60 minutes. There were no clinical 
signs of intolerance or safety signals observed in the study.  
In all six studies, detailed clinical observations of each animal were performed 
pretest and at various intervals post dosing ranging from 15 minutes up to 
120 minutes after dosing. The clinical observations included, but were not limited to, 
evaluation of the nose, oral cavity, skin, fur, eyes, ears, thorax, abdomen, external 
genitalia, limbs and feet, respiratory and circulatory effects, autonomic effects such 
as salivation, and nervous system effects. No observations were made indicating an 
issue with tolerability or irritation from the intranasal formulation to be used in the 
clinical trial.  
 
1.2.2. 
Clinical Studies 
This is the first Impel sponsored clinical study using INP103.  
1.3. 
Summary of Potential Risks and Benefits 
The risk/benefit profile of L-dopa in combination with benserazide is well known 
and is described in the Madopar® prescribing information. Similarly, the risk/benefit 
profile of L-dopa plus carbidopa is well described in the Sinemet® prescribing 
information. Inhaled formulations of L-dopa have previously undergone clinical 
investigation and have shown benefit in reversing OFF episodes. However, this is 
the first investigation of L-dopa using Impel’s proprietary POD Device technology, 
which is specifically designed to target delivery of a drug product to the upper nasal 
space. In addition, drug formulation and nonclinical work has shown beneficial PK 
effects of co-administration of carbidopa with levodopa when given by POD to 
primates, suggesting that PD patients may experience enhanced benefit by 
administering the L-dopa with carbidopa nasally compared to giving the DCI orally 
and L-dopa only by POD. 
Oral formulations of L-dopa are combined with carbidopa or benserazide to prevent 
L-dopa from being rapidly destroyed by the ubiquitous epithelial decarboxylase. By 
changing the route of administration from oral to intranasal, the administration of 
INP103 is anticipated to improve the benefit: risk profile of L-dopa by increasing 
L-dopa penetration of the blood brain barrier and decreasing systemic L-dopa. 
Nonetheless, inhibition of the nasal epithelial decarboxylase in primates (oral 
benserazide) continues to lead to much higher levels of L-dopa after intranasal 
dosing compared to primates receiving the same dose of intranasal L-dopa without 
benserazide. While all subjects in the present study will be required to suspend use 
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demonstrating proof of concept, subjects in Cohorts 1, 2 and 3 will still receive a 
single dose of oral benserazide 25 mg at 60 ± 5 minutes prior to dosing. Subjects in 
Cohort 4 receiving the combined L-dopa/carbidopa formulation will NOT receive 
oral benserazide, but will be dosed with INP103 containing carbidopa (or placebo) as 
soon as their OFF episode has been confirmed and all baseline assessments have 
been completed. All subjects will be permitted to resume use of their usual PD 
medication (usual morning dose as standard and rescue therapy if required) from 
120 minutes post-dosing.  
INP103 is designed to intranasally deliver a dry powder formulation of L-dopa with 
or without carbidopa.  
To date, there are no known risks of using the I231 POD Device. Nasal inspection 
will be conducted throughout the present study. 
INP103 is anticipated to have a favourable risk benefit ratio given the anticipated 
benefit of rapid delivery of L-dopa to and across the blood brain barrier for subjects 
experiencing an OFF episode, and the requirement of rapid resolution of OFF 
episodes in patients on steady L-dopa-containing medications who encounter 
regular OFF episodes. Given the anticipated favourable risk benefit ratio for INP103, 
and the ready availability of their usual oral L-dopa containing medication (120 
minutes post-dosing) during the study for patients who do not respond to INP103, 
the study is considered to have a favourable risk benefit ratio. 
 
1.4. 
Dosage and Treatment Periods 
Dosage will be in five placebo-controlled cohorts:  
Cohort 
Treatment (Study Drug) 
1 
INP103 35 mg L-dopa (n=6); (1 POD actuation) or Placebo (n=2) 
2 
INP103 70 mg L-dopa (n=6); (2 POD actuations) or Placebo (n=2) 
3 
INP103 140 mg L-dopa (n=6); (4 POD actuations) or Placebo (n=2) 
4 
INP103 70 mg L-dopa/7.0 mg carbidopa (n=6, maximum 9) (2 POD actuations) or 
Placebo (n=2, maximum 3) 
In the proposed clinical study, patients are to receive a single dose only, and thus 
any potential irritancy is expected to be minimal, transient and reversible.  
1.5. 
Study Population 
This study will be conducted in PD patients who are responsive to L-dopa and who 
meet all of the inclusion criteria and none of the exclusion criteria. Safety, 
tolerability, PK and PDyn parameters will be assessed. 

 
 
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1.6. 
Ethical Principles 
This study will be conducted in accordance with the principles of the current 
Declaration of Helsinki (Ethical Principles for Medical Research Involving Human 
Subjects), and with the National Health and Medical Research Council (NHMRC) 
National Statement on Ethical Conduct in Human Research (2007, incorporating all 
updates as at May 2015). The conduct of the study will be in accordance with the 
Notes for Guidance on Good Clinical Practice (GCP; CPMP/ICH/135/95) established 
from the International Conference on Harmonization guidelines and adopted by the 
Australian Therapeutic Goods Administration (2000). 
This study will be conducted under a protocol reviewed and approved by an EC 
responsible for each site and investigations will be undertaken by scientifically and 
medically qualified persons; where the benefits of the study are in proportion to the 
risks. The study will be overseen by a Principal Investigator (PI) who, prior to study 
start, will have read and agreed understanding of the protocol requirements and will 
agree to conduct the study in accordance with the above.

 
 
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2. 
OBJECTIVES 
2.1. 
Primary Objectives 
The primary objective of the study is: 
x To compare the safety and tolerability of intranasal single doses of INP103 
in the presence of a DCI with PD during an OFF episode 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
1. To characterize the PK of single doses of INP103  
2. To explore the effect of single doses of INP103 versus placebo on motor 
function 
3. To explore the PK/PDyn relationship of single doses of INP103 and motor 
function 
 

 
 
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3. 
STUDY DESIGN 
This is a Phase IIa randomized, double-blind, placebo controlled study to compare 
the safety and PK/PDyn of L-dopa following administration of INP103 in the 
presence of a DCI to that of placebo to PD patients during an OFF episode. See 
Figure 1 for a study design flow chart. 
Subjects will attend a Screening visit up to Day -21 (Visit 1). During the maximum 
21-day window between Screening and study dosing (i.e. between Visit 1 and Visit 
3), subjects deemed eligible from Visit 1 assessments will be invited to attend a 
second Screening visit (Visit 2) to the clinical unit to confirm dopaminergic 
responsiveness. For Visit 2, subjects will discontinue all PD medication from 22:00 
the previous evening (i.e. Day -10 if attending Visit 2 on Day -9). At the discretion of 
sites, patients may be domiciled overnight for this visit. In addition, subjects will 
miss their usual morning) L-dopa dose (50–250 mg). Missed morning dose will 
include missed DCI if a DCI (such as benserazide if Madopar, or carbidopa if 
Sinemet) comprises the subject’s usual PD medication. At the start of Visit 2, the 
subject will have their OFF state confirmed and characterised using the full 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 
scale. The subject will then take their usual L-dopa containing medication (including 
DCI if part of the subject’s usual PD medication) and repeat the MDS-UPDRS Part III 
test (motor examination) at 15, 30, 45, 60, 90 and 120 minutes thereafter for C1, C2, 
C3, and at 30, 60, 90 and 120 minutes for C4. Subjects showing at least a 30% 
improvement in MDS-UPDRS Part III score during this visit will be deemed to be 
dopamine responsive and will be eligible to be randomized and return for Visit 3 on 
Day 0. 
If subjects usually obtain a satisfactory response to their OFF treatment (in their 
opinion), but fail to do so on Visit 2, the Investigator is allowed to repeat the Visit 2 
response assessment within the screening period to determine if a more 
representative response (i.e. >30% improvement in MDS-UPDRS score) can be 
obtained. 
Subjects may be domiciled at the clinic overnight to enable scheduled assessments 
on the morning of, and prior to, Visit 2 (standard medications) and Visit 3 (test 
article) dosing, or will have transport provided to ensure they arrive at the clinical 
research unit on the morning of Visit 2 and Visit 3. Regardless of time of arrival at 
the study site, all subjects will be required to suspend dosing of usual PD medication 
(e.g. regular Madopar® or Sinemet® doses, DAs and/or COMT inhibitors doses and 
any required anti-OFF medication [e.g. Madopar rapid]) from 22:00 pm on Day -1, 
the day prior to study dosing. Suspension of usual PD medication will include on 
the morning of Day 0.  

 
 
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On Day 0, upon arrival at the research site (or upon waking if the subject was 
domiciled overnight at the research unit), and at 60 ± 5 minutes before dosing with 
INP103 or placebo, all subjects in Cohorts 1, 2, and 3 will take oral benserazide 
hydrochloride (benserazide) 25 mg (provided by the Sponsor). Subjects in Cohort 4 
will NOT receive oral benserazide. Subjects who arrive at the study site on Day 0 (or 
who were domiciled overnight) and are determined by the Investigator to be in an 
ON state up to the scheduled time of dosing will not be dosed and will be excluded 
from further study participation but may be replaced at Sponsor’s discretion. 
On their scheduled day of dosing (Day 0; or on arrival at the unit on Day -1), eight 
subjects in each of three dose cohorts (35, 70 or 140 mg of INP103 L-dopa) and at 
least eight (8) (maximum 12) subjects in Cohort 4 (70/7.0 mg of INP103 L-
dopa:carbidopa) will be randomized in a 3:1 fashion to one of two treatment arms. 
All subjects in Cohorts 1, 2 and 3 will receive oral benserazide 25 mg 60 ± 5 minutes 
before dosing with the study drug. Subjects in Cohort 4 will not receive oral 
benserazide before dosing with the study drug: 
x INP103 (n=6 or maximum 9 in Cohort 4)  
x Placebo (n=2 or maximum 3 in Cohort 4) 
Use of usual anti-PD medication (usual regular dosing [e.g. regular Madopar or 
Sinemet] and use of anti-OFF treatment, if required) may resume at 120 minutes 
after use of INP103 or placebo. 
Subjects will be monitored for 7 days after the final administration of INP103 or 
placebo. All subjects will be observed as in-patients for at least 240 minutes post-
dosing at visit 3. Follow-up evaluations will occur 7 days after dosing. 
Once dosing has been completed (for all subjects) in a cohort, data will be collected 
through to 7 days post dosing (Visit 4, follow-up). This data will then be reviewed by 
a Safety Monitoring Committee (SMC) for cohorts 1 and 2 only, and if no INP103 or 
placebo-related serious adverse events (SAEs) or severe AEs have been reported, 
dosing may commence in the next cohort. The SMC will have 7-14 days between 
dosing of cohorts to review safety and available PK data compiled by the site and the 
biostatistics analysis provider. 
Interim analysis of data will be conducted upon completion of Cohort 1 and 2 study 
procedures, at the discretion of the Sponsor, depending on rate of recruitment. In 
this scenario, Cohort 1 and 2 data will be soft-locked, treatment assignment will be 
unblinded (limited to CNS staff; Impel staff will remain blinded) and tables, listings 
and figures of selected collected data will be produced. Unblinding of Cohort 1 and 2 
data will not jeopardise blinding of any enrolled Cohort 3 (or subsequent Cohort) 
subjects at the time of the interim analysis. 
 

 
 
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Figure 1: 
Study Design 

 
 
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3.1. 
Primary Endpoints 
Safety and tolerability, including the assessment of physical examinations (including 
nasal inspection), electrocardiograms (ECGs), vital signs (including supine and 
standing blood pressure, all other vital signs supine only), clinical laboratory results, 
and AEs (specifically, levodopa induced dyskinesia assessment, see Section 6.4.2) 
over the immediate 240 minutes following dosing and over 7 days of follow-up. 
3.2. 
Secondary Endpoints 
1. PK profile of L-dopa (and carbidopa in Cohort 4) for 120 minutes following 
dosing (AUC0-2h, Cmax and Tmax) 
2. Motor function, evaluated as: 
x Change from baseline to 30 minutes post-dose in MDS-UPDRS Part III 
score (primary motor function endpoint)  
x Change from baseline to 15, 45, 60, 90, and 120 minutes post-dose in 
MDS-UPDRS Part III score for cohorts 1, 2, and 3, and 60, 90, and 120 
minutes in cohort 4. 
x Cumulative proportion of responders by post-dose time point (15, 30, 45, 
60, 90 and 120 minutes for cohorts 1, 2, and 3, and 30, 60, 90, and 120 
minutes in cohort 4), where response is defined as an improvement of 30% 
in MDS-UPDRS Part III score from baseline 
x Time to response, where response is defined as an improvement of 30% in 
MDS-UPDRS Part III score from baseline 
x Duration of response, where response is defined as an improvement of 
30% in MDS-UPDRS Part III score from baseline 
x Area Under the Curve (AUC) of changes in MDS-UPDRS Part III scores 
from pre-dose at 15, 30, 45, 60, 90 and 120 minutes for cohorts 1, 2, and 3, 
and 30, 60, 90, and 120 minutes in cohort 4 
x Maximum response in MDS-UPDRS Part III scores from pre-dose to 15, 30, 
45, 60, 90 and 120 minutes for cohorts 1, 2, and 3, and 30, 60, 90, and 120 
minutes in cohort 4 
x Subjective time to ON, as evaluated by the Investigator and subject self-
assessment 
3. The PK/PDyn relationship of single doses of INP103 and motor function 

 
 
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4. 
STUDY POPULATION 
4.1. 
Description of Numbers 
At least thirty-two (32) (maximum 36) L-dopa-responsive PD patients will be 
randomized into the study. 
4.2. 
Inclusion Criteria 
Subjects who meet all of the following criteria will be considered for inclusion in the 
study: 
1. Adult males and females, 40 to 80 years of age (inclusive) at the time of 
Screening (Visit 1) 
2. Diagnosed with Idiopathic PD (per UK Brain Bank Criteria) with Modified 
Hoehn & Yahr (H&Y) Stage I-III during an ON period at Visit 1 
3. Subjects who are prone to (and recognize) OFF episodes (when their usual PD 
medication has worn off)  
4. Shown to be responsive to L-dopa medication (≥ 30% improvement in MDS-
UPDRS Part III Motor Examination score) as assessed during Screening 
(Visit 2) 
5. On a stable dose of L-dopa containing medication for at least 2 weeks prior to 
Visit 1 (up to 1200 mg/day) with no single dose exceeding 250 mg. All other 
anti-PD medication (e.g. dopamine agonists [DAs], monoamine oxidase-B 
inhibitor (MAOB-I) or catechol-O-methyl transferase (COMT) inhibitors ARE 
allowed if the subject has been on a stable dose for at least 30 days prior to 
Visit 1. 
6. Willing to omit their (usual) PD drugs (e.g. usual regular anti-PD medication 
including any L-dopa containing medication, DAs and/or COMT inhibitors) 
and any required anti-OFF treatment) from 22:00 pm the evening prior to 
study dosing until 120 minutes post study treatment. 
Subjects in Cohorts 1, 2 and 3 ONLY will take oral benserazide 25 mg 60 ± 5 
minutes before Visit 3 dosing with INP103 or placebo.  
Cohort 4 will OMIT oral benserazide and may dose subjects once OFF episode 
confirmed and all baseline assessments have been completed. 
7. If female and of childbearing potential must agree to use adequate 
contraception (see Section 4.4) during the study 
8. Able and willing to attend the necessary visits at the study centre  
9. Willing to provide voluntary written informed consent signed prior to entry 
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4.3. 
Exclusion Criteria 
The presence of any of the following criteria will constitute cause for the exclusion of 
the subject: 
1. Severe dyskinesia (defined as per MDS-UPDRS) during a ‘normal day’ that 
would significantly interfere with the subject’s ability to perform study 
assessments 
2. In receipt of L-dopa containing medication at > 1200 mg/day 
3. History of significant psychotic episode(s) within the previous 12 months in 
the opinion of the Investigator, or currently receiving anti-psychotic 
medication at a moderate dose (quetiapine >50 mg/day, risperidone 
>1 mg/day or olanzapine >2.5 mg/day) 
4. Mini Mental State Examination (MMSE) ≤ 25, as documented within the 
previous 36 months or assessed by Investigator during Screening 
5. History of suicidal ideation or attempted suicide within previous 12 months 
6. Narrow-angle glaucoma 
7. Presence of skin lesions that, in the opinion of the Investigator, may be 
cancerous 
8. Females who are pregnant, planning a pregnancy or lactating 
9. Subjects with any underlying physical condition that, in the opinion of the 
Investigator, would make it unlikely that the subject will comply with or be 
able to complete the study requirements 
10. Use of any medication likely to interact with benserazide, carbidopa or 
INP103 (see Appendix 5) 
11. Laboratory test abnormalities at Screening (Visit 1) deemed clinically 
significant by the Investigator.  
12. History or presence of alcoholism or drug abuse within the 2 years prior to 
the first INP103 or placebo administration 
13. Administration of an investigational product in another trial within 30 days 
or 5 half-lives (whichever is longer) prior to the first INP103 or placebo 
administration 
14. Significant nasal congestion, physical blockage in either nostril, or 
significantly deviated nasal septum as evaluated by the PI or other suitably 
trained healthcare professional. 
15. Subjects who have previously shown hypersensitivity to L-dopa or 
benserazide (for Cohorts 1, 2 and 3), or L-dopa or carbidopa (for Cohort 4) or 
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4.4. 
Contraceptive Requirements 
Female subjects of childbearing potential must not become pregnant and must use 
two methods of adequate contraceptive during the study. Adequate contraception is 
defined as complete abstinence or a condom AND one other form of the following: 
x Birth control pills (The Pill)  
x Depo Shot or injectable birth control (e.g. Implanon) 
x IUD (Intrauterine Device)  
x NuvaRing®  
x Documented evidence of surgical sterilization at least 6 months prior to 
Screening Visit 1 (i.e., tubal ligation or hysterectomy).  
4.5. 
Concomitant Medication 
All medications including over-the-counter medications and herbal supplements 
will be recorded and reviewed by the Investigator. Prior and concomitant 
medications will be recorded by their generic name and will be coded using the most 
current World Health Organization (WHO) drug dictionary. 
Treatment with another investigational product (drug or device), or approved 
medication for investigational use within 30 days or 5 half-lives (whichever is 
longer) before anticipated dosing is prohibited.  
Anti-psychotic medication at a moderate dose (quetiapine >50 mg/day, risperidone 
>1 mg/day or olanzapine >2.5 mg/day) is prohibited. 
Any medication likely to interact with INP103 is prohibited (see Appendix 5). 
All subjects will be permitted to take their usual PD medications (e.g. regular 
Madopar® dosing) at all time points with the exception of: 
x From 22:00 on the evening prior to Visit 2 (study site visit between 
Screening [Visit 1] until they are confirmed to be OFF at Visit 2, and  
x From 22:00 on the evening prior to attending dosing on Day 0, Visit 3, 
until 120 minutes after administration of INP103 or placebo. 
In addition to exclusion of usual morning dose of anti-PD medication (e.g. regular 
Madopar or Sinemet morning dose), all anti-OFF medication is prohibited from 22:00 
on the evening prior to Day 0 until 120 minutes post-dose on Visit 3. 
Other regular medication required (provided it has been prescribed at a stable dose 
for at least 30 days) may be continued throughout the trial.  
4.6. 
Diet, Activity and Other Restrictions 
Subjects will refrain from consumption of alcohol for 24 hours before INP103 or 
placebo dosing and for the duration of the study.  

 
 
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Subjects should not consume food or drink containing grapefruit juice within 
14 days prior to initial dosing and during the entire study.  
INP103 or placebo should be administered whilst in a seated position.  
4.7. 
Meal Schedule 
Subjects who arrive at the study site the evening prior to dosing will receive a 
standard meal and snacks. All subjects will be offered, and encouraged to consume, 
a light breakfast in the morning 30 minutes prior to dosing. This is 30 minutes prior 
to dosing with normal PD medications in Visit 2 and 15 minutes before pre-dose 
blood draw at Visit 3. Thereafter, subjects may be offered a standard meal and/or 
snacks (if they can consume it in an OFF period, or once that OFF period has 
resolved). Light breakfast is defined as: cereal with milk or milk substitute, toast 
with jam or butter, muffin and applesauce, plain/fruit yogurt or suitable alternative 
as advised by local dietician. 

 
 
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5. 
STUDY MEDICATION 
5.1. 
Investigational Product Identification 
INP103 is a drug-device combination product where the drug component is L-dopa 
and the device component is the I231 POD Device. The I231 POD Device is a 
handheld, manually actuated, dose administration device intended to deliver a 
powder drug formulation to the nasal cavity (i.e. L-dopa).  
The INP103 product is designed to administer an intranasal dry powder formulation 
of L-dopa with a total target dose of 35 mg with each actuation. As such, Cohort 1 
will receive a total target dose of 35 mg delivered nasally by one actuation to one 
nostril. Cohort 2 will receive a total target dose of 70 mg delivered nasally by two 
actuations, one to each nostril, and Cohort 3 will receive a total target dose of 140 mg 
delivered nasally by four actuations, two to each nostril. 
Cohort 4 will receive INP103 containing a total target dose of 70 mg L-dopa plus 7.0 
mg carbidopa delivered nasally by two actuations, one to each nostril. 
Any technical issues occurring with the I231 POD Device should be reported to 
Impel as outlined in the Pharmacy Manual. 
Oral benserazide hydrochloride (25 mg), provided as pure active pharmaceutical 
ingredient (API) in a single dose of 1 Vcaps Plus (HPMC) size 3 capsule, will be 
administered to all subjects in Cohorts 1, 2 and 3 only, on the morning of Visit 3 
dosing upon waking at 60 ±5 minutes before dosing with L-dopa. 
5.1.1. 
Placebo 
Placebo will be microcrystalline cellulose. Microcrystalline cellulose is a fine white 
powder (similar to L-dopa with or without carbidopa) and will come packed and 
labelled as per identical capsules to those used for INP103 with or without 
carbidopa. Similar to INP103, placebo will be delivered using the I231 POD Device. 
The number of actuations will be matched between the placebo treatment and IP 
treatment. 
5.2. 
Randomization 
At least thirty-two (32), maximum 36, subjects will be randomized, and as this is a 
multi-centre study, centralized randomization will be performed. Treatment 
assignment will be randomised by blocks of 4 in sequential cohorts, with subjects 
assigned to either INP103 with or without carbidopa, or placebo delivered via the 
POD device with one, two, or four actuations, depending on cohort. Ratio of active 
to placebo assignment is 3:1. Randomization may occur on the day prior to (Day -1) 
or day of (Day 0) Visit 3 dosing. Subjects who are randomized but not dosed may be 
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5.3. 
Blinding 
This is a double-blind, randomized, placebo-controlled study. Doses of INP103 and 
placebo will be prepared by pharmacy personnel who will not be involved in the 
study assessments. Doses will be provided to blinded study personnel for 
administration. 
5.4. 
Dosage and Treatment 
5.4.1. 
Study Supplies 
Impel NeuroPharma will supply all INP103, oral benserazide, and placebo product 
through a third-party vendor, PCI Pharma Services (formerly known as 
Pharmaceutical Packaging Professionals, or PPP), to the investigational sites. INP103 
(with and without carbidopa), benserazide, and placebo supplies provided for this 
study will be manufactured under current good manufacturing practices (cGMP), 
subject to release, and suitable for human use. 
PCI will be responsible for the packaging and labelling of the investigational drug, 
benserazide, placebo, and device. Impel NeuroPharma will be responsible for 
providing details of batch numbers, safety, and stability data. 
PCI will label the products in accordance with local regulatory requirements and 
will ship INP103, benserazide, and placebo at a temperature below 25ºC in light-
resistant containers (not refrigerated or frozen) to the clinical site. 
5.4.2. 
Storage, Dispensing and Investigational Product Accountability 
Upon receipt at the investigational site, INP103, benserazide and placebo must be 
stored at controlled room temperature in light-resistant containers (not refrigerated 
or frozen), as specified in the pharmacy manual. A record will be maintained by the 
investigational site, which will account for all dispensing and return of any used and 
unused INP103, benserazide, or placebo. At the end of the study, INP103, 
benserazide and placebo will be reconciled, and a copy of the record given to the 
study monitor. 
Upon completion of the study, any surplus supplies will either be destroyed at the 
site in accordance with the site’s standard operating procedures (SOPs) and upon 
receipt of written approval from the Sponsor with evidence of destruction supplied 
to the study monitor or will be returned to an appropriate storage facility as 
indicated by the Sponsor.  
The Investigator will be fully responsible for the security, accessibility, and storage 
of all drug products whilst they are at the investigational site. 
Following training on the use of INP103 and the placebo by an authorized Impel 
NeuroPharma trainer, the Investigator will then be responsible for the education of 
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Further information about the storage, preparation and administration of drug 
products can be found in the Investigator’s Brochure, Pharmacy Manual and 
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6. 
STUDY PROCEDURES 
Study visits should be completed as indicated in the Study Schedule located in   
Table 1. 
Blood samples for L-dopa PK should be collected at the time points and within the 
windows designated in Table 1 
Sites should prioritise in the following order: PK blood draws; UPDRS/Dyskinesia  
assessments; other safety assessments. All procedures should be completed as close 
to the prescribed/scheduled times as possible and may be conducted in sequence by 
the sites according to their standard practice. Due to variability in assessment length, 
assessments collected out of window, with the exception of PK samples and UPDRS, 
will not be considered deviations. Any non-scheduled procedures required for 
urgent evaluation of safety concerns take precedence over all scheduled routine 
procedures. 
6.1. 
Medical History 
Medical history will be recorded at Screening (Visit 1). 
6.2. 
Demographics 
Date of birth, age (calculated), sex, ethnicity, and race will be recorded at Screening 
(Visit 1).  
6.3. 
Body Weight and Height/ Body Mass Index  
Body mass index (BMI) is calculated by dividing the subject’s body weight in 
kilograms by the subject’s height in meters squared (BMI = kg/m2). Body height 
(centimetres) and body weight (kilograms) will be measured at Screening (Visit 1). 
Body weight and height will be obtained with the subject’s shoes and jacket or coat 
removed. 
6.4. 
Safety Assessments 
This study primarily assesses the safety and tolerability of INP103. Safety will be 
determined by evaluating Physical Examination findings, ECGs, vital signs, clinical 
laboratory parameters, concomitant medication usage and AEs. If deemed necessary, 
additional safety measurements will be performed at the discretion of the PI and/or 
Sponsor’s Medical Monitor. 
6.4.1. 
Nasal Inspection  
Nasal inspection will be performed before and after the single dose at times noted in 
Table 1 and on an ongoing basis throughout the study. Any signs of inflammation, 
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6.4.2. 
Overall Dyskinesia Assessment  
Following dosing with INP103 or placebo, at each inquiry into AEs, or when 
conducting the MDS-UPDRS Part III assessment, the Investigator or suitably trained 
designee (who is familiar with rating dyskinesias), must assess the overall level of 
dyskinesia, based on the scale below. The most severe grade of dyskinesia observed 
at that time point, as determined by the same assessor (Investigator or suitable 
trained designate), and as per usual practice, will be recorded.  
0 (Normal) 
No dyskinesia. 
1 (Slight) 
Dyskinesias impact on a few activities. 
2 (Mild) 
Dyskinesias impact on many activities. 
3 (Moderate) 
Dyskinesias impact on activities to the point that the patient usually 
cannot perform some activities. 
4 (Severe) 
Dyskinesias impact on function to the point that the patient usually 
does not perform activities. 
6.4.3. 
Physical Examination 
Complete physical examinations will be performed by a licensed physician at the 
time-points specified in Table 1. 
Complete physical examinations include: general appearance, head, ears, eyes, 
throat, dentition, thyroid, chest (heart, lungs), abdomen, skin, neurological, 
extremities, back, neck, musculoskeletal, and lymph nodes. A nasal inspection will 
also be completed (Section 6.4.1). 
Directed physical examination (120 to 180 minutes post-dose only) includes: head, 
ears, eyes, throat, chest (heart, lungs), abdomen, skin, musculoskeletal, and lymph 
nodes and any pertinent system based on any prior findings.  
Physical examinations may be performed at various unscheduled time-points if 
deemed necessary by the PI. 
6.4.4. 
Mini Mental Status Examination (MMSE) 
Subjects should have an MMSE score of >25 documented within the previous 36 
months. If MMSE score is not available, the assessment should be conducted by the 
Investigator during Screening to confirm eligibility. 
6.4.5. 
Vital Signs 
Subjects should be resting in a supine position for at least 3 minutes prior to and 
during vital signs measurement obtained. Blood pressure, heart rate, respiration rate 
and temperature should be measured when the subject is supine. Immediately 
following supine vital signs assessments, blood pressure only will be measured 
again when standing. When the time of vital signs measurement coincides with a 

 
 
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blood draw, the vital signs will be taken after the scheduled blood draw, while 
ensuring the blood draw is within the window specified in the protocol. When vital 
signs and other safety assessments occur at the same timepoints, clinic staff may 
follow the sequence of their usual standard practice. 
Additional vital signs may be performed at other times if deemed necessary. 
6.4.6. 
Electrocardiogram Monitoring 
A 12-lead ECG will be taken at the time-points delineated in Table 1.Table 1ECGs 
(heart rate, PR, RR, RS, QRS, QT and assessment of clinical significance of 
abnormalities) will be performed with subjects in a recumbent position. Subjects 
must be in this position for at least 3 minutes before the reading is taken.  
All ECG tracings will be reviewed by the PI or his/her designate and classified as 
normal; abnormal, not clinically significant or abnormal and clinically significant. If 
possible, the ECG electrodes will remain in place until the last ECG in the domiciled 
period. 
When the time of ECG monitoring coincides with a blood draw, the ECG will be 
taken after the scheduled blood draw while ensuring the blood draw is within the 
window specified in the protocol. When ECG monitoring coincides with other 
assessments, clinic staff may follow the sequence of their usual standard practice. 
6.4.7. 
Laboratory Investigations 
Safety laboratory tests (haematology, serum chemistry, and urinalysis [UA]) will be 
performed at the time-points specified in Table 1and analysed by an appropriately 
certified central laboratory. 
Medically indicated laboratory tests (emergency or unscheduled tests) should be 
conducted at the local laboratory. 
6.4.7.1. 
Haematology and Serum Chemistry 
A blood sample will be taken from each subject for haematology and serum 
chemistry analysis at the time-points delineated inTable 1 (see Appendices 1 and 2 
for parameters to be tested). Additional clinical laboratory tests may be performed at 
other times if deemed necessary. 
6.4.7.2. 
Urinalysis 
A urinalysis test (dipstick) will be performed for each subject by a central laboratory. 
Urine analysis will be performed at Screening (Visit 1), and when the subject is 
admitted to the institution on Day 0 and other times according to the Study Schedule 
(see Appendix 3 for parameters to be tested). Urine microscopy will be performed in 
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A urine pregnancy test will be performed at Visit 2, 3 and 4 as specified in the 
Study Schedule. 
6.4.8. 
MDS-UPDRS 
A full MDS-UPDRS (Parts I-IV) will be assessed at Visit 1 (screening) and on arrival 
at clinic for dopaminergic responsiveness assessment (Visit 2). Subjects will omit 
their usual anti PD medication from 22:00 the previous evening and should arrive at 
the clinic for both Visits 2 and 3 in an OFF state. Once a full MDS-UPDRS assessment 
has been undertaken, at visit 2 they will take their usual regular PD medication as 
well as any additional rescue medication they would usually take for OFF episodes 
at home followed by MDS-UPDRS Part III (motor) assessment at +15, +30, +45, +60, 
+90 and +120 minutes post PD medication for Cohorts 1, 2 and 3, and +30, +60, +90, 
and +120 minutes for Cohort 4. Subjects demonstrating a 30% improvement in MDS-
UPDRS Part III at visit 2 will be deemed dopamine responsive and will be eligible 
for randomization.  
A full MDS-UPDRS (Parts I-IV) will also be assessed prior to dosing on Visit 3 and 
during follow-up (Visit 4). 
Further (post-dose) MDS-UPDRS III assessments (motor scores) will occur at the 
time points delineated in the Study Schedule in Table 1. 
MDS-UPDRS criteria and questions are provided in Appendix 4. 
6.4.9. 
Subject Questionnaire 
At 120 up to 180 minutes after dosing with INP103 or placebo, subjects will be asked 
the questions in the questionnaire provided in Appendix 6. This should follow all 
other assessments. 
6.5. 
Pharmacokinetic Assessments  
6.5.1. 
Sampling and Processing 
An intravenous cannula will be inserted prior to all medication dosing at Visit 3 to 
enable baseline PK and subsequent blood draws to be performed. 
Blood samples for PK analysis of L-dopa (and carbidopa in Cohort 4) will be 
obtained, according to the site’s SOPs, within 15 minutes prior to INP103 or placebo 
dosing and at the time-points (related to INP103/placebo dosing), and within the 
windows, delineated in the Study Schedule in Table 1. 
The actual collection time of each sample must be recorded in the source data 
documentation, on the collection tube and in the electronic case report form (eCRF). 
The allowed time deviation window for blood sample collection is + 1 minute for 
samples up to 30 minutes, and then ± 2 minutes for the 44, 59, 89 and 119 minutes 
sample time points (following INP103/placebo dosing) before a deviation is 
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assessment length, assessments collected out of window, with the exception of PK 
samples and UPDRS, will not be considered deviations 
The Sponsor will supply complete written instructions for handling, processing, 
storage, and shipping of PK samples in the laboratory manual prior to study 
initiation. 
6.5.2. 
Analytical Methods 
Plasma PK sample analyses will be performed using validated procedures and 
methods at AIT Bioscience. 
6.6. 
Pharmacodynamic Assessments 
6.6.1. 
MDS-UPDRS 
See Section 6.4.8. 
6.6.2. 
Assessment of ON 
Subjects will provide a self-assessment of their ON or OFF state, and Investigators 
will provide an assessment of the ON or OFF state of the subject, at the time points 
delineated in the Study Schedule in Table 1.

 
 
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7. 
STUDY SCHEDULE  
7.1. 
Screening (Up to 21 Days Prior to Visit 3 Dosing) (Visit 1) 
(Refer also to study synopsis and Table 1) 
Prior to enrolling in the study, and before performing any study-related procedures, 
potential subjects will attend the first of two Screening Visits, at which time they will 
be provided with full information concerning details of the study assessments and 
procedures. They will also be provided with the Subject Information Sheet and 
Informed Consent Form. Prior to being asked to sign the consent form, subjects will 
be given time to review study information and ask any questions.  
After the consent form is signed, Screening assessments will be carried out as 
follows: 
x Review of medications, medical history and inclusion/exclusion criteria. 
x Administer MMSE (if required) to confirm eligibility 
x Record of pre-treatment AEs. 
x Measurement of height and weight. 
x Recording demographic information. 
x Complete physical examination (including nasal examination), including 
full MDS-UPDRS (see Appendix 4). 
x 12-Lead ECG. 
x Vital signs (blood pressure [supine and standing]; and heart rate, 
respiratory rate and oral temperature [supine only]). 
x Clinical laboratory testing (non-fasting haematology, serum chemistry and 
urinalysis). 
x Serum pregnancy test (WOCBP only). 
x FSH (post-menopausal women only). 
Due to variability in assessment length, assessments collected out of window, with 
the exception of PK samples and UPDRS, will not be considered deviations. 
7.2. 
Admission to Clinic (Day prior to Visit 2 and Visit 3) 
Depending on private arrangements, capability, and logistics, subjects may be 
domiciled in the study clinic from the evenings prior to Visit 2 and Visit 3. Subjects 
will receive a standard meal and snacks and be offered a light breakfast in the 
morning before dosing and thereafter may be offered a standard meal and/or snacks. 
Subjects will not complete any study procedures until the morning of both Visit 2 
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7.3. 
Evaluation of Dopamine Responsiveness (Screening [Visit 2])  
Subjects considered eligible for study participation as per the outcome of Screening 
(Visit 1) are to return to the study clinic for Screening (Visit 2) on one day between 
Screening Visit 1 and Day 0 (Visit 3), i.e. within the maximum 21-day Screening 
window.  
For this visit (Visit 2), the subject will suspend their usual anti PD medication from 
22:00 pm the previous evening (including any DCIs). If not domiciled, they should 
arrive at the clinical research site in an OFF state, which will be confirmed and 
characterised by full MDS-UPDRS assessment. The subjects will then have a light 
breakfast 30 minutes before they take their usual L-dopa containing medication 
(including any rescue medication they would normally take for an OFF episode) and 
repeat the MDS-UPDRS Part III (motor examination) tests only at +15, +30, +45, +60, 
+90 and +120 minutes thereafter for Cohorts 1, 2 and 3, and +30, +60, +90 and 
+120 minutes for Cohort 4.  
Subjects showing at least a 30% improvement in MDS-UPDRS Part III score during 
this visit will be deemed to be dopamine responsive, will be eligible to be 
randomized and will proceed to Visit 3/Day 0.  
If the subject normally responds (subjective) to their dopaminergic medication but 
has an unexpectedly poor response (<30%) at Visit 2, which although unexpected 
could be explained (e.g. due to slow gastric emptying), then the dopamine 
responsiveness assessment may be repeated prior to Visit 3. 
Data from screen failures at the Visit 2 (dopamine responsiveness visit) will be 
collected and reviewed but data from screen failures at Visit 1 will not be recorded in 
the eCRF. Reasons for screen failures will be collected in study Screening logs. 
7.4. 
Dosing and Admission to Clinic (Day 0) (Visit 3) 
7.4.1. 
Before Dosing 
Subjects not domiciled in the study clinic on the evening of Day -1 will be 
transported to the study clinic as early as possible on the morning of Day 0. 
All subjects, irrespective of date or time of arrival at the study clinic, will have their 
usual anti-PD medication (e.g. usual regular Madopar® dosing and any required 
anti-OFF treatment [e.g. Madopar rapid]) withheld from 22:00 on the evening before 
Day 0 until at least 120 minutes post-dosing with INP103 or placebo. Subjects 
determined as being in an ON state during the pre-dose assessments will not 
participate further in the study.  
At visit 3, subjects will be offered, and encouraged to consume, a light breakfast, 30 
minutes before dosing (and 15 minutes before pre-dose PK blood draw). 

 
 
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Pre-dose PK sample will be obtained once an IV cannula has been inserted, 
approximately 15 minutes prior to INP103 or placebo dosing. Prior to dosing, 
subjects will be sequentially assigned a randomization number. The subject 
identification number will remain the same throughout the study.  
Subjects will be offered standard meal and/or snacks after dosing as appropriate.  
All subjects in Cohorts 1, 2 and 3 will receive oral benserazide (25 mg) 60 ± 5 minutes 
before INP103 or placebo dosing.  
Subjects in Cohort 4 will not receive oral benserazide but will be dosed with INP103 
(with carbidopa) or placebo once OFF state confirmed and all other baseline 
assessments have been completed. 
The following assessments will be carried out prior to dosing (in an order consistent 
with site’s standard practice) on Day 0: 
x Review to determine whether the subject continues to satisfy the study 
inclusion and exclusion criteria 
x Vital signs (blood pressure [supine and standing]; and heart rate, 
respiratory rate and oral temperature [supine only]) 
x 12-Lead ECG 
x Complete physical examination including nasal inspection 
x Safety laboratory analysis sample collection (haematology, clinical 
chemistry and urinalysis) 
x Urine pregnancy test (WOCBP only) 
x Record of pre-treatment AEs (post randomization, pre-treatment 
emergent, including rating of dyskinesias) 
x Review of the subject’s concomitant medications, including non-
prescription medications 
x Investigator and subject self-evaluation of ON/OFF 
x Full MDS-UPDRS assessment (I to IV) 
x Administration of Benserazide (60 ± 5 minutes before INP103 or placebo 
dosing – Cohorts 1, 2 and 3 only) 
x Blood sample collection for baseline PK readings (within 15 minutes prior 
to dosing) (see Table 1). 
Due to variability in assessment length, assessments collected out of window, with 
the exception of PK samples and UPDRS, will not be considered deviations. 

 
 
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7.4.2. 
Dosing (Visit 3) 
Subjects will be dosed by delegated clinic staff and according to the treatment arm to 
which they have been randomized. Additional details about the preparation and 
dosing of INP103 or placebo are provided in the Pharmacy Manual. 
7.4.3. 
After Dosing 
The subjects will remain in the study clinic post-dose through to the completion of 
all scheduled post-dose procedures 240 minutes after dosing.  
The subject’s usual rescue (anti-OFF [e.g. Madopar rapid]) medication will be 
permitted from 120 minutes post-dose (once all 120 minute assessments have been 
completed, but can precede ECG, physical examination and subject questionnaire) – 
if they are still OFF. In addition, subjects should take their regular anti PD 
medication (e.g. their regular morning Madopar dose) at 120 minutes post dosing 
whether or not they have returned to ON. 
The following in-patient assessments will be performed after dosing: 
1. Adverse Events (including overall dyskinesia rating) and concomitant 
medications will be continually monitored post-dose. 
2. Vital signs will be measured at 30, 60 and 120 minutes post-dose. Blood 
pressure (supine and standing) and heart rate, respiratory rate and oral 
temperature (supine only) will be measured at all time points. Vital signs 
will be collected after MDS-UPDRS assessment (where both procedures 
are scheduled at the same time point) and will not be deemed protocol 
deviations if they occur outside the time window at each timepoint. 
3. PK blood samples will be collected at 4, 9, 14, 29, (all + 1 minute) 44, 59, 89 
and 119 (all r 2 minutes at each timepoint) minutes post-dose and will 
precede UPDRS assessments.  
4. MDS-UPDRS III only at 15, 30, 45, 60, 90 and 120 minutes post-dose for 
Cohorts 1, 2 and 3) and 30, 60, 90, 120 minutes for Cohort 4 (r 2 minutes at 
each timepoint) 
5. Investigator and subject self-assessment of ON/OFF at 30, 45, 60, 90, 120 
and 240 minutes post-dose (r 10 minutes at each timepoint) 
6. At 120 minutes, the subject’s usual morning dose of all Parkinson’s 
medications should be given following completion of assessments 1-5, 
regardless of ON/OFF state. In addition, if subject is still OFF, their usual 
OFF medication may be given (prior to completing assessments 7, 8 and 
9). 
7. Directed physical examination (including nasal inspection) will be 
performed at 120-180 minutes post-dose 

 
 
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8. 12-Lead ECG will be performed at 120-180 minutes post dose. In cases 
where vital signs are scheduled at the same time point, ECG will be 
completed in sequence with vital signs per the usual practice of the study 
sites. 
9. Subject questionnaire will be completed as the last assessment from 120-180 
minutes post-dose  
Due to variability in assessment length, assessments collected out of window, with 
the exception of PK samples and UPDRS, will not be considered deviations. 
Subjects will be discharged from the study site following satisfactory completion of 
assessments. 
7.5. 
Follow-Up/End of Study (Day 7 + 2 days) 
The subjects will return to the institution on Day 7 (+2 days). In exceptional 
circumstances, if a subject is unable to attend the end of study visit on Day 7 
(+ 2 days, as indicated), the Investigator (or qualified designee) should discuss 
appropriate re-scheduling to a maximum of +4 days with the Sponsor’s Medical 
Monitor (or appropriate designee). The following assessments will again be carried 
out: 
x Adverse Events (including overall dyskinesia rating) and concomitant 
medications 
x 12-Lead ECG 
x Vital signs (blood pressure [supine and standing]; and heart rate, 
respiratory rate and oral temperature [supine only]) 
x Complete physical examination 
x Clinical laboratory testing (haematology, serum chemistry and urinalysis) 
x Full MDS-UPDRS 
Due to variability in assessment length, assessments collected out of window, with 
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8. 
ADVERSE EVENTS 
In this study, AEs will be reported for all subjects from signing of consent until the 
completion of the end of study Day 7 follow-up visit. SAEs will be reported in all 
subjects (enrolled and not enrolled) from the time of consent. Treatment-emergent 
AEs (TEAEs) will be reported from dosing on Day 0. Study procedure-related AEs 
will be evaluated specifically from the time of consent until INP103 or placebo 
administration. Treatment-emergent AEs will be evaluated from INP103 or placebo 
dosing until the end of study visit. AEs that are ongoing at the end of study visit will 
be marked as ongoing on the AE eCRF page.  
All AEs resulting from spontaneous subject self-reporting, direct enquiry or 
observation by study staff, will be recorded in the subject’s medical records and the 
eCRF. 
8.1. 
Safety Monitoring Committee 
Once dosing has been completed for all subjects in Cohort 1, a Safety Monitoring 
Committee (composed of the Principal Investigators, the contract research 
organization (CRO)’s Medical Monitor and the Sponsor’s Medical Monitor) will 
review the AEs reported for the completed cohort. If they assess the benefit:risk ratio 
of the completed cohort acceptable, that decision will be documented, and the 
subsequent cohort given permission to proceed with dosing. This will be repeated 
for Cohort 2. No SMC meeting is planned following Cohort 3, unless safety concerns 
were raised during the SMC meetings occurring after Cohorts 1 and 2. The rationale 
for no SMC meeting prior to Cohort 4 is because the dose of L-dopa and DCI is less 
than for Cohort 3. However, all other usual safety monitoring will remain in place 
for the duration of the study. 
8.2. 
Definition of an Adverse Event 
An AE is any event, side-effect, or other untoward medical occurrence that occurs in 
conjunction with the use of a medicinal product in humans, whether or not 
considered to have a causal relationship to this treatment. An AE can, therefore, be 
any unfavourable and unintended sign (that could include a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal 
product. 
Events meeting the definition of an AE include: 
x Exacerbation of a chronic or intermittent pre-existing condition including 
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x New conditions detected or diagnosed after INP103, or placebo 
administration that occur during the AE reporting periods, even though it 
may have been present prior to the start of the study 
x Signs, symptoms, or the clinical sequelae of a suspected interaction 
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
INP103 or placebo or a concomitant medication (overdose per se will not 
be reported as an AE/SAE) 
Events that do not meet the definition of an AE include: 
x Medical or surgical procedure (e.g., endoscopy, appendectomy); the 
condition that leads to the procedure should be reported as an AE if it 
meets the criteria of an AE 
x Situations where an untoward medical occurrence did not occur 
(e.g., social and/or convenience admission to a hospital) 
x Anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the study that do not 
worsen 
If there is evidence of an AE through report or observation, the Investigator or 
designee will evaluate further and record the following information: 
x Time of onset and resolution 
x Severity 
x Causality/relation to study treatment 
x Action taken regarding INP103 or placebo 
x Outcome 
8.2.1. 
Severity of an Adverse Event 
Severity of adverse events will be graded by the Investigator as one of: 
x Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living 
x Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of 
harm to the research subject 
x Severe: A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
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8.2.2. 
Causal Relationship of an Adverse Event 
The Investigator will assess the relationship between INP103 or placebo and the 
occurrence of each AE. The Investigator’s assessment of the relationship of each AE 
to investigational product will be recorded in the source documents and the eCRF. 
Alternative causes, such as medical history, concomitant therapy, other risk factors, 
and the temporal relationship of the event to INP103, or placebo administration 
should be considered and investigated, if appropriate. The following definitions are 
general guidelines to help assign grade of attribution:  
x Not related: The event is clearly related to other factors such as the 
subject’s clinical state, therapeutic interventions or concomitant drugs 
administered to the subject. This is especially so when an event occurs 
prior to the commencement of treatment with INP103 or placebo. 
x Unlikely: The event was most likely produced by other factors such as the 
subject’s clinical state, therapeutic interventions, or a concomitant drug 
administered to the subject and does not follow a known response to 
INP103 or placebo. 
x Possible: The event follows a reasonable temporal sequence from the time 
of INP103 or placebo administration or follows a known response to 
INP103 or placebo but could have been produced by other factors such as 
the subject's clinical state, other therapeutic interventions, or concomitant 
drugs administered to the subject. 
x Probable: The event follows a reasonable temporal sequence from the time 
of INP103 or placebo administration and follows a known response to 
INP103 or placebo and cannot be reasonably explained by other factors 
such as the subject's clinical state, other therapeutic interventions, or 
concomitant drugs administered to the subject. 
8.2.3. 
Action Taken with Study Medications 
Action taken with study medications will be recorded on the AE eCRF page, as one 
of the following options: 
x Dose Interrupted 
x Dose Withdrawn 
x Not Applicable 
x Unknown 
8.2.4. 
Outcome 
Outcome of an AE will be recorded on the AE eCRF as follows: 
x Recovered / Resolved 

 
 
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x Recovering / Resolving 
x Recovered / Resolved with Sequelae 
x Not Recovered / Not Resolving 
x Fatal 
x Unknown 
8.3. 
Definition of a Serious Adverse Event   
An SAE is any untoward medical occurrence that at any dose:  
x Results in death 
x Is life-threatening 
x Requires inpatient hospitalization or prolongation of existing 
hospitalization 
x Results in persistent or significant disability/incapacity, or 
x Is a congenital anomaly/birth defect 
Important medical events that may not be one of the above may be considered an 
SAE by the Investigator when, based upon appropriate medical judgement, are 
considered clinically significant and may jeopardise the subject, or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
An AE is considered life-threatening if, in the opinion of either the Investigator or 
the Sponsor, its occurrence places the subject at immediate risk of death. It does not 
include an AE that, had it occurred in a more severe form, might have caused death.  
8.3.1. 
Notification of a Serious Adverse Event 
In order to meet the requirements for expedited reporting of SAEs meeting specific 
requirements to applicable regulatory authorities and institutional ECs, all SAEs, 
must be reported to CNS within 24 hours from the time the site investigational team 
first become aware of the event. This may be initially achieved by telephone, or by 
completing an SAE report form and e-mailing to CNS via the email address  
Safety@clinical.net.au 
Initial notification of an SAE by telephone must be confirmed in writing 24 hours 
from the time the site investigational team first become aware of the event using the 
SAE report form as described above.  
As further information regarding the SAE becomes available, such follow-up 
information should be documented on a new SAE report form, marked as a follow-
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Withdrawal from the study in the event of a SAE and therapeutic measures taken 
shall be at the discretion of the Investigator. A full explanation for the 
discontinuation from the study should be made in the subject’s medical records and 
in the eCRF. 
8.4. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events and Serious Adverse Events 
Abnormal laboratory findings (e.g., clinical chemistry, haematology, and urinalysis) 
or other abnormal assessments (e.g., ECG and vital signs) per se are not reported as 
AEs. However, those abnormal findings that are deemed clinically significant or are 
associated with signs and/or symptoms must be recorded as AEs if they meet the 
definition of an AE (and recorded as an SAE if they meet the criteria of being 
serious) as described previously. Clinically significant abnormal laboratory or other 
abnormal findings that are detected after consent or that are present at baseline and 
worsen after consent are included as AEs (and SAEs if serious).  
The Investigator should exercise his or her medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. Usually, the abnormality should be associated with a clinically 
evident sign or symptom, or be likely to result in an evident sign or symptom in the 
near term, to be considered clinically significant. A clinically significant laboratory 
abnormality in the absence of clinical symptoms may jeopardize the subject and may 
require intervention to prevent immediate consequences. For example, a markedly 
low serum glucose concentration may not be accompanied by coma or convulsions, 
yet be of a magnitude to require glucose administration to prevent such sequelae. 
8.5. 
Documenting Adverse Events 
Any AE occurrence during the study must be documented in the subject’s medical 
records in accordance with the Investigator’s normal clinical practice and on the AE 
page of the eCRF. SAEs that occur during the study must be documented in the 
subject’s medical record, on the AE eCRF, and on the SAE form. 
The Investigator should attempt to establish a diagnosis of the event based on the 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis 
should be documented as the AE (and SAE if serious) and not the individual 
signs/symptoms. 
If a clinically significant abnormal laboratory finding or other abnormal assessment 
meets the definition of an AE, then the AE eCRF page must be completed as 
appropriate. In addition, if the abnormal assessment meets the criteria for being 
serious, the SAE form must also be completed. A diagnosis, if known, or clinical 
signs or symptoms if the diagnosis is unknown, rather than the clinically significant 
laboratory finding or abnormal assessment, should be used to complete the AE/SAE 
page. If no diagnosis is known and clinical signs or symptoms are not present, then 

 
 
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the abnormal finding should be recorded. If an SAE report is completed, pertinent 
laboratory data should be recorded on the SAE form, preferably with baseline values 
and copies of laboratory reports. 
The SAE page should be completed as thoroughly as possible and signed by the 
Investigator before transmittal to the study Sponsor and CNS. It is very important 
that the Investigator provide an assessment of the causal relationship between the 
event and INP103 or placebo at the time of the initial report, as this will be useful for 
submissions to regulatory authorities. 
8.6. 
Regulatory Authorities 
The reporting of any SAEs to applicable regulatory authorities will be the 
responsibility of the Sponsor in compliance with applicable country regulations. 
All SAEs must be reported to the HREC by the Investigator in accordance with their 
regulations. 
8.7. 
Follow-Up of Adverse Events and Serious Adverse Events 
All AEs and SAEs that are deemed related, possibly related or probably related to 
INP103 or placebo must be followed until resolution, until the condition stabilizes, 
until the event is otherwise explained, or until the subject dies or is lost to follow-up. 
The Investigator is responsible to ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature 
and/or causality of the AE/SAE. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
The Sponsor may request that the Investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations. If a subject dies during 
participation in the study or during a recognized follow-up period, the Sponsor 
should be provided with a copy of any post-mortem findings, including 
histopathology. 
8.8. 
Pregnancy 
Females who are pregnant, planning a pregnancy or lactating are to be excluded 
from the study. In the case of a pregnancy occurring during study participation or at 
any time during the 30 days following INP103 or placebo, it must be reported using 
a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be 
reported to CNS within 5 days of the PI learning of its occurrence. The pregnancy 
should be followed up to determine outcome (including premature termination) and 
status of mother and child. The subject will be requested to provide written 
informed consent to enable collection of information pertaining to the outcome of the 
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must be reported as an AE or SAE. Spontaneous abortions must be reported as an 
SAE. 
Any SAE occurring in association with a pregnancy brought to the Investigator’s 
attention after the subject has completed the study and considered by the 
Investigator as possibly related to INP103 or placebo, must be promptly reported to 
CNS. 
In addition, the Investigator must attempt to collect pregnancy information on any 
female partners of male study subjects who become pregnant while the subject is 
enrolled in the study. Pregnancy information must be reported to CNS as described 
above. 

 
 
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9. 
STUDY COMPLETION AND DISCONTINUATION 
9.1. 
Subject Withdrawal 
In accordance with applicable regulations, a subject has the right to withdraw from 
the study at any time and for any reason, without prejudice to his future medical 
care. 
Subjects may be withdrawn from the study for any of the following reasons:  
x Subject is unable or unwilling to continue participation in the study  
x Adverse event (whether or not related to INP103 or placebo) that precludes 
further participation in the study in the judgment of the Investigator and/or 
Sponsor  
x Protocol noncompliance  
x Informed consent withdrawn  
x The Investigator considers that it is in the subject’s best interest for the subject 
not to continue participation in the study  
If a subject is withdrawn because of an AE, the Investigator must arrange for the 
subject to have appropriate follow-up care until the AE is resolved or has stabilized. 
Unresolved AEs will be followed until the last scheduled follow-up visit or until the 
PI and Medical Monitor determine that further follow-up is no longer indicated. In 
addition to AEs, other reasons for removal of subjects from the study might include, 
but are not limited to, withdrawal of consent, administrative decision by the 
Investigator or the Sponsor, protocol deviation, or subject noncompliance. 
If a subject asks or decides to withdraw from the study, all efforts will be made to 
complete and report the observations, especially the listed primary and secondary 
objectives, as thoroughly as possible up to the date of withdrawal. The primary 
reason for withdrawal will be identified and recorded on the appropriate eCRF, 
along with the date of withdrawal. 
9.2. 
Subject Replacement 
At least thirty-two subjects are planned for enrolment in the study. Subjects who 
consent but then do not receive INP103 or placebo for any reason may be replaced at 
the Sponsor’s discretion. Subjects will not be replaced once dosed. 

 
 
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10. 
TERMINATION OR SUSPENSION OF THE STUDY 
The Sponsor, Investigator, and the HREC reserve the right to terminate or suspend 
the study at any time; however, this should be discussed between the relevant 
parties beforehand and the reason for such decision recorded. Should this occur, all 
data available will also be recorded in the eCRFs. The Investigator should notify the 
relevant institutional HREC in writing of the study’s completion or early 
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11. 
STUDY MONITORING AND DATA MANAGEMENT 
11.1. 
Study Monitoring 
The Sponsor has appointed Clinical Network Services (CNS) Pty Ltd to manage and 
monitor the study so as to assure them of the adequate conduct of the study and to 
act as the contact with the investigational site. A study monitor will be identified and 
will be responsible for liaison with, and support of, the investigational site. 
The study monitor and regulatory authority inspectors are responsible for contacting 
and visiting the investigative site for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the study (e.g., eCRFs, essential 
documentation, and other pertinent data) provided that subject confidentiality is 
respected. 
11.2. 
Access to the Study 
The Sponsor, study monitor, HREC and applicable regulatory agencies may require 
access to all study documents held at the investigational site, as well as access to all 
members of the investigational site personnel. It is expected that such access would 
normally be arranged by agreement with the investigational site.  
11.3. 
Source Document and Data Verification 
The study monitor will visit the investigational site periodically where s/he shall: 
x Meet with the Investigator and any other applicable site staff. 
x Inspect the eCRFs throughout the study to verify adherence to the 
protocol; completeness, accuracy, and consistency of the data; and 
adherence to local regulations on the conduct of clinical research. The 
monitor should have access to subject medical records and other study-
related records needed to verify the entries on the eCRFs. The Investigator 
will cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. The monitor will 
identify of any data to be recorded directly on the eCRFs (i.e. no prior 
written or electronic record of data), and to be considered to be source 
data. 
x Review the investigational site file and regulatory documentation. 
x Collect copies of documents and completed eCRFs for use by the 
appointed data management group and retention by the Sponsor.  
x Verify with reference to the INP103, benserazide, and placebo records, that 
drug products have been stored appropriately, and administered 
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All eCRFs should be maintained on the system with details of any changes logged 
accordingly. 
11.4. 
Data Management 
All data will be recorded in individual source documents. An eCRF will be created 
by the data management group for recording of the required data in the study 
database. All eCRF information is to be filled in by site staff. If an item is not 
available or is not applicable, this fact should be indicated. Blank spaces should not 
be present unless otherwise directed. 
The study monitor will perform source data verification of data entered into the 
eCRF; when discrepancies are noted, the study monitor will raise queries for 
correction by the site. The data entered into the eCRF will be subject to data 
validation checks for consistency and completeness by the data management group. 
Data queries will then be generated and sent to the investigational site for response 
before the database is locked and released for statistical analysis.

 
 
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12. 
STATISTICAL ANALYSES 
This protocol section describes the statistical analyses as they are foreseen at the time 
of planning the study. A separate Statistical Analysis Plan (SAP) will be prepared 
prior to performing any unblinded analysis. The SAP will serve as a complement to 
the study protocol and supersedes it in case of differences.  
12.1. 
Sample Size Calculation 
Thirty-two (32) subjects (8 per dose group) are considered sufficient for assessment 
of safety and tolerability of SADs of INP103. However, we are proposing that Cohort 
4 may enrol an additional 4 patients (for a maximum of 12) under the same 
randomization scheme (3:1). With at least eight subjects per group, the study has 
80% power to detect an improvement of 13 points from baseline in MDS-UPDRS 
Part III scores within each dose level, assuming a standard deviation of 11 points, 
using a two-sided significance level of 0.05. This study is not powered for between-
group comparisons of the pharmacodynamic endpoints. 
12.2. 
Analysis Populations 
Safety Population: All subjects who receive any amount of INP103 or placebo will 
be included in the Safety Population. A pooled placebo group (of subjects from each 
of the five cohorts) will be used for comparisons. The data will be analysed 
according to the treatment received. 
Benserazide Safety Population: All subjects who receive any amount of benserazide 
in Cohorts 1, 2 and 3 (as provided by the Sponsor) will be included in the 
Benserazide Safety Population. This population will be used for the analysis of the 
safety data collected after receiving benserazide (as provided by the Sponsor) and 
before receiving INP103 or placebo. This population will not be applicable to Cohort 
4. 
PK Population: All subjects who receive any amount of INP103 or placebo and have 
sufficient samples collected for non-compartmental analysis will be included in the 
PK Population. The data will be analysed according to the treatment received. 
Intention-to-Treat (ITT) Population: All randomized subjects who have baseline 
and at least one post-dose assessment of motor function will be included in the ITT 
Population. A pooled placebo group (of subjects from each of the five cohorts) will 
be used for comparisons. The data will be analysed according to the randomized 
treatment group. 

 
 
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12.3. 
Safety Analysis 
Continuous safety data will be summarised with descriptive statistics (arithmetic 
mean, SD, median, minimum, and maximum) by treatment. Categorical safety data 
will be summarised with frequency counts and percentages by treatment. 
AEs will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA®) available at CNS. A by-subject AE data listing, including 
verbatim term, preferred term, system organ class, treatment, severity, and 
relationship to INP103 or placebo, will be provided. A treatment emergent AE 
(TEAE) is defined as an AE with onset after the first dose of INP103 or placebo. The 
number of subjects experiencing TEAEs and number of individual TEAEs will be 
summarized by treatment, system organ class and preferred term. TEAEs will also 
be summarized by seriousness, severity, relationship to INP103 or placebo and the 
time of onset relative to dosing. 
In addition to the TEAEs, the AEs with onset after the first dose of benserazide (as 
provided by the Sponsor) and before the first dose of INP103 or placebo will be 
summarized by system organ class and preferred term. 
Dyskinesia assessment, nasal inspection, laboratory evaluations, vital signs 
assessments (including supine and standing blood pressure, all other vital signs 
supine only) and ECG parameters will be summarized by treatment and protocol 
specified collection time point. A summary of change-from-baseline at each protocol 
specified time-point by treatment will be presented.  
In addition, the proportion of subjects experiencing orthostatic hypotension or 
abnormal ECGs will be summarized by treatment group. The orthostatic 
hypotension is defined as a reduction in systolic blood pressure of 20 mmHg or 
more, and/or a reduction in diastolic blood pressure of 10 mmHg or more, for the 
standing measurement compared to the supine measurement. For ECGs, in addition 
to the overall assessment done by the physician, the proportion of subjects meeting 
the following criteria based on QTc values (defined both using the correction by 
Bazett and by Fridericia) will be summarized: QTc value >500 msec, QTc value 
increasing >15% from baseline if baseline value is ≥440 msec, QTc value increasing 
>30% from baseline if baseline value is <440 msec, QTc value increasing >30% from 
baseline, QTc value increasing >60% from baseline. 
Proportion of subjects with abnormal physical examination findings will be 
summarized by treatment group. 
Prior and concomitant medications will be listed by subject and coded using the 
most current WHO drug dictionary and summarized by therapeutic class (Level 4 
for anti-PD medications and Level 2 for other medications) and preferred name. 
Medical history will be listed by subject. 

 
 
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12.4. 
Pharmacokinetic Analysis  
The levodopa concentrations will be summarized with descriptive statistics 
(arithmetic and geometric mean, SD, median, minimum, and maximum) by 
treatment group and time point. In addition, the PK parameters (AUC0-0.5h, AUC0-1h, 
AUC0-2h, Cmax, Tmax) will be summarized with descriptive statistics by treatment 
group. Carbidopa concentrations from Cohort 4 will also be analysed and 
summarized. 
12.5. 
Pharmacodynamic Analysis 
The changes from baseline in MDS-UPDRS Part III scores will be summarized by 
treatment groups and estimated using a Mixed Model for Repeated Measures 
(MMRM) with treatment group (INP103 35 mg, INP103 70 mg, INP103 140 mg, 
INP103 70mg with 7.0 mg carbidopa, or placebo), time point (15, 30, 45, 60, 90 or 
120 minutes for INP103 and benserazide [C1, C2, C3] and 30, 60, 90, 120 minutes for 
INP103 and carbidopa [C4])) and the interaction between treatment group and time 
point as fixed factors. The baseline score will be included as a covariate. The focus will 
be on the estimation of changes within each treatment group. An unstructured 
covariance structure will be used for the MMRM. In case the model does not converge 
with the unstructured covariance structure, the heterogeneous compound symmetry 
(CSH) or heterogeneous Toeplitz structure (TOEPH) will be used instead. The 
denominator degrees of freedom will be computed using the Kenward-Roger method. 
The least square (LS) means, standard errors and two-sided 95% confidence intervals 
will be provided for changes within each treatment group. In addition, the differences 
between each treatment group and placebo will be estimated.  
The cumulative proportion of responders will be summarized descriptively by 
treatment group and time point.  
The endpoint related to time of response and time to ON will be evaluated with 
Kaplan-Meier methods. The figures of Kaplan-Meier estimate and summary statistics 
(25th percentile, median, and 75th percentile and their 95% confidence intervals) will 
be presented.  
For subjects who received study drug administration and achieve response within 120 
minutes post dosing, the duration of response will be summarized by treatment group.  If 
the subject did not achieve response after 120 minutes post dosing, this subject will be 
regarded as censored and the duration of response will be treated as missing.    
The AUC of MDS-UPDRS Part III scores from pre-dose to 15, 30, 45, 60, 90 and 120 
minutes will be calculated as AUC0-15, AUC0-30, AUC0-45, AUC0-60, AUC0-90 and AUC0-120 
(omitting AUC0-15 and AUC0-45 for Cohort 4). These AUC parameters will be 
summarized by treatment groups as well as analysed with an Analysis of Covariance 
(ANCOVA) model with treatment group as a fixed factor and baseline MDS-UPDRS 
Part III score as a covariate. The least square (LS) means, standard errors and two-

 
 
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sided 95% confidence intervals will be provided for changes within each treatment 
group. In addition, the differences between each treatment group and placebo will be 
estimated.  
The individual maximum response scores will be defined as the maximum MDS-
UPDRS Part III score post dosing from the baseline across all time points post dose 
(from 15, 30, 45, 60, 90 and 120 minutes for C1, C2, and C3, and 30, 60, 90, 120 minutes 
for C4) of each subject and will be summarized by treatment groups as well as 
analysed with an Analysis of Covariance (ANCOVA) model with treatment group as 
a fixed factor and baseline MDS-UPDRS Part III score as a covariate. The least square 
(LS) means, standard errors and two-sided 95% confidence intervals will be provided 
for changes within each treatment group. In addition, the differences between each 
treatment group and placebo will be estimated.  
12.6. 
Pharmacokinetic/Pharmacodynamic relationship 
The analyses required to investigate the PK/PDyn relationship of INP103 will be 
defined in the SAP which will be completed before the database is locked. 

 
 
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13. 
REGULATORY REQUIREMENTS 
13.1. 
Regulatory Approvals 
CNS will act as the legal Australian Representative for Impel NeuroPharma, the 
Sponsor of the study, and will fulfil the obligations that this role entails. CNS shall, 
to the extent required by the applicable laws and regulations, interact with 
Australian Therapeutic Goods Administration (TGA) on behalf of the Sponsor in 
connection with this study. The planned regulatory pathway for this trial is through 
the Clinical Trial Notification (CTN) Scheme. Aside from approval by the EC and 
notification of the TGA no other regulatory approval will be required. 
An L-dopa formulation, in the absence of a DCI, does not have marketing 
authorization in any ICH territory, although an inhaled form of L-dopa, CVT301, has 
now successfully completed clinical development. L-dopa in combination with DCI 
(benserazide or carbidopa) is approved in many regions/countries around the world, 
including in Australia (e.g. Madopar and Sinemet respectively). These products are 
administered orally. There are no globally approved L-dopa-containing or L-
dopa/carbidopa containing products for nasal administration. 
13.2. 
Human Research Ethics Committee (HREC) Approval 
Prior to the commencement of the study, written approval will be required by the 
relevant institutional HREC responsible for the investigational site. 
13.3. 
Subject Informed Consent 
It is the Investigator's responsibility to ensure that each subject gives informed 
consent to participate in the study. The Investigator will explain the nature of the 
study, its purpose, procedures, expected duration, and the potential benefits, risks 
and inconveniences in participation. In addition, a subject information sheet/consent 
form containing relevant information will be prepared by Impel in conjunction with 
the investigational site and will be provided to all subjects. 
The subjects will be informed of their rights to privacy but will be made aware that 
the study data will be submitted to the Sponsor and possibly to drug regulatory 
authorities for review and evaluation. They will be informed also that the study 
monitor may inspect their medical records to verify the accuracy and completeness 
of the study records and results. 
The subjects will be informed of their right to withdraw from the study at any time 
without prejudice. 
The subjects will be given an opportunity to ask questions and allowed sufficient 
time to decide whether they wish to participate. If the subject decides to participate 
in the study, they will voluntarily sign the written informed consent form. 

 
 
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The acquisition of informed consent should be documented in the subject’s medical 
records, as required by Notes for Guidance on GCP (CPMP/ICH/135/95), as adopted 
by the Australian Therapeutic Goods Administration (2000), and the NHMRC 
National Statement on Ethical Conduct in Human Research (2007, incorporating all 
updates as at May 2015). The informed consent form will be signed and personally 
dated by the subject and by the person who conducted the informed consent 
discussion (not necessarily an investigator). The original signed informed consent 
form will be retained in accordance with institutional policy, and a copy of the 
signed consent form will be provided to the subject or legal representative. The date 
that informed consent was signed will be recorded on the eCRF. 
13.4. 
Data Protection 
Subjects will be informed that data will be held on file by Impel and that these data 
may be viewed by staff including the study monitor and by external auditors on 
behalf of Impel and appropriate regulatory authorities. Subjects will also be 
informed that a study report will be prepared and may be submitted to regulatory 
authorities and for publication. However, subjects will be identified in such reports 
only by study identification number, gender and age. All subject data will be held in 
strict confidence.

 
 
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14. 
ADMINISTRATIVE PROCEDURES 
14.1. 
Liability/Indemnity/Insurance 
The study Sponsor will ensure sufficient insurance is available to enable it to 
indemnify and hold the Investigator(s) and relevant staff as well as any hospital, 
institution, EC or the like, harmless from any claims for damages for unexpected 
injuries, including death, that may be caused by INP103, benserazide or placebo but 
only to the extent that the claim is not caused by the fault or negligence of the 
subjects or Investigator(s).  
14.2. 
Recording of Data and Retention of Records 
All source data, clinical records and laboratory data relating to the study will be 
archived for 15 years after the completion of the study. All data will be available for 
retrospective review or audit. 
Source documents are original documents, data, and records from which the 
subject’s eCRF data are obtained. These include, but are not limited to: hospital 
records, clinical and office charts, laboratory and pharmacy records, diaries, 
microfiches, radiographs, angiograms, investigational product accountability logs, 
and correspondence. eCRF entries may be considered source data if the eCRF is the 
site of the original recording (i.e., there is no other written or electronic record of 
data). In this case, a note to the file should indicate which eCRFs are considered 
source documents. 
The Investigator and study staff are responsible for maintaining a comprehensive 
filing system of all study-related (essential) documentation. These include, but are 
not limited to:  EC correspondence, investigational product accountability logs, and 
curricula vitae of all personnel participating in the study. These files must be suitable 
for inspection at any time by the Sponsor, monitor, and/or applicable regulatory 
authorities. All essential documentation should be retained by the institution for 
15 years (as required in Australia). 
No study document should be destroyed without prior written agreement between 
the Sponsor and the Investigator. If the Investigator wishes to assign the study 
records to another party or move them to another location, he/she must notify the 
Sponsor in writing of the new responsible person and/or the new location. 
14.3. 
Publication of Results 
Publication and reporting of results and outcomes of this trial will be accurate and 
honest, undertaken with integrity and transparency and in accordance with Impel’s 
Publication Policy.  

 
 
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Publication of results will be subjected to fair peer-review. Authorship will be 
discussed between researchers prior to study commencement (or as soon as possible 
thereafter) and reviewed whenever there are changes in participation.  
All conflicts arising through disputes about authorship will be reviewed by Impel. 
Authorship should be consistent with the guidelines described in the Australian 
Code for Responsible Conduct of Research (section on Authorship). 
Acknowledgment will be given to collaborating institutions and hospitals and other 
individuals and organisations providing finance or facilities. Subject confidentiality 
will be maintained by referring to individual subjects by their identifying code used 
in the trial. Data will not be released publicly until the manuscript is accepted for 
publication. In the case of no publication, information will only be released to the 
public and media in accordance with Impel’s Policy. 
The study protocol and subsequent results summary will be posted to a Clinical 
Trials Registry as required by legal agreement, local law or regulation. 
14.4. 
Disclosure and Confidentiality 
By signing this protocol, the Investigator agrees to keep all information provided by 
the Sponsor in strict confidence and to request similar confidentiality from his/her 
staff and the local EC. Study documents provided by the Sponsor (protocol, IB, 
eCRFs, etc.) will be stored appropriately to ensure their confidentiality. The 
information provided by the Sponsor to the Investigator may not be disclosed to 
others without direct written authorization from the Sponsor, except to the extent 
necessary to obtain informed consent from subjects who wish to participate in the 
study. 
The Investigator must ensure that the subject’s anonymity is also maintained. 
Subjects should only be identified by their initials and a subject study number on the 
eCRFs and other source documents. Other study-related documents (e.g., signed 
informed consent forms) should be kept in strict confidence by the Investigator.

 
 
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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1. 
Compliance with Good Clinical Practice 
The study will be carried out in accordance with the current version of the 
Declaration of Helsinki, concerning medical research in humans (Ethical Principles 
for Medical Research Involving Human Subjects), ICH harmonised tripartite 
guideline for GCP (ICH GCP) 1996 adopted by TGA (2000), the national statement 
on ethical conduct in human research (NHMRC, 2007), and the applicable local 
regulations. 
15.2. 
Archiving and Regulatory Inspection 
All study-related documents and records are to be retained for a minimum of 
15 years after trial completion. Written agreement from the Sponsor must precede 
destruction of the same. 
In accordance with ICH GCP, this study may be selected for audit. Inspection of site 
facilities (e.g., pharmacy, medication storage areas, laboratories) and review of 
study-related records may occur by the Sponsor, Sponsor’s representative or 
regulatory authority to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements.

 
 
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16. 
CLINICAL STUDY REPORT 
A clinical study report will be prepared with reference to ICH Guidance E3 to 
include: 
x Details of where the study was carried out 
x Dates of the start and completion of each period of the study 
x Details of the investigational product and a statement of production will 
be provided by Impel  
x A statement confirming that the applicable HREC gave written approval 
for the study in accordance with local regulations 
x A demographic listing for all subjects 
x A list of all adverse events according to INP103, benserazide, or placebo 
x Details of any occurrences which may be of significance to the study 
outcome 
x Details of all operations, calculations and transformations performed on 
the reported data 
x The statistical analysis plan and report will be produced by Impel, or their 
agents, and will be incorporated into the final report. 
x All data from any withdrawn subject not included in the statistical 
analysis not including screen failures 
x A scientific interpretation of the results 
x A description of the study methods used 
Consideration will be given to any comments on a draft report. The report will 
incorporate the analytical and statistical results and methods produced by Impel or 
their agents. A final report will be prepared to contain all the sections in the draft 
report and responses to comments on the draft report.  A statement of compliance 
covering all the areas of the study conducted according to GCP at the investigational 
site and the report, will be included. The report will be issued under the Sponsor’s 
responsibility. 
Where required by the applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The Investigator will 
be provided reasonable access to statistical tables, figures and relevant reports and 
will have the opportunity to review complete study results. Impel will also provide 
the Investigator with the full summary of study results.

 
 
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17. 
SPONSOR AND INVESTIGATOR OBLIGATIONS 
17.1. 
Protocol Amendments 
Neither the Investigator nor the Sponsor will modify or alter this protocol without 
the agreement of the other. All agreed protocol amendments will be clearly recorded 
on a protocol amendment form and will be signed and dated by the original protocol 
approving signatories. All protocol amendments will be submitted to the relevant 
institutional EC for approval before implementation, as required by local 
regulations. The only exception will be when the amendment is necessary to 
eliminate an immediate hazard to the trial subjects. In this case, the necessary action 
will be taken first, with the relevant protocol amendment following shortly 
thereafter. 
17.2. 
Protocol Deviations 
Should any significant protocol deviation occur, it must be reported to the study 
monitor as soon as is reasonably practical. The deviation and the reason for its 
occurrence must be documented, reported to the relevant HREC (if required) and 
included in the study report.  
Protocol deviations are to be reported to the institutional EC as per each HRECs 
guidelines and captured in the eCRF with the following attributes: 
x Date 
x Protocol Deviation category 
x In/Exclusion criteria not met 
x INP103, benserazide or placebo not taken as per protocol 
x Non-compliance with visit schedule 
x Other 
x Description of the deviation 
A deviation will be categorized as major if it meets any one of the following criteria: 
x Compromises the safety of the subject 
x Creates a potentially unsafe condition for other subjects on the cohort or 
study 
x Compromises the validity of results for a cohort or the study 
x Impairs conduct of the study 
x Violates regulatory constraints or guidance 
x Prematurely unblinds a study subject 

 
 
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x Compromises the privacy of a subject 
All major protocol deviations are also to be reported to the study monitor within 
24 hours of awareness on a protocol deviation form.

 
 
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18. 
REFERENCES  
1.  Tolosa E, Marti MJ, Valldeoriola F, Molinuevo JL. History of levodopa and 
dopamine agonists in Parkinson’s disease treatment. Neurology. 1998 
Jun;50(6 Suppl 6):S2-10; discussion S44-48.  
2.  Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous 
system. Adv Drug Deliv Rev. 2012 May 15;64(7):614–28.  
 

 
 
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APPENDIX 1: BLOOD BIOCHEMISTRY PARAMETERS  
The following parameters will be tested: 
x Urea (UREA) 
x Creatinine (CREAT) 
x Total Bilirubin (BILI) and Direct Bilirubin (BILDIR) 
x Albumin (ALB) 
x Total Protein (PROT) 
x Alkaline Phosphatase (ALP) 
x Creatine Kinase (CK) 
x Gamma-Glutamyl Transferase (GGT) 
x Aspartate Amino Transferase (AST) 
x Alanine Amino Transferase (ALT) 
x Glucose (GLUC)  
x Sodium (SODIUM) 
x Potassium (K) 
x Calcium (CA) 
x Chloride (CL) 
x Phosphate (PHOS) 
x Bicarbonate (BICARB) 
 
 
 

 
 
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APPENDIX 2: HAEMATOLOGY PARAMETERS  
The following parameters will be tested: 
x Haemoglobin (HGB) 
x Haematocrit (HCT)  
x Erythrocytes (RBC)  
x Platelets (PLAT)  
x Leukocytes (WBC) with differential [(including Eosinophils (EOS), 
Neutrophils (NEUT), Basophils (BASO), Lymphocytes (LYM), Monocytes 
(MONO) and Reticulocytes (RETI)] 
 
 

 
 
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APPENDIX 3: URINARY ANALYSIS PARAMETERS  
The following parameters will be tested: 
Macroscopic: 
x 
pH (PH) 
x Specific Gravity (SPGRAV) 
x Protein (PROT) 
x Glucose (GLUC) 
x Ketones (KETONES) 
x Total Bilirubin (BILI) 
x Occult Blood (OCCBLD) 
x Nitrite (NITRITE) 
x Urobilinogen (UROBIL)  
x Leukocytes (WBC) 
If abnormality is noted for protein, blood, nitrite or leukocyte esterase, at the 
discretion of the Investigator a microscopic examination of RBC, WBC, bacteria and 
casts will be performed.

 
 
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APPENDIX 4: MDS-UPDRS 
Provided as an external file. 
 
 
 

 
 
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APPENDIX 5: PROHIBITED CONCOMITANT MEDICATIONS 
The following medications will be prohibited in the study: 
x Atrosept 
x Azuphen MB 
x Balacet 
x Benzoic acid 
x Cystemms-V 
x Methylene blue 
x Darcalma 
x Darpaz 
x Darvocet A500/Darvocet N100/N50 
x Darvon/-N 
x Dolsed 
x Furazolidone 
x Hyolev MB 
x Hyophen 
x Hyoscyamine/methanamine/phenyl salicylate 
x Indiomin MB 
x Isocarboxazid 
x Linezolid 
x Olanzapine >2.5 mg/day 
x Procarbazine 
x Propoxyphene (e.g. with acetaminophen or aspirin and caffeine) 
x Phenelzine 
x Quetiapine >50 mg/day  
x Risperidone >1 mg/day  
x Sodium oxybate 
x Tranylcypromine 

 
 
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APPENDIX 6: SUBJECT QUESTIONNAIRE 
 
Site:  
 
Randomisation number: 
 
 
Instructions: 
Please ask the patient the following questions during the assessment at 120 (up to 180) minutes 
post-dosing. Please record the patient’s answers on this sheet and also transcribe into the eCRF: 
 
1. How did it feel to use the POD device to deliver your dose of L-dopa via your nose? Tick one 
response only 
a. 
 
Comfortable 
b. 
 
Uncomfortable 
 
2. How would you feel about using a POD device, and delivering your (OFF episode) rescue drug with it 
on a long-term basis?  Tick one response only 
 
a. 
 
Very happy 
b. 
 
Acceptable 
c. 
 
No opinion/it was just OK (why?) 
d. 
 
Unacceptable (why?) 
e. 
 
I really did not like it (why?) 
 
If the subject answers c, d or e above, please record the reason given below: 
 
 
 
 
3. What drug do you normally take when you have an “OFF” episode?  
 
(Please ensure this is also captured in the eCRF Concomitant medication page) 
 
 

 
 
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4) If the POD was available tomorrow, which would you prefer to use for “Off” episodes? Please record 
reason below 
 
“usual” treatment 
 
New POD  
 
Why: 
 
 
 
 
To be completed by the site staff conducting the interview and entering the responses on  this 
sheet: 
 
Name (printed) 
 
 
 
 
 
 
Signed 
 
 
 
 
Date 
 
 
 

MDS-UPDRS Permissions 
 
Permission is required to use the MDS-developed Rating Scales (with the exception of 
personal/individual use). Reproduction, translation, modification, sale, or distribution of any 
portion of the MDS Rating Scales is strictly prohibited. MDS Rating Scales may not be 
incorporated into clinical trials, training or certification programs or materials, software programs, 
or otherwise except through use of the Permissions Request Form and payment of applicable 
fees. 
 
 
Continue to p. 2 to view the MDS-UPDRS 

July 1, 2008 
Page 1 
Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
MDS-UPDRS 
 
 
The Movement Disorder Society (MDS)-sponsored new version of the UPDRS is founded on the critique 
that was formulated by the Task Force for Rating Scales in Parkinson’s disease (Mov Disord 2003;18:738-750). 
Thereafter,  the  MDS  recruited  a  Chairperson  to  organize  a  program  to  provide  the  Movement  Disorder 
community with a new version of the UPDRS that would maintain the overall format of the original UPDRS, but 
address  issues  identified  in  the  critique  as  weaknesses  and  ambiguities.  The Chairperson identif ied  
subcommittees with chairs and members. Each part was written by the appropriate subcommittee members 
and then reviewed and ratified by the entire group. These members are listed below. 
 
 
The MDS-UPDRS has four parts:   Part I (non-motor experiences of daily living), Part II (motor 
experiences of daily living, Part III (motor examination) and Part IV (motor complications).   Part I has two 
components: IA concerns a number of behaviors that are assessed by the investigator with all pertinent 
information from patients and caregivers, and IB is completed by the patient with or without the aid of the 
caregiver, but independently of the investigator.  These sections can, however, be reviewed by the rater to 
ensure that all questions are answered clearly and the rater can help explain any perceived ambiguities. Part II 
is designed to be  a  self-administered  questionnaire  like  Part  IB,  but  can  be  reviewed  by  the 
investigator  to  ensure  completeness and clarity. Of note, the official versions of Part IA, Part IB and Part II of 
the MDS-UPDRS do not have separate on or off ratings.  However, for individual programs or protocols the same 
questions can be used separately for on and off. Part III has instructions for the rater to give or demonstrate 
to the patient; it is completed by the rater.  Part IV has instructions for the rater and also instructions to be read 
to the patient. This part integrates patient-derived information with the rater’s clinical observations and judgments 
and is completed by the rater. 
The authors of this new version are: 
Chairperson: Christopher G. Goetz 
Part I: Werner Poewe (chair), Bruno Dubois, Anette Schrag 
Part II: Matthew B. Stern (chair), Anthony E. Lang, Peter A. LeWitt 
Part III:  Stanley Fahn (chair), Joseph Jankovic, C. Warren Olanow 
Part IV: Pablo Martinez-Martin (chair), Andrew Lees, Olivier Rascol, Bob van Hilten 
Development Standards: Glenn T. Stebbins (chair), Robert Holloway, David Nyenhuis 
Appendices: Cristina Sampaio (chair), Richard Dodel, Jaime Kulisevsky 
Statistical Testing: Barbara Tilley (chair), Sue Leurgans, Jean Teresi, 
Consultant: Stephanie Shaftman, Nancy LaPelle 
 
Contact person: Christopher G. Goetz, MD 
Rush University Medical Center 
1725 W. Harrison Street, Suite 755 
Chicago, IL USA 60612 
 
Telephone 312-942-8016 
Email: cgoetz@rush.edu 
 
July 1, 2008 

July 1, 2008 
Page 2 
Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
Part I: Non-Motor Aspects of Experiences of Daily Living (nM-EDL) 
 
Overview: This portion of the scale assesses the non-motor impact of Parkinson's disease (PD) on patients’ 
experiences of daily living. There are 13 questions. Part 1A is administered by the rater (six questions) and focuses 
on complex behaviors. Part 1B is a component of the self-administered Patient Questionnaire that covers seven 
questions on non-motor experiences of daily living. 
 
Part 1A: 
In administering Part IA, the examiner should use the following guidelines: 
 
1.  Mark at the top of the form the primary data source as patient, caregiver, or patient and caregiver in equal 
proportion. 
2.  The response to each item should refer to a period encompassing the prior week including the day on which the 
information is collected. 
3. All items must have an integer rating (no half points, no missing scores). In the event that an item does not 
apply or cannot be rated (e.g., amputee who cannot walk), the item is marked UR for Unable to Rate. 
4. The answers should reflect the usual level of function and words such as “usually”, “generally”, “most of the time” 
can be used with patients. 
5. Each question has a text for you to read (Instructions to patients/caregiver). After that statement, you can 
elaborate and probe based on the target symptoms outlined in the Instructions to examiner. You should NOT 
READ the RATING OPTIONS to the patient/caregiver, because these are written in medical terminology. From 
the interview and probing, you will use your medical judgment to arrive at the best response. 
6. Patients may have co-morbidities and other medical conditions that can affect their function. You and the patient 
must rate the problem as it exists and do not attempt to separate elements due to Parkinson’s disease from other 
conditions. 
 
EXAMPLE OF NAVIGATING THROUGH THE RESPONSE OPTIONS FOR PART 1A 
 
Suggested strategies for obtaining the most accurate answer: 
After reading the instructions to the patient, you will need to probe the entire domain under discussion to determine 
Normal vs. problematic: If your questions do not identify any problem in this domain, record 0 and move on to the 
next question. 
 
If your questions identify a problem in this domain, you should work next with a reference anchor at the mid-range 
(option 2 or Mild) to find out if the patient functions at this level, better or worse. You will not be reading the choices of 
responses to the patient as the responses use clinical terminology. You will be asking enough probing questions to 
determine the response that should be coded. 
 
Work up and down the options with the patient to identify the most accurate response, giving a final check by 
excluding the options above and below the selected response. 
 
 
Is this item normal for you? 
 
‘No, I have problems.’ 
 
Consider mild (2) as a reference point 
and then compare with slight (1). 
 
If mild is closer than slight. 
 
Consider moderate (3) to see if this 
answer fits better. 
 
If moderate is closer than mild. 
 
Consider severe (4) to see if this 
answer fits better. 
‘Yes’. 
 
 
 
 
‘Yes, slight is closest’. 
 
 
 
 
 
‘No, moderate is too severe’. 
 
 
 
 
 
‘No, severe is too severe’. 
 
Mark (0) Normal. 
 
 
 
 
Confirm and mark (1) Slight. 
 
 
 
 
 
Confirm and mark (2) Mild. 
 
 
 
 
 
Confirm and mark (3) Moderate. 
 
 
 
‘Yes, severe is closest.’ 
Confirm and mark (4) Severe.

July 1, 2008 
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Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
 
 
________________________________ 
Patient Name or Subject ID 
    _______________ 
Site ID 
  
 -   
  -   
 
(mm-dd-yyyy) 
Assessment Date 
  ________________ 
Investigator’s Initials 
 
 
MDS UPDRS 
Part I: Non-Motor Aspects of Experiences of Daily Living (nM-EDL) 
Part 1A: Complex behaviors: [completed by rater] 
Primary source of information: 
 Patient 
 Caregiver 
 Patient and Caregiver in Equal Proportion 
To be read to the patient: I am going to ask you six questions about behaviors that you may or may not experience. 
Some questions concern common problems and some concern uncommon ones. If you have a problem in one of the 
areas, please choose the best response that describes how you have felt MOST OF THE TIME during the PAST 
WEEK. If you are not bothered by a problem, you can simply respond NO. I am trying to be thorough, so I may ask 
questions that have nothing to do with you. 
1.1 COGNITIVE IMPAIRMENT 
Instructions to examiner: Consider all types of altered level of cognitive function including cognitive 
slowing, impaired reasoning, memory loss, deficits in attention and orientation. Rate their impact on 
activities of daily living as perceived by the patient and/or caregiver. 
Instructions to patients [and caregiver]: Over the past week have you had problems remembering things, 
following conversations, paying attention, thinking clearly, or finding your way around the house or in 
town? [If yes, examiner asks patient or caregiver to elaborate and probes for information.] 
0: Normal: 
No cognitive impairment. 
1: Slight: 
Impairment appreciated by patient or caregiver with no concrete interference with 
the patient’s ability to carry out normal activities and social interactions. 
2: Mild: 
Clinically evident cognitive dysfunction, but only minimal interference with 
the patient’s ability to carry out normal activities and social interactions. 
3: Moderate: 
Cognitive deficits interfere with but do not preclude the patient’s ability to carry 
out normal activities and social interactions. 
4: Severe: 
Cognitive dysfunction precludes the patient’s ability to carry out normal activities and 
social interactions. 
 
 
 SCORE 
 

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1.2 HALLUCINATIONS AND PSYCHOSIS 
Instructions to examiner: Consider both illusions (misinterpretations of real stimuli) and hallucinations 
(spontaneous false sensations). Consider all major sensory domains (visual, auditory, tactile, olfactory 
and gustatory). Determine presence of unformed (for example sense of presence or fleeting false 
impressions) as well as formed (fully developed and detailed) sensations. Rate the patient’s insight into 
hallucinations and identify delusions and psychotic thinking. 
Instructions to patients [and caregiver]: Over the past week have you seen, heard, smelled or felt things 
that were not really there? [If yes, examiner asks patient or caregiver to elaborate and probes for 
information.] 
0: Normal: 
No hallucinations or psychotic behavior. 
1: Slight: 
Illusions or non-formed hallucinations, but patient recognizes them without loss of 
insight. 
2: Mild: 
Formed hallucinations independent of environmental stimuli. No loss of 
insight. 
3: Moderate: 
 Formed hallucinations with loss of insight. 
4: Severe: 
 Patient has delusions or paranoia. 
  SCORE 
 
1.3 DEPRESSED MOOD 
Instructions to examiner: Consider low mood, sadness, hopelessness, feelings of emptiness or loss of 
enjoyment. Determine their presence and duration over the past week and rate their interference with 
the patient’s ability to carry out daily routines and engage in social interactions. 
Instruction to the patient (and caregiver): Over the past week have you felt low, sad, hopeless or unable 
to enjoy things? If yes, was this feeling for longer than one day at a time? Did it make it difficult for you 
carry out your usual activities or to be with people? [If yes, examiner asks patient or caregiver to 
elaborate and probes for information.] 
0: Normal: 
 No depressed mood. 
1: Slight:        Episodes of depressed mood that are not sustained for more than one day at a 
time. No interference with patient’s ability to carry out normal activities and social 
interactions. 
2: Mild: 
Depressed mood that is sustained over days, but without interference with 
normal activities and social interactions. 
3: Moderate: 
Depressed mood that interferes with, but does not preclude, the patient’s ability 
to carry out normal activities and social interactions. 
4: Severe: 
Depressed mood precludes patient’s ability to carry out normal activities and social 
interactions. 
 

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1.4 ANXIOUS MOOD 
Instructions to examiner: Determine nervous, tense, worried or anxious feelings (including panic attacks) 
over the past week and rate their duration and interference with the patient’s ability to carry out daily 
routines and engage in social interactions. 
Instructions to patients [and caregiver]:  Over the past week have you felt nervous, worried or tense? If 
yes, was this feeling for longer than one day at a time? Did it make it difficult for you to follow your usual 
activities or to be with other people? [If yes, examiner asks patient or caregiver to elaborate and probes 
for information.] 
0: Normal: 
No anxious feelings. 
1: Slight: 
Anxious feelings present but not sustained for more than one day at a time. No 
interference with patient’s ability to carry out normal activities and social interactions. 
2: Mild: 
Anxious feelings are sustained over more than one day at a time, but without 
interference with patient’s ability to carry out normal activities and social interactions. 
3: Moderate: Anxious feelings interfere with, but do not preclude, the patient’s ability to carry out 
normal activities and social interactions. 
4: Severe: 
Anxious feelings preclude patient’s ability to carry out normal activities and social 
interactions. 
SCORE 
 
1.5 APATHY 
Instructions to examiner: Consider level of spontaneous activity, assertiveness, motivation and initiative 
and rate the impact of reduced levels on performance of daily routines and social interactions. Here the 
examiner should attempt to distinguish between apathy and similar symptoms that are best explained by 
depression. 
Instructions to patients (and caregiver): Over the past week, have you felt indifferent to doing activities 
or being with people? [If yes, examiner asks patient or caregiver to elaborate and probes for information.] 
0: Normal:      No apathy. 
1: Slight: 
Apathy appreciated by patient and/or caregiver, but no interference with daily 
activities and social interactions. 
2: Mild: 
Apathy interferes with isolated activities and social interactions. 
3: Moderate:  Apathy interferes with most activities and social interactions. 
4: Severe: 
Passive and withdrawn, complete loss of initiative. 
 

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1.6 FEATURES OF DOPAMINE DYSREGULATION SYNDROME 
 
Instructions to examiner: Consider involvement in a variety of activities including atypical or 
excessive gambling (e.g. casinos or lottery tickets), atypical or excessive sexual drive or 
interests (e.g., unusual interest in pornography, masturbation, sexual demands on partner), 
other repetitive activities (e.g. hobbies, dismantling objects, sorting or organizing), or taking 
extra non-prescribed medication for non-physical reasons (i.e., addictive behavior). Rate the 
impact of such abnormal activities/behaviors on the patient’s personal life and on his family and 
social relations (including need to borrow money or other financial difficulties like withdrawal of 
credit cards, major family conflicts, lost time from work, or missed meals or sleep because of the 
activity). 
 
Instructions to patients [and caregiver]:  Over the past week, have you had unusually strong 
urges that are hard to control? Do you feel driven to do or think about something and find it 
hard to stop? [Give patient examples such as gambling, cleaning, using the computer, taking 
extra medicine, obsessing about food or sex, all depending on the patients.] 
0: Normal: 
No problems present.  
SCORE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
1: Slight: 
Problems are present but usually do not cause any difficulties for the patient or  
family/caregiver. 
 
2: Mild: 
Problems are present and usually cause a few difficulties in the patient’s personal 
and family life. 
 
3: Moderate: 
Problems are present and usually cause a lot of difficulties in the patient’s personal 
and family life. 
 
4: Severe: 
Problems are present and preclude the patient’s ability to carry out normal 
activities or social interactions or to maintain previous standards in personal and 
family life. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The remaining questions in Part I (Non-motor Experiences of Daily Living) [Sleep, Daytime Sleepiness, Pain and 
Other Sensation, Urinary Problems, Constipation Problems, Lightheadedness on Standing, and Fatigue] are in the 
Patient Questionnaire along with all questions in Part II [Motor Experiences of Daily Living]. 

July 1, 2008 
Page 7 
Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
Patient Questionnaire: 
 
 
 
 
Instructions: 
 
This questionnaire will ask you about your experiences of daily living. 
 
There are 20 questions.  We are trying to be thorough, and some of these questions may 
therefore not apply to you now or ever.  If you do not have the problem, simply mark 0 for NO. 
 
Please read each one carefully and read all answers before selecting the one that best 
applies to you. 
 
We are interested in your average or usual function over the past week including today. Some 
patients can do things better at one time of the day than at others. However, only one answer 
is allowed for each question, so please mark the answer that best describes what you can do 
most of the time. 
 
You may have other medical conditions besides Parkinson’s disease.  Do not worry about 
separating Parkinson’s disease from other conditions.  Just answer the question with your 
best response. 
 
Use only 0, 1, 2, 3, 4 for answers, nothing else.  Do not leave any blanks. 
 
Your doctor or nurse can review the questions with you, but this questionnaire is for patients 
to complete, either alone or with their caregivers. 
 
 
 
 
Who is filling out this questionnaire (check the best answer): 
 Patient 
 Caregiver 
 Patient and Caregiver in Equal Proportion 

July 1, 2008 
Page 8 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
Part I: Non-Motor Aspects of Experiences of Daily Living (nM-EDL) 
1.7  SLEEP PROBLEMS 
Over the past week, have you had trouble going to sleep at night or staying asleep 
through the night? Consider how rested you felt after waking up in the morning. 
0: Normal: 
No problems. 
1: Slight: 
Sleep problems are present but usually do not cause trouble 
getting a full night of sleep. 
2: Mild: 
Sleep problems usually cause some difficulties getting a full night 
of sleep. 
3: Moderate: 
Sleep problems cause a lot of difficulties getting a full night of 
sleep, but I still usually sleep for more than half the night. 
4: Severe: 
I usually do not sleep for most of the night. 
SCORE 
 
1.8  DAYTIME SLEEPINESS 
Over the past week, have you had trouble staying awake during the daytime? 
0: Normal: 
No daytime sleepiness. 
1: Slight: 
Daytime sleepiness occurs but I can resist and I stay awake. 
2: Mild: 
Sometimes I fall asleep when alone and relaxing.  For example, 
while reading or watching TV. 
3: Moderate: 
I sometimes fall asleep when I should not. For example, while 
eating or talking with other people. 
4: Severe: 
I often fall asleep when I should not. For example, while eating or 
talking with other people. 
 

July 1, 2008 
Page 9 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
1.9  PAIN AND OTHER SENSATIONS 
Over the past week, have you had uncomfortable feelings in your body like pain, aches 
tingling or cramps? 
0: Normal: 
No uncomfortable feelings. 
1: Slight: 
I have these feelings. However, I can do things and be with other 
people without difficulty. 
2: Mild: 
These feelings cause some problems when I do things or am with 
other people. 
3: Moderate: 
These feelings cause a lot of problems, but they do not stop me 
from doing things or being with other people. 
4: Severe: 
These feelings stop me from doing things or being with other 
people. 
SCORE 
 
1.10  URINARY PROBLEMS 
Over the past week, have you had trouble with urine control?  For example, an urgent 
need to urinate, a need to urinate too often, or urine accidents? 
0: Normal: 
No urine control problems. 
1: Slight: 
I need to urinate often or urgently.  However, these problems do 
not cause difficulties with my daily activities. 
2: Mild: 
Urine problems cause some difficulties with my daily activities. 
However, I do not have urine accidents. 
3: Moderate: 
Urine problems cause a lot of difficulties with my daily activities, 
including urine accidents. 
4: Severe: 
I cannot control my urine and use a protective garment or have a 
bladder tube. 
 

July 1, 2008 
Page 10 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
1.11  CONSTIPATION PROBLEMS 
Over the past week have you had constipation troubles that cause you difficulty 
moving your bowels? 
0: Normal: 
No constipation. 
1: Slight: 
I have been constipated.  I use extra effort to move my bowels. 
However, this problem does not disturb my activities or my being 
comfortable. 
2: Mild: 
Constipation causes me to have some troubles doing things or 
being comfortable. 
3: Moderate: 
Constipation causes me to have a lot of trouble doing things or 
being comfortable.  However, it does not stop me from doing 
anything. 
4: Severe: 
I usually need physical help from someone else to empty my 
bowels. 
SCORE 
 
1.12  LIGHT HEADEDNESS ON STANDING 
Over the past week, have you felt faint, dizzy or foggy when you stand up after sitting 
or lying down? 
0: Normal: 
No dizzy or foggy feelings. 
1: Slight: 
Dizzy or foggy feelings occur. However, they do not cause me 
troubles doing things. 
2: Mild: 
Dizzy or foggy feelings cause me to hold on to something, but I do 
not need to sit or lie back down. 
3: Moderate:    Dizzy or foggy feelings cause me to sit or lie down to avoid 
fainting or falling. 
4: Severe:        Dizzy or foggy feelings cause me to fall or faint. 
 

July 1, 2008 
Page 11 
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1.13  FATIGUE 
Over the past week, have you usually felt fatigued?  This feeling is not part of being 
sleepy or sad. 
0: Normal: 
No fatigue. 
1: Slight: 
Fatigue occurs. However it does not cause me troubles doing 
things or being with people. 
2: Mild: 
Fatigue causes me some troubles doing things or being with 
people. 
3: Moderate: 
Fatigue causes me a lot of troubles doing things or being with 
people.  However, it does not stop me from doing anything. 
4:  Severe: 
Fatigue stops me from doing things or being with people. 
SCORE 
 
Part II: Motor Aspects of Experiences of Daily Living (M-EDL) 
2.1  SPEECH 
Over the past week, have you had problems with your speech? 
0: Normal: 
Not at all (no problems). 
1: Slight: 
My speech is soft, slurred or uneven, but it does not cause others 
to ask me to repeat myself. 
2: Mild: 
My speech causes people to ask me to occasionally repeat 
myself, but not everyday. 
3: Moderate: 
My speech is unclear enough that others ask me to repeat myself 
every day even though most of my speech is understood. 
4: Severe: 
Most or all of my speech cannot be understood. 
 

July 1, 2008 
Page 12 
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2.2 SALIVA AND DROOLING 
Over the past week, have you usually had too much saliva during when you are 
awake or when you sleep? 
0: Normal: 
Not at all (no problems). 
1: Slight: 
I have too much saliva, but do not drool. 
2: Mild: 
I have some drooling during sleep, but none when I am awake. 
3: Moderate: 
I have some drooling when I am awake, but I usually do not need 
tissues or a handkerchief. 
4: Severe: 
I have so much drooling that I regularly need to use tissues or a 
handkerchief to protect my clothes. 
SCORE 
 
2.3  CHEWING AND SWALLOWING 
Over the past week, have you usually had problems swallowing pills or eating meals? 
Do you need your pills cut or crushed or your meals to be made soft, chopped or 
blended to avoid choking? 
0: Normal: 
No problems. 
1: Slight: 
I am aware of slowness in my chewing or increased effort at 
swallowing, but I do not choke or need to have my food specially 
prepared. 
2: Mild: 
I need to have my pills cut or my food specially prepared because 
of chewing or swallowing problems, but I have not choked over 
the past week. 
3: Moderate. 
I choked at least once in the past week. 
4: Severe: 
Because of chewing and swallowing problems, I need a feeding 
tube. 
 

July 1, 2008 
Page 13 
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2.4  EATING TASKS 
Over the past week, have you usually had troubles handling your food and using 
eating utensils?  For example, do you have trouble handling finger foods or using 
forks, knives, spoons, chopsticks? 
0: Normal: 
Not at all (no problems). 
1: Slight: 
I am slow, but I do not need any help handling my food and have 
not had food spills while eating. 
2: Mild: 
I am slow with my eating and have occasional food spills.  I may 
need help with a few tasks such as cutting meat. 
3: Moderate: 
I need help with many eating tasks but can manage some alone. 
4: Severe: 
I need help for most or all eating tasks. 
SCORE 
 
2.5  DRESSING 
Over the past week, have you usually had problems dressing?  For example, are you 
slow or do you need help with buttoning, using zippers, putting on or taking off your 
clothes or jewelry? 
0: Normal: 
Not at all (no problems). 
1: Slight: 
I am slow but I do not need help. 
2: Mild: 
I am slow and need help for a few dressing tasks (buttons, 
bracelets). 
3: Moderate: 
I need help for many dressing tasks. 
4: Severe: 
I need help for most or all dressing tasks. 
 

July 1, 2008 
Page 14 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
2.6  HYGIENE 
Over the past week, have you usually been slow or do you need help with washing, 
bathing, shaving, brushing teeth, combing your hair or with other personal hygiene? 
0: Normal: 
Not at all (no problems). 
1: Slight: 
I am slow but I do not need any help. 
2: Mild: 
I need someone else to help me with some hygiene tasks. 
3: Moderate: 
I need help for many hygiene tasks. 
4:  Severe: 
I need help for most or all of my hygiene tasks. 
SCORE 
 
2.7  HANDWRITING 
Over the past week, have people usually had trouble reading your handwriting? 
0: Normal: 
Not at all (no problems). 
1: Slight: 
My writing is slow, clumsy or uneven, but all words are clear. 
2: Mild: 
Some words are unclear and difficult to read. 
3: Moderate: 
Many words are unclear and difficult to read. 
4: Severe: 
Most or all words cannot be read. 
 
2.8  DOING HOBBIES AND OTHER ACTIVITIES 
Over the past week, have you usually had trouble doing your hobbies or other things 
that you like to do? 
0: Normal: 
Not at all (no problems). 
1: Slight: 
I am a bit slow but do these activities easily. 
2: Mild: 
I have some difficulty doing these activities. 
3: Moderate: 
I have major problems doing these activities, but still do most. 
4:  Severe: 
I am unable to do most or all of these activities. 
 

July 1, 2008 
Page 15 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
2.9  TURNING IN BED 
Over the past week, do you usually have trouble turning over in bed? 
0: Normal: 
Not at all (no problems). 
1: Slight: 
I have a bit of trouble turning, but I do not need any help. 
2: Mild 
I have a lot of trouble turning and need occasional help from 
someone else. 
3: Moderate: 
To turn over I often need help from someone else. 
4: Severe: 
I am unable to turn over without help from someone else. 
SCORE 
 
2.10  TREMOR 
Over the past week, have you usually had shaking or tremor? 
0: Normal: 
Not at all. I have no shaking or tremor. 
1: Slight: 
Shaking or tremor occurs but does not cause problems with any 
activities. 
2: Mild: 
Shaking or tremor causes problems with only a few activities. 
3: Moderate: Shaking or tremor causes problems with many of my daily 
activities. 
4: Severe: 
Shaking or tremor causes problems with most or all activities. 
 
2.11  GETTING OUT OF BED, A CAR, OR A DEEP CHAIR 
Over the past week, have you usually had trouble getting out of bed, a car seat, or a 
deep chair? 
0: Normal: 
Not at all (no problems). 
1: Slight: 
I am slow or awkward, but I usually can do it on my first try. 
2: Mild: 
I need more than one try to get up or need occasional help. 
3: Moderate: 
I sometimes need help to get up, but most times I can still do it on 
my own. 
4: Severe: 
I need help most or all of the time. 
 

July 1, 2008 
Page 16 
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2.12  WALKING AND BALANCE 
Over the past week, have you usually had problems with balance and walking? 
0: Normal: 
Not at all (no problems). 
1: Slight: 
I am slightly slow or may drag a leg. I never use a walking aid. 
2: Mild: 
I occasionally use a walking aid, but I do not need any help from 
another person. 
3: Moderate: 
I usually use a walking aid (cane, walker) to walk safely without 
falling. However, I do not usually need the support of another 
person. 
4: Severe: 
I usually use the support of another person to walk safely without 
falling. 
SCORE 
 
2.13  FREEZING 
Over the past week, on your usual day when walking, do you suddenly stop or freeze 
as if your feet are stuck to the floor. 
0: Normal: 
Not at all (no problems). 
1: Slight: 
I briefly freeze but I can easily start walking again. I do not need 
help from someone else or a walking aid (cane or walker) because 
of freezing. 
2: Mild: 
I freeze and have trouble starting to walk again, but I do not need 
someone’s help or a walking aid (cane or walker) because of 
freezing. 
3: Moderate: 
When I freeze I have a lot of trouble starting to walk again and, 
because of freezing, I sometimes need to use a walking aid or 
need someone else’s help. 
4: Severe: 
Because of freezing, most or all of the time, I need to use a 
walking aid or someone’s help. 
 
This completes the questionnaire.  We may have asked about problems you do not even have, 
and may have mentioned problems that you may never develop at all.  Not all patients develop all 
these problems, but because they can occur, it is important to ask all the questions to every 
patient. Thank you for your time and attention in completing this questionnaire. 

July 1, 2008 
Page 17 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
Part III: Motor Examination 
 
 
 
Overview: This portion of the scale assesses the motor signs of PD. In administering Part III of the MDS-UPDRS 
the examiner should comply with the following guidelines: 
 
At the top of the form, mark whether the patient is on medication for treating the symptoms of Parkinson's disease 
and, if on levodopa, the time since the last dose. 
 
Also, if the patient is receiving medication for treating the symptoms of Parkinson’s Disease, mark the patient’s 
clinical state using the following definitions: 
ON is the typical functional state when patients are receiving medication and have a good response. 
OFF is the typical functional state when patients have a poor response in spite of taking medications. 
 
The investigator should “rate what you see”. Admittedly, concurrent medical problems such as stroke, paralysis, 
arthritis, contracture, and orthopedic problems such as hip or knee replacement and scoliosis may interfere with 
individual items in the motor examination. In situations where it is absolutely impossible to test (e.g., amputations, 
plegia, limb in a cast), use the notation “UR” for Unable to Rate. Otherwise, rate the performance of each task as the 
patient performs in the context of co-morbidities. 
 
All items must have an integer rating (no half points, no missing ratings). 
 
Specific instructions are provided for the testing of each item. These should be followed in all instances. The 
investigator demonstrates while describing tasks the patient is to perform and rates function immediately thereafter. 
For Global Spontaneous Movement and Rest Tremor items (3.14 and 3.17), these items have been placed 
purposefully at the end of the scale because clinical information pertinent to the score will be obtained throughout the 
entire examination. 
 
At the end of the rating, indicate if dyskinesia (chorea or dystonia) was present at the time of the examination, and if 
so, whether these movements interfered with the motor examination. 
 
 
 
 
 
 
 
 
3a  Is the patient on medication for treating the symptoms of Parkinson’s Disease? 
 No  Yes 
 
 
 
 
3b 
If the patient is receiving medication for treating the symptoms of Parkinson’s Disease, 
mark the patient’s clinical state using the following definitions: 
 
 ON: On is the typical functional state when patients are receiving medication and have a good response. 
 
 OFF: Off is the typical functional state when patients have a poor response in spite of taking medications. 
 
 
 
3c  Is the patient on Levodopa ? 
 No  Yes 
 
3.C1 If yes, minutes since last levodopa dose:    
 

July 1, 2008 
Page 18 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
3.1 SPEECH 
Instructions to examiner: Listen to the patient’s free-flowing speech and engage in conversation if 
necessary. Suggested topics: ask about the patient’s work, hobbies, exercise, or how he got to the 
doctor’s office. Evaluate volume, modulation (prosody) and clarity, including slurring, palilalia (repetition 
of syllables) and tachyphemia (rapid speech, running syllables together). 
0: Normal: 
No speech problems. 
1: Slight: 
Loss of modulation, diction or volume, but still all words easy to understand. 
2: Mild: 
Loss of modulation, diction, or volume, with a few words unclear, but the overall 
sentences easy to follow. 
3: Moderate:  Speech is difficult to understand to the point that some, but not most, sentences are 
poorly understood. 
4: Severe: 
Most speech is difficult to understand or unintelligible. 
SCORE 
 
3.2 FACIAL EXPRESSION 
Instructions to examiner: Observe the patient sitting at rest for 10 seconds, without talking and also 
while talking. Observe eye-blink frequency, masked facies or loss of facial expression, spontaneous 
smiling and parting of lips. 
0: Normal: 
Normal facial expression. 
1: Slight: 
Minimal masked facies manifested only by decreased frequency of blinking. 
2: Mild: 
In addition to decreased eye-blink frequency, Masked facies present in the lower 
face as well, namely fewer movements around the mouth, such as less 
spontaneous smiling, but lips not parted. 
3: Moderate:   Masked facies with lips parted some of the time when the mouth is at rest. 
4: Severe: 
Masked facies with lips parted most of the time when the mouth is at rest. 
 

July 1, 2008 
Page 19 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
 
3.3 RIGIDITY 
Instructions to examiner: Rigidity is judged on slow passive movement of major joints with the patient in 
a relaxed position and the examiner manipulating the limbs and neck. First, test without an activation 
maneuver. Test and rate neck and each limb separately. For arms, test the wrist and elbow joints 
simultaneously. For legs, test the hip and knee joints simultaneously. If no rigidity is detected, use an 
activation maneuver such as tapping fingers, fist opening/closing, or heel tapping in a limb not being 
tested. Explain to the patient to go as limp as possible as you test for rigidity. 
0: Normal: 
No rigidity. 
1: Slight: 
Rigidity only detected with activation maneuver. 
2: Mild: 
Rigidity detected without the activation maneuver, but full range of motion is easily 
achieved. 
3: Moderate:   Rigidity detected without the activation maneuver; full range of motion is achieved 
with effort. 
4: Severe: 
Rigidity detected without the activation maneuver and full range of motion not 
achieved. 
SCORE 
 
Neck 
 
RUE 
 
LUE 
 
RLE 
 
LLE 
3.4 FINGER TAPPING 
Instructions to examiner: Each hand is tested separately. Demonstrate the task, but do not continue to 
perform the task while the patient is being tested.  Instruct the patient to tap the index finger on the 
thumb 10 times as quickly AND as big as possible.  Rate each side separately, evaluating speed, 
amplitude, hesitations, halts and decrementing amplitude. 
0: Normal: 
No problems. 
1: Slight:        Any of the following: a) the regular rhythm is broken with one or two interruptions or 
hesitations of the tapping movement; b) slight slowing; c) the amplitude decrements 
near the end of the 10 taps. 
2: Mild: 
Any of the following: a) 3 to 5 interruptions during tapping; b) mild slowing; c) the 
amplitude decrements midway in the 10-tap sequence. 
3: Moderate:   Any of the following: a) more than 5 interruptions during tapping or at least one 
longer arrest (freeze) in ongoing movement; b) moderate slowing; c) the amplitude 
decrements starting after the 1st tap. 
4: Severe: 
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements. 
 
R 
 
L 

July 1, 2008 
Page 20 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
3.5 HAND MOVEMENTS 
Instructions to examiner: Test each hand separately. Demonstrate the task, but do not continue to 
perform the task while the patient is being tested. Instruct the patient to make a tight fist with the arm 
bent at the elbow so that the palm faces the examiner. Have the patient open the hand 10 times as fully 
AND as quickly as possible. If the patient fails to make a tight fist or to open the hand fully, remind him/ 
her to do so. Rate each side separately, evaluating speed, amplitude, hesitations, halts and 
decrementing amplitude. 
0: Normal: 
No problem. 
1: Slight: 
Any of the following: a) the regular rhythm is broken with one or two interruptions or 
hesitations of the movement; b) slight slowing; c) the amplitude decrements near 
the end of the task. 
2: Mild: 
Any of the following: a) 3 to 5 interruptions during the movements; b) mild slowing; 
c) the amplitude decrements midway in the task. 
3: Moderate:   Any of the following: a) more than 5 interruptions during the movement or at least 
one longer arrest (freeze) in ongoing movement; b) moderate slowing; c) the 
amplitude decrements starting after the 1st open-and-close sequence. 
4: Severe: 
 Cannot or can only barely perform the task because of slowing, interruptions or 
decrements. 
SCORE 
 
R 
 
L 
3.6  PRONATION-SUPINATION MOVEMENTS OF HANDS 
Instructions to examiner: Test each hand separately. Demonstrate the task, but do not continue to 
perform the task while the patient is being tested. Instruct the patient to extend the arm out in front of 
his/her body with the palms down; then to turn the palm up and down alternately 10 times as fast and as 
fully as possible. Rate each side separately, evaluating speed, amplitude, hesitations, halts and 
decrementing amplitude. 
0: Normal:       No problems. 
1: Slight: 
Any of the following: a) the regular rhythm is broken with one or two interruptions or 
hesitations of the movement; b) slight slowing; c) the amplitude decrements near 
the end of the sequence. 
2: Mild: 
Any of the following: a) 3 to 5 interruptions during the movements; b) mild slowing; 
c) the amplitude decrements midway in the sequence. 
3: Moderate:   Any of the following: a) more than 5 interruptions during the movement or at least 
one longer arrest (freeze) in ongoing movement; b) moderate slowing c) the 
amplitude decrements starting after the 1st supination-pronation sequence. 
4: Severe: 
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements. 
 
R 
 
L 

July 1, 2008 
Page 21 
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3.7 TOE TAPPING 
Instructions to examiner: Have the patient sit in a straight-backed chair with arms, both feet on the floor. 
Test each foot separately. Demonstrate the task, but do not continue to perform the task while the 
patient is being tested. Instruct the patient to place the heel on the ground in a comfortable position and 
then tap the toes 10 times as big and as fast as possible. Rate each side separately, evaluating speed, 
amplitude, hesitations, halts and decrementing amplitude. 
0:   Normal: 
No problem. 
1: Slight: 
Any of the following: a) the regular rhythm is broken with one or two interruptions 
or hesitations of the tapping movement; b) slight slowing; c) amplitude 
decrements near the end of the ten taps. 
2: Mild: 
Any of the following: a) 3 to 5 interruptions during the tapping movements; b) mild 
slowing; c) amplitude decrements midway in the task. 
3: Moderate: 
Any of the following: a) more than 5 interruptions during the tapping movements 
or at least one longer arrest (freeze) in ongoing movement; b) moderate slowing; 
c) amplitude decrements after the first tap. 
4: Severe: 
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements. 
SCORE 
 
R 
 
L 
3.8 LEG AGILITY 
Instructions to examiner: Have the patient sit in a straight-backed chair with arms. The patient should 
have both feet comfortably on the floor. Test each leg separately. Demonstrate the task, but do not 
continue to perform the task while the patient is being tested. Instruct the patient to place the foot on the 
ground in a comfortable position and then raise and stomp the foot on the ground 10 times as high and 
as fast as possible. Rate each side separately, evaluating speed, amplitude, hesitations, halts and 
decrementing amplitude. 
0: Normal: 
No problems. 
1: Slight: 
Any of the following: a) the regular rhythm is broken with one or two interruptions 
or hesitations of the movement; b) slight slowing; c) amplitude decrements near 
the end of the task. 
2: Mild: 
Any of the following: a) 3 to 5 interruptions during the movements; b) mild 
slowness; c) amplitude decrements midway in the task. 
3: Moderate:     Any of the following: a) more than 5 interruptions during the movement or at 
least one longer arrest (freeze) in ongoing movement; b) moderate slowing in 
speed; c) amplitude decrements after the first tap. 
4: Severe: 
    Cannot or can only barely perform the task because of slowing, interruptions        
                            or decrements. 
 
R 
 
L 

July 1, 2008 
Page 22 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
3.9 ARISING FROM CHAIR 
Instructions to examiner: Have the patient sit in a straight-backed chair with arms, with both feet on the 
floor and sitting back in the chair (if the patient is not too short). Ask the patient to cross his/her arms 
across the chest and then to stand up. If the patient is not successful, repeat this attempt a maximum up 
to two more times. If still unsuccessful, allow the patient to move forward in the chair to arise with arms 
folded across the chest. Allow only one attempt in this situation. If unsuccessful, allow the patient to 
push off using his/her hands on the arms of the chair. Allow a maximum of three trials of pushing off. If 
still not successful, assist the patient to arise. After the patient stands up, observe the posture for item 
3.13. 
0: Normal: 
No problems. Able to arise quickly without hesitation. 
1: Slight:              Arising is slower than normal; or may need more than one attempt; or may 
need to move forward in the chair to arise. No need to use the arms of the 
chair. 
2: Mild: 
Pushes self up from arms of chair without difficulty. 
3: Moderate: 
Needs to push off, but tends to fall back; or may have to try more than one time 
using arms of chair, but can get up without help. 
4: Severe: 
Unable to arise without help. 
SCORE 
 
3.10 GAIT 
Instructions to examiner: Testing gait is best performed by having the patient walking away from and 
towards the examiner so that both right and left sides of the body can be easily observed 
simultaneously. The patient should walk at least 10 meters (30 feet), then turn around and return to 
the examiner. This item measures multiple behaviors: stride amplitude, stride speed, height of foot lift, 
heel strike during walking, turning, and arm swing, but not freezing. Assess also for “freezing of gait” 
(next item 3.11) while patient is walking. Observe posture for item 3.13. 
0: Normal: 
No problems. 
1: Slight: 
Independent walking with minor gait impairment. 
2: Mild: 
Independent walking but with substantial gait impairment. 
3: Moderate: 
Requires an assistance device for safe walking (walking stick, walker) but not a 
person. 
4: Severe: 
Cannot walk at all or only with another person’s assistance. 
 

July 1, 2008 
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Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
3.11 FREEZING OF GAIT 
Instructions to examiner:  While assessing gait, also assess for the presence of any gait freezing 
episodes. Observe for start hesitation and stuttering movements especially when turning and reaching 
the end of the task. To the extent that safety permits, patients may NOT use sensory tricks during the 
assessment. 
0: Normal: 
No freezing. 
1: Slight:            Freezes on starting, turning or walking through doorway with a single halt during 
any of these events, but then continues smoothly without freezing during straight 
walking. 
2: Mild: 
 Freezes on starting, turning or walking through doorway with more than one halt 
during any of these activities, but continues smoothly without freezing during 
straight walking. 
3: Moderate: 
Freezes once during straight walking. 
4: Severe: 
Freezes multiple times during straight walking. 
SCORE 
 
3.12 POSTURAL STABILITY 
Instructions to examiner: The test examines the response to sudden body displacement produced by a 
quick, forceful pull on the shoulders while the patient is standing erect with eyes open and feet 
comfortably apart and parallel to each other. Test retropulsion. Stand behind the patient and instruct 
the patient on what is about to happen. Explain that s/he is allowed to take a step backwards to avoid 
falling. There should be a solid wall behind the examiner, at least 1-2 meters away to allow for the 
observation of the number of retropulsive steps. The first pull is an instructional demonstration and is 
purposely milder and not rated. The second time the shoulders are pulled briskly and forcefully towards 
the examiner with enough force to displace the center of gravity so that patient MUST take a step 
backwards. The examiner needs to be ready to catch the patient, but must stand sufficiently back so as 
to allow enough room for the patient to take several steps to recover independently. Do not allow the 
patient to flex the body abnormally forward in anticipation of the pull. Observe for the number of steps 
backwards or falling. Up to and including two steps for recovery is considered normal, so abnormal 
ratings begin with three steps. If the patient fails to understand the test, the examiner can repeat the 
test so that the rating is based on an assessment that the examiner feels reflects the patient’s limitations 
rather than misunderstanding or lack of preparedness. Observe standing posture for item 3.13 
0: Normal: 
No problems: Recovers with one or two steps. 
1: Slight: 
3-5 steps, but subject recovers unaided. 
2: Mild: 
More than 5 steps, but subject recovers unaided. 
3: Moderate: 
Stands safely, but with absence of postural response; falls if not caught by 
examiner. 
4: Severe: 
Very unstable, tends to lose balance spontaneously or with just a gentle pull on 
the shoulders. 
 

July 1, 2008 
Page 24 
Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
3.13 POSTURE 
Instructions to examiner: Posture is assessed with the patient standing erect after arising from a chair, 
during walking, and while being tested for postural reflexes. If you notice poor posture, tell the patient 
to stand up straight and see if the posture improves (see option 2 below). Rate the worst posture seen 
in these three observation points. Observe for flexion and side-to-side leaning. 
0: Normal: 
No problems. 
1: Slight: 
Not quite erect, but posture could be normal for older person. 
2: Mild: 
Definite flexion, scoliosis or leaning to one side, but patient can correct posture 
to normal posture when asked to do so. 
3:  Moderate: 
Stooped posture, scoliosis or leaning to one side that cannot be corrected 
volitionally to a normal posture by the patient. 
4:   Severe: 
Flexion, scoliosis or leaning with extreme abnormality of posture. 
SCORE 
 
3.14 GLOBAL SPONTANEITY OF MOVEMENT (BODY BRADYKINESIA) 
Instructions to examiner: This global rating combines all observations on slowness, hesitancy, and 
small amplitude and poverty of movement in general, including a reduction of gesturing and of crossing 
the legs. This assessment is based on the examiner’s global impression after observing for 
spontaneous gestures while sitting, and the nature of arising and walking. 
0: Normal: 
No problems. 
1: Slight: 
Slight global slowness and poverty of spontaneous movements. 
2: Mild: 
Mild global slowness and poverty of spontaneous movements. 
3: Moderate: 
Moderate global slowness and poverty of spontaneous movements. 
4:   Severe: 
Severe global slowness and poverty of spontaneous movements. 
 
3.15 POSTURAL TREMOR OF THE HANDS 
 Instructions to examiner: All tremor, including re-emergent rest tremor, that is present in this posture is 
to be included in this rating. Rate each hand separately. Rate the highest amplitude seen. Instruct the 
patient to stretch the arms out in front of the body with palms down. The wrist should be straight and 
the fingers comfortably separated so that they do not touch each other. Observe this posture for 10 
seconds. 
0: Normal: 
No tremor. 
1: Slight: 
Tremor is present but less than 1 cm in amplitude. 
2: Mild: 
Tremor is at least 1 but less than 3 cm in amplitude. 
3: Moderate: 
Tremor is at least 3 but less than 10 cm in amplitude. 
4:   Severe: 
Tremor is at least 10 cm in amplitude. 
 
R 
 
L 

July 1, 2008 
Page 25 
Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
3.16 KINETIC TREMOR OF THE HANDS 
Instructions to examiner: This is tested by the finger-to-nose maneuver. With the arm starting from the 
outstretched position, have the patient perform at least three finger-to-nose maneuvers with each hand 
reaching as far as possible to touch the examiner’s finger. The finger-to-nose maneuver should be 
performed slowly enough not to hide any tremor that could occur with very fast arm movements. Repeat 
with the other hand, rating each hand separately. The tremor can be present throughout the movement 
or as the tremor reaches either target (nose or finger). Rate the highest amplitude seen. 
0: Normal: 
No tremor. 
1: Slight: 
Tremor is present but less than 1 cm in amplitude. 
2: Mild: 
Tremor is at least 1 but less than 3 cm in amplitude. 
3: Moderate: 
Tremor is at least 3 but less than 10 cm in amplitude. 
4:   Severe: 
Tremor is at least 10 cm in amplitude. 
SCORE 
 
R 
 
L 
3.17  REST TREMOR AMPLITUDE 
Instructions to examiner: This and the next item have been placed purposefully at the end of the 
examination to allow the rater to gather observations on rest tremor that may appear at any time during 
the exam, including when quietly sitting, during walking and during activities when some body parts are 
moving but others are at rest. Score the maximum amplitude that is seen at any time as the final score. 
Rate only the amplitude and not the persistence or the intermittency of the tremor. 
As part of this rating, the patient should sit quietly in a chair with the hands placed on the arms of the 
chair (not in the lap) and the feet comfortably supported on the floor for 10 seconds with no other 
directives. Rest tremor is assessed separately for all four limbs and also for the lip/jaw. Rate only the 
maximum amplitude that is seen at any time as the final rating. 
Extremity ratings 
0: Normal: 
No tremor. 
1: Slight: 
≤ 1 cm in maximal amplitude. 
2: Mild: 
> 1 cm but < 3 cm in maximal amplitude. 
3: Moderate: 
3 - 10 cm in maximal amplitude. 
4: Severe: 
> 10 cm in maximal amplitude. 
Lip/Jaw ratings 
0: Normal: 
No tremor. 
1: Slight: 
≤ 1 cm in maximal amplitude. 
2: Mild: 
> 1 cm but ≤ 2 cm in maximal amplitude. 
3: Moderate: 
> 2 cm but ≤ 3 cm in maximal amplitude. 
4: Severe: 
> 3 cm in maximal amplitude. 
 
RUE 
 
LUE 
 
RLE 
 
LLE 
 
Lip/Jaw 

July 1, 2008 
Page 26 
Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
3.18 CONSTANCY OF REST TREMOR 
Instructions to examiner: This item receives one rating for all rest tremor and focuses on the constancy 
of rest tremor during the examination period when different body parts are variously at rest. It is rated 
purposefully at the end of the examination so that several minutes of information can be coalesced into 
the rating. 
0: Normal: 
No tremor. 
1: Slight: 
Tremor at rest is present ≤ 25% of the entire examination period. 
2: Mild: 
Tremor at rest is present 26-50% of the entire examination period. 
3: Moderate: 
Tremor at rest is present 51-75% of the entire examination period. 
4: Severe: 
Tremor at rest is present > 75% of the entire examination period. 
SCORE 
 
DYSKINESIA IMPACT ON PART III RATINGS 
A. Were dyskinesias (chorea or dystonia) present during examination? 
  No   Yes 
B. If yes, did these movements interfere with your ratings? 
  No   Yes 
HOEHN AND YAHR STAGE 
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. 
 

July 1, 2008 
Page 27 
Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
Part IV: Motor Complications 
 
 
Overview and Instructions: In this section, the rater uses historical and objective information to assess two motor 
complications, dyskinesias and motor fluctuations that include OFF-state dystonia. Use all information from patient, 
caregiver, and the examination to answer the six questions that summarize function over the past week including 
today. As in the other sections, rate using only integers (no half points allowed) and leave no missing ratings. If the 
item cannot be rated, place UR for Unable to Rate. You will need to choose some answers based on percentages, 
and therefore you will need to establish how many hours generally are awake hours and use this figure as the 
denominator for “OFF” time and dyskinesias. For “OFF dystonia”, the total “Off” time will be the denominator. 
Operational definitions for examiner’s use. 
 
Dyskinesias: Involuntary random movements 
Words that patients often recognize for dyskinesias include “irregular jerking”, “wiggling”, “twitching”. It is essential to 
stress to the patient the difference between dyskinesias and tremor, a common error when patients are assessing 
dyskinesias. 
 
Dystonia: contorted posture, often with a twisting component: 
Words that patients often recognize for dystonia include “spasms”, “cramps”, “posture”. 
 
Motor fluctuation: Variable response to medication: 
Words that patients often recognize for motor fluctuation include “wearing out”, “wearing off”, “roller-coaster effect”, 
“on-off”, “uneven medication effects”. 
 
OFF: Typical functional state when patients have a poor response in spite of taking mediation or the typical functional 
response when patients are on NO treatment for parkinsonism. Words that patients often recognize include “low 
time”, “bad time”, “shaking time”, “slow time”, “time when my medications don’t work.” 
 
ON: Typical functional state when patients are receiving medication and have a good response: 
Words that patients often recognize include “good time”, “walking time”, “time when my medications work.” 
 
A. DYSKINESIAS [exclusive of OFF-state dystonia] 
 
                                                                                                                                                         SCORE 
4.1 TIME SPENT WITH DYSKINESIAS  
 
Instructions to examiner:  Determine the hours in the usual waking day and then the hours of 
dyskinesias. Calculate the percentage. If the patient has dyskinesias in the office, you can point them 
out as a reference to ensure that patients and caregivers understand what they are rating. You may also 
use your own acting skills to enact the dyskinetic movements you have seen in the patient before or 
show them dyskinetic movements typical of other patients. Exclude from this question early morning 
and nighttime painful dystonia. 
 
Instructions to patient [and caregiver]: Over the past week, how many hours do you usually sleep on a 
daily basis, including nighttime sleep and daytime napping? Alright, if you sleep ___ hrs, you are awake 
____ hrs. Out of those awake hours, how many hours in total do you have wiggling, twitching or jerking 
movements? Do not count the times when you have tremor, which is a regular back and forth shaking 
or times when you have painful foot cramps or spasms in the early morning or at nighttime. I will ask 
about those later. Concentrate only on these types of wiggling, jerking and irregular movements. Add 
up all the time during the waking day when these usually occur. How many hours ____ (use this 
number for your calculations). 
 
 
0: Normal: 
No dyskinesias. 
1: Slight: 
≤ 25% of waking day. 
2: Mild: 
26 - 50% of waking day. 
1. Total Hours Awake: 
  
 
3: Moderate: 
51 - 75% of waking day. 
2. Total Hours with Dyskinesia: 
  
 
4: Severe: 
> 75% of waking day. 
3. % Dyskinesia = ((2/1)*100): 
  
 

July 1, 2008 
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Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
1. Total Hours Awake: 
  
 
2. Total Hours OFF: 
  
 
3. % OFF = ((2/1)*100): 
  
 
 
4.2 FUNCTIONAL IMPACT OF DYSKINESIAS 
 
Instructions to examiner:  Determine the degree to which dyskinesias impact on the patient’s daily 
function in terms of activities and social interactions. Use the patient’s and caregiver’s response to your 
 question and your own observations during the office visit to arrive at the best answer. 
 
Instructions to patient [and caregiver]: Over the past week, did you usually have trouble doing things or 
being with people when these jerking movements occurred? Did they stop you from doing things or 
from being with people? 
 
0: Normal: 
No dyskinesias or no impact by dyskinesias on activities or social interactions. 
 
1: Slight: 
Dyskinesias impact on a few activities, but the patient usually performs all 
activities and participates in all social interactions during dyskinetic periods. 
 
2: Mild: 
Dyskinesias impact on many activities, but the patient usually performs all 
activities and participates in all social interactions during dyskinetic periods. 
 
3: Moderate: 
Dyskinesias impact on activities to the point that the patient usually does not 
perform some activities or does not usually participate in some social activities 
during dyskinetic episodes. 
 
4: Severe: 
Dyskinesias impact on function to the point that the patient usually does not 
perform most activities or participate in most social interactions during 
dyskinetic episodes. 
SCORE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B. MOTOR FLUCTUATIONS 
 
 
4.3 TIME SPENT IN THE OFF STATE 
 
Instructions to examiner: Use the number of waking hours derived from 4.1 and determine the hours 
spent in the “OFF” state. Calculate the percentage. If the patient has an OFF period in the office, you 
can point to this state as a reference. You may also use your knowledge of the patient to describe a 
typical OFF period. Additionally you may use your own acting skills to enact an OFF period you have 
seen in the patient before or show them OFF function typical of other patients. Mark down the typical 
number of OFF hours, because you will need this number for completing 4.6. 
 
Instructions to patient [and caregiver]: Some patients with Parkinson’s disease have a good effect from 
their medications throughout their awake hours and we call that “ON” time. Other patients take their 
medications but still have some hours of low time, bad time, slow time or shaking time. Doctors call these 
low periods “OFF” time. Over the past week, you told me before that you are general awake ____ hrs 
each day. Out of these awake hours, how many hours in total do you usually have this type of low level 
or OFF function ____ (use this number for your calculations).
 
0: Normal: 
No OFF time. 
 
1: Slight: 
≤ 25% of waking day. 
 
2: Mild: 
26 - 50% of waking day. 
 
3: Moderate: 
51 - 75% of waking day. 
 
4: Severe: 
> 75% of waking day. 

July 1, 2008 
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This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society 
 
 
4.4 FUNCTIONAL IMPACT OF FLUCTUATIONS 
Instructions to examiner:  Determine the degree to which motor fluctuations impact on the patient’s daily 
function in terms of activities and social interactions. This question concentrates on the difference 
between the ON state and the OFF state. If the patient has no OFF time, the rating must be 0, but if 
patients have very mild fluctuations, it is still possible to be rated 0 on this item if no impact on activities 
occurs. Use the patient’s and caregiver’s response to your question and your own observations during 
the office visit to arrive at the best answer. 
Instructions to patient [and caregiver]: Think about when those low or “OFF” periods have occurred over 
the past week. Do you usually have more problems doing things or being with people than compared to 
the rest of the day when you feel your medications working? Are there some things you usually do 
during a good period that you have trouble with or stop doing during a low period? 
0: Normal: 
No fluctuations or No impact by fluctuations on performance of activities or 
social interactions. 
1: Slight: 
Fluctuations impact on a few activities, but during OFF, the patient usually 
performs all activities and participates in all social interactions that typically 
occur during the ON state. 
2: Mild:                  Fluctuations impact many activities, but during OFF, the patient still usually 
performs all activities and participates in all social interactions that typically 
occur during the ON state. 
3: Moderate: 
Fluctuations impact on the performance of activities during OFF to the point that 
the patient usually does not perform some activities or participate in some 
social interactions that are performed during ON periods. 
4: Severe: 
Fluctuations impact on function to the point that, during OFF, the patient usually 
does not perform most activities or participate in most social interactions that 
are performed during ON periods. 
SCORE 
 
4.5 COMPLEXITY OF MOTOR FLUCTUATIONS 
Instructions to examiner:  Determine the usual predictability of OFF function whether due to dose, time 
of day, food intake or other factors. Use the information provided by the patients and caregiver and 
supplement with your own observations. You will ask if the patient can count on them always coming at 
a special time, mostly coming at a special time (in which case you will probe further to separate slight 
from mild), only sometimes coming at a special time  or are they totally unpredictable?  Narrowing down 
the percentage will allow you to find the correct answer. 
Instructions to patient [and caregiver]:  For some patients, the low or “OFF” periods happen at certain 
times during day or when they do activities like eating or exercising. Over the past week, do you usually 
know when your low periods will occur? In other words, do your low periods always come at a certain 
time? Do they mostly come at a certain time? Do they only sometimes come at a certain time? Are 
your low periods totally unpredictable?” 
0: Normal: 
No motor fluctuations. 
1: Slight: 
OFF times are predictable all or almost all of the time (> 75%). 
2: Mild: 
OFF times are predictable most of the time (51-75%). 
3: Moderate: 
OFF times are predictable some of the time (26-50%). 
4:   Severe: 
OFF episodes are rarely predictable (< 25%). 
 

July 1, 2008 
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C. “OFF” DYSTONIA 
4.6 PAINFUL OFF-STATE DYSTONIA 
Instructions to examiner: For patients who have motor fluctuations, determine what proportion of the 
OFF episodes usually includes painful dystonia? You have already determined the number of hours of 
“OFF” time (4.3). Of these hours, determine how many are associated with dystonia and calculate the 
percentage. If there is no OFF time, mark 0. 
Instructions to patient [and caregiver]:  In one of the questions I asked earlier, you said you generally 
have ____ hours of low or “OFF” time when your Parkinson's disease is under poor control. During 
these low or “OFF” periods, do you usually have painful cramps or spasms? Out of the total ____ hrs of 
this low time, if you add up all the time in a day when these painful cramps come, how many hours would 
this make? 
0: Normal: 
No dystonia OR NO OFF TIME. 
1: Slight: 
≤ 25% of time in OFF state. 
2: Mild: 
26-50% of time in OFF state. 
3: Moderate: 
51-75% of time in OFF state. 
4: Severe: 
> 75% of time in OFF state. 
 
1. Total Hours Off: 
2.  Total Off Hours w/Dystonia: 
  
 
3.  % Off Dystonia = ((2/1)*100): 
  
 
Summary statement to patient: READ TO PATIENT 
This completes my rating of your Parkinson’s disease.  I know the questions and tasks have taken several minutes, 
but I wanted to be complete and cover all possibilities. In doing so, I may have asked about problems you do not 
even have, and I may have mentioned problems that you may never develop at all. Not all patients develop all these 
problems, but because they can occur, it is important to ask all the questions to every patient. Thank you for your 
time and attention in completing this scale with me. 

Page 31 
 
Patient Name or Subject ID 
Site ID 
  
 -   
  -   
 
(mm-dd-yyyy) 
Assessment Date 
Investigator’s Initials 
 
MDS UPDRS Score Sheet 
 
1.A 
Source of information 
Patient 
Caregiver 
Patient + Caregiver 
3.3b 
Rigidity– RUE 
3.3c 
Rigidity– LUE 
Part I 
3.3d 
Rigidity– RLE 
1.1 
Cognitive impairment 
3.3e 
Rigidity– LLE 
1.2 
Hallucinations and psychosis 
3.4a 
Finger tapping– Right hand 
1.3 
Depressed mood 
3.4b 
Finger tapping– Left hand 
1.4 
Anxious mood 
3.5a 
Hand movements– Right hand 
1.5 
Apathy 
3.5b 
Hand movements– Left hand 
1.6 
Features of DDS 
3.6a 
Pronation- supination movements– Right hand 
1.6a  Who is filling out questionnaire 
         Patient 
         Caregiver 
          Patient + Caregiver 
3.6b 
 Pronation- supination movements– Left hand 
 
3.7a 
 Toe tapping– Right foot 
 
1.7 
Sleep problems 
3.7b 
Toe tapping– Left foot 
1.8 
Daytime sleepiness 
3.8a 
Leg agility– Right leg 
1.9 
Pain and other sensations 
3.8b 
Leg agility– Left leg 
1.10 
Urinary problems 
  3.9 
Arising from chair 
1.11 
Constipation problems 
3.10 
Gait 
1.12 
Light headedness on standing 
3.11 
Freezing of gait 
1.13 
Fatigue 
3.12 
Postural stability 
Part II 
3.13 
Posture 
2.1 
Speech 
3.14 
Global spontaneity of movement 
2.2 
Saliva and drooling 
3.15a 
Postural tremor– Right hand 
2.3 
Chewing and swallowing 
3.15b 
Postural tremor– Left hand 
2.4 
Eating tasks 
3.16a 
Kinetic tremor– Right hand 
2.5 
Dressing 
3.16b 
Kinetic tremor– Left hand 
2.6 
Hygiene 
3.17a 
Rest tremor amplitude– RUE 
2.7 
Handwriting 
3.17b 
Rest tremor amplitude– LUE 
2.8 
Doing hobbies and other activities 
3.17c 
Rest tremor amplitude– RLE 
2.9 
Turning in bed 
3.17d 
Rest tremor amplitude– LLE 
2.10 
Tremor 
3.17e 
Rest tremor amplitude– Lip/jaw 
2.11 
Getting out of bed 
3.18 
Constancy of rest 
2.12 
Walking and balance 
Were dyskinesias present? 
No 
Yes 
2.13 
Freezing 
Did these movements interfere with ratings? 
No 
Yes 
3a 
 Is the patient on medication? 
        No            Yes 
 Hoehn and Yahr Stage 
3b 
Patient’s clinical state 
             Off          On 
Part IV 
3c 
Is the patient on Levodopa? 
             No 
  Yes 
4.1 
Time spent with dyskinesias 
3.C1 
If yes, minutes since last dose: 
4.2 
Functional impact of dyskinesias 
Part III 
4.3 
Time spent in the OFF state 
3.1 
Speech 
4.4 
Functional impact of fluctuations 
3.2 
Facial expression 
4.5 
Complexity of motor fluctuations 
3.3a 
Rigidity– Neck 
4.6 
Painful OFF-state dystonia 
 
 
July 1, 2008 
 
Copyright © 2008 International Parkinson and Movement Disorder Society. All rights reserved 
This scale may not be copied, distributed or otherwise used in whole or in part without prior written consent of the International Parkinson and Movement Disorder Society