Conditions: Early Parkinson Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 513
Healthy volunteers: no

Brief summary:
This study consists of 2 parts. Part 1 of the study is conducted to evaluate the efficacy, safety, and tolerability of two doses of K0706 compared to placebo in subjects with early Parkinson's Disease who are not receiving dopaminergic therapy. Part 2 is an optional long term extension study for subjects who have completed week 40 of Part 1

Detailed description:
This study is designed to assess the ability of K0706 to slow the progression of PD. Preclinical animal model data have already demonstrated that K0706 has neuroprotective activity, but further development will require human clinical experience.

This study will also allow determination of safety and tolerability of K0706 over many months in subjects with PD.

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: K0706 intervention 2: K0706 intervention 3: placebo
Intervention descriptions: intervention 1: low dose, orally, once-daily intervention 2: high dose, orally, once-daily intervention 3: placebo, orally, once-daily

Protocol document:
Prot_000.pdf: 














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Name of Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
Name of Investigational Product: K0706 / placebo  
 
Secondary Endpoints: 
 
Change from baseline to Week 40 in the sum of the MDS-UPDRS Parts II and III total scores. 
 
Change from baseline to Weeks 8 through 40 in MDS-UPDRS Part IA, Part IB, Part I total, Part II 
total, and Part III sub-scores.  
 
Change in MDS-UPDRS grand total score (sum of Parts I, II, and III) from the baseline. 
 
Evaluation of slopes of the mean MDS-UPDRS Parts II and III scores over time during Part 1 by 
treatment group. 
 
Time from the first dose in Part 1 to initiation of symptomatic PD medications  
 
Change in HRQoL using the EQ-5D-5L from Baseline to Week 40 
 
Change in CGIS from Baseline to Week 40 
 
Change in the SCOPA-AUT from Baseline to Week 40 
 
Pharmacokinetics – Plasma and CSF levels of K0706 and any relevant metabolites. 
Safety / Tolerability Endpoints: 
 
Vital Signs 
 
Electrocardiography (ECG) 
 
Laboratory values 
 
Adverse Events (AEs) 
 
 
Exploratory Endpoints:   
 
Skin pathological findings that correlate with PD, 
  
 
  
 
Blood and CSF levels of emerging biomarkers (
) that predict or track PD 
progression or target engagement of K0706. 
 
Brain DaT SPECT - an imaging tool that is a marker of dopaminergic cell health. 
 
 
 
Part 2 (Weeks 40 to 80)  


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Name of Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
Name of Investigational Product: K0706 / placebo  
Primary endpoint: 
 
Incidence of treatment-emergent adverse events 
Secondary endpoints: 
 
Change from Week 40 (Baseline for Part 2) to Week 76 of the long-term extension study in the 
MDS-UPDRS Part III score  
 
Change from Week 40 (Baseline for Part 2) to Week 76 of the long-term extension study in MDS-
UPDRS Parts II and III sum score 
 
Change from Week 40 (Baseline for part 2) through Week 76 in MDS-UPDRS Part IA, Part IB, 
Part I total, Part II total, and Part III sub-scores  
 
Change in MDS-UPDRS grand total score (sum of Parts I, II, and III) from Week 40 (Baseline for 
part 2) through Week 76 
 
Time from Week 40 (Baseline for Part 2) to initiation of symptomatic PD medications in the long-
term extension study 
Exploratory endpoints: 
 
Change in the mean MDS- UPDRS Parts I, II and III scores between the early-start and delayed-
start groups at 76 weeks 
 
Evaluation of slopes of the mean MDS-UPDRS Parts II and III scores over time in part 2 for the 
early-start group as compared to the delayed-start group 
 
The proportion of patients starting symptomatic PD treatment 
Study Design  
This is a randomized, 
 double-blind, placebo-controlled, 
, to evaluate the 
efficacy, safety and tolerability of two doses of K0706 compared to placebo in subjects with early PD 
 
. This study consists of two parts. Part 1 is designed to evaluate the 
efficacy, safety, and tolerability of two dose levels of K0706 compared to placebo in subjects with early 
PD who are not receiving dopaminergic therapy. Part 2 is an optional long-term extension study to assess 
the long-term safety/tolerability of K0706 in subjects with early PD.  
 
  
Part 1: 


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Name of Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
Name of Investigational Product: K0706 / placebo  
Subjects will visit the clinic for the part 1 Screening Visit for evaluation of the eligibility criteria. All the 
screening assessments will be conducted after the subject provides informed consent. Confirmation of 
eligibility at the Part 1 Baseline visit will require the availability of laboratory results, as well as 
interpretation by the investigator of a Magnetic Resonance Imaging (MRI) of the brain and by the central 
reader of a DaT SPECT scan (obtained prior to, or as part of this study).  
 
 
 
 
 
 
 
The activities that are to be performed during the Screening period are summarized in the Screening Period 
Flow Diagram (Figure 17-1).  
Following confirmation of eligibility at the Part 1 Baseline visit, all subjects will be randomized, have 
baseline assessments, and receive the first dose of study drug. Planned visits will occur according to the 
Schedules of Assessment. The part 1 treatment assessment for efficacy will be performed at Week 40. 
 
Subjects will provide blood for measurement of standard safety laboratory parameters as well as levels of 
K0706. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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Name of Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
Name of Investigational Product: K0706 / placebo  
Should an unusual circumstance such as public health emergency (i.e., pandemic with an infectious agent), 
natural disaster or any other serious unforeseeable circumstance preclude the safe participation at the 
investigative site in the opinion of the Sponsor and Principal Investigator, an evaluation by video or 
teleconference will be an acceptable alternative. The timing and the assessments performed during such a 
remote evaluation should follow the prescribed schedule of visits whenever possible.   
Part 2 (Optional) 
Subjects who complete the EoT visit of part 1 (V11/Week 40) and who confirm their willingness to 
participate in part 2 of the study will be screened according to Part 2 eligibility criteria. Subjects who had 
been randomized to placebo in Part 1 will be rolled over to a high dose K0706 (
 
 at Week 40. Subjects that had been randomized to either dose of 
K0706 in part 1 of the study will continue on the same dosing regimen in Part 2 of the study. All subjects 
will continue treatment 
. Subjects, Investigators, and site staff not directly providing kits 
on behalf of the Sponsor, and the Sponsor will remain masked to treatment assignments until the last 
subject completes the Week 40 assessments for efficacy and the database is locked for analysis of Part 1. 
In Part 2, all subjects will be informed that they are receiving the active study drug, but will not be 
informed of the dosage or the treatment received in Part 1.  
At Week 40, all subjects in the placebo-randomized treatment arm in Part 1 who consent to participate in 
Part 2 of the study and who meet all eligibility criteria for participation in Part 2, will cross over to receive 
K0706 high dose (
 once a day 
 
. 
This will enable the collection of additional safety data for the high dose level.  Subjects who had been 
randomized to either high-dose or low-dose K0706 in Part 1 of the study will remain on the same dosing 
regimen in Part 2, thus staying on the same dose 
 of the entire study. 
Subjects will be followed for new AEs and serious adverse events (SAEs) up to 4 weeks following the last 
study drug administration. The end of the study is defined as the time the last subject completes the last 
study visit. 
 
For subjects who discontinue the study agent prior to Part 2 
 the last study 
visit is the final safety visit (4 weeks after the last administration of the study agent). 
Study Treatments and Dosage: 
Part 1 
Subjects will be equally randomized (1:1:1) to receive K0706 low dose (
 
, or high dose 
 
, or matching placebo. 
 
 
 
 


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Name of Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
Name of Investigational Product: K0706 / placebo  
 
   
Subjects will be instructed to take the study drug orally once daily. 
 
 
 
 
 
 
 
 
 Compliance with self-administration of the study drug will be verified by 
 counts and by examination of the subject diary. 
 
 
 
 
Part 2 
Subjects who had been randomized to either high dose or low dose K0706 in Part 1 of the study will 
continue to receive the same dose /equivalent dose 
 
that they were receiving on V11/Week 40. 
 
 
Subjects who had been randomized to placebo in Part 1 of the study will be rolled over to high dose K0706 
(
 in Part 2. All subjects will receive active drug 
in the long-term extension study. 
Duration of Treatment:  
Part 1 
Subjects will take the study drug (K0706 or placebo) orally, once daily, for 40 weeks. 
Part 2 
Subjects will take the study drug (K0706) orally, once daily, 
. 
Study Population:  
Subjects aged ≥ 50 years in whom an initial diagnosis of PD had been made within three years of the 
Screening visit, who score on a modified Hoehn and Yahr stage  2 
 
 will be eligible for screening.  


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Name of Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
Name of Investigational Product: K0706 / placebo  
Number of Subjects Planned:  
Approximately 506 subjects are planned in the 
 
 (placebo, low dose, and high dose K0706). 
 
   
 Eligibility Criteria  
Subjects aged ≥ 50 years with a diagnosis of PD within three years of the Screening visit, and modified 
Hoehn and Yahr stage  2 who are 
 will be eligible for screening.  
Part 1: 
Inclusion Criteria: 
1. The subject has given written informed consent and is willing to participate in the study  
2. Subject is able to understand and comply with all study procedures (requires literacy in the 
available language of all patient-reported outcome measures); 
3. Males or females aged ≥ 50 years; 
4. Body mass index (BMI) greater than 18.5 kg/m2 and less than 45 kg/m2;  
5. Diagnosed with “Clinically Probable PD” according to the MDS clinical diagnostic 
criteria, with a documented diagnosis of PD per the treating physician’s records within 
three years of the Screening visit. Disease severity according to modified Hoehn & Yahr 
stage  2; 
6. Projected to not require to start dopaminergic therapy within  months from Baseline; 
7. 
 
 
 
  
 
 
 
 
 
 
 
 
 


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Name of Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
Name of Investigational Product: K0706 / placebo  
Exclusion Criteria: 
1. Current, or within 60 days of Screening, use of any prescription, investigational, or over-
the-counter medication for the symptomatic treatment of PD or to slow the progression of 
PD. Treatment with Monoamine Oxidase B (MAOB) inhibitors will be allowed if the dose 
is stable for at least 30 days prior to Screening and subjects agree to remain on it for the 
duration of the study;  
2. Prior use of dopaminergic therapy (e.g., levodopa, dopamine agonist, amantadine) for 30 
or more days at any time in the past;  
3. A diagnosis of a significant central or peripheral nervous system disease affecting the 
subject’s cognition or motor function at any time, such as another neurodegenerative 
disorder, multiple sclerosis or stroke. This does not include transient neurological deficits 
such as transient ischemic attacks or migraine aura; 
4. A diagnosis of a medical condition that could interfere with the interpretation of the MDS-
UPDRS during the trial (e.g., musculoskeletal disorders);  
5. Contraindications to receiving an MRI; 
6. Contraindications to receiving a DaT SPECT scan (e.g., hypersensitivity to the active 
substance, any of the excipients, or iodine) if a new DaT SPECT scan is required for the 
study; 
7. Most recent DaT SPECT scans not compatible with PD (i.e., Scans Without Evidence of 
Dopaminergic Deficit [SWEDD]) based on a central reading by a study physician; 
8. MRI of the brain performed after the onset of PD suggestive of secondary Parkinsonism 
(e.g., subdural hematoma, normal pressure hydrocephalus, or infarcts of the basal ganglia); 
9. Severe tremors as defined by a score of “severe” on any of the MDS-UPDRS Parts II and 
III tremor severity (not constancy) items; 
10. Montreal cognitive assessment score < 25; 
11. History of any surgery on the brain itself, including deep brain stimulation for PD (note 
this does not include surgeries in the skull that do not affect the brain, e.g., small 
meningioma removal); 
12. History of hypersensitivity (e.g., bronchospasm, anaphylaxis, serious drug rash) to 
contents of the study drug or other tyrosine kinase inhibitors;  


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Name of Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
Name of Investigational Product: K0706 / placebo  
13. Clinically significant or unstable psychiatric or medical condition, vital sign, or laboratory 
abnormality that in the opinion of the Investigator, interferes with participation in the 
study;   
14. 
 
 
 
 
15. 
 
  
16. 
 
   
 
 
 
 
18. History of surgery within 4 weeks prior to the Screening visit or expectation of a planned 
surgical or invasive diagnostic procedure during the course of the study; 
19. Participation in other investigational drug trials within 30 days prior to Screening; 
20. 
 
 
21. Recent use of medications that can cause Parkinsonism and suspicion of the investigator 
that it could have worsened the subject’s Parkinsonism. This includes neuroleptics (e.g., 
olanzapine, risperidone, haloperidol), some anti-nausea medications (e.g., 
prochlorperizine, metoclopramide) and others (e.g., flunarizine, methyldopa); 
22. Use of medications that affect the dopaminergic system within 60 days of Screening. This 
includes stimulants (e.g., methylphenidate, amphetamine derivatives, modafinil) and 
Monoamine Oxidase A (MAOA) inhibitors (e.g., phenelzine, and tranylcypromine). Note 
that antidepressants are acceptable as long as the subject has remained on them at a stable 
dose for over 60 days prior to Screening and plans to remain on them through the study;  
23. Any malignant disease (other than basal cell carcinoma of the skin) with evidence of 
disease within the past 5 years and with the potential for recurrence; 
 
 


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Name of Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
Name of Investigational Product: K0706 / placebo  
 
 
 
 
 
 
 
Part 2 - Long Term Extension Study: 
Inclusion Criteria:  
1. Subject has completed part 1 of the study.  
2. Subject projected not to need dopaminergic treatment except for treatment with Monoamine 
Oxidase B (MAOB) inhibitors. MAOB inhibitors will be allowed if the patient was already taking 
the same during part 1 of the study.  
3. Subject has received K0706/placebo, as appropriate, within 4 weeks prior to the end of part 1 of 
the study. 
4. Male subjects enrolled in the study should not father a child and are advised to prevent the passage 
of semen to their sexual partner during intercourse using an effective method, as judged by the 
Investigator, for the duration of the study and for 3 months after the last dose of the study drug. 
Exclusion Criteria: 
1. Clinically significant or unstable psychiatric or medical condition, vital sign, or laboratory 
abnormality that in the opinion of the Investigator, interferes with participation in the study 
2. Any condition that, in the opinion of the Investigator, represents an obstacle to study conduct 
and/or represents a potentially unacceptable risk for the subject. 
3. Subject has any concurrent medical condition or uncontrolled, clinically significant systemic 
disease (e.g., renal failure, heart failure, hypertension, liver disease, diabetes, or anemia) that, in 
the opinion of the Investigator, could cause continued treatment to be detrimental to the subject. 
Statistical Method for 
: Part 1 (Day 0 to Week 40)   
Mean changes from baseline in the primary outcome measurement MDS-UPDRS Part III total score will 
be analyzed 
 The 
analysis will be performed by 
 
 
 the dependent variable based on the 
.  The analysis will include the 
treatment arm, analysis visit, region, baseline MAOB inhibitor user status, and the interaction term of 
treatment by analysis visit as the fixed, categorical effects, 
 
. 
 
 




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Name of Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
Name of Investigational Product: K0706 / placebo  
Sample size estimate 
Part 1 
Part 1 sample size estimates for this study are based on information from 
 subjects in a large cohort 
study (Parkinson’s Progression Markers Initiative) who remained off symptomatic PD medications from 
   
For this study, assuming a 
 improvement at Week 
 for the K0706 group mean over the placebo 
group mean of 
 points in change-from-baseline MDS-UPDRS Parts II and III sum score, the target 
delta is 
 points. 
 
  
Assuming a common standard deviation across treatment groups of 
 points, a sample size of 
 
evaluable 
 subjects in the high dose and placebo groups will be required to achieve 
 power. The 
comparison for the low dose group (
) will also have at least 
 power under the same 
assumptions. Additional subjects may be enrolled. 
 
 
  
Based on the data of PASADENA trial in early PD subjects (www.clinicaltrials.gov NCT03100149), the 
contribution of the MDS-UPDRS Part II to the effect size is expected to be negligible or negative, thus by 
excluding Part II and using Part III alone as the primary efficacy outcome is expected to have at least the 
same power compared to using the sum of Parts II and III. . 
 estimates in Part 2 are based on the number of subjects who complete Part 1 successfully and 
elect to participate in ongoing treatment rather than the number of subjects needed to test a statistical 
hypothesis of interest.   
  


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TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 LIST OF ABBREVIATIONS 
Abbreviation 
Expanded Form 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALL 
Acute Lymphocytic Leukemia 
AST 
Aspartate Aminotransferase 
BCRP 
Breast Cancer Resistance Protein 
BMI 
Body Mass Index 
c-Abl 
Cellular Abelson Tyrosine Kinase 
CGIS 
Clinician’s Global Impression Severity 
Cmax 
Maximum concentration 
CML 
Chronic Myeloid Leukemia 
CNS 
Central Nervous System 
CRO 
Contract Research Organization 
CSF 
Cerebrospinal fluid 
 
 
CYP 
Cytochrome P450 
DB 
Double Blind  
DaT SPECT 
Dopamine Transporter Single Photon Emission Computed Tomography 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ED 
Early Discontinuation  
EDC 
Electronic Data Capture 
EoT 
End of Treatment 
EQ-5D-5L 
EuroQol - 5 Dimensional - 5 Level 
FSH 
Follicular Stimulating Hormone 
GCP 
Good Clinical Practice  
hERG 
Human Ether a-go-go Related Gene 
HRQoL 
Health-Related Quality of Life 
 
 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
INR 
International Normalized Ratio 
IP Manual 
Investigational Product Manual 
IRB 
Institutional Review Board 
 
 
IWRS 
Interactive Web Response System 
MAOB 
Monoamine Oxidase B 
MDS-UPDRS 
Movement Disorder Society - Unified Parkinson's Disease Rating Scale  


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Mg/kg/day 
Milligrams per kilogram per day 
mL 
Milliliter 
 
 
MoCA 
Montreal Cognitive Assessment 
MRI 
Magnetic Resonance Imaging  
MSA 
Multiple System Atrophy 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
ng/mL 
Nanograms per Milliliter 
Ph+ ALL 
Philadelphia Chromosome Positive Acute Lymphocytic Leukemia  
PD 
Parkinson’s Disease 
PFF 
Pre-formed Fibril 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PSP 
Progressive Supranuclear Palsy 
aPTT 
Activated Partial Thromboplastin Clotting Time 
QTc 
Heart-rate corrected QT interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCOPA-AUT 
Scales for Outcome in Parkinson’s disease – Autonomic 
SOP 
Standard Operating Procedure 
SPARC 
Sun Pharma Advanced Research Company 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
SWEDD 
Scans Without Evidence of Dopaminergic Deficit 
TEAE 
Treatment Emergent Adverse Event 
TH 
Tyrosine Hydroxylase 
TKI 
Tyrosine Kinase Inhibitor 
WBC 
White Blood Cell 
WHO 
World Health Organization 
°C 
degrees Celsius  
°F 
degrees Fahrenheit  
 
 
 


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2.0 
BACKGROUND INFORMATION 
2.1 
Background 
Parkinson’s disease (PD) is a neurodegenerative disease that typically presents in late life and is 
primarily characterized by progressive worsening of symptoms of slowness of movement, 
tremors, and postural instability. It also causes changes in mood, autonomic system dysfunction, 
and sleep. As the disease progresses, patients become progressively less mobile with high rates 
of falls and develop swallowing difficulty, hallucinations, and dementia. One study found that 
within 10 years, 55% had died, 68% had postural instability, and 46% had dementia 
  
Pathologically, PD is characterized by progressive loss of dopamine-producing neurons in the 
substantia nigra (part of the midbrain) and formation of Lewy Bodies also in the midbrain, but 
elsewhere in the brain as well. Loss of dopamine is thought to explain the motor symptoms of the 
disease, as dopamine replacement (through the dopamine precursor L-dopa or dopamine 
agonists) improves movement speed. The underlying pathophysiology of the disease is not fully 
understood but is thought to relate to the aggregation of a protein called α -synuclein, a major 
component of Lewy Bodies. Neuronal loss and dysfunction may be directly from α -synuclein 
aggregates or indirectly through multiple other pathways, including inflammation and 
programmed cell death. 
Treatment for PD currently consists only of medications to replace the loss of dopamine 
production. These treatments can improve many (but not all) symptoms of the disease, but as the 
degeneration continues, the treatments become less and less effective. There are no interventions 
proven to slow disease progress (i.e., disease modification). To date, all attempts to modify the 
course of PD have been unsuccessful (
 
 
 
One approach for disease modification is the inhibition of c-Abl (cellular [as opposed to viral] 
Abelson Tyrosine Kinase). C-Abl has multiple roles in the maintenance of neuronal health and 
function, but its over-activation has been shown to play a role in the pathophysiology of multiple 
neurodegenerative diseases, including PD, Alzheimer’s disease, and others (
 
 C-Abl can be activated by oxidative stress (a known predictor of neurodegenerative 
diseases) as well as by α-synuclein (
 
Activated c-Abl can then lead to neurodegeneration through its phosphorylation of parkin and α-
synuclein, leading to cell death through a variety of pathways (
 
Multiple lines of evidence suggest that inhibition of c-Abl will slow the degenerative process 
underlying PD and will do so through multiple pathways, including those involving parkin and 
α-synuclein. Ko and colleagues demonstrated that inhibition of c-Abl prevents phosphorylation 
of parkin and thereby reduces neurotoxicity in the 1-methyl-4-phenyl-1, 2, 3, 6-
tetrahydropyridine (MPTP) model of PD (
 Parkin is a ubiquitin E3 ligase that 


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helps in the breakdown of proteins, and reduction in its function through phosphorylation or 
genetic mutations (e.g., autosomal recessive PD), is associated with the pathological 
underpinnings of PD. Brahmachari and colleagues further showed that c-Abl also acts via the α-
synuclein pathway – levels of c-Abl activity regulated α-synuclein activity, promoting or 
inhibiting the pathology associated with PD 
 α-Synuclein 
is a widely expressed neuronal protein that has been found to aggregate in the Lewy bodies that 
define PD pathologically, and mutations in the α-synuclein gene are associated with autosomal 
dominant PD. 
There are at least five c-Abl TKIs currently approved by the United States Food and Drug 
Administration as therapeutics in the clinical management of Chronic Myeloid Leukemia 
(CML), a disease driven by the constitutively active tyrosine kinase breakpoint cluster 
region/abelson murine leukemia viral oncogene homolog 1 (BCR::ABL1) (
 
 
  Nilotinib has been shown to cross the blood-brain barrier and thus 
has been used in various preclinical models of neurodegenerative diseases. Nilotinib has been 
shown to protect dopamine neurons and reduce motor deficits in at least three animal models of 
PD (
). Nilotinib was also 
evaluated in an open-label clinical trial on 12 patients with PD or Lewy Body Dementia (a 
similar disease to PD also associated with α-synuclein), and was associated with improved 
cognitive and motor functions in > 90% of the patients in this small unblinded study 
 
. Nilotinib, however, has significant risks, including an FDA black-box warning of QT 
prolongation, suggesting that safer alternatives should be developed for Parkinson’s disease. 
Subsequent controlled studies of nilotinib failed to confirm efficacy and demonstrated 
inadequate penetration of the blood brain barrier in humans, unlike in rodents 
 
 
2.2 
Investigational Product 
2.2.1 
Name and Description 
K0706 is a novel Abl tyrosine kinase inhibitor developed by Sun Pharma Advanced Research 
Company Limited (SPARC). It is also being investigated for the treatment of patients with CML 
or Philadelphia Chromosome Positive Acute Lymphocytic Leukemia (Ph+ ALL). 
 
 
 
2.2.2 
Non-clinical Data 
2.2.3 
Non-clinical Evidence of Efficacy 
 
MPTP is a toxin that leads to 
rapid destruction of dopaminergic substantia nigra pars compacta neurons, producing a 
Parkinsonian condition that mimics some, but not all features of PD. It was initially discovered 


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when it was inadvertently administered by heroin users leading to a rapid onset, severe, 
Parkinsonian state.  
 
 Nilotinib, a 
second-generation c-Abl TKI, was included in the study as a reference as it has previously 
reported efficacy in this model 
 Administration of MPTP in mice 
caused a marked loss of SNpc dopaminergic neurons. K0706 administration significantly 
prevented the neurodegeneration induced by MPTP. 
 
 
  
K0706 was also studied in a rat model of PD based on the injection of a virus that has been 
engineered to produce large amounts of human α-synuclein; model described in 
 
 
. In this model, 
 injection of the virus into the rat’s 
substantia nigra produces progressive loss of dopamine-producing neurons and leads to a 
Parkinsonian state. After 6 weeks, animals were sacrificed, and dopamine neuron health was 
quantified using 
 to tyrosine hydroxylase (TH, the enzyme that produces 
dopamine). 
 
 
 
 
  






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 clinical signs were observed in any 
animal, but
 
 
 
 
 
 
 
 
 
K0706 was found to be 
 in ICH battery of 
 
 
 
 
 
 The high dose of K0706 
 
 
 
 K0706 
 appear to be a potent direct or 
time-dependent inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. 
CYP inhibition profile for CYP2C8 is being investigated.  
 
 
 
. 
2.2.5 
Clinical Data  
K0706 has been investigated 
 
 
 
 
 
 
 
 
 
 
 trial in subjects with early to late-stage PD. In this 
study, 
 
 
 Subjects 
 were the same, and 




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There were no deaths. Subject 
 reported 2 SAEs: troponin increased and chest pain. 
These events occurred before the administration of the study treatment. Hence, these events were 
not considered as TEAEs.  
Overall, K0706 demonstrated reasonable safety and tolerability in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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study was designed to evaluate 
 K0706 
. 
There were 
cohorts studied, 
 K0706 
 
 
   
A total of 
subjects were screened, of which
 subjects were enrolled in the study. The safety 
population comprised 
 subjects, and the PK population comprised 
 subjects. 
There were 
 deaths, SAEs, or other significant AEs reported during the study. 
Overall, 
 clinically relevant or significant findings related to clinical laboratory results, vital 
signs, electrocardiograms, or physical examinations were observed. 
subjects 
 subjects reported 
 TEAEs.
 subjects reported  treatment-related 
TEAEs. There were 
 SAEs. Of these, TEAEs unlikely related or unrelated to study treatment 
were reported in 
 of subjects, respectively. The TEAEs were mild (
 subjects) 
to moderate (
 subjects) in intensity, and 
 were more intense.  
 fatal or unknown 
outcomes were reported. Only one subject reported one TEAE, which had not been resolved by 
the end of the study. Overall, 
 clinically relevant or significant findings related to clinical 
laboratory results, vital signs, ECGs, or physical examinations were observed. 
K0706 was safe and generally well tolerated at the doses administered in this study 
.
 
 




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2.2.6 
Summary of the Known and Potential Risks and Benefits, if any, to Human 
Subjects 
Adverse events associated with K0706 are described in the IB and in sections 2.2.5 and 6.3.  
K0706 is a BCR-ABL tyrosine kinase inhibitor with limited off-target effects. Based on its 
mechanism of action and the results of the pre-clinical toxicology studies, the anticipated 
potential toxicities in humans with K0706 include 
 
. 
K0706 is a teratogen, as are other BCR-ABL tyrosine kinase inhibitors, in view of the role of 
ABL signaling in embryo-fetal development. Otherwise, non-clinical toxicology studies with 
K0706 demonstrate a safety profile that supports administration to human subjects. 
In healthy controls, K0706 has been studied 
 Potentially-related 
TEAEs were mild and typically caused 
. The
 
 
In Parkinson’s subjects, K0706 has been studied up to 
. TEAEs were 
typically 
 and typically 
 across subjects. 
 
 
is a common TEAE with other ABL inhibitors and is typically managed with stopping the 
treatment and often does not recur with restarting of the medication). 
 
. In the Ph+ 
CML study population enrolled in 
, in the emerging clinical data, the most 
commonly observed TEAEs included the following:  
 
. 
 
 
 
 
 
 
 
  
Additionally, certain class effects are known with the clinical use of BCR-ABL tyrosine kinase 
inhibitors such as Imatinib mesylate, Dasatinib, Nilotinib, and Ponatinib in the treatment of 
Philadelphia-positive leukemia. While some of the observed AEs are common between the 
BCRABL tyrosine kinase inhibitors and contribute as a class effect, specific adverse reactions 
are associated with the structure of the BCRABL tyrosine kinase inhibitors and are unique for 
the particular TKI (e.g.: Thromboembolic episodes in patients treated with Ponatinib). Since 
K0706 is being developed as a tyrosine kinase inhibitor for the treatment of Philadelphia-positive 
leukemia, AEs commonly observed with the approved BCRABL tyrosine kinase inhibitors class 
of drugs may be observed with the clinical use of K0706.  The following AEs have been reported 


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during clinical studies and clinical use of BCR-ABL TKIs such as imatinib, dasatinib, nilotinib, 
ponatinib, and bosutinib: 
 Fluid retention: It is advised to monitor subjects for the development of signs and symptoms 
of fluid retention 
 Myelosuppression: It is advised to monitor complete blood counts regularly 
 Cardiac arrhythmias: Subjects should be advised to report signs and symptoms of slow or 
rapid heart rate. 
 Hepatic impairment: Caution is recommended in subjects with hepatic impairment 
 Heart failure: Subjects should be monitored for signs or symptoms consistent with cardiac 
dysfunction and should be treated appropriately 
 Hepatotoxicity: It is advised to monitor liver function tests regularly 
 Pancreatitis: Caution is recommended in subjects with a history of pancreatitis 
 Hemorrhage: Caution is indicated in subjects requiring medications that inhibit platelet 
function or anticoagulants 
 Pregnancy: Women should be advised of the potential hazard to the fetus and to avoid 
becoming pregnant 
 Compromised wound healing and gastrointestinal perforation 
Nilotinib is approved for CML at doses up to 1200 mg daily (European Union) and up to 800 mg 
daily (United States of America), where it carries a black box warning for QT interval 
prolongation. Sudden cardiac death and electrolyte disturbances have been reported in patients 
taking nilotinib, and it can also cause myelosuppression. In non-clinical studies of nilotinib, 
potentially pro-arrhythmic effects as evidenced by inhibition of hERG current, prolongation of 
action potential duration, and induction of triangulation and beat-to-beat variability in the 
in-vitro assay systems were observed 
 
 
 
 
 
 
 
 
 
 
Ponatinib use is associated with hepatic impairment, neuropathy, ocular toxicity, and vascular 
occlusion (arterial and venous) 
 


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There has been one open-label trial of nilotinib of five subjects with Dementia with Lewy Bodies 
(a similar condition to PD with early cognitive impairment) and 7 subjects with mid to late-stage 
PD (all but one with cognitive impairment) 
 SAEs in that study included 
myocardial infarction, hospitalization for urinary tract infection, and hospitalization for 
pneumonia. All other side effects were considered mild. Of note, most participants experienced 
increased psychotic symptoms and dyskinesias, which the authors noted suggested a 
symptomatic benefit of nilotinib (i.e., increased dopamine levels). 
Regarding potential benefits, non-clinical evidence of efficacy in animal models of PD is 
described in section 2.2.3. There have been no studies in humans regarding the effectiveness of 
K0706 on Parkinson’s disease. 
2.3 
Rationale  
2.3.1 
Rationale for the Trial and Selected Subject Population 
This study is designed to serve as a 
 trial for the ability of K0706 to slow the 
progression of PD. Preclinical animal model data have already demonstrated that K0706 has 
neuroprotective activity, but further development will require human clinical experience. This 
study will also allow the determination of the safety and tolerability of K0706 over many months 
in subjects with PD. Finally, it will provide insights into relationships between blood and CSF 
levels of K0706 and efficacy, as well as other exploratory outcome measures, all of which will 
help in the design of pivotal phase 3 trials. 
This trial is being performed in early-stage PD subjects as the primary outcome is based on 
symptoms and signs of PD (using the Movement Disorder Society - Unified PD Rating Scale 
[MDS-UPDRS]). Mid and late-stage PD subjects are not being studied as they are typically on 
dopamine replacement medication, which markedly ameliorates symptoms and signs of the 
disease, making the MDS-UPDRS no longer reflective of disease progression. There are no 
validated ways of tracking disease progression in patients on dopamine replacement medications, 
though it is an active area of research and may become available for future trials. 
The study is a 40-week trial as clinical experience and prior clinical trials, e.g., The Parkinson 
Study Group, 2004 (
) and observational studies e.g., Parkinson Progression 
Marker Initiative, 2011 
 suggest that the great majority of early-stage PD 
subjects can remain off of dopamine replacement medications for 40 weeks. An extension study 
has been designed to evaluate the safety and efficacy of the study drug at 76 weeks. This will 
help gather additional safety and efficacy data beyond 40 weeks. 
This study is powered (i.e., number of subjects chosen) to detect a 
slowing in PD 
progression over 40 weeks as measured by the sum of the MDS-UPDRS Parts II and III, when 
comparing the subjects on K0706 versus placebo. 
 
  


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2.3.2 
Rationale for Dose Selection 
Subjects enrolled under Protocol Amendment 01 or 02 were treated with 
 K0706 
(or placebo) 
 with Protocol Amendment 03, K0706 doses are changed 
 
of K0706 (or placebo) 
 formulation. Dose selection is based on an attempt to 
 the 
human K0706 
 concentration to the most effective 
 concentration in animal models of 
PD. 
 
 To 
determine the target CSF concentration, a separate group 
 
 
 
 
  
The 
formulation will be used to allow for a higher dose but minimize 
 (as 
the 
 formulation is dosed with 
). The high dose will be increased from 
 
 to 
, and the low dose will be increased from 
 to 
 
 Note that these are approximately 
  increases, as preliminary PK results from study 
 (Section 2.2.5.3 and the IB) shows that the 
 
 
 
 
 
 
Note that since animal studies suggest the potential for efficacy at doses less than 
 
, there is potential for subjects 
in the low-dose group to show efficacy as well.  
K0706 will be administered once daily as the half-life is approximately 
 
Subjects are asked to take the study drug in the 
 
 
 
 
 
 
 
 
 


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2.3.3 
Rationale for the Use of Comparator 
The comparator will be a placebo matched in appearance to K0706 to evaluate the efficacy of 
K0706 to slow PD progression accounting for the “placebo effect” of enrollment in the study and 
of taking of a daily medication. The use of a placebo is ethically justified as there are no 
medications proven to slow PD progression.  
2.3.4 
Rationale for DaT SPECT Scan as an Enrichment Tool 
PD is a pathological diagnosis that can be challenging to diagnose as other syndromes have 
similar appearance, especially in the early stages. A recent study found that in subjects with a 
clinical phenotype of PD <5 years from onset with positive response to levodopa, only 8 out of 
15 had PD when it came to autopsy 
 In that study and others, the alternative 
diagnoses included Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), 
Alzheimer's Disease, Vascular Dementia, and multiple cases with no pathology found. Other 
conditions that can mimic PD in early stages include drug-induced Parkinsonism (typically from 
dopamine antagonists) and essential tremor. As K0706 has been shown only to act on the 
pathology that causes PD, it is essential to aim to limit this trial to subjects with the highest 
likelihood of having pathologically proven PD. 
The first step for ensuring accurate diagnosis is based on the MDS clinical diagnostic criteria for 
PD (
 using the “Clinically Probable PD” Criteria. This will 
ensure subjects have clinical features consistent with PD and not those clearly consistent with 
other causes of Parkinsonism. 
To further rule out other causes of Parkinsonism, all subjects must have a Dopamine Transporter 
Single Photon Emission Computed Tomography (DaT SPECT) consistent with the diagnosis of 
PD. A DaT SPECT scan is a brain scan that quantifies the binding of a radioactive “ligand” (a 
chemical) to the dopamine transporter and serves as an indirect measure of the health of 
dopamine-producing neurons. Subjects with PD or other disorders of dopamine-producing 
neurons will have a loss of binding of the ligand, typically asymmetrically. Patients with 
Parkinsonism but normal DaT SPECT scans (i.e., Scans without Evidence of Dopaminergic 
Deficit [SWEDD]) typically have essential tremor or drug-induced Parkinsonism and therefore 
will not be included in the study. One clinical trial of early-stage PD found that 15% of subjects 
who otherwise met the criteria for PD had negative DaT SPECT scans 
 
However, DaT SPECT scanning cannot separate subjects with other neurodegenerative forms of 
Parkinsonism from those with PD. 
2.3.5 
Rationale for Primary Efficacy Endpoint 
The MDS-UPDRS is a revision of the UPDRS 
 designed to be more 
 sound and have improved instructions. The MDS-UPDRS or its predecessor the 
UPDRS has been the primary outcome measure in the great majority of clinical trials in PD 
 and a large 


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ongoing cohort study (
 thereby allowing a 
broader interpretation of the results of this study. 
The MDS-UPDRS has a total of 4 parts – Part I is non-motor experiences of daily living, Part II 
is motor experiences of daily living, Part III is motor examination, and Part IV is motor 
complications. Only Parts II and III are the measures likely to be sensitive to change in early PD, 
while Part I shows only minimal change in early PD, and Part IV is only relevant for patients on 
symptomatic medication 
 
Parts II and III both quantify the severity of movement deficits typical of PD, with Part II 
focusing on how these deficits are experienced by the patient (i.e., symptoms) while Part III is 
how they are observed by the examiner (i.e., signs).  
One recent study 
 recommends against summing parts of the MDS-UPDRS 
scores as the primary or secondary clinical outcomes for the PD clinical trials. Based on the 
concept of clinimetrical validity, the authors advocate using the MDS-UPDRS as it was 
originally envisioned and soundly tested, that is, reporting the individual parts of the MDS-
UPDRS scores separately. By taking the up-to-date external information into account, the MDS-
UPDRS Part III total score is taken as the primary efficacy outcome. 
2.3.6 
Rationale for Secondary Efficacy Endpoints 
Parts I, II, and III of MDS-UPDRS, and combinations of these scores will also be evaluated from 
baseline to earlier visits to determine the onset and time course of effect of K0706 on PD 
progression versus placebo.  
The Clinician’s Global Impression of Severity (CGIS) (
 is a single-
question, clinician-scored measure of overall disease severity widely used in neurological and 
clinical trials and validated in PD 
 
 
 The CGIS 
will serve as an overall measure of PD severity in the view of the investigator. It is possible that 
the effect of K0706 on PD progression over  months may not be detectable by a change in the 
CGIS, so results from this study will determine its potential utility in a future pivotal trial. 
PD affects autonomic nervous function causing constipation, orthostatic hypotension, and other 
symptoms. To measure this, subjects will fill out the Scales for Outcomes in PD - Autonomic 
questionnaire (SCOPA-AUT) questionnaire, which measures symptoms over the past month 
. 
This is a validated scale of autonomic symptoms recommended by the Movement Disorders 
Society 
 
Time to initiation of PD symptomatic medication will also be measured as this is an indirect 
measure of the progression of disability. This measure was used as the primary outcome measure 
in earlier trials (
 though its interpretation can be confounded 


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by the subject’s work status/profession as well as treating physician preference (
 
2011). 
Health-Related quality of life (HRQoL) will be measured using the European Quality of Life 
Questionnaire 5 level version (EQ-5D-5L) 
 
 The scale has a total of six questions, 
5 with a 5-level response and one with a visual analog scale response. It is a generic HRQoL 
scale that was initially validated in PD using the 3-level version 
 
 and more recently with the 5-level 
version 
 designed to have less of a ceiling effect than the 3-level 
version. By using this generic HRQoL scale rather than a PD-specific scale, the results of this 
study will be able to be incorporated into cost-utility analysis models. A literature review in 
April 2018 suggested that there is no data on the ability of the EQ-5D-5L to detect change in 
early-stage PD subjects, so results from this study will determine the potential utility of this 
measure in a future pivotal trial of K0706. 
2.3.7 
Rationale for Exploratory Efficacy Endpoints 
Blood will be collected at multiple time points and stored frozen for later analysis. There are 
currently no validated blood-based tests that can predict the rate of PD progression, objectively 
track PD progression, or identify target engagement of K0706, but this is an active area of 
research. Possible tests include neurofilament light chains, genetic markers of different PD 
subtypes and neuronal-origin “exosomes” which allow quantification of substances in the brain 
 Once putative tests become available, stored samples 
will be analyzed to validate them in this dataset.  
Subjects may be provided with smartphone applications, which will be used to track their motor 
behavior. Smartphones (e.g., using Android or iOS operating systems) contain sensors that can 
be used to quantify movement and speech, including touch screens, accelerometers, GPS, 
gyroscopes, and microphones. Behavior can be quantifiable through active tasks (e.g., asking 
subjects to tap on the screen or walk a set path with the phone in a pants pocket), or passive (e.g., 
recording gait throughout the day with the phone in the pants pocket). Compared to the standard 
outcome measures performed in the clinic by an expert rater, use of smartphones offers the 
potential to quantify motor behavior more accurately and objectively, as well as at a much higher 
frequency (as the devices can be used at home) 
 
 While still in the early stage of development, smartphone measures have been shown to 
distinguish patients with PD from controls
 and quantify disease severity in a 
cross-sectional study 
 Another study also showed the feasibility of using 
smartphones in a longitudinal clinical trial 
 This approach is still 
considered exploratory as the best combination of outcome measures is not known, and validity 
has not been definitively shown. Therefore, feasibility analyses will be conducted during this 
trial, likely leading to modifications throughout the trial. 


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 DaT SPECT scan (described in Section 2.3.4) will 
be used as a marker of disease progression as it has in previous trials 
 
 CSF will be used to measure K0706 levels (as a marker of brain 
penetration), as well as stored frozen for later analysis of biomarkers of PD progression or target 
engagement of K0706. There are currently no validated 
 biomarkers for these purposes, but 
there are multiple under active development, such as markers of cell death, gene expression 
arrays, and others 
 
Skin punch biopsy (Section 7.6) will be sent for pathological analysis, including quantification of 
 deposition in the autonomic nerves. Multiple studies have shown that the presence of 
phosphorylated α-synuclein in the autonomic nerves of the skin is highly specific for diseases 
caused by abnormal α-synuclein deposition (e.g., PD, MSA, Primary Autonomic Failure) and, 
therefore, should be able to exclude conditions not due to α-synuclein deposition (e.g., PSP or 
vascular Parkinsonism) and therefore progress differently  
 
 Total α-synuclein deposition in the autonomic nerves 
has been shown to correlate with the severity of PD  
 so progression of this 
marker may prove useful as a marker of target engagement of K0706. Biopsies will be performed 
from a proximal site, such as the posterior neck, as proximal sites are more sensitive to α-
synuclein deposition than distal ones 
 
 
 
 
 
  
2.3.8 
Rationale for the long-term extension study 
The long-term extension study is designed to evaluate the long-term safety and efficacy of 
K0706 in subjects who have completed part 1 of the study.  
2.4 
Compliance Statement for Study Conduct in Accordance With Protocol, GCP and 
Applicable Regulatory Requirements 
The study protocol, amendments to the protocol, IB, procedures for the recruitment of subjects 
(e.g., advertisements), the subjects’ information and informed consent form as well as consent 
form updates (if applicable), written information to be provided to the subjects, available safety 
information, information about payment and compensation available to subjects, the 
investigator’s current curriculum vitae and/or other documentation evidencing qualifications, and 
any other documents will be submitted to the Institutional Review Board (IRB)/Ethics 
Committee (EC), which is constituted according to local law to obtain approval before initiation 
of the study and as applicable thereafter. 


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The study will only be initiated after receipt of approval from the IRB or EC and/or regulatory 
authority. The investigator will report promptly to the IRB/EC new information that may 
adversely affect the safety of the subjects or the conduct of the study. 
The Principal Investigator (PI) will follow the protocol in conformity with Good Clinical 
Practice (GCP) described in Guideline E6 of the ICH (International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use) and applicable regulatory 
requirements. 
Before admission into the study, the written informed consent form must be signed and 
personally dated by the subject and by the PI or designee who conducted the informed consent 
discussion. 
In obtaining and documenting informed consent, the Principal Investigator must comply with the 
applicable regulatory requirement(s) and adhere to GCP. 
The PI must inform the subject of all pertinent aspects of the study, including the written 
information approved/favorably assessed by the IRB/EC.


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3.0 
STUDY OBJECTIVES 
3.1 
Part 1 (Day 0 to Week 40) 
3.1.1 
Primary Objective 
 To determine if K0706 reduces the rate of progression of early-stage PD versus placebo over 
40 weeks, as assessed by the MDS-UPDRS (Movement Disorder Society – Unified 
Parkinson’s Disease Rating Scale) Part III (motor examination) total score. 
3.1.2 
Secondary Objectives 
 To determine if K0706 reduces the rate of progression of early-stage PD versus placebo over 
40 weeks by a greater magnitude in the subgroup of patients excluding mild-motor 
predominant sub-type (
). The rate of progression is assessed by the 
MDS-UPDRS Part III total score. 
 To determine if K0706 reduces the rate of progression of early-stage PD versus placebo over 
40 weeks by a greater magnitude in the subgroup of patients with serum NfL value ≥ 13 
pg/mL at baseline (
). The rate of progression is assessed by the MDS-
UPDRS Part III total score. 
 To determine if K0706 reduces the rate of progression of early-stage PD versus placebo over 
40 weeks, as assessed by the sum of the MDS-UPDRS Parts II and III total scores. 
 To determine if K0706 slows early-stage PD progression compared to placebo by increasing 
the time to significant worsening on the MDS-UPDRS Parts I, II, and III.  
 
 
 
 To evaluate the efficacy of K0706 compared to placebo in terms of Health-Related Quality of 
Life (HRQoL) as measured by the European Quality of Life Questionnaire 5 level version 
(EQ-5D-5L). 
 To determine if K0706 slows the progression of early-stage PD compared to placebo over 40 
weeks in terms of overall severity of PD as measured by the Clinician Global Impression 
Severity (CGIS) scale. 
 To evaluate the effect of K0706 compared to placebo on autonomic nervous system 
dysfunction related to PD as measured by the Scales for Outcome in PD - Autonomic 
(SCOPA-AUT). 
 To evaluate the safety and tolerability of K0706.  
 To evaluate the relationship between plasma and cerebrospinal fluid (CSF) concentrations of 
K0706 and the measures of efficacy and safety.  
3.1.3 
Exploratory Objectives: 
 To evaluate the effect of K0706 on skin pathology markers of PD. 
 To evaluate the effect of K0706 on blood and cerebrospinal fluid (CSF) biomarkers linked to 
PD and target engagement of K0706. 


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 To investigate genetic and clinical markers that predict the degree of progression of early-
stage PD and/or response to K0706. 
 To evaluate the effect of K0706 on dopamine cell health in PD as detected via Dopamine 
Transporter Single Photon Emission Computed Tomography (DaT SPECT) brain imaging. 
 
 
 
3.2 
Part 2 (Week 40 to Week 80) 
3.2.1 
Primary Objective 
To assess the long-term safety/tolerability of K0706 in subjects with early PD 
3.2.2 
Secondary Objective 
To assess the initial and long-term efficacy of K0706 in subjects with early PD 
3.2.3 
Exploratory Objective 
To assess the efficacy of K0706 in subjects with delayed treatment initiation relative to those 
with early treatment initiation 
3.3 
 Events: Part 1 (Day 0 to Week 40) 
 To support the primary objective of the trial for Part 1, the 
 will be used 
for the 
 analysis. Part 1 of this trial is to clarify the efficacy of the K0706 in 
improving the MDS-UPDRS Part III score in a 
 situation had 
 subjects had an 
 
 
. 
 
 
 


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4.0 
SELECTION OF SUBJECTS 
4.1 
Description of the Study Population 
Subjects aged ≥ 50 years with a diagnosis of PD made 
 
and modified Hoehn and Yahr stage  2 who are 
 
 will be eligible for screening.  
4.2 
Part 1 
4.2.1 
Inclusion Criteria 
1. The subject has given written informed consent and is willing to participate in the study;  
2. Subject is able to understand and comply with all study procedures (requires literacy in 
the available language of all patient-reported outcome measures); 
3. Males or females aged ≥ 50 years; 
4. Body mass index (BMI) greater than 18.5 kg/m2 and less than 45 kg/m2;  
5. Diagnosed with “Clinically Probable PD” according to the MDS clinical diagnostic 
criteria, with a documented diagnosis of PD per the treating physician’s records within 
three years of the Screening visit. Disease severity according to modified Hoehn & Yahr 
stage  2; 
6. Projected to not require starting dopaminergic therapy within  months from Baseline; 
7. 
 
 
 
  
 
 
 
 
 
9. 
 
 
 
4.2.2 
Exclusion Criteria 
1. Current, or within 60 days of Screening, use of any prescription, investigational, or over-
the-counter medication for the symptomatic treatment of PD or to slow the progression of 
PD. Treatment with Monoamine Oxidase B (MAOB) inhibitors will be allowed if the 
dose is stable for at least 30 days prior to Screening and subjects agree to remain on it for 
the duration of the study;  


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2. Prior use of dopaminergic therapy (e.g., levodopa, dopamine agonist, amantadine) for 
30 or more days any time in the past;  
3. A diagnosis of a significant central or peripheral nervous system disease affecting the 
subject’s cognition or motor function at any time, such as another neurodegenerative 
disorder, multiple sclerosis, or stroke. This does not include transient neurological 
deficits such as transient ischemic attacks or migraine aura; 
4. A diagnosis of a medical condition that could interfere with the interpretation of the 
MDS-UPDRS during the trial (e.g., musculoskeletal disorders);  
5. Contraindications to receiving an MRI; 
6. Contraindications to receiving a DaT SPECT scan (e.g., hypersensitivity to the active 
substance, any of the excipients, or iodine) if a new DaT SPECT scan is required for the 
study; 
7. Most recent DaT SPECT scans are not compatible with PD (i.e., Scans Without Evidence 
of Dopaminergic Deficit [SWEDD]) based on a central reading by a study physician; 
8. MRI of the brain obtained after the onset of PD suggestive of secondary Parkinsonism 
(e.g., subdural hematoma, normal pressure hydrocephalus, or infarcts of the basal 
ganglia); 
9. Severe tremors as defined by a score of “severe” on any of the MDS-UPDRS Parts II or 
III tremor severity (not constancy) items; 
10. Montreal cognitive assessment score < 25; 
11. History of any surgery on the brain itself, including deep brain stimulation for PD (note 
this does not include surgeries in the skull that do not affect the brain, e.g., small 
meningioma removal); 
12. History of hypersensitivity (e.g., bronchospasm, anaphylaxis, serious drug rash) to 
contents of the study drug or other tyrosine kinase inhibitors;  
13. Clinically significant or unstable psychiatric or medical condition, vital sign, or 
laboratory abnormality that, in the opinion of the Investigator interferes with participation 
in the study;   
14. 
 
 
 
 
 
15. 
 
  


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18. History of surgery within 4 weeks prior to the Screening Visit or expectation of a planned 
surgical or invasive diagnostic procedure during the course of the study; 
19. Participation in other investigational drug trials within 30 days prior to Screening; 
20. Any concomitant medication or medication excluded that could put the subject at risk or 
interfere with study evaluations (Section 6.4); 
21. Recent use of medications that can cause Parkinsonism and suspicion of the investigator 
that it could have worsened the subject’s Parkinsonism. This includes neuroleptics (e.g., 
olanzapine, risperidone, haloperidol), some anti-nausea medications (e.g., 
prochlorperizine, metoclopramide), and others (e.g., flunarizine, methyldopa); 
22. Use of medications that affect the dopaminergic system within 60 days of Screening. This 
includes stimulants (e.g., methylphenidate, amphetamine derivatives, modafinil) and 
Monoamine Oxidase A (MAOA) inhibitors (e.g., phenelzine, and tranylcypromine). Note 
that antidepressants are acceptable as long as the subject has remained on them at a stable 
dose for over 60 days prior to Screening and plans to remain on them through the study;   
23. Any malignant disease (other than basal cell carcinoma of the skin) with evidence of 
disease within the past 5 years and with the potential for recurrence; 
 
 
 
 
 
 
 
 
 
 
4.3 
Part 2 
4.3.1 
 Inclusion Criteria 
1. Subject has completed part 1 of the study 
2. Subject projected not to need dopaminergic treatment except for treatment with 
Monoamine Oxidase B (MAOB) inhibitors. MAOB inhibitors will be allowed if the 
patient was already taking the same during part 1 of the study. 
3. Subject has received K0706/placebo within 4 weeks prior to the end of part 1 of the 
study. 


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4. Male subjects enrolled in the study should not father a child and are advised to prevent 
the passage of semen to their sexual partner during intercourse using an effective method, 
as judged by the Investigator, for the duration of the study and for 3 months after the last 
dose of study drug. 
4.3.2 
 Exclusion Criteria 
1. Clinically significant or unstable psychiatric or medical condition, vital sign, or 
laboratory abnormality that, in the opinion of the Investigator interferes with participation 
in the study 
2. Any condition that, in the opinion of the Investigator, represents an obstacle for study 
conduct and/or represents a potentially unacceptable risk for the subject. 
3. Subject has any concurrent medical condition or uncontrolled, clinically significant 
systemic disease (e.g., renal failure, heart failure, hypertension, liver disease, diabetes, or 
anemia) that, in the opinion of the Investigator, could cause continued treatment to be 
detrimental to the subject.


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5.0 
STUDY DESIGN 
5.1 
Description of Type and Design of Study  
This is a randomized, multicenter, double-blind, placebo-controlled, 
 study to 
evaluate the efficacy, safety, and tolerability of two dose levels of K0706 in subjects with early 
PD who are not receiving symptomatic therapy. This study consists of two parts. Part 1 is 
designed to evaluate the efficacy, safety, and tolerability of two dose levels of K0706 compared 
to placebo in subjects with early stage PD. Part 2 is an optional long-term extension study assess 
the long-term safety/tolerability of K0706 in subjects with early PD. 
 
 
 
 
Part 1 
Subjects will visit the clinic for the part 1 Screening Visit, be screened based on the eligibility 
criteria, and provide written informed consent. Confirmation of eligibility at the Part 1 Baseline 
visit will require the availability of laboratory results, as well as Investigator interpretation of 
Magnetic Resonance Imaging (MRI) of the brain and central reading of a DaT SPECT scan 
(obtained prior to or as part of this study).  
 
 
 
 
 
 
. The screening 
period is summarized in the Screening Period Flow Diagram (Figure 17-1). Following 
confirmation of eligibility at the Part 1 Baseline visit, all subjects will be randomized, have 
baseline assessments performed, and receive the first dose of the study drug. This will be 
followed by planned visits as per the Schedule of Assessments. The part 1 treatment assessment 
for efficacy will be performed at Week 40. Subjects choosing not to continue in part 2 will return 
for a follow-up visit at Week 44. 
Subjects will provide blood for the measurement of standard safety laboratory parameters and of 
levels of K0706. 
 
 
. 
 
 
 


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If a subject chooses to begin taking symptomatic PD medication during the trial, they will be 
discontinued from the study and will be asked to come in for an Early Discontinuation (ED) visit 
for their final assessment. They will be requested to perform this visit prior to initiation of 
symptomatic medication. The date of initiation of symptomatic medication will be documented 
appropriately in source notes and eCRF. 
Should an unusual circumstance such as public health emergency (i.e., pandemic with an 
infectious agent) or a natural disaster, or any other serious unforeseeable circumstances arise, 
video conference or teleconference between the subject and site Investigator will be permitted to 
ensure the safe participation of the subjects in case onsite visits are not possible as assessed by a 
visit at the Investigative site in the opinion of the Sponsor and PI. The timing of these 
tele/videoconferences should be as per the visit schedule so far as possible. The assessments 
which are possible to be done remotely should be completed in so far as possible. These remote 
evaluations should follow the schedule of visits whenever possible.   
Part 2 (Optional) 
Subjects who complete the EoT visit of part 1 (v11/Week 40) and who consent to participate in 
part 2 of the study will be screened according to Part 2 eligibility criteria. Subjects who had been 
randomized to placebo dosing in Part 1 will be rolled over to a high dose 
 
at Week 40 or their first dosing opportunity in Part 2. This 
will enable the collection of additional safety data for the high dose level. Subjects who were 
randomized to K0706 (either dose level) in Part 1 of the study will remain on the same dosing 
regimen in Part 2. All part 2 subjects will continue treatment for up to 36 additional weeks. 
Treatment assignments will remain masked to subjects, Investigators, and site staff not directly 
provisioning kits on behalf of the Sponsor, and the Sponsor will remain masked to treatment 
assignments until the last subject completes the Week 40 assessments for efficacy and the 
clinical database is locked for the analysis of part 1. In Part 2, all subjects will be informed that 
they are receiving the active study drug but will not be informed of the dosage or the treatment 
received in Part 1. 
5.2 
General Instructions for Study Visits 
The Schedule of Assessments (Appendix 1) provides an overview of the timing of each visit, 
with an allowed time window for the visit, along with events to occur at each visit. Individual 


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trial procedures are described below, though efficacy assessments are described in more detail in 
Section 7.0, and AE reporting is described in more detail in Section 8.0.  
If a subject misses a visit, they should be asked to come in as soon as possible for that visit, but 
no later than 2 weeks prior to the subsequent visit for visits spaced 4 or 8 weeks apart, and no 
later than 1 week prior to the subsequent visit for visits spaced 2 weeks apart.  
If a subject misses two visits in a row without making the visit for a reasonable amount of time, 
the Sponsor should be notified; in these cases, the Sponsor has the right to remove the subject 
from the study. 
If a subject misses a visit with extra testing (e.g., K0706 blood level or CSF collection), then that 
testing can be performed before the subsequent visit and should be marked as an unscheduled 
visit.  
Instructions on the collection, processing, storage, and shipment of samples are provided in a 
separate Laboratory Manual.   
Table 5-1 summarizes the approximate blood volumes for sampling during part 1 of the study. 
Additional samples may be drawn if needed for safety purposes at the discretion of the 
Investigator. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 Table 5-2 summarizes the approximate blood volume sampling for the long-term extension 
study. Additional samples may be drawn if needed for safety purposes or based on the 
Investigator's discretion. 


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Some visits require a blood draw for determination of K0706 levels prior to administration of a 
dose (i.e., trough level). If the subject inadvertently takes the study drug prior to the visit, the 
subject should be asked to return within the following week for a blood draw for a pre-dose PK 
sample.  
Subjects should be called within 1 week prior to each scheduled visit to remind them of the visit 
date, as well as to bring in their diary, 
 and any remaining study 
drug for 
count. Remind the subject to perform the s
tasks when relevant 
(Section 7.10). Remind subjects to have a typical amount of caffeine intake on all visits days to 
avoid caffeine withdrawal as well as excessive use exacerbating any tremor.  
5.3 
Schedule of Assessments  
Part 1 (Day 1 to Week 40) 
 
 
   
 
 
  
 
 
  
 
 
 
 


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 
 
 
 
 
 
 
 


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For subjects choosing to participate in part 2 long-term extension, please see Section 5.3.17 


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5.3.16 
Unscheduled Visits 
An unscheduled visit is defined as any visit to the Investigator site outside of the protocol-
specified time points because of safety reasons or when a repeated measurement is required (e.g., 
obvious measurement errors, confirmation of out-of-range results), or if a test is missed at a visit 
and needs to be performed, or for dispensing study drug to the subject, where the subject is seen 
by study personnel. 
All unscheduled visits and assessments performed during the visits will be recorded in the 
subject’s source documents and electronic Case Report Form (eCRF). During any unscheduled 
visits the Investigator will record any AEs and concomitant medications. They will also perform 
any assessments, collect samples that they deem necessary and will record having done so. 
Part 2 (Weeks 40 – 80) 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
   
 
 
 
  
 
 


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5.4 
Measures Taken to Avoid Bias 
5.4.1 
Subject Number 
Subjects will be allotted a unique Subject number at the time of consent. The Subject Number 
will appear on all study documents relating to that subject and will be cross-referenced by the 
subject’s year of birth. 
5.4.2 
Randomization 
A computer-generated randomization scheme will be produced by the Sponsor or its designee.  
Randomization will be 1:1:1 to each dose group and 
 based on assignment to 
 
 region (United States or non-United States), and use of a Monoamine Oxidase B 
(MAOB) Inhibitor.  
5.4.3 
Blinding 
In order to maintain the double-blind nature of the study, all study-related individuals, including 
the subjects, ancillary study center staff, clinical monitor(s), Investigator, Sponsor and Contract 
Research Organization (CRO) staff, will remain blinded to the administered treatment. The 
blinding code will be stored in the IWRS system, available only to parties independent of study 
conduct. The bioanalytical team will remain unblinded to obviate the need to analyze samples 
from subjects assigned to placebo. 
The treatment code will be broken after Part 1 database is cleaned and locked. Before the 
database lock for the final analysis of Part 1, a data review will be undertaken to identify the per-
protocol population (Section 9.5). After the database lock for the final analysis of Part 1, 
unblinding will be performed by matching the randomization codes to the data in the database, 
and the results will be analyzed. 
The treatment code may be revealed on an individual basis in the case of an SAE, for which the 
investigator must know the identity of the study medication to initiate appropriate treatment. The 
investigator will use the IWRS to unblind the subject. Only Principal Investigators or 
appropriately delegated sub-Investigators will be given access to open the blind for an individual 
subject. If the blind is broken, the site must inform the medical monitor or designee and report 
the reason for unblinding. The date, time and reason for unblinding, with the Investigator’s 
signature, must be recorded. All SAEs will be evaluated for causality by the investigator or 
designee. A designated Sponsor’s safety team member will be unblinded for any SUSAR for 
regulatory reporting purposes. Unblinding is for regulatory reporting purposes only and all other 
study-related individuals, including the subjects, ancillary study center staff, clinical monitor(s), 
Investigator, Sponsor, and CRO staff, will remain blinded to the administered treatment. 




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5.5.1 
Lost to Follow-Up 
Randomized subjects who have received at least one dose of the study drug but not evaluated for 
subsequent visits will be considered as lost to follow-up. The Investigator will make every effort 
to contact subjects lost to follow-up and ask them to return for an Early Discontinuation Visit. 
Subjects lost to follow-up will not be replaced. 
5.5.2 
Discontinued due to Adverse Event 
Subjects who discontinued the study drug due to the occurrence of an AE will be recorded as 
dropouts. The AE will be recorded. All subjects, irrespective of the time of dropout (after being 
randomized and having taken at least one dose of study treatment), will be considered for 
inclusion in the safety analysis. 
5.5.3 
Replacement of Subjects 
Subjects who drop out after randomization or who are discovered to have major protocol 
deviations (defined in Statistical Analysis Plan) may be replaced as per Sponsor preference. 
5.5.4 
Premature Discontinuation of the Complete Study 
If the trial is prematurely terminated or suspended for any reason, the Investigator/Institution 
should promptly inform the trial subjects, should assure appropriate therapy and follow-up for 
the subjects, and, where required by the applicable regulatory requirement(s), should inform the 
regulatory authority (ies). Additionally: 
1) If the investigator terminates or suspends a trial without the prior agreement of the Sponsor, 
the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/EC and should 
provide the sponsor and the IRB/EC a detailed written explanation of the termination or 
suspension. 
The sponsor may discontinue the entire study at any time, for business, ethical, or scientific reasons, 
in agreement with the investigator. If the sponsor terminates or suspends a trial, the 
investigator should promptly inform the institution where applicable and the 
investigator/institution should promptly inform the IRB/EC and provide the IRB/EC a 
detailed written explanation of the termination or suspension. 
If the IRB/EC terminates or suspends its approval/favorable opinion of a trial, the investigator 
should inform the institution where applicable, and the investigator/institution should 
promptly notify the sponsor and provide the sponsor with a detailed written explanation of 
the termination or suspension. 
5.6 
The Identification of Any Data to be Recorded Directly in the eCRF 
No data will be directly recorded in eCRF. Subjects’ information will be documented on source 
documents and then transferred to the individual eCRFs. The original reports, e.g., laboratory 


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reports, will be kept at the study site. The date and time of the report will be transcribed to 
specific sections in the eCRF.


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6.0 
TREATMENT OF SUBJECTS 
6.1 
Investigational Medicinal Products 
6.1.1 
Study Medication 
The study medication comes as a 
 
 Other formulations are being developed. 
 
  
(Table 6-1).   
 
 
The placebo 
 formulation will contain the same excipients as that of the K0706 
formulation and match the K0706 formulation in shape, size, and color.  
 
 
 
  
6.1.2 
Handling Requirements of the Investigational Product 
The study drug will be stored 
 
 in the storage 
area of the study center, in a secure, 
 and locked environment with 
restricted access. Other handling and excursion requirements for the study drug are described in 
the Investigational Product (IP) manual. 
No special procedures for the safe handling of K0706/placebo are required. The Sponsor will be 
permitted upon request to audit the supplies, storage, dispensing procedures, and records 
provided that the blind of the study is not compromised. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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6.1.3 
Dispensing (Labeling and Packaging) and Compliance 
The study drug will be supplied to the study centers by a CRO appointed by the Sponsor. The 
IWRS (Interactive Web Response System) supports drug supply process. 
A sufficient quantity of K0706 and a matching placebo prepared for human studies will be 
supplied to study centers. Study drug will be supplied and stored in compliance with Good 
Manufacturing Practice conditions and labeled in accordance with local regulations. 
The study center pharmacist / appropriately qualified designee will dispense individual subject 
treatments 
. 
 
  
All clinical study materials will be packaged and labeled to comply with applicable regulations. 
The study drug will be clearly labeled according to local requirements regarding use for clinical 
study investigation only.  
The following minimum information will be given on the label: 
 Sponsor name 
 Protocol number 
 IP name 
 Study medication / IP number 
 Manufacturing / Expiry date (as per local regulatory requirement) 
 Storage conditions 
 Subject number 
 Investigator’s name 
Other information as per the local regulatory requirements may be added, e.g., caution statement 
for USA “Caution: New Drug-- Limited by Federal (or United States) law to investigational 
use.” 
For further details see the IP Manual.   
6.1.4 
Investigational Product Numbering 
Each investigational product container will be uniquely numbered. The study medication 
number(s) will be recorded in the source documents. 


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6.1.5 
Accountability Procedures for the Investigational Product 
The Sponsor will supply sufficient quantities of the study drug to allow the completion of this 
study in an appropriate package deemed to maintain the integrity of the products. In accordance 
with GCP, the study site will account for all supplies of the study drug. The supplies will be 
stored as per label instructions until dispensed, in a secure, temperature-controlled, and locked 
environment with restricted access, accessible only to the pharmacist or other authorized person. 
Details of receipt, storage, assembly, dispensing, and return will be recorded. All unused supplies 
of study drug will either be destroyed by a designated vendor or will be returned to the study 
Sponsor at the end of the study in accordance with instructions by the Sponsor. The end of the 
study is defined as the time the last subject completes the last study visit. 
6.2 
Dosage and Dosage Regimen 
6.2.1 
General Dosing Instructions 
See IP manual regarding instructions for dispensation of study drug at each visit.  
Subjects will be instructed to self-administer the study drug once daily, 
 
 
 
 
 
. The date and time of study drug self-administration will be recorded 
in the subject’s daily diary. The study drug will be administered under the supervision of in-
clinic staff at certain visits (Appendix 1). 
 
 
  
 
 
 
 
. Alternate 
formulations under development will require different dosing instructions and preparation of 
matching placebos. Subjects are to bring the daily diary and remaining study drug and used / 
unused containers with them to each visit to allow for 
count and compliance 
check. 
6.2.2 
Dose 
In earlier versions of this protocol (Amendment 01 and 02), subjects were dosed on 
 
 (low dose) or 
 (high dose) of K0706 or matching placebo. The study 
continued with that formulation and dose until 
, at which 
point newly enrolled subjects were randomized to 
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dose) or 
 (high dose) of K0706 or placebo 
 Subjects who started the study on 
 formulation were switched to the 
 dose for their corresponding dose group 
(placebo stays on placebo, 
 
). Subjects who had a 
 dose reduction to 
 or to placebo (from placebo) remained on the same dose level of the 
 formulation. Subjects who had a dose reduction from 
 were 
discontinued from the study 
 
  
An 
 
 
 development may further displace the current 
 
formulation. Transitions will occur in a blinded manner via the IWRS and will occur at the 
subject’s subsequent visit. 
 
 
  
6.2.3 
Dose Holding and Dose Reduction Guidance for TEAEs 
TEAEs (AEs occurring after the first dose of the study drug) considered mild (Section 8.5) 
should be managed supportively. For moderate or more severe TEAEs, the Investigator has the 
option to withhold the study drug for up to  weeks and then rechallenge the subject at the same 
dose if deemed safe or start the subject at a lower dose. Investigators will be allowed to reduce a 
subject’s dose once during the trial, and it will be enacted in a blinded fashion via the IWRS. The 
dose may not be increased once it has been reduced. If the AE recurs, the dose can then be 
reduced (if not reduced already) or the subject should be withdrawn from the study. See the IP 
Manual for more details on dose reduction. For dose reductions, subjects’ daily dose will be 
reduced in half from their current dose, though subjects on a placebo will remain on a placebo.  
6.3 
Warnings and Precautions 
Potential adverse reactions from K0706 based on limited existing data, and similar medications, 
are described in section 2.2.6.  


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. It occurred within the first 
-day cycle. It is 
likely that this 
 was due to the intended effect of 
 reducing the 
numbers of 
 but it is not possible to rule out at this 
time that it may be seen in subjects without leukemia. 
 was not seen in subjects with 
PD treated for up to 2 weeks in study 
, though one subject 
 had a reduction 
in total 
 that resolved after stopping the study drug and was not felt to be an AE by the 
investigator. If 
 occurs, subjects will be at increased 
. For 
 
 
 
 
 
 
 
 Once values have returned to normal, subjects may be restarted on the 
study drug at the same or lower dose if deemed safe by the investigator (Section 6.2.3).  
6.4 
Medication(s)/Treatment(s) Permitted and Not Permitted Before and/or During the 
Study 
Concomitant medications are any medications taken by the subject other than the assigned study 
drug, and these will be recorded in the source document as concomitant medications. 
Any medications (other than those excluded by the inclusion/exclusion criteria) that are 
considered mandatory for the subjects’ welfare and that are not anticipated by the Investigator to 
be likely to interfere with the pharmacokinetics of K0706 may be given at the discretion of the 
Investigator. 
Medications other than those specifically excluded in this study may be administered for the 
management of concomitant illness, AEs, or symptoms associated with the administration of 
K0706 as needed.  These medications include, but are not limited to, analgesics, anti-nausea 
medications, antihistamine, antianxiety medications, and medication for pain management 
(narcotic agents are included). For nausea, medications that inhibit dopamine (e.g., 
metoclopramide, chlorpromazine) should be avoided. 
6.4.1 
Use of Medications for Parkinson’s Disease (Symptomatic or Disease Modifying) 
During the trial, subjects are not permitted to take any prescription, investigational, or over-the-
counter medication for the symptomatic treatment of PD or disease modification (to slow the 
progression of PD). The only exception is an 
 inhibitor they are on at 
 
(Section 4.2.2), though subjects are not permitted to increase the dose. If a subject stops the use 
of an MAOB inhibitor or switches to an equivalent dose of a different MAOB inhibitor during 
the study, the timing and reason should be noted, but the subject can continue in the study.  


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6.4.2 
Use of Anti-clotting Agents 
Serious bleeding events, including fatalities, have occurred in patients treated with K0706 in 
 (section 2.2.5), as well as other Abl TKIs 
used for leukemia. Cerebral hemorrhage and gastrointestinal hemorrhage were the most 
commonly reported serious bleeding events in studies of other Abl tyrosine kinase inhibitors, 
with most hemorrhagic events occurring in patients with Grade 4 thrombocytopenia. Most likely, 
the cause of bleeding in these subjects was disease progression, but until further information is 
available, caution is indicated in patients requiring medications that inhibit platelet function or 
anticoagulants. 
6.4.3 
Use of Substances Related to Specific Transporters 
K0706 inhibits the transporters P-gp (p-glycoprotein) and Breast Cancer Resistance Protein 
(BCRP), so medications affected by these transporters should be avoided or used with caution. 
P-gp and BCRP transport substances out of the brain, so medications with CNS penetration and 
side effects should be avoided or used with caution, especially digoxin. 
Reference: 
. 
6.4.4 
Use of Substances Related to Specific Cytochrome Inhibitors 
K0706 is only weakly metabolized by cytochrome P450 enzymes, so there is minimal concern 
about the use of inhibitors of these enzymes.  
Based on preliminary investigation, K0706 may be an inhibitor of the enzyme CYP2C8, and 
further investigation is ongoing to confirm its inhibition potential.  However, to be cautious, 
sensitive substrates of CYP2C8 with a narrow therapeutic index should be avoided or used with 
caution. Clinically significant CYP2C8 substrates include, but are not limited to those listed 
 
 
 
 
 
 
 
 
 
 
 


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K0706 may have the potential to 
 CYP3A4 enzyme expression. Most common CYP3A4 
 include drugs such as dexamethasone, anti-epileptic agents (e.g., phenobarbital and 
phenytoin), and St. John’s Wort, among many others. The serum/plasma levels of concomitantly 
consumed medications that are substrates of CYP3A4 (i.e., metabolized by CYP3A4) may 
 and this may require a dose adjustment. Examples of concomitant drugs that may be so 
affected include many statins (e.g., lovastatin, simvastatin, atorvastatin), some antidepressants 
(e.g., venlafaxine, amitriptyline, citalopram, sertraline), antiplatelet-agents (clopidogrel) and 
calcium channel blockers (e.g., amlodipine, diltiazem). 
 
 
 
 
Subjects receiving such medications 
 by CYP3A4 should be closely monitored, and 
the dosage of such medications should be adjusted if necessary after consultation with their 
treating physician. 
6.4.5 
Use of Substances Related to Uridine Diphosphate Glucuronosyl Transferase 
(UGT1A1) Enzyme 
K0706 may have the potential to 
 the uridine diphosphate glucuronosyl transferase 
(UGT1A1) enzyme. K0706 may 
 the drug levels of concomitant medications that are 
predominately metabolized by UGT1A1, which may lead to toxicities. 
More commonly used drugs whose levels might increase without significant safety concerns 
include naproxen, estradiol, ethinylestradiol, raloxifene, and some statins (See extensive list 
https://go.drugbank.com/categories/DBCAT003871). 
6.4.6 
Additional Treatments Not Permitted 
The following non-drug therapies must not be undertaken or administered during the study (or 
within 4 weeks before the start of study drug administration): 
 
 
 
 
; 
 
. 
 Major surgery (excluding diagnostic biopsy) 
 
 
 


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 
 
All subjects will be questioned about the use of any pre-study and concomitant treatments that 
might interfere with the study outcome. All concomitant treatments must be appropriately 
recorded in the source documents and described in the eCRF. 
6.4.7 
Use of Calcium and Magnesium-Containing Medications and Supplements 
In vitro data suggest that calcium may reduce the absorption of K0706 and therefore lead to 
reduced blood and brain concentrations. Therefore, subjects taking calcium or magnesium-
containing medications or supplements should be requested to take those substances at a 
different time of day from K0706, ideally at least 2 hours apart.  The sponsor is conducting 
additional studies to better understand the role of magnesium and calcium-containing substances 
in K0706 pharmacokinetics. If these studies reveal the effect to be non-significant, then sites will 
be notified in writing to notify the subjects that no restriction on their co-administration is 
necessary. 
6.5 
Procedure(s) for Monitoring Subject Compliance 
Study medication will be dispensed by the site personnel. Dispensation will be documented in 
the drug accountability log or equivalent document. Subjects will be instructed to bring their 
daily diary and used and unused study drug containers at all scheduled visits to allow for 
 count and compliance checks. If the subject fails to bring the study drug container 
on the designated day, non-compliance to the protocol will be recorded. Subjects will also be 
asked to record in a daily diary the date and time at which they took the study drug and their 
adherence to 
 
. For scheduled visits greater than 4 weeks apart, subjects will be called and asked 
about compliance with the study drug.   
 
 


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7.0 
ASSESSMENT OF EFFICACY 
The following efficacy assessments will be undertaken, as outlined in the Schedule of 
Assessments (Appendix 1). The rationale for the choice of these outcome measures is in Section 
2.3.  
7.1 
MDS-UPDRS  
MDS-UPDRS (Goetz et al., 2008) Parts I and II can be performed by a clinician or a coordinator; 
Part III must be performed by a trained clinician who has completed the MDS formal training 
program 
 within 1 year of their first subject 
(exceptions to this may be made in writing by the Sponsor). Part III should be performed by the 
same examiner at all visits. The examiner performing the scale will place their name on the 
scoring form to track who performed it. 
At the Part 1 Screening visit, only the MDS-UPDRS tremor severity (not constancy) items will 
be performed (items 2.10, 3.15, 3.16, and 3.17). They will be performed by a trained clinician, 
though not necessarily the same clinician who will perform the remainder of the assessments, 
i.e., at later visits. 
Performance of MDS-UPDRS Part III may be video-recorded for one or more assessments per 
clinician. Whenever possible, the video record will be transmitted to an expert rater who will 
then give feedback to the clinician on performance and scoring of the assessment to improve 
future testing. Typically, the clinician’s first subject’s first assessment 
 may 
be recorded, though subsequent subjects or visits may be recorded if requested by the expert rater 
to ensure implementation of feedback or as requested by the Sponsor. Final decisions on the 
scoring of subjects will be with the clinician at the site. 
Subjects will be notified about the purpose and use of the video and be given the opportunity to 
decline to have it performed. Sites, where sharing of subject video is not permitted (e.g., by the 
ethics committee or regulatory authority) will not participate in video recording the assessment.  
This video recording for quality assurance is useful as the MDS-UPDRS Part III is a relatively 
new scale, and accurate performance and scoring are essential for the validity of the trial. 
Recording of the subjects’ face and body is required to score the test accurately (e.g., facial 
expression is scored). To limit the loss of privacy, the video will only be accessible to staff at the 
site where the subject is participating and to the expert rater and their video support team. Video 
will be recorded and stored within a Health Insurance Portability and Accountability Act and 
General Data Protection Regulation Act-compliant smartphone application that prohibits local 
storing of the video on the phone and therefore sharing of the file with other applications (see 
separate manual for instructions). The application will permit a full audit trail of everyone who 
accessed every video file.  


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7.2 
CGIS  
The CGIS (Appendix 4) should be scored by the same examiner who performs the MDS-UPDRS 
Part III, which should be done by the same examiner at all time points. The examiner should 
score the subject’s severity of Parkinson’s disease using all information available about the 
subject 
 Scoring should only be based on the subject’s symptoms 
and signs related to Parkinson’s disease (
 
 
7.3 
Time to Initiation of Symptomatic PD Medications 
This will be defined by the day the subject reports they begin taking symptomatic PD 
medications. These medications include: levodopa, dopamine agonists, amantadine, or an 
MAOB inhibitor started or when the dose is increased after randomization. 
7.3.1 
EQ-5D-5L (HRQoL Measure) 
The ED-QD-5L is available in multiple languages and is filled out by the subject following the 
instructions in the document.  
7.4 
DaT SPECT 
Subjects in the Biomarker sub-study will have a DaT SPECT scan performed at visits described 
in the Schedule of Assessment as an exploratory outcome measure. DaT SPECT scans are to be 
performed using the 123I-FP-CIT tracer; other tracers may be approved with written approval 
from the Sponsor. Scans will be uploaded to the Sponsor or Sponsor’s collaborating imaging 
laboratory (see relevant manual) for quantitative analysis.  
7.5 
SCOPA-AUT 
The SCOPA-AUT is an instrument that is used to evaluate autonomic symptoms in patients with 
Parkinson’s disease as well as patients with MSA. The scale is self-completed by patients and 
consists of 25 items assessing the following domains: gastrointestinal (7), urinary (6), 
cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 
items for women).  The development of the SCOPA-AUT is part of a larger research project, the 
Scales for Outcomes in Parkinson’s disease (SCOPA), in which practical and clinimetric sound 
instruments for all relevant regions in PD are selected or developed.   
 
  
 
 
 
 


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7.7 
Blood Tests of PD Progression and K0706 Target Engagement 
For subjects who provide consent in Part 1, blood will be collected for genetic markers and 
future tests at the Baseline visit and at other visits as described in the Schedule of Assessments. 
Details of the collection and processing of blood will be in the separate lab manual. The specific 
genetic and other future tests (e.g., proteins, nucleic acids, metabolites, or sugars) to be tested 
have not yet been determined at the time of the writing of the protocol.  Markers tested will be 
ones that have been shown to link to PD or efficacy or safety of K0706 and may include 
substances associated with PD pathology, such as misfolded or phosphorylated α-synuclein, or 
may include markers of the types of cell death that occur in PD. Exploratory analyses may be 
performed at a later date by the Sponsor or collaborating entity.  
7.8 
CSF Biomarkers of PD Progression and K0706 Target Engagement 
 Subjects will need to consent to 
have future tests of the CSF performed. Details of the collection and processing of CSF will be in 
the separate lab manual. The specific biomarkers (e.g., proteins, nucleic acids, metabolites, or 
sugars) to be tested have not yet been determined at the time of the writing of the protocol. 
Markers tested will be ones that have been shown to link to PD or target engagement of K0706 
and may include substances associated with PD pathology, such as misfolded or phosphorylated 
α-synuclein, or may include markers of the types of cell death that occur in PD. Exploratory 
analyses may be performed at a later date by the Sponsor or collaborating entity. If subjects 
experience an adverse event related to the first or second spinal tap, they may be permitted to 
skip the subsequent spinal tap(s). 
7.9 
Pharmacokinetic Analysis 
Plasma and CSF samples will be sent to the sponsor or a collaborating entity in a coded fashion 
and analyzed for levels of K0706 and any relevant metabolites. Details are in the Lab Manual. 
 
 
 
 
 
 
 
 
 
 
 


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8.0 
ASSESSMENT OF SAFETY 
8.1 
Description of Safety Parameters 
The following safety parameters will be assessed during the study as per the Schedules of 
Assessments and are described below:   
8.1.1 
Vital Signs Measurements 
Blood pressure and pulse will be measured at each clinic visit throughout study participation. 
Measurements will be made with the subject in a supine position for at least 5 minutes, followed 
by standing after 3 minutes. Weight will also be measured at each visit. Results will be evaluated 
against pre-specified criteria for clinically significant change.   
8.1.2 
Clinical Laboratory Testing 
The following tests will be performed by a central laboratory: 
Hematology 
 Hemoglobin, hematocrit 
 Total WBC count 
 Automated differential WBC count with reflex to manual differential if abnormality seen 
 Platelet count 
Chemistry 
 Sodium 
 Potassium 
 Chloride 
 CO2 
 Glucose 
 Blood Urea Nitrogen (BUN) 
 Creatinine 
 Calcium 
 Alanine Aminotransferase (ALT) 
 Aspartate Aminotransferase (AST) 
 Alkaline phosphatase 
 Total bilirubin  


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 Total protein 
 Albumin 
 Amylase 
 Lipase 
Lipid Profile 
 Total Cholesterol 
 High-Density Lipoprotein (HDL) 
 Low-Density Lipoprotein (LDL) 
 Triglyceride 
Urinalysis 
 Routine testing, including dipstick for pH, specific gravity, protein, glucose, ketones, 
bilirubin, urobilinogen, blood, nitrite, leukocyte esterase  
 Microscopic examination of the sediment only if abnormality seen on routine tests  
Serology 
 HIV, hepatitis panel  
Results for clinical laboratory parameters will be evaluated for clinically significant values 
according to pre-specified criteria. Laboratory tests may also be repeated between scheduled 
visits at the discretion of the Investigator. In addition, repeat testing should be performed at the 
end of the study to follow any clinically significant abnormality to resolution/stabilization. 
Clinically significant results will be reported as AEs. 
8.1.3 
12-Lead ECG 
12-lead ECG measurements will be collected in triplicate in a supine position after 5 minutes of 
rest. Within the triplicate series, ECGs are to be spaced no more than 2 minutes apart. The QTc 
data will be corrected using Fridericia’s correction.  In addition to the QT interval, the following 
parameters will be collected: PR interval, QRS, and ventricular rate, the presence of T-waves.   
Clinically significant abnormalities will be reported as AEs. 
8.1.4 
Physical Examination 
A complete physical examination is to be performed at Screening. It must include, at minimum 
examination of skin, musculoskeletal, neurological, cardiovascular, and respiratory systems, with 
other systems optional. At other visits, targeted physical examinations are to be performed only 
as necessary in response to AEs.  


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8.2 
Definitions of Adverse Events 
8.2.1 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans in a 
clinical investigation, whether or not considered drug related. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
Untoward medical experience occurring during medication-free pre-treatment periods does not 
meet the above-mentioned definition of an AE. Nevertheless, they have to be documented in the 
same way as AE. Each subject will be queried generally for the occurrence of adverse 
experiences prior to study drug administration and throughout the subject’s participation in the 
study. During and following a subject's participation in this study, the Investigator has to ensure 
that adequate medical care is provided to a subject for any AE, including clinically significant 
laboratory values. The subject will be treated and/or followed up until the symptom(s) return to 
normal, as judged by the Investigator. 
8.2.2 
Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose 
 Results in death 
 Is life-threatening 
 Requires in-subject hospitalization or prolongation of existing hospitalization* 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 


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 Important medical event: Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered as SAEs when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.), 
convulsions that do not result in hospitalization or the development of drug dependency or 
drug abuse. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event, which, 
hypothetically, might have caused death if it were more severe. 
*A planned hospitalization for a pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health, or if the hospitalization is clearly not 
associated with an AE (e.g., hospitalization due to social/logistic reason) is not to be considered 
as SAEs. 
8.3 
Pregnancy 
Male subjects enrolled in the study will be instructed to avoid the passage of semen to their 
partner by using an acceptable contraceptive method to avoid fathering a child. If a female 
subject becomes pregnant during the study, the pregnancy will be recorded as a significant 
medical event and reported per SAE reporting procedures, and the subject will be withdrawn 
from the study immediately. If a female partner of a male subject becomes pregnant during the 
study, the medical event will be recorded appropriately with the ‘Pregnancy Reporting Form’ 
and submitted to the Sponsor’s safety physician/CRO. All pregnancies shall be followed every 
three months until the outcome and up to one-month post-delivery to assess the functional status 
of the child. If any SAE occurs during pregnancy, then it will be reported using SAE forms as 
per section 8.6. Any congenital abnormalities or birth defects in the newborn will be followed 
three months post-delivery.  
8.4 
Eliciting, Documentation and Reporting of Adverse Events 
Information on AEs will be derived by questioning the subjects in general terms (e.g., "How do 
you feel?” or “How have you been feeling since the last questioning?” respectively), by subjects' 
spontaneous reports, or by observation. 
AEs will be documented on the source document. Trained monitors will check the entries on the 
source document. The AE will be transcribed to the AE eCRF-sections. The following 
information will be given for each AE: Description of the AE, start date, stop date, severity, 
pattern, action taken, outcome, seriousness, dose of study drug, and relationship to the study 
medications. The dose of the study drug assigned to an AE will be the dose the subject was 
assigned to take on the date the subject reported the AE first began.   


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The AE / SAE collection period for safety surveillance begins when the subject signs the 
Informed Consent Form and continues until the follow-up visit, or if the follow-up visit does not 
occur within the defined time window, then 30 days post the end of treatment visit or 30 days 
post the last dose of study drug for subjects with early discontinuation.  
8.5 
Rating of Adverse Events 
The following system will be used to assess the treatment relationship: Unrelated, unlikely, 
possibly, probably, and certainly. 
TERM 
DEFINITION 
CLARIFICATION 
Unrelated 
Those AEs which, after careful consideration, are clearly due to extraneous causes (medical 
history, demography details, disease, environment, etc.) 
Unlikely 
A clinical event, including 
laboratory test abnormality, with a 
temporal relationship to drug 
administration that makes a causal 
relationship improbable and in 
which other drugs, chemicals or 
underlying disease provide 
plausible explanations. 
1. It does not follow a reasonable temporal sequence 
(Improbable temporal relationship) from the 
administration of the drug. 
2.  It could also be explained by the patient's 
concurrent disease, environmental factors, medical 
history and other concomitant drugs or chemicals, 
including food-drug interactions 
Possibly 
A clinical event, including 
laboratory test abnormality, with a 
reasonable time sequence to the 
administration of the drug, but 
which could also be explained by 
concurrent disease or other drugs 
or chemicals. Information on drug 
withdrawal may be lacking or 
unclear. 
1. It follows a reasonable temporal sequence from the 
administration of the drug. 
2.  It could also be explained by the patient's 
concurrent disease, environmental factors, medical 
history, and other concomitant drugs or chemicals 
(including food-drug interactions). 
3. There is no information or uncertainty with regard 
to what has happened after stopping the drug. 
Probably 
A clinical event, including 
laboratory test abnormality, with a 
reasonable time sequence to the 
administration of the drug, 
unlikely to be attributed to 
concurrent disease or other drugs 
or chemicals, and which follows a 
clinically reasonable response on 
withdrawal (dechallenge). 
Rechallenge information is not 
required to fulfil this definition. 
1. It follows a reasonable temporal sequence from the 
administration of the drug. 
2. It could not be readily explained (unlikely) by the 
patient’s concurrent disease, environmental factors, 
medical history, and other concomitant drugs or 
chemicals, including food-drug interactions. 
3. It disappears or decreases in severity on cessation 
or reduction in dose or on administration of a specific 
antagonist wherever possible. There are important 
exceptions when an AE does not disappear upon 
discontinuation of the drug, yet drug relatedness 
clearly exists. 
4. No rechallenge information is available or possible. 


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TERM 
DEFINITION 
CLARIFICATION 
Certainly 
A clinical event, including 
laboratory test abnormality, 
occurring in a plausible time 
relationship to drug administration 
and which cannot be explained by 
concurrent disease or other drugs 
or chemicals. The response to the 
withdrawal of the drug 
(dechallenge) should be clinically 
plausible. The event must be 
definitive pharmacologically or 
phenomenologically, using a 
satisfactory rechallenge procedure 
if necessary. 
1. It follows a plausible time sequence to drug intake; 
this means that there is a positive argument in 
sufficient detail to support the view that the drug is 
causally involved, pharmacologically or 
pathologically, e.g., pharmacokinetics and type of 
reaction. 
2. It could not be explained by the patient's concurrent 
disease, environmental factors, medical history and 
other concomitant drugs or chemicals, including food-
drug interactions (i.e., no alternative causes). 
3. It disappears or decreases in severity on cessation 
or reduction in dose or on administration of a specific 
antagonist wherever possible. 
4. It is an objective and specific medical disorder or a 
recognized pharmacological phenomenon for 
instance, ‘grey baby syndrome’ and chloramphenicol 
or anaphylaxis immediately after the administration of 
a drug that had been given previously. This means 
that any other event is automatically excluded and 
can never qualify for ‘Certain’ (even in the case of a 
positive rechallenge observation). 
5. It reappears on re-administration of the drug (only 
if ethically correct i.e., in case of non-serious and 
easily treatable AEs). 
The severity of an AE is characterized as: 
 Mild: AE, which is easily tolerated 
 Moderate: AE sufficiently discomforting to interfere with daily activity. 
 Severe: AE, which prevents normal daily activities. 
 Life-threatening: The subject is at risk of death due to the AE as it occurred. This does not 
refer to an event that hypothetically might have caused death if it were more severe. 
 Death: Death related to AE 
Event outcome at time last follow-up is recorded is categorized as “Fatal”, “Resolved”, 
“Resolved with Sequelae”, “Resolving”, “Not Resolved”, or “Unknown”. 
Action taken with respect to study drug is categorized as “none”, “study drug discontinued / 
withdrawn”, “study drug discontinued and restarted”, “dose reduced”, “required concomitant 
medication”, “required procedure”, or “other”. 


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Assessment of Expectedness will be determined by the version of the IB effective at the time of 
onset of the adverse event. 
8.6 
Documentation and Reporting of Immediately Reportable Adverse Events 
All SAEs must be reported according to ICH GCP or local regulations, applying the regulation 
with the stricter requirements. The report will contain as much available information concerning 
the SAE to enable the Sponsor’s safety physician / CRO to file a report which satisfies regulatory 
reporting requirements. The SAE report will be notified by Investigator within 24 hours of his / 
her awareness to the Sponsor’s safety physician / CRO. These timelines apply to initial reports of 
SAEs and to all follow-up reports. 
All AEs/SAEs will be recorded on the AE Report Form in the eCRF and source documents.  
As much information as possible should be supplied at the time of the initial report with at least 
the following information using SAE Report Form. 
 Name, address, and telephone number of the reporting Investigator 
 Investigational product(s) 
 Protocol number 
 Subject identification number, initials, sex, and date of birth 
 Description of the AE, reason considered serious, measures taken, and outcome (if resolved) 
 Likelihood of drug causation of the AE was assessed by the Investigator. 
Additional follow-up information should be completed on an SAE follow-up form with a copy 
sent to the Sponsor’s safety physician/CRO. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone. 
In these cases, a written report must be sent immediately thereafter by e-mail to the Sponsor’s 
safety physician/CRO. 
Relevant pages from the source document and eCRF may be provided in parallel (e.g., medical 
history, concomitant drugs). Additional documents may be provided by the Investigator, if 
available (e.g., laboratory results, hospital report, autopsy report). In all cases, the information 
provided on the SAE Report Form must be consistent with the data about the event recorded in 
the eCRF. 
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor’s safety physician / CRO may have on the SAE. This is necessary to ensure prompt 
assessment of the event by the Sponsor’s safety physician to allow the Sponsor to meet strict 
regulatory timelines associated with expedited safety reporting obligations. 


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Requests for follow-up will usually be made via the Sponsor’s safety physician / CRO. 
8.6.1 
Serious Adverse Events/Suspected Unexpected Serious Adverse Reactions 
(SUSARs) Reporting to Regulatory Authorities/EC/IRBs/Participating 
Investigators 
The Sponsor’s Safety Physician/CRO shall notify the applicable Regulatory Authorities of any 
SAE/SUSAR, as per local Regulatory Authorities' guidelines and timeframe specified as per 
local regulation.  
All participating Investigators, EC/IRB, and other stakeholders shall be notified of any SAE/ 
SUSAR by CRO as per local regulatory requirements. 
The contact details of the Sponsor’s Safety Physician and CRO’s Medical Monitor are listed on 
Page 5. 
Progress reports: Where required by applicable regulatory requirements, the investigator should 
submit written summaries of the trial’s status to the institution. The investigator/institution 
should submit written summaries of the status of the trial to the IRB/EC annually or more 
frequently, as requested. The investigator should promptly provide written reports to the 
Sponsor, the IRB or EC, and, where required by the applicable regulatory requirements, the 
institution on any changes significantly affecting the conduct of the trial and/or increasing the 
risk to the subjects. 
8.7 
Analysis of Adverse Events 
The Sponsor and/or CRO will perform an approximately monthly review of safety data. Any 
suspicious signals will be analyzed further.  
If approximately 15% or more of subjects have a dose reduction or a similar degree of concern 
regarding adverse events, an appropriately qualified independent data safety monitoring board 
(DSMB) will be convened to review the unblinded safety data. Should the DSMB recommend a 
dose reduction, ongoing subjects who have not already had a dose reduction would undergo a 
dose reduction as detailed in Section 6.2.3), and newly enrolled subjects would be dosed at 1/2 of 
the current dose of the 
 formulation; no further dose reductions would be allowed. Further 
use of the DSMB will depend upon their recommendations and any future safety signals.  
8.8 
Follow-Up of Subjects After Adverse Events (Serious and Non-Serious) 
8.8.1 
Unresolved Events 
If an AE/SAE is continuing when the subject has completed the study, the event must be 
followed and reported until resolution/stabilization as per the medical judgment of the 
Investigator. 


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8.8.2 
Post-study Events 
Any AE/SAE that occurs up until the follow-up visit, or if the follow-up visit does not occur 
within the defined time window, then 30 days post the end of treatment visit or 30 days post the 
last dose of study drug for subjects with early discontinuation, should be reported and included in 
the safety analysis of the study.  
Any AE/SAE which occurs past this date will be reported if it is considered related to study drug 
by the Investigator. 
 
 


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9.0 
STATISTICAL ANALYSES 
A detailed SAP will be written and finalized in advance of any database lock. The plan will 
follow the outline of the statistical analyses, including but will not be limited to points presented 
below, and all the details necessary to complete the statistical analyses will be provided. 
Continuous variables will be summarized using mean, standard deviation, minimum, median, 
and maximum. Categorical variables will be summarized using frequency counts and 
percentages. All subject data will be presented in by-subject data listing(s). For time-to-event 
variables, 
, 
, and other 
 will be presented. 
9.1 
Subject Disposition 
Subject disposition will be based on all subjects who are screened for this study. The number of 
subjects randomized, completed, and the number discontinuing at each visit will be presented. A 
summary of reasons for early discontinuation will be provided. Reasons for early discontinuation 
include adverse events, lack of efficacy, protocol deviation or non-compliance with IP, subject’s 
withdrawal of consent, or other (to be specified by the Investigator). The number of subjects in 
each of the 
 (Parts 1 and 2), PP, PK, and safety analysis sets will be presented. 
9.2 
 Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively overall and by 
treatment in the ‘all randomized subjects’ set, comprising all subjects randomized in the study. 
The following demographic and Baseline variables will be included: 
 Age (years) 
 Gender  
 Race 
 Ethnicity 
 Weight (kg) 
 Weight category (≤90 kg or >90 kg) 
 Height (cm) 
 BMI (kg/m2) 
 Baseline MDS-UPDRS (Parts I, II, and III) 
9.3 
Study Drug Exposure and Compliance 
Study drug exposure will be evaluated using the 
 formulation dosing 
separately and as pooled per visit total number of doses administered for Part 1 and 
 
 Part 2. All exposures will be summarized using nominal units (mg) as well 
as equivalence-adjusted units in periods for each study part and overall for the entire treatment 


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period. The number and percent of doses administered per subject and the number of subjects 
with doses administered at each scheduled visit will be summarized using descriptive statistics 
by treatment arm (Part 1 and Part 2 separately) and in total for the Safety Population. 
Cumulative observed exposure will sum per visit for nominal and equivalence-adjusted dosing 
separately at each visit, study part, and overall by formulation and as pooled across both 
formulations as applicable. 
For Part 1, the percentage of doses administered per subject will also be summarized 
descriptively, defined as the total number of doses received per visit and overall in Part 1 divided 
by the total planned dose per visit and overall in Part 1, expressed as a percentage. Part 2 will be 
handled similarly, and the total overall in the pooled periods will also be described similarly. 
Relative dosing intensity will be calculated as the cumulative observed exposure per visit, study 
part and overall divided by the expected per visit, study part, and overall exposure, respectively. 
The result will be expressed in units of percentage.  
Incomplete 
 dosing and its impact on exposure and compliance metrics will be evaluated 
as a potential protocol deviation prior to unblinding for any planned analysis. If confirmed, 
relevant exposure and compliance metrics will be adjusted accordingly. 
All study drug administration data will be listed by subject.  
9.4 
Prior and Concomitant Medications 
All prior and concomitant medications will be coded to preferred drug names and therapeutic 
drug class using the World Health Organization (WHO) Drug Dictionary. The incidence of 
concomitant medication usage will be summarized for each therapeutic drug class and each 
preferred drug name. Prior medications will include medications with a documented stop 
date/time prior to the first dose of IP. Concomitant medications are those with start date/time on 
or after the date/time of dosing or that started prior to the date/time of dosing but are indicated as 
continuing into the treatment period. Any medications with partial start and/or stop dates will be 
considered concomitant if the assignment is uncertain. 
9.5 
Analysis Populations 
Part 1 (Week 0 to Week 40) and Part 2 (Week 40 to Week 80)  
Intent-To-Treat Population: 
 
 
 
 






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 Target Population: subjects aged ≥ 50 years in whom an initial diagnosis of PD was within 
3 years of the screening visit, who score on a modified Hoehn and Yahr stage  2, 
 
 who meet the protocol-
specified inclusion and exclusion criteria.  
 Endpoint: Change from Baseline to Week 40 in the MDS-UPDRS Part III total score  
 
 
  
 
 
follow-up prior to Week 40. 
 Population-level summary: difference in endpoint means between each of the two K0706 
treatment arms (high dose, low dose) and placebo treatment arm.  
Estimation for the 
 will be carried out as follows. 
Mean changes from baseline in the MDS-UPDRS Part III total score will be analyzed 
 
 
 
 
  The analysis will include the 
treatment arm, analysis visit, region, baseline MAOB inhibitor user status (yes/no), and the 
interaction term of treatment by analysis visit as the fixed, categorical effects, and will include 
the interaction term of baseline Part III score by analysis visit as the continuous, fixed covariates. 
An unstructured covariance structure will be used to model the within-subject error. 
 
 
 
 
 
 
 to estimate the denominator degrees of freedom. 
Three contrasts of group means (i.e., the difference in least-square means for each active dose 
and the pooled dose of the K0706 vs. placebo) at Week 40 will be estimated from the interaction 
term of treatment by analysis visit 
. These contrasts at Week 40 will 
serve as the primary comparisons. 
 
 
  
9.6.2 Analyses of the Primary Efficacy Endpoint 
 
 
. 
 proposed 


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clinical criteria for dividing 
patients into “
 
 
. The proposed criteria for the mild motor-
predominant subtype will be adapted to define Subgroup A for the Proseek trial. The Proseek 
cohort is considerably similar in demographics and baseline disease characteristics to the de 
novo PD cohort of the PPMI study. This similarity justifies the use of the subtype criteria 
developed in 
 Specific criteria will be specified in the SAP. Per 
, the intermediate and diffuse malignant subtype had faster PD 
progression compared to the mild motor-predominant subtype. Thus, 
 is considered 
at risk of faster PD progression relative to its complement.  
 is determined by having baseline serum NfLvalue ≥ 13 pg/mL, which is the mean 
NfL from the baseline data of the de novo PD patients of the PPMI study. Several studies 
(including 
) reported positive correlations between 
serum NfL value and clinical measures of PD severity.  Built on the longitudinal data of the de 
novo PD patients in the PPMI study, the predictive modeling of 
 quantified that 
for each increase of 10 pg/mL in serum Nfl at baseline, there was an yearly increase of 0.52 
points in the MDS-UPDRS Part III score 
  
The 
 analysis of the primary efficacy endpoint performed on the overall sample will be 
repeated for the two subgroups. Multiplicity adjustment will be applied to the testing of the same 
primary efficacy endpoint in 3 populations (i.e., the overall sample, Subgroup A, and Subgroup 
B). See Section 9.10. 
9.6.3 Secondary Endpoints (Part 1) 
Secondary endpoints in Part 1 include the following: 
 Change from baseline to Week 40 in the sum of the MDS-UPDRS Parts II and III total 
scores. 
 Change from baseline to Weeks 8 through 40 in MDS-UPDRS Part IA, Part IB, Part I 
total, Part II total, and Part III sub-scores.  
 Change in MDS-UPDRS grand total score (sum of Parts I, II, and III) from the baseline. 
 Evaluation of slopes of the mean MDS-UPDRS Parts II and III scores over time during 
Part 1 by treatment group. 
 Time from the first dose in Part 1 to initiation of symptomatic PD medications  
 Change in HRQoL using the EQ-5D-5L from Baseline to Week 40 
 Change in CGIS from Baseline to Week 40 
 Change in the SCOPA-AUT from Baseline to Week 40 
 Pharmacokinetics – Plasma and CSF levels of K0706 and any relevant metabolites. 


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Comparison of MDS-UPDRS Part III total score among treatment groups at all other time points 
are secondary. A similar 
 approach will be used for the secondary analyses of the MDS-
UPDRS Part IA, Part IB, Part I, Part II, Part III sub-domain scales, and the sum of the individual 
scales (i.e., Parts II and III, Parts I, II and III). Note that any MDS-UPDRS assessments captured 
for a subject after the start of symptomatic PD medications (e.g., at the ED visit for a subject 
leaving the study early) are treated as missing when implementing the 
 approach.  These 
assessments, however, may be utilized as part of an exploratory analysis.  
 
 
In addition to these analyses, all modeling and testing will be repeated on the Per Protocol 
population as secondary analyses, along with alternative models which implement multiple 
imputation methods to account for missing observations at various time points.  
A random coefficients regression analysis with random terms for intercept and slope (i.e., time is 
treated as a linear random effect) will be used to estimate mean changes from baseline in UPDRS 
Part III total score over time (in weeks) during Part 1 by treatment group, and the linear trend of 
the estimated mean change-from-baseline in the MDS-UPDRS Part III total score will be 
displayed graphically. This analysis will be repeated for the sum of Parts II and III total scores.  
A secondary outcome measure will be defined as the waiting time from the first administration 
of the study drug in Part 1 to the time-point when a subject begins taking symptomatic PD 
medications. These symptomatic medications include levodopa, dopamine agonists, amantadine, 
or initiation or increase in the dose of an MAOB inhibitor.  If a subject does not go on any 
symptomatic PD medications through completion of Part 1, the waiting time variable will be 
censored at the time of the last available data point. This secondary endpoint will be summarized 
and analyzed by treatment group 
  The proportion of non-
censored subjects within each treatment group will also be compared 
 
 
The EQ-5D-5L score, CGIS score, and the SCOPA-AUT score will be summarized within each 
treatment group and will be tested for differences between groups for change from baseline to 
end of Part 1 
. As with the MDS-UPDRS endpoints, all 
assessments captured after the start of symptomatic PD medications will be treated as missing 
values for the Part 1 analyses. 
K0706 plasma and CSF concentration data will be summarized by treatment group and 
assessment time-point by using descriptive statistics (such as number of subjects, mean, standard 
deviation, geometric mean, coefficient of variation (CV%), minimum, median, and maximum 
values). 
9.6.4 Exploratory Endpoints (Part 1) 
Exploratory endpoints for Part 1 include the followings: 


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 
Skin pathological findings that correlate with PD, 
 
  
 
Blood and CSF levels of emerging biomarkers (
) that predict or track PD 
progression or target engagement of K0706. 
 
Brain DaT SPECT - an imaging tool that is a marker of dopaminergic cell health. 
 
 
 
 parameters will be summarized descriptively by treatment group and time point 
(visit).   
 parameters or characteristics that may be predictive of PD progression in 
terms of MDS-UPDRS scores, such as genetic tests, blood and CSF biomarkers, DaT SPECT 
quantitative results of DaT SPECT scans will be examined by using summary statistics, 
graphical display 
), and linear models (
).  
When relevant based on existing data, some of these outcomes may be treated as secondary 
endpoints and, hence, summarized and tested for differences between treatment groups.  
 
. These methods will be described in detail within SAP. 
 
 
 
 
 
 
9.6.5 Efficacy Endpoint Analyses (Part 2) 
All efficacy analyses in Part 2 will be considered secondary or exploratory.   
Part 2 efficacy analyses will be performed for the following secondary endpoints:  
 Change from Week 40 (Baseline for Part 2) to Week 76 of the long-term extension study 
in the MDS-UPDRS Part III score  
 Change from Week 40 (Baseline for Part 2) to Week 76 of the long-term extension study 
in MDS-UPDRS Parts II and III sum score 
 Change from Week 40 (Baseline for Part 2) through Week 76 in MDS-UPDRS Part IA, 
Part IB, Part I total, Part II total, and Part III sub scores  
 Change in MDS-UPDRS grand total score (sum of Parts I, II, and III) from Week 40 
(Baseline for part 2) through Week 76 
 Time from Week 40 (Baseline for Part 2) to the initiation of symptomatic PD medications 
in the long-term extension study 


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Part 2 efficacy analyses will be performed for the following exploratory endpoints: 
 Change in the mean MDS-UPDRS Parts I, II and III scores between the early-start and 
delayed-start groups at 76 weeks 
 Evaluation of slopes of the mean MDS-UPDRS Parts II and III scores over time in part 2 
for the early-start group as compared to the delayed-start group. 
 The proportion of patients starting symptomatic PD treatment 
The change from Part 2 baseline value in the MDS-UPDRS assessments (including Part IA 
score, Part IB score, Part-I total score, Part II total score, Part III sub-domain scores, Part III total 
score, Parts II and III sum score, and Parts I, II and III sum score) across all time points (visits) 
up to the Week 76 visit will be summarized by treatment group (early-start of K0706 Low Dose, 
early-start of K0706 High Dose, and delayed-start of K0706)  Mean difference in the above-
mentioned MDS-UPDRS scores between treatment groups will be extracted from the 
 
models for each scheduled visit in Part 2. 
The same random coefficients 
 analysis for Part 1 (see Section 9.6.3) will be used for 
Part 2, with Part 2’s treatment groups being the early-start of K0706 (that is, the previous Low 
Dose group and High Dose group in Part 1) and the delayed-start of K0706 (that is, the previous 
Placebo group in Part 1). Note that Part 2’s baseline will be used as the baseline value for this 
analysis. Time (in weeks) from first dose of the study drug in Part 2 to the initiation of 
symptomatic PD medications in Part 2 will be analyzed by treatment group (the early-start with 
Low Dose, early-start with High Dose, and the delayed-start of K0706) by using the 
method. 
The difference and its 
 CI between treatments in the binomial proportion of subjects starting 
symptomatic PD medication in Part 2 will be calculated for the K0706 early-start group vs the 
delayed-start group. 
 
9.7 
Pharmacokinetic Analysis 
Blood in all subjects, 
 will be analyzed for levels of 
K0706 and any relevant metabolites. Exploratory analyses will be performed to determine the 
relationship between these values and the safety and efficacy endpoints. The PK analysis 
population will be used. 
9.8 
Safety Analyses 
The analysis of safety parameters will be based on the Safety Population. In general, missing 
safety data will be analyzed without imputation or substitution. Treatment-emergent events will 
be described for Part 1 separately and for Parts 1 and 2 overall. Events will be considered 


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treatment-emergent if first appearing or worsening following initiation of study therapy and 
within 4 weeks after study therapy discontinues.  See additional details in the SAP.  
9.8.1 
Adverse Event Analysis 
An AE is considered treatment-emergent if it was not present prior to the first dose of treatment 
or, if it was present, it worsened in severity or treatment attribution. AEs will be coded using the 
most recent version available of Medical Dictionary for Regulatory Activities (MedDRA) and 
assigned severity levels as described in Section 8.5.  
The number and percentage of subjects reporting TEAEs will be tabulated by severity, system 
organ class, causality, and preferred term, with a breakdown by treatment group. Similarly, the 
number and percentage of subjects reporting treatment-emergent SAEs will be tabulated, as well 
as TEAEs leading to discontinuation of study drugs. 
Deaths, other SAEs, and other significant AEs, including those leading to discontinuation of 
study drugs, will be listed. AEs will also be summarized by actual dose at the time of onset of the 
AE to account for possible dose reductions over the course of the study. 
9.8.2 
Clinical Laboratory Evaluation, Vital Signs Analysis, and ECG 
Individual data for clinical laboratory, vital signs, and ECG parameters will be presented in 
tabular form with descriptive statistics, including the number of observations, arithmetic mean, 
median, standard deviation, and range (minimum and maximum) as appropriate. The data will be 
summarized by treatment groups and scheduled visits. For the laboratory safety data, out-of-
range values will be flagged in the data listings, and a list of clinically significantly abnormal 
values will be presented. Individual results will be reviewed for any treatment-emergent changes 
of possible clinical significance. 
9.8.3 
Physical Examination 
Findings from the physical examination at baseline will be summarized by the treatment group. 
A listing of physical examinations will also be provided. 
 
 
 
 
 
 
 


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9.8.5 
Other Safety Analysis 
Concomitant medications will be coded using the current version of the WHO drug dictionary. 
The number and percentage of subjects taking concomitant medications will be summarized by 
treatment group. 
9.9 
 Sample Size and Power Calculations 
Sample size estimates for this study are based on information from 
 subjects in an ongoing 
large cohort study (Parkinson’s Progression Markers Initiative) who remained off symptomatic 
medication from study entry to the -month visit. In these subjects, the mean change from 
baseline in the sum of the MDS-UPDRS Parts II and III was 
points with a standard 
deviation of 
 points at the -month assessment. The results from a clinical trial called the 
 trial (
) were also analyzed. In this study, a group of 
70 early-stage PD subjects receiving a placebo showed a change on the sum of the UPDRS Parts 
II and III (older but similar scale to the MDS-UPDRS) of 
 points with a standard deviation 
of 
points over 
 weeks (data for analysis obtained from the National Institute of 
Neurological Disorders and Stroke, National Institute of Health, United States of America). 
For this study, assuming 
 improvement at Week 40 for the K0706 group mean over the 
placebo group mean of 
 in change-from-baseline MDS-UPDRS Parts II and III sum 
score, the target delta is 
. 
 
  
Assuming a common standard deviation across treatment groups 
, a sample size of 
 in the high-dose and placebo groups will be required to achieve 
 
power. The comparison for the low-dose group (
) will also have 
 
power under the same assumptions. Additional subjects may be enrolled. 
With an evaluable sample size of 
, the target 
 of 
 is 
considered to be the minimal improvement that would be considered clinically meaningful. 
 
 
 
Based on the data of PASADENA trial in early PD subjects (
 the 
contribution of the MDS-UPDRS Part II to the effect size is expected to be negligible or negative, thus by 
excluding Part II and using Part III alone as the primary efficacy outcome is expected to have at least the 
same power compared to using the sum of Parts II and III. 
Sample size estimates for Part 2 
 consideration but are based on 
the 
 successfully and elect to participate in 
ongoing treatment.      


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9.10 
 Planned Three-Stage Analysis 
The data for this study will be evaluated in three stages as follows: 
Stage 1 - 
 
 
 
 
 
. The study team will remain blinded 
until the completion of Part 1. Details will be provided in the SAP along with the 
 
  
Stage 2 – At the completion of Part 1. The primary efficacy analysis will be performed at this 
stage. The primary efficacy analysis will be performed when all the planned 
 
subjects have completed Part 1 or been discontinued early from Part 1. The primary efficacy 
endpoint will be analyzed together with all other efficacy and safety endpoints or outcomes. An 
overall alpha of 0.099 (two-sided) will be allocated to the primary efficacy analysis at this stage.  
A parallel gatekeeping procedure will be used to test the combined family of 6 hypotheses (i.e., 
cross-combination of 2 dose comparisons and 3 patient populations) pertaining to the primary 
endpoint, aiming for a strong control of the familywise error rate at 9.9% level (two-sided).  The 
combined family for inferences includes 2 comparisons (High Dose vs Placebo, Low Dose vs 
Placebo) in Gate-1 family concerning the overall sample, and the same 2 comparisons in Gate-2a 
family concerning 
 and the same 2 comparisons in Gate-2b family concerning 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Stage 3 – At the completion of Part 2. This analysis will evaluate the long-term extension data 
and will constitute the final analysis of Part 2. The primary efficacy endpoints of interest for Part 
2 is the change from Part 2 baseline to Week 76 in the MDS-UPDRS Part III score. The change 
from Part 2 baseline in the MDS-UPDRS assessments (including Part I score, Part IA score, Part 
IB score, Part II score, Part III score, Part III sub-domain scores, Parts II and III sum score, and 
Parts I, II and III sum score) across all time points up to Week 76 will be summarized by 
treatment group.  
 


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10.0 
STUDY MANAGEMENT 
10.1 
Monitoring 
On-site or remote monitoring will be performed during the study. Remote monitoring may be 
necessary for data sites due to the impact of a pandemic (COVID-19) or natural disaster. The 
monitor will ensure that the study is conducted, recorded, and reported in accordance with the 
protocol, Standard Operating Procedure (SOP), GCP, and the applicable regulatory requirements. 
The monitor will check the accuracy and completeness of the eCRF entries, source documents, 
and other study-related records against each other.  The monitor will follow written SOPs as well 
as those procedures that are specified by CRO for monitoring a specific study.  The monitor will 
record the date of each visit together with a summary of the status and progress of the study. 
Proposed actions will be confirmed with the Investigator in writing. 
Considering the COVID pandemic situation, remote monitoring will be allowed wherever 
possible. 
The Investigator will provide direct access to source data/documents for study-related 
monitoring. It is important that the Investigator and/or other staff are available at these visits.  
The Investigator should maintain source documents such as laboratory reports, history, and 
physical examination reports, etc., for possible review. 
10.2 
Documentation at the Study Site 
Data relating to the study will be documented in the source documents and eCRFs. The 
Investigator will ensure the accuracy, completeness, legibility, and timeliness of the data 
recorded in the source documents and eCRFs. Any change or correction to a source document or 
eCRF will be dated, initialed, and explained (if necessary) and will not obscure the original 
entry. 
At the beginning of the study, a site master file will be established at the investigational site. The 
Investigator will maintain the study documents as specified in the ICH Guideline of GCP and as 
required by the applicable regulatory requirements. The Investigator will take measures to 
prevent accidental or premature destruction of these documents. The Investigator will permit 
study-related monitoring, audits, and IRB/EC or regulatory inspection, providing direct access to 
source data or documents. 
Prior to the start of the study, a Signature and Delegation Log will be completed showing the 
signatures and hand-written initials of all study staff. This log allows the PI to delegate study 
tasks to individual members of his/her team, identifies site staff participating in the study and the 
start/stop times of their participation, and provides a handwriting sample for all site staff 
participating in the study. 


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10.3 
Subject Data and Data Protection 
To protect the subject's identity, a subject number will be assigned by the Investigator to each 
study subject and used in lieu of the subject's name when the Investigator reports AEs and/or 
other study-related data. Personal information will be treated as confidential but may need to be 
reviewed by authorized representatives of CRO (if applicable) (monitor and auditor), IRB/EC, 
and regulatory authorities. The subject's consent for direct access to his/her original medical 
records for data verification purposes has to be obtained prior to a subject's participation in the 
study. 
The Investigator must maintain a list of names and identifying information (e.g., initials, date of 
birth, subject identification code, and date of study randomization) of all subjects enrolled in the 
study. The Investigator will keep the subject identification code list in the site master file. 
10.4 
Data Management  
A Code of Federal Regulations Title 21 Part 11-compliant EDC (Electronic Data Capture) 
system will be used for this study.  The eCRFs will be produced for each subject. The majority of 
study data collected on the source documents will be entered by the study center staff or directly 
captured from devices and submitted to the database. Data will be available for Sponsor review 
via predefined reports extracted from the database at agreed intervals. The eCRFs must be kept 
in order and up-to-date so that they reflect the latest observations on the enrolled subjects. 
All source documents will be retained. Photocopies of completed source documents will be 
provided only if essential (i.e., for regulatory purposes) at the request of the Sponsor. 
Safety laboratory data are managed and stored within the appropriate system and the date and 
time of sampling will be recorded in the eCRF. Safety laboratory data will be integrated with the 
consolidated clinical data before interim and final database locks. 
The informed consent will be kept with a copy of the completed source documents in the 
appropriate file folder provided by the sponsor/designated personnel; alternately a note to 
indicate where the records are located will be provided by the sites. All records should be kept in 
conformance to applicable national laws and regulations. 
Data validity and consistency will be checked by employing pre-programmed data validation 
rules that will be applied to the data extracted from the EDC system during the study. The data 
management team will raise queries in the EDC system to resolve discrepancies. The 
Investigator must verify that all data entries in the eCRFs are accurate and correct per the source 
document. At the interim 40-week time point and after completion of the study, when all 
collected data is validated, the database will be locked. Interim and Final data will be extracted 
from the EDC system in the form of SAS® datasets for the purpose of analysis. A portable 
document format copy of the eCRF will be produced for each study subject and included in the 
interim and final deliveries as required. 


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All eCRF entries, corrections, and alterations must be made by the Investigator or other 
authorized, study center staff and only by individuals who have received training to use the EDC 
system. Study center staff may only be allowed access to the system after the relevant training is 
completed. Training must be documented, and a log of all EDC users and their rights within the 
system must be maintained. 
Adverse events will be coded using the current MedDRA thesaurus; concomitant medications 
will be coded using World Health Organization’s Drug Dictionary. 
The EDC system will keep track of all data entry, alterations and query entry and resolution in an 
audit trail.  The audit trail will form an integral part of the database and will be archived 
alongside the data. 
10.5 
Compliance with Protocol 
The investigator or institution should conduct the trial in compliance with the protocol agreed to 
by the Sponsor and, if required, by the regulatory authority (ies) and which was approved or 
given a favorable opinion by the IRB/EC. 
The Investigator will not implement any deviation from or changes to the protocol without 
agreement by the Sponsor and prior review and receipt of documented approval or a favorable 
opinion from the IRB/EC of an amendment, except where necessary to eliminate immediate 
hazards to a study subject or when the changes involve only logistical or administrative aspects 
of the study (e.g. change in monitor(s), change in telephone numbers). 
10.6 
Amendments to the Protocol 
All changes to or deviations from the trial protocol must be confirmed in writing. The 
amendments to the protocol will be made jointly among the CRO (if applicable), the Sponsor, 
and Investigator(s). Protocol amendment(s) will be signed off in the same way as the original 
protocol. 
10.7 
Investigator Responsibilities 
10.7.1 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by the Sponsor 
or designee and given approval/approval/favorable opinion by the IRB/EC and the appropriate 
regulatory authorities. The Investigator will sign this protocol to confirm the agreement (see 
Principal Investigator Signature Page). 
10.7.2 
Protocol Deviations 
The Investigator should not implement any deviation from or change to the protocol without 
prior agreement with the Sponsor or designee. When immediate deviation from the protocol is 
required to eliminate an immediate hazard(s) to subjects, the Investigator will contact Sponsor or 


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designee, if circumstances permit, to discuss the planned course of action. Any departures from 
the protocol must be fully documented and submitted to the IRB/EC in accordance with the 
IRB/EC’s reporting requirements.


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11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance and quality control systems are implemented and maintained using written 
SOPs to ensure that the study is conducted and data are generated, documented (recorded) and 
reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s). 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
11.1 
Audit 
Sponsor or designee may conduct an internal or external audit. In such an instance, the auditor 
will be allowed direct access to the source medical records, the study drug storage area, the 
eCRFs, and the Site’s master file for the study.


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12.0 
ETHICS 
Before initiation of the study, Sponsor will seek permission from the regulatory authorities and 
EC for conducting the study.  All documents required by the appropriate authorities will be 
submitted.  Any notification/submission will be dated and contain sufficient information to 
identify the protocol. 
12.1 
Ethics Committee (EC) or Institutional Review Board (IRB) 
This study will be initiated after the protocol is reviewed and approved by the concerned IRB or 
EC. All documents required by the appropriate authorities will be submitted. Any 
notifications/submission will be dated and contain sufficient information to identify the protocol.  
12.2 
Ethical Conduct of the Study 
This study will be carried out in conformity with GCP described in Guideline E6 of the ICH.   
This study will also be carried out in conformity with the laws, rules and regulations prevailing 
in the state and country of the investigational site. 
12.3 
Subject Information and Consent 
Subjects will be screened and included in Part 1 and/or Part 2 of the study only after having been 
given adequate and appropriate information, and having obtaining a written informed consent 
form. The subject will be given sufficient time to consider the study’s implications before 
deciding whether to participate. The subject will be provided with a copy of the signed informed 
consent form. The confidentiality of the subject’s records will be maintained. If there is any 
major amendment in the protocol affecting the subject’s participation in the study e.g., a change 
in any procedure, the ICF will be amended to incorporate this modification and previously 
consented subjects will sign an amended consent form (when relevant). The Investigator is 
responsible for obtaining the subject’s freely given written consent.


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13.0 
DATA HANDLING AND RECORD KEEPING 
The Investigator must maintain all documentation relating to this study.  Essential documents (as 
defined in the ICH Guideline of GCP) must be retained until at least 2-years after the last 
approval of a marketing application in an ICH region, and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2-years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
must be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by Sponsor. 
In any case, all study records such as, but not limited to: CRFs, regulatory documents, the subject 
identification code list, subject files and other source data that support CRFs must be retained for 
at least 15 years after the completion or discontinuation of the study.  If the Investigator retires, 
relocates or for other reasons withdraws from the responsibility of keeping the study records, 
custody must be transferred and Sponsor notified in writing. The Sponsor will notify the 
Investigator in writing when the study-related records are no longer needed.


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14.0 
FINANCING AND INSURANCE 
The Sponsor is covered by a liability insurance that also covers liability towards subjects in 
clinical trials. Sponsor is covered by a General and Products liability insurance that includes 
clinical trials.


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15.0 
PUBLICATION POLICY 
The CRO and Investigator agree to keep strictly confidential all unpublished information and 
results concerning this study.  In the event Institution or Investigator wants to publish or present 
any or all of the technical developments, it shall submit to Sponsor the manuscript, abstract or 
other proposed publication at least 30 days prior to submission, and in the case of poster boards 
or other presentations, at least 45 days prior to the presentation itself. Sponsor shall timely 
review the proposed publication, and may revise the manuscript or other proposed publication to 
ensure protection of Sponsor’s confidential information. Any publication or disclosure by the 
investigator contrary to the provisions of this section or without prior written consent of Sponsor 
shall be void-ab-initio. Sponsor reserves all the rights to declare any of its data confidential or of 
business importance and will provide it only to the regulatory authorities of concern on 
request/demand.


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16.0 
REFERENCES 
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Arora, S., et al. (2018). Smartphone motor testing to distinguish idiopathic REM sleep behavior 
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Athauda, D., et al. (2017). Exenatide once weekly versus placebo in Parkinson's disease: a 
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Biglan, K., et al. (2017). A novel design of a Phase III trial of isradipine in early Parkinson 
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Brahmachari S Fau - Ge, P., et al. (2016). Activation of tyrosine kinase c-Abl contributes to α-
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Busner, J., & Targum, S. D. (2007). The clinical global impressions scale: applying a research 
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Daily, E. B., & Aquilante, C. L. (2009). Cytochrome P450 2C8 pharmacogenetics: a review of 
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Donadio, V., et al. (2014). Skin nerve α-synuclein deposits: a biomarker for idiopathic Parkinson 
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Eusebi, P., et al. (2017). Diagnostic utility of cerebrospinal fluid α-synuclein in Parkinson's 
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Gibbons, C. H., Garcia, J., Wang, N., Shih, L. C., & Freeman, R. (2016). The diagnostic 
discrimination of cutaneous α-synuclein deposition in Parkinson disease. (1526-632X 
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Gleevec [imatinib] PI. (2016). Gleevec (imatinib) prescribing information. Retrieved from 
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Goetz, C. G., et al. (2023). It Is as It Was: MDS-UPDRS Part III Scores Cannot Be Combined 
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Goetz, C. G., et al. (2008). Movement Disorder Society-sponsored revision of the Unified 
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Goetzl, E. J., et al. (2015). Altered lysosomal proteins in neural-derived plasma exosomes in 
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Hebron, M. L., Lonskaya I Fau - Moussa, C. E. H., & Moussa, C. E. (2013). Nilotinib reverses 
loss of dopamine neurons and improves motor behavior via autophagic degradation of α-
synuclein in Parkinson's disease models. (1460-2083 (Electronic)). 
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Herdman, M., et al. (2011). Development and preliminary testing of the new five-level version of 
EQ-5D (EQ-5D-5L). Quality of Life Research, 20(10), 1727-1736. Retrieved from 
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Iclusig [ponatinib] PI. (2016). Iclusig (ponatinib) prescribing information. Retrieved from 
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Janssen, M. F., et al. (2013). Measurement properties of the EQ-5D-5L compared to the EQ-5D-
3L across eight patient groups: a multi-country study. (1573-2649 (Electronic)). 
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Karuppagounder, S. S., et al. (2013). The c-Abl inhibitor, nilotinib, protects dopaminergic 
neurons in a preclinical animal model of Parkinson's disease. (2045-2322 (Electronic)). 
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Kenneth Marek, D. J., Shirley Lasch, Andrew Siderowf, Caroline Tanner, Tanya Simuni, Chris 
Coffey, Karl Kieburtz, Emily Flagg, Sohini Chowdhury, Werner Poewe, Brit 
Mollenhauer, Paracelsus-Elena Klinik, Todd Sherer, Mark Frasier, Claire Meunier, Alice 
Rudolph, Cindy Casaceli, John Seibyl, Susan Mendick…Peggy Taylor. (2011). The 
Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol, 95(4), 629-635. 
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Ko, H. S., et al. (2010). Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's 
ubiquitination and protective function. (1091-6490 (Electronic)). 
doi:10.1073/pnas.1006083107 
Koprich, J. B., Johnston Th Fau - Reyes, M. G., Reyes Mg Fau - Sun, X., Sun X Fau - Brotchie, 
J. M., & Brotchie, J. M. (2010). Expression of human A53T alpha-synuclein in the rat 
substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with 
protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with 
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Koprich, J. B., Kalia, L. V., & Brotchie, J. M. (2017). Animal models of α-synucleinopathy for 
Parkinson disease drug development. (1471-0048 (Electronic)). doi:10.1038/nrn.2017.75 
Lee, S., et al. (2018). The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical 
Parkinson's disease mouse model. (1460-2083 (Electronic)). doi:10.1093/hmg/ddy143 
Lipsmeier, F., et al. (2018). Evaluation of smartphone-based testing to generate exploratory 
outcome measures in a phase 1 Parkinson's disease clinical trial. (1531-8257 
(Electronic)). doi:10.1002/mds.27376 
Luk, K. C., et al. (2012). Pathological α-synuclein transmission initiates Parkinson-like 
neurodegeneration in nontransgenic mice. (1095-9203 (Electronic)). 
doi:10.1126/science.1227157 


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Marras, C., et al. (2011). Predictors of Time to Requiring Dopaminergic Treatment in 2 
Parkinson's Disease Cohorts. Movement Disorders, 26, 608-613. doi:10.1002/mds.23581 
Martínez-Martín, P., et al. (2016). Analysis of four scales for global severity evaluation in 
Parkinson's disease. (2373-8057 (Print)). doi:10.1038/npjparkd.2016.7. eCollection 2016 
Mary E. Nilsson, S. S., Cristiana Gassmann-Mayer, Sarah, & Dubrava, P. M., and Kaihong 
Jiang. . (2013). Columbia–Suicide Severity Rating Scale 
Scoring and Data Analysis Guide. Retrieved from https://cssrs.columbia.edu/wp-
content/uploads/ScoringandDataAnalysisGuide-for-Clinical-Trials-1.pdf 
Mollenhauer, B., et al. (2017). Longitudinal CSF biomarkers in patients with early Parkinson 
disease and healthy controls. (1526-632X (Electronic)). 
doi:10.1212/WNL.0000000000004609 
Mollenhauer, B., et al. (2020). Validation of Serum Neurofilament Light Chain as a Biomarker 
of Parkinson's Disease Progression. Mov Disord, 35(11), 1999-2008. 
doi:10.1002/mds.28206 
Mustapic, M., et al. (2017). Plasma Extracellular Vesicles Enriched for Neuronal Origin: A 
Potential Window into Brain Pathologic Processes. Frontiers in Neuroscience, 11. 
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NINDS exploratory trials. (2015). Pioglitazone in early Parkinson's disease: a phase 2, 
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Olanow, C. W., et al. (2009). A double-blind, delayed-start trial of rasagiline in Parkinson's 
disease. (1533-4406 (Electronic)). doi:10.1056/NEJMoa0809335 
Pagan, F., et al. (2016). Nilotinib Effects in Parkinson's disease and Dementia with Lewy bodies. 
(1877-718X (Electronic)). doi:10.3233/JPD-160867 
Parkinson study group. (1993). Effects of tocopherol and deprenyl on the progression of 
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Parkinson Study Group. (2002). Dopamine transporter brain imaging to assess the effects of 
pramipexole vs levodopa on Parkinson disease progression. (0098-7484 (Print)). 
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Parkinson study group. (2007). Mixed lineage kinase inhibitor CEP-1347 fails to delay disability 
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Pavy-Le Traon, A., et al. (2011). The Movement Disorders task force review of dysautonomia 
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Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid. (2168-6157 
(Electronic)). doi:10.1001/jamaneurol.2016.4547 
Simuni, T., et al. (2018). Baseline prevalence and longitudinal evolution of non-motor symptoms 
in early Parkinson's disease: the PPMI cohort. (1468-330X (Electronic)). 
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Simuni, T., et al. (2018). Longitudinal Change of Clinical and Biological Measures in Early 
Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort. Movement 
Disorders, 33(5), 771-782. doi:https://doi.org/10.1002/mds.27361 
Sprycel [dasatinib] PI. (2023). Dasatinib Prescribing Information. Retrieved from 
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Visser, M., Marinus J Fau - Stiggelbout, A. M., Stiggelbout Am Fau - Van Hilten, J. J., & Van 
Hilten, J. J. (2004). Assessment of autonomic dysfunction in Parkinson's disease: the 
SCOPA-AUT. (0885-3185 (Print)). doi:10.1002/mds.20153 
Walsh, R. R., et al Walsh, R. R., et al. (2023). Plasma and cerebrospinal fluid pharmacokinetics 
of vodobatinib, a neuroprotective c-Abl tyrosine kinase inhibitor for the treatment of 


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Parkinson's disease. Parkinsonism Relat Disord, 108, 105281. 
doi:10.1016/j.parkreldis.2023.105281 
Williams-Gray, C. H., et al. (2013). The CamPaIGN study of Parkinson's disease: 10-year 
outlook in an incident population-based cohort. (1468-330X (Electronic)). 
doi:10.1136/jnnp-2013-305277 
Ye, R., et al. (2021). Serum NFL levels predict progression of motor impairment and reduction 
in putamen dopamine transporter binding ratios in de novo Parkinson's disease: An 8-
year longitudinal study. Parkinsonism Relat Disord, 85, 11-16. 
doi:10.1016/j.parkreldis.2021.02.008 
Zhan, A., et al. (2018). Using Smartphones and Machine Learning to Quantify Parkinson Disease 
Severity: The Mobile Parkinson Disease Score. (2168-6157 (Electronic)). 
doi:10.1001/jamaneurol.2018.0809 
Zhao, Y. J., et al. (2010). Progression of Parkinson's disease as evaluated by Hoehn and Yahr 
stage transition times. (1531-8257 (Electronic)). doi:10.1002/mds.22875 
 
 


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17.0 
APPENDICES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
   
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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9. 
 
 
  
 
  
  
 
 
 
  
 
 
 


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APPENDIX 2: 
MDS CLINICAL DIAGNOSTIC CRITERIA FOR PD : 
 
 


 
 
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APPENDIX 4: 
CLINICIAN GLOBAL IMPRESSION SCALE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
















































































 
 
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DAY. 




 
 
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APPENDIX 9: 
SCOPA-AUT  
 
SCOPA-AUT 
 
e 
 
on 
 
 
 


 
 
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SAP_001.pdf: 
Statistical Analysis Plan 
CONFIDENTIAL 
 
 
Protocol Reference: CLR_18_06 
 
 
Sponsor Final, Version 3.0, 14FEB2024 
Page 1 of 78 
 
 
 
 
Statistical Analysis Plan 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY OF K0706 IN SUBJECTS WITH EARLY 
 
Statistical Analysis Plan: Final 
Statistical Analysis Plan: 3.0 
Statistical Analysis Plan Date: 14Feb2024  
Investigational Product: K0706 
Protocol Reference: CLR_18_06 
  
Sponsor: Sun Pharma Advanced Research Company Limited (SPARC) 
 
 
 
Information described herein is confidential and may be disclosed only with the express written 
permission of the sponsor. 
 
 


Statistical Analysis Plan 
CONFIDENTIAL 
 
 
Protocol Reference: CLR_18_06 
 
 
Sponsor Final, Version 3.0, 14FEB2024 
Page 2 of 78 
 
 
 
 
Signature Page 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
             
                                                                                                                                                   
Date (dd mmm yyyy) 
 
 


Statistical Analysis Plan 
CONFIDENTIAL 
 
 
Protocol Reference: CLR_18_06 
 
 
Sponsor Final, Version 3.0, 14FEB2024 
Page 3 of 78 
 
 
 
 
Table of Contents 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Reviewers 
The following reviews of the Statistical Analysis Plan (SAP) were conducted: 
 
 
 
 






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 or to placebo (from placebo) remained on the same dose level of the 
powder formulation. Subjects who had a dose reduction from 
 
were discontinued from the study 
. See Table 1 for 
an overview of the currently available 
 formulations. An alternate 
formulation under development may further displace the current 
 formulation. 
Transitions occur in a blinded manner via the Interactive Web Response System (IWRS) and 
occur at the 
 
 
 
 
 
Treatment assignments will remain masked to subjects, Investigators, site staff not directly 
provisioning kits on behalf of the Sponsor, and unless specified otherwise, the Sponsor will 
remain masked to treatment assignments until the last subject completes the Week 40 
assessments for efficacy and the clinical database is locked for the final analysis of Part 1. 
Sponsor and affiliates may be unblinded to perform the final analysis of Part 1 (Week 40) data 
and report those results at that time. 
2.1.2 
Part 2 (Week 40 to Week 80) 
Subjects who complete the EOT visit of Part 1 (Visit 11/Week 40) and who consent to 
participate in Part 2 of the study will be screened according to Part 2 eligibility criteria. Subjects 
randomized to placebo dosing in Part 1 will be rolled over to a high dose 
 
 at Week 40 or their first dosing opportunity in Part 2. This 
will enable the collection of additional safety data for the high dose level. Subjects randomized 
to K0706 (either dose level) in Part 1 of the study will remain on the same dosing regimen in 
Part 2. All Part 2 subjects will continue taking the study drug (K0706) orally, once daily, for an 
additional 36 weeks. The Week 76 visit (Visit 19) is the EOT visit of Part 2. The Week 80 visit 
(Visit 20) is the follow-up visit of Part 2 to collect safety outcomes. 


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2.2 
Study Objectives 
2.2.1 
Part 1 (Day 1 to Week 40) 
2.2.2 
Primary Efficacy Objective 
To determine if K0706 reduces the rate of progression of early-stage PD versus placebo over 40 
weeks, as assessed by the Movement Disorder Society  
Scale (MDS-UPDRS) Part-III (motor examination) total score. 
2.2.2.1 
Secondary Objectives 
The secondary objectives of the base study are: 
 To determine if K0706 reduces the rate of progression of early-stage PD versus placebo 
over 40 weeks by a greater magnitude in the subgroup of patients excluding the mild-
motor predominant sub-type (
 The rate of progression is 
assessed by the MDS-UPDRS Part III total score. 
 To determine if K0706 reduces the rate of progression of early-stage PD versus placebo 
over 40 weeks by a greater magnitude in the subgroup of patients with serum NfL value 
at baseline (
). The rate of progression is assessed by 
the MDS-UPDRS Part III total score. 
 To determine if K0706 reduces the rate of progression of early-stage PD versus placebo 
over 40 weeks, as assessed by the sum of the MDS-UPDRS Parts II and III total scores. 
 To determine if K0706 slows early-stage PD progression by increasing the time to 
significant worsening of PD on the MDS-UPRDS Parts I, II and III versus placebo. 
 
 
 
 To evaluate efficacy of K0706 compared to placebo in terms of Health Related Quality 
of Life (HRQoL) as measured by the European Quality of Life Questionnaire 5 level 
version (EQ-5D-5L). 
 To determine if K0706 slows progression of early-stage PD versus placebo over 40 
weeks in terms of overall severity of PD as measured by the Clinician Global Impression 
Severity of (CGIS) scale. 
 To evaluate the effect of K0706 versus placebo on autonomic nervous system 
dysfunction related to PD as measured by the Scales for Outcome in PD-Autonomic 
(SCOPA-AUT) 
 To evaluate the safety and tolerability of K0706. 
 To evaluate the 
 
 measures of efficacy and safety. 




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 in the early PD subjects 
 
, the contribution of the MDS-UPDRS Part II to the effect size is expected to be 
negligible or negative, thus by excluding Part II and using Part III alone as the primary efficacy 
outcome it is expected to have 
 power compared to using the sum of Parts II and 
III.  
 
.  
The sample size estimate for Part 2 
 consideration but is based on 
the 
 successfully and elect to participate in the extension 
study.  
 
 
 


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3.0 
ANALYSIS POPULATIONS (SETS) 
The following analysis populations (sets) will be used for the analyses. 
 
3.1 
All Screened Set 
The All Screened Set will include all subjects who signed the informed consent form. This 
population will be used only for summaries of disposition and the associated listing. 
3.2 
All Randomized Set, Part 1 
All subjects randomized will be included in the All Randomized Set, Part 1. This population will 
be used for summaries of demographics and baseline characteristics, medical history, and prior 
and concomitant medications for Part 1 of the study. 
3.3 
Efficacy Analysis Set 
3.3.1 
Efficacy Analysis Set, Part 1 
The Efficacy Analysis Set, Part 1 will consist of all subjects who were randomized, received at 
least one dose of the study medication in Part 1 of the study, and had a non-missing baseline and 
at least one non-missing post-baseline assessment(s) in the primary efficacy variable MDS-
UPDRS Part-III total score in Part 1 of the study.  This population will be used for all the 
efficacy analyses for Part 1. 
3.3.2 
Efficacy Analysis Set, Part 2 
The Efficacy Analysis Set, Part 2 will consist of all subjects who received at least one dose of 
study medication in Part 2 of the study, and who did not start symptomatic PD medications in 
Part 1, and who had a non-missing baseline and at least one non-missing post-baseline 
assessment(s) in the primary efficacy variable MDS-UPDRS Part-III total score in Part 2 of the 
study.  This population will be used for all the efficacy analyses for Part 2. 
3.4 
Per Protocol Set 
3.4.1 
Per Protocol Set, Part 1 
Per Protocol Set (PPS), Part 1 will consist of all subjects in the Efficacy Analysis Set, Part 1 
without any important protocol deviations leading to exclusion from the PPS during the Part-1 
period of the study. The PPS, Part 1 will be used as supportive analyses of primary and 
secondary endpoints for Part 1 only. 
Protocol deviations are defined as any change, divergence, or departure from the study design or 
procedures defined in the study protocol. Important protocol deviations are a subset of protocol 
deviations that may significantly impact the correctness, accuracy, and / or reliability of the 






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3.8 
All Enrolled Set, Part 2 
All subjects who had a Part 2 visit, including the Part 2 baseline visit (e.g., eCRF Visit 13), will 
be included in the All Enrolled Set, Part 2. This population will be used for the summary of 
disposition, demographics and baseline characteristics for Part 2. 


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4. DATA HANDLING 
4.1 Time Points and Visit Windows 
4.1.1 General Definitions 
All assessment days will be related to the first day of the first dose of study drug administration. 
Day 1 is defined as the day when the first dose of the study drug is administered. 
 
  
 
  
 
 
The date of the first dose of study drug administration for each subject will be taken from the 
Study Drug  or Date Drug Admin Form eCRF forms at the Baseline Visit. If the date in these 
eCRF forms is missing, alternatively, the date of randomization will be used. 
For all Part 2 subjects, the date of the first dose of study drug administration in Part 2 will be 
taken from the Study Drug form-2  eCRF form at Visit 13/11 (Baseline visit for Part 2, Week 
40). If the date in this eCRF form is missing, alternatively, the date of the Visit 13/11 (Baseline 
visit for Part 2, Week 40) will be used. 
The date of the last dose of study drug administration for each subject will be taken from the 
Last Study Drug Details  eCRF form. If the date on this eCRF form is missing, alternatively, 
the date of the last dose from 
 will be used for the imputation. 
 
4.1.2 Definition of Baseline Value for Part 1 and Part 2  
For all subjects, the Baseline period for Part 1 is defined as the period from informed consent to 
the first dose of study drug administration. For some variables, data from more than one 
assessment within the Baseline Period are collected prior to the first dose of study drug 
administration. 
Unless otherwise specified, the baseline value for a variable for Part 1 is defined as the value of 
the last non-missing assessment or observation collected before the first dose of study drug 
administration for Part 1. 
Assessments carried out on the day of the first dose of study drug administration, i.e., Day 1, are 
considered to have taken place before the first dose of study drug administration if the 
corresponding times have not been recorded.  


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Unless otherwise specified, for all Part 2 subjects, the baseline value for a variable for Part 2 is 
defined as the non-missing value collected at Visit 11 (i.e., the Week 40 visit of Part 1). Note 
that the baseline visit for Part 2 is labeled as Visit 13, and the baseline value is simply taken 
from Visit 11, per the study schedule. Also, per the study schedule, the start (i.e., first dose) of 
the study drug for Part 2 is scheduled to be administered on the same day of the visit date of 
Visit 11.  However, in some cases, the start of the study drug administration for Part 2 actually 
took place after the visit date of Visit 11.  That is, the study drug start date in Part 2 can be 
greater than the visit date of Visit 11. In such cases, the non-missing assessment or observation 
immediately prior to the start of the study drug administration for Part 2 will be taken as the 
baseline value for Part 2.   
4.1.3 Treatment Period 
If the time (HH:MM) of data collection is not recorded but the protocol and / or eCRF includes 
an instruction to the effect that all Day 1 assessments are to be performed prior to the first dose 
of study drug administration, the data collected at Day 1 will be assigned to the Baseline period. 
However, adverse events (AEs) and medications starting on Day 1 with missing onset time 
(HH:MM), will be assigned to the Treatment Period. 
The Treatment Period is defined as the period from the date/time of the first dose of study drug 
administration up to and including the date of the last dose of study drug administration. 
4.1.4 Visit Windows  
4.1.4.1 Part 1 
Table 3 provides the relative study day ranges to be applied to the assessment/sample collection 
dates to derive the analysis Visits for efficacy analyses and some safety assessments (vital signs, 
laboratory assessments, and C-SSRS, by Visits for Part 1).  
The following considerations are to be followed when deriving the analysis Visits:  
 
 
 
 Both scheduled and unscheduled assessments are included for visit windowing 
 
 
 






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4.2.2 Handling of Missing Safety Data 
In general, missing clinical laboratory data, vital signs, and ECG data will not be imputed.  
Adverse event imputations for missing severity or relationship are described in Section 9.1.  
Unknown or partial medication and AE date imputations are given below and are to be used only 
for the assessment of prior/concomitant status for medications and treatment-emergent status for 
AEs. 
4.2.3 Handling of Partial and Missing Dates for Adverse Events, Prior / Concomitant 
Medications, and Last Dose of Study Drug 
For AEs with partial or missing onset or stop dates: 
 AE stop date will be imputed first as: 
o If the stop date is completely missing, assume it is ongoing (no imputation); 
o For a partial AE stop date: 
 the day is missing, then take the last day of the month 
 both day and month are missing, then take December 31st. 
o If the imputed AE stop date is after the End of the Study date, then the stop date 
will be set to the End of the Study date. 
 Then AE onset date will be imputed as: 
o If the onset date is completely missing, the first dose date; 
o For a partial AE onset date: 
 Day is missing: 
 Partial date < the first dose date: last day of the month 
 Partial date = the first dose date: the first dose date 
 Partial date > the first dose date: first day of the month 
 Both day and month are missing, ie, only the year is available: 
 Partial date < the first dose date: 31st December  
 Partial date = the first dose date: the first dose date 
 Partial date > the first dose date: 1st January. 
o If the imputed AE onset date is after the AE stop date/imputed AE stop date, then 
the onset date will be set to the AE stop date/imputed AE stop date. 
In the event that a partial date (month/year or year) for concomitant medication is available, 
concomitant medication start and stop dates will be imputed as: 


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 When both month and year are available  the first day of the month will be used for the 
start date, and the last day of the month will be used for the stop date. 
 When only year is available  01 January will be used for the start date and 31 December 
will be used for the stop date. 
Study drug last dose date 
will be used for 
calculating the exposure to study drug. If the study drug last dose date is missing, alternatively 
used for the imputation. This 
imputation of the study drug last dose date will be applied to both Part 1 and Part 2 of the study.  
The imputed dates will not be listed. Study day relative to the first dose of the study drug and 
duration associated with missing or partial dates will not be displayed in AE and concomitant 
medication listings. 
4.2.4 Handling of Plasma and CSF Concentrations that are Below the Lower Limit of 
Quantification  
Plasma and CSF concentrations that are below the lower limit of quantification (BLQ) will be 
handled as follows for descriptive statistics: 
 Values that are BLQ will be set to 0 for the calculation of summary statistics. 
 Arithmetic mean or median values that are BLQ will be presented as 0. 
 If any BLQ results (treated as 0) are in a series of summarized data, the geometric mean 
and coefficient of variation (CV)% of the geometric mean will be reported as not 
calculated (NC). 
 
 


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5.0 
STUDY CONDUCT 
5.1 
Subject Disposition and Definition of Completers for Part 1 and Part 2 
Subject disposition for Part 1 of the study will be summarized by treatment group and overall, 
where appropriate, for the All Screened Set. The following information will be reported:  
 Number of subjects for the following category: 
o Screened 
 Number and percentage of subjects for the following categories: 
o Randomized, 
o Treated, 
o Not Treated, 
o Completed Part 1 of the study,  
o Ongoing in Part 1 of the study 
o Discontinued from Part 1 of the study, 
o Reasons for Part 1 study discontinuation. 
 Number and percentage of subjects who failed and did not fail screening prior to 
randomization, including the primary reason for screen failure; 
Subject disposition for Part 2 of the study will be summarized by treatment group and overall, 
where appropriate, for the All Enrolled Set, Part 2. The following information will be reported:  
 Number and percentage of subjects for the following categories: 
o Completed Part 2 of the study,  
o Ongoing in Part 2 of the study 
o Discontinued from Part 2 of the study, 
o Reasons for Part 2 study discontinuation. 
 
Moreover, the following information will be reported for the All Randomized Set, Part 1:  
 Number and percentage of subjects included in each study population (All Randomized 
Set, Part 1; Efficacy Analysis Set, Part 1; Efficacy Analysis Set, Part 2; PPS, Part 1; 
Safety Analysis Set, Part 1; Safety Analysis Set, Part 2, BM Analysis Set, Part 1; and PK 
Analysis Set, Part 1); 
 Number and percentage of subjects by country and site; 
 Number and percentage of subjects by stratification factors 
 region [
], and use of an MAOB Inhibitor [
 at Baseline). Each 
 variable will be presented by the 
 collected in IWRS, except the use 


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of a MAOB Inhibitor at Baseline which will be presented both by the 
 collected 
in IWRS and the 
 collected in the eCRF. 
The MAOB Inhibitors at the Baseline will be determined using the Chemical Subgroup (ATC-
Level 4). The ATC-Level 4 that determines the MAOB Inhibitors is MONOAMINE OXIDASE 
(ATC-Level 4 code: N04BD), based on WHO Drug Global Dictionary 
(version Mar 2022 or a later version if updated during the study), ATC Classification codes.  
Completers of Part 1 and Part 2 of the study will be respectively defined as follows. A subject 
will be regarded as Part 1 completer if the subject attended the Visit 11 - Week 40 visit, at which 
the MDS-UPDRS Part III assessment on the subject was collected.  A subject will be regarded as 
Part 2 completer if the subject attended the Visit 19 - Week 76 visit, at which the MDS-UPDRS 
Part III assessment on the subject was collected. A subject will be considered as having 
discontinued the study if the subject had an eCRF status of early study discontinuation. 
Otherwise, the subject will be considered as ongoing in the study. 
A listing of all subjects with their treatment and study completion status, including the reason for 
study discontinuations, will be presented for the All Randomized Set, Part 1. 
A listing of all screen-failed subjects with their reasons for screen failure will be presented for 
the All Screened Set. A separate listing of subjects who failed at least one inclusion/exclusion 
criteria, including a text description of the criterion failed, will be presented for the All Screened 
Set. 
A listing of all randomized subjects with their randomization details, including first dose date 
and actual treatment received, will be presented for the All Randomized Set, Part 1. 
A listing of all subjects with mis-stratification will be presented for the All Randomized Set, Part 
1. 
A listing of all subjects excluded from at least one analysis set will be presented for the All 
Randomized Set, Part 1. 
5.2 
Protocol Deviations 
All important protocol deviations will be summarized for Parts 1 and 2 of the study separately, 
using the All Randomized Set, Part 1 and All Enrolled Set, Part 2, respectively, and all important 
protocol deviations leading to exclusion from the PPS, Part 1 (see Section 3.4.2) will be 
summarized for the Efficacy Analysis Set, Part 1 by treatment group and overall as described 
below: 


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 The number of unique subjects with at least one important protocol deviation as well as 
the number of subjects in each important protocol deviation category, will be presented 
by default descriptive summary statistics for categorical variables.  
 The number of unique subjects with at least one important protocol deviation that led to 
exclusion from the PPS, Part 1 as well as the number of subjects in each important 
protocol deviation category, will be presented by default descriptive summary statistics 
for categorical variables.  
A listing of the important protocol deviations will be presented for Parts 1 and 2 of the study 
separately, using the All Randomized Set, Part 1 and All Enrolled Set, and Part 2, respectively. 
5.3 
Measurement of Treatment Compliance 
For scheduled visits 
, subjects are asked about compliance with study 
drug, and any deviation in compliance could feed into a protocol deviation. 
The number of doses missed since the last visit is collected in the eCRF and taken into account 
for the derivations of study exposure. Details regarding these derivations are provided in Section 
9.8. 
5.4 
Data Monitoring 
The 
 independent of the study team and consisting of 
external members only, will be formed for this trial. The 
 will be responsible for the 
periodic review of the unblinded safety data and the ongoing monitoring of the safety of the 
study subjects according to the 
 Charter. When warranted due to safety concerns based on 
accumulated data and evidence, the 
 could make recommendations (such as dose 
reduction or trial termination) to the Sponsor. However, the decision of whether to follow 
resides in the Sponsor. 
 
 


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6.0 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
6.1 
Demographic Characteristics 
Demographic characteristics will be summarized for the All Randomized Set, Part 1, by 
treatment group and overall as described below. All missing data will be presented as part of a 
missing category, if appropriate. Standard descriptive statistics will be presented for the 
continuous variables of: 
 Age at Screening (years) 
 Weight (kg) at Screening 
 Height (cm) at Screening 
 Body mass index (kg/m2) at Screening (calculated as [body weight / height2] where 
weight is in kg and height is in m) and presented to one decimal precision 
Total counts and percentages of subjects will be presented for the categorical variables of: 
 Age group (years): 
 <= 65 
 > 65 to <= 75 
 > 75 
 Gender 
 Childbearing potential (females only; classified as [yes], [no, surgically sterile], [no, 
post-menopausal], [no, other]) 
 Race 
 Ethnicity 
 Weight category (kg) at Screening: 
 <= 90 
 > 90 kg 
6.2 
Baseline Characteristics  
Baseline characteristics will be summarized for the All Randomized Set, Part 1 by treatment 
group and overall as described below. All missing data will be presented as part of a missing 
category, if appropriate. 
Standard descriptive statistics will be presented for the continuous variables of: 


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 Baseline MDS-UPDRS (Part I total score, Part II total score, Part III total score, the sum 
of the Parts II and III total scores, the sum of the Parts I, II and III total scores) 
 Time between onset of PD symptoms and initiation of study 
 
 
 
 Time between diagnosis of PD and initiation of the study 
 
 
 
 Number of years of education 
 Montreal cognitive assessment score at Screening 
Total counts and percentages of subjects will be presented for the categorical variables of: 
 History of Sleep dysfunction 
 
 
 
 History of Autonomic dysfunction 
 
 
 
 History of Hyposmia 
 
 History of Psychiatric dysfunction (
 
 Magnetic Resonance Imaging (MRI) scan of the brain suggestive of secondary 
Parkinsonism (
 
 
 DaT SPECT scan performed to determine eligibility conclusion: 
 
 
 Meet criteria for clinically probable PD by MDS Clinical Diagnostic criteria:
 
 Serological tests:  
 Hepatitis B Virus Surface Antigen: 
 
 Hepatitis C Virus Antibody: 
 
 Human Immunodeficiency Virus (HIV) 1 and 2 Antigen/Antibody: 
 
 Smoking history: 
 
 Alcohol consumption: 
 
 Caffeine consumption: 
 
 Currently working: 
 


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No formal tests of statistical significance will be performed on the demographic and baseline 
characteristics data. 
6.3 
Medical History 
Medical history is defined as any condition, except for the study indication, that the subject may 
have had prior to enrollment in the study, including any chronic conditions diagnosed prior to 
entry in the study. 
The medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) (version 23.0 or a later version if updated during the study) and will be presented by 
System Organ Class (SOC) and Preferred Term (PT).  
Active medical history is defined as ticked on eCRF as ongoing (with or without treatment) and 
otherwise is defined as past.  
Active and past medical history records will be summarized separately for the All Randomized 
Set, Part 1 by treatment group and overall as follows: 
 The number and percentage of subjects with at least one active/past medical history 
record will be presented.  
 The number and percentage of subjects with at least one active/past medical history 
record within each primary SOC and PT will be presented. The summary will be sorted 
using the internationally agreed order for SOC and using the descending order of overall 
numerical counts for PT. Where terms tie, these will be sorted alphabetically. 
 
 




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(3) All visits or assessments with a date after the date of the first intake of symptomatic PD 
medication during Part 1 will be marked as 
date of symptomatic PD 
medications  
7.2 
Start Date of Symptomatic PD Medications for Part 2 
Subjects who started symptomatic PD medications in Part 1 will be withdrawn from the study 
and cannot enter Part 2. Subjects entering Part 2 are either still naïve to symptomatic PD 
medications or on MAO-B inhibitors (without an increase in dose) since the Part 1 baseline.   
The start of symptomatic PD medications for Part 2 should be after the start of the study drug 
administration for Part 2. The start date of symptomatic PD medications for Part 2 will be 
derived and flagged using the same algorithm as above. 
 
 


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8.0 
EFFICACY ANALYSES 
All efficacy analyses for Part 1 (the double-blind treatment phase) of the study will be performed 
on the Efficacy Analysis Set, Part 1, and subjects will be included in the treatment group as 
randomized.  
All efficacy analyses for Part 2 (the long-term extension phase) of the study will be performed 
on the Efficacy Analysis Set, Part 2, and subjects will be included in the treatment group as 
assigned at the baseline visit (Visit 13) of Part 2. 
For all efficacy analyses, the values of stratification strata (for example, baseline user status of 
MAO-B inhibitors) as collected in the eCRF will be used instead of the values entered by the 
investigator into the IWRS, except for the supplementary analyses described in Section 8.1.6 
below. 
8.1 
Primary Efficacy Analyses (Part 1) 
The week 40 visit of Part 1 is a landmark time-point for this trial when the last assessment of the 
primary efficacy outcome for the double-blind treatment phase will be collected. The primary 
efficacy outcome variable is the MDS-UPDRS III total score, which is the sum of the rater-based 
Motor Examination (
). The primary endpoint is the change from baseline to 
Week 40 in the MDS-UPDRS Part III total score.   
8.1.1 
Primary 
  
This trial seeks to clarify the efficacy of K0706 in delaying the progress of PD in the ideal 
scenario of no intercurrent events and full adherence to the assigned 40-week treatment regimen 
dosed once daily in all randomized subjects. It is thus appropriate to employ the hypothetical 
 for the primary efficacy analyses, with the use of a hypothetical strategy for handling 
intercurrent events. The primary 
 is described by five attributes as follows. 
 
 Treatment: the treatment condition of interest includes the 
 high dose and the 
 low dose of K0706 in 
 formulation administered once daily for 40 weeks. The 
alternative treatment condition to which the comparison will be made is Placebo in 
 
formulation administered once daily for 40 weeks. 
 
 Target Population: s
an initial diagnosis of PD was 
within 3 years of the scr
 who meet the 
protocol-specified inclusion and exclusion criteria.  
 
 Endpoint: Change from Baseline to Week 40 in the MDS-UPDRS Part III total score  


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During the course of this trial, the COVID-19 pandemic broke out. There were occasionally 
virtual visits (or say, remote assessments) and possibly early discontinuation of treatment 
directly or indirectly related to the pandemic. Virtual visits in the pandemic environment will not 
be handled 
. Subjects who dropped out for a reason related to the 
COVID-19 pandemic will be handled as if they would have dropped out for other reasons if the 
pandemic had not happened. The hypothetical strategy for handling 
 will be 
used to clarify the efficacy of K0706 had there been no occurrence of 
 
regardless of being COVID-19 related or not.  
8.1.2 
Method of Estimation 
Mean changes from baseline in the MDS-UPDRS Part III score will be analyzed using the 
The analysis will be 
performed by fitting the 
 model with an unstructured 
 
in which the change from the baseline in the Part III total score (Weeks 4, 8, 12, 20, 28, 36, 40) 
will be the dependent variable based on the observed case data.  The analysis will include 
treatment arm, analysis visit, region (
 
), baseline MAOB inhibitor user status (
/
 and the 
interaction term of treatment by analysis visit as the fixed, categorical effects, and will include 
the interaction term of baseline Part III score by analysis visit as the continuous, fixed 
covariates. An unstructured covariance structure will be used to model the within-subject error. 
In case of the convergence problem with the 
 model with the 
 
matrix, the following structures will be used in the order of 
 
 
 to the best fit will be used as the 
primary analysis. 
The 
 will be used to estimate the denominator degrees of 
freedom. Three contrasts of group mean (i.e., difference in least-square means for each active 
dose and the pooled dose of the K0706 vs. placebo) at Week 40 will be estimated from the 
interaction term of treatment by analysis visit based on the 
 model. These contrasts at 
Week 40 will serve as the primary comparison. Test of significance for each contrast will be 
performed by using a 
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inhibitors user status (from eCRF) as covariates. Of note, the change-from-baseline data at Week 
40 will be imputed using 
 approach for the above analysis. 
The primary efficacy analyses will be repeated on the Per Protocol Set, Part 1. If any clinical 
sites are identified by audit as having had non-compliance issues prior to database lock, the 
primary efficacy analyses will be repeated on the data excluding the non-compliant sites. 
The distribution-free permuation test (
) will be used to test the robustness of 
the overall treatment effect (for the pairwise comparison of each dose group, and the pooled dose 
group vs the placebo group) over repeated assessments of the primary efficacy outcome during 
Part 1. Specifically, the 
 for the observed mean difference at each post-baseline 
assessment will be calculated, and thus the mean 
 over repeated assessments will be 
calculated based on the actual data of the trial. In order to calculate the corresponding p-value, 
the permutation test will be conducted in which subjects will be permuted randomly (without 
breaking repeated observations at each subject) between 3 treatment arms. The process will be 
repeated 
 times in order to construct frequency distribution for the simulated 
. The 
 p-value for each pairwise comparison (using the placebo group as the reference group) 
will be computed by calculating the percentage of the simulated mean 
 that are more 
favorable (i.e., having larger treatment effect) than the actual observed mean 
A small 
 p-value tends to support the presence of the overall treatment effect over multiple 
assessments. 
Model fit of the primary 
 analysis will be examined. If the model fit calls into question, 
additional 
 analyses will be performed post-hoc. 
If the dropout rate is differential across treatment groups, additional 
 analyses will be 
performed post hoc. 
8.2 
Secondary Efficacy Analyses 
8.2.1 
Part 1 (Day 1 to Week 40) 
The secondary efficacy variables or endpoints of interest for Part 1 of the study are as follows. 
 Change from baseline through Week 40 in the sum of the MDS-UPDRS Parts II and III 
total scores. 
 Change from baseline through Week 40 in the MDS-UPDRS Part IA sub-score, Part IB 
sub-score, Part I total score, Part II total score, and the four sub-scores of Part III 
 
. 
 Change from baseline through Week 40 in the grand sum of the MDS-UPDRS Parts I, II 
and III total scores. 


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 Evaluation of slopes of the mean change in MDS-UPDRS Parts III total score over time 
during Part 1 by treatment group. 
 Time from first dose of study drug in Part 1 to initiation of symptomatic PD medications 
in Part 1. 
 Change in HRQoL using the EQ-5D-5L scale from Baseline to Week 40. 
 Change in severity of PD using the CGIS scale from Baseline to Week 40. 
 Change in autonomic nervous system dysfunction related to PD using the SCOPA-AUT 
scale from Baseline to Week 40. 
8.2.1.1 
The 
 analysis 
Analyses of other efficacy endpoints pertaining to the MDS-UPDRS scores will be performed by 
using the same 
 model for the primary efficacy analysis. 
 
 
 
 
  
The same 
 analysis will also be performed for all time points prior to Week 40 for each 
of the above-mentioned efficacy endpoints. 
 
 
 
 
 
A random coefficients regression analysis with random terms for intercept and slope (i.e., time is 
a linear random effect) will be used to estimate mean changes from baseline in UPDRS Part III 
total score over time (in weeks). 
Change-from-baseline MDS-UPDRS Part III total score over time will be analyzed using a 
structured random coefficient model with the inclusion of treatment, time (as a continuous 
variable in weeks), region (
), baseline user status 
of MAOB inhibitors 
, the treatment-by-time interaction, and the baseline score-by-time 
interaction as the explanatory variables.  
Like the data handling rule for the primary efficacy analysis, if any MDS-UPDRS assessments 
assessments will be set as missing. 
From the 
 the mean change-from-baseline in the MDS-UPDRS 
Part III total score at each time point and its associated SE and the LS mean difference (using 




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For the Part 1 early discontinued subject having not had the event of interest during Part 1, the 
subject will be 
 at the date of early treatment discontinuation, or loss to follow-up, or 
death, whichever occurs first. Of note, the maximum time-point of Week 44 
 
 will be applied to this 
.Time in weeks to 
 
 
  
 
 
 
For the on-going subject having not had the event of interest during Part 1, 
 
 
  
 
 
 
The number and percentage of subjects who had the event of interest or who were censored will 
be tabulated by the treatment group.  
Time to event (or say, survival time in weeks) will be analyzed using 
. 
The 
 percentile, median, and 
 percentile of the survival time together with 
 CI will be 
estimated by treatment group. The 
 CI estimates will be computed based on 
 with the use of a log-log transformation. The cumulative survival experience in 
weeks will be displayed graphically by treatment group using the 
. 
The equality (vs. inequality) in the survival time between each dose of K0706 vs. placebo will be 
tested using the 
, with Region (
) and baseline MAO-B 
inhibitors usage status (
) as the stratification factor. 
-sided p-value for each 
comparison will be extracted from the test.   
In addition, 
 will be performed with the inclusion 
of Region (
) and baseline MAO-B inhibitors usage status (
 as covariates for 
the model.  The 
 ratio (with placebo being the reference group) and its 
 CI, and the 
-sided p-value for each test (for testing 
 ratio = 
 against 
 will be 
estimated and extracted based on the proportional 
 model. 
The above analyses will be repeated for the comparison of the pooled dose of K0706 vs. placebo.  
 To determine if K0706 delays the initiation of symptomatic PD medications or the early 
withdrawal due to PD-related AEs, as compared to placebo. 
The event of interest consists of two sub-events as follows. 
 
 




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8.2.2 
Part 2 (Week 40 to Week 80) 
There are 3 treatment groups for Part 2: (
 
 
.  Note that, for some analyses for Part 2, groups (2) and (3) will 
be pooled together 
group, in addition to being separate.   
The secondary efficacy analyses for Part 2 are specified as follows. 
 Change from Week 40 (Baseline for Part 2) through Week 76 (EOT visit for Part 2) in 
the MDS-UPDRS Part III total score. 
The baseline value for Part 2 is defined as the value collected at the end-of-trial visit (i.e., the 
Week 40 visit) of Part 1. But there are exceptions in some circumstances. Refer to Section 4.1.2 
for the definition of baseline value for Part 2.  
The MDS-UPDRS Part III total score 
 at baseline and at each post-
baseline analysis visit (as derived per Table 5) during Part 2, and the change from baseline will 
be summarized by the treatment group using standard descriptive statistics. Moreover, the mean 
values of the MDS-UPDRS Part-III total score together with the corresponding SEs or 
 CIs 
will be displayed graphically (plotted) by dose group over the Week (Analysis Visit).   


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 Change from Week 40 (Baseline visit for Part 2) through Week 76 (EOT visit for Part 2) 
in the MDS-UPDRS Part IA sub-score, Part IB sub-score, Part I total score, Part II total 
score, sub-scores of the Part III sub-domains, the sum of Parts II and III total scores, and 
the grand sum of Parts I, II and III total scores.  
The MDS-UPDRS Part IA sub-score is the sum of 
  The Part IB sub-score is the 
sum of 
.  The Part I total score is the sum of Items 
 The Part II total 
score is the sum of 
 The Part III tremor sub-score is the sum of 
 
 The Part III rigidity sub-score is simply the 
. The Part III 
 sub-
score is the sum of 
. The Part III axial symptoms sub-score is the 
sum of 
 
Analyses for each of the above-mentioned efficacy variables will be similar to that for the Part 
III total score in the preceding paragraph.  
 Time from Week 40 (Baseline for Part 2) to the initiation of symptomatic PD 
medications in Part 2.  
The event of interest is the initiation of symptomatic PD medications in Part 2. The 
 
rule and the time-to-event analyses for Part 2 will be similar to that for Part 1. Of note, the 
starting time-point for this time-to-event analysis is Day 1 (first dose date) of Part 2.  
8.3 
 
 
 
 
  
8.3.1 
Part 1 (Day 1 to Week 40) 
Biomarker analyses for Part 1 will be performed on 
. 
 
  
The biomarker variables or endpoints of interest for Part 1 are: 
 Skin pathological findings that correlate with PD, 
 
 
 
 Blood and CSF levels of emerging biomarkers 
 that predict or 
track PD progression or target engagement of K0706. 
 Brain DaT SPECT - an imaging tool that is a marker of presynaptic dopamine transporter 
levels. 


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Biomarker analyses for Part 1 are pre-specified as follows: 
 To evaluate the effect of K0706 on skin pathology markers of PD. 
Specific skin pathology biomarkers (parameters) of interest for PD have not yet been fully 
determined at the time of writing this SAP.  
. Samples of skin biopsies will be collected at baseline and Week 36 
(Visit 10).  For each parameter, assayed values at each visit and the change from baseline value 
at each visit will be summarized by dose group by using standard descriptive statistics (such as 
Mean, SD, Median, and Quartiles). For each parameter, graphical displays in the forms of Tukey 
box and whisker plots will be used to summarize the data by dose group and by visit  
 To evaluate the effect of K0706 on blood and cerebrospinal fluid (CSF) biomarkers 
linked to PD and target engagement of K0706. 
The specific blood and CSF biomarkers (parameters) linked to PD have not yet been fully 
determined at the time of the writing of this SAP. Potential parameters may include -synuclein, 
total Tau, ratio of total Tau/ -synuclein, amyloid, etc.  For each parameter, graphical displays in 
the forms of mean plots and Tukey box and whisker plots will be used to summarize the data by 
dose group and visit. 
In addition, the statistical correlation of each biomarker parameter with the efficacy endpoint 
will be explored in the following ways. (1) Pearson  
correlation coefficient 
(and its 
 CI) between the change-from-baseline parameter value and the change-from-
baseline MDS-UPDRS Part III score at the end of Part 1 (Week 40) will be estimated.   (2) 
Subjects will be divided into 3 categories 
and 
specified, the tertiles of change-from-baseline at Week 40  in the Part-III score will be used as 
the cutoffs. Tukey  box and whisker plots of the change-from-baseline at Week 40  in each 
biomarker parameter will be plotted by category of the primary clinical outcome.  
 To investigate genetic and clinical markers that predict the degree of progression of 
early-stage PD and / or response to K0706. 
Specific genetic and clinical biomarkers (parameters) may be identified as potential candidates 
predictive of the degree of progression of early-stage PD. For each parameter, the exploratory 
analyses will be similar to those in the preceding paragraph.   
 To evaluate the effect of K0706 on dopamine cell health in PD as detected via Dopamine 
Transporter Single Photon Emission Computed Tomography (DaT SPECT) brain 
imaging. 


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DaT SPECT brain imaging will be performed at baseline and at the EOT visit (Week 40). The 
following parameters or quantities may be of relevance: left caudate Striatal Binding Ratio (SBR), 
right caudate SBR, left putamen SBR, right putamen SBR, and minimum putamen SBR, etc. For 
each parameter, the exploratory analyses will be similar to those in the preceding paragraph.   
8.3.2 
Part 2 (Week 40 to Week 80) 
For the exploratory efficacy analyses for Part 2, treatment groups are defined identically to that 
for the secondary efficacy analyses for Part 2. See Section 8.2.2.  
The exploratory efficacy analyses are pre-specified as follows: 
 Change in the MDS-UPDRS Part III total score, compared between the early and delayed 
groups at 76 weeks. 
For Part 2 of the study, the change from Week 40 (Baseline for Part 2) to Week 76 (EOT visit 
for Part 2) in the MDS-UPDRS Part III score will be presented for the early-start and delayed-
start K0706 groups. The early-start and delayed-start cohorts will be defined as: 
 Early-start  the cohort of subjects randomized to K0706 treatment groups in Part 
1 
K0706 Pooled
. 
 Delayed-start  the cohort of subjects randomized to Placebo treatment group in 
Part 1 and transitioned to K0706 High dose therapy at the beginning of Study Part 
2 
Prior Placebo transitioned to K0706 High Dose
tables). 
The above summaries are covered in the first bullet under the Secondary Efficacy Analysis for 
Part 2. 
 Evaluation of slopes of the mean change in MDS-UPDRS Part-III total score over time in 
Part 2 for the early treatment groups as compared to the delayed treatment group. 
The random coefficient regression analyses for Part 2 will be similar to that for Part 1. Note that 
the prior Placebo group transitioned to K0706 high dose will be used as the reference group for 
the testing and estimating for the LS mean difference at each time-point during Part-2.  Note that 
the starting time-
III total score will be repeated for the analysis of the sum of Parts II and III total scores. 
 Proportion of subjects initiating  symptomatic treatment.   
The difference (and its 90% CI) in the proportion of subjects initiating  symptomatic PD 
medications in Part 2 between each dose of K0706 versus the Prior Placebo transitioned to 


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K0706 High dose arm will be calculated. In addition, the above statistics will also be presented 
for the comparison of the early-start group versus delayed-start group. 
 
 
 


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9.0 
SAFETY ANALYSES  
All safety data will be summarized for Parts 1 and 2 of the study separately, using the Safety 
Analysis Set, Part 1 and Safety Analysis Set, Part 2, respectively. 
9.1 
Adverse Events 
All AEs recorded on the eCRF will be coded using the MedDRA dictionary (version 23.0 or a 
later version if updated during the study) and classified as either pre-treatment AEs or TEAEs 
for Part 1 or Part 2 of the study as follows: 
 Pre-treatment AEs are events that start prior to the start of the Treatment Period. 
 TEAEs are either events with start date / time on or after the start of the Treatment 
Period, or events with start date / time prior to the start of the Treatment Period whose 
severity worsens on or after the start of the Treatment Period.  
 TEAEs for Part 1 of the study are all TEAEs for those subjects not participating in Part 2 
of the study and those TEAEs with start date / time before the date of first dose for Part 2 
of the study for subjects participating in Part 2 of the study. 
 TEAEs for Part 2 of the study are those TEAEs with start date / time on or after the date 
of first dose for Part 2 of the study. 
 Serious TEAEs will be defined as TEAEs regarded by the investigator as Serious = 
 
 The relationship between TEAE and study medication is assessed as certainly, probably, 
possibly, unlikely or unrelated. A study treatment related TEAE will be defined as a 
TEAE considered by the investigator as certainly, probably, or possibly related to study 
medication or with missing relationship to study medication. 
 Assessment of AE severity will be characterized as mild, moderate, severe, life-
threatening and death.  
 
 
 TEAEs leading to discontinuation of study treatment are defined as TEAEs where 
 
AEs will be summarized by default descriptive summary statistics for categorical variables by 
treatment group and overall, for Parts 1 and 2 of the study separately, using the Safety Analysis 
Set, Part 1 and Safety Analysis Set, Part 2 respectively, as follows: 
 An overview of TEAEs including the number and percentage of subjects with at least one 
of each mentioned TEAE type: 


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 Any TEAE 
 Leading to discontinuation of study treatment 
 Leading to death 
 Severity: mild 
 Severity: moderate 
 Severity: severe 
 Severity: life-threatening 
 Severity: death 
 Any study treatment-related TEAE 
 Leading to discontinuation of study treatment 
 Leading to death 
 Any serious TEAE 
 Leading to discontinuation of study treatment 
 Leading to death 
 Any serious study treatment-related TEAE 
 Leading to discontinuation of study treatment 
 Leading to death 
 The number and percentage of subjects reporting each TEAE and the count of 
number of events will be summarized by SOC and PT for the following types of 
TEAEs: 
 TEAEs 
 TEAEs Leading to Discontinuation of Study Treatment 
 TEAEs Leading to Death 
 TEAEs by Maximum Severity 
 TEAEs by Relationship to Treatment 
 TEAEs by Relationship and Maximum Severity 
 Study Treatment-Related TEAEs 
 Study Treatment-Related TEAEs Leading to Discontinuation of Study 
Treatment 
 Study Treatment-Related TEAEs Leading to Death 


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 Serious TEAEs 
 Serious TEAEs Leading to Discontinuation of Study Treatment 
 Serious TEAEs Leading to Death 
 Study Treatment-Related Serious TEAEs 
 Study Treatment-Related Serious TEAEs Leading to Discontinuation of Study 
Treatment 
 Study Treatment Related Serious TEAEs Leading to Death 
 The number and percentage of subjects who died will be summarized 
 The number and percentage of subjects reporting each TEAE and the number of events 
will be summarized by PT 
 
 
 
 
 
  
 
 
AEs for Part 1 of the study will be summarized by default descriptive summary statistics for 
categorical variables by formulation category and overall, using the Safety Analysis Set, Part 1, 
as follows: 
 An overview of TEAEs including the number and percentage of subjects with at least one 
of each mentioned TEAE type above. 
 The number and percentage of subjects reporting each TEAE and the number of events 
will be summarized by SOC and PT. 
 The number and percentage of subjects reporting each TEAE and the count of number of 
events will be summarized by PT. 
In the above summaries, subjects with more than one TEAE within a particular SOC are counted 
only once for that SOC. Similarly, subjects with more than one TEAE within a particular PT are 
counted only once for that PT. 
For summaries by maximum severity, subjects with multiple TEAEs within a particular SOC or 
PT will be counted under the category of their most severe TEAE within that SOC or PT. 
TEAEs with missing severity will be included in the overall count of subjects with TEAEs, but 
will not be included in the counts of subjects with TEAEs within a SOC or PT. 


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Summaries by SOCs and PTs will be sorted by SOCs by their Internationally Agreed Order 
(MedDRA) and PTs within SOC by descending order of total incidence. Where PTs tie, PTs will 
be sorted alphabetically. 
 statistical comparisons of AEs between treatment groups will be performed. 
All AE data will be listed and Pre-treatment AEs and TEAEs will be presented together. 
Treatment-emergence status will be flagged in the listing. The listing will present the relative 
start and stop day of the AE calculated relative to the first dose of treatment and will be 
presented for those subjects who received at least one dose of study treatment. If the AE is 
calculated. Only original dates will be presented in the listing even though the relative day may 
be based on an imputed date. 
In addition, the following listings will be presented for Parts 1 and 2 of the study separately, 
using the Safety Analysis Set, Part 1 and Safety Analysis Set, Part 2, respectively: 
 Listing of Deaths 
 Listing of AEs Leading to Discontinuation of Study Treatment 
 Listing of AEs resulting in death 
 Listing of Serious AEs 
9.2 
Laboratory Evaluations 
Data for the following hematology, serum chemistry, urinalysis, serology, lipid profile and 
coagulation analytes received from central laboratory and recorded in the eCRF are to be 
measured at the scheduled visits indicated in the study flowchart (Table 5).  






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 Weight (kg); 
 An investigator assessment of both, systolic and diastolic blood pressure in supine 
position, systolic and diastolic blood pressure in standing position, pulse rate in supine 
position and pulse rate in standing position classified as Normal / Abnormal, Not 
Clinically Significant / Abnormal, Clinically Significant. 
In accordance with the Baseline value definitions for Part 1 and Part 2 in Section 0. For Part 1, the 
absolute change from Baseline at post-Baseline analysis visits (as defined in ) will be derived as 
follows:  
  
 
 
  
  
 
The following will be summarized by treatment group and overall for Parts 1 and 2 of the study 
separately: 
  Observed values and change from Baseline at each analysis visit (as defined in  and ) for 
each vital sign parameter using default summary statistics for continuous variables. 
 The worst post-Baseline investigator assessment will be summarized for the blood pressure 
(both supine and standing position together), and pulse rate (both supine or standing 
position together) by providing number and percentage of subjects within each assessment 
category. 
A listing of all vital signs data including derived change from Baseline will be provided for Parts 
1 and 2 of the study separately, using the Safety Analysis Set, Part 1 and Safety Analysis Set, Part 
2, respectively. 
9.4 
Electrocardiograms  
The following ECG assessments will be taken in triplicate for Part 1 of the study only: 
 Heart rate (bpm); 
 PR interval (msec); 
 RR interval (msec); 
 QRS interval (msec); 
 QT interval (msec); 




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9.5 
Physical Examinations 
Abnormalities identified from physical examination are recorded in the eCRF as AEs and will be 
listed and summarized as such (See Section 6.3 [Medical History] and Section 9.1 [Adverse 
Events]). 
In accordance with the Baseline value definitions for Part 1 and Part 2 in Section 4.1.2, for each 
physical examination body system, the number and percentage of subjects with abnormalities at 
Baseline will be summarized by treatment group and overall for Parts 1 and 2 of the study 
separately. 
Physical examination findings (Normal / Abnormal, Not Clinically Significant / Abnormal, 
Clinical Significant) and details of abnormalities will be listed for each subject at each scheduled 
visit for Parts 1 and 2 of the study separately. 
9.6 
Other Safety Outcomes 
A categorical summary of the 
composite endpoints at Baseline, at each analysis visit 
and the worst post-Baseline result will be provided using counts and percentages by treatment 
group and overall for Parts 1 and 2 of the study separately. See Section 13.5 on the 
 
composite endpoints.  
9.7 
Prior and Concomitant Medications 
All medications will be coded using the World Health Organization (WHO) Drug Global 
Dictionary, (version Mar 2022 or a later version if updated during the study), Anatomical 
Therapeutic Chemical (ATC) classification codes. 
Prior and concomitant medications are defined as follows: 
 Prior medications are those medications with a stop date prior to the start of the 
Treatment Period. 
 Concomitant medications are those with a start date on or after the start of the Treatment 
Period, or those with a start date before the start of the Treatment Period and either a stop 
date on or after the start of the Treatment Period, or are ongoing at the end of the study. 
 Concomitant medications for Part 1 of the study are all concomitant medications for 
those subjects not participating in Part 2 of the study and those concomitant medications 
with start date before the date of first dose for Part 2 of the study for subjects 
participating in Part 2 of the study. 
 Concomitant medications for Part 2 of the study are those concomitant medications with 
start date on or after the date of first dose for Part 2 of the study. 


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See Section  for imputation of missing or partial dates for medication.   
Prior and concomitant medications will be summarized by treatment group and overall for Parts 
1 and 2 of the study separately, using the All Randomized Set, Part 1 and All Enrolled Set, Part 
2, respectively, as follows: 
 The number and percentage of subjects with at least one prior / concomitant medication 
will be presented. 
 The number and percentage of subjects with at least one prior / concomitant medication 
within each Therapeutic Subgroup (ATC-Level 2), Chemical Subgroup (ATC-Level 4), 
and PT will be presented. The summary will be sorted using numerical counts by 
descending order of Therapeutic Subgroup, then descending order of Chemical 
Subgroup, then descending order of PT in the total column. Where groups or terms tie 
these will be sorted alphabetically. 
Prior medications will be listed for the All Randomized Set, Part 1. Concomitant medications for 
Parts 1 and 2 of the study will be listed separately, using the All Randomized Set, Part 1 and All 
Enrolled Set, Part 2, respectively. In the listings the relative start and stop day of prior / 
concomitant medication use will be calculated relative to the first dose date of study drug in the 
corresponding Part period and will be presented for those subjects who received at least one dose 
ndicated as such in the 
listing and the relative stop day will not be calculated. Only original dates will be presented in 
the listing even though the relative day may be based on an imputed date. 
9.8 
Extent of Exposure 
Duration of exposure will be calculated in weeks as: 
  
 
Duration of exposure will be summarized by treatment group and overall for Parts 1 and 2 of the 
study separately. 
The total number and percent of doses administered per subject (and the number of subjects with 
doses administered since previous visit) at each scheduled site visit will be summarized using 
descriptive statistics by treatment group and overall. 
The percentage of doses administered per subject will be calculated as the total number of doses 
administered divided by the total planned doses, expressed as a percentage. 
Total number of doses administered per Visit will be defined as: 
 For Part 1 of the study: 


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 For the first post-Baseline visit 
 (Date of the visit  date of first dose for Part 1 
 number of doses missed since last visit) 
 For subsequent visits 
 (Date of the visit  date of the prior visit  number of 
doses missed since last visit) 
 For the last on-treatment visit 
 (Date of the last dose for Part 1  date of the 
prior visit  number of doses missed since last visit + 1) 
 For Part 2 of the study: 
 For the first post-Baseline visit 
 (Date of the visit  date of first dose for Part 2 
 number of doses missed since last visit) 
 For subsequent visits 
 (Date of the visit  date of the prior visit  number of 
doses missed since last visit) 
 For the last on-treatment visit 
 (Date of the last dose for Part 2  date of the 
prior visit  number of doses missed since last visit + 1) 
Total number of doses administered in Part 1 or Part 2 will be calculated as the sum of the doses 
administered per Visits in Part 1 or Part 2, respectively.  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
A listing of overall treatment exposure data, including the first and last dates of treatment, 
transition dates from capsules to powder formulation, and dates of the study treatment dose 
reductions will be presented for Parts 1 and 2 of the study separately, using the Safety Analysis 
Set, Part 1 and Safety Analysis Set, Part 2, respectively.  


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10.0 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic (PK) analyses will be performed on the PK Analysis Set, Part 1. There is no PK 
study in Part 2. 
 
  
See Section 4.2.4 for the handling of plasma and CSF concentrations that are BLQ.  
K0706 plasma and CSF concentration data will be summarized by dose group and assessment 
time-point by using descriptive statistics (such as number of subjects, mean, standard deviation, 
geometric mean, coefficient of variation (CV%), minimum, median, and maximum values).  
PK analyses and modelling will be detailed in a separate SAP.  
 
 
 


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12.0 
CONVENTIONS 
12.1 
Software  
The Statistical Analysis System® (SAS®, version 9.4 or newer) will be used for all statistical 
analysis and reporting.  
12.2 
 General rules for Statistical Reporting 
In general, statistical reporting and analyses will be created separately for Part 1 and Part 2.  
The default summary statistics for quantitative variables will be the number of observations (n), 
mean, SD, median, minimum (min) and maximum (max), for those subjects with data. In 
addition, geometric mean and CV% of geometric mean will be reported for PK parameters. 
All summary statistics will be rounded (using the 
) and presented to 1 
more decimal place than the raw value, except for the SD and SE values that will be presented to 
2 more decimal places than the raw value, and minimum and maximum values that will be 
presented with the same decimal precision as the raw value. All summary statistics for PK data 
will be rounded (using the 
) and presented to 3 significant figures, 
except for the geometric CV values that will be presented to 1 decimal place. 
For qualitative variables, the number (n) and percentage (%) of subjects with non-missing data 
per category will be the default summary presentation, and where appropriate and present, the 
The number of subjects in the analysis 
population will be used as denominator for percentages calculation, unless stated otherwise in 
Tables, Figures and Listings (TFL) mock shell(s). 
All statistical comparisons and tests will be performed at the 
-sided 
 significance level 
unless specifically stated otherwise.  
All central laboratory test results will be provided in International System of Units (SI) and all 
local laboratory test results will be provided in conventional units.  
For the TFL, the results will be summarized or presented in 
 Refer to Appendix of the 
TLF mock shells for the SI unit corresponding to each laboratory test and the precision level in 
which each laboratory test is reported by the central laboratory. 
Specifications for table, figures and data listing formats can be found in the TFL shells 
shells for more details on presentation of results. 






Statistical Analysis Plan 
CONFIDENTIAL 
 
 
Protocol Reference: CLR_18_06 
 
 
Sponsor Final, Version 3.0, 14FEB2024 
Page 65 of 78 
 
 
 
 
 




Statistical Analysis Plan 
CONFIDENTIAL 
 
 
Protocol Reference: CLR_18_06 
 
 
Sponsor Final, Version 3.0, 14FEB2024 
Page 67 of 78 
 
 
 
 
 
 
 
 
 
 
 
 
 
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