Safety and Efficacy of DA-9805 for Parkinson's Disease

Study Overview
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Brief Summary
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This is a phase IIa, first in human, randomized, double-blind, multicenter study to evaluate the safety, tolerability and efficacy of DA-9805 at 45mg, 90mg versus placebo in subjects diagnosed with early Parkinson's disease.

Detailed Description
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Parkinson's disease (PD) is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years. There are 2 major neuropathologic findings: the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies. Parkinson's disease affects an estimated 1.5 million persons in the United States, with over ten million affected worldwide, and these estimates are expected to increase substantially in the next few decades. Despite the increasing prevalence, the approved agents for the early management of Parkinson's disease have changed little in the past decade; however, there have been advances in drug delivery, dosing, and the use of combination therapy in an attempt to reduce adverse events. The most important, unmet medical need in targeting Parkinson's disease is developing agents with neuroprotective potential. So far, no drug has been shown to reduce or slow down the progression of PD. DA-9805 is a botanical drug product composed of three main raw herbal materials. It is expected that DA-9805 will help treat PD by prevention of dopaminergic neurodegeneration via recovery of mitochondrial dysfunction, anti-inflammatory effect and relief from Endoplasmic reticulum (ER) stress and oxidative stress.

Official Title
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A Phase IIa, Randomized, Multicenter, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Efficacy of DA-9805 in Subjects With Parkinson's Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: DA-9805 45mg
* Drug: DA-9805 90mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects who are between 30 and 79 years old inclusive with a clinical diagnosis of Parkinson's disease as per UK Brain Bank Criteria for two (2) years or less at screening. Hoehn and Yahr I or II at screening. Subjects who are newly diagnosed & currently not on any Parkinson's disease medication (or) subjects who are on stable doses for at least 4 weeks prior to screening on Amantadine or anticholinergics for treatment of Parkinson's disease *Note: Subjects that had anti-parkinsonian medication (including levodopa, dopamine agonists, entacapone and monoamine oxidase-B inhibitors) discontinued at least 60 days prior to screening, e.g., for intolerance, may be considered eligible if all other eligibility requirements are met. Women of child-bearing potential should use reliable contraception. Acceptable methods of contraception include: surgical sterilization (e.g. bilateral tubal ligation), hormonal contraception (implantable, patch, and oral), and double-barrier methods (condom, diaphragm and spermicide are each considered a barrier). Women of child-bearing potential are defined as women physiologically capable of becoming pregnant, UNLESS they meet the following criteria: (1)Post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum Follicle Stimulating Hormone (FSH) levels > 40mIU/m, OR; (2)6 weeks post surgical bilateral oophorectomy with or without hysterectomy If a male and heterosexually active with a female of childbearing potential, the subject must agree to use a double barrier method of birth control (or must have been surgically sterilized) and to not donate sperm during the study. Without clinically significant abnormalities in physical exam, neurological exam and laboratory assessments (urine/blood routine, biochemical tests and ECG) which would exclude the subject from the study in the opinion of the Investigator. For Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) the screening levels should be ≤ 2 times upper limit normal Subject is capable of providing informed consent and is willing to sign the ICF prior to study Screening and agrees to comply with the study protocol requirements. Exclusion Criteria: Subject has an atypical parkinsonian syndrome or secondary parkinsonism (e.g., due to drugs, metabolic neurogenetic disorders, encephalitis, cerebrovascular disease or degenerative disease). Subjects with history of neurosurgical intervention for Parkinson's disease. Subjects who meet the DSM-V criteria at screening for bipolar disorder, major depressive disorder, psychotic disorders, or any other comorbid mental disorders that in the opinion of the Investigator may interfere with study conduct and results interpretation. Subjects with clinical diagnosis of dementia (MMSE score <24) as determined by the investigator using Mini-Mental State Examination (MMSE). Female subjects who are pregnant or breast feeding. Initiation of any anti-parkinsonian medication (including levodopa, dopamine agonists, entacapone and monoamine oxidase-B inhibitors) for the duration of the trial. Initiation of Amantadine or anticholinergics for newly diagnosed subjects or change in the dosage of Amantadine or anticholinergics during the trial for subjects who were on stable doses for 4 weeks prior to screening. Subjects who used investigational drugs or devices within 60 days prior to screening or investigational biologics within the last 6 months prior to screening. Subjects with a clinically significant or surgical condition, including major surgeries within 28 days prior to enrollment

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>placebo, tid | Other: Placebo<br>* Placebo, tid<br>|
| Experimental: DA-9805 low<br>DA-9805 45mg | Drug: DA-9805 45mg<br>* DA-9805 15mg tid<br>* Other names: DA-9805;|
| Experimental: DA-9805 high<br>DA-9805 90mg | Drug: DA-9805 90mg<br>* DA-9805 30mg tid<br>* Other names: DA-9805;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Motor MDS-UPDRS Score From Baseline at Week 12 | Analysis of the Change from Baseline in the sum of the Movement Disorders Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part II, Part III and Part IV at week 12. (Change from baseline = Post Baseline Measurement - Baseline Measurement) MDS-UPDRS is a multimodal scale assessing both impairment and disability and is separated into 4 subscales. Each parkinsonian sign or symptom is rated on a 5-point severity scale (ranging from 0 to 4). The maximum total UPDRS score is 272, indicating the worst possible disability from PD. Part I: This assesses non-motor experiences of daily living (13 items, Score range: 0 52) Part II: This assesses motor experiences of daily living (13 items, Score range: 0 52) Part III: This assesses the motor signs of PD (33 items, Score range: 0 132) Part IV: This assesses motor complications, dyskinesias and motor fluctuations using historical and objective information (6 items, Score range: 0 26) | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Total MDS- UPDRS Score | Analysis of the Change from Baseline in the sum of the Movement Disorders Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part I, Part II, Part III and Part IV at week 12. (Change from baseline = Post Baseline Measurement - Baseline Measurement) MDS-UPDRS is a multimodal scale assessing both impairment and disability and is separated into 4 subscales. Each parkinsonian sign or symptom is rated on a 5-point severity scale (ranging from 0 to 4). The maximum total UPDRS score is 272, indicating the worst possible disability from PD. Part I: This assesses non-motor experiences of daily living (13 items, Score range: 0 52) Part II: This assesses motor experiences of daily living (13 items, Score range: 0 52) Part III: This assesses the motor signs of PD (33 items, Score range: 0 132) Part IV: This assesses motor complications, dyskinesias and motor fluctuations using historical and objective information (6 items, Score range: 0 26) | 12 weeks | 
| Change in MDS-UPDRS Subscale scores_Part I | Analysis of the Change from Baseline in the sum of the Movement Disorders Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part I at week 12. (Change from baseline = Post Baseline Measurement - Baseline Measurement) MDS-UPDRS is a multimodal scale assessing both impairment and disability and is separated into 4 subscales. Each parkinsonian sign or symptom is rated on a 5-point severity scale (ranging from 0 to 4). The maximum total UPDRS score is 272, indicating the worst possible disability from PD. Part I: This assesses non-motor experiences of daily living (13 items, Score range: 0 52) Part II: This assesses motor experiences of daily living (13 items, Score range: 0 52) Part III: This assesses the motor signs of PD (33 items, Score range: 0 132) Part IV: This assesses motor complications, dyskinesias and motor fluctuations using historical and objective information (6 items, Score range: 0 26) | 12 weeks | 
| Change in S&E Total Score | Change in Schwab and England (S&E) Scale total score from baseline at week 12. (Change from baseline = Post Baseline Measurement - Baseline Measurement) The Schwab & England Activities of Daily Living (ADL) scale reflects the speed, ease, and independence with which an individual performs daily activities, or personal chores, such as eating, toileting, and dressing. This scale uses a rating scale from 0% to 100%, with 100% representing complete independence in performing daily activities and 0% representing a vegetative, bedridden state. | 12 weeks | 
| Change in PDQ-39 Score- Summary Index | Change in Parkinson's Disease Questionnaire (PDQ-39) total score from baseline at week 12.(Change from baseline = Post Baseline Measurement - Baseline Measurement) The PDQ-39 is a self-administered questionnaire which comprises 39 items addressing eight domains of health (mobility [10 items], activities of daily living [6 items], emotional wellbeing [6 items], stigma [4 items], cognition [4 items], social support [3 items], communication [3 items] and bodily discomfort [3 items]) which subjects consider to be adversely affected by the disease. Each item is scored on the following 5-point scale. The PDQ-39 Summary Index (PDQ-SI) is the sum of all answers divided by the highest score possible (i.e., number of answers multiplied by 4) which is multiplied by 100 to put the score on a 0 - 100 scale where lower scores indicate a better perceived health status and higher scores are ass | 12 weeks | 
| Change in H&Y Total Score at Week 12 | Change in Hoehn and Yahr (H&Y) scale total score from baseline at week 12. (Change from baseline = Post Baseline Measurement - Baseline Measurement) H&Y describes five stages to PD progression (Score 1 5). A lower score represent a lower amount of symptoms. | 12 weeks | 
| Change in MDS-UPDRS Subscale scores_Part II | Analysis of the Change from Baseline in the sum of the Movement Disorders Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part II at week 12. (Change from baseline = Post Baseline Measurement - Baseline Measurement) MDS-UPDRS is a multimodal scale assessing both impairment and disability and is separated into 4 subscales. Each parkinsonian sign or symptom is rated on a 5-point severity scale (ranging from 0 to 4). The maximum total UPDRS score is 272, indicating the worst possible disability from PD. Part I: This assesses non-motor experiences of daily living (13 items, Score range: 0 52) Part II: This assesses motor experiences of daily living (13 items, Score range: 0 52) Part III: This assesses the motor signs of PD (33 items, Score range: 0 132) Part IV: This assesses motor complications, dyskinesias and motor fluctuations using historical and objective information (6 items, Score range: 0 26) | 12 weeks | 
| Change in MDS-UPDRS Subscale scores_Part III | Analysis of the Change from Baseline in the sum of the Movement Disorders Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part III at week 12. (Change from baseline = Post Baseline Measurement - Baseline Measurement) MDS-UPDRS is a multimodal scale assessing both impairment and disability and is separated into 4 subscales. Each parkinsonian sign or symptom is rated on a 5-point severity scale (ranging from 0 to 4). The maximum total UPDRS score is 272, indicating the worst possible disability from PD. Part I: This assesses non-motor experiences of daily living (13 items, Score range: 0 52) Part II: This assesses motor experiences of daily living (13 items, Score range: 0 52) Part III: This assesses the motor signs of PD (33 items, Score range: 0 132) Part IV: This assesses motor complications, dyskinesias and motor fluctuations using historical and objective information (6 items, Score range: 0 26) | 12 weeks | 
| Change in MDS-UPDRS Subscale scores_Part IV | Analysis of the Change from Baseline in the sum of the Movement Disorders Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part IV at week 12. (Change from baseline = Post Baseline Measurement - Baseline Measurement) MDS-UPDRS is a multimodal scale assessing both impairment and disability and is separated into 4 subscales. Each parkinsonian sign or symptom is rated on a 5-point severity scale (ranging from 0 to 4). The maximum total UPDRS score is 272, indicating the worst possible disability from PD. Part I: This assesses non-motor experiences of daily living (13 items, Score range: 0 52) Part II: This assesses motor experiences of daily living (13 items, Score range: 0 52) Part III: This assesses the motor signs of PD (33 items, Score range: 0 132) Part IV: This assesses motor complications, dyskinesias and motor fluctuations using historical and objective information (6 items, Score range: 0 26) | 12 weeks | 
| Change in Clinical Global Impression-Severity (CGI-S) | The Global Impression-Severity (CGI) measures global severity of illness at a given point in time, and the improvement from baseline at visits following the initial baseline visit. (Change from baseline = Post Baseline Measurement - Baseline Measurement) At the screening and baseline visit, the investigator assessed the severity on a seven-point scale. At subsequent visits, the investigator was to assess the subject's severity (CGI-S) and improvement (CGI-I) relative to baseline. Severity of Illness (CGI-S) Rating should account for severity of the patient's illness. 0 = Not assessed = Normal, not at all ill = Borderline ill = Mildly ill = Moderately ill = Markedly ill = Severely ill = Extremely ill | 12 weeks | 
| Scores of Clinical Global Impression-Improvement (CGI-I) | The Global Impression-Severity (CGI) measures global severity of illness at a given point in time, and the improvement from baseline at visits following the initial baseline visit. At the screening and baseline visit, the investigator assessed the severity on a seven-point scale. At subsequent visits, the investigator was to assess the subject's severity (CGI-S) and improvement (CGI-I) relative to baseline. Global Improvement (CGI-I): Compared to the patient's condition at the baseline of this study, how much has the patient's illness improved or worsened? 0 = Not assessed = Very much improved = Much improved = Minimally improved = No change = Minimally worse = Much worse = Very much worse | 12 weeks |