Study Assessing Efficacy and Safety of AKST4290 in Subjects With Parkinson's Disease on Stable Dopaminergic Treatment (TEAL)

• ClinicalTrials.gov Identifier: NCT04369430
• Recruitment Status: Completed
• First Posted: April 30, 2020
• Results First Posted: October 10, 2022
• Last Update Posted: October 10, 2022
• Sponsor: Alkahest, Inc.
• Information provided by (Responsible Party): Alkahest, Inc.

Tracking Information

• First Submitted Date: April 13, 2020
• First Posted Date: April 30, 2020
• Results First Submitted Date: April 11, 2022
• Results First Posted Date: October 10, 2022
• Last Update Posted Date: October 10, 2022
• Actual Study Start Date: January 16, 2020
• Actual Primary Completion Date: February 11, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 10, 2022)

Change in Motor Function During Levodopa Withdrawal. [ Time Frame: Baseline to 12 weeks ]

Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part 3 Motor Examination has 33 scores based on 18 questions with several right, left, or both body distribution scores. Each Parkinsonian sign or symptom is rated on a 5-point Likert-type scale (ranging from 0 to 4), with higher scores indicating more severe impairment. The minimum score on the MDS-UPDRS Part 3 is 0 and the maximum is 132. Outcome is the mean change from Baseline in motor function during the practically defined off-medication state, defined as at least 12 hours off levodopa, at Week 12, with lower score representing better outcome.

Original Primary Outcome Measures (submitted: April 28, 2020)

Change in motor function during levodopa withdrawal. [ Time Frame: Baseline to 12 weeks ]

Change from Baseline in motor function during the practically defined off-medication state, defined as at least 12 hours off levodopa, at Week 12 as measured by Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part 3 Motor Examination (33 scores based on 18 questions with several right, left, or both body distribution scores). Each Parkinsonian sign or symptom is rated on a 5-point Likert-type scale (ranging from 0 to 4), with higher scores indicating more severe impairment. The minimum score on the MDS-UPDRS Part 3 is 0 and the maximum is 132.

Current Secondary Outcome Measures (submitted: October 6, 2022)

• Safety as Assessed by the Incidence, Seriousness and Severity of Adverse Events (AEs). [ Time Frame: Baseline to week 14 ]
  Incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs, grouped by severity, relationship to study treatment, and AEs leading to discontinuation of study participation. Incidence was presented as number of subject with TEAEs and serious TEAEs, grouped by severity, relationship to study treatment, and AEs leading to discontinuation of study participation, throughout study duration.
• Evaluation of Laboratory Changes. [ Time Frame: Baseline to week 14 ]
  Incidence of of abnormalities or clinically significant changes from Baseline in laboratory test data (chemistry, hematology, coagulation, and urinalysis). Incidence was presented as number of subjects abnormal labs indicating serious condition occurred within the analysis population throughout study duration.
• Evaluation of Vital Sign Changes. [ Time Frame: Baseline to week 12 ]
  Incidence of abnormalities or clinically-significant changes from Baseline in Vital sign measurements (blood pressure as measured in mmHg, heart rate as measured in beats per minute, and temperature as measured in degrees Fahrenheit or Celsius). Incidence was presented as number of subjects with abnormalities or clinically-significant changes from Baseline in Vital sign measurements within the analysis group throughout study duration.
• Evaluation of Electrocardiogram Changes. [ Time Frame: Baseline to week 12 ]
  Incidence of abnormalities or clinically-significant changes from Baseline in 12-lead electrocardiogram (ECG) QT-interval. Incidence was presented as number of subject with ECG changes throughout study duration.
• The Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts 1-4, Change From Baseline During the On-medication State. [ Time Frame: Baseline to week 12 ]
  The MDS-UPDRS has 4 components (details below). The rating for each item is from 0 (normal) to 4 (severe). The score for each Part is obtained from the sum of the corresponding item scores, with higher scores indicating more severe impairment. Part I, Non-Motor Aspects (Mentation, Behavior, and Mood) of Experiences of Daily Living (13 items), score range is 0-52. Part II, Motor Aspects of Experiences of Daily Living (13 items), score range is 0-52. Part III, Motor Examination (33 items), score range is 0-132. Part IV, Motor Complications (6 items), score range is 0-24. The outcome is the mean change from Baseline motor function during the on-medication state at Week 12, with lower value representing a better outcome.
• The Montreal Cognitive Assessment (MoCA), Change From Baseline in MoCA During the On-medication State. [ Time Frame: Baseline to week 12 ]
  The Montreal Cognitive Assessment (MoCA) is a neuropsychological tool that requires approximately 15 minutes to assess the following domains: attention, executive function, memory, language, visuoconstructional skills, and orientation. MoCA scores range between 0 and 30, with higher scores indicating more intact cognition. The MoCA is administered at Baseline and Week 12 in the on-medication state. The total score will be summarized at each scheduled time point. The outcome is mean change from baseline in MoCA during the on-medication state at Week 12, with higher value representing a better outcome.
• The Schwab and England Activities of Daily Living (SE-ADL) Scale, Change From Baseline in SE-ADL During the On-medication State. [ Time Frame: Baseline to week 12 ]
  The SE-ADL evaluates patients' perceptions of global functional capacity and dependence. Scoring is expressed in terms of percentage, in 10 steps from 100 to 0 (100% indicates completely independent, 0% indicates bedridden with impaired vegetative functions), so that the lower the score, the worse the functional status. Scores will be summarized descriptively at each scheduled time point (i.e. n, %) by treatment group. A Generalized Estimating Equations (GEE) for alternating logistic regression (ALR) with an exchangeable working correlation structure will be employed to analyze change from baseline. Outcome is mean change from baseline in SE-ADL during the on-medication state at Week 12, with higher values represents a better outcome.
• The Clinical Impression of Severity Index - PD (CISI-PD), Change From Baseline in CISI-PD During the On-medication State. [ Time Frame: Baseline to week 12 ]
  The CISI-PD is a severity index formed by four items (motor signs, disability, motor complications, and cognitive status), rated 0 (not at all) to 6 (very severe or completely disabled). A total score is calculated by summing the item scores, total scores range from 0-24. The outcome is the mean change from baseline in CISI-PD during the on-medication state at Week 12, with lower score represents a better outcome.
• The Parkinson's Disease Quality of Life Questionnaire-39 (PDQ-39), Change From Baseline in PDQ-39 During the On-medication State. [ Time Frame: Baseline to week 12 ]
  The PDQ-39 is a patient-reported outcome of 39 questions relating to 8 key areas of health and daily activities, including both motor and non-motor symptoms. The eight dimensions include: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. It is scored on a scale of 0-100 with lower scores indicating better health and high scores indicating more severe symptoms, applying to all dimensions reported in the data table. Outcome is the mean change from baseline in PDQ-39 during the on-medication state at Week 12, with lower score represents a better outcome.
• The Sheehan-Suicidality Tracking Scale (S-STS), Change From Baseline in S-STS During the On-medication State. [ Time Frame: Baseline to week 12 ]
  The standard version of the S-STS is a 16-item scale that assesses the seriousness of suicidality phenomena on a Likert-type scale (0-4) ranging from "not at all" (0) to "extremely" (4), where higher scores indicate more risk of suicidality. It also assesses the frequency of key phenomena and the overall time spent in suicidality. Total score is a sum of all items; total score ranges from 0-64. Outcome is the mean change from baseline in S-STS during the on-medication state at Week 12, with higher score represents a worse outcome.
• 10-meter Timed Walk, Change in Baseline 10-meter Timed Walk During the on and Off-medication State [ Time Frame: Baseline to week 12 ]
  The 10-meter walk test is a commonly used tool for assessing gait speed in individuals with gait limitations. Gait speed is positively correlated with the amount of community ambulation and quality of life, and it is an important measure of mobility in individuals with PD, with higher value corresponds to better mobility. Outcome is the mean change from baseline comfortable walking speed (gait), fast walking speed (gait), during the on and off-medication state at Week 12, with higher score represents a better outcome.
• Hauser 3-Day Patient Diary, Change in Baseline Mean Time Spent With and Without Troublesome Dyskinesia as Measured by the Hauser 3-Day Patient Diary [ Time Frame: Baseline to week 12 ]
  The Hauser Patient Diary was developed to assess functional status over a period of time in patients with motor fluctuations and dyskinesia by recording patient motor state for half-hour intervals over a 24-hour period. The outcome is mean change of Mean Time Spent with and without troublesome dyskinesia from Baseline at Week 12. ON/OFF-time is time when medication is providing/not providing benefit with regard to mobility, slowness, and stiffness, respectively. Troublesome dyskinesia is defined as dyskinesia that interfere with function or causes meaningful discomfort. Bad time is defined as the sum of off time and on time with troublesome dyskinesia. Lower value represents a better outcome. Good time is defined as the on time without dyskinesia plus on time with non-troublesome dyskinesia. Higher value represents a better outcome.

Original Secondary Outcome Measures (submitted: April 28, 2020)

• Safety as assessed by the incidence, seriousness and severity of adverse events (AEs). [ Time Frame: Baseline to 14 weeks ]
  Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) identified by the Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) and grouped by MedDRA System Organ Class (SOC).
• Evaluation of laboratory changes. [ Time Frame: Baseline to week 12 ]
  Incidence of abnormalities or clinically-significant changes from Baseline in laboratory test data (chemistry, hematology, and urinalysis).
• Evaluation of Vital Sign changes. [ Time Frame: Baseline to week 12 ]
  Incidence of abnormalities or clinically-significant changes from Baseline in Vital sign measurements (blood pressure as measured in mmHg, heartrate as measured in beats per minute, and temperature as measured in degrees Fahrenheit or Celsius).
• Evaluation of Electrocardiogram changes. [ Time Frame: Baseline to week 12 ]
  Incidence of abnormalities or clinically-significant changes from Baseline in 12-lead electrocardiogram (ECG) QT-interval.
• The Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts 1-4, change from baseline during the on-medication state. [ Time Frame: Baseline to week 12 ]
  Part I, Non-Motor Aspects of Experiences of Daily Living (13 items); Part II, Motor Aspects of Experiences of Daily Living (13 items); Part III, Motor Examination (33 items); and Part IV, Motor Complications (6 items). Each Parkinsonian sign or symptom is rated on a 5-point Likert-type scale (ranging from 0 to 4), with higher scores indicating more severe impairment. The maximum total MDS-UPDRS score is 272, indicating the worst possible disability from Parkinson's Disease.
• The Montreal Cognitive Assessment (MoCA), change from baseline in MoCA during the on-medication state. [ Time Frame: Baseline to week 12 ]
  The Montreal Cognitive Assessment (MoCA) is a neuropsychological tool that requires approximately 15 minutes to assess the following domains: attention, executive function, memory, language, visuoconstructional skills, and orientation. MoCA scores range between 0 and 30, with higher scores indicating more intact cognition.
• The Schwab and England Activities of Daily Living (SE-ADL) Scale, change from baseline in SE-ADL during the on-medication state. [ Time Frame: Baseline to week 12 ]
  The SE-ADL evaluates patients' perceptions of global functional capacity and dependence. Scoring is expressed in terms of percentage, in 10 steps from 100 to 0 (100% indicates completely independent, 0% indicates bedridden with impaired vegetative functions), so that the lower the score, the worse the functional status. The assessment is conducted by a trained clinician.
• The Clinical Impression of Severity Index - PD (CISI-PD), change from baseline in CISI-PD during the on-medication state. [ Time Frame: Baseline to week 12 ]
  The CISI-PD is a severity index formed by four items (motor signs, disability, motor complications, and cognitive status), rated 0 (not at all) to 6 (very severe or completely disabled).
• The Parkinson's Disease Quality of Life Questionnaire-39 (PDQ-39), change from baseline in PDQ-39 during the on-medication state. [ Time Frame: Baseline to week 12 ]
  The PDQ-39 is a patient-reported outcome of 39 questions relating to 8 key areas of health and daily activities, including both motor and non-motor symptoms. The eight dimensions include: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. It is scored on a scale of 0-100 with lower scores indicating better health and high scores indicating more severe symptoms.
• The Sheehan-Suicidality Tracking Scale (S-STS), change from baseline in S-STS during the on-medication state. [ Time Frame: Baseline to week 12 ]
  The standard version of the S-STS is a 16-item scale that assesses the seriousness of suicidality phenomena on a Likert-type scale (0-4) ranging from "not at all" (0) to "extremely" (4), where higher scores indicate more risk of suicidality.
• 10-meter timed walk. [ Time Frame: Baseline to week 12 ]
  Change from baseline in a 10-meter timed walk during the on-medication state and the off-medication state.
• The Hauser 3-Day Patient Diary, change from baseline in the Hauser 3-Day Patient Diary during the on-medication state. [ Time Frame: Baseline to week 12 ]
  The Hauser Patient Diary was developed to assess functional status over a period of time in patients with motor fluctuations and dyskinesia. The diary is designed to record patient motor state for half-hour intervals over a 24-hour period.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Assessing Efficacy and Safety of AKST4290 in Subjects With Parkinson's Disease on Stable Dopaminergic Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AKST4290 in Subjects With Parkinson's Disease on Stable Dopaminergic Treatment
• Brief Summary: This study will evaluate the efficacy and safety of AKST4290 in subjects with Parkinson's Disease who are currently on stable dopaminergic treatment.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Parkinson Disease

Intervention

• Drug: AKST4290
  Oral AKST4290
• Drug: Placebo
  Oral Placebo

Study Arms

• Experimental: AKST4290
  Subjects will receive AKST4290, 400 mg twice daily, for 12 weeks.
  Intervention: Drug: AKST4290
• Placebo Comparator: Placebo
  Subjects will receive placebo, twice daily, for 12 weeks.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 11, 2021): 110
• Original Estimated Enrollment (submitted: April 28, 2020): 120
• Actual Study Completion Date: March 10, 2021
• Actual Primary Completion Date: February 11, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Diagnosis of clinically established or clinically probable PD according to MDS-PD criteria with at least 1 year of PD symptoms.
• Modified Hoehn and Yahr ≤2.5.
• Have notable motor worsening during off-medication state.
• Clear-cut improvement of motor response to levodopa medications, as assessed by the investigator.
• Must be on stable dopaminergic therapy (e.g., levodopa, dopamine agonists, monoamine oxidase inhibitors, catechol-O-methyl transferase inhibitors, amantadine), for at least 8 weeks prior to enrollment and remain on stable dose during the 12-week treatment period.
• Female subjects must not be pregnant or breastfeeding. Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening. WOCBP must agree to use highly effective contraception prior to study entry. Male subjects must be willing to use a barrier method of contraception.

Key Exclusion Criteria:

• Secondary or atypical parkinsonian syndromes, for example, patients with parkinsonism from encephalitis, metabolic disorders, vascular parkinsonism, drug-induced parkinsonism, multiple system atrophy, corticobasal ganglia degeneration, progressive supranuclear palsy, Lewy body dementia.
• History of any brain surgery for PD (e.g., pallidotomy, deep brain stimulation, or fetal tissue transplant).
• Conditions affecting the peripheral or central nervous system, unless related to PD, that would affect the ability to adequately perform the MDS-UPDRS and motor assessments: i.e., severe sensory neuropathy affecting arm or leg function, or stroke affecting motor or gait function.
• Significant alcohol or drug abuse within past 2 years.
• Based on ECG reading, subjects with a risk of QT prolongation.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Estonia, Germany, Poland, Slovakia, United States
• Removed Location Countries: Hungary

Administrative Information

• NCT Number: NCT04369430
• Other Study ID Numbers: AKST4290-211
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Alkahest, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Alkahest, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Alkahest Medical Monitor; Alkahest, Inc.

• PRS Account: Alkahest, Inc.
• Verification Date: October 2022