A Study of TAK-071 in People With Parkinson Disease

Study Overview
=================
Brief Summary
-----------------
It is hoped that TAK-071 will help people with Parkinson's disease to walk with better balance. The main aim of the study is to check if there is a difference in how participants walk after treatment with TAK-071. Another aim is to see if it improves how participants think and remember. At the first visit, the study doctor will check who can take part. Participants who can take part will be picked for 1 of 2 groups by chance. Both groups will have 2 treatments but in a different order. The treatments are TAK-071 tablets or placebo. In this study, a placebo will look like the TAK-071 but will not have any medicine in it. One group will take TAK-071 for 6 weeks, have at least a 3-week break, then take a placebo for 6 weeks. The other group will take a placebo for 6 weeks, have at least a 3-week break, then take TAK-071 for 6 weeks. The participants will not know the order of their 2 treatments, nor will their study doctors. This is to help make sure the results are more reliable. The participants will visit the clinic at the beginning and end of each treatment for a check-up. 14 days after the 2nd treatment, clinic staff will telephone the participants for a final check-up.

Detailed Description
-----------------
The drug being tested in this study is TAK-071. TAK-071 is being tested to treat people with PD who have cognitive impairment and are at risk for falls and who are not concurrently taking acetylcholinesterase inhibitors. The study will look at the efficacy and safety of TAK-071 in participants with PD who take TAK-071 versus placebo. The study will also evaluate the PK of TAK-071 in healthy participants (sentinel cohort) older than 55 years. The study will enroll approximately 74 participants. An initial sentinel cohort of 10 healthy participants will be included to estimate age effects. Participants aged 56 to 75 years will be randomly assigned in 3:1 ratio to one of the two treatments: Sentinel Cohort: TAK-071 7.5 mg Sentinel Cohort: Placebo Enrolment for participants aged 40 to ≤ 85 years in the main study will start simultaneously with sentinel cohort. Based on PK, safety, and physiologically based PK modelling data from sentinel cohort, dosing will be decided for the remaining participants. Participants with maximum age of 66 to 85 years, inclusive, will be enrolled at a dose of 5 mg, and the dose for subjects aged 40 to 65 years, inclusive, will be 7.5 mg. All participants will be asked to take one tablet at the same time each day throughout the study. The remaining participants aged 40 years to <=85 years will be randomly assigned in 1:1 ratio to one of two treatment sequences in crossover design: TAK-071 + Placebo Placebo + TAK-071 The study will be conducted in the United States. The minimum time to participate in this study is approximately 15 weeks. Participants will make multiple visits to the clinic and will have home assessments during the third Week of each 6-week treatment period, and will be contacted by telephone at 14 days after completion of the last period for a follow-up assessment.

Official Title
-----------------
A Randomized, Double-blind, Placebo-Controlled, 2-Period Crossover, Phase 2 Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral TAK-071 in Parkinson Disease Patients With Cognitive Impairment and an Elevated Risk of Falls

Conditions
-----------------
Parkinson Disease, Healthy Participants

Intervention / Treatment
-----------------
* Drug: TAK-071
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Is an outpatient of any sex aged between 40 and ≤ 85 years, inclusive, at the time of consent. Has a diagnosis of PD according to Movement Disorders Society (MDS) clinical diagnostic criteria for PD. Participants with DLB (i.e., dementia diagnosed before onset of motor symptoms or up to 1 year after onset of motor symptoms) are also eligible, consistent with MDS clinical diagnostic criteria for PD. Has Hoehn and Yahr stage ≥2 and <4 at the screening visit. Has elevated risk for falls as indicated by at least 1 fall in the last 12 months before the screening visit based on the Fall History Assessment where in the opinion of the investigator the falls were a consequence of PD and are at continued elevated risk of falls per investigator judgment. Investigator judgment on fall risk may be informed by information such as, but not limited to, history, physical examination and/or a score ≥2 on item 3.10 on Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III. Has evidence of cognitive impairment as indicated by a Montreal Cognitive Assessment (MoCA) score between 11 and 26, inclusive and additionally can complete the cognitive assessments at screening (as specified in the study manual). Can walk without aid for 2 minutes while doing serial 3 subtraction (with site staff ensuring participant safety in case of falls). Participants who require aids for walking can be included as long as they can complete the walk test without aid. Inclusion For Healthy Participants: 1. The participant is a healthy individual of either sex aged between 56 and 75 years, inclusive (for initial set of participant in the sentinel cohort) at the time of consent. Older participants may be enrolled after analysis of data from participants aged 56 to 75 years, inclusive. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply Key Exclusion Criteria: Has orthostatic hypotension at screening, as defined as a decline in systolic blood pressure greater than 20 mm Hg or a decrease of 10 mm Hg in diastolic blood pressure on standing measured within 1 minute after being supine for at least 5 minutes. Has dyskinesia of sufficient severity to interfere with digital gait assessments during visits (as defined by Movement Disorders Society - Unified Parkinson's Disease Rating Scale [MDS-UPDRS] section 4.1 Time spent with dyskinesias and/or section 4.2 Functional Impact of Dyskinesias scores greater than [>] 2), or in the opinion of the investigator the participant's dyskinesia is likely to interfere with the digital gait assessments. Has significant risk factors for seizures (a history of seizures as an adult, a history of brain injury, or other risk factors deemed relevant by the investigator). Is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the participant has attempted suicide within the past year before screening. Participants who have positive answers on item number 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) (based on the past year) before randomization are excluded. Is unwilling or unable to discontinue taking cholinesterase inhibitors and/or moderate or strong cytochrome P-450 3A4 inhibitors or inducers at least 30 days before randomization. Exclusion For Healthy Participants: Participants has body mass index (BMI) less than 18 or greater than 40. Has significant risk factors for seizures (a history of seizures as an adult, a history of brain injury, or other risk factors deemed relevant by the investigator). The participant is unwilling or unable to discontinue taking cholinesterase inhibitors and/or moderate or strong CYP 3A4 inhibitors or inducers at least 30 days before randomization. The participant is taking warfarin. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sentinel Cohort: TAK-071 7.5 mg (Healthy Participants)<br>A single dose of TAK-071 ≤ 7.5 milligrams (mg), tablet, orally, on Day 1. | Drug: TAK-071<br>* TAK-071 tablet.<br>|
| Experimental: Sentinel Cohort: Placebo (Healthy Participants)<br>A single dose of TAK-071 placebo-matching mg, tablet, orally, on Day 1. | Drug: Placebo<br>* TAK-071 placebo-matching tablet.<br>|
| Experimental: TAK-071 + Placebo (PD Participants)<br>TAK-071 tablets, orally, once daily for up to first 6 weeks in Period 1, followed by ≥3 weeks washout period, followed by TAK-071 placebo-matching tablets, orally, once daily for up to next 6 weeks in Period 2. | Drug: TAK-071<br>* TAK-071 tablet.<br>Drug: Placebo<br>* TAK-071 placebo-matching tablet.<br>|
| Experimental: Placebo + TAK-071 (PD Participants)<br>TAK-071 placebo-matching tablets, orally, once daily for up to first 6 weeks in Period 1, followed by ≥3 weeks washout period, followed by TAK-071 tablets, orally, once daily for up to next 6 weeks in Period 2. | Drug: TAK-071<br>* TAK-071 tablet.<br>Drug: Placebo<br>* TAK-071 placebo-matching tablet.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Gait Variability during a 2-minute Dual-Task Walking Test After 6-week Treatment with TAK-071 Compared with Placebo | Variability in gait will be measured at baseline and after 6 weeks of taking TAK-071 or placebo. Participants will be asked to walk back and forth along a 10-meter long hallway for 2 minutes with and without serial subtraction. | Baseline and Week 6 (for each study period) | 
| Sentinel Cohort, Cmax: Maximum Observed Plasma Concentration for TAK-071 in Healthy Participants |  | Day 1: pre-dose and Day 2 to 8: post-dose and at multiple time-points (up to approximately 168 hours) | 
| Sentinel Cohort, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-071 in Healthy Participants |  | Day 1: pre-dose and Day 2 to 8: post-dose and at multiple time-points (up to approximately 168 hours) | 
| Sentinel Cohort, AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours for TAK-071 in Healthy Participants |  | Day 1: pre-dose and Day 2 to 8: post-dose and at multiple time-points (up to approximately 168 hours) | 
| Sentinel Cohort, AUClast: Area Under The Concentration-Time Curve From Time 0 To The Last Quantifiable Concentration in Healthy Participants |  | Day 1: pre-dose and Day 2 to 8: post-dose and at multiple time-points (up to approximately 168 hours) | 
| Sentinel Cohort, AUCinf: Area Under The Concentration-Time Curve From Time 0 To Infinity in Healthy Participants |  | Day 1: pre-dose and Day 2 to 8: post-dose and at multiple time-points (up to approximately 168 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Global Cognition Profile | Global cognition profile will be assessed using battery of tests to assess attention, executive functioning and memory. All tests would be combined to provide a composite score such that a higher score will indicate better performance. | Baseline and Week 6 (for each study period) | 
| Ctrough: Observed Concentration at the End of a Dosing Interval for TAK-071 in Parkinson's Disease (PD) Participants |  | Periods 1 and 2, Day 42: pre-dose and at multiple time-points post-dose | 
| Cmax: Maximum Observed Plasma Concentration for TAK-071 in PD Participants |  | Days 1 and 105: pre-dose and at multiple time-points post-dose | 
| AUC(0-24): Area Under the Plasma Concentration-time Curve for TAK-071 in PD Participants |  | Days 1 and 105: pre-dose and at multiple time-points post-dose | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-071 in PD Participants |  | Days 1 and 105: pre-dose and at multiple time-points post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Drug Therapy