Clinical trial NCT04334317: A Study of TAK-071 in People With Parkinson Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson Disease
Healthy Participants
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Michael J. Fox Foundation for Parkinson's Research
First posted: 2020-04-06
Enrollment: 64
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: Key Inclusion Criteria:

1. Is an outpatient of any sex aged between 40 and ≤ 85 years, inclusive, at the time of consent.
2. 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.
3. Has Hoehn and Yahr stage ≥2 and \<4 at the screening visit.
4. 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.
5. 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).
6. 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:

1. 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.
2. 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.
3. 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).
4. 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.
5. 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:

1. Participants has body mass index (BMI) less than 18 or greater than 40.
2. 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).
3. 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.
4. The participant is taking warfarin.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Primary outcomes:
measure: Main Cohort: Change From Baseline in Stride Time (Gait) Variability During a 2-minute Dual-Task Walking Test After 6-week Treatment With TAK-071 Compared With Placebo
timeFrame: Baseline and Week 6 (for each study period)
measure: Sentinel Cohort, Cmax: Maximum Observed Plasma Concentration for TAK-071 in Healthy Participants
timeFrame: Day 1: pre-dose and Day 2 to 8: post-dose and at multiple time-points (up to approximately 168 hours)
measure: Sentinel Cohort, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-071 in Healthy Participants
timeFrame: Day 1: pre-dose and Day 2 to 8: post-dose and at multiple time-points (up to approximately 168 hours)
measure: Sentinel Cohort, AUC24: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours for TAK-071 in Healthy Participants
timeFrame: Day 1: Predose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours post dose
measure: Sentinel Cohort, AUClast: Area Under The Concentration-Time Curve From Time 0 To The Last Quantifiable Concentration in Healthy Participants
timeFrame: Day 1: pre-dose and Day 2 to 8: post-dose and at multiple time-points (up to approximately 168 hours)
measure: Sentinel Cohort, AUCinf: Area Under The Concentration-Time Curve From Time 0 To Infinity in Healthy Participants
timeFrame: Day 1: pre-dose and Day 2 to 8: post-dose and at multiple time-points (up to approximately 168 hours)
Secondary outcomes:
measure: Main Cohort: Change From Baseline in Global Cognition Z-score
timeFrame: Baseline and Week 6 (for each study period)
measure: Main Cohort: Ctrough: Observed Concentration at the End of a Dosing Interval for TAK-071 in Parkinson Disease (PD) Participants
timeFrame: Day 42 of Period 1 and Period 2: pre-dose and at multiple time-points post-dose
measure: Main Cohort, Cmax: Maximum Observed Plasma Concentration for TAK-071 in PD Participants
timeFrame: Day 1 of Period 1 and Period 2: pre-dose and at multiple time-points post-dose
measure: Main Cohort: Cmax,ss: Maximum Observed Plasma Concentration at Steady State for TAK-071 in PD Participants
timeFrame: Day 42 of Period 1 and Period 2: pre-dose and at multiple time-points post-dose
measure: Main Cohort: AUC24: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours for TAK-071 in PD Participants
timeFrame: Day 1 of Period 1 and Period 2: pre-dose and at multiple time-points post-dose
measure: Main Cohort, AUCtau: Area Under the Plasma Concentration-time Curve During a Dosing Interval for TAK-071 in PD Participants
timeFrame: Day 42 of Period 1 and Period 2: pre-dose and at multiple time-points post-dose
measure: Main Cohort, Tmax,ss: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State for TAK-071 in PD Participants
timeFrame: Day 1 of Period 1 and Period 2: pre-dose and at multiple time-points post-dose
measure: Main Cohort: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-071 in PD Participants
timeFrame: Day 42 of Period 1 and Period 2: pre-dose and at multiple time-points post-dose
Other outcomes:
Locations:
city: Garden Grove
country: United States
facility: Collaborative Neuroscience Network, LLC
state: California
city: Irvine
country: United States
facility: University of California Irvine Medical Center
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Englewood
country: United States
facility: Rocky Mountain Movement Disorders Center
state: Colorado
city: Orlando
country: United States
facility: PPD Phase 1 Clinic
state: Florida
city: Sunrise
country: United States
facility: Infinity Clinical Research, LLC
state: Florida
city: Tampa
country: United States
facility: USF Medical Clinic
state: Florida
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Chicago
country: United States
facility: Feinberg School of Medicine Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health Neuroscience Center
state: Indiana
city: Farmington Hills
country: United States
facility: Quest Research Institute - Hunt - PPDS
state: Michigan
city: Golden Valley
country: United States
facility: Park Nicollet Health Services
state: Minnesota
city: Rochester
country: United States
facility: University of Rochester Medicine - Movement Disorders Unit
state: New York
city: Dayton
country: United States
facility: Neurology Diagnostics, Inc. - ERG - PPDS
state: Ohio
city: Philadelphia
country: United States
facility: University of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina - PPDS
state: South Carolina
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Round Rock
country: United States
facility: Central Texas Neurology
state: Texas
city: Norfolk
country: United States
facility: Meridian Clinical Research
state: Virginia
city: Kirkland
country: United States
facility: Evergreen Hospital Medical Center
state: Washington
city: Spokane
country: United States
facility: Inland Northwest Research
state: Washington
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: