Clinical trial NCT04046276: Intensity of Aerobic Training and Neuroprotection in Parkinson's Disease
Official title: Neuroprotective, Motor and Cognitive Impact of a Long-standing Aerobic Training Program in Parkinson's Disease. A Multicenter Comparison of the Effects of Two Aerobic Programs of Graded Intensities and a Conventional Physical Therapy Program Prolonged for 9 Months on Nigrostriatal, Motor and Cognitive Functions.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Parkinson's Disease
Keywords: Parkinson's disease
Aerobic Exercises
High Intensity Training
Neuroprotection
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2019-08-06
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single-blind randomized study, three parallel groups (n= 7 or 8 per group and per center, over 3 centers):

* Group 1 "Conventional Physical Therapy", CPT
* Group 2 "Medium Intensity Aerobic program", MIA (50% VO2 max);
* Group 3 "High Intensity Aerobic program", HIA (70% VO2 max); HIA and MIA groups are experimental groups and CPT group is the control group. Each group will attend 3 weekly 45-minute sessions at the hospital for 9 months.
Primary purpose: TREATMENT

Brief summary: In phenotypic animal models of Parkinson's Disease (PD), chronic physical exercise has produced nigrostriatal neuroprotection and symptom improvement, provided training was of high-intensity and prolonged duration (\>3 months in rodent models). Conventional physical therapy in Parkinson's disease (PD) has traditionally avoided fatigue and high intensity workouts. Yet, in PD controlled studies have shown that: (i) an acute aerobic stress produces endogenous dopamine immediately after the exercise and (ii) short term (a few weeks) high intensity aerobic training enhances D2 striatal receptor density and cortical excitability and clinically improves walking, upper limb and executive functions; (iii) long-term (six months) high intensity aerobic treadmill training is associated with less deterioration of subjective UPDRS III score compared to a waiting list. Long-term high intensity aerobic training has not been compared to low or medium intensity training in PD patients for its objective motor, cognitive and putative neuroprotective effects.

Detailed description: A short description, 5000 characters Intro: In phenotypic animal models of Parkinson's Disease (PD), chronic physical exercise has produced nigrostriatal neuroprotection and symptom improvement, provided training was of high-intensity and prolonged duration (\>3 months in rodent models). Conventional physical therapy in Parkinson's disease (PD) has traditionally avoided fatigue and high intensity workouts. Yet, in PD controlled studies have shown that: (i) an acute aerobic stress produces endogenous dopamine immediately after the exercise and (ii) short term (a few weeks) high intensity aerobic training enhances D2 striatal receptor density and cortical excitability and clinically improves walking, upper limb and executive functions; (iii) long-term (six months) high intensity aerobic treadmill training is associated with less deterioration of subjective UPDRS III score compared to a waiting list. Long-term high intensity aerobic training has not been compared to low or medium intensity training in PD patients for its objective motor, cognitive and putative neuroprotective effects.

Hypothesis/Objective

Hypothesis High-intensity aerobic exercises practiced over 9 months will produce greater symptomatic motor and cognitive benefits and neuroprotective effects in PD patients, than low or medium intensity training.

Primary Objective To compare the motor effects of a 9-month conventional physical therapy program (light aerobic exercises), an aerobic program of medium intensity on stationary bicycle (50% maximal oxygen uptake, VO2 max), and an aerobic program of high intensity (70% VO2 max) in Parkinson's disease.

Secondary Objectives

* To evaluate aerobic capacities before and after the program.
* To evaluate cognitive functions, depression, quality of life before and after each program as well as 3 months following program termination and motor function 3 months following program termination.
* To explore potential neuroprotective effects of a 9-month aerobic program through specialized brain imaging (123I-Ioflupane SPECT) and a potential aerobic intensity-effect of such neuroprotection.

Primary outcome measure Change in MDS-UPDRS III Score (Movement Disorders Society - Unified Parkinson's Disease Rating Scale) in the " OFF " state between Day 1 and Month 9.

Secondary outcome measures OFF-state at Day 1, Month 9, Month 12

* Two-minute walking test from D1 to M9
* Modified 20-meter up-and-go test (AT20)
* 2-minute walk test (from M1 to M12)
* Global Mobility Task (GMT) scale (standing up off the floor)
* Upper limb performance in activities of daily living (Mount Sinai Parkinsonism Impairment Rating Scale, MSPIR)
* Static posturography
* Maximal aerobic capacity (VO2 max)
* Montreal Cognitive Assessment test (MoCA)
* Digit span task (forward and backward)
* Trail Making Test

ON-state at D1, M9, M12

* MDS-UPDRS III Score;
* Mean number of steps performed over the past three weeks (pedometry);
* Monthly incidence of falls in the past 3 months (questionnaire)
* Daily consumption of dopaminergic medications
* Quality of life (EQ-5D)
* Depression (GDS15)
* Dopaminergic striatal function by SPECT \[123I\] beta-CIT striatal uptake at D1, M12.

Method Design

Single-blind randomized study, 3 parallel groups (n= 7 or 8 per group and per center, over 3 centers):

* Group 1 " High Intensity Aerobic exercise ", HIA (70% VO2 max);
* Group 2 " Medium Intensity Aerobic exercise ", MIA (50% VO2 max);
* Group 3 " Conventional Physical Therapy ", CPT HIA and MIA groups are experimental groups and CPT group is the control group. Each group will attend 3 weekly 45-minute sessions at the hospital for 9 months.

Number of subjects needed: 69 Inclusion criteria Patients with diagnosis of PD according to the UKPDSBB criteria to distinguish idiopathic PD from atypical parkinsonism such as multi-system atrophy, progressive supra-nuclear paralysis or vascular parkinsonism; Previous MRI available, to further help distinguish idiopathic PD from atypical parkinsonism; Hoehn \& Yahr Stage 1-3 in OFF state; Age \> 18; Signed informed consent to participate in study.

Non-inclusion criteria Patients lacking motivation or ability to participate in training sessions for 9 months, in the investigator's opinion; contra-indications to high-intensity aerobic training in the cardiologist's opinion; contra-indications to perchlorate de potassium or to the use of 123I-FP-CIT; concurrent severe co-morbidities; cognitive deficit limiting participation to the program; Montreal Cognitive Assessment test (MoCA)\<23; uninsured patient; participation in another ongoing interventional clinical trial (drug therapy, surgical treatment, another rehabilitation treatment, medical device); Pregnancy or current lactation, or no efficacious contraception during the 9 months of intervention.

Recruitment period: 1 year; Study duration: 26 months (24 patients recruited in 2 centers and 21 patients in the other 2 centers) Participation duration for each patient: 14 months Number of participating centers: 3

Eligibility criteria: Inclusion Criteria:

* Diagnosis of PD according to the UKPDSBB criteria
* Previous MRI available, to further help distinguish idiopathic PD from atypical parkinsonism Hoehn \& Yahr Stage 1-3 in OFF state
* Age \> 18
* Signed informed consent to participate in study

Exclusion Criteria:

* Patients lacking motivation or ability to participate in training sessions for 9 months, in the investigator's opinion
* Contra-indications to high-intensity aerobic training in the cardiologist's opinion
* Contra-indications to perchlorate de potassium or to the use of 123I-FP-CIT
* Concurrent severe co-morbidities
* Cognitive deficit limiting participation to the program in the investigator's opinion
* Montreal Cognitive Assessment test (MoCA)\<23
* Uninsured patient
* Participation in another ongoing interventional clinical trial (drug therapy, surgical treatment, another rehabilitation treatment, medical device)
* Pregnancy or current lactation, or no efficacious contraception during the 9 months of intervention.

Primary outcomes:
measure: Change in MDS-UPDRS III Score (Movement Disorders Society - Unified Parkinson's Disease Rating Scale) in the " OFF " state between Day 1 and Month 9.
timeFrame: at day 1 and 9 Months
Secondary outcomes:
measure: Two-minute walking test at maximal speed
timeFrame: at day 1, 9 Months and 12 Months
measure: Modified 20-meter up-and-go test (AT20)
timeFrame: at day 1, 9 Months and 12 Months
measure: Global Mobility Task (GMT)
timeFrame: at day 1, 9 Months and 12 Months
measure: Upper limb performance in activities of daily living (Mount Sinai Parkinsonism Impairment Rating Scale, MSPIR)
timeFrame: at day 1, 9 Months and 12 Months
measure: Maximal aerobic capacity (VO2 max)
timeFrame: at day 1, 9 Months and 12 Months
measure: Montreal Cognitive Assessment test (MoCA)
timeFrame: at day 1, 9 Months and 12 Months
measure: Digit span task (forward and backward)
timeFrame: at day 1, 9 Months and 12 Months
measure: Trail Making Test
timeFrame: at day 1, 9 Months and 12 Months
Other outcomes:
Locations:
city: Créteil
country: France
facility: Henri Mondor Hospital
city: Reims
country: France
facility: Sébastopol hospital
city: Toulouse
country: France
facility: Rangueil hospital
Study officials:
affiliation: Assistance Publique Hôpitaux de Paris (AP-HP)
name: Jean-Michel GRACIES, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: