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“The Role of Research in Parkinson’s Disease”- APDA Webinar Notes

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In early November, the American Parkinson Disease Association (APDA) hosted a webinar on research in Parkinson’s disease (PD). The webinar featured expert physical therapist for PD Dr. Terry Ellis and movement disorder specialist Dr. Marie Saint-Hilaire. Dr. Saint-Hilaire discussed the role of clinical trials in PD, how to find ongoing trials, and the benefits of participating in a trial.  Dr. Ellis reviewed two current exercise trials.

According to Dr. Saint-Hilaire, a clinical trial is any research study that assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.  Clinical trials determine if treatments are safe and effective.  There are two kinds of clinical trials:

  • Interventional studies are where participants are assigned to receive one or more interventions, and include drug studies, surgical studies, and rehabilitative therapies.
  • Observational studies are a collection of data in a systematic way without influencing or interfering with the behavior of the participant and can include social-behavioral studies and biomarkers.  

There are five phases of clinical research:

  • Preclinical: non-human, in a lab, goal is to support that a therapy is reasonably safe and many be effective (five in 5,000 make it past this stage)
  • Phase 1: small group of volunteers, goal is to assess risk and side effects
  • Phase 2: 80-150 volunteers with the condition, goal is dosage finding and determining safety
  • Phase 3: 300 volunteers, large data collection that will allow the FDA to make approval decisions
  • FDA approval (can take 6-11 years) 
  • Phase 4: after a medication is approved, ongoing research to understand long-term safety and effectiveness and find rare side effects

The first study that Dr. Ellis reviewed is the SPARX 3 study.  It is led by a team at Northwestern University and studies the effect of exercise on the brain and if exercise can decrease the progression of PD.  The study measures what is happening in the brain, as well as changes in behavior.  Half of the participants exercise on a treadmill at 80-85% heart rate maximum, with the other half at 60-65% heart rate maximum.  The trial includes supervised visits and takes two years. There are many sites across the US for this study, please look at the contact information in the notes below if you are interested in joining as sign-ups are still open. 

The second study mentioned by Dr. Ellis is the WHIP-PD study, which focuses on changes in walking in people with PD over one year.  The goal is to improve walking function, as well as prevent decline of walking function.  The study splits participants into two groups — one exercises with a tailored home exercise plan with written instructions, the other uses a mobile health exercise app and continuous monitoring by a physical therapist.  The participants are monitored over a year and the outcomes are measured by improvement in walking and any changes in the severity of motor signs of PD. People who live near near Boston, Massachusetts or St. Louis, Missouri can still sign up. 

To find ongoing clinical trials:

  • ask your health care team,
  • visit clinicaltrials.gov, or 
  • The Michael J. Fox Trial Finder

As Dr. Ellis mentioned the value of exercise, note that Stanford Parkinson’s Community Outreach has an online list of live, virtual PD exercise classes

For a recording of this webinar, please see this APDA YouTube webpage.

See my notes below of the November 2nd webinar. 

Regards, 

– Joëlle Kuehn

“The Role of Research in Parkinson’s Disease”- Webinar Notes  

Speakers: 

  • Marie Saint-Hilaire, MD, movement disorder specialist, Boston University (APDA center for advanced research)
  • Terry Ellis, PhD, PT, director, Center for Neurorehabilitation, Boston University 

Webinar Host:  American Parkinson Disease Association Massachusetts Chapter

Webinar Date:  November 2, 2021

Summary by Joëlle Kuehn, Stanford Parkinson’s Community Outreach 

Role and benefits of clinical trials:  (Dr. Saint-Hilaire)

What is a clinical trial:

  • Any research study that assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes
  • Clinical trials determine if treatments are safe and effective

Purpose of clinical trial:

  • Determine safety and efficacy of a therapy
  • Observe characteristics of a disease or impact on an individual.  How disease affects the individual
  • Understand how a therapy works (i.e. pharmacokinetics of a drug).  How therapy affects the individual with the condition
  • Learn information that can be applied to a broader group of people
  • Clinical trials are the best way for researchers to learn how to diagnose, treat, and prevent PD

Types of clinical studies:

  • Interventional study:
    • Participants are assigned to receive one or more interventions, or no intervention (placebo), so researchers can evaluate the effects on group of people who received treatment based on health-related outcomes criteria
    • Examples:
      • Drug studies:
        • New medication to treat symptoms or slow progression
        • New ways to deliver a medication
        • New indications of a previously approved medication
      • Surgical studies:
        • Deep brain stimulation
        • Cell/gene transplants
      • Rehabilitative therapies:
        • Exercise, PT, OT, speech
        • Cognitive behavioral 
  • Observational study:
    • Researchers observe behavior or collect data in a systematic way without influencing or interfering with the behavior
    • No intervention
    • Important and as regulated as interventional trials
    • If people are weary to take part in an interventional study or weary to take new medication, they can still take part in an observational study
    • Examples:
      • Biomarkers:
        • Characteristics of a disease that can be tested
        • Test blood, spinal fluid, urine, saliva, skin, genes, imaging, neuropsych
        • Ex. PPMI study by the Michael J. Fox Foundation
      • Risk factors for PD
      • Social-behavioral studies
      • Exercise (natural course of physical activity in PD)
      • Cognition and depression in PD

Phases of Clinical Research:

  • Preclinical:
    • Studies are done in the lab to support that a therapy is reasonably safe and may be effective
    • Non-human
    • 5 in 5,000 drug compounds in preclinical stages go on to be tested in humans
  • Phase 1:
    • Very small group of people
    • Healthy volunteers
    • Studied to assess the risk and side effects of a drug or other therapy
  • Phase 2:
    • 80-150 volunteers who have the condition the drug is designed to treat (ex. PD)
    • Studies provide additional information about safety and also help determine dosage of the drug to be tested in future trials
    • Trials may be too small to determine the drugs benefit or efficacy
    • More for dosage finding and safety 
  • Phase 3:
    • Increase number of volunteers, usually greater than 300
    • These studies are conducted at multiple sites across the US and beyond
    • Data collected from phase 3 studies are important for the FDA to make decisions about approving a drug or therapy    
  • Phase 4:
    • After a medication is approved 
    • FDA often recommends these studies be done after approved
    • Researchers continue to monitor the health of people taking the medication or therapy to better understand long-term safety and effectiveness
    • When large amounts of people are now taking the medication, you can start to see side effects that are rare that aren’t seen before because the sample size was smaller 
    • It is often “open-label” studies (anyone can get it) that may provide more info on populations of individuals that may not have been included in the original studies
  • Note: it takes between 6 and 11 years for a drug to obtain FDA approval  

Who sponsors a study?

  • Government:
    • NIH
    • NINDS
    • DOD (Department of Defense)
    • NSF
  • Industry:
    • Pharmaceutical companies
    • Biotech companies
  • Foundations:
    • Ex. Michael J. Fox Foundation
    • May co-sponsor a study or provide research funding

Clinical study design:

  • Open label:
    • Everyone receives drug or therapy
  • Randomized controlled:
    • Drug or therapy is compared to placebo or a control group
    • Participants are assigned randomly to each group
  • Single blind placebo controlled:
    • Subject does nto know what group they are assigned
  • Double blind placebo controlled:
    • Gold standard
    • Both subject and researchers do not know to which group the subject is assigned

Finding ongoing clinical trials:

Ongoing PD trials:

  • PPMI/PPMI2:  Observational studies
  • Neurally Study (Exenatide used in diabetes)
  • TOPAZ:  prevention of fractures in parkinsonism
  • RAD PD:  PSG, deep brain stimulation observational study
  • Synuclein-One study:  biomarker for Parkinson’s
  • Bright light modulation of non-motor symptoms in PD (light therapy treatment)

Advantages to participants:

  • Potential of benefits just from participating
  • See medical specialists and receive funds on condition and health status
  • Align research visits with doctor visits
  • Benefit of joining in the fight against PD
  • Undergo a new experience and become a resource
  • Utilize the time traveled to see family/friends
  • Some studies are short and only have 1-2 visits
  • Stipends help offset costs of effort and transportation

Examples of Clinical Trials in Exercise: (Dr. Ellis)

SPARX study:

  • Phase 3 clinical trial
  • “Study in Parkinson’s Disease of Exercise” (SParX)
  • Impact of exercise on PD patients (treadmill)
  • Question: Does exercise actually decrease the progression of the disease?
  • Measure what is happening in the brain and changes in behavior
  • What is it about:
    • There is an effect of exercise on the brain.  Impacts motor skills and task practices
    • Impacts:
      • Synapses:
        • Neurotransmitters
        • Receptors
        • Dendritic spines
      • Brain health:
        • Trophic factors
        • Blood flow
        • Immune system
        • Neurogenesis
        • Metabolism
    • Synapses and brain health impact circuitry system:
      • Basal ganglia
      • Cortex
      • Thalamus
      • Cerebellum
      • Brainstem
    • This impacts behavior:
      • Motor (conscious/automatic)
      • Cognitive (executive function)
      • mood/motivation
  • 29 sites in US/Canada
  • Led by a team at Northwestern University
  • Study design:
    • Physician or self-referral
    • Screening / Consent
    • Initial baseline assessment (370 participants)
    • Stratified randomized within sites:
      • ½ (185 participants) exercise at 80-85% heart rate maximum
      • ½ (185 participants) exercise at 60-65% heart rate maximum
    • 6 months masked assessment
    • 12 month masked assessment
    • 18 month assessment
    • 24 month assessment
  • Exercise is walking on a treadmill
  • Exercise schedule:
    • Week 1 and 2:
      • With a therapist at a clinic
    • Week 3:
      • 4 unsupervised sessions
    • Week 4:
      • 1 supervised session
      • 3 unsupervised sessions
    • Month 2-18:
      • 2 supervised sessions each month
  • Outcomes:
    • Clinical measure of motor signs of PD.  Measure of speed of movement of hand/legs and stiffness
    • Does the exercise actually reduce the severity of the motor symptoms
    • What happens to walking speed/quality
    • Brain scan is done to see if there are any changes in are of brain most impacted by PD due to exercise 
    • Blood tests to test markers that are indicators of overall brain health
  • Eligibility for SPARX3:
    • Have been diagnosed with PD within the last 3 years
    • Not yet taking medication for your PD symptoms
    • Do not plan to start taking medications for PD within the next 6 months
    • Are willing to take part in a regular treadmill exercise program 4x/week for 18 months, and participate in study visits periodically for 23 months
    • 40 – 80 years old
    • Are not already participating in a structured exercise program
  • [If you live in the Boston area] For more information/to take part:
  • [Editor’s note:  If you live outside of the Boston area, and would like more information or are interested in enrolling see https://www.sparx3pd.com/ for sites near you]

WHIP-PD: 

  • “Walking Health Is Paramount in PD”
  • Funded by National Institute of Health (NIH) and National Center for Medical Rehab Research (NCMRR)
  • Phase 2 clinical trial
  • Why are we looking at walking:
    • Of 10 domains of functioning, patients with PD rated the following in order of importance:
      • 1. Walking
      • 2. Slowness
      • 3. Activities of daily living
      • 4. Fatigue
      • 5. Stiffness
      • 6. Sleep
      • 7. Thinking
      • 8. Tremor
      • 9. Emotional distress
      • 10. Pain
    • Walking is rated as the most important 
    • People very interested in improving walking function, and preventing decline of walking function
  • Changes in walking in people with PD over one year (based on observational study):
    • Decline in amount of walking people did (-12%) in 1 year
    • Decline (-40%) of moderate intensity minutes of walking (fast walking)
    • People with PD were walking less, and more slowly 
    • Want to intervention to prevent this from happening
  • Important to make exercise a habit
  • “MHealth app” – mobile health technology to promote physical activity in people with PD
    • Use app: Wellpepper
      • Wellpepper is a platform that shows an interactive customized treatment plan given to the patient by their doctor 
    • Editor Note: The app can be used outside of the trial but requires a doctor’s treatment plan, you cannot create your own
  • Study design:
    • Baseline assessment (mostly around walking)
    • 1-week step activity monitor:  Sensor around ankle for walking
    • Randomized into:
      • Mobile health (mHealth) physical therapy + Exercise
        • 8 in-person PT visits
        • Mobile health exercise platform (online application):
          • Tailored exercise videos
          • Monitoring by a PT
          • Visual feedback
          • CBT (cognitive behavioral therapy) elements
      • Exercise only:
        • 8 in-person PT visits
        • Home exercise program:
          • Tailored printed photos of exercise
          • Written instructions 
    • Assess at 3 months
    • Assess at 6 months 
    • Assess at 1 year 
  • Give participants an iPad or install on phone
  • People are paired with a physical therapist 
  • Help people identify a personal goal- exercise can help you continue to do the things that are important to you.  Ex. hike, spend time with grandchildren, work, travel
  • Outcomes measured by:
    • Improvement in walking
    • Motor signs of PD – change in severity?
  • Eligibility for WHIP PD:
    • Diagnosis of PD
    • Ability to walk without assistance from another person for at least 10 continuous minutes
    • Can attend the physical therapy sessions and evaluation sessions at the Center for Neurorehabilitation at Boston University, or are willing to have a staff member come to your home   
  • [If you live in the Boston area and] are interested in enrolling/learning more, please contact:
  • Editor’s note:  The other site for this study is in St. Louis, Missouri. If you live in the area and would like more information or are interested in enrolling, please contact:

Questions & Answer:

Question:  If I participate in a research study, will I find out the results or what group I was in?

Answer (Dr. Saint-Hilaire):  Yes, although it may take a while because not everyone may finish the study when you do, so you won’t know until they close the study. 

Question: Do you think research has slowed down with the pandemic?

Answer (Dr. Ellis):  At the beginning it did, but by late summer/early fall 2020 we started things up again.  During the pandemic we’ve become more creative, such as sending therapists to people’s homes or telemedicine.

Question:  How long is the WHIP-PD walking study?

Answer (Dr. Ellis):  It is a year long.  The visits with the therapist are within the first 3 months, and then there is some remote connection through the mobile health app.  People come back for assessments at 3 months, 6 months, and a year, so we can see how people are doing.  Even when the study ends, the hope is that people continue on and exercise. 

Question:  Would I find out if there is a new side effect from the medicine while participating in the study?  Once the new medicine is FDA approved, how do I find out the information on side effects?

Answer (Dr. Saint-Hilaire):  When you are in the research trial and there is a new side effect discovered, the trial team is informed quickly and we have to tell every participant very quickly as well.  If anything happens during the trial, the people monitoring the trial, the safety monitoring board, will tell everyone.  If a new side effect is discovered after the medication has been approved, then it is your physician who should know about that. 

Question:  In your view, what is the most promising area of research related to PD?

Answer (Dr. Ellis):  The SPARX3 trial is very exciting.  It’s a more definitive trial in being able to really understand the best dose of exercise and the impact it has on many aspects of people with PD.  We are getting closer to having more answers on what exercise is for people with PD.

Answer (Dr. Saint-Hilaire):  I like the biomarkers trial.  It will help to diagnose PD more efficiently, for example through skin biopsies.  Some trials that are done for genetic forms of PD and specific medications for genetic forms are also interesting and can be more expandable to other forms of PD. 

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