Placebo Effects for Stroke Recovery

Overseen By Elly Pichardo, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Spaulding Rehabilitation Hospital

Disqualifiers: Prefrontal lesion, Unstable conditions, Pregnancy, others

Compensation: Varies

Number of Visits: 10

Duration: 2 weeks

56 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how placebo effects might aid stroke recovery. It seeks to determine if taking a placebo, either openly or unknowingly, triggers a unique brain response that could enhance rehabilitation. Participants will join one of several groups: receiving active brain stimulation (repetitive Transcranial Magnetic Stimulation, or rTMS), taking placebo pills, or continuing their usual treatment. Adults who have experienced a stroke and have had muscle weakness on one side of their body for six months or more may qualify.

As an unphased trial, this study provides a unique opportunity to contribute to groundbreaking research that could improve future stroke rehabilitation strategies.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that repetitive transcranial magnetic stimulation (rTMS) is usually safe when performed according to guidelines. It can aid stroke recovery by altering brain activity. However, safety can vary among individuals, as some may not tolerate the same dose as well as others.

For open placebo, a "fake" treatment used to study the placebo effect, there are no major safety concerns. Placebos are often used in studies and are considered safe because they lack active medicine.

Overall, research indicates that both treatments are generally well-tolerated. However, since individual reactions can vary, consulting a doctor is important before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores the power of placebo effects in stroke recovery, which is a fresh angle compared to the usual rehabilitation therapies like physical therapy and medication. The study looks at active repetitive transcranial magnetic stimulation (rTMS) and open placebo treatments, aiming to understand how belief and expectation can impact healing. Active rTMS is intriguing because it uses magnetic fields to stimulate nerve cells in the brain, which could potentially enhance motor recovery more effectively than current methods. Meanwhile, open placebos challenge the traditional notion that a pill must contain active ingredients to produce real effects, which could revolutionize how we think about treatment efficacy. This trial could lead to new, non-invasive strategies that complement existing stroke recovery methods.

What evidence suggests that this trial's treatments could be effective for stroke recovery?

Research has shown that repetitive transcranial magnetic stimulation (rTMS), which participants in this trial may receive as Active rTMS, can aid stroke recovery. Studies have found that rTMS improves movement and cognitive skills in stroke patients. This treatment uses magnetic fields to activate nerve cells in the brain.

Another treatment arm in this trial involves Open Placebo. Research suggests that open placebo can influence brain activity and assist in learning new movements. The placebo effect can alter brain connectivity and function, aiding stroke recovery. While not a direct treatment, its psychological impact can support rehabilitation efforts. ^{1 4 5 6 7}

Who Is on the Research Team?

Felipe Fregni, MD, PhD, MPH

Principal Investigator

Spaulding Rehabilitation Hospital/Harvard Medical School

Are You a Good Fit for This Trial?

This trial is for adults over 18 who've had a stroke at least 6 months ago, resulting in one-sided weakness but still have some arm movement. They should not be severely disabled before the stroke and must understand instructions. People with joint pain, certain brain injuries from their stroke, pregnancy, unstable health conditions or electronic implants near the brain can't join.

Inclusion Criteria

I had a stroke more than 6 months ago.

You had difficulty with daily activities before the stroke.

Your upper arm and hand movement score on the Fugl-Meyer scale is between 11 and 56.

Exclusion Criteria

I had a stroke affecting the front part of my brain, confirmed by EEG.

Pregnancy

I have joint pain that could affect my ability to participate in assessments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized into one of four groups: open placebo, sham rTMS, no intervention, or active rTMS, and undergo 2 weeks of daily intervention visits

2 weeks

10 sessions (in-person)

Follow-up

Participants are monitored for changes in motor function and brain activity after the treatment phase

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Active rTMS
• Open Placebo
• Sham rTMS

Trial Overview

The study tests if different types of placebo (openly given as a placebo or disguised) and active repetitive Transcranial Magnetic Stimulation (rTMS), which is a non-invasive brain stimulation technique, affect recovery in chronic stroke patients differently.

How Is the Trial Designed?

Group I: No Intervention Active Control 1 Intervention

It consists of treatment-as-usual group.

Group II: Active rTMS Active Control 1 Intervention

The participant will receive a session of low frequency rTMS to the contralesional primary motor cortex. Low frequency rTMS stimulation will be applied according to the following parameter: intensity of 80% MT (intensity could be adjusted if not comfortable to the subject), frequency of 1 Hz, 1200 pulses as a single, continuous train lasting 20 minutes.

Group III: Sham rTMS Placebo Group 1 Intervention

The investigators will place the coil in the same location, usually used for the active stimulation with the same stimulation parameters. However, the investigators will replace the active coil with a sham coil to ensure no stimulation is provided.

Group IV: Open Placebo Placebo Group 1 Intervention

The open placebo will consist of typical prescription medicine bottle of placebo pills with a label clearly marked "placebo pills" "take 2 pills twice daily." The placebo pills are made from Microcrystalline Cellulose.

Active rTMS is already approved in United States, European Union for the following indications:

Approved in United States as rTMS for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)
• Smoking Cessation
• Chronic Pain Syndrome

Approved in European Union as rTMS for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)
• Chronic Pain Syndrome
• Generalized Anxiety Disorder (GAD)
• Bipolar Disorder

Who Is Running the Clinical Trial?

Spaulding Rehabilitation Hospital

Lead Sponsor

Trials

143

Recruited

11,200+

Published Research Related to This Trial

Sham transcranial magnetic stimulation (TMS) is commonly used in research to differentiate real effects from side effects, but it has limitations in accurately controlling for placebo and sensory effects.

The authors argue that sham TMS cannot fully serve as a control condition because it does not adequately demonstrate the specificity of TMS effects, suggesting that it should be used alongside other control strategies in TMS studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rethinking the role of sham TMS. Duecker, F., Sack, AT.[2020]

Repetitive transcranial magnetic stimulation (rTMS) significantly improved motor function in stroke patients within the first month after treatment, particularly in upper limb function, as shown by various motor functional scores assessed over time.

The benefits of rTMS on upper extremity function were observed to last for up to one year, indicating its potential as a long-term therapeutic intervention for motor recovery after stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of repetitive transcranial magnetic stimulation (rTMS) after acute stroke: A one-year longitudinal randomized trial. Guan, YZ., Li, J., Zhang, XW., et al.[2021]

In a study involving 15 chronic stroke patients, five sessions of low-frequency repetitive transcranial magnetic stimulation (rTMS) on the unaffected hemisphere significantly improved motor function in the affected hand for up to 2 weeks, compared to a sham treatment.

The study found that this increased rTMS treatment did not lead to any cognitive side effects or increased risk of seizures, indicating it is a safe intervention for enhancing motor recovery in stroke patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Fregni, F., Boggio, PS., Valle, AC., et al.[2022]

The study found that healthy volunteers who believed they received an effective treatment (TENS) showed increased force output and enhanced excitability in the corticospinal system, indicating a placebo effect on motor performance.

Using transcranial magnetic stimulation (TMS), researchers demonstrated that this placebo effect was linked to cognitive factors, as the excitability changes occurred even when all subjects exerted the same force, suggesting a top-down influence on motor control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-induced changes in excitatory and inhibitory corticospinal circuits during motor performance. Fiorio, M., Emadi Andani, M., Marotta, A., et al.[2022]

A meta-analysis of 26 placebo-controlled trials involving 381 patients showed that placebo repetitive transcranial magnetic stimulation (rTMS) has a medium and significant effect on improving motor recovery after a stroke, with an effect size of 0.466.

The number of treatment sessions was found to significantly influence the placebo effect size, indicating that more sessions may enhance the perceived benefits of sham rTMS, which also showed sustained motor improvement for at least 3 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo effect of rTMS on post-stroke motor rehabilitation: a meta-analysis. Jin, Y., Pu, T., Guo, Z., et al.[2022]

The new real electro-magnetic placebo (REMP) device effectively simulates the scalp sensations of real repetitive transcranial magnetic stimulation (rTMS) while ensuring that it does not produce any biologically active electric fields, making it a more reliable sham for clinical trials.

In tests, naive subjects were more likely to mistake the REMP-attenuated TMS for real rTMS compared to other sham methods, indicating that the REMP device provides a superior placebo experience, which is crucial for accurately assessing the efficacy of rTMS treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real electro-magnetic placebo (REMP) device for sham transcranial magnetic stimulation (TMS). Rossi, S., Ferro, M., Cincotta, M., et al.[2021]

In a study of 45 patients, the timing of sham rTMS relative to active rTMS significantly influenced pain relief, with placebo analgesia occurring only when sham sessions followed successful active rTMS, indicating a potential conditioned learning effect.

The findings suggest that even modest analgesic effects (around 10%) from active rTMS can enhance placebo responses, implying that the threshold for clinically significant pain relief in trials may need to be reconsidered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

On the importance of placebo timing in rTMS studies for pain relief. André-Obadia, N., Magnin, M., Garcia-Larrea, L.[2022]

In a meta-analysis of 93 randomized controlled trials involving repetitive transcranial magnetic stimulation (TMS), the overall incidence of adverse events (AEs) was found to be higher in the active TMS group (29.3%) compared to the placebo group (13.6%), indicating a 2.60 times greater risk of experiencing AEs with active treatment.

Despite the higher incidence of AEs, TMS is considered a safe and well-tolerated intervention, with common side effects including headache and dizziness, highlighting the importance of recognizing nocebo effects in both clinical trials and practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Nocebo Phenomena During Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Placebo-Controlled Clinical Trials. Zis, P., Shafique, F., Hadjivassiliou, M., et al.[2022]

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