Mechanisms of Open and Hidden Placebo in Stroke Recovery

This trial aims to investigate whether placebo in isolation (open and hidden) has a specific neural signature in stroke subjects thus providing a novel mechanism to explain placebo effects that can be used to ultimately enhance stroke rehabilitation therapies.

Study Overview

• Status: Recruiting
• Conditions: Stroke; Hemiparesis
• Intervention / Treatment: Device: Active rTMS; Device: Sham rTMS; Dietary supplement: Open Placebo

Detailed Description

Placebo effect leads to significant effects on brain excitability and connectivity, ultimately influencing clinical outcomes, including motor learning in stroke. This trial will provide critical mechanistic data to improve the understanding of placebo in stroke clinical trials, as to solve methodological and ethical dilemma in research designs, and to improve its clinical outcomes. It aims to investigate whether placebo in isolation (open and hidden) has a specific neural signature in stroke subjects. For this purpose, the investigators plan to recruit 56 chronic stroke participants, that will be randomized using blocked randomization in a 2:2:2:1 proportion to one of the following groups, respectively: 1) open placebo (OP) alone (16 subjects); 2) sham rTMS alone (16 subjects); 3) no intervention (16 subjects); or 4) active rTMS alone (8 subjects). All four groups will undergo 2 weeks of daily intervention visits (10 sessions).

• Study Type: Interventional
• Enrollment (Estimated): 56
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Felipe Fregni, MD, PhD, MPH; Phone Number: 6179526156; Email: fregni.felipe@mgh.harvard.edu
• Study Contact Backup: Name: Elly Pichardo, MD; Phone Number: 6179526154; Email: epichardo@partners.org

Study Locations

• United States
  • Massachusetts
    • Cambridge, Massachusetts, United States, 02138
      • Recruiting
      • Spaulding Hospital Cambridge
      • Contact: Elly Pichardo, MD; Phone Number: 617-952-6158; Email: epichardo@partners.org
      • Principal Investigator: Felipe Fregni, MD, PhD, MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults with hemiparesis due to chronic stroke
2. Stroke duration of 6 months or more
3. Fugl-Meyer scale upper extremity motor assessment score of > 11 and ≤ 56
4. Pre-stroke disability (defined as a score of < 3 on the Modified Rankin Scale)
5. Age 18 or older

Exclusion Criteria:

1. Stroke of anterior cerebral artery territory with prefrontal lesion and stroke-related decreased EEG power in the prefrontal cortex
2. Unable to understand instructions
3. TMS contraindications: electronic hardware in close contact to the discharging coil such as cochlear implant, internal pulse generator or medical pump
4. Concurrent unstable medical conditions
5. A score of 24 or higher on the Hamilton Depression Rating Scale (HDRS)
6. Joint or paretic extremity pain likely to interfere with assessments
7. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active rTMS; 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.	Device: Active rTMS; Subjects will undergo repetitive transcranial magnetic stimulation, each session lasting 20 minutes.
Sham Comparator: Sham rTMS; 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.	Device: Sham rTMS; Subjects will undergo sham repetitive transcranial magnetic stimulation, each session lasting 20 minutes.
Placebo Comparator: Open Placebo; 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.	Dietary supplement: Open Placebo; The open placebo will consist of an inactive substance pill commonly used in clinical trials and given to the subject in a regular pill dispenser.
No Intervention: No Intervention; It consists of treatment-as-usual group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electroencephalography (EEG): Frontal alpha asymmetry	The FAA score will be calculated by subtracting the natural log-transformed alpha power in the left frontal region (F3, F7, Fp1) from the natural log-transformed power in the right frontal region (F4, F8, Fp2).	Change from 2 weeks to baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fugl-Meyer motor scale (FM)	The investigators will use this tool for motor function after stroke. It is valid, responsive to change, and widely used for motor function and recovery assessment in stroke patients. Items are scored on a 3-point ordinal scale, being 0 the lowest and 2 the highest value. A higher score means a better outcome.	Change from 2 weeks to baseline
Premotor-M1 (PM-M1) connectivity	For the PM-M1 connectivity computation, the investigators will calculate the spectral coherence score, which indicates the functional connectivity in brain activity between two cortical regions and is calculated as a function of frequency.	Change from 2 weeks to baseline

Collaborators and Investigators

• Sponsor: Spaulding Rehabilitation Hospital
• Investigators: Principal Investigator: Felipe Fregni, MD, PhD, MPH, Spaulding Rehabilitation Hospital/Harvard Medical School

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: March 24, 2023
• First Submitted That Met QC Criteria: April 24, 2023
• First Posted (Actual): April 27, 2023

Study Record Updates

• Last Update Posted (Estimated): September 17, 2025
• Last Update Submitted That Met QC Criteria: September 15, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: stroke; placebo
• Additional Relevant MeSH Terms: Neurologic Manifestations; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Stroke; Paresis
• Other Study ID Numbers: 2023P000884

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No