LIFT: Life Improvement Trial (LIFT)

The LIFT will be conducted at Brigham and Women's Hospital (BWH) of Harvard Medical School, focusing on the effect of Pyridostigmine (Mestinon) and Low-Dose Naltrexone (LDN) in subjects aged 18-70 meeting the Canadian consensus criteria (CCC) for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) as well as having specifically Orthostatic Intolerance (OI). Long COVID (LC) subjects will also be included if they meet CCC and have OI.

This double-blind, placebo-controlled study will involve 160 participants randomized into one of four possible groups: Pyridostigmine/LDN (40), Pyridostigmine/Placebo (40), LDN/Placebo (40), Placebo/Placebo (40). The dose of Pyridostigmine will be carefully titrated from 30mg to 60mg three times a day, and the dose of LDN will be titrated from 1.5 mg to 4.5 mg once daily.

The trial includes a scale-back plan, allowing participants to reduce their dosage if they experience intolerance symptoms, with adjustments made during weekly visits. This plan provides a personalized approach to medication tolerance, ensuring participant's safety and comfort throughout the trial.

The time commitment for the participant is approximately three (3) months, and during this time, there will be three (3) in-person visits to BWH and four (4) virtual visits. Study procedures will include two (2) submaximum cardiopulmonary exercise tests, questionnaires (virtually completed), and blood and urine collection. We will be recruiting from the BWH Dyspnea Clinic as well as the Open Medicine Foundation (OMF) StudyME Registry and anticipate the entire trial will take two (2) years to complete.

The LIFT represents a significant endeavor to improve treatment options for ME/CFS patients and contribute to the broader understanding of this debilitating condition.

Study Overview

• Status: Recruiting
• Conditions: Long COVID; ME/CFS; PASC
• Intervention / Treatment: Drug: Pyridostigmine; Drug: Low-Dose Naltrexone; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Research Coordinator; Phone Number: 617-525-6797; Email: jsquires1@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Clinical Research Coordinator; Phone Number: 617-525-6797; Email: jsquires1@bwh.harvard.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Meet National Academy of Medicine Criteria, Canadian Consensus Criteria (See appendix), and demonstrate orthostatic intolerance for diagnosis of ME/CFS
2. Participant is ≥ 18 and ≤ 70 years of age at screening, inclusive.
3. The onset of symptoms prior to December 2023.

4. Female participant is not pregnant and at least 1 of the following conditions apply:

   1. Not a woman of childbearing potential
   2. Woman of childbearing potential who agrees to follow the contraceptive guidance. from the time of informed consent.
5. Participant agrees and can adhere to the study requirements for the length of the study.
6. Participant has a body mass index (BMI) range of 17 to 40 kg/m2, inclusive.
7. Participant agrees not to participate in another interventional study while participating in the present study.
8. Participant has a functioning smart phone to download and run the DANA Brain Vital Mobile Application.

Exclusion Criteria:

1. Pregnant, planning to become pregnant, or breastfeeding.
2. Any use of opioid medications within 30 days of screening.
3. Positive urine test for opioids
4. History of alcohol, opioid or other substance misuse
5. Participation in another interventional clinical trial in the last 30 days or planned during the trial period.
6. Allergy to medication components
7. Participant has any condition which, in the investigator's opinion, makes the participant unsuitable for study participation.
8. Participant has diabetes mellitus (type 1 or 2).
9. Participant has undergone an inpatient hospitalization within the 30 days prior to the randomization or has a planned hospitalization or a surgical procedure during the study, which may affect the study assessments, in the opinion of the investigator.
10. Participant has clinically significant respiratory disease (such as chronic obstructive pulmonary disease, cystic fibrosis, severe asthma, lung infections including tuberculosis, sarcoidosis, thoracic endometriosis, pulmonary fibrosis, and lung cancers) and/or cardiac disease (medical history or current clinical findings)
11. Participant has an active malignancy or any other cancer.
12. Participant has initiated an exercise regimen within 4 weeks prior to randomization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pyridostigmine/LDN; Pyridostigmine will be taken as liquid suspension three times a day, scaling up from 20mg (1.67mL) to 60mg (5mL) (180mg/day). Low dose naltrexone will be taken as liquid suspension once a day, scaling up from 1.5mL to 4.5mL (4.5mg/day).	Drug: Pyridostigmine; Pyridostigmine timeline: Weeks 0-2: 20mg TID (1.67 mL TID) Weeks 2-4: 40mg TID (3.33 mL TID) Weeks 5-13: 60mg TID (5mL TID); Other Names: Mestinon; Drug: Low-Dose Naltrexone; LDN timeline: Weeks 0-2: 1.5mg QD (1.5mL QD) Weeks 2-4: 3.0mg QD (3.0mL QD) Weeks 5-13: 4.5mg QD (4.5mL QD); Other Names: LDN
Active Comparator: Pyridostigmine/Placebo; Pyridostigmine will be taken as liquid suspension three times a day, scaling up from 20mg (1.67mL) to 60mg (5mL) (180mg/day). Placebo will be taken as liquid suspension once a day, scaling up from 1.5mL to 4.5mL.	Drug: Pyridostigmine; Pyridostigmine timeline: Weeks 0-2: 20mg TID (1.67 mL TID) Weeks 2-4: 40mg TID (3.33 mL TID) Weeks 5-13: 60mg TID (5mL TID); Other Names: Mestinon; Other: Placebo; Placebo timeline: Weeks 0-2: 20mg TID (1.67mL TID)/1.5mg QD (1.5mL QD) Weeks 2-4: 40mg TID (3.33mL TID)/3.0mg QD (3.0mL QD) Weeks 5-13: 60mg TID (5mL TID)/4.5mg QD (4.5mL QD)
Active Comparator: Placebo/LDN; Placebo will be taken as liquid suspension three times a day, scaling up from 1.67mL to 5mL. Low dose naltrexone will be taken as liquid suspension once a day, scaling up from 1.5mL to 4.5mL (4.5mg/day).	Drug: Low-Dose Naltrexone; LDN timeline: Weeks 0-2: 1.5mg QD (1.5mL QD) Weeks 2-4: 3.0mg QD (3.0mL QD) Weeks 5-13: 4.5mg QD (4.5mL QD); Other Names: LDN; Other: Placebo; Placebo timeline: Weeks 0-2: 20mg TID (1.67mL TID)/1.5mg QD (1.5mL QD) Weeks 2-4: 40mg TID (3.33mL TID)/3.0mg QD (3.0mL QD) Weeks 5-13: 60mg TID (5mL TID)/4.5mg QD (4.5mL QD)
Placebo Comparator: Placebo/Placebo; Placebo will be taken as liquid suspension three times a day, scaling up from 1.67mL to 5mL. Placebo will be taken as liquid suspension once a day, scaling up from 1.5mL to 4.5mL .	Other: Placebo; Placebo timeline: Weeks 0-2: 20mg TID (1.67mL TID)/1.5mg QD (1.5mL QD) Weeks 2-4: 40mg TID (3.33mL TID)/3.0mg QD (3.0mL QD) Weeks 5-13: 60mg TID (5mL TID)/4.5mg QD (4.5mL QD)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physiologic Response - Oxygen Uptake Efficiency Slope (OUES)	Changes in % of predicted oxygen uptake efficiency slope (OUES) between baseline and follow-up measured during a non-invasive cardiopulmonary exercise test (CPET)	13 weeks
Physiologic Response - Oxygen Utilization (VO2)	Changes in % of predicted extrapolated peak oxygen utilization (extrapolated max VO2) between baseline and follow-up measured during a submaximum CPET	13 weeks
Physiologic Response - Heart Rate Recovery (HRR)	Changes in 1-min heart rate recovery (HRR) in beats per minute (bpm) between baseline and follow-up measured during a submaximum CPET	13 weeks
Functional Capacity	Change in the total FUNCAP55 questionnaire score The FUNCAP55 is a questionnaire developed to assess the functional capacity of patients. Each question is answered on a 6-point scale. The greater the score, the better the functioning.	15 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-Exertional Malaise	Change in DePaul Symptom Questionnaire-1 (DSQ1) score The questionnaire lists 5 symptoms that are scored based on frequency and severity. Each question is answered on a 4-point scale. The greater the score, the greater the frequency and severity of the symptom.	15 weeks
PROMIS-29-Pain	Change in PROMIS-29 questionnaire score Reflected as combination of the "pain interference" (0 to 5) and "pain intensity" (0 to 10) sections of the questionnaire will be secondary outcomes. The greater the score, the greater the pain experienced.	15 weeks
Daily Activity	Change in daily steps (steps/day) measured using Garmin Vivosmart 5	15 weeks
Heart Rate Variability	Change in heart rate variability (HRV) defined as the specific change in time (ms) between successive heart beats. All collected via Garmin VivoSmart5	15 weeks
Blood Oxygen	Change in blood oxygen saturation (%) measured with Garmin VivoSmart 5	15 weeks
Resting Heart Rate	Change in resting heart rate (bpm) using Garmin VivoSmart 5	15 weeks
DANA Brain Vital-Simple Reaction Time (SRT)	Change in time (ms) required to recognize the presence of an object and tap the object	15 Weeks
DANA Brain Vital-Procedural Reaction Time (PRT)	Change in time (ms) required to recognize 1 of 4 numbers and tap 1 of 2 buttons	15 weeks
DANA Brain Vital-Memory Search (MS)	Change in time (ms) required to recognize letters that have previously been memorized	15 weeks

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Open Medicine Foundation
• Investigators: Principal Investigator: David Systrom, MD, Massachusetts General Hospital

Publications and helpful links

Helpful Links

• MGB Rally - LIFT

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: March 20, 2024
• First Submitted That Met QC Criteria: April 10, 2024
• First Posted (Actual): April 16, 2024

Study Record Updates

• Last Update Posted (Estimated): October 22, 2025
• Last Update Submitted That Met QC Criteria: October 21, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Cognitive Impairment; Long COVID; Orthostatic Intolerance; Mestinon; Chronic fatigue; Low Dose Naltrexone; Post exertional malaise
• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Post-Infectious Disorders; COVID-19; Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Mental Disorders; Pathologic Processes; Encephalomyelitis; Neuromuscular Diseases; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Neurocognitive Disorders; Lung Diseases; Cognition Disorders; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Primary Dysautonomias; Autonomic Nervous System Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Post-Acute COVID-19 Syndrome; Fatigue Syndrome, Chronic; Cognitive Dysfunction; Orthostatic Intolerance; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Alkaloids; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Naloxone; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Pyridinium Compounds; Naltrexone; Pyridostigmine Bromide
• Other Study ID Numbers: 2024P000087

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after de-identification(text, tables, figures, and appendices) will be available for researchers who provide a methodologically sound proposal to achieve aims in the approved proposal.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication.
• IPD Sharing Access Criteria: Proposals should be directed to jsquires1@bwh.harvard.edu. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: SAP; ICF; CSR

Drug and device information, study documents

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