Naltrexone + Pyridostigmine for Chronic Fatigue Syndrome

(LIFT Trial)

Overseen By Research Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brigham and Women's Hospital

Must not be taking: Opioids

Disqualifiers: Pregnancy, Diabetes, Respiratory disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 13 weeks

160 Participants Needed

Trial Summary

What is the purpose of this trial?

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 18-65 meeting the Canadian consensus criteria (CCC) for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) as well as having specifically Orthostatic Intolerance. 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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use opioid medications within 30 days of screening. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of Low-Dose Naltrexone and Pyridostigmine for Chronic Fatigue Syndrome?

Low-Dose Naltrexone has shown potential benefits in other conditions like fibromyalgia and Gulf War Illness, which share some symptoms with Chronic Fatigue Syndrome. Additionally, Pyridostigmine has been reported to improve symptoms in some patients with Chronic Fatigue Syndrome, suggesting it might help with fatigue and related issues. ^{1 2 3 4 5}

Is the combination of Naltrexone and Pyridostigmine safe for humans?

Low-dose naltrexone has been used safely in small-scale trials for conditions like Crohn's disease and fibromyalgia, while pyridostigmine has shown safety in case reports for chronic fatigue syndrome. Both drugs have been used in humans with generally mild and manageable side effects. ^{1 2 3 4 6}

How does the drug combination of Naltrexone and Pyridostigmine differ from other treatments for chronic fatigue syndrome?

This drug combination is unique because it combines low-dose naltrexone, which is used off-label for immune-related conditions, with pyridostigmine, which may help with neuromuscular transmission and autonomic function. Unlike other treatments, this combination targets both immune modulation and neuromuscular issues, offering a novel approach for a condition with no standard treatment. ^{1 2 3 6 7}

Research Team

David Systrom, MD

Principal Investigator

Mass General Brigham

Eligibility Criteria

The LIFT trial is for adults aged 18-65 with ME/CFS who meet specific criteria, including orthostatic intolerance. Participants must not be women of childbearing potential or agree to contraception, have a BMI between 17 and 40, and commit to the study without joining another trial. They need a smartphone for an app used in the study.

Inclusion Criteria

I cannot become pregnant.

I agree to follow the contraceptive advice given.

I agree not to join another clinical trial while in this study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Pyridostigmine and/or Low-Dose Naltrexone or placebo, with dosage titration and weekly adjustments based on tolerance

13 weeks

3 visits (in-person), 4 visits (virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of functional capacity and physiological responses

2 weeks

Treatment Details

Interventions

• Low-Dose Naltrexone
• Pyridostigmine

Trial Overview This study at Brigham and Women's Hospital tests Pyridostigmine (30mg-60mg) and Low-Dose Naltrexone (1.5mg-4.5mg) on ME/CFS patients with Orthostatic Intolerance. It's double-blind with four groups: both drugs, each drug alone with placebo, or double placebo.

Participant Groups

Group I: Pyridostigmine/Placebo Active Control 2 Interventions

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.

Group II: Placebo/LDN Active Control 2 Interventions

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).

Group III: Pyridostigmine/LDN Active Control 2 Interventions

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).

Group IV: Placebo/Placebo Placebo Group 1 Intervention

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 .

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Open Medicine Foundation

Collaborator

Trials

1

Recruited

160+

Findings from Research

In a retrospective review of 3 patients with chronic fatigue syndrome (CFS) who had not benefited from standard treatments, the addition of modafinil to cognitive-behavioral therapy (CBT) resulted in significant improvements in energy and pain/concentration for 2 out of 3 patients.

All 3 patients achieved social recovery, suggesting that modafinil may enhance the effectiveness of CBT in treating treatment-resistant CFS over a medium-term period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recovery from refractory chronic fatigue syndrome with CBT and modafinil. Garg, H., Douglas, M., Turkington, GD., et al.[2023]

Low-dose naltrexone (LDN) has shown potential efficacy in treating chronic immune-modulated disorders, with case reports indicating varied responses in patients with chronic fatigue syndrome, ranging from significant improvement to partial symptom relief.

Despite promising anecdotal evidence and small-scale trials for other conditions, there is a lack of clinical trials specifically investigating LDN for chronic fatigue syndrome, suggesting a need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose naltrexone as a treatment for chronic fatigue syndrome. Bolton, MJ., Chapman, BP., Van Marwijk, H.[2020]

In three cases of Chronic Fatigue Syndrome (CFS), patients exhibited defects in neuromuscular transmission and dysautonomia, which were linked to their fatigue symptoms.

All three patients showed significant improvement in their symptoms after treatment with the acetylcholinesterase inhibitor pyridostigmine, suggesting that cholinergic dysautonomia may play a role in the fatigue experienced by some CFS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Kawamura, Y., Kihara, M., Nishimoto, K., et al.[2020]

In a 6-week study involving 20 patients with chronic fatigue syndrome, dexamphetamine significantly improved fatigue severity in 9 out of 10 patients compared to only 4 out of 10 in the placebo group.

While there were notable improvements in quality of life measures like vitality and physical functioning, these changes were not statistically significant, suggesting that further research with a larger sample size is needed to confirm dexamphetamine's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot randomized controlled trial of dexamphetamine in patients with chronic fatigue syndrome. Olson, LG., Ambrogetti, A., Sutherland, DC.[2013]

Pilot studies, like the one reporting positive results for granisetron in chronic fatigue syndrome, can show promising outcomes but may not always predict success in larger trials due to issues like selection bias and nonvalidated measurement methods.

A larger, more rigorous clinical trial of granisetron is currently underway to better assess its efficacy in treating chronic fatigue syndrome, following the initial favorable results observed in a small group of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot studies: one swallow does not make a summer... van Gelder, T., Smits, P.[2004]

In a study of 49 patients with chronic fatigue syndrome, moclobemide showed small but significant reductions in fatigue, depression, and anxiety over 6 weeks, with the most notable improvements seen in patients who also had major depressive illness.

Moclobemide may be beneficial for chronic fatigue syndrome patients with co-existing major depressive disorder, but it is not supported as an effective treatment for chronic fatigue syndrome alone, indicating the need for further randomized, placebo-controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open study of the efficacy and adverse effects of moclobemide in patients with the chronic fatigue syndrome. White, PD., Cleary, KJ.[2019]

In a study of 31 patients with chronic fatigue syndrome (CFS), those treated with oral NADH showed a significant reduction in fatigue symptoms during the first trimester of treatment compared to those receiving conventional therapies.

While NADH demonstrated initial effectiveness, the symptom improvements were not sustained in later trimesters, suggesting that further research with a larger sample size is needed to fully evaluate its long-term efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome. Santaella, ML., Font, I., Disdier, OM.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Recovery from refractory chronic fatigue syndrome with CBT and modafinil. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Low-dose naltrexone as a treatment for chronic fatigue syndrome. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. [2020]

4. England pubmed.ncbi.nlm.nih.gov

A pilot randomized controlled trial of dexamphetamine in patients with chronic fatigue syndrome. [2013]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Pilot studies: one swallow does not make a summer... [2004]

6. England pubmed.ncbi.nlm.nih.gov

An open study of the efficacy and adverse effects of moclobemide in patients with the chronic fatigue syndrome. [2019]

7. Puerto Rico pubmed.ncbi.nlm.nih.gov

Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome. [2015]