Clinical trial NCT05430152: Low-dose Naltrexone for Post-COVID Fatigue Syndrome
Official title: A Double Blind Randomized Trial of Low-dose Naltrexone for Post-COVID Fatigue Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Post-Viral Fatigue Syndrome
Keywords: Post-COVID Fatigue Syndrome
Long-COVID
COVID-19
SARS-CoV-2
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: University of British Columbia
name: Canadian Institutes of Health Research (CIHR)
name: Provincial Health Services Authority
name: Women's Health Research Institute of British Columbia
First posted: 2022-06-24
Enrollment: 160
Sex: ALL
Minimum age (years): 19
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized parallel group double-blinded placebo-controlled trial
Primary purpose: TREATMENT

Brief summary: This study aims to determine if low-dose naltrexone (LDN) reduces fatigue, improves related symptoms, and reduces inflammatory markers in peripheral blood in cases with Post-COVID-19 Fatigue Syndrome (PCFS) from COVID-19 (i.e. confirmed SARS-CoV-2 case). LDN refers to naltrexone given in doses of 1-4.5 mg. Overall, studies have found that LDN is safe and well-tolerated. It may help to reduce pain and inflammation and improve well-being and immune function.The trial will be conducted by the Complex Chronic Diseases Program (CCDP) at BC Women's Hospital and will demonstrate whether LDN could benefit a large number of people with PCFS.

Detailed description: There is a growing number of individuals who do not recover to previous levels of health and function following an acute infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but rather develop what has been referred to as 'Long-COVID'. Long-COVID is believed to be multi-causal, with a significant proportion of Long-COVID cases developing a clinical picture indistinguishable from myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) or post-viral fatigue syndrome (PVFS), which we will refer to as post-COVID-19 fatigue syndrome (PCFS). It is characterized by persistent disabling fatigue and other symptoms, such as nonrestorative sleep and post-exertional malaise. Diagnosis is clinical and based on symptom reports owing to the absence of diagnostic biomarkers. Viral and other infections are 25 times more likely to trigger ME/CFS than any other factors. This highlights the possibility of COVID-19 survivors having post-viral symptoms which progress to PCFS, either as the only sequelae or combined with other dysfunctions. Other Long-COVID symptom profiles in addition to PCFS include: a) post-intensive care syndrome; b) organ damage; and c) other debilitating symptoms related to mental health and other conditions.

There is no evidence-based treatment for PVFS, however, low-dose naltrexone (LDN), i.e. in doses up to 4.5 mg/day, has been used with some success in cases not related to COVID-19, due to its potential anti-inflammatory, analgesic properties and other mechanisms, targeting potential key mechanisms involved in the development of PVFS and the persistence of symptoms long-term.

Previous literature has demonstrated the safety and effectiveness of LDN in other chronic conditions, such as fibromyalgia (FM). The use of LDN as an off label treatment for fibromyalgia and myalgic encephalomyelitis has been used extensively within the BC Women's Hospital + Health Center's Complex Chronic Diseases Program (CCDP) to treat symptoms of pain and fatigue in these clinical populations. The experience of doctors in the CCDP in administering LDN as a medication for these related diseases follows international clinical experience with LDN and the recommended usage from clinical trials in fibromyalgia.

Naltrexone is an opiate antagonist approved by Health Canada for treatment for alcohol and opiate use disorders. It is used off label at low doses for conditions such as ME/CFS, fibromyalgia and Crohn's disease, with good safety profile and some evidence of benefit.

The impact the COVID-19 pandemic makes finding evidence for an effective and safe treatment for PCFS urgent. With currently no curative treatment for ME/CFS or PCFS, a larger number of people are predicted to be impacted by the long-term morbidity and disability associated with these conditions, with high costs to healthcare and social services.

The Double Blind Randomized Trial of Low-Dose Naltrexone for Post-COVID Fatigue Syndrome (PCFS) is a randomized parallel group double-blinded placebo-controlled trial of daily oral capsules of LDN or placebo for individuals 19-69 years old of both sexes for the treatment of PCFS. 160 participants will be treated with either LDN or placebo for 16 weeks.

Eligibility criteria: Inclusion Criteria:

1. Male and female patients ages 19 to less than 70 years
2. Case of SARS-CoV-2 over 3 previously, confirmed by a positive test result or clinical confirmation by a physician
3. Meet the clinical diagnostic criteria for PCFS
4. Agree to maintain any other regular medications at current doses for the duration of the trial (except for essential need of new medication or dose change, as prescribed by a physician)
5. Agree to use effective contraception for the trial duration, as appropriate, if female.
6. The participant resides within the delivery area for the drug as determined by FedEx Clinical Trial Services

Exclusion Criteria:

1. Pregnant, planning to become pregnant, or breastfeeding
2. Opioid medications:

   * Any use within last 15 days, as reported by the patient
   * During the trial
3. A positive urine test for opioids (only for the first 16 participants)
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. Confirmed ME/CFS or FM existing prior to SARS-CoV-2 infection
7. Allergy to naltrexone or medication components
8. Acute hepatitis, liver failure, or severe kidney failure.
9. Current or recent use of naltrexone in the last 30 days
10. The participant is not an ideal candidate for the study, in the opinion of the investigator, for any other reason (ie. personal or logistic, medication, condition, etc.) that could impact the participant's safety or the results of the study.

Opioid Washout Period:

Potential participants who are currently taking opioid medications who wish to enrol the study will be instructed they can stop taking opioid medications for 15 days before continuing the screening process. They will be instructed that they should speak with their family doctor before stopping any prescribed medications.

Positive Urine Test for Opioids:

As regular use of opioid medications is an exclusion criterion, we will do a quality control check with the first 16 participants to test for the presence of opioids in their urine. Any participants with a positive test, will be excluded from the study, and such finding will be discussed at the Trial Steering Committee or DSMB for potential trial modification.

Primary outcomes:
measure: Fatigue Intensity
timeFrame: 16 weeks
Secondary outcomes:
measure: Pain Severity
timeFrame: 16 weeks
measure: Symptom Severity
timeFrame: 16 weeks
measure: Activity Levels
timeFrame: 16 weeks
measure: Self-reported Quality of Life
timeFrame: 16 weeks
Other outcomes:
measure: Exploratory outcome: Changes in inflammatory marker values in peripheral blood
timeFrame: 16 weeks
measure: Exploratory outcome: Disease Severity
timeFrame: 16 weeks
measure: Exploratory outcome: Reverse triiodothyronine (rT3) profile (as an indirect marker of disease severity)
timeFrame: 16 weeks
measure: Exploratory outcome: Visual Analogue Scale (VAS) Fatigue Score
timeFrame: 16 weeks
measure: Exploratory outcome: Prevalence markers of Postural Orthostatic Tachycardia Syndrome (POTS) or Postural Hypotension
timeFrame: 16 weeks
measure: Exploratory outcome: Sleep SQ-2
timeFrame: 16 weeks
measure: Exploratory outcome: Sleep-VAS
timeFrame: 16 weeks
measure: Exploratory outcome: Depression
timeFrame: 16 weeks
measure: Exploratory outcome: Anxiety
timeFrame: 16 weeks
measure: Exploratory outcome: Self-reported Health
timeFrame: 16 weeks
measure: Exploratory outcome: Improves low AM blood cortisol
timeFrame: 16 weeks
measure: Exploratory outcome: Improves Adrenocorticotropic hormone (ACTH)
timeFrame: 16 weeks
measure: Exploratory outcome: Improves Functional Status
timeFrame: 16 weeks
measure: Clinical Endurance/ Hand Grip Strength Parameters
timeFrame: 16 weeks
measure: Clinical Endurance/ Sit and Stand Strength Parameters
timeFrame: 16 weeks
Locations:
city: Vancouver
country: Canada
facility: Women's Health Research Institute
state: British Columbia
Study officials:
affiliation: WHRI / University of British Columbia
name: Luis Nacul, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: