Low-dose Naltrexone for Post-COVID Fatigue Syndrome
Study Details
Study Description
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) in the past 3-6 months. 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 the Post-COVID Recovery Clinics (PCRC) in British Columbia and will demonstrate whether LDN could benefit a large number of people with PCFS.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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
- 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Low-Dose Naltrexone The Low-Dose Naltrexone (LDN) will be provided as a compounded capsule starting at a strength of 1mg/day of naltrexone and increasing up to a maximum of 4.5 mg/day. The compounding pharmacy will compound the needed doses in Capsugel® empty gelatin based capsules using Naltrexone Hydrochloride Tablets and CELLULOSE. |
Drug: Low-Dose Naltrexone
Study drug dosing schedule (LDN):
Week 1: 1 mg/day (1 mg cap)
Week 2: 2 mg/day (two 1 mg caps)
Week 3: 3 mg/day (three 1mg caps)
Weeks 4-6: 4.5 mg/day (three 1 mg caps, plus one 1.5 mg cap = 4.5 mg/day)
Weeks 7-16: 4.5 mg/day (one 4.5 mg cap) OR based on self-titration dosage (one 1mg, 2mg, or 3mg cap)
|
| Placebo Comparator: Placebo Matching placebo capsule will be created by compounding pharmacy to look exactly like the LDN doses. The compounding pharmacy will compound the placebo in Capsugel® empty gelatin based capsules using CELLULOSE. |
Other: Placebo
Study drug dosing schedule (Placebo; capsules made to match LDN doses):
Week 1: 1 mg/day (1 mg cap)
Week 2: 2 mg/day (two 1 mg caps)
Week 3: 3 mg/day (three 1mg caps)
Weeks 4-6: 4.5 mg/day (three 1 mg caps, plus one 1.5 mg cap = 4.5 mg/day)
Weeks 7-16: 4.5 mg/day (one 4.5 mg cap) OR based on self-titration dosage (one 1mg, 2mg, or 3mg cap)
|
Outcome Measures
Primary Outcome Measures
- Fatigue Intensity [12 weeks and 16 weeks]
Change in the Fatigue Severity Scale (FSS) total score by 4.7 points or over
Secondary Outcome Measures
- Pain Severity [12 weeks and 16 weeks]
Change in Pain Visual Analogue Scale (VAS) 0-10 score
- Symptom Severity [12 weeks and 16 weeks]
Change in Patient Phenotyping Questionnaire Short Form (PQSymp-12) score
- Clinical Endurance/ Strength Parameters [12 weeks]
Changes in 1) average number of steps over 7 days; 2) maximum hand grip strength over 3 attempts; 3) sit and stand test in 30 seconds
- Self-reported Quality of Life. [12 weeks]
Change in EuroQol-5 Dimension (EQ-5D) total score
Other Outcome Measures
- Exploratory outcome: Changes in inflammatory marker values in peripheral blood [12 weeks]
Changes in Interleukin 6 (IL-6), Interferon gamma (IFNγ), C-reactive protein (hsCRP), & cytokine profile (Human High Sensitivity T-Cell 14-plex Discovery Assay® Array) values
- Exploratory outcome: Disease Severity [12 weeks]
Change in Creatine kinase (CK) plasma concentration
- Exploratory outcome: Reverse triiodothyronine (rT3) profile (as an indirect marker of disease severity) [12 weeks]
Change in concentration of Reverse triiodothyronine (rT3) (in conjunction Thyroid stimulating hormone (TSH), Free Triiodothyronine (free T3) & Free Thyroxine (free T4))
- Exploratory outcome: Visual Analogue Scale (VAS) Fatigue Score [12 weeks and 16 weeks]
Change in the fatigue Visual Analogue Scale (VAS) 0-10 score
- Exploratory outcome: Prevalence markers of Postural Orthostatic Tachycardia Syndrome (POTS) or Postural Hypotension [12 weeks]
Change in the prevalence of POTS or postural hypotension symptoms based on serial blood pressure and heart rate measurement
- Exploratory outcome: Sleep [12 weeks and 16 weeks]
Changes in the Sleep Questionnaire (SQ-2)
- Exploratory outcome: Depression [12 weeks and 16 weeks]
Changes in the Patient Health Questionnaire-2 (PHQ-2) Score
- Exploratory outcome: Anxiety [12 weeks and 16 weeks]
Changes in the Generalized Anxiety Disorder-2 (GAD-2) Score
- Exploratory outcome: Self-reported Health [12 weeks and 16 weeks]
Changes in the self-reported Visual Analogue Scale (VAS) health scale
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male and female patients ages 19 to less than 70 years
-
Case of SARS-CoV-2, between 3 and 6 months previously, accepted by the PCRC based on positive test result or clinical confirmation by a physician
-
Meet the clinical diagnostic criteria for PCFS
-
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)
-
Agree to use effective contraception for the trial duration, as appropriate, if female.
Exclusion Criteria:
-
Pregnant, planning to become pregnant, or breastfeeding
-
Any use of opioid medications:
-
Within last 15 days, as reported by the patient (or recorded in clinical system used by PCRC clinician)
-
During the trial
-
A positive urine test for opioids (only for the first 16 participants; see below)
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History of alcohol, opioid or other substance misuse
-
Participation in another interventional clinical trial in the last 30 days or planned during the trial period
-
Confirmed ME/CFS or FM existing prior to SARS-CoV-2 infection
-
Allergy to naltrexone or medication components
-
Acute hepatitis or liver failure
-
Current or recent use of naltrexone in the last 30 days
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | BC Women's Hospital + Health Centre | Vancouver | British Columbia | Canada | V6H 3N1 |
Sponsors and Collaborators
- Luis Nacul
- BC Women's Hospital & Health Centre
- University of British Columbia
- Canadian Institutes of Health Research (CIHR)
- Provincial Health Services Authority
- Providence Health & Services
- Vancouver Coastal Health
- Fraser Health
Investigators
- Principal Investigator: Luis Nacul, MD, PhD, BC Women's Hospital + Health Centre/ University of British Columbia
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- H21-02254