Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001042639
Ethics application status
Approved
Date submitted
31/08/2023
Date registered
26/09/2023
Date last updated
21/06/2024
Date data sharing statement initially provided
26/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Low Dose Naltrexone for the treatment of long COVID-19
Scientific title
Efficacy of Low Dose Naltrexone for the treatment of symptoms of Post COVID-19 Condition
Secondary ID [1] 310510 0
Nil known
Universal Trial Number (UTN)
Trial acronym
NALCOVID Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
long COVID 331314 0
Post COVID-19 Condition 331315 0
Post-acute sequelae of COVID-19 331316 0
Condition category
Condition code
Infection 328071 328071 0 0
Other infectious diseases
Respiratory 328149 328149 0 0
Other respiratory disorders / diseases
Inflammatory and Immune System 328150 328150 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Active agent: Naltrexone Hydrochloride at low doses (low dose naltrexone [LDN], 3-6mg/day).
Ingredients: Cellulose and Hypromellose
Description: white to off-white capsules.
Storage: Store medicine in a cool dry place where the temperature will stay below 25oC.
Administration: Orally, once per day preferably at night for 12 weeks.
Doses: dose escalation will commence from week 1 for approximately 3 to 4 weeks. All participants will start at 1.5mg/day and will increase their dose by 1.5mg/day until their maximum dose is reached (target 4-6mg/day). Maximum dose will be monitored by study clinicians as the maximum tolerated dose. LDN at differing doses will be distributed using different coloured labels/lids.
Protocol compliance: investigational product will be return at the end of the study for pill counts, in addition to online questionnaire (diary).
Intervention code [1] 326904 0
Treatment: Drugs
Comparator / control treatment
Placebo (Gelatin capsules)
Description: white to off-white capsules.
Storage: Store medicine in a cool dry place where the temperature will stay below 25oC.
Administration: Orally, once per day preferably at night for 12 weeks.
Protocol compliance: product will be return at the end of the study for pill counts, in addition to online questionnaire (diary).
Control group
Placebo

Outcomes
Primary outcome [1] 335938 0
DSQ Symptom Inventory Questionnaire
Determine detectable change in symptom presentation and severity.
Timepoint [1] 335938 0
Baseline, six weeks (mid-trial), and 12 weeks (primary endpoint) after intervention commencement.
Secondary outcome [1] 426198 0
36 item short form health survey
Changes in quality of life
Timepoint [1] 426198 0
Baseline, 6 weeks (mid-trial) and 12 weeks post intervention commencement.
Secondary outcome [2] 426199 0
Fibromyalgia Impact Questionnaire Revised (FIQR)
Assess body pain and impact on health.
Timepoint [2] 426199 0
Baseline, 6 weeks (mid-trial) and 12 weeks post intervention commencement.
Secondary outcome [3] 426200 0
Checklist Individual Strength (CIS)
Determine changes in the impact fatigue, concentration, motivation and activity has on health.
Timepoint [3] 426200 0
Baseline, 6 weeks (mid-trial) and 12 weeks post intervention commencement.
Secondary outcome [4] 426201 0
Clinical Global Impression
Track any changes in symptoms.
Timepoint [4] 426201 0
Measured fortnightly from baseline until week 12 (endpoint).

Eligibility
Key inclusion criteria
Participants with long COVID according to the World Health Organization working case definition (Individuals with a history of probable or confirmed SARS-CoV-2 (COVID-19) three months from COVID-19 onset with symptoms lasting at least two months).

Present with symptoms including cognitive disturbances (brain fog), sleep disturbances, and/or body pain.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i. Current respiratory infections
ii. Intercurrent SARS-CoV-2 reinfection during trial period (this will be considered drop-out)
iii. Previous clinical diagnosis of ME/CFS
iv. Chronic pain history prior to long COVID onset
v. Adverse reaction to LDN or compounded constituents
vi. Chronic opioid or substitution therapy
vii. Daily opioid use in three months prior to, or during trial
viii. Substance abuse, dependence, addiction
ix. History of drug, alcohol abuse and recreational drugs
x. Pregnancy or breastfeeding
xi. Renal dysfunction (eGFR greater than 30 ml/min/1.73m2), liver dysfunction (ALT or AST greater than 300 IU/L).
xii. Active cancer.
xiii. Inflammatory (rheumatological, GIT, dermatological) or neurological condition (demyelinating).
xiv. Neuroimmune modulators: DMARDs, steroids, minocycline, metformin.
xv. History of anxiety, depression and/or other psychiatric concerns.
xvi. Language, cognition, no computer literacy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be completed off-site at Griffith University Randomisation Unit and communicated via an online portal.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using computer software (Griffith University Randomisation Unit)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Efficacy
Statistical methods / analysis
Preliminary data collected by the NCNED on retrospective improvement of LDN in a cohort of ME/CFS patients, with overlapping clinical presentation as Long COVID, has demonstrated at improvement in 83% of participants. At baseline, severity scores of cognitive disturbances were 70.83% ± 18.82% (based on a 0-100 scale, 100 being more severe), following LDN treatment, severity scores were 45.83% ± 18.82%. In this study, a minimal clinical difference was defined as a reduction in severity by 25%, corresponding to a reduction of 1.0 reduction in severity on a Likert scale. Further, effect size using Cohen’s d and Hedges’ g was calculated at 1.389. Using a reduction of 25%, SD of 18.82%, a statistical power of at least 80%, and a statistical significance level of 0.05, a total of 20 participants are required, i.e., 10 in each group (placebo and treatment). Taking into consideration a 10% drop out rate, a total of 22 participants will be recruited at minimum. Cohen’s d of 0.8 predicts 2 groups of 26 (n=52) for 80% power and p=0.05, therefore, sample size can be further increased to n=56 in total to avoid variability in patients and further drop out.

Primary analysis will be calculation of between group differences in the continuous outcomes such as change scores for primary and key secondary outcomes using Repeated-Measures Analysis of Covariance (ANCOVA) procedures based on linear mixed model, which is valid under the assumption that missing data is missing at random. In an ANCOVA any potential between group differences at baseline will be adjusted for subsequently in the statistical analysis by adjusting for the level at baseline. Secondarily an analysis of number of responders in the two groups will be carried out. A responder is defined as a participant who reports a more than 15%, 30%, and 50% decrease in symptom severity after 12 weeks of treatment with LDN. For these dichotomous outcomes logistic regression will be used to calculate relative differences between the two groups. The prespecified efficacy analyses will be based on the data for full analysis set; the intention-to-treat (ITT) population, which includes all participants that are assessed and randomized at baseline. In the case of missing data during the 12 week trial, repeated measure linear mixed models will adjust for that indirectly. In order to confirm the robustness of the findings for the primary and key secondary outcomes, sensitivity analyses will be performed to the primary analyses, including the (i) ‘As Observed’ population (assuming data were missing completely at random), (ii) non-responder imputation (using baseline observation carried; potentially valuable if data is not missing at random), and (iii) the ‘Per Protocol’ population. Per protocol population will be defined as: Participants with an adherence to the treatment of at least 80%.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/10/2023
Actual
1/04/2024
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
1/04/2025
Actual
Sample size
Target
56
Accrual to date
14
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 314714 0
Charities/Societies/Foundations
Name [1] 314714 0
Mineral Resources Pty Ltd
Country [1] 314714 0
Australia
Primary sponsor type
University
Name
Griffith University
Address
170 Kessels Road, Nathan, QLD, 4111
Country
Australia
Secondary sponsor category [1] 316685 0
None
Name [1] 316685 0
Address [1] 316685 0
Country [1] 316685 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313724 0
Griffith University Human Research Ethics Committee
Ethics committee address [1] 313724 0
Griffith University170 Kessels Road, Nathan, QLD, 4111
Ethics committee country [1] 313724 0
Australia
Date submitted for ethics approval [1] 313724 0
20/01/2023
Approval date [1] 313724 0
13/03/2023
Ethics approval number [1] 313724 0
2023/086

Summary
Brief summary
Naltrexone (NTX) is an opioid receptor antagonist commonly used to treat opioid withdrawal at a dose of 50.0-100.0 mg daily. Low dose NTX (LDN), within a specific dosage window of 1-5 mg/day as been used off-label since the mid-1980s due to improvements in chronic pain, stamina, cognition, fatigue, and inflammation for many autoimmune disorders, chronic pain syndromes, malignancies, and mental health disorders to target symptoms overlapping with long COVID. There is evidence to suggest the use of LDN will be beneficial to treat patient outcomes for those with Long COVID.
A randomised dose ranging double blind placebo controlled 12-week clinical trial is proposed to determine the efficacy of LDN based on clinical symptoms and quality of life.
Primary and secondary outcomes will be assessed through a series of online questionnaires to determine changes in symptom presentation (primary outcome) and through a series of validated patient reported outcome measures for quality of life.
Trial website
Trial related presentations / publications
Public notes
Li Z, You Y, Griffin N, Feng J, Shan F. Low-dose naltrexone (LDN): A promising treatment in immune-related diseases and cancer therapy. Int Immunopharmacol 2018;61:178–84. https://doi.org/10.1016/j.intimp.2018.05.020

Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol 2014;33:451–9. https://doi.org/10.1007/s10067-014-2517-2.

Sasso EM, Muraki K, Eaton-Fitch N, Smith P, Lesslar OL, Deed G, et al. Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients. Mol Med 2022;28:98. https://doi.org/10.1186/s10020-022-00528-y.

Cabanas H, Muraki K, Staines D, Marshall-Gradisnik S. Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Front Immunol 2019;10. https://doi.org/10.3389/fimmu.2019.02545.

Cote B, Ross B, Fortner J, Rao D. The Use and Utility of Low-dose Naltrexone Capsules for Patients with Fibromyalgia. Int J Pharm Compd 2018;22:252–6

Contacts
Principal investigator
Name 129146 0
Prof Sonya Marshall-Gradisnik
Address 129146 0
Griffith University, Ian O'Connor Building, Health Drive, Southport, QLD, 4222
Country 129146 0
Australia
Phone 129146 0
+61 7 56780725
Fax 129146 0
Email 129146 0
s.marshall-gradisnik@griffith.edu.au
Contact person for public queries
Name 129147 0
Ms Tania Manning
Address 129147 0
Griffith University, Ian O'Connor Building, Health Drive, Southport, QLD, 4222
Country 129147 0
Australia
Phone 129147 0
+61 7 56789283
Fax 129147 0
Email 129147 0
ncned@griffith.edu.au
Contact person for scientific queries
Name 129148 0
Dr Natalie Eaton-Fitch
Address 129148 0
Griffith University, Ian O'Connor Building, Health Drive, Southport, QLD, 4222
Country 129148 0
Australia
Phone 129148 0
+61 7 56789282
Fax 129148 0
Email 129148 0
n.eaton-fitch@griffith.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.