The Study of Brave-LC LDN Treatment Trial

Prior treatment

• Known acute SARS CoV 2 infection </= 30 days before randomization.
• Current or recent opioid use in the 7 days before randomization, as reported by the participant or their parent/legal guardian.
• Plans to have elective surgery or procedure which may involve use of opioid medication during the study intervention.
• Current or recent use of naltrexone in the 14 days before randomization.
• History of use of LDN for >/= 30 days duration to treat Long COVID in the 6 months before randomization.
• Has recent active malignancy (received chemotherapy or radiotherapy in the 12 months prior to randomization) or active malignancy at randomization*.
  • Long COVID patients with non-melanoma skin carcinoma (basal cell or squamous cell skin cancer), or low-grade cervical squamous intraepithelial lesions, which are considered cured and not requiring ongoing therapy, may be enrolled at the discretion of the investigator.
• Began taking a new medication*, supplement, or vitamin or changed doses of a medication, supplement, or vitamin the 14 days prior to randomization.
  • *Topical and intranasal (non-opioid) medications are not exclusionary.
• Diagnosed in the 3 months prior to randomization with a new medical condition*, other than Long COVID, causing new or worsening fatigue that is unresolved at time of randomization.
  • *Medical conditions that could cause new or worsening fatigue include but are not limited to iron deficiency with or without severe anemia, hypothyroidism, infectious mononucleosis (Epstein-Barr Virus or cytomegalovirus infection), celiac disease, type 1 diabetes mellitus, acute leukemia or hematologic malignancy, adrenal insufficiency, cardiac disease (e.g. myocarditis, arrythmia, or cardiomyopathy), metabolic disease, renal disease, or a primary sleep disorders (e.g. obstructive sleep apnea, restless legs syndrome, narcolepsy, or parasomnia).
• Has a clinically significant mental health condition defined by history of one or more of the following:
  • History of prior suicide attempt. b. Hospitalized in the 6 months prior to randomization for mental health symptoms or worsening of a known mental health condition.
  • Has moderate-risk or high-risk score on C SSRS at Visit 01A, as applicable. d. Has a diagnosis of severe conduct disorder*that, in the site investigator's judgment, may pose a safety risk or interfere with the ability to adequately assess clinical trial endpoints.
  • *The American Psychiatric Association defines conduct disorder as a repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate societal norms or rules are violated (e.g., history of recurrent aggressive behavior toward people or animals, and/or serious violations of rules or laws like running away, possessing or using weapons, vandalism). If the site Investigator is unsure if a participant has a diagnosis of severe conduct disorder, they may refer to the DSM-5-TR criteria.

Other illness

• Known allergy/sensitivity/hypersensitivity to naltrexone or its components.
• Has known active Hepatitis B (HBV) infection, active Hepatitis C (HCV) infection, or unstable Human Immunodeficiency Virus (HIV) (i.e., not on antiretroviral therapy (ART) or on ART but has detectable viral load).
• Has any medical condition*, ** that, in the site investigator's judgment, pose a safety risk or interfere with the ability to adequately assess clinical trial endpoints.
  • Medical conditions include but are not limited to severe esophagitis or a condition that precludes participant from taking study product; an active unstable or progressive major psychiatric or neurologic condition, including severe developmental disabilities, new or untreated psychosis or schizophrenia, new or untreated bipolar I disorder; and acute opioid withdrawal disorder to include participants maintained on opiate agonists (methadone) or partial agonists (buprenorphine) and those who has failed a naloxone challenge test.
  • Of note, an abnormal vital sign alone is not exclusionary at baseline. However, the abnormal vital sign may be indicative of an exclusionary medical condition as described above.

Lab values

• Has known active acute hepatitis or a history of chronic liver disease (known Child-Pugh Class B or C) or known severe chronic kidney disease and/or kidney failure (Estimated Glomerular Filtration Rate [eGFR] < 30 ml/min/1.73 m\^2).

Other

• Enrolled at the time of consent/assent or planned enrollment in another interventional clinical trial during the trial.
• Plans to become pregnant or to father a child during the trial or is pregnant or breastfeeding at randomization.
• Has a positive pregnancy test at Visit 01A.* *All participants of childbearing potential will have a urine pregnancy test at Visit 01A, with results confirmed as negative before randomization.

• Aged 6 to 25 years, inclusive, at the time of randomization.
• Fluent in English and/or Spanish.
• History of SARS CoV 2 infection shown by (1) a positive nucleic acid amplification test (NAAT) or antigen test, OR (2) meeting clinical criteria* AND an epidemiologic link** to a confirmed case.
  • *Clinical criteria is defined as either (1) acute onset of fever AND cough; OR (2) acute altered/loss of taste or smell + one additional symptom including: fever, cough, general weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, nausea, diarrhea, or anorexia; OR (3) three or more symptoms, including fever, cough, general weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, nausea, diarrhea, or anorexia.
  • Epidemiologic link is defined as having contact (within 6 feet for at least 15 minutes) with someone sick with SARS CoV 2 test-positive COVID 19 illness.
• Clinical evidence of Long COVID* and Long COVID symptoms that cannot be attributed to another cause upon investigator review of medical history and workup participant received prior to study entry.
  • *Participants must meet the 2024 National Academies of Sciences, Engineering, and Medicine definition for Long COVID.
• Has new fatigue*, ** that began either during or in the six months following the onset of the qualifying SARS CoV 2 infection or COVID 19 illness (see inclusion Criterion #3):
  • *New fatigue symptoms can fluctuate but the total duration of fatigue must be at least 3 months at time of randomization and fatigue must be present for more days than not in the 30 days prior to randomization.
  • **For this trial, fatigue is defined as having physical fatigue and/or cognitive fatigue (e.g., has trouble with memory, focus/attention, or decision-making, or is slow to process information, and is sometimes referred to as having "brain fog"). Fatigue is a persistent state of physical and/or cognitive exhaustion that is not substantially alleviated by sleep or rest, and that interferes with normal functioning, is often profound, and is not the result of ongoing or unusual excessive exertion.
• Has at least one new or worsening symptom*, ** that began either during or in the six months following the onset of the qualifying SARS CoV 2 infection or COVID 19 illness:
  • *List of qualifying symptoms include: systemic symptoms (chills, Post-Exertional Malaise [PEM]); neurological symptoms (headache, dysautonomia/ Postural Orthostatic Tachycardia Syndrome [POTS], dizziness, unsteadiness, or neuropathy); sleep disturbance resulting in unrefreshing sleep; cardiopulmonary symptoms (chest pain, palpitations, shortness of breath, cough, fainting spells); musculoskeletal symptoms (muscle pain/aches, neck pain, back pain, joint pain); or gastrointestinal symptoms (nausea, diarrhea).
  • **While the qualifying symptom(s) may fluctuate, the total duration of at least one qualifying symptom must be at least 3 months at time of randomization. In addition, that symptom must be present for more days than not in the 30 days prior to randomization.
• Participant scores <70 on the Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL-MFS) at Visit 01A.
• Willing and able to provide informed consent and assent (as applicable) before initiation of any study procedures.
• Able to understand and agree to comply with all planned study procedures and be available for all study visits.
  • *Participants still may enroll if they decline genetic testing or if they are unable or unwilling to complete blood draw(s) for biomarkers. An initial blood draw for baseline clinical laboratory assessments is required to be completed prior to randomization.
• Participants of childbearing potential* must agree to use highly effective contraception** or practice true abstinence*** throughout the study (Visit 08).
  • *Persons of childbearing potential is defined as post-menarchal biological females who have not reached menopause or undergone surgical sterilization. Menopause is defined as having no menses for at least 12 months without an alternative medical cause for amenorrhea.
  • **Highly effective contraception includes hormonal contraception (oral, implant, injection, transdermal patch, vaginal ring), intrauterine device (IUD), bilateral tubal ligation, or partner vasectomy.
  • ***True abstinence is defined as no heterosexual vaginal/penile intercourse at any time during the study
• Participants capable of fathering a child* and having sex with women of childbearing potential must agree to use contraception (i.e., condoms) throughout the study (Visit 08).
  • *Persons capable of fathering a child are biological males who are post-pubertal and not permanently sterile by bilateral orchidectomy or vasectomy
• Agrees to utilize electronic data capture for the e-Memory Aid and electronic PROs and have access to a device connected to the internet for completion.
• Agrees to adhere to all lifestyle considerations.