Post-acute COVID-19 SyndromePhase 3NCT07916259
The Study of Brave-LC LDN Treatment Trial
A Phase 3 study testing naltrexone in people with Post-acute COVID-19 Syndrome, run by National Institute of Allergy and Infectious Diseases (NIAID) at 13 sites in United States.
Trial summary
This is a randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy and safety of a 16-week course of low-dose naltrexone (LDN) in approximately 1,300 participants aged 6 to 25 years with fatigue associated with Long COVID. Read more about this study
- Who is it for?
- Ages 6 to 25 years
- Conditions the study is for
- Post-acute COVID-19 Syndrome
- What is being tested?
- naltrexone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,300 participants
- Where
- 13 sitesUnited States
- Study dates
- 16 Nov 2026to 1 Jan 2029
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 25 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
- Known allergy/sensitivity/hypersensitivity to naltrexone or its components.
- 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.
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- 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.
- 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).
- 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 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.
- 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.
Trial locations and contacts
13 sites in 1 country. Contact the study team or a site near you to ask about taking part.
13 sites in 1 country
United States13 sites
Kennedy Krieger Institute
Baltimore, Maryland, 21205
Children's of Alabama Child Health Research Unit (CHRU)
Birmingham, Alabama, 35233-0011
Brigham and Women's Hospital
Boston, Massachusetts, 02115-6110
NYU Langone Hospital - Brooklyn
Brooklyn, New York, 11220
Rush University Medical Center
Chicago, Illinois, 60612
Exalt Clinical Research Inc.
Chula Vista, California, 91910
Denver Health
Denver, Colorado, 80204-4506
University of Florida Health
Gainesville, Florida, 32610
Baylor College of Medicine
Houston, Texas, 77030
Dartmouth Health
Lebanon, New Hampshire, 03756-1000
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey, 08901-1935
Columbia University
New York, New York, 10032
University of Massachusetts Chan Medical School
Worcester, Massachusetts, 01655
About this study
Official title: Brave-LC: A Phase 3 Randomized Double-blind, Placebo-controlled Trial to Evaluate the Efficacy of a 16-week Course of Low-dose Naltrexone to Reduce Fatigue Severity in Persons Aged 6 Through 25 Years With Long COVID
This is a randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy and safety of a 16-week course of low-dose naltrexone (LDN) in approximately 1,300 participants aged 6 to 25 years with fatigue associated with Long COVID. Participants will be enrolled across three age cohorts (6-11, 12-17, and 18-25 years) and randomized 1:1 to receive LDN capsules or matching placebo capsules. LDN will be initiated at 1.5 mg daily and titrated weekly to a maximum tolerated dose of up to 4.5 mg daily. Randomization will be stratified by age cohort, and participants will also be randomized to a pharmacokinetic (PK) sampling window. Primary objective is to compare the change in fatigue severity from baseline to 16 weeks between participants aged 6 to 25 years with Long COVID randomized to a 16-week course of LDN or placebo.
Read the detailed description
This is a randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy and safety of a 16-week course of low-dose naltrexone (LDN) in approximately 1,300 participants aged 6 to 25 years with fatigue associated with Long COVID. Participants will be enrolled across three age cohorts (6-11, 12-17, and 18-25 years) and randomized 1:1 to receive LDN capsules or matching placebo capsules. LDN will be initiated at 1.5 mg daily and titrated weekly to a maximum tolerated dose of up to 4.5 mg daily. Randomization will be stratified by age cohort, and participants will also be randomized to a pharmacokinetic (PK) sampling window. Primary objective is to compare the change in fatigue severity from baseline to 16 weeks between participants aged 6 to 25 years with Long COVID randomized to a 16-week course of LDN or placebo. Secondary objectives: To compare the change in fatigue severity from baseline to 16 weeks between participants with Long COVID in age groups: 6 to 11 years, 12 to 17 years and 18-25 years. Each participant will be randomized to a 16-week course of LDN or placebo.
- Conditions
- Post-acute COVID-19 Syndrome
- Being tested
- naltrexone, Placebo
- Keywords
- Brave-LC, Fatigue Severity, Long Covid, Low-Dose Naltrexone (LDN), Naltrexone, RECOVER-TLC
- Medical subject headings
- Post-Acute COVID-19 Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
naltrexoneDrug
Opioid receptor antagonist used to treat opioid and alcohol use disorders in adults. Formulated as naltrexone hydrochloride, a white, crystalline compound freely soluble in water.
PlaceboOther
Matching placebo capsule that is visually identical to the active study product and is administered orally once daily according to the same dosing schedule and titration scheme for 16 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Low-Dose Naltrexone | Experimental | Participants will receive a low-dose naltrexone (LDN) capsule that will be administered orally once daily for 16 weeks. LDN will be initiated at 1.5 mg daily and titrated weekly to a maximum tolerated dose of up to 4.5 mg daily. N=650 Receives: Drug: naltrexone |
| Placebo | Placebo comparator | Participants will receive a matching placebo capsule that will be administered orally once daily for 16 weeks. The placebo arm will follow the same dosing schedule and titration scheme as the LDN arm. N=650 Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) total score.
The Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) contains 18 Likert-type items and is scored from 0 to 100; higher scores represent lower levels of fatigue.
Measured: Baseline to 16 weeks after randomization
Secondary outcomes (32)
Change from baseline Delis-Kaplan Executive Function System (D-KEFS) Category Fluency t-score
The D-KEFS Verbal Fluency Category Fluency condition measures verbal fluency and executive function.
Participants generate as many words as possible beginning with a specified letter within a fixed time.
Performance score is scored by the number of correct words and interpreted using age-appropriate normative data.
This outcome applies to English-speaking participants aged 8 to 25 years.
Measured: Baseline to 16 weeks after randomization
Change from baseline Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency t-score
The D-KEFS Verbal Fluency Letter Fluency condition measures verbal fluency and executive function.
Participants generate as many words as possible beginning with a specified letter within a fixed time.
Performance score is scored by the number of correct words and interpreted using age-appropriate normative data.
This outcome applies to English-speaking participants aged 8 to 25 years.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Behavior Rating Inventory of Executive Function-Second Edition (BRIEF-2) Global Executive Composite t-score
The BRIEF-2 is a standardized questionnaire assessing executive function and self-regulation in participants aged 6 to 17 years.
Scores are interpreted using age- and sex-appropriate normative data. Higher scores indicate greater impairment in executive functioning.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Behavior Rating Inventory of Executive Function-Second Edition (BRIEF-2A) Global Executive Composite t-score
The BRIEF-2A is a standardized 75-item self-report assessment of executive functioning in participants aged 18 years and older.
Scores are interpreted using age- and sex-appropriate normative data. Higher scores indicate greater impairment in executive functioning.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Conners Continuous Performance Test-Third Edition (CPT-3) Detectability t-score.
The CPT-3 is a computerized assessment of sustained attention and response control for participants aged 8 years and older.
Performance is automatically recorded and interpreted using age-appropriate normative data.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Conners Continuous Performance Test-Third Edition (CPT-3) Hit Reaction Time t-score
The CPT-3 is a computerized assessment of sustained attention and response control for participants aged 8 years and older.
Performance is automatically recorded and interpreted using age-appropriate normative data.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Connors Kiddie Continuous Performance Test (K-CPT-2) Detectability t-score.
The K-CPT-2 Computerized assessment of sustained attention and response control for participants aged 6 to 7 years. Performance is automatically recorded and interpreted using age-appropriate normative data.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Connors Kiddie Continuous Performance Test (K-CPT-2) Hit Reaction Time t-score
The K-CPT-2 Computerized assessment of sustained attention and response control for participants aged 6 to 7 years. Performance is automatically recorded and interpreted using age-appropriate normative data.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Developmental Neuropsychological Assessment (NEPSY-II) Semantic Word Generation Scaled score.
The NEPSY-II Word Generation subtest measures verbal fluency and executive function. Participants generate words within semantic category during 60-second time limit.
Performance is scored by the number of correct words[TS3.1] and interpreted using age-appropriate normative data.
This outcome applies to English-speaking participants aged 6 to 7 years.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Digit Span-Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V) t-score.
The WISC-V Digit Span subtest assesses attention and working memory in participants aged 6 to 15 years.
Raw scores are based on Digit Span Forward, Backward, and Sequencing tasks and are interpreted using age-appropriate normative data.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Digit Span-Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) t-score.
The WISC-IV Digit Span subtest assesses attention and working memory in participants aged 16 years and older.
Raw scores are based on Digit Span Forward, Backward, and Sequencing tasks and are interpreted using age-appropriate normative data.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Functional Disability Inventory (FDI) total score.
The Functional Disability Inventory (FDI) contains 15 items rated from 0 ('no trouble') to 4 ('impossible').
Total scores range from 0 to 60. Higher scores represent greater functional disability and more impairment in daily functioning.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Patient Global Impression of Severity (PGI-S)
The Patient Global Impression of Severity (PGI-S) is a single-item questionnaire rated on a 5-point Likert scale from 1 ('None') to 5 ('Very severe').
Higher scores reflect greater perceived illness or symptom severity.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Adult Pain Intensity Scale t-score in participants aged 18 to 25 years.
The Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity Scale asks about pain over the past 7 days.
Items are rated on a 5-point scale from 1 ('not at all') to 5 ('very much'). Results are reported as T-scores. Higher scores representing greater pain intensity.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Adult Pain Interference Scale t-score in participants aged 18 to 25 years.
The Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity Scale asks how pain affects activities, mood, and social participation over the past 7 days.
Items are rated on a 5-point scale from 1 ('not at all') to 5 ('very much'). Results are reported as T-scores. Higher scores representing greater pain interference.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Parent-Proxy Pain Intensity Scale t-score in participants aged 6 to 7 years.
The Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity scale asks about pain over the past 7 days.
Items are rated on a 5-point scale from 1 ('not at all') to 5 ('very much'). Results are reported as T-scores, with higher scores representing greater pain intensity.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Parent-Proxy Pain Interference Scale t-score in participants aged 6 to 7 years.
The Patient-Reported Outcomes Measurement Information System (PROMIS) Parent-Proxy Pain Interference Scale asks how pain affects activities, mood, and social participation over the past 7 days.
Items are rated on a 5-point scale from 1('not at all') to 5('very much'). Results are reported as T-scores. Higher scores representing greater pain interference.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Intensity Scale t-score in participants aged 8 to 17 years.
The Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Intensity Scale asks about pain over the past 7 days.
Items are rated on a 5-point scale from 1 ('not at all') to 5 ('very much'). Results are reported as T-scores. Higher scores representing greater pain intensity.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Interference Scale t-score in participants aged 8 to 17 years.
The Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Interference scale asks how pain affects activities, mood, and social participation over the past 7 days.
Items are rated on a 5-point scale from 1 ('not at all') to 5 ('very much'). Results are reported as T-scores. Higher scores representing greater pain interference.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Pediatric Quality of Life (PedsQL) Generic Core Scales Short Form 15 total score.
The PedsQL Generic Core Scales Short Form 15 contains 15 Likert-type items across physical, emotional, social, and school functioning and is scored from 0 to 100.
Higher scores represent better quality of life.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) subscale scores.
The Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) contains 18 Likert-type items and includes general fatigue, sleep/rest fatigue, and cognitive fatigue subscales. Scores are reported on a 0 to 100 scale.
Higher scores represent lower levels of fatigue.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) total score in participants aged 12 to 17 years.
The Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) contains 18 Likert-type items and is scored from 0 to 100; higher scores represent lower levels of fatigue.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) total score in participants aged 18 to 25 years.
The Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) contains 18 Likert-type items and is scored from 0 to 100; higher scores represent lower levels of fatigue.
Measured: Baseline to 16 weeks after randomization
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) total score in participants aged 6 to 11 years.
The Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) contains 18 Likert-type items and is scored from 0 to 100; higher scores represent lower levels of fatigue.
Measured: Baseline to 16 weeks after randomization
Change in Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL-MFS) total score from 16 to 26 weeks after randomization.
The Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL-MFS) contains 18 Likert-type items and is scored from 0 to 100.
Higher scores represent lower levels of fatigue.
Measured: 16 to 26 weeks after randomization
Incidence of new infections.
New infections will be summarized by frequency, percentage, and incidence rate. Severity and relatedness will also be summarized as applicable.
Measured: First administration of study product through 6 months after randomization
Incidence of new-onset chronic medical conditions (NOCMCs).
NOCMCs will be assessed by number, severity, and relatedness and summarized by frequency, percentage, and incidence rate.
Measured: First administration of study product through 6 months after randomization
Incidence of solicited adverse events (AEs).
Solicited AEs will be assessed by number, severity, and relatedness according to the DAIDS table for Grading the Severity of Adult and Pediatric Adverse Event, version 2.1.
Measured: First administration of study product through 8 weeks after randomization
Incidence of treatment emergent serious adverse events (SAEs).
Treatment-emergent SAEs will be assessed by number, severity, and relatedness and summarized by frequency, percentage, and incidence rate.
Measured: First administration of study product through 6 months after randomization
Incidence of treatment emergent unsolicited adverse events (AEs).
Treatment-emergent unsolicited AEs will be assessed by number, severity, and relatedness according to the DAIDS table for Grading the Severity of Adult and Pediatric Adverse Event, version 2.1.
Measured: First administration of study product through 16 weeks after randomization
Incidence of treatment-emergent medically attended adverse events (MAAEs).
Treatment-emergent MAAEs will be assessed by number, severity, and relatedness and summarized by frequency, percentage, and incidence rate.
Measured: First administration of study product through 6 months after randomization
Patient Global Impression of Change (PGI-C) at 16 weeks after randomization
The PGI-C is a 7-point self-report scale ranging from 'very much improved'[TS4.1] to 'very much worse'[TS5.1] and measures overall improvement from treatment.
Measured: 16 weeks after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 2026
- Study start16 Nov 2026 (estimated)
- Primary completion31 Dec 2028 (estimated)
- Study completion1 Jan 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Post-acute COVID-19 SyndromeStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 1,300 participants (estimated)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Laura Malone, MD PhD, Principal investigator, Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07916259
- Sponsor's protocol ID
- 25-0018
- Other IDs
- 1OT2HL156812
- Status last verified
- 28 Oct 2026
- First submitted
- 29 Oct 2026
- Last updated
- 4 Nov 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Brave-LC: A Phase 3 Randomized Double-blind, Placebo-controlled Trial to Evaluate the Efficacy of a 16-week Course of Low-dose Naltrexone to Reduce Fatigue Severity in Persons Aged 6 Through 25 Years With Long COVID
- ClinicalTrials.gov ID
- NCT07916259
- Acronym / sponsor ID
- 25-0018
- Conditions
- Post-acute COVID-19 Syndrome
- Keywords
- Brave-LC, Fatigue Severity, Long Covid, Low-Dose Naltrexone (LDN), Naltrexone, RECOVER-TLC
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 1,300 participants (estimated)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- 16 Nov 2026 (estimated)
- Primary completion
- 31 Dec 2028 (estimated)
- Study completion
- 1 Jan 2029 (estimated)
- First posted
- 4 Nov 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy and safety of a 16-week course of low-dose naltrexone (LDN) in approximately 1,300 participants aged 6 to 25 years with fatigue associated with Long COVID. Participants will be enrolled across three age cohorts (6-11, 12-17, and 18-25 years) and randomized 1:1 to receive LDN capsules or matching placebo capsules. LDN will be initiated at 1.5 mg daily and titrated weekly to a maximum tolerated dose of up to 4.5 mg daily. Randomization will be stratified by age cohort, and participants will also be randomized to a pharmacokinetic (PK) sampling window. Primary objective is to compare the change in fatigue severity from baseline to 16 weeks between participants aged 6 to 25 years with Long COVID randomized to a 16-week course of LDN or placebo.
Detailed description
This is a randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy and safety of a 16-week course of low-dose naltrexone (LDN) in approximately 1,300 participants aged 6 to 25 years with fatigue associated with Long COVID. Participants will be enrolled across three age cohorts (6-11, 12-17, and 18-25 years) and randomized 1:1 to receive LDN capsules or matching placebo capsules. LDN will be initiated at 1.5 mg daily and titrated weekly to a maximum tolerated dose of up to 4.5 mg daily. Randomization will be stratified by age cohort, and participants will also be randomized to a pharmacokinetic (PK) sampling window. Primary objective is to compare the change in fatigue severity from baseline to 16 weeks between participants aged 6 to 25 years with Long COVID randomized to a 16-week course of LDN or placebo. Secondary objectives: To compare the change in fatigue severity from baseline to 16 weeks between participants with Long COVID in age groups: 6 to 11 years, 12 to 17 years and 18-25 years. Each participant will be randomized to a 16-week course of LDN or placebo.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Low-Dose Naltrexone | Experimental | Drug: naltrexoneParticipants will receive a low-dose naltrexone (LDN) capsule that will be administered orally once daily for 16 weeks. LDN will be initiated at 1.5 mg daily and titrated weekly to a maximum tolerated dose of up to 4.5 mg daily. N=650 |
| Placebo | Placebo comparator | Other: PlaceboParticipants will receive a matching placebo capsule that will be administered orally once daily for 16 weeks. The placebo arm will follow the same dosing schedule and titration scheme as the LDN arm. N=650 |
Who may qualify
- Ages
- 6 to 25 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (25 listed)
- 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.
- 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.
Key exclusion criteria (24 listed)
- 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.
- Known allergy/sensitivity/hypersensitivity to naltrexone or its components.
- Current or recent use of naltrexone in the 14 days before randomization.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| naltrexoneOpioid receptor antagonist used to treat opioid and alcohol use disorders in adults. Formulated as naltrexone hydrochloride, a white, crystalline compound freely soluble in water. | Drug | Low-Dose Naltrexone |
| PlaceboMatching placebo capsule that is visually identical to the active study product and is administered orally once daily according to the same dosing schedule and titration scheme for 16 weeks. | Other | Placebo |
Primary outcome
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) total score.
Time frame: Baseline to 16 weeks after randomization
The Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) contains 18 Likert-type items and is scored from 0 to 100; higher scores represent lower levels of fatigue.
32 secondary outcomes
Change from baseline Delis-Kaplan Executive Function System (D-KEFS) Category Fluency t-score
Time frame: Baseline to 16 weeks after randomization
Change from baseline Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency t-score
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Behavior Rating Inventory of Executive Function-Second Edition (BRIEF-2) Global Executive Composite t-score
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Behavior Rating Inventory of Executive Function-Second Edition (BRIEF-2A) Global Executive Composite t-score
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Conners Continuous Performance Test-Third Edition (CPT-3) Detectability t-score.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Conners Continuous Performance Test-Third Edition (CPT-3) Hit Reaction Time t-score
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Connors Kiddie Continuous Performance Test (K-CPT-2) Detectability t-score.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Connors Kiddie Continuous Performance Test (K-CPT-2) Hit Reaction Time t-score
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Developmental Neuropsychological Assessment (NEPSY-II) Semantic Word Generation Scaled score.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Digit Span-Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V) t-score.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Digit Span-Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) t-score.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Functional Disability Inventory (FDI) total score.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Patient Global Impression of Severity (PGI-S)
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Adult Pain Intensity Scale t-score in participants aged 18 to 25 years.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Adult Pain Interference Scale t-score in participants aged 18 to 25 years.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Parent-Proxy Pain Intensity Scale t-score in participants aged 6 to 7 years.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Parent-Proxy Pain Interference Scale t-score in participants aged 6 to 7 years.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Intensity Scale t-score in participants aged 8 to 17 years.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Interference Scale t-score in participants aged 8 to 17 years.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Pediatric Quality of Life (PedsQL) Generic Core Scales Short Form 15 total score.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) subscale scores.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) total score in participants aged 12 to 17 years.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) total score in participants aged 18 to 25 years.
Time frame: Baseline to 16 weeks after randomization
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) total score in participants aged 6 to 11 years.
Time frame: Baseline to 16 weeks after randomization
Change in Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL-MFS) total score from 16 to 26 weeks after randomization.
Time frame: 16 to 26 weeks after randomization
Incidence of new infections.
Time frame: First administration of study product through 6 months after randomization
Incidence of new-onset chronic medical conditions (NOCMCs).
Time frame: First administration of study product through 6 months after randomization
Incidence of solicited adverse events (AEs).
Time frame: First administration of study product through 8 weeks after randomization
Incidence of treatment emergent serious adverse events (SAEs).
Time frame: First administration of study product through 6 months after randomization
Incidence of treatment emergent unsolicited adverse events (AEs).
Time frame: First administration of study product through 16 weeks after randomization
Incidence of treatment-emergent medically attended adverse events (MAAEs).
Time frame: First administration of study product through 6 months after randomization
Patient Global Impression of Change (PGI-C) at 16 weeks after randomization
Time frame: 16 weeks after randomization
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Laura Malone, MD PhD principal investigator
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
13 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing naltrexone in people with Post-acute COVID-19 Syndrome, run by National Institute of Allergy and Infectious Diseases (NIAID) at 13 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 4 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact RECOVER Central Contact (667-205-4128, RECOVERTLCHelp@mail.nih.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from baseline in Pediatric Quality of Life - Multidimensional Fatigue Scale (PedsQL-MFS) total score. (time frame: Baseline to 16 weeks after randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2026.