Table 1

Summary of study objectives and associated outcomes

Primary objective	Primary outcome
To determine if LDN, administered at 1–4.5 mg/day to individuals with PCFS, reduces fatigue severity.	FSS score at 16 weeks.

Secondary objectives		Secondary outcomes
To determine if LDN, administered at 1–4.5 mg/day to individuals with PCFS:	Reduces pain.	Pain VAS score at 16 weeks.
	Improves severity of symptoms associated with PCFS.	PQSymp-12 score at 16 weeks.
	Increases activity levels.	Average number of steps over 7 days at 16 weeks.
	Improves self-reported quality of life.	EQ-5D-5L health utility score at 16 weeks.

Exploratory objectives		Exploratory outcomes
To determine if LDN, administered at 1–4.5 mg/day to individuals with PCFS:	Reduces inflammatory marker values in peripheral blood.	IL-6, IFNγ and CRP values at 16 weeks. Cytokine profile values using Human Cytokine Proinflammatory Focused 15-plex Discovery Assay Array at 16 weeks.
	Improves disease severity associated with PCFS.124	CK level at 16 weeks.
	Improves rT3 as an indirect marker of disease severity.125	rT3 in conjunction with TSH, free T3 and free T4 at 16 weeks.
	Improves AM blood cortisol and improves ACTH.	AM blood cortisol level at 16 weeks. ACTH level at 16 weeks.
	Reduces fatigue VAS score.	Fatigue VAS score at 16 weeks.
	Improves sleep.	SQ-2 at 16 weeks. Sleep VAS score at 16 weeks.
	Improves depression symptoms.	PHQ-9 score at 16 weeks.
	Improves anxiety symptoms.	GAD-7 score at 16 weeks.
	Improves self-reported health.	Self-reported health VAS score at 16 weeks.
	Improves functional status.	Post-COVID-19 Functional Status Scale at 16 weeks.
	Reduces prevalence markers of POTS or postural hypotension.*	Prevalence of POTS or postural hypotension symptoms based on serial blood pressure and heart rate measurements at 16 weeks.
	Improves clinical endurance/strength parameters in subjects with PCFS.*	Hand grip strength at 16 weeks.126 Sit and stand test results at 16 weeks.

*Optional in-person visits.
ACTH, adrenocorticotropic hormone; CK, creatine kinase; CRP, C reactive protein; EQ-5D-5L, EuroQol 5 Dimension 5-level; FSS, Fatigue Severity Scale; GAD-7, General Anxiety Disorder-7; IFN, interferon; IL-6, interleukin-6; LDN, low-dose naltrexone; PCFS, post-COVID fatigue syndrome; PHQ-9, Patient Health Questionnaire-9; POTS, postural orthostatic tachycardia syndrome; PQSymp-12, Patient Phenotyping Questionnaire Short Form-12; rT3, reverse triiodothyronine; SQ-2, Sleep Questionnaire-2; T3, triiodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone; VAS, Visual Analogue Scale.