Efavirenz for the Treatment of Creutzfeldt-Jakob Disease (NCT07482085)

Key facts

• Sponsor is Xuanwu Hospital, Beijing; the listed principal investigator is Liyong Wu and the central contact is Zhongyun Chen.
• Design: phase 3, 1:1 randomisation, parallel groups, participant and investigator masked, with a data monitoring committee; 246 participants planned.
• Eligibility: age 18 to 80, probable sporadic CJD by WHO criteria or genetically confirmed hereditary CJD, MRC Prion Disease Rating Scale score above 10, and a caregiver able to provide information.
• Dosing: efavirenz 200 mg at bedtime for the first week, then 400 mg at bedtime, against matching placebo tablets, until death or study end.
• Primary endpoint is median survival, counted in days from randomisation to death, followed for up to 36 months. Secondary endpoints are time to loss of independent feeding, loss of bowel and bladder control, akinetic mutism, and change in MRC-PDRS and Barthel scores.
• Exclusions include severe cardiac disease with QTc prolongation history, advanced liver or kidney disease, malignancy, pregnancy and drugs that cannot be combined with efavirenz.
• Record inconsistencies: summary mentions 21 centres but one site is listed; the placebo arm text partly repeats the active drug description. The registry shows no results posted.
• Preclinical basis: low-dose efavirenz in drinking water (about 0.09 mg/kg/day, far below the HIV dose) lengthened survival in mice expressing human PrP and infected with sporadic CJD prions by a mean of 17 to 23 days, even when started at 130 days after infection.
• Earlier mouse work with RML prions found 11 to 19 days longer survival, and reduced Cyp46A1 in terminal infected mouse brain and in sporadic CJD patient brain tissue.
• Proposed mechanism: efavirenz allosterically activates CYP46A1, the brain enzyme that turns cholesterol into 24S-hydroxycholesterol; treated mice showed more of the enzyme and product and less activated SREBF2 and cholesterol. The causal link to survival is inferred, not tested.
• Doses in the trial (400 mg) are far above the mouse-equivalent doses, so the preclinical dose-response does not transfer directly. This is an observation from comparing the two sources, not a claim in either.
• No human pilot or case series of efavirenz in prion disease, and no link of this work to Mallucci's group, was found in search; the efavirenz work comes from Gilch and Schatzl in Calgary.

Timeline

1. 2021Calgary group reports efavirenz extends survival of RML-infected mice and implicates Cyp46A1.
2. 2025JCI Insight paper reports survival benefit in a human-prion mouse model.
3. 2026Trial first submitted (6 March) and posted (19 March) on ClinicalTrials.gov.
4. 2026Trial start recorded as 14 April 2026 (actual).
5. 2026Last registry update posted 3 September 2026.
6. 2028Primary and study completion estimated.