Trientine Tetrahydrochloride Noninferior to Penicillamine to Treat Wilson Disease

Penicillamine may not need to remain the first-line therapy for Wilson disease.

Trientine tetrahydrochloride proved noninferior to penicillamine for the maintenance treatment of patients with Wilson disease, according to findings published in the Lancet Gastroenterology and Hepatology.

Wilson disease is a rare disease of copper metabolism that requires continuous treatment to prevent toxic accumulation of copper throughout the tissues in the body.

Researchers conducted a randomized, open-label, noninferiority, phase 3, clinical trial (CHELATE) between June 4, 2018 and March 10, 2020. The trial lasted 24 weeks and was extended for another 24 weeks.

Researchers randomly assigned 53 patients with Wilson disease to 2 groups — 27 to the penicillamine group and 26 to the trientine tetrahydrochloride group.

Overall, TETA4 was safe and well tolerated as a newly initiated treatment within this open-label trial design, with no reported serious adverse events during the trial.

Tests and measures included serum nonceruloplasmin-bound copper levels, 24-hour urinary copper excretion, and alanine aminotransferase levels at baseline, 24, and 48 weeks. Clinical outcomes included the Clinical Global Impression of Change and the Unified Wilson Disease Rating Scale (neurological evaluation).

After 24 weeks, patients taking trientine tetrahydrochloride excreted less urinary copper in 24 hours than those taking penicillamine (mean difference, 237.5 µg/24 h; 99% CI, 115.6-359.4). After 48 weeks, urinary copper excretion was not significantly different between the 2 treatments and stayed within the therapeutic range in both groups (mean difference, 124.8 µg/24 h; 99% CI, -37.6 to 287.1).

Additionally, the serum nonceruloplasmin-bound copper levels of the 2 groups differed by -9.1 µg/L (95% CI, -24.2 to 6.1). After 48 weeks, trientine tetrahydrochloride again proved noninferior to penicillamine with serum nonceruloplasmin-bound copper levels differing by -15.5 µg/L (95% CI, -34.5 to 3.6).

At week 24, mean total serum copper and ceruloplasmin levels changed by 17.6 µg/L (99% CI, -9.5 to 44.7)  and 1.8 mg/L (99% CI, -19.2 to 22.8) in the penicillamine group, and -6.3 µg/L (99% CI, -34.7 to 22.1) and -2.2 mg/L (99% CI, -6.1 to 1.7) in the trientine group, respectively.

Patients in both groups demonstrated similar levels of liver enzymes at week 24, but those taking trientine tetrahydrochloride showed elevated levels of alanine aminotransferase at week 48.

The researchers did not observe any significant differences between groups on the Clinical Global Impression of Change or the Unified Wilson Disease Rating Scale.

The most serious adverse events, such as hepatocellular cancer, leukopenia, and cholangiocarcinoma, all occurred in the penicillamine group, while none occurred in the trientine group.

“The efficacy of TETA4 [trientine tetrahydrochloride] as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease,” the study authors wrote.

Study limitations include potential selection bias, relatively short-term length of follow-up, small and non-diverse sample size due to the rarity of the studied disease, affecting generalizability of the study results.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Schilsky ML, Czlonkowska A, Zuin M, et al. Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. Published online September 29, 2022. doi:10.1016/S2468-1253(22)00270-9