Off Treatment Urinary Copper Excretion in Wilson Disease, Pilot Study

Monitoring of Therapy in Wilson Disease With Off-Treatment Urinary Copper Excretion (OT-UCE): Comparison With Serum Non-Ceruloplasmin Copper (NCC) Assays

This is a prospective study that will determine the optimal timing for 24-hour urinary copper excretion (UCE) measurement after temporary discontinuation of standard therapies in Wilson Disease (WD) patients. The primary objective is to assess whether off-treatment UCE (OT-UCE) correlates with non-ceruloplasmin-bound copper (NCC) levels, aiming to validate OT-UCE as a surrogate marker for systemic copper bioavailability and disease stability. Stable WD patients will be enrolled, temporarily taken off treatment under close monitoring, and undergo UCE and NCC testing. If OT-UCE is validated, it could serve as a practical biomarker for monitoring WD treatment and stability in clinical practice and future trials.

Study Overview

• Status: Recruiting
• Conditions: Wilson Disease

Detailed Description

Study procedures will include providing multiple urine samples over a 24-hour period, storing the urine samples, and returning them during the end-of-study visit. Blood samples will be collected to measure copper levels and liver function. An in-person end-of-study visit will be attended.

Participation in this study will involve a brief stoppage of current Wilson Disease treatment.

Participants will perform 24-hour urine collections and communicate with study personnel daily during the brief time medication is not taken.

At the end-of-study visit, the investigators will collect urine samples, obtain blood samples, perform a physical exam, and review safety evaluations (communication with study personnel) made during the study.

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Sefa Keserci, MD; Phone Number: 203 737 2702; Email: sefa.keserci@yale.edu
• Study Contact Backup: Name: Hatice Maras, MD; Email: hatice.maras@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with confirmed Wilson Disease (Leipzig score ≥4), and stable disease will be screened and recruited for this pilot. This will include patients 18 years old and above as the intervention for this study is a temporary discontinuation of therapy, and this group of patients will tolerate this intervention with minimal risk.

Description

Inclusion Criteria:

• Patients with Wilson Disease as defined by Leipzig score ≥4.
• Provision of signed and dated informed consent form.
• Stated willingness to comply with all study procedures (serial 24 h urine collections and local collection of samples for NCC, liver function and estimated GFR) and availability for the duration of the study.
• Treated WD for at least 12 months prior to study entry.
• Aminotransferase values (ASAT and ALAT) < 2 times the upper limit of normal (ULN).
• INR < 1.5 or stable INR for those with initial elevated INR for at least six months prior to study entry in the absence of anticoagulation therapy.
• Renal function defined as eGFR > 30 cc/min.
• No change of WD therapy during the previous 6 months of study enrollment.

Exclusion Criteria:

• Current dual / mixed therapy for WD (i.e. zinc and d-penicillamine or trientine at the same time)
• Current Pregnancy or lactation. *
• Recent estrogen-based treatment (in the last month).
• Cirrhosis with recent hepatic decompensation (within the last 6 months) - new onset of ascites, spontaneous bacterial peritonitis, esophageal variceal bleeding, or hepatic encephalopathy
• Investigator believes the patient will be unable to do the required 24-hour urine studies and participate in the follow up visits as expected.

• Previous non-compliance for therapy and/or to low-copper diet that would compromise the evaluation of previous UCE and/ or results from the off-treatment period.

  • Childbearing aged patients recruited outside of the registry will be reviewed, and the patients will be asked to perform an initial urine pregnancy test prior to the recommended blood testing (approximately 60 to 90 days prior to intervention). They will be permitted to continue with the screening process if the result is negative. They will be asked to perform a second urine pregnancy test as close as possible prior to study intervention (discontinuation of treatment). If the result of the second pregnancy test is negative they will be permitted to continue with the protocol, but if the result is positive they will be excluded from further participation at that time.

Childbearing aged patients recruited from the registry who meet inclusion criteria and may move directly to the study intervention will be required to perform a urine pregnancy test as close as possible to the time prior to the initiation of the study protocol (discontinuation of treatment).

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
OT-UCE and NCC for Zinc treated WD patients; OT-UCE and NCC will be measured in WD patients on Zinc therapy
OT-UCE and NCC for Trientine treated WD patients; OT-UCE and NCC will be measured in WD patients on trientine therapy
OT-UCE and NCC for Penicillamine treated WD patients; OT-UCE and NCC will be measured in WD patients on Penicillamine therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean concentration of OT-UCE for each standard of care WD treatment	Urine samples will be collected daily for 4 days after stopping WD medications. The sequential evaluation of OT-UCE over a maximum of 4 days after treatment withdrawal will allow investigators to define the optimal ranges for UCE and select the best time-point for OT-UCE evaluations for WD patients on the 3 different therapies.	days 1, 2, 3 and 4 post stopping WD meds
Mean NCC concentration for each WD treatment	Measure NCC and assess the correlation between NCC and OT-UCE Urine samples will be collected daily for 4 days after stopping WD medications. The sequential evaluation of NCC over a maximum of 4 days after treatment withdrawal will allow investigators to assess the correlation between NCC and OT-UCE.	days 1, 2, 3 and 4 post stopping WD meds

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean OT-UCE Ranges for each WD med	Urine samples will be collected daily for 4 days after stopping WD medications. The sequential evaluation of OT-UCE over a maximum of 4 days after treatment withdrawal will allow investigators to define the optimal ranges for UCE for WD patients on the 3 different therapies.	days 1, 2, 3 and 4 post stopping WD meds
Assess the best timepoints for performance of OT-UCE for each drug	The day (or the minimal number of consecutive days) after treatment interruption at which 24-hour OT-UCE stabilizes (defined as a plateau with less than 10% variability between two consecutive measurements) for each drug (zinc, penicillamine, trientine). This will define the optimal timing of OT-UCE monitoring for each treatment.	days 1, 2, 3 and 4 post stopping WD meds

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Michael L Schilsky, MD FAASLD, Yale University

Publications and helpful links

General Publications

• Solovyev N, Ala A, Schilsky M, Mills C, Willis K, Harrington CF. Biomedical copper speciation in relation to Wilson's disease using strong anion exchange chromatography coupled to triple quadrupole inductively coupled plasma mass spectrometry. Anal Chim Acta. 2020 Feb 15;1098:27-36. doi: 10.1016/j.aca.2019.11.033. Epub 2019 Nov 15.
• Harrington CF, Carpenter G, Coverdale JPC, Douglas L, Mills C, Willis K, Schilsky ML. Accurate non-ceruloplasmin bound copper: a new biomarker for the assessment and monitoring of Wilson disease patients using HPLC coupled to ICP-MS/MS. Clin Chem Lab Med. 2024 Jul 30. doi: 10.1515/cclm-2024-0213. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2026
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): September 30, 2028

Study Registration Dates

• First Submitted: December 22, 2025
• First Submitted That Met QC Criteria: December 22, 2025
• First Posted (Actual): December 24, 2025

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 4, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Urine copper excretion; Non-ceruloplasmin bound copper
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Digestive System Diseases; Neurodegenerative Diseases; Liver Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Metal Metabolism, Inborn Errors; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Hepatolenticular Degeneration
• Other Study ID Numbers: 2000040776; 1R01DK137861-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No