Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson's Disease
Condition: Wilson Disease
MeSH terms: Hepatolenticular Degeneration
Intervention: Penicillamine (D1-W12); TETA 4HCL (W12-60); Penicillamine (W12-W60); TETA 4HCL (60-<W108)
Intervention description: Penicillamine during baseline period (D1-W12); TETA 4HCL during post randomisation and 1st extension period (W12-W60); Penicillamine during rondomisation and 1st extension period period (W12-W60); TETA 4HCL during 2nd extension period (W60-<W108)
Intervention MeSH terms: Penicillamine; Trientine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 77.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      This is a multicenter, randomized, open-label study with an active standard-of-care
      comparator (penicillamine)
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patient is able to provide, and has provided, written informed consent

          2. Written documentation has been obtained in accordance with the relevant country and
             local privacy requirements, where applicable, including: For US sites: Authorization
             for Use and Release of Health Research Study Information and for EU sites: Data
             Protection Consent

          3. Male or female, aged ≥ 18 and ≤ 75 years of age at time of consent

          4. Patient has a diagnosis of Wilson's disease, as defined by a prior or current Leipzig
             score of ≥ 4

          5. Patient's Wilson's disease is clinically stable, in the opinion of the investigator,
             and being treated with penicillamine for at least 1 year (52 weeks) prior to the
             screening/enrolment visit

          6. Patient is on a stable dose and regimen of penicillamine for at least 4 months (16
             weeks) prior to the screening/enrolment visit (other prescribed treatments for
             Wilson's disease not permitted during this study)

          7. No anticipated need that patient will require additional pharmacological therapies
             other than study medication, including prescribed zinc therapy, for the management of
             copper levels during the study

          8. Patient must be willing to maintain stable diet throughout the study, and avoid foods
             with high copper content, including the Penicillamine Baseline Period

          9. Patient considered suitable to receive therapy with both TETA 4HCl and penicillamine
             administered twice a day

         10. Negative central laboratory tests for HIV and viral hepatitis (results will be
             available after start of run-in period)

         11. For female patients of childbearing potential, negative urine pregnancy test (at
             screening/enrolment visit and prior to randomization)

         12. For females of childbearing potential, use of a reliable form of contraceptive

         13. Patient is considered as able to complete study requirements and attend the study
             visits, in the opinion of the investigator

             Additional inclusion criteria following receipt of Screening laboratory results

         14. Patient is adequately controlled and tolerating penicillamine therapy as defined by
             fulfilment of all of the following: a. Serum non-ceruloplasmin bound copper (NCC)
             level between ≥ 25 and ≤ 150 μg/L* b. 24-hour urinary copper excretion of between ≥
             100 and ≤ 900 μg/24 hours* c. Alanine transaminase (ALT) < 2 times upper limit of
             normal* d. No other laboratory or clinical findings that would prevent continuation of
             maintenance therapy, in the opinion of the investigator

             * Based on results from screening/enrolment visit samples for which can be taken
             within ± 7 days of visit. Result should be within the assay limits of quantification
             for the sample. The ranges in μmol of copper are 0.40 to 2.38 μmol/L for NCC and 1.59
             to 14.29 for 24-hour urinary copper excretion (using division by 63 of value in μg per
             Walshe, 2011). In the event that one or more of the above lab values fall outside the
             specified range, it can be repeated, including at the Week 4 and Week 8 visits.

             Additional inclusion criteria at Week 12 visit (end of Penicillamine Baseline Period)
             and prior to randomization

         15. Patient is adequately controlled and tolerating penicillamine therapy as defined by
             fulfilment of all of the following criteria:

               1. Serum non-ceruloplasmin bound copper (NCC) level between ≥ 25 and ≤ 150 μg/L*

               2. 24-hour urinary copper excretion of between ≥ 100 and ≤ 900 μg/24 hours**

               3. Alanine transaminase (ALT) < 2 times upper limit of normal*

               4. No other laboratory or clinical findings that would prevent continuation of
                  maintenance therapy, in the opinion of the investigator

                    -  Based on lab values from Week 8 visit; ** Based on lab value from Week 4
                       visit as routinely not performed at Week 8 visit, however can also be based
                       on value at Week 8 visit if a repeat (unscheduled) urinary copper excretion
                       was performed at this visit. Result should be within the assay limits of
                       quantification for the sample. The ranges in μmol of copper are 0.40 to 2.38
                       μmol/L for NCC and 1.59 to 14.29 for 24-hour urinary copper excretion (using
                       division by 63 of value in μg per Walshe, 2011). In the event that one or
                       more of the above lab values fall outside the specified range, it can be
                       repeated. The repeat value(s) must be available prior to randomization at
                       Week 12 and, if within specified range, the patient can continue to
                       randomization. If a patient fails this additional criterion at the end of
                       the Penicillamine Baseline Period, the patient can return to the start of
                       the run-in period i.e. Day 1 (but only once). A negative urinary pregnancy
                       test is also required prior to randomization for females of childbearing
                       potential.

        Exclusion Criteria:

          1. Patient is in 'de-coppering' phase of treatment for Wilson's disease, in the opinion
             of the investigator

          2. Patient evidence of uncontrolled liver disease, including but not limited to:

               1. Modified Nazer score of > 4 (result may not be available until after start of run
                  in period since based on lab results*)

               2. decompensated cirrhosis

               3. acute hemolytic anemia

               4. acute hepatitis

               5. hepatic malignancy

               6. evidence of acute liver failure

          3. Cause of patient's liver disease is due to another condition, in the investigator's
             opinion

          4. Patient has severe anemia defined as hemoglobin of ≤ 9 g/dL (result will be available
             after start of run-in period*)

          5. Patient has experienced a gastrointestinal bleed within 6 months (24 weeks) prior to
             screening/enrolment visit

          6. Patient has renal impairment defined as creatinine clearance of ≤ 30 mL/min (result
             may not be available until after start of run-in period*), or patient has nephritis or
             nephrotic syndrome, in the opinion of the investigator

          7. Patient has neurological disease that prevents swallowing of study medication (e.g.,
             requires a nasogastric feeding tube) or requires intensive in-patient medical care

          8. Patient is currently taking medication containing trientine for management of Wilson's
             disease or has taken it within 4 months (16 weeks) of screening/enrolment visit

          9. Patient is currently receiving prescribed zinc therapy for management of Wilson's
             disease or has taken it within 4 months (16 weeks) of screening/enrolment visit

         10. Patient is taking any of the following concomitant therapies: gold therapy,
             antimalarial therapy, cytotoxic drugs, oxyphenbutazone, phenyl butazone

         11. Patient has a known intolerance, allergy or sensitivity to penicillamine (that is
             uncontrolled) or to TETA 4HCl, including any component of the study medication

         12. For female patients of childbearing potential, planning a pregnancy during study
             period or currently nursing

         13. For female patients of childbearing potential, unable or unwilling to use a reliable
             form of contraceptive throughout the study

         14. Patient is currently participating in another therapeutic study, or has previously
             participated in a therapeutic study within 30 days of screening/enrolment visit (or
             longer, if local requirements specify this)

         15. Patient has any condition or in any situation which, in the investigator's opinion,
             puts the patient at significant risk, could confound study results, or may interfere
             significantly with the patient's participation in the study