Brief Title
Single Daily Dosage of Trientine for Maintenance Treatment for Wilson Disease
Official Title
Single Daily Dosage of Trientine for Maintenance Treatment for Wilson Disease
Brief Summary
Hypothesis: The investigators postulate that patients with Wilson disease who are
asymptomatic or who have been effectively treated for their symptoms and are in a maintenance
phase therapy can be safely and effectively treated with a single daily dosage of the
chelating agent trientine.
Specific Aims: To demonstrate that a single daily treatment with trientine is as effective or
better than a patient's current maintenance therapy. This will be accomplished by performance
of a case control prospective study of patients on their prior therapy, and during a period
of treatment with a single weight based dose regimen of trientine.
The primary endpoint for this study is the demonstration of equivalence to a patient's prior
therapy. Secondary endpoints include: 1) demonstration of stability or improvement in
parameters of copper metabolism; 2) improvement in adherence to therapy; 3) no progression of
liver disease (defined by changes in synthetic function, albumin and INR, and fibrosis by
Fibrotest).
Detailed Description
Wilson disease is a genetic disorder of copper metabolism inherited in an autosomal recessive
fashion that afflicts ~1/30,000 individuals. Treatment for these individuals consists of
medical therapy, which is life-long, or liver transplantation. Medical therapy utilizes
chelating agents, penicillamine and trientine, or zinc, each given in multiple daily dosages
(1). It is estimated that ~10-50% of individuals have some period of non-adherence to their
therapy during their life-time. The consequences of non-adherence include liver injury, liver
failure, neurological impairment and death. Some non-adherent individuals can be rescued by
reinstitution of medical therapy, while others require liver transplantation (1-4). In
addition to the human suffering engendered by the advance in an individuals disease suffered
from non-adherence, the physical or mental disability suffered or the need for liver
transplantation adds greatly to their cost of life-time care. Simplifying the current
treatment regimen for long-term maintenance therapy for Wilson disease should improve patient
adherence. This will translate into a positive long-term benefit for patients, their
caregivers and supports, and for society as a whole.
Current maintenance therapy for Wilson disease includes the chelating agents penicillamine
and trientine, or zinc. Multiple daily dosages (three or four) are recommended from early
studies on these medications, by the manufacturer and by treating physicians (1,5-8). As
noted above, patient adherence to treatment, and in particular to multiple daily dosages is
often incomplete. There has been an increase in the treatment of other common disorders with
medication that can be administered as a single daily dosage. As an example, some
anti-hypertensives and antidepressants are available in extended release formulations, making
a single daily dosage possible. None of the currently available agents for the treatment of
Wilson disease has a comparable formulation. Furthermore, even if an extended release oral
formulation were available, it is not certain that it would be effective. In an extended
release formulation, the site of absorption of the medication may not be sustained
adequately, and binding to ingested food may interfere with its function.
The choice of trientine as the single agent for use for study comes from personal experience
of the Principal Investigator with its' use in the clinical setting and in a clinical trial
(1, 9). This drug has an excellent safety profile and is effective in removing copper from
the body when given apart from meals (1,4,10). Previous studies have shown the effectiveness
of copper removal by administration in multiple daily dosages (10,11). The amount of copper
excreted in the urine of patients on a daily basis is dosage dependent, and is also dependent
on the phase of treatment. In the initial treatment period, there is a larger efflux of
copper in the urine of patients treated with chelation agents, and with time this amount
decreases. For example, patients maintained on d-penicillamine initially may excrete over one
milligram of copper in a 24 hour period, but over time will excrete ~250 mcg copper per day.
Similarly, patients maintained on trientine as a single therapy may excrete slightly less but
comparable amounts of copper (11). In the trials of trientine for neurological disease, the
amount of free serum copper and urine copper was stable by the end of the initial 8 week
period in most patients (9). Once equilibrium is achieved with respect to copper balance and
liver function is stabilized, maintenance therapy is geared towards a smaller net negative
removal of copper on a daily basis. Therefore, adequate copper removal should be possible to
achieve with an appropriate dosage of trientine given once daily since there is known to be a
dose response between trientine and copper excretion.
Supportive evidence suggesting that the single daily dosage proposed in this study will be
effective therapy was recently obtained by review of three individual case studies. These
three patients, two followed by the principal investigator (MLS) and the third known to him
but followed locally, reported taking their trientine as a single daily dosage. Two of the
patients had presented with neurological Wilson disease, while the third was a presymptomatic
patient identified by family screening; all were years out from their initial treatment. Two
of the three changed their regimens to once a day treatment on their own without the advice
of their physician due to difficulty taking multiple dosages during their working hours or
interference with taking other medications, and the third did so at the advice of another
physician. Each of these patients had used single dose therapy for years (range 2-15).
Laboratory data for these individuals demonstrated normal liver function and good copper
control, and examinations showed them to be clinically stable. All three had previously been
treated with d- Penicillamine and then trientine in multiple daily dosages.
Experimental Design & Methods:
Experimental design: Patients meeting inclusion criteria will be asked for their consent to
participate in this study before entry into the clinical trial. Patients will be evaluated
prior to the start of the study by the Principal Investigator or a co-investigator to
document the medical history and physical exam findings. Initial lab studies will be
performed to determine the current status of the patient's liver disease and copper balance.
A history will be obtained about treatment for their Wilson disease, and patients will be
asked to complete a pre-study questionnaire.
Blood and urine studies prior to entry will include: CBC with platelets; Liver function panel
(AST, ALT, alkaline phosphatase, total bilirubin, direct bilirubin, GGPT, albumin), INR,
serum copper, serum ceruloplasmin, ANA with titer, ESR, pregnancy test, 24 hour urine for
copper and zinc and volume, urinalysis and a non-invasive test for liver fibrosis (Fibrotest,
Prometheus) A questionnaire will be administered prior to entry into this study and at the
end of the study period. This questionnaire is designed to focus on a patients use of their
current medications, and at the end of the period, to determine whether the once a day
regimen was a useful intervention for them.
For the first part of the study (3 months), the patient will be observed on their current
therapy with labs performed prior to study entry and monthly for baseline measurements of
liver function and copper status. Subsequently, and throughout the remainder of the study
period, patients will be given Trientine at a dosage of ~15 mg/kg rounded upwards to the
nearest 250 or 300 mg in a single daily dosage. The entire daily dosage will be taken at once
in the AM an hour before any meal. Patients will be monitored monthly for the first three
months, and thereafter, every third month by repeat blood and urine testing as noted above,
with the exception of the Fibrotest, ANA and ESR that will be administered before the study
drug is given, and 12 months later. This interval of monitoring exceeds the frequency at
which patients are normally seen for their maintenance therapy, which varies from 3-6 month
intervals with the upper limit for those patients with good adherence to past therapy.
Patients will be examined at the beginning of the trial, after 3 months after being given
study drug, and again after 6 and 12 months of treatment (end of the trial). A monthly study
log will be kept by the patient to record their medication administration and any adverse
effects of their treatment, and will be sent to the study coordinator.
For long-term follow-up, patients may visit with Dr. Schilsky in our clinic at 6 month
intervals for up to ten years (the routine interval for follow-up care for most patients with
Wilson disease on maintenance therapy) and standard of care lab testing will be performed.
The patient will be asked to fill out a short questionnaire, and data from this visit will be
collected and recorded on the case report form. If a patient is unable to travel to the study
site, the questionnaire can be filled out by telephone interview and laboratory requests may
be sent to the patient for them to have testing and physical examination done locally.
Results of these tests and evaluation will be forwarded to our site for review and for data
entry.
The study pharmacy will dispense medications at the visit after the third month of monitoring
(prior to the initial start of the medication), and thereafter at 90 day intervals. All
unused medication will be returned to the study pharmacy.
Methodology Study Group: Patients with an established diagnosis of Wilson disease that have
been treated for their disease for at least one year, compensated liver disease and/or stable
neurological or psychiatric disease. Biochemical testing must demonstrate normal or minimal
elevation of serum ALT (<2 times the upper limit of normal) and a non-ceruloplasmin copper <
25 mcg/dl. Patients must be willing to participate for a 15 month time period and undergo
initial monthly blood and urine testing to determine their baseline on their current therapy,
and then interval testing for up to 12 months. A pilot study of 5 patients is proposed, with
a larger study to follow pending review of the initial pilot data.
Study Type
Interventional
Primary Outcome
ALT
Secondary Outcome
INR
Condition
Wilson Disease
Intervention
Once a day Trientine
Study Arms / Comparison Groups
Once a day Trientine
Description: Patients receive once a day trientine
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
8
Start Date
January 2010
Completion Date
July 2011
Primary Completion Date
July 2011
Eligibility Criteria
Inclusion Criteria:
Established diagnosis of Wilson Disease:
- That have been treated for at least 1 year
- Compensated liver disease and/or stable neurological or psychiatric disease.
- Normal or minimal elevation of serum ALT (<2 times upper limit of normal)
- Non-ceruloplasmin copper <25 mcg/dl
Exclusion Criteria:
- Wilson disease diagnosis not well established Wilson disease treated for less than one
year Decompensated liver disease (ascites, jaundice, encephalopathy, bleeding due to
portal hypertension) Liver disease with elevations of ALT > 2 times upper limit of
normal A female who is pregnant or intends to become pregnant
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Michael Schilsky, MD, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01472874
Organization ID
0902004694
Secondary IDs
ORPH-SYP-001
Responsible Party
Sponsor
Study Sponsor
Yale University
Collaborators
Bausch Health Americas, Inc.
Study Sponsor
Michael Schilsky, MD, Principal Investigator, Yale University
Verification Date
April 2020