Single Daily Dosage of Trientine for Maintenance Treatment for Wilson Disease

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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