Doxycycline and TUDCA in Patients With Transthyretin Amyloid Cardiomyopathy
Condition: Amyloidosis; Heart (Manifestation); Senile Cardiac Amyloidosis
MeSH terms: Cardiomyopathies; Amyloidosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The objective of the study is to determine whether the combination of the bile acid TUDCA,
      and doxycycline will slow the progression of familial and senile amyloidosis.
    

Detailed description: 
      Primary objectives The study is designed to prospectively evaluate the efficacy of
      doxycycline and TUDCA, prescribed together, on cardiac disease progression in patients with
      senile systemic amyloidosis or familial amyloidosis due to a TTR mutation. The definition of
      progression will be defined, primarily, by echocardiographic indices , as well as by serial
      cardiac biomarkers, specifically NT-proBNP.

      . Echocardiographic details

      . Standard parameters of wall thickness, chamber size, Doppler echocardiographic assessment
      of valvular function and diastolic function will be measured.

      The primary endpoint is the response rate to doxycycline + TUDCA treatment at month 12 and
      18, based upon echocardiographic findings. Since the precise echocardiographic findings will
      determine the definition of a responder, an approximate figure on which progression is based
      will be given here, based on our previous, preliminary data. A responder will be defined as a
      patient with echocardiographic evidence of stability of speckle strain parameters at 12
      months of therapy with doxycycline/TUDCA. Based on our preliminary work, this is currently
      defined as a change in absolute longitudinal strain of < -2%, but the use of this parameter
      may alter slightly after the part 1 analysis.

      Secondary endpoints

      Secondary endpoints of the study are:

        -  to assess the tolerability and safety of the treatment, based on evaluation of the
           development of recognized side-effects, such as photosensitivity, drug sensitivity,
           gastrointestinal disturbance and superinfection, as well as any other unexpected effects
           potentially attributed to therapy.

        -  to assess change from baseline in QoL (SF-36 scale) at months 6, 12 and 18;

      This is an 18-month, open label treatment period in which doxycycline (100 mg twice daily)
      and TUDCA (250 mg, three times daily) are administered to 30 consenting subjects with SSA
      amyloidosis and 10 subjects with ATTR amyloidosis. Subjects will be evaluated at baseline,
      and then after 6, 12, and 18 months of doxycycline plus TUDCA treatment or at time of
      premature treatment discontinuation. Monthly phone contacts and regular blood tests will be
      performed to monitor potential adverse events.

      All eligible subjects will receive doxycycline hyclate (100 mg twice daily) as well as TUDCA
      250 mg three times a day orally. Treatment will be initiated with doxycycline 100 mg daily
      for 1 week, to assess tolerance, and then increased to twice daily for week 2, following
      which repeat blood tests of BUN, creatinine , electrolytes and liver function tests will be
      drawn. If these are stable, TUDCA will be added at the above dose, and the combination will
      be administered for 17.5 months. TUDCA, formulated in capsules of 250 mg, will be provided at
      enrolment and at subsequent study visits. Doxycycline will be prescribed through the
      patient's own pharmacy as it is a widely available drug and is already being used as a single
      agent in some patients with cardiac amyloidosis (including in our own program).

      In patients in whom doxycycline is poorly tolerated due to gastrointestinal symptoms and/or
      mild, transient reduction in blood cell counts, the treatment schedule will be modified
      according to the protocol of Obici et al and doxycycline will be administered cyclically (200
      mg/day for 28 days every six weeks up to 18 months). In these patients TUDCA will continue to
      be administered at 250 mg, three times daily.

      The following study procedures will be performed at scheduled visits. Entry evaluation

      After obtaining consent, subjects will undergo:

        1. Physical examination

        2. ECG

        3. Quality of Life questionnaire (SF-36)

        4. A full echocardiographic study (standard clinical practice)

        5. Serum creatinine, AST, ALT, total bilirubin, CBC, NT-proBNP, troponin I, alkaline
           phosphatase, and pregnancy test (if applicable)

      6-monthly visits

      Every 6 months subjects will follow-up with the Investigator for standard blood work and
      physical examination, to evaluate tolerability of the treatment, and to have an
      echocardiogram. ) .

      Phone contacts 3-Monthly phone contacts between clinic visits will be performed by the
      research coordinator for monitoring of the treatment safety. to the IRB, as per IRB
      regulations.

      Echocardiograms will be read blindly to determine standard echocardiographic parameters, with
      an emphasis on those that may change in progressive cardiac amyloidosis (LV mean wall
      thickness, quantitative LV ejection fraction, LV dimensions etc)..

      Study Endpoints Response will be evaluated at Month 12 by means of the percentage of subjects
      with stability in echocardiographic parameters, as initially defined based on the 40 patients
      studied by serial echocardiography. Analysis will be performed both as an evaluation of the
      percentage of the group whose cardiac function remains stable, and as an analysis of the mean
      change in echocardiographic parameters compared to the historical control group. Details of
      the drug regimen tolerability will also be analyzed. Patients will continue in the study for
      an additional 6 months (duration of treatment 18 months) with a repeat (secondary) analysis
      of the same parameters at 18 months (secondary endpoint).

      .

      Subjects discontinuing study participation prematurely due to drug intolerance will, if
      agreeable, undergo a full Study Site visit evaluation. This assessment will include the
      routine 6-montly tests, with the exclusion of a repeat echocardiogram if one has been done in
      the past 4 months.

      Efficacy observations and measurements For efficacy evaluation, subjects will be interviewed
      and examined every 6 months. Echocardiograms, obtained at 0, 6, 12 and 18 months will be
      analyzed for standard measurements as well as by strain imaging using a dedicated Echo-Pac
      analysis system. Cardiac biomarkers will be obtained every 6months.

      SF-36 Quality of Life questionnaires will be administered at baseline and 6, 12, and 18
      months.
    

Intervention name(s): Tauroursodeoxycholic Acid and Doxycycline
Intervention type(s): Drug
Other intervention name(s): Doxycycline:Vibramycin, Monodox, Acticlate, Atridox, Avidoxy, Doxy, Doxycin, Doryx, Oracea, Periostat, Adoxa, Ocudox, and Doryx MPC.
Intervention MeSH terms: Doxycycline; Ursodoxicoltaurine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: amyloid; amyloidosis; cardiac amyloidosis; senile amyloidosis; familial amyloidosis; transthyretin amyloidosis