A Study of Doxycycline and Tauroursodeoxycholic Acid (Doxy/TUDCA) Plus Standard Supportive Therapy Versus Standard Supportive Therapy Alone in Cardiac Amyloidosis Caused by Transthyretin

Inclusion Criteria:

Subjects must meet all of the following criteria:

• Diagnosis of ATTRwt amyloidosis, or ATTRm p.Ile68Leu and p.Val122Ile;

• the diagnosis of amyloidosis needs to be biopsy-proven, and amyloid deposits need tobe characterized as ATTR-type by immuno-electron microscopy or mass spectrometry.Biopsy can be omitted in patients with a positive (score 3) cardiac 99mTc-DPDscintigraphy, provided serum and urine immunofixation does not show monoclonalcomponents. Wild-type and mutated ATTR amyloidosis will be differentiated by DNAanalysis;

• 18 years or older;

• cardiac involvement (mean left ventricular wall thickness >12 mm in the absence ofother causes);

• history of occurrence of at least 1 event of symptomatic heart failure;

• stable diuretic dosage for at least 2 weeks before treatment initiation;

• female patients who are postmenopausal for at least 1 year before the screeningvisit, or are surgically sterile, or if they are of childbearing potential, agree topractice effective methods of contraception from the time of signing the informedconsent through 30 days after the last dose of study drug, or agree to completelyabstain from intercourse;

• voluntary written consent must be given before performance of any study-relatedprocedure not part of standard medical care with the understanding that consent maybe withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

Subjects must meet none of the following criteria:

• Non-ATTR amyloidosis;

• NYHA class IV;

• enzyme-documented myocardial infarction within 6 months before enrollment;

• pregnant or nursing women;

• uncontrolled bacterial, viral, fungal, HIV, HBV, or HCV infection;

• presence of other active malignancy with the exception of non-melanoma skin cancer,cervical cancer, treated early-stage prostate cancer provided that prostate specificantigen is within normal limit, or any completely resected carcinoma in situ;

• known allergy to any of the study medications, their analogues, or excipients in thevarious formulations;

• treatment with drugs potentially affecting doxycycline absorption;

• significant acute gastrointestinal symptoms;

• active peptic ulceration and/or esophageal reflux disease;

• treatment with any investigational products within 28 days before the first dose ofstudy drug;

• requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or anyancillary therapy considered to be investigational;

• any other serious medical or psychiatric illness that could, in the investigator'sopinion, potentially interfere with the completion of treatment according to thisprotocol