Cardiac amyloidosis caused by transthyretin either mutated (in ATTRm amyloidosis) or wildtype (in ATTRwt, formerly senile, amyloidosis) is a rare disease but is diagnosed with increasing frequency thanks to the availability of non-invasive scintigraphy-based means. Cardiac ATTR amyloidosis is characterized by progressive heart failure with a median survival of less than 4 years, and there is no standard treatment for this disease. It was proved that the marketed antibiotic doxycycline (Doxy) disrupts amyloid fibrils in vitro and in animal models synergistically with tauroursodeoxycholic acid (TUDCA). Based on these pre-clinical data, a clinical trial of Doxy/TUDCA in ATTR Amyloidosis (NCT01171859) was conducted.

Treatment was well tolerated and was able to prevent progression of cardiac dysfunction.

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 to be characterized as ATTR-type by immuno-electron microscopy or mass spectrometry. Biopsy can be omitted in patients with a positive (score 3) cardiac 99mTc-DPD scintigraphy, provided serum and urine immunofixation does not show monoclonal components. Wild-type and mutated ATTR amyloidosis will be differentiated by DNA analysis;
• 18 years or older;
• cardiac involvement (mean left ventricular wall thickness >12 mm in the absence of other 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 screening visit, or are surgically sterile, or if they are of childbearing potential, agree to practice effective methods of contraception from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to completely abstain from intercourse;
• voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.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 specific antigen is within normal limit, or any completely resected carcinoma in situ;
• known allergy to any of the study medications, their analogues, or excipients in the various 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 of study drug;
• requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered to be investigational;
• any other serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol