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

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ClinicalTrials.gov Identifier: NCT03481972
Recruitment Status : Recruiting
First Posted : March 29, 2018
Last Update Posted : May 14, 2018
Sponsor:
Information provided by (Responsible Party):
GIOVANNI PALLADINI, IRCCS Policlinico S. Matteo

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
TTR Cardiac Amyloidosis Drug: Doxycycline and tauroursodeoxycholic acid Drug: Standard of care Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Randomized Study of Doxycycline and Tauroursodeoxycholic Acid (Doxy/TUDCA) Plus Standard Supportive Therapy Versus Standard Supportive Therapy Alone in Cardiac Amyloidosis Caused by Transthyretin
Actual Study Start Date : April 11, 2018
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : April 2021


Arm Intervention/treatment
Experimental: Doxy/TUDCA

doxycicline (100 mg / BID)

tauroursodeoxycholic acid (250 mg / TID)

Drug: Doxycycline and tauroursodeoxycholic acid
doxycicline and tauroursodeoxycholic acid
Other Name: Standard of care therpay

Active Comparator: Standard of care
Standard of care therapies.
Drug: Standard of care
Standard of care




Primary Outcome Measures :
  1. evaluate the efficacy of Doxy/TUDCA in patients with cardiac ATTR amyloidosis, comparing survival free at 18 months of patients receiving Doxy/TUDCA + standard supportive therapy with that of patients in standard supportive therapy alone. [ Time Frame: 18 MONTHS ]
    Doxy/TUDCA efficacy


Secondary Outcome Measures :
  1. Compare overall survival at 18 and 30 months of patients receiving Doxy/TUDCA in addition to standard supportive therapy with that of patients receiving standard supportive therapy alone. [ Time Frame: 18 and 30 months ]
    Survival



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03481972


Contacts
Contact: Giovanni Palladini, Prof 00390382502994 g.palladini@smatteo.pv.it
Contact: Claudia Sforzini 0382502994 claudiasforzini@gmail.com

Locations
Italy
Fondazione IRCCS Policlinico San Matteo Recruiting
Pavia, Italy, 27100
Contact: Claudia Sforzini    +390382502994    claudiasforzini@gmail.com   
Sponsors and Collaborators
IRCCS Policlinico S. Matteo

Responsible Party: GIOVANNI PALLADINI, Professor, IRCCS Policlinico S. Matteo
ClinicalTrials.gov Identifier: NCT03481972     History of Changes
Other Study ID Numbers: AC 011 IT
First Posted: March 29, 2018    Key Record Dates
Last Update Posted: May 14, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Doxycycline
Tauroursodeoxycholic acid
Taurochenodeoxycholic Acid
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Antiviral Agents
Cholagogues and Choleretics
Gastrointestinal Agents