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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

Primary Purpose

TTR Cardiac Amyloidosis

Status
Completed
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Doxycycline and tauroursodeoxycholic acid
Standard of care
Sponsored by
IRCCS Policlinico S. Matteo
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for TTR Cardiac Amyloidosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.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

Sites / Locations

  • Fondazione IRCCS Policlinico San Matteo

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Doxy/TUDCA

Standard of care

Arm Description

doxycicline (100 mg / BID) tauroursodeoxycholic acid (250 mg / TID)

Standard of care therapies.

Outcomes

Primary Outcome Measures

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.
Doxy/TUDCA efficacy

Secondary Outcome Measures

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.
Survival

Full Information

First Posted
March 16, 2018
Last Updated
July 6, 2023
Sponsor
IRCCS Policlinico S. Matteo
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1. Study Identification

Unique Protocol Identification Number
NCT03481972
Brief Title
A Study of Doxycycline and Tauroursodeoxycholic Acid (Doxy/TUDCA) Plus Standard Supportive Therapy Versus Standard Supportive Therapy Alone in Cardiac Amyloidosis Caused by Transthyretin
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
April 11, 2018 (Actual)
Primary Completion Date
January 18, 2023 (Actual)
Study Completion Date
June 22, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
IRCCS Policlinico S. Matteo

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
TTR Cardiac Amyloidosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
102 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Doxy/TUDCA
Arm Type
Experimental
Arm Description
doxycicline (100 mg / BID) tauroursodeoxycholic acid (250 mg / TID)
Arm Title
Standard of care
Arm Type
Active Comparator
Arm Description
Standard of care therapies.
Intervention Type
Drug
Intervention Name(s)
Doxycycline and tauroursodeoxycholic acid
Other Intervention Name(s)
Standard of care therpay
Intervention Description
doxycicline and tauroursodeoxycholic acid
Intervention Type
Drug
Intervention Name(s)
Standard of care
Intervention Description
Standard of care
Primary Outcome Measure Information:
Title
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.
Description
Doxy/TUDCA efficacy
Time Frame
18 MONTHS
Secondary Outcome Measure Information:
Title
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.
Description
Survival
Time Frame
18 and 30 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Facility Information:
Facility Name
Fondazione IRCCS Policlinico San Matteo
City
Pavia
ZIP/Postal Code
27100
Country
Italy

12. IPD Sharing Statement

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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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