Safety, Efficacy and Pharmacokinetics of Doxycycline Plus Tauroursodeoxycholic Acid in Transthyretin Amyloidosis

NCT01171859 | Completed Phase 2 DMC

• 2 other identifiers: DOXYTUDCA20102010-020422-17
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being conducted to explore the potential benefits of a twelve-month doxycycline (at the best tolerated dose of 200 mg/day) and tauroursodeoxycholic acid (750 mg/day) treatment on disease progression in patients affected by transthyretin amyloidosis, including: 1) patients not eligible for liver transplantation; 2) patients eligible for liver transplantation, as a "bridge" therapy between the time of diagnosis and surgery, with the aim of stabilizing the disease; 3) patients showing disease progression after liver transplantation performed since at least 1 year. It is a phase II, therapeutic exploratory, two-part, 18-month, single centre, prospective study. Part I is a 12-month, open label treatment period in which doxycycline (200 mg/day, continuously) and tauroursodeoxycholic acid (750 mg/day continuously) are administered to 40 consenting subjects with transthyretin amyloidosis. Part II is a withdrawal period in which subjects will be monitored for disease progression. During part I, subjects will be evaluated at baseline (study Day 0), and then after 3, 6, 9 and 12 months of doxycycline plus tauroursodeoxycholic acid treatment or at premature treatment discontinuation; during part II, they will be assessed at months 15 and 18. Monthly phone contacts and blood tests will be performed to monitor potential adverse events.

Conditions

Transthyretin Amyloidosis

Keywords

amyloidosis; transthyretin; doxycycline; Tauroursodeoxycholic acid

Outcome Measures

Primary Outcomes (1)

• Response rate to doxycycline + tauroursodeoxycholic acid treatment

  A responder is a subject with: * a modified body mass index (mBMI) reduction of less than 10% and a change in the Neurologic Impairment Score-Lower Limbs (NIS-LL) \<2 (in subjects with peripheral neuropathy); * a modified body mass index (mBMI) reduction of less than 10% and an increase in N-terminal natriuretic peptide type B (NT-proBNP) concentration of less than 30% or \< 300 pg/mL (in subjects with isolated cardiomyopathy).

  One year

Secondary Outcomes (6)

• Number of patients experiencing treatment-emergent adverse events

  One year

• Change in quality of life

  Every six months

• doxycycline pharmacokinetics (PK)

  Every three months

• response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement

  One year

• neurologic response

  One year

Study Arms (1)

Doxycycline + Tauroursodeoxycholic acid

EXPERIMENTAL

Drug: Doxycycline + Tauroursodeoxycholic acid

Interventions

Doxycycline + Tauroursodeoxycholic acid DRUG

doxycycline 100 mg twice a day for 12 months; tauroursodeoxycholic acid 250 mg three times a day for 12 months

Doxycycline + Tauroursodeoxycholic acid

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histochemical diagnosis of amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens;
• Molecular definition of the transthyretin (TTR) mutation or immunohistochemical staining of amyloid fibrils with anti-TTR antibody;
• ECOG performance status (PS) 0, 1, 2;
• New York Heart Association (NYHA) class ≤III
• Systolic blood pressure ≥100 mmHg (standing)
• Must have symptomatic organ involvement with amyloid to justify therapy; must have evidence of neuropathy and/or cardiomyopathy progression after liver transplantation performed since at least one year.
• Contraception for women of childbearing potential. Medically approved contraception could include abstinence. A negative serum pregnancy test is required prior to initiation of treatment with study medication.

You may not qualify if:

• Liver transplantation in the previous 12 months or liver transplantation anticipated in less than 6 months;
• ALT and/or AST ≥ 2 x Upper Normal Limit (UNL);
• Alkaline phosphatase ≥ 2 x UNL;
• Creatinine clearance \< 30 ml/min;
• Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study;
• Echocardiographic ejection fraction \< 50%;
• Other neuropathies, due to vitamin B12 deficiency, alcoholism, hypothyroidism, uremia, diabetes mellitus, vasculitides;
• History of poor compliance;
• History of hypersensitivity to any of the ingredients of the study therapies;
• Use of any investigational drug, device (or biologic) within 4 weeks prior to study entry or during the study.

Sponsors & Collaborators

• Fondazione IRCCS Policlinico San Matteo di Pavia: lead

Study Sites (1)

Amyloid Research and Treatment Centre, Biotechnology Research Laboratories

Pavia, Pavia, 27100, Italy

Location

Related Publications (3)

• Cardoso I, Saraiva MJ. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J. 2006 Feb;20(2):234-9. doi: 10.1096/fj.05-4509com.

  PMID: 16449795 BACKGROUND

• Macedo B, Batista AR, Ferreira N, Almeida MR, Saraiva MJ. Anti-apoptotic treatment reduces transthyretin deposition in a transgenic mouse model of Familial Amyloidotic Polyneuropathy. Biochim Biophys Acta. 2008 Sep;1782(9):517-22. doi: 10.1016/j.bbadis.2008.05.005. Epub 2008 Jun 3.

  PMID: 18572024 BACKGROUND

• Cardoso I, Martins D, Ribeiro T, Merlini G, Saraiva MJ. Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med. 2010 Jul 30;8:74. doi: 10.1186/1479-5876-8-74.

  PMID: 20673327 BACKGROUND

MeSH Terms

Conditions

Amyloidosis, Hereditary, Transthyretin-Related; Amyloidosis

Interventions

Doxycycline; ursodoxicoltaurine

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Giampaolo Merlini, MD

  IRCCS Policlinico San Matteo

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: July 27, 2010
• First Posted: July 29, 2010
• Study Start: July 1, 2010
• Primary Completion: April 1, 2015
• Study Completion: October 1, 2015
• Last Updated: February 25, 2016

Record last verified: 2016-02

Locations

IT (1)