Safety and Effect of Doxycycline in Patients With Amyloidosis

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

John L. Berk, Boston University

ClinicalTrials.gov Identifier:

NCT01677286

First received: August 21, 2012

Last updated: June 5, 2017

Last verified: June 2017

History of Changes

Results First Received: March 19, 2017

Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment; Masking: No masking; Primary Purpose: Treatment
Condition:	Amyloidosis
Intervention:	Drug: Doxycycline 100 mg po bid x 12 months

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Patients referred to an amyloidosis center and no longer requiring active treatment to control progressive disease were recruited to the study.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Doxycycline 100 mg po Bid x 12 Months	Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months.

Participant Flow: Overall Study

	Doxycycline 100 mg po Bid x 12 Months
STARTED	25
COMPLETED	14
NOT COMPLETED	11

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Doxycycline 100 mg po Bid x 12 Months	Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months.

Baseline Measures

Doxycycline 100 mg po Bid x 12 Months

Overall Participants Analyzed
[Units: Participants]

Age
[Units: Years]
Median (Full Range)

Participants Analyzed
[Units: Participants]

65
(36 to 82)

Sex: Female, Male
[Units: Participants]
Count of Participants

Participants Analyzed
[Units: Participants]

Female

6 24.0%

Male

19 76.0%

Race/Ethnicity, Customized
[Units: Participants]
Count of Participants

White

Participants Analyzed
[Units: Participants]

White

Multiple

Participants Analyzed
[Units: Participants]

Multiple

Not hispanic or latino

Participants Analyzed
[Units: Participants]

Not hispanic or latino

Unknown/not reported

Participants Analyzed
[Units: Participants]

Unknown/not reported

Region of Enrollment
[Units: Participants]
Count of Participants

United States

Participants Analyzed
[Units: Participants]

United States

Brain Natriuretic Peptide (BNP) ^[1] [2]
[Units: pg/mL]
Mean (Standard Deviation)

Participants Analyzed
[Units: Participants]

385 (294)

^[1]	Study participants with predominant cardiac amyloid involvement.
^[2]	Patients with predominant amyloid cardiomyopathy constituted the "cardiac group" (n=12). Serial cardiac biomarkers (BNP, Troponin I) determinations were used to assess the effect of doxycycline on cardiac amyloid disease progression.

Troponin I ^[1] [2]
[Units: ng/mL]
Mean (Standard Deviation)

Participants Analyzed
[Units: Participants]

0.11 (0.07)

^[1]	Study participants with predominant cardiac amyloid involvement.
^[2]	Patients with predominant amyloid cardiomyopathy constituted the "cardiac group" (n=12). Serial cardiac biomarkers (BNP, Troponin I) determinations were used to assess the effect of doxycycline on cardiac amyloid disease progression.

Creatinine Clearance (mL/min) ^[1] [2]
[Units: mL/min]
Mean (Standard Deviation)

Participants Analyzed
[Units: Participants]

83.3 (36.5)

^[1]	Study participants with predominant renal amyloid involvement.
^[2]	Patients with predominant amyloid nephropathy constituted the "renal group" (n=10). Serial creatinine clearance and proteinuria were used to assess the effect of doxycycline on renal amyloid disease progression.

Proteinuria (g/day) ^[1] [2]
[Units: G/day]
Mean (Standard Deviation)

Participants Analyzed
[Units: Participants]

5.99 (3.15)

^[1]	Study participants with predominant renal amyloid involvement.
^[2]	Patients with predominant amyloid nephropathy constituted the "renal group" (n=10). Serial creatinine clearance and proteinuria were used to assess the effect of doxycycline on renal amyloid disease progression.

Outcome Measures

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1. Primary:

Amyloid Cardiomyopathy: BNP [ Time Frame: 12 months ]

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2. Primary:

Amyloid Cardiomyopathy: Troponin I [ Time Frame: 12 months ]

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3. Primary:

Amyloid Nephropathy: Creatinine Clearance [ Time Frame: 12 months ]

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4. Primary:

Amyloid Nephropathy: Proteinuria [ Time Frame: Data were assessed at baseline, 6 and 12 months, with change at end of study reported ]

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact:

Name/Title: John Berk, MD
Organization: Boston Medical Center
phone: 617-638-4494
e-mail: jberk@bu.edu

Publications:

Cardoso I, Merlini G, Saraiva MJ. 4'-iodo-4'-deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters. FASEB J. 2003 May;17(8):803-9.

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.

Forloni G, Colombo L, Girola L, Tagliavini F, Salmona M. Anti-amyloidogenic activity of tetracyclines: studies in vitro. FEBS Lett. 2001 Jan 5;487(3):404-7.

Ward JE, Ren R, Toraldo G, Soohoo P, Guan J, O'Hara C, Jasuja R, Trinkaus-Randall V, Liao R, Connors LH, Seldin DC. Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis. Blood. 2011 Dec 15;118(25):6610-7. doi: 10.1182/blood-2011-04-351643. Epub 2011 Oct 12.

Obici L, Cortese A, Lozza A, Lucchetti J, Gobbi M, Palladini G, Perlini S, Saraiva MJ, Merlini G. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid. 2012 Jun;19 Suppl 1:34-6. doi: 10.3109/13506129.2012.678508. Epub 2012 May 2.

Giorgetti S, Raimondi S, Pagano K, Relini A, Bucciantini M, Corazza A, Fogolari F, Codutti L, Salmona M, Mangione P, Colombo L, De Luigi A, Porcari R, Gliozzi A, Stefani M, Esposito G, Bellotti V, Stoppini M. Effect of tetracyclines on the dynamics of formation and destructuration of beta2-microglobulin amyloid fibrils. J Biol Chem. 2011 Jan 21;286(3):2121-31. doi: 10.1074/jbc.M110.178376. Epub 2010 Nov 10.

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.

Responsible Party:	John L. Berk, Boston University
ClinicalTrials.gov Identifier:	NCT01677286 History of Changes
Other Study ID Numbers:	H-31546
Study First Received:	August 21, 2012
Results First Received:	March 19, 2017
Last Updated:	June 5, 2017

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