Safety and Effect of Doxycycline in Patients With Amyloidosis

• Sponsor: Boston University
• Information provided by (Responsible Party): John L. Berk, Boston University

Study Type	Interventional
Study Design	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Amyloidosis
Intervention	Drug: Doxycycline 100 mg po bid x 12 months
Enrollment	25

Participant Flow

Recruitment Details	Patients referred to an amyloidosis center and no longer requiring active treatment to control progressive disease were recruited to the study.
Pre-assignment Details

Arm/Group Title	Doxycycline 100 mg po Bid x 12 Months
Arm/Group Description	Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months.
Period Title: Overall Study
Started	25
Completed	14
Not Completed	11

Baseline Characteristics

Arm/Group Title		Doxycycline 100 mg po Bid x 12 Months
Arm/Group Description		Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months.
Overall Number of Baseline Participants		25
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	25 participants
		65; (36 to 82)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	25 participants
	Female	6 24.0%
	Male	19 76.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
White	Number Analyzed	25 participants
		24 96.0%
Multiple	Number Analyzed	25 participants
		1 4.0%
Not hispanic or latino	Number Analyzed	25 participants
		24 96.0%
Unknown/not reported	Number Analyzed	25 participants
		1 4.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	25 participants
		25 100.0%
Brain Natriuretic Peptide (BNP) [1] [2]; Mean (Standard Deviation); Unit of measure: pg/mL
	Number Analyzed	12 participants
		385 (294)
		[1] Measure Description: Study participants with predominant cardiac amyloid involvement.; [2] Measure Analysis Population Description: 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]; Mean (Standard Deviation); Unit of measure: ng/mL
	Number Analyzed	12 participants
		0.11 (0.07)
		[1] Measure Description: Study participants with predominant cardiac amyloid involvement.; [2] Measure Analysis Population Description: 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]; Mean (Standard Deviation); Unit of measure: mL/min
	Number Analyzed	10 participants
		83.3 (36.5)
		[1] Measure Description: Study participants with predominant renal amyloid involvement.; [2] Measure Analysis Population Description: 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]; Mean (Standard Deviation); Unit of measure: G/day
	Number Analyzed	10 participants
		5.99 (3.15)
		[1] Measure Description: Study participants with predominant renal amyloid involvement.; [2] Measure Analysis Population Description: 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

1. Primary Outcome

Title	Amyloid Cardiomyopathy: BNP
Description	Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at end of study reported
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Analysis is limited to the patients with predominant amyloid heart involvement at enrollment. Mixed models analyses of change from baseline levels of cardiac biomarkers (BNP, Troponin I) were performed to include all collected data.

Arm/Group Title	Cardiomyopathy
Arm/Group Description:	Patients with predominant amyloid involvement of the heart.
Overall Number of Participants Analyzed	12
Mean (Standard Deviation); Unit of Measure: pg/mL
	883 (703)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cardiomyopathy
	Comments	BNP pg/mL, baseline versus end study values
	Type of Statistical Test	Other
	Comments	P-values and confidence intervals are not adjusted for multiple testing
Statistical Test of Hypothesis	P-Value	0.035
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	degrees of freedom = 12
Method of Estimation	Estimation Parameter	Mean outcome change
	Estimated Value	171
	Confidence Interval	(2-Sided) 95%; 14.1 to 328
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Amyloid Cardiomyopathy: Troponin I
Description	Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at change at end of study reported
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Patients with predominant amyloid involvement of the heart.

Arm/Group Title	Cardiomyopathy
Arm/Group Description:	Patients with predominant amyloid involvement of the heart.
Overall Number of Participants Analyzed	12
Mean (Standard Deviation); Unit of Measure: ng/mL
	0.15 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cardiomyopathy
	Comments	Troponin I ng/mL, baseline versus end study levels.
	Type of Statistical Test	Other
	Comments	P-values and confidence intervals are not adjusted for multiple testing
Statistical Test of Hypothesis	P-Value	0.340
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	degrees of freedom = 12
Method of Estimation	Estimation Parameter	Mean outcome change
	Estimated Value	0.0072
	Confidence Interval	(2-Sided) 95%; -0.009 to 0.0234
	Estimation Comments	[Not Specified]

3. Primary Outcome

Title	Amyloid Nephropathy: Creatinine Clearance
Description	Creatinine clearance (ml/min) and proteinuria (g/day) were assessed at baseline, 6 and 12 months, with change at change at end of study reported
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Analysis is limited to the patients with predominant amyloid kidney involvement at enrollment. Mixed models analyses of change from baseline levels of creatinine clearance (ml/min) and proteinuria (g/day) were performed to include all collected data.

Arm/Group Title	Amyloid Nephropathy
Arm/Group Description:	Patients with predominant amyloid kidney involvement at enrollment.
Overall Number of Participants Analyzed	10
Mean (Standard Deviation); Unit of Measure: ml/min
	82.4 (48.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amyloid Nephropathy
	Comments	Creatinine clearance, baseline versus end study levels.
	Type of Statistical Test	Other
	Comments	P-values and confidence intervals are not adjusted for multiple testing
Statistical Test of Hypothesis	P-Value	0.017
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	degrees of freedom = 10
Method of Estimation	Estimation Parameter	Change in outcome measure
	Estimated Value	-7.39
	Confidence Interval	(2-Sided) 95%; -13.12 to -1.67
	Estimation Comments	[Not Specified]

4. Primary Outcome

Title	Amyloid Nephropathy: Proteinuria
Description	Patients with predominant amyloid kidney involvement at enrollment.
Time Frame	Data were assessed at baseline, 6 and 12 months, with change at end of study reported

Outcome Measure Data

Analysis Population Description

Analysis is limited to the patients with predominant amyloid kidney involvement at enrollment. Mixed models analyses of change from baseline levels of creatinine clearance (ml/min) and proteinuria (g/day) were performed to include all data collected at baseline, 6 and 12 months.

Arm/Group Title	Amyloid Nephropathy: Proteinuria (g/Day)
Arm/Group Description:	Patients with predominant amyloid kidney involvement at enrollment.
Overall Number of Participants Analyzed	10
Mean (Standard Deviation); Unit of Measure: g/day
	5.91 (3.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amyloid Nephropathy: Proteinuria (g/Day)
	Comments	Proteinuria (g/24 hours), baseline versus end study levels.
	Type of Statistical Test	Other
	Comments	P-values and confidence intervals are not adjusted for multiple testing
Statistical Test of Hypothesis	P-Value	0.603
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	degrees of freedom = 10
Method of Estimation	Estimation Parameter	Change in outcome measure
	Estimated Value	0.091
	Confidence Interval	(2-Sided) 95%; -0.285 to 0.466
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Doxycycline 100 mg po Bid x 12 Months
Arm/Group Description	Open-label doxycycline 100 mg twice daily by mouth was administered to subjects for 12 months, if tolerated.
All-Cause Mortality
	Doxycycline 100 mg po Bid x 12 Months
	Affected / at Risk (%)
Total	0/25 (0.00%)
Serious Adverse Events
	Doxycycline 100 mg po Bid x 12 Months
	Affected / at Risk (%)	# Events
Total	12/25 (48.00%)
Blood and lymphatic system disorders
osteonecrosis *	1/25 (4.00%)	1
Deep vein thrombosis *	1/25 (4.00%)	1
Cardiac disorders
Fluid overload † [1]	3/25 (12.00%)	4
Arrhythmia * [2]	1/25 (4.00%)	1
Gastrointestinal disorders
Bloating † [3]	1/25 (4.00%)	1
Hernia *	1/25 (4.00%)	1
Infections and infestations
Cytomegalovirus infection *	1/25 (4.00%)	1
Musculoskeletal and connective tissue disorders
Hip disease *	2/25 (8.00%)	2
Renal and urinary disorders
Urinary retention †	1/25 (4.00%)	1
Skin and subcutaneous tissue disorders
Sun hypersensitivity † [4]	1/25 (4.00%)	1
Skin cancer *	1/25 (4.00%)	1
Surgical and medical procedures
Orthopedic issues *	2/25 (8.00%)	2
* Indicates events were collected by non-systematic assessment; † Indicates events were collected by systematic assessment; [1] SOB, edema; [2] Ventricular trachycardia; [3] Abdominal distension; [4] Burns/desquamation induced by sun hypersensitivity
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Doxycycline 100 mg po Bid x 12 Months
	Affected / at Risk (%)	# Events
Total	21/25 (84.00%)
Gastrointestinal disorders
GI disorder †	9/25 (36.00%)	18
Infections and infestations
Infection *	5/25 (20.00%)	8
Skin and subcutaneous tissue disorders
Skin disruption †	15/25 (60.00%)	21
† Indicates events were collected by systematic assessment; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

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

EMail: 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
First Submitted:	August 21, 2012
First Posted:	September 3, 2012
Results First Submitted:	March 19, 2017
Results First Posted:	June 6, 2017
Last Update Posted:	August 1, 2017