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Doxycycline to Upgrade Organ Response in Light Chain (AL) Amyloidosis Trial (DUAL)

Primary Purpose

Primary Systemic Amyloidosis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Doxycycline
Sponsored by
Medical College of Wisconsin
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Systemic Amyloidosis focused on measuring AL amyloidosis, amyloidosis, light chain amyloidosis

Eligibility Criteria

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

Inclusion Criteria:

  1. Patients with biopsy proven AL amyloidosis.
  2. Patients ≥ 18 years of age are eligible.
  3. Patient must provide informed consent.
  4. All patients must have measurable amyloid organ involvement of a vital organ (eg. heart, liver, kidneys). Localized amyloidosis will also be eligible as long as the amyloid involvement is radiologically measurable.
  5. A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted.
  6. Patients who have previously been taking doxycycline will be eligible as long as there is no contraindication to stay on doxycycline 100 mg twice daily (BID) for 1 year in the opinion of the treating physician.
  7. Creatinine clearance of >25 ml/min.

Exclusion Criteria:

  1. Patients with severe malabsorption syndrome precluding absorption of oral agents will be excluded.
  2. Known intolerance or allergic reactions with doxycycline.
  3. Previous chemotherapy for AL amyloidosis.

Sites / Locations

  • Froedtert & Medical College of Wisconsin

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Doxycycline

Arm Description

Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.

Outcomes

Primary Outcome Measures

Hematologic Response
This measure will record the number of subjects for each grade of response to therapy for subjects with Systematic Disease (hematologic) only. Hematologic response will be determined as follows. Complete response (CR) - Negative serum/urine immunofixation with normal Free Light Chain (FLC) ratio Very Good Partial Response (VGPR)- Difference between involved and uninvolved FLCs (dFLC) < 40 mg/L Partial Response (PR)- dFLC decrease > 50% No Response (NR)- less then PR.

Secondary Outcome Measures

Amyloid Organ Response
This measure is the number of subjects (systemic disease only) for each grade of response. Efficacy will be measured in heart, liver, or kidney. Heart N-terminal (NT)-proBNP response >30% and > 300 ng/L decrease in patients with baseline NT-proBNP ≥650 ng/L (Patients with progressively worsening renal function cannot be scored for NT-proBNP progression). Improvement by 2 New York Heart Association (NYHA) classes without an increase in diuretic use or in echocardiographic wall thickness ≥ 2 mm reduction in the interventricular septal thickness by echocardiogram or improvement of ejection fraction by ≥20%. Liver ≥50% decrease in an initially elevated alkaline phosphatase level, or Decrease in liver size by at least 2 cm by ultrasound. Kidney 50% reduction in 24-hour urine protein excretion (at least 0.5 g/day) without worsening of creatinine or creatinine clearance by 25% over baseline. Soft Tissue RECIST criteria will be used.
Mortality
The number of living subjects will be determined at Baseline, 3 months, 6 months and 1 year
Patient-reported Health Quality of Life
Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the physical health score. T-scores for this domain range from 16.2 to 67.7. Higher scores indicate poorer physical health.
Patient-reported Mental Quality of Life
Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the mental health score. T-scores for this domain range from 21.2 to 67.6. Higher scores indicate poorer mental health.

Full Information

First Posted
July 23, 2014
Last Updated
June 18, 2021
Sponsor
Medical College of Wisconsin
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT02207556
Brief Title
Doxycycline to Upgrade Organ Response in Light Chain (AL) Amyloidosis Trial
Acronym
DUAL
Official Title
Doxycycline to Upgrade Organ Response in Light Chain (AL) Amyloidosis (DUAL) Trial: A Phase II Open Label Study of Oral Doxycycline Administered as an Adjunct to Plasma Cell Directed Therapy in Light Chain (AL) Amyloidosis
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
October 1, 2014 (Actual)
Primary Completion Date
July 31, 2017 (Actual)
Study Completion Date
May 19, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical College of Wisconsin
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
In this study the investigators want to find out more about the addition of the antibiotic, doxycycline, to standard anti-amyloid therapy in people with amyloidosis. The investigators want to find out whether doxycycline improves the response to standard anti-amyloid therapy and whether it causes any problems (side effects).
Detailed Description
Organ response to anti-plasma cell therapy in AL amyloidosis tends to lags behind hematologic response as chemotherapy may not clear pre-formed organ amyloid. Doxycycline has been shown to have inhibitory effects on amyloid fibril formation as well as de-fibrillogenic effects and shown to be beneficial in in vitro, murine models and other preclinical studies. The investigators will prospectively evaluate the safety and efficacy of doxycycline in AL amyloidosis patients when used in conjunction with anti-plasma cell chemotherapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Systemic Amyloidosis
Keywords
AL amyloidosis, amyloidosis, light chain amyloidosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Doxycycline
Arm Type
Experimental
Arm Description
Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.
Intervention Type
Drug
Intervention Name(s)
Doxycycline
Other Intervention Name(s)
Doxycycline monohydrate
Intervention Description
Doxycycline will be continued until one of the following criteria is met: Patient has completed 1 year of doxycycline therapy Patient develops any grade 3-4 toxicity related to doxycycline use.
Primary Outcome Measure Information:
Title
Hematologic Response
Description
This measure will record the number of subjects for each grade of response to therapy for subjects with Systematic Disease (hematologic) only. Hematologic response will be determined as follows. Complete response (CR) - Negative serum/urine immunofixation with normal Free Light Chain (FLC) ratio Very Good Partial Response (VGPR)- Difference between involved and uninvolved FLCs (dFLC) < 40 mg/L Partial Response (PR)- dFLC decrease > 50% No Response (NR)- less then PR.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Amyloid Organ Response
Description
This measure is the number of subjects (systemic disease only) for each grade of response. Efficacy will be measured in heart, liver, or kidney. Heart N-terminal (NT)-proBNP response >30% and > 300 ng/L decrease in patients with baseline NT-proBNP ≥650 ng/L (Patients with progressively worsening renal function cannot be scored for NT-proBNP progression). Improvement by 2 New York Heart Association (NYHA) classes without an increase in diuretic use or in echocardiographic wall thickness ≥ 2 mm reduction in the interventricular septal thickness by echocardiogram or improvement of ejection fraction by ≥20%. Liver ≥50% decrease in an initially elevated alkaline phosphatase level, or Decrease in liver size by at least 2 cm by ultrasound. Kidney 50% reduction in 24-hour urine protein excretion (at least 0.5 g/day) without worsening of creatinine or creatinine clearance by 25% over baseline. Soft Tissue RECIST criteria will be used.
Time Frame
6 months and 1 year
Title
Mortality
Description
The number of living subjects will be determined at Baseline, 3 months, 6 months and 1 year
Time Frame
Baseline, 3 months, 6 months, 1 year
Title
Patient-reported Health Quality of Life
Description
Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the physical health score. T-scores for this domain range from 16.2 to 67.7. Higher scores indicate poorer physical health.
Time Frame
Baseline, 3, 6, 9 and 12 months
Title
Patient-reported Mental Quality of Life
Description
Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the mental health score. T-scores for this domain range from 21.2 to 67.6. Higher scores indicate poorer mental health.
Time Frame
Baseline, 3, 6, 9 and 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with biopsy proven AL amyloidosis. Patients ≥ 18 years of age are eligible. Patient must provide informed consent. All patients must have measurable amyloid organ involvement of a vital organ (eg. heart, liver, kidneys). Localized amyloidosis will also be eligible as long as the amyloid involvement is radiologically measurable. A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted. Patients who have previously been taking doxycycline will be eligible as long as there is no contraindication to stay on doxycycline 100 mg twice daily (BID) for 1 year in the opinion of the treating physician. Creatinine clearance of >25 ml/min. Exclusion Criteria: Patients with severe malabsorption syndrome precluding absorption of oral agents will be excluded. Known intolerance or allergic reactions with doxycycline. Previous chemotherapy for AL amyloidosis.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anita D'Souza, MD
Organizational Affiliation
Medical College of Wisconsin
Official's Role
Principal Investigator
Facility Information:
Facility Name
Froedtert & Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32529175
Citation
D'Souza A, Szabo A, Flynn KE, Dhakal B, Chhabra S, Pasquini MC, Weihrauch D, Hari PN. Adjuvant doxycycline to enhance anti-amyloid effects: Results from the dual phase 2 trial. EClinicalMedicine. 2020 Jun 5;23:100361. doi: 10.1016/j.eclinm.2020.100361. eCollection 2020 Jun.
Results Reference
derived

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Doxycycline to Upgrade Organ Response in Light Chain (AL) Amyloidosis Trial

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