Conditions: Primary Systemic Amyloidosis
Keywords: AL amyloidosis amyloidosis light chain amyloidosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

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.

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

Interventions: intervention 1: Doxycycline
Intervention descriptions: intervention 1: 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.

Protocol document:
Prot_SAP_000.pdf: 
Version Date 08-19-16 
1 
 
 
A Phase II open label study of Oral Doxycycline 
administered as an adjunct to plasma cell directed 
therapy in light chain (AL) amyloidosis. 
 
 
 
Principal Investigator: 
Anita D’Souza, MD 
 
Assistant Professor of Medicine   
 
Division of Hematology and Oncology 
 
Froedtert Hospital and the Medical College of Wisconsin 
 
9200 W. Wisconsin Ave. 
 
Milwaukee, WI 53226 
 
Co-Investigators: 
Parameswaran Hari, MD 
 
Carlos Arce-Lara, MD 
 
 
 
Statistician: 
Mei-Jie Zhang, PhD 
 
Division of Biostatistics 
 
Medical College of Wisconsin 
 
8701 Watertown Plank Road 
 
Milwaukee, WI 53226 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Coordinators 
Paulette Jacobs, BS, MS, CCRP 
Clinical Research Manager 
Cancer Center Clinical Trials Office 
Froedtert Hospital and the Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Phone: 414-805-4594 
Fax: 414-805-0596 
Email: pjacobs@mcw.edu  
 
Kirsten Jacobson, RN, MS  
Clinical Research Nurse 
Cancer Center Clinical Trials Office  
Froedtert Hospital and the Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI   53226 
Phone: (414) 805-0769  
Fax: (414) 805-8840 
 
 
Pharmacists 
Kristin Busse, Pharm D. 
Investigational Drug Pharmacy 
Froedtert Hospital  
9200 W Wisconsin Ave 
Milwaukee, WI 53226 
 
 
Abbreviations: 
AL amyloidosis- immunoglobulin light chain amyloidosis 
H&P- history & physical 
CBC- complete blood count 
β-HCG- Beta human chorionic gonadotropin 
KPS- Karnofsky Performance Status 
LVEF- left ventricular ejection fraction 
NT-proBNP- N-terminal pro-Brain Natriuretic Peptide 
BID- twice daily 
CyBorD- Cyclophosphamide/Bortezomib/Dexamethasone 
CyBorP- Cyclophosphamide/Bortezomib/Prednisone 
Mel/Dex- Melphalan/Dexamethasone 
 
 
 


Version Date 08-19-16 
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Synopsis 
A Phase II open label study of Oral Doxycycline 
administered as an adjunct to plasma cell directed 
therapy in light chain (AL) amyloidosis. 
 
PRIMARY OBJECTIVES: 
1. Determine the efficacy of adjunctive doxycycline in addition to specific anti plasma cell 
therapy in patients with AL amyloidosis in improving amyloid organ response at 1 year.  
2. Assess the safety of doxycycline + anti-plasma cell chemotherapy regimen in AL 
amyloidosis. 
 
SECONDARY OBJECTIVES: 
1. To assess rates of hematologic response. 
2. To assess rates of mortality at 1 month, 6 months and 1 year. 
3. To measure patient reported outcomes at baseline, 3, 6, 9 and 12 months. 
4. To evaluate biomarkers associated with anti-amyloid response. 
 
STUDY DESIGN: 
This is a phase II study of doxycycline for 1 year, used as an adjunct to plasma cell directed 
therapy, to improve amyloid organ response. 
 
PATIENT ELIGIBILITY CRITERIA: 
 
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 
(heart, liver, kidneys). Localized amyloidosis will 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 with history of intolerance or allergic reactions with doxycycline will not 
be eligible.  
7. Patients who have previously been taking doxycycline will be eligible as long as 
there is no contraindication to stay on doxycycline 100 mg BID for 1 year in the 
opinion of the treating physician. 
8. Creatinine clearance of >25 ml/min. 


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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. 
 
 
Patient Treatment Plan 
 
 
 
 
Step 1
•Registration
•Baseline evaluations per table of events for systemic or localized 
amyloidosis
Step 2
•Start doxycycline 100 mg BID orally
•Acceptable anti-amyloid regimens include CyBorD, Mel/Dex, CyBorP, high 
dose melphalan
•If no systemic therapy is planned for AL amyloidosis, patients may still be 
enrolled if they have measurable renal, cardiac, liver or localized 
amyloidosis.
Step 3
•Continue doxycycline until: (1) Day +360 or until patient is off IST, (2) patient 
develops progressive disease necessitating change of treatment, or (3) 
patient develops any grade 3-4 toxicity related to doxycycline.
•Monthly  visits for systemic amyloid ; Every 3 month visits for localized 
amyloid
•Months 6, 12- correlative serum specimens


Version Date 08-19-16 
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TABLE OF CONTENTS_ 
1. INTRODUCTION: .................................................................................................................................................. 7 
1.1 Amyloidosis: ....................................................................................................................................................... 7 
1.2 Tetracyclines: ...................................................................................................................................................... 7 
1.3 Doxycycline effects in Amyloidosis: .................................................................................................................. 8 
1.4 Clinical experience with Doxycycline: ............................................................................................................... 8 
1.5 Clinical data of Doxycycline in Amyloidosis: .................................................................................................... 9 
1.6 Limitations of current AL amyloidosis therapy: ................................................................................................. 9 
1.7 Study Rationale: ................................................................................................................................................ 11 
2.  OBJECTIVES ....................................................................................................................................................... 11 
2.1 Primary Objectives: .......................................................................................................................................... 11 
2.2 Secondary Objectives: ...................................................................................................................................... 11 
3. PATIENT ELIGIBILITY: .................................................................................................................................... 11 
3.1 Inclusion Criteria: ............................................................................................................................................. 11 
3.2 Exclusion Criteria: ............................................................................................................................................ 12 
4.  REGISTRATION PROCEDURE: ...................................................................................................................... 12 
4.1 Registration ....................................................................................................................................................... 12 
5. TREATMENT PLAN: .......................................................................................................................................... 12 
5.1 Administration schedule to Patients .................................................................................................................. 12 
5.2 Dose modification ............................................................................................................................................. 14 
5.3 Duration of therapy ........................................................................................................................................... 14 
5.4 Data Safety Monitoring Plan ............................................................................................................................ 14 
6.  MEASUREMENT OF EFFECT: ........................................................................................................................ 15 
6.1 Visit Schedule: .................................................................................................................................................. 15 
6.2 Amyloid Response Assessment: ....................................................................................................................... 15 
7.  STUDY PARAMETERS (STUDY CALENDAR): ............................................................................................ 16 
7.1 Patient Study Calendar:..................................................................................................................................... 16 
8. 
DRUG FORMULATION AND PROCUREMENT ...................................................................................... 20 
8.1 Doxycycline monohydrate ................................................................................................................................ 20 
8.1.1 Drug description ............................................................................................................................................ 20 
8.1.2 Pharmacodynamics ........................................................................................................................................ 21 
8.1.3 Pharmacokinetics .......................................................................................................................................... 21 
8.1.4 Contraindications .......................................................................................................................................... 21 
8.1.5 Drug Interactions ........................................................................................................................................... 22 
8.1.6 Adverse Events:............................................................................................................................................. 22 
8.2 How supplied and Storage/Handling ................................................................................................................ 23 
8.3 Methods of procurement ................................................................................................................................... 23 
9. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 24 
10. ADVERSE EVENT REPORTING REQUIREMENTS ................................................................................... 25 
10.1  Definitions ..................................................................................................................................................... 25 
11. PATIENT CONSENT AND PEER REVIEW STATEMENT ......................................................................... 29 
11.1 Subject Information and Informed Consent .................................................................................................... 29 
12.  PATIENT REPORTED OUTCOMES ASSESSMENT .................................................................................. 30 
13. CORRELATIVE SPECIMENS ......................................................................................................................... 30 


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14.  REFERENCES ................................................................................................................................................... 31 
15. 
APPENDIX A ................................................................................................................................................... 34 
16. 
APPENDIX B ................................................................................................................................................... 36 
 
 
 
 
 


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1. INTRODUCTION:   
1.1 Amyloidosis: 
The amyloidoses are a diverse group of protein misfolding diseases wherein proteins 
aggregate and form fibrillar deposits (amyloid) in tissues.1 Examples of amyloid diseases 
include Alzheimer’s disease, hereditary transthyretrin-associated familial amyloid 
polyneuropathy, dialysis related amyloidosis, AA amyloidosis with chronic systemic 
inflammatory states and immunoglobulin-derived AL amyloidosis. Human amyloid-
associated illnesses pose a therapeutic challenge since amyloid is a long-lived protein and 
there are no approved drugs demonstrated to disrupt pre-formed amyloid.  
AL amyloidosis is a malignant plasma cell disease characterized by the formation of amyloid 
from immunoglobulin light chains produced by clonal plasma cells.1 The amyloid deposits 
into vital organs such as the heart, liver, kidney, and nerves resulting in inexorable systemic 
decline in function and culminating in death. Of the 27 known proteins resulting in 
amyloidosis in humans, AL amyloidosis is the most common and the most rapidly fatal with 
a median survival of 6 months in advanced disease.2 The drugs most frequently used to treat 
AL amyloidosis eradicate cells that produce AL amyloid protein but have no effect on pre-
formed amyloid (see below). 
1.2 Tetracyclines:  
The tetracyclines are a well-established family of broad-spectrum antimicrobials first isolated 
from Streptomyces aureofaciens in 1947 from soil screening.3 Semisynthetic tetracyclines 
were developed for antibacterial use, of which doxycycline is one. Their antibiotic effect is 
primarily mediated by binding to the bacterial ribosome and inhibiting protein synthesis.  
Separate from their anti-microbial effect, tetracyclines, including doxycycline, possess the 
ability to inhibit members of the matrix metalloproteinase (MMP) family of endopeptidases. 
The MMPs are zinc-dependent proteases involved in a gamut of physiological and 
pathophysiological processes such as embryogenesis, tissue remodeling, inflammation and 
tumor invasion.4 It is hypothesized that overproduction of MMPs can result in AL renal and 
cardiac damage.5,6 High levels of MMPs appear to correlate with diastolic dysfunction and 
clinical manifestations of AL cardiomyopathy.6 Doxycycline-induced inhibition of MMPs 
appears to be beneficial in conditions associated with pathologic MMP-mediated proteolysis 
of the extracellular matrix, including cardiac remodeling, periodontitis, arthritis and cancer.7-9 


Version Date 08-19-16 
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Owing to its lipophilicity, doxycycline also concentrates in organs at sites of injury including 
gums in gingivitis, brain in meningitis and the myocardium in infarcts.10  
1.3 Doxycycline effects in Amyloidosis: 
The first report of the anti-amyloidogenic activity of doxycycline was suggested in a study of 
Alzheimer’s disease.11 Forloni, et al, showed that co-incubation of tetracyclines with β 1-42 
synthetic peptide, which is highly represented in Alzheimer amyloid deposits, resulted in a) 
marked reduction of amyloid fibril formation, b) inhibition of amyloid aggregation and c) de-
fibrillogenic effect against pre-formed amyloid fibrils.11 Cardoso, et al, tested various 
tetracyclines and showed doxycycline to be the most effective of the family in disrupting 
transthyretrin amyloid fibrils after incubation.12 This group also showed that the anti-amyloid 
effect is independent of the amyloid precursor protein.13 Doxycycline also disrupted amyloid 
in animal models, including a familial amyloid polyneuropathy transgenic mouse model.14 
Further studies showed that tetracyclines also produced de-structuration of β2-microglobulin 
in dialysis related amyloidosis15 In AL amyloidosis, Ward, et al, showed that doxycycline 
can inhibit amyloid fibril aggregation and can destroy preformed amyloid in vitro and in a 
transgenic murine AL model.16 
1.4 Clinical experience with Doxycycline: 
Doxycycline is well-tolerated and safe, and is widely used in clinical practice for 
antibacterial prophylaxis, community acquired pneumonia and chronic obstructive 
pulmonary disease. It is also efficacious in unusual infections such as Lyme disease, cholera, 
syphilis, plague and malaria.10 The side-effect profile of doxycycline is well-studied. 
Prolonged doxycycline administration at doses of 100 -200 mg daily for 6-24 months is well 
tolerated.17-19 Commonly described adverse events with doxycycline use are cutaneous 
photosensitivity and self-limiting non-specific gastrointestinal symptoms.18,19 Within our 
oncology practice, doxycycline is commonly used in patients with solid tumors and 
hematologic malignancies for anti-microbial prophylaxis in the setting of chemotherapy-
induced neutropenia, particularly in patients with penicillin allergies with good tolerance.17,20 
 
 


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1.5 Clinical data of Doxycycline in Amyloidosis: 
There are limited but positive data suggesting an anti-amyloid efficacy of doxycycline in 
humans. Montagna, et al, treated 3 patients with severe painful arthropathy related to β2-
microglobulin dialysis related amyloidosis with resolution of arthropathy in all three 
patients.21 Kumar, et al, reviewed a large cohort of AL patients who underwent stem cell 
transplantation for therapy, and received a year of doxycycline treatment for anti-bacterial 
prophylaxis. They found that among patients who had a hematologic response to stem cell 
transplantation, those patients on doxycycline prophylaxis had a higher survival rate than 
those on penicillin G prophylaxis.20 This study also suggested the tolerability and safety of 
doxycycline administration in AL amyloidosis patients even in the critical post-transplant 
setting.20 Doxycycline is currently being studied in patients with familial amyloid 
polyneuropathy. 
1.6 Limitations of current AL amyloidosis therapy: 
The current paradigm of AL amyloid treatment is focused upon eradicating the underlying 
malignant plasma cell clone with cytotoxic agents. This produces a hematologic response by 
clearing circulating immunoglobulin light chains which would have eventually been 
deposited into amyloid. Treatments range from high dose therapy with autologous stem cell 
transplantation in eligible patients, or anti-myeloma chemotherapy regimens such as 
melphalan/dexamethasone.22 Newer anti-myeloma agents such as thalidomide,23,24 
lenalidomide,25-28 pomalidomide,29 and bortezomib30,31 have excellent anti-plasma cell 
efficacy in amyloidosis but are also associated with organ and tissue toxicity making their 
use in clinical practice challenging, particularly in advanced AL disease.32  Treatment of AL 
amyloidosis thus remains a frustrating journey for patients and their treating physicians, 
where clinically tenuous and frail patients with compromised vital organ function are treated 
with cytotoxic chemotherapy that often rapidly clears light chains from serum (i.e. 
hematologic response) but does not rapidly improve organ function.  Many of these patients 
succumb to organ failure despite hematologic response.  Indeed, in many patients with 
advanced stage cardiac amyloidosis, use of newer anti-myeloma drugs such as lenalidomide 
and bortezomib causes an initial worsening in cardiac biomarkers and even death.25,30,32 
Patients with advanced stage amyloidosis have a 40% risk of mortality in the first year 
following diagnosis, a number that has not changed since the 1970s (Figure 1) 2 despite the 


Version Date 08-19-16 
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availability of more effective anti-myeloma chemotherapy that have clearly improved 
myeloma outcomes during the same time frame.33  
 
 
Figure 1. Overall survival of AL amyloidosis divided over three time periods. This figure 
shows that in the first year following diagnosis, 40% of patients die with no change in the 
three time periods.2 
As outlined above, there is a clear need to identify treatments that do more than eradicate 
the malignant clone (the primary objective of anti-myeloma therapies) to improve the 
high early mortality that occurs even while on “effective” chemotherapy. Thus, 
consideration of therapies that complement current cytotoxic anti-amyloid treatment by 
hastening organ response is required. The compelling preclinical data of doxycycline’s 
potential to benefit amyloidosis support prospective investigation of testing the use of 
doxycycline for AL amyloidosis treatment. The current study aims to generate key safety 
and efficacy data of doxycycline administration to AL amyloidosis patients. Our patients 
will potentially benefit from a novel mechanism of anti-amyloid effect in conjunction 
with anti-plasma cell chemotherapy with minimal additional risks and side-effects and, 
perhaps, even an added benefit of simultaneous anti-microbial activity.  
 


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1.7 Study Rationale: 
Organ response to anti-plasma cell therapy in AL amyloidosis lags behind hematologic 
response as chemotherapy has no effect on pre-formed amyloid.32 Doxycycline has 
pleiotropic, de-fibrillogenic and inhibitory effects on amyloid fibrils shown to be 
beneficial in in vitro, in murine  models and other preclinical studies. We will 
prospectively evaluate the safety and efficacy of  doxycycline in AL amyloidosis 
patients. 
2.  OBJECTIVES 
2.1 Primary Objectives: 
1. Determine the efficacy of adjunctive doxycycline in addition to specific anti plasma cell 
therapy in patients with AL amyloidosis in improving amyloid organ response at 1 year.  
2. Assess the safety of doxycycline + anti-plasma cell chemotherapy regimen in AL 
amyloidosis. 
2.2 Secondary Objectives: 
1. To assess rates of hematologic response. 
2. To assess rates of amyloid organ response at months 6 and 12. 
3. To assess rates of mortality at 1 month, 6 months and 1 year. 
4. To measure patient reported outcomes at baseline, 3, 6, 9 and 12 months. 
5. To evaluate biomarkers associated with anti-amyloid response. 
3. PATIENT ELIGIBILITY: 
3.1 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 (heart, 
liver, kidneys). Localized amyloidosis will 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 doxycyline will be eligible as long as there is 
no contraindication to stay on doxycycline 100 mg BID for 1 year in the opinion of the 
treating physician. 
7. Creatinine clearance of >25 ml/min. 


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3.2 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. 
4.  REGISTRATION PROCEDURE: 
4.1 Registration  
• 
All source documents that support eligibility including a signed informed 
consent/HIPAA and signed eligibility checklist, should be available review and 
eligibility verification.   
• 
At the point of registration, the research nurse or data manager will register the patient in 
the electronic database, including demographic, consent and on-study information.  The 
patient will be assigned a unique sequence number for the study. 
5. TREATMENT PLAN: 
This is a phase II study of doxycycline as an adjunct to anti-amyloid treatment in patients with 
AL amyloidosis.  
5.1 Administration schedule to Patients  
1. Doxycycline will be administered at dose of 100mg orally twice daily. Baseline blood 
and urine laboratory testing must be completed within 28 days prior to starting 
doxycycline. 
2. Patients who have previously been taking doxycycline will be eligible as long as there 
is no contraindication to take doxycycline (200mg/day) and continue for 1 year in the 
opinion of the treating physician.  
3. Patients undergoing chemotherapy for AL amyloidosis can receive one of following 
regimens: 
a. Melphalan/Dexamethasone (Palladini regimen)22 
Oral Melphalan 0.22 mg/kg + Dexamethasone 40 mg , Days 1-4, every 28 
days 
b. Cyclophosphamide/Bortezomib/Dexamethasone.34  


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Cyclophosphamide 300 mg/m2 + Bortezomib 1.3 mg/m2 + Dexamethasone 40 
mg, days 1, 8, 15 every 28 days. Any combinations of these medications will 
be allowed based on treating clinician’s judgement. 
c. High dose Melphalan/Stem Cell rescue.35 
IV Melphalan 140-200 mg/m2 followed by autologous stem cell infusion 
d. Other chemotherapy regimens will be permitted after consultation with study 
PI. Dose modifications in treatments will be allowed per opinion of the 
treating physicians. 
4. Antibiotic prophylaxis in patients undergoing high dose melphalan will be given 
according to institutional guidelines. Routine antibacterial prophylaxis will be 
substituted with doxycycline. If clinically indicated, additional antibacterial coverage 
will be provided depending on physician judgment. 
5. Temporary interruption (≤10-14days) of doxycycline is permitted in patients unable 
to tolerate oral intake secondary to severe nausea, vomiting, mucositis etc. In case 
doxycycline therapy is interrupted, the time interval should be recorded. 
6. Patients with severe macroglossia from amyloid involvement will have the option of 
using doxycycline oral suspension. 
7. Toxicity will be evaluated according to CTCAE v4.0. 
8. Hematologic response following treatment will be recorded at monthly intervals until 
chemotherapy is stopped or no longer indicated. 
9. Organ response will be recorded at 6 and 12 months using RECIST criteria.36 
10. Overall survival will be measured at 1 month, 6 months, 12 months, and yearly until 
five years. 
11. If chemotherapy is switched due to inadequate hematologic response, continued 
doxycycline use will be permitted.  
12. Patients on warfarin will be monitored as doxycycline may enhance anticoagulant 
effect of warfarin. 
13. Patients on antacids containing aluminum, calcium or magnesium and iron-containing 
preparations can impair absorption of doxycycline. Doxycycline administration will 
be 2 hours before or after any of these medications. Since dairy products also contain 


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calcium, patients will be counselled to avoid dairy products 2 hours before and after 
doxycycline ingestion.  
5.2 Dose modification 
1. Patients experiencing a grade 3-4 hematological or non-hematological toxicity (as 
specified in CTCAE v4.0) thought to be related to doxycycline will be removed from 
the study permanently. The following dose modifications for doxycycline will be 
permitted : Dose lowering down to 50 mg BID may be permitted if patient cannot 
tolerate 100 mg BID due to side effects. 
5.3 Duration of therapy 
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. 
Patients experiencing an amyloid hematologic relapse can continue doxycycline at the 
discretion of treating physician as long as there is no organ worsening.  
Patients who discontinue prior to 1 year of doxycycline therapy should have an End of 
Treatment visit.  
5.4 Data Safety Monitoring Plan 
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data 
Safety Monitoring Committee (MCW CC DSMC). A summary of the MCW CC DSMC 
activities are as follows:  
• 
Review the clinical trial for data integrity and safety  
• 
Review all unexpected grade 3, and all grade 4, and 5 adverse events, as 
well as any others requiring expedited reporting as defined in this 
protocol. Review all DSM reports  
• 
Submit a summary of any recommendations related to study conduct  
• 
Terminate the study if deemed unsafe for patients  
A copy of the MCW CC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee 


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will review reports from the study PI twice annually (or more frequently if needed) and 
provide recommendations on trial continuation, suspension or termination as necessary. 
 
Any available DSMC letters will be submitted to the IRB of record as required. 
6.  MEASUREMENT OF EFFECT: 
6.1 Visit Schedule: 
The schedule for the study is shown in the table below. 
Study Visit  
Target Day  
Baseline  
 Day -1 to -42 
Month 1 
Day 0  
Month 2 
Day 30 ± 5 
Month 3 
Day 60 ± 7  
Month 4 
Day 90 ± 10  
Month 5 
Day 120 ± 10  
Month 6 
Day 150 ± 10  
Month 7 
Day 180 ± 15  
Month 8 
Day 210 ± 15  
Month 9 
Day 240 ± 15  
Month 10 
Day 270 ± 21  
Month 11 
Day 300 ± 21  
Month 12 
Day 330 ± 28  
End of study treatment 
Day 360 ± 30 
 
*After 12months, patients will be followed at least yearly for survival, amyloid 
relapse and cause of death for 5 years post treatment. 
 
6.2 Amyloid Response Assessment: 
Amyloid hematologic response assessment will be undertaken at monthly intervals using 
serologic studies with a serum protein electrophoresis, immunofixation electrophoresis and 
free light chain analysis. Monthly troponin-T, NT-pro BNP, alkaline phosphatase, creatinine 
will also be obtained per clinical physician’s judgment. 
Formal organ assessments will be undertaken at months 6 and 12. For patients with cardiac 
involvement, an echocardiogram will be repeated in addition to troponin-T and NT-pro 
BNP. For patients with liver involvement, an abdominal ultrasound and alkaline 
phosphatase will be done. For patients with renal involvement, a 24 hour urinary protein 
with urine protein electrophoresis and immunofixation electrophoresis will be checked. 


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16 
 
For patients with localized amyloidosis, radiologic testing with a CT scan will be conducted.  
 
Hematologic Response Grading37(See Appendix A) 
Complete response (CR) – Negative serum/urine immunofixation with normal 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. 
 
 
Organ Response Grading32(See Appendix A) 
Heart 
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 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. 
 
7.  STUDY PARAMETERS (Study Calendar): 
7.1 Patient Study Calendar:  
The table below summarizes the patient clinical assessments over the course of the study.* 


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17 
 
Systemic Amyloidosis 
 
Months 
 
 
Baseline^ 
1^ 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
End of Treatment (within 30 
days) 
Inclusion & Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
H & PE1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
NYHA class 
X 
 
 
 
 
 
X8 
 
 
 
 
 
X8  
X8 
Complete Blood Count with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistries panel3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Amyloid subtype# 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta2 microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Myeloma screening panel4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow aspirate/biopsy 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
Β-HCG serum pregnancy test 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone survey11 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
2D echocardiogram (IVS + LVEF) 
X 
 
 
 
 
 
X8 
 
 
 
 
 
 
X8† 
Troponin-T, NT-proBNP 
X 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8† 
Abdominal Imaging 
X7 
 
 
 
 
 
X9 
 
 
 
 
 
 
X9† 
24 hour urinary protein with 
UPEP/immunofixation 
X10 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
 
X10 † 
Toxicity assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Research specimens 6 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X† 
Patient questionnaire (Appendix B) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Version Date 08-19-16 
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Notes  
H & PE= history and physical examination 
ECOG- Eastern Co-operative Oncology Group performance score 
NYHA- New York Heart Association Class 
2D echocardiogram- Two-dimensional transthoracic echocardiogram 
IVS- interventricular septal thickness 
LVEF- left ventricular ejection fraction 
^ Baseline and Month 1 can occur within 7 days without the need to repeat the Month 1 testing. 
# If a patient has had amyloid subtyping performed in the past, this need not be repeated again. 
† May be performed anytime during cycle 12 or within 30 days of the last dose of doxycycline 
1History is only required at baseline. 
2Vital signs: blood pressure, pulse rate, respiratory rate and temperature. 
3Serum chemistries panel: electrolytes, BUN, ALT, AST, creatinine, bilirubin, alkaline phosphatase, 
LDH, albumin, uric acid. Electrolytes to include sodium, potassium, chloride, carbon dioxide, and 
calcium. 
4Myeloma screening panel includes serum protein electrophoresis, immunofixation electrophoresis, 
free light chain assay 
5Females of reproductive potential only. 
6Peripheral blood specimens: draw 6 mL in  green top  (heparin containing) tube at indicated time 
points and send to the Tissue Bank at MCW after processing. Samples should be labeled with patient 
study number, date of collection, time point (baseline, 6 months or End of Treatment and MCW/FH 
IRB PRO number. 
7 May be performed within 3 months of baseline 
8Cardiac assessment will be followed only if baseline cardiac involvement 
9Abdominal imaging will be performed only if there is a suspicion of hepatic or splenic involvement 
based on hepatomegaly or splenomegaly on physical examination or labs (increased alkaline 
phosphatase greater than or equal to twice the upper limit of normal) and repeated only if there is 
baseline organ involvement 
10Urinary studies: A urine protein/creatinine ratio which has ~100% concordance to 24 hour urinary 
protein will be allowed to test for baseline renal involvement. Urinary studies will be repeated only if 
baseline renal involvement. The urine test will remain consistent for a given patient, eg. if baseline 
urinary test was 24 hour urinary protein, the follow up tests for that patient will also be 24 hour 
urinary protein. 
11 Not required if ≤10% plasma cells in bone marrow 


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Classic localized amyloidosis 
 
 
Baseline^ 
1^ 
4 
7 
10 
End of Treatment (within 30 
days) 
Inclusion & Exclusion criteria 
X 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
H & PE1 
X 
X 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
 
X 
X 
X 
X 
Complete Blood Count with differential 
X 
X 
X 
X 
X 
X 
Serum chemistries panel3 
X 
X 
X 
X 
X 
X 
Amyloid subtype# 
X 
 
 
 
 
 
Beta2 microglobulin 
X8 
 
 
 
 
 
Myeloma screening panel4 
X 
X8 
X8 
X8 
X8 
X8 
Β-HCG serum pregnancy test 5 
X 
 
 
 
 
 
Troponin-T, NT-proBNP 
X8 
 
 
 
 
 
24 hour urinary protein with UPEP/immunofixation 
X8* 
 
 
 
 
 
Bone marrow aspirate/biopsy 
X* 
 
 
 
 
 
2D echocardiogram (IVS + LVEF) 
X* 
 
 
 
 
 
Abdominal Imaging 
X* 
 
 
 
 
 
Radiologic imaging7 
X 
 
 
X 
 
X† 
Toxicity assessment 
 
X 
X 
X 
X 
 
Research specimens 6 
X 
 
 
X 
 
X† 
Patient questionnaire (Appendix B) 
X 
 X 
X 
X   X 
X 
 
Notes 
H & PE= history and physical examination 
ECOG- Eastern Co-operative Oncology Group performance score 
^ Baseline and Month 1 can occur within 7 days without the need to repeat the Month 1 testing. 
† May be performed anytime during cycle 12 or within 30 days of the last dose of doxycycline 
*Bone marrow evaluation, 2D echocardiogram, Abdominal Ultrasound and 24 hour urine protein test 
may be held based on the treating physician’s judgment. 
# If a patient has had amyloid subtyping performed in the past, this need not be repeated again. 
1History is only required at baseline. 


Version Date 08-19-16 
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2Vital signs: blood pressure, pulse rate, respiratory rate and temperature. 
3Serum chemistries panel: electrolytes, BUN, ALT, AST, creatinine, bilirubin, alkaline phosphatase, 
LDH, albumin, uric acid. Electrolytes to include sodium, potassium, chloride, carbon dioxide, and 
calcium. 
4Myeloma screening panel includes serum protein electrophoresis, immunofixation electrophoresis, 
free light chain assay. 
5Females of reproductive potential only. 
6Peripheral blood specimens: draw 6 mL in green top (heparin containing) tube at indicated time 
points and send to the Tissue Bank at MCW after processing. Samples should be labeled with patient 
study number, date of collection, time point (baseline, 7 months or End of Treatment) and MCW/FH 
IRB PRO number. 
7Radiologic imaging: as clinically indicated  
8 Per MD discretion  
8. Drug Formulation and Procurement 
8.1 Doxycycline monohydrate 
8.1.1 Drug description 
Doxycycline is a synthetic antibacterial drug derived from oxytetracycline and 
available for oral administration. Doxycycline monohydrate has the empirical 
formula of C22H24N2O8.H2O and a molecular weight of 462.46. The chemical 
designation for doxycycline is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-
octahydro-3,5,10,12,12a pentahydroxy-6-methyl-1,11-dioxo-2-
naphthacenecarboxamide monohydrate. It is a light yellow crystalline powder and 
very slightly soluble in water. It has a high degree of lipod solubility and a low 
affinity for calcium binding. It is highly stable in normal human serum. It is 
available in syrup, capsule, oral suspension and tablet formulations. Inert 
ingredients in the tablet formulation are ethylcellulose; hypromellose; magnesium 
stearate; microcrystalline cellulose; propylene glycol; sodium lauryl sulfate; talc; 
titanium dioxide; Yellow 6 Lake. Inert ingredients for the oral suspension 
formulation are: carboxymethylcelluose sodium; Blue 1; methylparaben; 
microcrystalline cellulose; propylparaben; raspberry flavor; Red 28; simethicone 
emulsion; sucrose. 


Version Date 08-19-16 
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 8.1.2 Pharmacodynamics 
Tetracyclines are readily absorbed and bound to plasma proteins in varying 
degree. They are concentrated by the liver in the bile, and excreted in the urine 
and feces at high concentrations and in a biologically active form. Doxycycline is 
virtually completely absorbed after oral administration. 
8.1.3 Pharmacokinetics 
Doxycycline is virtually completely absorbed after oral administration. 
Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 
2.6 mcg/ml of doxycycline at 2 hours, decreasing to 1.45 mcg/ml at 24 hours. 
Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with 
normal renal function. This percentage excretion may fall as low as 1-5%/72 
hours in individuals with severe renal insufficiency (creatinine clearance below 10 
ml/min). Studies have shown no significant difference in serum half-life of 
doxycycline (range 18-22 hours) in individuals with normal and severely impaired 
renal function.  
 8.1.4 Contraindications  
Hypersensitivity to any Component of this Medication 
Pregnancy 
Nursing Mothers 
Children under 8 years 
Active Clostridium difficile associated disease 
 


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 8.1.5 Drug Interactions 
 
Interacting Agents                          
Prescribing Recommendations 
Antacids containing aluminum, calcium, or 
magnesium and iron-containing preparations can 
impair absorption 
Avoid doxycycline administration for 2 
hours before and after any of these 
medications. 
Barbiturates, carbamazepine, and phenytoin 
increase the half-life of doxycycline 
No dose modifications recommended. 
                                               
8.1.6 Adverse Events: 
Gastrointestinal side-effects 
Anorexia, nausea, vomiting, diarrhea, glossitis can occur. Rare instances of 
esophagitis and esophageal ulcerations have been reported in patients receiving 
capsule and table forms of the drug. Most of these patients took the medications 
immediately before going to bed. 
 
Cutaneous reactions 
Photosensitivity manifested by an exaggerated sunburn reaction has been 
observed. Patients should be advised against direct sunlight exposure and to use 
adequate sun protection with sunscreen. Uncommon skin reactions include toxic 
epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, 
maculopapular and erythematous rashes and exfoliative dermatitis. 
Renal toxicity 
An increase in blood urea nitrogen from an anti-anabolic action has been reported 
from doxycycline. 
Immune 
Hypersensitivity reactions including urticarial, angioneurotic edema, anaphylaxis, 
anaphylactoid purpura, serum sickness, pericarditis, exacerbation of systemic 
lupus erythematosus and drug rash with eosinophilia and systemic symptoms 
(DRESS) syndrome have been rarely reported. 
 
 


Version Date 08-19-16 
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Hematologic 
Hemolytic anemia, thrombocytopenia, neutropenia and eosinophilia have been 
reported. 
Dental 
The use of tetracyclines during tooth development (last half of pregnancy, infancy 
and childhood to the age of 8 years) may cause permanent discoloration of teeth 
(yellow-gray-brown). Enamel hypoplasia has also been reported.  
Clostridium difficile associated diarrhea (CDAD) 
CDAD has been reported with the use of nearly all antibacterial agents, including 
doxycycline, and may range in severity from mild diarrhea to fatal colitis.  
8.2 How supplied and Storage/Handling  
Doxycycline monohydrate is available in salmon colored film-coated tablets containing 
doxycycline monohydrate equivalent to 100 mg of doxycycline, bottles of 50 (NDC 
0069-0990-50) 
Doxycycline monohydrate for oral suspension is available as a raspberry-flavored, dry 
powder for oral suspension. When reconstituted, each 5 ml contains doxycycline 
monohydrate equivalent to 25 mg of doxycycline: 2 oz (60 ml) bottles (NDC 0069-0970-
65) 
All products are to be stored below 86ºF (30ºC) and dispensed in tight, light-resistant 
containers (USP). 
8.3 Methods of procurement         
The Froedtert Hospital Departments of Pharmacy will order Doxycycline 100 mg and 
receive drug specifically for this study.  The CTO (at MCW) will be billed for the cost of 
the drug which will be paid for by study funds.  The drug will be dispensed per patient (1 
month supply at a time for systemic amyloidosis; 3 month supply at a time for local 
amyloidosis) and labeled according to more stringent state or federal law.  Drug 
accountability and inventory records will be created and maintained within the 
Investigational Drug Services. 
 
 


Version Date 08-19-16 
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9. STATISTICAL CONSIDERATIONS 
 
The study is a single-arm phase II trial evaluating the safety and efficacy of doxycycline used in 
adjunct to anti-amyloid treatment to improve organ response in patients with AL amyloidosis. 
The primary objective of this study is to evaluate the cumulative organ response at 1 year. The 
incidence of organ response to conventional chemotherapy at 1 year is approximately 20-25%. 
At the time of publication the results of the study will be retrospectively compared against AL 
amyloidosis patients undergoing chemotherapy alone at our institution in the last 5 years. 
 
For this phase II study, we will use an exact single-stage phase II design. We will consider the 
“experimental” regimen of doxycycline with conventional anti-amyloid treatment to be no more 
effective than conventional anti-amyloid treatment alone, the true probability of organ response 
at 1 year is no less than 25% (p0). We will assume that the new experimental regimen is worthy 
of further study of the true probability of organ response greater than 50% (p1). In statistical 
terms, we are testing the null hypothesis H0: p≤0.25, versus the alternate H1: p≥0.5, where p is 
probability of organ response. Our power analysis indicated that we will need 26 patients to have 
80% power to detect the designed difference at 5% significance level. We will increase the 
sample size by 15% to 30 in order to account for patients with advanced disease who may die 
prior to response. Patients dying prior to response are a competing risk event. The probability of 
response will be calculated using the cumulative incidence curve to accommodate for competing 
risks. Six month and twelve month cumulative incidence rates of response with 95% confidence 
intervals will be reported. Point-wise test will be considered to compare response rates of study 
patients to response rates under standard treatment using historical controls from published 
literature.  
In the final analysis, if 11 or more of the patients develop organ response we will reject the null 
hypothesis. 
We anticipate that a maximum of 30 patients will be accrued to the study. Descriptive statistics 
(i.e. means, standard deviations, 95% confidence intervals for continuous variables, and 
frequencies for discrete data) will be computed for all correlative laboratory parameters. Patients 
who receive <1 month of doxycycline therapy and withdraw from the study will be replaced. 
 
 


Version Date 08-19-16 
25 
 
Safety/Stopping Rules: 
1. 
Development of grade 3-4 adverse events deemed to be related to doxycycline in 6 or 
more patients, will mandate halting further patient accrual until review by DSMB. 
 
Accrual Estimate: 26-30 patients. Patients experiencing mortality within 30 days of starting 
treatment due to disease progression, will be replaced to fully assess 1 year amyloid organ 
response. However, all patients will be included in toxicity and survival analysis. 
 
Accrual Period :  Approximately 12-24 months 
 
 
Follow-Up Period : One year to evaluate incidence of amyloid (hematologic and organ) 
response and relapse pattern. Five years for survival outcomes, relapse, and mortality.  
10. ADVERSE EVENT REPORTING REQUIREMENTS 
10.1  Definitions 
The following are definitions of adverse events as defined by 21CFR312.32. 
 
Types of Adverse Events 
 
Adverse Event means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not consider drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction:  An 
adverse event or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
Serious adverse event or serious suspected adverse reaction:  An adverse event or 
suspected adverse reaction is considered “serious” if, in the view of the investigator or 
sponsor, it results in any of the following outcomes: 
• Death, 
• A life-threatening prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
• A congenital anomaly/birth defect. 


Version Date 08-19-16 
26 
 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent of the outcomes listed above.   
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  “Reasonable possibility” means there 
is evidence to suggest a causal relationship between the drug and the adverse event.  
Suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any adverse event caused by a drug. 
 
Unexpected adverse event or unexpected suspected adverse reaction:  An adverse 
event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; 
or, if an investigator brochure is not required or available, it is not consistent with the risk 
information currently described.   
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
 
 
Adverse Event Grading 
 
Grade 
Description 
 
0 
No AE (or within normal limits). 
 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
 
2 
Moderate; minimal, local or noninvasive intervention (e.g., packing 
cautery) indicated; limiting age-appropriate instrumental activities of 
daily living (ADL). 
 


Version Date 08-19-16 
27 
 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
 
4 
Life-threatening consequences; urgent intervention indicated. 
 
5 
Death related to AE 
 
 
Adverse Event Attribution 
 
Relationship 
Attribution 
Description 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to 
the intervention 
Unlikely 
The AE is doubtfully related to 
the intervention 
Related to investigational 
agent/intervention 
Possible 
The AE may be related to the 
intervention 
Probable 
The AE is likely related to the 
intervention 
Definite 
The AE is clearly related to the 
intervention 
 
 
Reporting of Adverse Events 
Because all of the study transplant recipients will be receiving potentially toxic preparative 
therapy, significant regimen related toxicity is expected.  A study specific toxicity CRF 
will be designed to capture information regarding these expected events.  Unexpected 
adverse events will be reported throughout the study. 
 
Unexpected Adverse Events 
Unexpected Grades 3-5 (severe, life threatening, disabling, or fatal) require expedited 
reporting and will be submitted to the DSMC within 5 calendar days of discovery for 
review.  If the Grade 3-5 event is determined to be an unanticipated problem, the event will 
be forwarded to the MCW/FH IRB for review as required by their policy.  Unexpected 
adverse events, regardless of severity, will be reported to the DSMC and reviewed on a 
quarterly basis. 
 
 


Version Date 08-19-16 
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Expected Adverse Events 
Grade 4 (non hematologic) and Grade 5 (fatal) expected adverse events require expedited 
reporting and will be reported to the DSMC within 5 calendar days for review.  Expected 
Grade 4 hematologic and GI toxicity adverse events do not require expedited reporting. 
Expected adverse events that are being captured on the study toxicity form will be reported 
at the time of the form’s scheduled due date.   
 
All DSMC reports and recommendations will be submitted to the IRB for their review. 
 
Adverse Events Occurring after the End of the Study 
 
Follow-up of AEs 
Any unexpected AEs ongoing at the time of study discontinuation will be followed until 
resolution or stable for at least 2 months.  
 
FDA Reporting Procedures  
 
Commercial Agents:    Commercial agents are those agents not provided under an IND 
but obtained instead from a commercial source.  In some cases an agent obtained 
commercially may be used for indications not included in the package label.  The 
following procedures should be followed to determine if an adverse is reportable to the 
FDA: 
 
Refer to the pharmaceutical section of the protocol to determine if an agent is 
investigational or commercial.   
• 
WHAT TO REPORT:  An unexpected, life-threatening (Grade 4) or unexpected, fatal 
(Grade 5) adverse event with an attribution of possible, probable or definite. 
 
• 
WHEN TO REPORT:  These events should be reported within (7) working days. 
 
• 
WHERE TO REPORT:  These adverse events with commercial agents must be 
reported to the FDA using the MedWatch form.  A copy of the MedWatch form can be 


Version Date 08-19-16 
29 
 
obtained from theFDA’s MedWatch web site at www.fda.gov/medwatch.  You can mail 
the reports to the address below or fax it 1-800-332-0178. 
MedWatch 
 
5600 Fishers Lane 
Rockville, MD 20852-9787 
 
11. PATIENT CONSENT AND PEER REVIEW STATEMENT 
11.1 Subject Information and Informed Consent 
 
Written informed consent must be obtained from the subject prior to study participation. 
 
The informed consent document must be signed and dated by the subject and properly 
witnessed (if applicable) before initiation of any study procedures including any change in 
medication or initiation of study drug dosing.   
 
Subjects must be consented in accordance with all local regulatory and legal requirements.  
This process must include a verbal explanation of the nature, scope, and possible 
consequences of the study provided in plain language.  The information should be 
presented by the investigator unless a designee is permitted by local regulations.  The 
potential study subject should be encouraged to ask questions about the study.   
 
The informed consent document must be prepared in accordance with GCP guidelines and 
with local regulatory and legal requirements.  A copy of the signed consent form will be 
given to the subject and the original document must be safely archived by the investigator 
so that the forms can be retrieved at any time for monitoring, auditing, and inspection 
purposes. 
 
The informed consent will be updated as appropriate (e.g., due to protocol amendment or 
if significant new safety information that may be relevant to consent of the subjects 
becomes available).  If the informed consent is revised, it is the investigator’s responsibility 


Version Date 08-19-16 
30 
 
to ensure that an amended consent form is reviewed and signed by all subjects subsequently 
entered into the study and those currently in the study. 
12.  PATIENT REPORTED OUTCOMES ASSESSMENT 
We will collect patient-reported health quality of life in this study.   
 
At baseline, at each subsequent study visit and End of Treatment visit, the study coordinator will 
ask patients to complete a questionnaire to report on common domains of health-related quality 
of life using the Patient Reported Outcomes Measurement Informations System (PROMIS) 
Global Health instrument (See Appendix B), a 10-item standardized patient-reported outcome 
measure that provides global ratings of physical function, fatigue, pain, emotional distress, social 
health, as well as perceptions of general health that cut across these key domains.38 
We will describe the patient experience over the course of the year.  
13. CORRELATIVE SPECIMENS 
We will collect serum from patients at baseline, months 6 and 12. These specimens will be stored 
in the Tissue Bank at MCW. We will perform serum inflammatory markers known to be 
associated with doxycycline use8 to identify possible biomarkers of amyloid response to 
doxycycline. We will obtain MMP-2, MMP-7, MMP-8, MMP-9 and TIMP-1 (tissue inhibitor of 
metalloproteinase-1) levels in all patients at baseline, months 6 and 12 of doxycycline use. To 
measure MMP activity, zymograms will be performed on sera from all the patients.  Briefly, 
zymography is a simple sensitive and functional assay to analyze MMP activity.  Proteins are 
separated by electrophoresis utilizing SDS-PAGE gels containing the according MMP substrate, 
MMP2 and 9 are gelatinases therefore the gel will contain gelatin.  The gel for MMP7 will 
contain casein and for MMP8 collagen-I.  The MMP activity will be measured by the 
degradation of the substrate and therefore the inability of Coomassie Blue to stain the gel at the 
molecular weight appropriate spot.  The TIMP-1 expression will be measured by ELISA utilizing 
TIMP-1 ELISA kit (abcam #ab100651).39,40  Briefly, ELISA is a test that uses antibodies and 
color change to identify an antigen in a liquid substrate measured with a microplate reader. These 
tests will be performed in the Weihrauch Laboratory at MCW using techniques that have already 
been optimized and validated in human sera and myocardial interstitial fluid.41-45 Descriptive 
statistics will be computed for all the correlative laboratory parameters. If a significant difference 


Version Date 08-19-16 
31 
 
is seen in these biomarkers at 6 and 12 months, and organ response is seen (i.e. positive study), 
these results will be used to for further hypothesis generating questions, and phase III design.  
 
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Blood 118:827-8, 2011 
 
32. 
Dispenzieri A, Gertz MA, Buadi F: What do I need to know about 
immunoglobulin light chain (AL) amyloidosis? Blood Rev 26:137-54, 2012 


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33. 
Kumar SK, Rajkumar SV, Dispenzieri A, et al: Improved survival in multiple 
myeloma and the impact of novel therapies. Blood 111:2516-20, 2008 
 
34. 
Venner CP, Lane T, Foard D, et al: Cyclophosphamide, bortezomib, and 
dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and 
prolonged progression-free survival. Blood 119:4387-90, 2012 
 
35. 
Jaccard A, Moreau P, Leblond V, et al: High-dose melphalan versus melphalan 
plus dexamethasone for AL amyloidosis. N Engl J Med 357:1083-93, 2007 
 
36. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
 
37. 
Palladini G, Dispenzieri A, Gertz MA, et al: New criteria for response to 
treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and 
cardiac biomarkers: impact on survival outcomes. J Clin Oncol 30:4541-9, 2012 
 
38. 
Hays RD, Bjorner JB, Revicki DA, et al: Development of physical and mental 
health summary scores from the patient-reported outcomes measurement information system 
(PROMIS) global items. Qual Life Res 18:873-80, 2009 
 
39. 
Xu H, Krolikowski JG, Jones DW, et al: 4F decreases IRF5 expression and 
activation in hearts of tight skin mice. PLoS One 7:e52046, 2012 
 
40. 
Xu H, Zaidi M, Struve J, et al: Abnormal fibrillin-1 expression and chronic 
oxidative stress mediate endothelial mesenchymal transition in a murine model of systemic 
sclerosis. Am J Physiol Cell Physiol 300:C550-6, 2011 
 
41. 
Weihrauch D, Lohr NL, Mraovic B, et al: Chronic hyperglycemia attenuates 
coronary collateral development and impairs proliferative properties of myocardial interstitial 
fluid by production of angiostatin. Circulation 109:2343-8, 2004 
 
42. 
Snoek-van Beurden PA, Von den Hoff JW: Zymographic techniques for the 
analysis of matrix metalloproteinases and their inhibitors. Biotechniques 38:73-83, 2005 
 
43. 
Matsunaga T, Weihrauch DW, Moniz MC, et al: Angiostatin inhibits coronary 
angiogenesis during impaired production of nitric oxide. Circulation 105:2185-91, 2002 
 
44. 
Ludwig LM, Tanaka K, Eells JT, et al: Preconditioning by isoflurane is mediated 
by reactive oxygen species generated from mitochondrial electron transport chain complex III. 
Anesth Analg 99:1308-15; table of contents, 2004 
 
45. 
Gogly B, Groult N, Hornebeck W, et al: Collagen zymography as a sensitive and 
specific technique for the determination of subpicogram levels of interstitial collagenase. Anal 
Biochem 255:211-6, 1998 
 
 
 


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15. APPENDIX A 
 
Hematologic response definition 
 
 
 
 


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Organ response criteria 
 
 
 


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16. APPENDIX B 
 
 


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ICF_001.pdf: 
Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00022850  
IRB Approval Period: 9/14/2016 – 2/10/2017  
Page 1 of 12 
Version: 08-18-16  
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MCW/FH IRB
 
Medical College of Wisconsin and Froedtert Hospital 
CONSENT TO PARTICIPATE IN RESEARCH 
 
Name of Study Subject: ____________________________ 
 
A Phase II open label study of oral Doxycycline administered as an adjunct to 
plasma cell directed therapy in light chain (AL) amyloidosis 
 
Anita D’Souza, MD 
Department of Medicine 
414-805-6800 
Froedtert & the Medical College of Wisconsin 
9200 W. Wisconsin Avenue 
Milwaukee WI 53226 
414-805-6800 
 
You are invited to take part in this research study. This form tells you why this research 
study is being done, what will happen in the research study, possible risks and benefits 
to you, your choices, and other important information. If there is anything that you do not 
understand, please ask questions. Then you can decide if you want to join this study or 
not.   
 
A1. INTRODUCTION – WHY ARE WE ASKING YOU ABOUT THIS STUDY? 
You are being invited to participate in this research study because you have systemic or 
localized Amyloid light chain (AL) amyloidosis. 
 
A total of about 30 people are expected to participate in this study at the Medical 
College of Wisconsin/Froedtert Hospital. 
 
The Director of the study is Anita D’Souza, MD in the Department of Medicine. A study 
team works with Dr. D’Souza. You can ask who these people are.  
 
The study is funded through an American Cancer Society Institutional Research Grant 
through the Medical College of Wisconsin Cancer Center pilot grant program. 
 
A2. DO I HAVE TO BE IN THIS STUDY? 
You can decide whether to take part in this study or not. You are free to say yes or no. If 
you say no, your regular medical care will not change. Even if you join this study, you do 
not have to stay in it. You may stop at any time.  
 
A research study is different from routine medical care in three ways: 1) there are extra 
risks that we will tell you about in this form; 2) you may have some extra medical tests 
and visits; 3) the study procedures, tests and visits follow a set plan that must be kept. 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
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IRB Approval Period: 9/14/2016 – 2/10/2017  
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A3. WHY IS THIS RESEARCH STUDY BEING DONE? 
In this study we want to find out more about the addition of the antibiotic, doxycycline, to 
standard anti-amyloid therapy in people with AL amyloidosis. We want to find out 
whether doxycycline improves the response to standard anti-amyloid therapy and 
whether it causes any problems (side effects). Everyone in this study will receive 
doxycycline which is approved by the U.S. Food and Drug Administration for use in 
patients but not with your condition.  We are testing doxycycline to see what effect it has 
on people with light chain (AL) amyloidosis. Results from this study might be used in a 
future study. 
 
B1. WHAT WILL HAPPEN IF I TAKE PART IN THE STUDY?   
 
Screening procedures:  
If you decide to join the study, you will be asked to sign this consent form. You will have 
the following screening tests to see if you are eligible to take part in the study: 
 Medical History:  A complete past and current medical history will be taken 
including any medications you have used or are currently using. 
 Physical Exam with Vital Signs: A complete physical exam will be conducted with 
measurement of your blood pressure, pulse rate, respiratory rate and 
temperature  
 Your level of activity will be assessed 
 Blood Samples: Blood (approximately 4 teaspoons) for routine laboratory testing 
to monitor your blood counts, blood chemistry, light chains and heart function. 
 Pregnancy Test:  If you are a woman who is able to have a baby, a blood sample 
will be taken to make sure you are not pregnant.   
 If your doctor determines it is necessary, urine samples will be collected over a 
24 hour period of time.  You will be provided collection cups for the collection of 
urine while you are at home.  Your doctor will decide if you need to provide 
additional urine samples during the rest of the study. 
 You will be asked to complete a questionnaire about how you are feeling. This 
questionnaire will take about 15 minutes to complete 
 If you have localized amyloidosis and if your doctor determines it is necessary, 
you will have a CT scan to assess your disease.  A CT Scan is a type of x-ray 
using computers. 
 
The following screening procedures will be performed for patients with systemic 
amyloidosis. If you have localized amyloidosis, your study doctor will decide if you need 
to have the procedures done. 
 Abdominal Imaging: Imaging of the abdomen will be performed. Your doctor will 
determine what type of imaging you will receive Your doctor will decide if you 
need additional imaging of the abdomen during the rest of the study.  
 Echocardiogram (also called an “echo”): echocardiogram is a test in which 
ultrasound is used to examine heart function. Your doctor will decide if you need 
additional echocardiograms during the rest of the study.  


Medical College of Wisconsin & Froedtert Hospital  
 
 
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 Bone survey: A bone survey may be done if your doctor determines it is 
necessary. A bone survey is a series of X-rays that evaluates the major bones of 
the body. 
 Bone marrow aspirate and biopsy: You may have a bone marrow biopsy within 
42 days before you first begin study treatment. A bone marrow biopsy is a 
procedure that you may have had done before. It requires the removal of a small 
piece of bone by a special needle, which is usually inserted into the back of the 
pelvis. As part of the same procedure, a bone marrow aspiration will be 
performed, which means that blood will be drawn out of the middle of the bone to 
examine cells in the bone marrow. This procedure is usually done with local 
anesthesia. 
 
If the screening information shows that you meet the requirements, then you will be able 
to start the study. If the screening information shows that you cannot be in the research 
study, the study doctors will discuss other options with you and/or refer you back to your 
regular doctor.  
 
Study Treatment Period:   
Once it has been determined that you are able to participate in this study, you will be 
enrolled into the study and begin study treatment (the portion of the study where you will 
be taking the study drug).   
 
You may receive a standard anti-amyloid therapy as determined by your study doctor. 
This anti-amyloid therapy will be selected by the study doctor from a group of drugs or 
treatments commonly used for patients with AL amyloidosis. The anti-amyloid therapy 
may consist of one or several drugs in combination. In addition, all patients in this study 
will receive the study drug, doxycycline. You will take 100 mg of doxycycline by mouth 
twice a day during the study. If you are taking an antacid containing aluminum, calcium 
or magnesium, or if you are taking iron-containing preparations, you must take the 
doxycycline at least 2 hours before or at least 2 hours after taking medications 
containing the ingredients listed above. Since dairy products contain calcium you should 
avoid dairy products 2 hours before and after taking doxycycline.  
 
Systemic amyloidosis subjects 
If you have systemic amyloidosis, you will come to the clinic once a month during the 
study. Below is a list of the standard of care tests and procedures that will be done each 
month for 12 months during your participation in the study, unless otherwise specified: 
 
 
Physical exam – A physical exam will be done including taking your vital signs 
each month. You will be asked how you are feeling and if you are having or have 
had any symptoms or side effects from your last visit. You will be asked about 
any medications you have used or are currently using. 
 As part of routine clinical care, approximately 4 teaspoons of blood will be 
collected to monitor your blood cell counts, blood chemistries and light chains 
each month. These tests would be done even if you were not participating in this 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
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study. Additional blood tests may be performed if your doctor determines it is 
necessary. These tests would be done even if you were not participating in this 
study. 
 Your level of activity will be assessed (months 3, 6, 9 and 12) 
 If your doctor determines it is necessary, a 24 hour urine sample will be collected 
(months 3, 6, 9 and 12) 
 If your doctor determines it is necessary, you will have imaging of the abdomen 
(month 6) 
 If your doctor determines it is necessary, you will have an echocardiogram 
(month 6) 
 Doxycycline capsules will be dispensed for you to take as scheduled at home.  
Following Month 1, you will bring any empty or partially empty containers with 
you every month. 
 
Localized Amyloidosis Subjects 
If you have localized amyloidosis, you will come to the clinic every 3 months during the 
study. Below is a list of the standard of care tests and procedures that will be done 
every 3 months for 12 months during your participation in the study, unless otherwise 
specified: 
 
 
Physical exam – A physical exam will be done including taking your vital signs 
every 3 months. You will be asked how you are feeling and if you are having or 
have had any symptoms or side effects from your last visit. You will be asked 
about any medications you have used or are currently using. 
 As part of routine clinical care, approximately 4 teaspoons of blood will be 
collected to monitor your blood cell counts, blood chemistries every three 
months. Additional blood tests may be performed if your doctor determines it is 
necessary. These tests would be done even if you were not participating in this 
study. 
 Your level of activity will be assessed  
 If your doctor determines it is necessary, you will have a CT scan to assess your 
disease (month 7).  
 Doxycycline capsules will be dispensed for you to take as scheduled at home.  
Following Month 1, you will bring any empty or partially empty containers with 
you every 3 months. 
 
For all subjects, the following will be performed for research purposes: 
 
 A part of this research study includes the collection of blood samples for research 
laboratory tests. Approximately 1.2 teaspoons of blood (6 mL) will be collected at 
the time of a routine blood collection at the start of the study and then again at 
your 7 month and End of Study visits.  
 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
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IRB Approval Period: 9/14/2016 – 2/10/2017  
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These samples will be stored at the Medical College of Wisconsin Tissue Bank 
 
and used by Dr. D’Souza for research related to this study.   
 
 Each visit you will be asked to complete a questionnaire about how you are 
feeling. This questionnaire will take about 5-10 minutes to complete. 
 
End of Treatment (for all subjects unless otherwise specified): 
 
You will have a final visit within 30 days after you stop the study. You will be asked to 
bring any empty or partially empty containers with you to this visit.  The following 
procedures will be done: 
 
 Physical exam including taking your vital signs 
 Your level of activity will be assessed  
 Approximately 4 teaspoons of blood will be collected to monitor your blood cell 
counts, blood chemistries.  Additional blood tests may be performed if your 
doctor determines it is necessary.  
 Approximately 1.2 teaspoons of blood will be collected for research laboratory 
tests 
 You will be asked to complete a questionnaire about how you are feeling. This 
questionnaire will take about 5-10 minutes to complete. 
 If you have localized amyloidosis and if your doctor determines it is necessary, 
you will have a CT scan to assess your disease.   
 
If you have systemic amyloidosis the following procedures may also be performed if 
your doctor determines it is necessary:  
 Abdominal imaging 
 Echocardiogram  
 A 24 hour urine sample  
 
Long Term Follow-Up: 
After your End of Treatment visit we will contact you or review your medical records 
once a year for 5 years to see how you are doing and if you have received any other 
treatments for your amyloidosis. 
 
B2. HOW LONG WILL I BE IN THE STUDY? 
You will be in the study for approximately 6 years. 
 
B3. CAN I STOP BEING IN THE STUDY?   
You are free to withdraw from the study at any time. If you leave, your regular medical 
care will not change. If you are thinking about leaving, please tell the study doctor.  
 
 The doctor can tell you about the effects of stopping, and you and the doctor can talk 
about what follow-up care would help you the most. 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00022850  
IRB Approval Period: 9/14/2016 – 2/10/2017  
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 You will be asked to come back for one more visit to check your health. 
 You will be asked to return your research drug containers. 
 
The study doctor may take you out of this study at any time. This would happen if: 
 
They think it is in your best interest. 
 
You do not follow the study rules. 
 
The whole study is stopped. 
If this happens, the study doctor will tell you. 
 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE STUDY?  
If you are taking an antacid containing aluminum, calcium or magnesium, or if you are 
taking iron-containing preparations, you must take doxycycline at least 2 hours before or 
at least 2 hours after taking medications containing the ingredients listed above. Since 
dairy products contain calcium you should avoid dairy products 2 hours before and after 
taking doxycycline. 
 
Doxycycline can also cause increased sensitivity to sun exposure. You should use 
adequate sun protection with sunscreen. 
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE STUDY? 
There are risks to taking part in any research study. There is a risk that you may get a 
drug that does not help your condition or may make it worse.  There also may be 
problems (side effects) we do not know about yet, from drug itself, or how it combines 
with other drugs you are taking. If we learn about new important side effects, we will tell 
you.  
 
We watch everyone in the study for problems (side effects). You need to tell the study 
doctor or a member of the study team immediately if you experience any 
problems, side effects, or changes in your health.   
 
C2. RISKS OF DOXYCYCLINE 
The research drug may cause problems (side effects).  Side effects may be mild or very 
serious.  Some can last a long time or never go away or cause death.  Many go away 
soon after you stop taking doxycycline. Drugs can affect individuals in different ways.  
 
Doxycycline has been in use for many decades and has been fairly well tolerated. Some 
of the side effects seen with doxycycline are listed below:  
 nausea  
 stomach upset  
 skin rash in sun exposed areas (sun burn) 
 diarrhea 
 
Less likely but more serious side effects include: 
 allergic reaction to the drug,  


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
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 low blood counts,  
 eosinophilia  
 Clostridium difficile diarrhea, a form of antibiotic-induced infectious diarrhea 
ranging from mild diarrhea to fatal colitis. 
 
Rare serious side effect includes: 
 Drug-induced cutaneous lupus, an allergic reaction leading to skin inflammation 
and damage  
 
C3. OTHER RISKS OF THIS RESEARCH STUDY 
Other drugs and procedures that are part of the study also involve some risks: 
 
Blood samples: In addition to the possibility of pain while blood samples are being 
drawn from your arm, there is the risk of bleeding or bruising at the needle site or risk of 
infection.  Some people may feel dizzy or light-headed after having blood drawn. 
 
Bone marrow aspirate and biopsy: Risks associated with the procedure include pain, 
discomfort, soreness, redness, swelling, bleeding (may be excessive), bruising, and/or 
drainage (such as pus) at the needle site, infection, fever, allergic reaction to the 
medication used to numb the skin over the biopsy site. You may be asked to sign a 
separate consent form for this procedure. 
 
Bone (Skeletal) Survey: X-rays are fairly safe, but excessive use can pose some 
health risks. One skeletal survey in this study is equivalent to approximately 1 year of 
“background” radiation that you would receive from natural sources (sun, soil, food, 
water). The effects of radiation from repeated X-rays collect over a lifetime. Too much 
exposure can lead to serious illness. These include blood disorders, cataracts, skin 
problems, and cancer. However, healthcare providers are aware of these risks. They 
consider the person's total exposure before X-ray tests. 
 
CT Scan: CT scanners use special equipment to take pictures of the inside of your 
body. The CT scanner is a large machine shaped like a doughnut and has a bed in the 
middle of the circle that you lie on. The bed can slide backwards and forwards through 
the hole of the doughnut. Pictures of your internal organs are taken as you move 
through the machine. CT scans may be used to follow your treatment. You will have 
some radiation exposure. Generally, the amount of radiation received during this 
procedure is the same as a normal person gets from exposure to natural sources of 
radiation in the environment in a 2- to 3-year period. The potential long-term risks from 
this radiation are uncertain, but have not been associated with any definite change in 
overall medical condition.  
 
Echocardiogram (ECHO): This test uses ultrasound to produce images of your heart. 
During the echocardiogram, electrodes will be placed onto your chest to allow for an 
ECG to be performed. Then a transducer (a device that looks like a computer mouse) 
will be applied. You may feel slight pressure on your chest from the transducer. In 


Medical College of Wisconsin & Froedtert Hospital  
 
 
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addition, you may be asked to breathe in a certain way or to rest on your side during the 
test. 
 
 
 
 
C4. REPRODUCTIVE RISKS 
Risks to women who could become pregnant 
The drug in this study might affect a baby, before or after the baby is born. We do not 
want anyone who might be pregnant to enter the study. You should not become 
pregnant or nurse a baby while in this study. You must tell the study doctor right away if 
you think you are pregnant. You will be asked to have a pregnancy test to be sure you 
are not pregnant at the start of the study.  
 
Birth control methods women who could become pregnant  
Check with the study doctor about the birth control methods needed for this study and 
how long to use them. Some methods might not be good enough for this study. If you 
are having sex that could lead to pregnancy, you should use birth control while you are 
in this study.   
This may include: 
 Not having vaginal sex (abstinence) 
 Taking birth control pills orally 
 Having birth control shots or patches such as Depo-Provera 
 Surgical sterilization (hysterectomy or tubal ligation) 
 Use of an intrauterine device (IUD) 
 Use of diaphragm with contraceptive jelly 
 Use of condoms with contraceptive foam 
 Use of diaphragm with condoms (“double barrier”) 
 Limiting sexual activity to a male partner who has had a vasectomy 
You should continue using birth control for 1 month after stopping the study drug. 
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE STUDY? 
 
We don’t know if this study will help you. Your condition may get better but it could stay 
the same or even get worse. We hope the information from this study will help us 
develop better treatments for amyloidosis. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE STUDY? 
Most of the medical care that you will receive in this study is considered routine care for 
your condition and would be recommended whether you join the study or not.  Costs for 
routine care will be billed to you or your insurance carrier.  Activities / costs that are part 
of the study will not be billed to you or your insurance company. The study drug, 
doxycycline, and the processing of blood samples for research purposes will be 
provided at no cost to you. If your study physician feels that it is necessary to order any 


Medical College of Wisconsin & Froedtert Hospital  
 
 
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IRB Approval Period: 9/14/2016 – 2/10/2017  
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additional tests, procedures or exams for your care these will be billed to you or your 
insurance carrier. Some insurers will not pay for drugs, tests or hospitalization that are 
part of research studies, so check with your insurer before you join this study. If you 
have questions regarding study costs, please contact Dr. D’Souza. 
 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE STUDY? 
You will not be paid for participating in the study. 
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this study. You are free to say yes or no. If you do not join this 
study, your doctor can discuss other healthcare choices with you.  
 
Your other choices may include: 
 
Getting treatment or care for your amyloidosis without being in a study 
 
Joining a different research study 
 
Getting no treatment 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE STUDY? 
If we learn any important new information about the study drug that might change your 
mind about being in the study, we will tell you about it right away.  You can then decide 
if you want to stay in the study. 
 
D5. WHAT HAPPENS IF I AM HARMED BECAUSE I TOOK PART IN THE STUDY?  
No funds have been set aside to pay any costs if you become ill or are harmed because 
of this study. If you think that you have become ill or were harmed because of this 
study, let the study doctors know right away by calling 414-805-6800.  By signing this 
form, you do not give up your right to seek payment for harm you receive while 
participating in this study. 
 
By signing this form, you do not give up your right to seek payment for harm you receive 
while participating in this study. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
 
If you have more questions about this study at any time, you can call Dr. D’Souza 
at 414-805-6800. 
 
If you have questions about your rights as a study participant, want to report any 
problems or complaints, obtain information about the study, or offer input, you can 
call the MCW/Froedtert Hospital Research Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this study? 
To do this research study, we need your permission to collect and use some of your 
health information, or you cannot be in the study. This information may come from 


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questions we ask, forms we ask you to fill out, or your medical record, as described 
below. We will only collect and use information needed for the study.  
 
 
The health information to be collected and used for this study is:  
 Hospital/Medical Records 
 Physician/Clinic Reports 
 Lab and/or Pathology Reports 
 Radiological Reports 
 Biological Samples 
 Interviews/Questionnaires 
 Data Previously Collected for Clinical Purposes 
 
E2. Who will see the health information collected for this study? 
The only MCW/Froedtert Hospital employees allowed to handle your health information 
are those on the study team, those on the Institutional Review Board (IRB) and those 
who check on the research activities to make sure the hospital’s rules are followed. 
 
We may record your research information, including results of tests and procedures 
done for research, in your Froedtert Hospital and/or Medical College of Wisconsin 
medical record. As a result, this research information may be seen by people allowed to 
see your medical records for healthcare operations or treatment, by those you allow to 
see your medical records by giving written permission, and by others when required by 
law. 
 
We will not use your personal health information for a different study without your 
permission or the permission of a hospital research review board (IRB). Once all 
personal identification is removed, the information might be used or released for other 
purposes without asking you. Results of the study may be presented in public talks or 
written articles, but no information will be presented that identifies you. 
 
E3. What are the risks of sharing this health information? 
One risk of taking part in a research study is that more people will handle your personal 
health information collected for this study. The study team will make every effort to 
protect the information and keep it confidential, but it is possible that an unauthorized 
person might see it. Depending on the kind of information being collected, it might be 
used in a way that could embarrass you or affect your ability to get insurance. If you 
have questions, you can talk to the study doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this study? 
If you sign this form, we plan to keep your information without any end-date in case we 
need to check it again for this study. 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00022850  
IRB Approval Period: 9/14/2016 – 2/10/2017  
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Version: 08-18-16  
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E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health 
information, you need to send a letter to Dr. D’Souza at Froedtert Hospital & Medical 
College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226. The letter 
must say that you have changed your mind and do not want the researcher to collect 
and share your health information. At that time, we may decide that you cannot continue 
to be part of the study. We may still use the information we have already collected.  
 
 
F1. FOR MORE INFORMATION ABOUT THE STUDY 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
You can look up this study by referring to the ClinicalTrials.gov number (NCT02207556) 
or by asking the study team for a printed copy.    


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00022850  
IRB Approval Period: 9/14/2016 – 2/10/2017  
Page 12 of 12 
Version: 08-18-16  
EFFECTIVE 
 
9/14/2016 
 
MCW/FH IRB
 
CONSENT TO PARTICIPATE IN THE STUDY 
 
By signing my name below, I confirm the following: 
 I have read (or had read to me) this entire consent document.  All of my questions 
have been answered to my satisfaction. 
 The study’s purpose, procedures, risks and possible benefits have been explained to 
me.   
 I agree to let the study team use and share the health information and other 
information gathered for this study. 
 I voluntarily agree to participate in this research study.  I agree to follow the study 
procedures as directed.  I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please 
keep it where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date    
 
 
 
Name of Legally Authorized 
Representative (if applicable)  
please print  
Signature of Legally Authorized 
Representative 
Date 
 
 
 
Name of Witness (if applicable) please 
print  (for short form consent process, or 
consent of blind or illiterate subject) 
Signature of Witness 
 
Date 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date 
* A member of the study team trained and authorized by the Principal Investigator to act on her/his behalf 
in obtaining informed consent according to the protocol.  In all research study protocols the Principal 
Investigator is responsible and accountable for the study.