Conditions: Headache Cognitive Disturbance Skin Hyperpigmentation Arthralgia
Keywords: gadolinium deposition GBCA Extremity Pain Skin Pain Chest Wall Pain
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
Purpose: There are two goals we have for this prospective single arm study; to see an increase in the amount of gadolinium in 24 hour urine collection following each infusion treatment with Calcium and Zinc DTPA, and to see a reduction or elimination of gadolinium deposition disease (GDD) symptoms.

Participants: Twenty (20) patients who are suffering from gadolinium deposition disease (GDD)

Procedures: Over a series of three (3) treatment time-points patients will be treated with IV Ca-DTPA on day one, and Zn-DTPA on day two.

Detailed description:

Arms:
arm 1: Subjects will receive IV administration of Ca-DTPA on Day 1 and Zn-DTPA on Day 2 at each of treatment time-points. Three identical treatment time-points are scheduled on Month 1, Month 2 and Month 3.

Interventions: intervention 1: Calcium DTPA intervention 2: Zinc DTPA
Intervention descriptions: intervention 1: On Day 1, 2.5 mL of Ca-DTPA (1 g/5 mL) will be administered over a period of 1 minute. A solution of normal saline will then be administered at a rate of 300 mL/hr over 30 minutes. Patients will be seated with hands lowered to their sides to allow the chelator to dwell slightly in the soft tissues of the hands and feet. Patients will then be moved to a supine position and the infusion rate increased to 750 mL/hr over the next 60 minutes. At 90 minutes the remaining 2.5 mL of Ca-DTPA will administered IV over a period of 1 minute, and the normal saline will continue for the remaining 9 minutes. The IV line will then be removed. Patients will be instructed to drink plenty of fluids that evening.

The same treatment therapy will consist of 3 time-points, approximately 1 month apart. intervention 2: On Day 2, 2.5 mL of Zn-DTPA (1 g/5 mL) will be administered over a period of 1 minute. A solution of normal saline will then be administered at a rate of 300 mL/hr over 30 minutes. Patients will be seated with hands lowered to their sides to allow the chelator to dwell slightly in the soft tissues of the hands and feet. Patients will then be moved to a supine position and the infusion rate increased to 750 mL/hr over the next 60 minutes. At 90 minutes the remaining 2.5 mL of Zn-DTPA will administered IV over a period of 1 minute, and the normal saline will continue for the remaining 9 minutes. The IV line will then be removed. Patients will be instructed to drink plenty of fluids that evening.

The same treatment therapy will consist of 3 time-points, approximately 1 month apart.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Effects of IV-Administered Ca-DTPA and Zn-DTPA To Treat Patients 
With Gadolinium Deposition Disease 
 
 
NCT number 02947022 
Document Date December 15, 2016 
 


 
CONFIDENTIAL 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
INVESTIGATOR-INITIATED INVESTIGATIONAL NEW DRUG 
(IND) 
APPLICATION 
TO 
STUDY 
THE 
EFFECTS 
OF 
INTRAVENOUSLY ADMINISTERED CA-DTPA AND ZN-DTPA 
TO TREAT PATIENTS WITH GADOLINIUM DEPOSITION 
DISEASE 
 
 
 
 
 
Regulatory Sponsor: 
Richard C Semelka, MD 
Department of Radiology 
101 Manning Drive, Chapel Hill, NC 27599 
919-966-7890 
Funding Sponsor: 
Richard C. Semelka, MD 
Study Product: 
Ca-DTPA and Zn-DTPA (Diethylene Triamine Penta-acetic 
Acid) 
Protocol Number: 
GDD-001 
IND Number: 
130528 
 
 
 
 
 
 
 
Initial version: March 8, 2016 
Amended: July 27, 2016 
 
Amended: October 18, 2016 
Amended: December 15, 2016  


 
ii 
 
 
Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 2 
1.3 
PRECLINICAL DATA ........................................................................................................................ 3 
1.4 
CLINICAL DATA TO DATE................................................................................................................. 3 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 4 
2 
STUDY OBJECTIVES ......................................................................................................................... 4 
3 
STUDY DESIGN ................................................................................................................................... 4 
3.1 
GENERAL DESIGN .......................................................................................................................... 4 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 5 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 5 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 5 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 5 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 5 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 6 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 6 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 6 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 6 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 6 
5 
STUDY DRUG ...................................................................................................................................... 6 
5.1 
DESCRIPTION ................................................................................................................................. 6 
5.2 
TREATMENT REGIMEN .................................................................................................................... 7 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................... 7 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ..................................................................... 7 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................... 7 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................... 7 
5.7 
PACKAGING ................................................................................................................................... 8 
5.8 
BLINDING OF STUDY DRUG (IF APPLICABLE) ..................................................................................... 8 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................ 8 
5.9.1 
Receipt of Drug Supplies ......................................................................................................... 8 
5.9.2 
Storage .................................................................................................................................... 8 
5.9.3 
Dispensing of Study Drug ........................................................................................................ 8 
5.9.4 
Return or Destruction of Study Drug ....................................................................................... 8 
6 
    STUDY PROCEDURES ................................................................................................................... 8 
7 
STATISTICAL PLAN ......................................................................................................................... 10 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 10 
8.1 
DEFINITIONS ................................................................................................................................ 10 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 12 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 13 
8.3.1 
Investigator reporting: notifying the study sponsor................................................................ 13 
8.3.2 
Investigator reporting: ............................................................................................................ 13 
8.3.3 
Sponsor reporting: Notifying the FDA ................................................................................... 14 
8.4 
STOPPING RULES ......................................................................................................................... 15 
8.5 
MEDICAL MONITORING ................................................................................................................. 15 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 16 


 
iii 
 
9.1 
CONFIDENTIALITY ......................................................................................................................... 16 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 16 
9.3 
CASE REPORT FORMS.................................................................................................................. 16 
9.4 
RECORDS RETENTION .................................................................................................................. 16 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 17 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 17 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 17 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 17 
12 
STUDY FINANCES ............................................................................................................................ 17 
12.1 
FUNDING SOURCE ........................................................................................................................ 17 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 17 
13 
PUBLICATION PLAN ........................................................................................................................ 18 
14 
REFERENCES ................................................................................................................................... 18 
15 
APPENDICES ( .................................................................................................................................. 18 
 


 
iv 
 
 
 
List of Abbreviations  
 
 
 
DTPA—Diethylene Triamine Penta-acetic Acid 
 
Gd—Gadolinium 
 
GBCA—Gadolinium Based Contrast Agent 
 
MRI—Magnetic Resonance Imaging  
 
 
 
 
 
 
 
 
 


Appendix A 
 
CONFIDENTIAL 
Study Summary 
Title 
INVESTIGATOR-INITIATED 
INVESTIGATIONAL 
NEW 
DRUG 
(IND) 
APPLICATION 
TO 
STUDY 
THE 
EFFECTS 
OF 
INTRAVENOUSLY 
ADMINISTERED CA-DTPA AND ZN-DTPA TO TREAT PATIENTS WITH 
GADOLINIUM DEPOSITION DISEASE 
 
Short Title 
Ca/Zn DTPA for GDD 
Protocol Number 
GDD-001 
Phase 
Feasibility study 
Methodology 
Open label, non-randomization 
Study Duration 
1 year 
Study Center(s) 
Single center 
Objectives 
To see an increase in the elimination of Gd as measured by analysis of 24 
hour urine collections.  
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
Gadolinium Deposition Disease (GDD)— 
*Symptoms of pain, depressed levels of consciousness, and skin induration 
post administration of a GBCA as well as elevated levels of gadolinium in 24 hr 
urine, greater than 30 days post administration of a GBCA 
 
Study Product, Dose, 
Route, Regimen 
Ca –DTPA (0.5 gm) administered IV push over 1 minute at the beginning of 
infusion, along with normal saline (over a 90 minute period), ending with 
another 0.5 gm DTPA dose with 10 minutes left of saline infusion. This will be 
followed the next day with Zn-DTPA (0.5 gm) administered IV push over 1 
minute with normal saline (over a 90 minute period), ending with another 0.5 
gm DTPA dose with 10 minutes left of saline infusion. A total of 1 gm of DTPA 
is administered at each treatment.  
This sequence will be administered 3 times, approximately 1 month apart.  
Duration 
of 
administration 
3 months 
Reference therapy 
No treatments established for this condition 
Statistical 
Methodology 
R, a language and environment for statistical computing (R Core Team, 
Vienna, Austria), will be used for all statistical computing. Statistical 
significance will be defined as p value less than 0.05.  
 


 
2 
 
1 Introduction 
 
This document is a clinical research protocol and the described study will be conducted in compliance 
with the protocol, Good Clinical Practices standards and associated Federal regulations, and all 
applicable University research requirements. This study involves the treatment of patients with 
Gadolinium Deposition Disease (GDD) by intravenous administration of the chelating agents Ca-DTPA 
and Zn-DTPA. These chelating agents are approved for the treatment of individuals who have been 
contaminated by the actinide elements Plutonium (Pu), Americium (Am) and Curium (Cm). Based on the 
similarity of Gadolinium (Gd) to these elements and the use of DTPA as a chelate in Gd-based contrast 
agents (GBCAs) used in Magnetic Resonance Imaging (MRI), it is expected that Ca-DTPA and Zn-DTPA 
will be effective in reducing the total body burden of Gd in patients suffering from GDD.   
 
1.1 Background 
Gadolinium (Gd) is a heavy metal that is a principal component of many MRI contrast agents. Gd is 
always administered as a chelate in which the chelating agent (ligand) is expected to tightly bind the Gd 
ions. The Gd-chelate prevent the toxic Gd ions from directly interacting with cells and tissues. They also 
help to promote rapid elimination of the contrast agent from the body after the imaging procedure is 
complete. There are several commercially available Gd-based contrast agents (GBCAs).  There have 
been growing concerns about the in vivo stability of some of these chelators.  Nephrogenic Systemic 
Fibrosis (NSF) was first described in 2007 and was directly attributed to the release of Gd ions from MRI 
contrast agents, OptiMARK and Omniscan in particular, in patients with renal failure. More recently, 
patients with normal renal function have been reporting serious illnesses after administration of all classes 
of GBCAs.   
1.2 Investigational Agent 
Ca-DTPA (Pentetate calcium trisodium injection) and Zn-DTPA (Pentetate zinc trisodium injection) are 
FDA-approved products for removal of the radioactive actinides americium (Am), curium (Cm) and 
plutonium (Pu) for use in a radiological disaster or following nuclear terrorism event. Their mechanism of 
action is to chelate (bind) heavy metals in the circulation and enhance their renal elimination. 
         
 
Pentetate calcium trisodium injection contains the sodium salt of calcium diethylenetriaminepentaacetate. 
Pentetate calcium trisodium is also known as trisodium calcium diethylenetriaminepentaacetate and is 
commonly referred to as Ca-DTPA. It has a molecular formula of Na3CaC14H18N3O10 and a molecular 
weight of 497.4 Daltons.  Ca-DTPA is supplied as a clear, colorless, hyperosmolar (1260 mOsmol/kg) 
solution in a colorless ampoule containing 5 mL. The ampoule contents are sterile, non-pyrogenic and 
suitable for intravenous administration. Each mL of solution contains the equivalent of 200 mg pentetate 


 
3 
 
calcium trisodium (obtained from 158.17 mg pentetic acid, 40.24 mg calcium carbonate and NaOH) in 
Water for Injection, USP. The pH of the solution is adjusted with NaOH and is between 7.3 - 8.3. 
 
Pentetate zinc trisodium injection contains the sodium salt of zinc diethylenetriaminepentaacetate. 
Pentetate zinc trisodium is also known as trisodium zinc diethylenetriaminepentaacetate and is commonly 
referred to as Zn-DTPA. It has a molecular formula of Na3ZnC14H18N3O10 and a molecular weight of 522.7 
Daltons. Zn-DTPA is supplied as a clear, colorless, hyperosmolar (1260 mOsmol/kg) solution in a 
colorless ampoule containing 5 mL. The ampoule contents are sterile, non-pyrogenic and suitable for 
intravenous administration. Each mL of solution contains the equivalent of 200 mg pentetate zinc 
trisodium (obtained from 150.51 mg pentetic acid, 31.14 mg zinc oxide and NaOH) and water for 
injection, USP. The pH of the solution is adjusted with NaOH and is between 6.5 – 7.5. 
 
Ca-DTPA and Zn-DTPA form stable chelates with metal ions by exchanging calcium or zinc for a metal of 
greater binding capacity. The radioactive chelates are then excreted by glomerular filtration into the urine 
1.3 Preclinical Data 
The log of thermodynamic binding constant (log K) of DTPA for Gd is comparable to those of the three 
heavy metals for which Ca-DTPA and Zn-DTPA are approved and far greater than the two most relevant 
physiological metals (Ca and Zn): 
                         
                        Log K 
Am 
 
22.92 
Cm 
 
22.99 
Pu3+ 
 
20.58 
Gd 
 
22.46 
Ca 
 
10.74 
Zn 
 
18.75 
 
Note that these are log binding constants; thus, Gd binds to DTPA as tightly as the approved metals (Am, 
Cm and Pu) and 4-12 orders of magnitude greater than Zn and Ca. 
1.4 Clinical Data to Date 
Prior to formal approval by the FDA in 2005, Ca-DTPA and Zn-DTPA had been used to treat 
contaminated workers in the nuclear energy industry.  In the period from 1958 to 1987, 485 patients 
received a total of 3077 doses of DTPA, about two-thirds as the calcium salt. Minor transient effects were 
observed in 12 patients, but no serious or long-term effects were reported.  One worker was administered 
a total of 583 g of DTPA, primarily as the zinc salt, over a 4-year period without any observed 
toxicological effects (the usual recommended human dosage for a single administration is 0.5 to 1 gram). 


 
4 
 
In France, over 500 workers have been given a single dose of these agents by slow intravenous infusion 
and over 200 workers have received multiple dosages without adverse effects. 
 
One of the most widely used GBCA, Magnevist, is actually a chelate of Gd and DTPA.  It is estimated that 
80 million doses Magnevist have been administered to patients undergoing an MRI procedure, and it has 
exhibited a very high safety profile. Of note, 50 million doses of Omniscan, which employs a di-amide 
chelator, have been administered to patients. This agent incorporates 5% free ligand in order to improve 
safety as it serves to scavenge Gd ions released from its chelated form. A similar di-amide Gd chelate, 
Optimark, contains 10% free ligand for the same reason.  
 
DTPA is also used as a chelator for radiopharmaceuticals employing other heavy metals, e.g., 99mTc-
DTPA (TechneScan®DTPA) and 111In-DTPA (Pentetate Indium Disodium In 111®) used as diagnostic 
agents in nuclear medicine. These agents have been safely used in millions of patients over the past four 
decades. 
1.5 Dose Rationale and Risk/Benefits 
The doses selected (1 gram each of Ca-DTPA and Zn-DTPA) are based on information in the package 
insert of these products for use as radionuclide decorporation agents. 
 
It is worth emphasizing that DTPA (and other chelators in different GBCA products) represents the 
component that makes MRI contrast agents 'safe', and we will administer it in approximately 1/4 the 
standard dose of the MR contrast agents. As a side note, it should be observed that the total amount of 
DTPA ligand is approximately the same amount of free ligand that is delivered when a magnetic 
resonance angiogram is performed using Optimark as the contrast agent. Thus, the precedent exists for 
this in clinical practice, with the comparable intention of scavenging free Gd to minimize the potential for 
deposition. 
2 Study Objectives 
 
Primary Objective: 
• 
To observe an increase in the elimination of Gd as measured by analysis of 24-hour urine 
collections. 
 
Secondary Objective: 
• 
To observe a measurable reduction or elimination of symptoms caused by administration of a 
GBCA.   
• 
Evaluate chemokine mediators and function of the mononuclear phagocyte system prior to and 
after treatment with DTPA. 
3 Study Design 
3.1 General Design 
This is an open-label study. Patients will be evaluated at a baseline visit to determine eligibility and obtain 
informed consent before proceeding on to study-related procedures. Most patients coming for treatment 
will have had prior gadolinium testing greater than 30 days post MRI/contrast agent that shows an 
elevated result, thus eligibility for chelation therapy. 
 
In addition to previous gadolinium testing, subjects will be instructed to perform a 24-hour urine collection 
(at visit 0) to determine a baseline for evaluating the elimination of gadolinium before initiating the first 
treatment. 
 
At the first and subsequent chelation therapy visits, a baseline blood pressure will be obtained, an IV will 
be placed by Vascular Interventional Radiology (VIR) nursing staff, and 1L of normal saline will be 
connected. Initially, 2.5 mL of Ca-DTPA (1 g/5 mL) will be administered over a period of 1 minute. Five (5) 


 
5 
 
minutes post DTPA blood pressure will be collected again.  The saline will then be administered at a rate 
of 300 mL/hr over 30 minutes with the patient seated and with hands lowered by their sides to allow the 
chelator to dwell slightly in the soft tissues of the hands and feet. The patient will then be positioned in a 
supine position on a hospital bed/gurney and the infusion rate will then be increased to 750 mL/hr over 
the next 60 minutes. With 10 minutes remaining (80 minutes after the start of infusion), the remaining 2.5 
mL of Ca-DTPA will be administered I.V. over a period of 1 minute. The infusion of saline will continue 
another 9 minutes, and the I.V. line will then be removed.  The patient will be instructed to drink plenty of 
fluids that evening. The following day, the treatment will be repeated using Zn-DTPA.  
 
The patient will be instructed to collect 24-hour total urine samples beginning once chelation therapy 
starts, and bring back to the lab the following days.  
 
The process will be repeated monthly, for a total of 3 chelation treatment time-points.   
 
Patients will come to clinic for follow up to be assessed for adverse events one week following each 
treatment. Patients will be asked to fill out pain/QOL questionnaires and given a brief physical exam. 
Patients who live greater than 3 hours away will be assessed via phone call and instructed to get labs 
drawn locally. Patients may be advised to seek medical attention if the investigator feels any adverse 
reaction is not expected or is severe.  
 
 
The number and function of monocytes and macrophages will be evaluated using 6 mL of blood. 
A 6 mL blood sample will be obtained in a heparin (green-top) tube and used to determine of the number 
and function of monocytes and macrophages via flow cytometry (phagocytosis and respiratory burst). 
This sample will be kept at ambient temperature, and must be processed within 39 hours. These assays 
will be performed in accordance with the standard operating procedures in Dr. William Zamboni’s 
laboratory and the UNC Flow Cytometry Core Facility.  
 
 
Mediators of the MPS, including cytokines/chemokines, will be measured with a 6 mL blood 
sample obtained in a heparin (green-top) tube. Blood will be processed to plasma by centrifugation at 
1500 x g for 5 minutes at 4°C. Plasma should be removed using a pipet and distributed evenly between 
two screw-top tubes. Plasma should be processed within 2 hours and stored at -80C until evaluation in 
accordance with standard operating procedures within Dr. William Zamboni’s laboratory.  
3.2 Primary Study Endpoints 
To observe a reduction or elimination of symptoms caused by gadolinium deposition after 
administration of a GBCA. 
3.3 Secondary Study Endpoints 
To observe increased elimination of gadolinium in 24-hour urine collections post infusion therapy, 
estimated at greater than two-fold increase.  
The pre-chelation Gd amount in urine should decrease from the first to third treatment.  
3.4 Primary Safety Endpoints 
Clinically significant hypocalcemia will be monitored.  
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. 
Have been administered a GBCA ≥ 30 days, but less than 10 years, prior with a confirmation lab 
result of elevated levels by 24 hour urine  
2. 
Exhibiting ≥ 3 of the following symptoms which must be present after having been administered a 
GBCA:  
a. 
Cognitive disturbance 
 


 
6 
 
b. 
Extremity pain 
c. 
Headache  
d. 
Chest wall pain 
e. 
Skin induration 
f. 
Skin hyperpigmentation 
g. 
Skin pain 
h. 
Arthralgia 
 
4.2 Exclusion Criteria 
 
1. 
Pregnant/lactating 
2. 
Less than 18 years old 
3. 
If there is no evidence of gadolinium (has to have shown previous demonstration of Gd by bone 
biopsy or urine analysis) 
4. 
Known connective tissue disease such as Systemic Lupus Erythematosus and scleroderma  
5.  
Severe hemochromatosis or Wilson’s disease  
6. 
Glomerular filtration rate (GFR) ≤60   
7. 
Have not had an investigational drug within the past 30 days 
8.  
Unable to give written consent 
9.  
Multiple sclerosis 
10. 
Chronic heart failure 
11. 
Cirrosis of the liver 
 
4.3 Subject Recruitment and Screening 
Study subjects will be recruited as they seek us out from patient activist groups of gadolinium toxicity. In 
most cases it will be a first come first serve basis, but patients will also be prioritized based on levels of 
incapacitation by the gadolinium deposition disease.  
 
 
Screening will include: 
 
 
24-hour gadolinium urine 
 
 
Pain/QOL assessments 
 
 
Blood chemistries: calcium, zinc, manganese, magnesium, sodium, potassium, chloride,  
 
 
Creatinine, BUN, CO2, Phosphorus, CBC/Diff, urinalysis, creatinine clearance.   
4.4 Early Withdrawal of Subjects 
Patients may remove themselves from the study at any time for any reason. The investigators may 
remove patients from the study for any reason, such as non-compliance, or patient safety concerns.  
4.4.1 When and How to Withdraw Subjects 
Study subjects will be withdrawn from the study if they experience any known or unknown severe adverse 
event following administration of either Ca-DTPA or Zn-DTPA. Treatment will be discontinued 
immediately following any severe adverse event.  
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
The same labs done at screening will be collected, and a follow up phone call will be made one week 
after the event. 
5 Study Drug  
5.1 Description 
Ca-DTPA (Pentetate calcium trisodium injection 1g/5 mL) and  


 
7 
 
Zn-DTPA (Pentetate zinc trisodium injection 1 g/5 mL).    
        
 
5.2 Treatment Regimen 
Initially, 2.5 mL of Ca-DTPA (1 g/5 ml) will be administered over a period of 1 minute. A solution of normal 
saline will then be administered at a rate of 300 mL/hr over 30 minutes. The patient will be seated with 
hands lowered to their sides to allow the chelator to dwell slightly in the soft tissues of the hands and feet. 
The patient will then be moved to a supine position and the infusion rate will then be increased to 750 
mL/hr over the next 60 minutes. At 90 minutes the remaining 2.5 mL of Ca-DTPA will administered I.V. 
over a period of 1 minute, and the normal saline will continue for the remaining 9 minutes. The I.V. line 
will then be removed.  The patient will be instructed to drink plenty of fluids that evening. The following 
day, the treatment will be repeated using Zn-DTPA. The same treatment therapy will consist of 3 time-
points, approximately 1 month apart.  
5.3 Method for Assigning Subjects to Treatment Groups 
No randomization will be used. All patient subjects will receive the same treatment therapy. 
5.4 Preparation and Administration of Study Drug 
The appropriate doses will be drawn into a syringe from the Ca-DTPA and Zn-DTPA ampoules by the 
trained nursing staff and administered intravenously by a physician through an IV infusion line with the 
agents administered through a T-valve connection as a bolus. No placebo will be used. 
5.5 Subject Compliance Monitoring 
Subjects are treated and discharged from the clinic. They will be instructed to drink plenty of fluids, and 
collect urine for the following 24 hours to be returned the following day. Subjects will also have blood 
chemistries drawn the day following the second infusion for monitoring. Subject treatment will discontinue 
if they do not collect the 24 hour urine sample for testing following the infusion therapy, or refuse blood 
chemistry monitoring.  
5.6 Prior and Concomitant Therapy 
We will be excluding patients who have had an investigational product administered within the previous 
30 days.  
 


 
8 
 
5.7 Packaging 
The study drug will be used as supplied by the manufacturer. Vials will be received from the manufacturer 
packaged as 10 ampoules (1g/5 mL) Ca-DTPA and 10 ampoules (1gm/5 mL) of Zn-DTPA. A total of four 
packages (40 ampoules) of each product will be received.  This will allow enough doses for each subject 
to be administered up to three doses of Ca-DTPA and three doses of Zn-DTPA as well as allowing extra 
vials for breakage, spillage, etc.    
5.8 Blinding of Study Drug (if applicable) 
No blinding of drug will be incorporated. All patient subjects will be treated with the same therapy 
regimen. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Study drug receipt, storage, and dispensing and accountability will be managed by our Investigational 
Drug Services pharmacy. Upon receipt of the of the study treatment supplies, an inventory is performed 
and a drug receipt log filled out and signed by the person accepting the shipment.  The investigator must 
notify study sponsor of any damaged or unusable study treatments that were supplied to the 
investigator’s site. 
5.9.2 Storage 
The manufacturer recommends that the products be stored between 15 - 30°C (59 - 86°F), and will be 
stored in the Investigation Drug pharmacy. 
5.9.3 Dispensing of Study Drug 
Study drug receipt, storage, and dispensing and accountability will be managed by our Investigational 
Drug Services pharmacy. The pharmacy must notify study sponsor of any damaged or unusable study 
treatments that were supplied to the investigator’s site. Regular study drug reconciliation will be 
performed to document drug assigned and when.  
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and 
drug remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of 
unused study drug.  Drug destroyed on site will be documented in the study files. 
 
6 
    Study Procedures 
 
6.1 
Visit 0- The patient will be seen and evaluated by a UNC clinician regarding symptoms, 
assessments, a physical exam, a medication history and lab values up to one week prior to anticipated 
therapy start date. After agreeing to participate in the study, a coordinator will obtain informed consent 
signatures and the patient will be instructed to collect a 24-hour urine so that gadolinium can be 
measured for pre-treatment values.  
 
6.2 
Visit 1- The patient will come for infusion chelation therapy with Ca-DTPA to be done in the 
Clinical and Translational Research Center. Patient will void and have a baseline blood pressure taken 
before start of treatment. A urine pregnancy test will be performed if the subject is a woman of child-
bearing potential. Blood samples will be collected by phlebotomy trained staff at the Clinical & 
Translational Research Center (CTRC) at UNC Memorial hospital. Patient blood samples will be obtained 
just prior to intravenous administration of Ca-DTPA or Zn-DTPA. The IV will be placed by nursing staff, 
and the infusion of normal saline will begin. The first injection of Ca-DTPA is performed by the 
investigator, or one of the co-investigators. Five (5) minutes post injection of Ca-DTPA another blood 


 
9 
 
pressure will be taken. Saline will continue for another 80 minutes, and the second injection of Ca-DTPA 
will be given by an investigator, followed by the last 10 minutes of saline infusion. IV will be discontinued, 
vitals checked, and patient will be discharged home. Patient will begin 24-hour urine collection once the 
infusion is started. They will be instructed to drink plenty of fluids. Analog pain scale sheets will be given 
to the subject to fill out starting with day 1 through day 6 post treatment, which will be returned on the day 
7 visit. Urine is to be brought in on 2nd day of therapy.  
 
6.3 
Visit 2- The patient subject will come for the second infusion therapy with Zn-DTPA. Patient will 
void and have a baseline blood pressure taken prior to initiation of therapy. Blood samples will be 
collected by phlebotomy trained staff at the Clinical & Translational Research Center (CTRC) at UNC 
Memorial hospital. Patient blood samples will be obtained just prior to intravenous administration of Ca-
DTPA or Zn-DTPA.  IV placement will be done by nursing staff, normal saline infusion started, and Zn-
DTPA injections will be done by investigator or one of the co-investigators exactly as the day prior. Five 
(5) minutes post injection of Zn-DTPA another blood pressure will be taken. Another 24-hour urine 
sample will be collected beginning after chelation therapy is initiated, to be returned then next day.  
 
6.4   
Visit 3- The patient will return to the hospital to drop off 24 hour urine for gadolinium testing, as 
well as a creatinine clearance. Blood chemistries calcium, zinc, magnesium and manganese will be 
evaluated, along with BUN, creatinine, sodium, potassium, chloride, phosphorus and CO2. 
 
6.5 
Visit 4- The patient subject will come for a follow up assessment by a clinician 1 week (+5 days) 
following IV therapy, where pain and overall health assessments will be performed. If the patient lives 
more than 3 hours away, a phone-call follow up will be done and questionnaires will be supplied to be 
filled out and emailed prior to leaving the infusion therapy. The second therapy session will be scheduled 
for the following month.  
 
6.6. 
Visit 5- Patient will return for 2nd round of infusion therapy to be done exactly as first, with day 
one of Ca-DTPA including pregnancy testing on women of child-bearing potential and pain scale 
assessment sheets for the week.  Blood samples will be collected by phlebotomy trained staff at the 
Clinical & Translational Research Center (CTRC) at UNC Memorial hospital. Patient blood samples will 
be obtained just prior to intravenous administration of Ca-DTPA or Zn-DTPA. 
 
6.7       Visit 6- Patient returns for day two of infusion therapy with Zn-DTPA.  Blood samples will be 
collected by phlebotomy trained staff at the Clinical & Translational Research Center (CTRC) at UNC 
Memorial hospital. Patient blood samples will be obtained just prior to intravenous administration of Ca-
DTPA or Zn-DTPA 
 
6.8 
Visit 7- The patient will return to the hospital to drop off 24-hour urine for gadolinium testing, as 
well as a creatinine clearance. Blood chemistries calcium, zinc, magnesium and manganese will be 
evaluated, along with BUN, creatinine, sodium, potassium, chloride, phosphorus and CO2.  
 
6.9 
Visit 8- One week post treatment follow up visit for health assessments as before. Third therapy 
session will be scheduled for one month out.  
 
6.10 
Visit 9-  Patient returns for final round of infusion therapy to be done exactly as first two 
treatments with day one of Ca-DTPA, including pregnancy testing on women of child-bearing potential 
and pain assessment sheets for the week.  Blood samples will be collected by phlebotomy trained staff at 
the Clinical & Translational Research Center (CTRC) at UNC Memorial hospital. Patient blood samples 
will be obtained just prior to intravenous administration of Ca-DTPA or Zn-DTPA 
 
6.11 
Visit 10- Patient returns for day two of infusion therapy with Zn-DTPA.  Blood samples will be 
collected by phlebotomy trained staff at the Clinical & Translational Research Center (CTRC) at UNC 
Memorial hospital. Patient blood samples will be obtained just prior to intravenous administration of Ca-
DTPA or Zn-DTPA 
 


 
10 
 
6.12 
Visit 11- The patient will return to the hospital to drop off 24-hour urine for gadolinium testing, as 
well as a creatinine clearance. Blood chemistries calcium, zinc, magnesium and manganese will be 
evaluated, along with BUN, creatinine, sodium, potassium, chloride, phosphorus and CO2.  
 
6.13 
Visit 12- Subject returns for final follow up assessments 1 week (+5 days) following last infusion 
therapy. If patient lives more than 3 hours away, a phone-call will be done by the treating physician or 
clinician.  
 
6.14 
Visits 13-14- Subjects will receive a phone call from the coordinator to go over pain the pain 
assessment scale at months 6 and 12 following treatment.  
 
At any time in between treatments if the clinician or patient feels they need to be seen, they will be 
brought in to the clinic (or to their local healthcare provider) for evaluation and possible discontinuation of 
therapy.  
7 Statistical Plan 
7.1 Sample Size Determination 
Twenty subjects will be evaluated to determine the safety profile of chelation in this setting and to 
provide information on potential endpoints for future studies in this area.  The distributions of urinary 
measures of Gd excretion as well as for pain and quality of life will be evaluated at baseline and after 
each treatment, as will the differences in these measures between baseline and each treatment. 
7.2  Statistical Methods 
Changes between baseline and each treatment will be evaluated for direction and magnitude. 
Although the goal is estimation of effect size and variation, statistical tests for changes pre/post 
treatment will be evaluated to understand the pre/post changes toward development of a future trial.  
These tests will evaluate the null hypothesis of no change in urine measures or symptoms (via 
questionnaire). If the changes in measures are normally distributed, then paired t-tests will be used. 
However, it is more likely that the data will not be normally distributed and that Wilcoxon signed-rank 
tests will be need. For any nominal (yes/no) questionnaire data, a McNemar’s or sign test will be used 
for the paired contingency table.  Since these tests will likely be used in future studies, direction of 
effect measures (differences) and ranges of estimates (confidence intervals) will provide information 
on what to expect in testing and analyzing more individuals 
Subject Population(s) for Analysis 
All-treated population:  All subjects consenting to study will be treated with the same therapy, 
receiving at least one dose of study drug. 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research, 


 
11 
 
• Serious (as defined below)  “Serious” is different than “severe” as reported in the CTC 
criteria that applies a grade to the AE. 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
For the purpose of this trial, the following will be considered expected adverse events: 
 
Ca-DTPA—headache, lightheadedness, chest pain, allergic reaction, dermatitis, metallic 
taste, nausea and diarrhea, and injection site reactions. 
  
Zn-DTPA—headache, lightheadedness, and pelvic pain.  
 
Possible “flare effect”, resulting in exacerbation of current symptoms. 
 
 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
General Physical Examination Findings 


 
12 
 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an 
adverse event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study.  
The sponsor should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any 
condition responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately. 


 
13 
 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats 
and requirements of the various entities to which they are responsible, but at a minimum those events 
that must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 8.1).   
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of 
the initial report includes: 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator 
assessment 
of 
the 
association 
between the event and study treatment 
 
8.3.1 Investigator reporting: notifying the study sponsor 
 
Any study-related unanticipated problem posing risk of harm to subjects or others, and any type of 
serious adverse event, must be reported to the study sponsor by telephone within 24 hours of the event.  
To report such events, a Serious Adverse Event (SAE) form must be completed by the investigator and 
faxed to the study sponsor within 24 hours.  The investigator will keep a copy of this SAE form on file at 
the study site.  Report serious adverse events by phone and facsimile to: 
 
 
Within the following 48 hours, the investigator must provide further information on the serious adverse 
event or the unanticipated problem in the form of a written narrative.  This should include a copy of the 
completed Serious Adverse Event form, and any other diagnostic information that will assist the 
understanding of the event.  Significant new information on ongoing serious adverse events should be 
provided promptly to the study sponsor 
8.3.2 Investigator reporting:  
 
For reportable deaths, the initial submission to the UNC IRB may be made by contacting the IRB Director 
or Associate Director. The AE/Unanticipated Problem Form is required as a follow up to the initial 
submission. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the UNC IRB: 
• Any adverse experience that, even without detailed analysis, represents a serious unexpected 
adverse event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic necrosis, 
Stevens-Johnson syndrome). 
• Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or 
informed consent form, or would prompt other action by the IRB to assure protection of human 
subjects. 
• Information that indicates a change to the risks or potential benefits of the research, in terms of 
severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to treatment than 
initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more frequent than 
initially expected. 


 
14 
 
– A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in 
a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
• Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot 
be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 
protocol) that in the opinion of the investigator placed one or more participants at increased risk, or 
affects the rights or welfare of subjects. 
8.3.3 Sponsor reporting: Notifying the FDA 
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  
These written notifications of adverse events are referred to as IND safety reports. The following 
describes the safety reporting requirements by timeline for reporting and associated type of event: 
 
• Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening, and  
 
• Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, teratogenicity, 
or carcinogenicity. 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events will be submitted on FDA Form 3500A or in a narrative format, along with FDA form 1571.  
If supplied as in a narrative format, the minimum information to be supplied is noted above at the 
beginning of section 8.3.  
 


 
15 
 
8.4 Stopping Rules  
The study will be stopped for review if there is greater than 2 of the first 3 patients, or 5 of the first 10 
patients experience an unanticipated severe adverse event, or more than one grade IV expected adverse 
events as defined by CTCAE v.4.0.  
 
Study subjects will be withdrawn from the study if they experience any unknown severe adverse event 
(grade 3 or 4) following administration of either Ca-DTPA or Zn-DTPA. We will be using the CTCAE v.4.0 
scale to measure severity of adverse events.  
  
Any patient who shows a Grade 3 hypocalcemia (<7.0-6.0 mg/dl) post infusion therapy will be 
discontinued from the study.  
 
The study will be stopped for any study-related death.  
 
8.5 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see 
section 9 Auditing, Monitoring and Inspecting).  Medical monitoring will include a regular assessment of 
the number and type of serious adverse events. 
 
Safety Monitoring will be performed by Jeff Neitlich, MD, who is not a study investigator. The CRFs and 
any relevant source documents will be sent to the medical safety monitor (as above) who will review them 
after treatment is complete for subject 1, 3, 10 and 20. 
 
The research coordinator will complete the appropriate report form and logs; assist the PI to prepare 
reports and notify the IRB, FDA, and/or safety monitor of all Unanticipated Problems/SAE’s. 
 
The research coordinator and co-principal investigators will confirm that all Adverse effects (AE) are 
correctly entered into the AE log by the coordinator; be available to answer any questions that the 
coordinators may have concerning AEs; notify the IRB and FDA of all Unanticipated Problems/SAEs and 
AEs as appropriate. All assessments of AEs will be made by a licensed medical professional who is an 
investigator on the research. 
 
Complications will be assessed by the co-PIs, categorized into major and minor categories and recorded 
on the CRF. CRFs and appropriate source documents will be made available to this individual for bi-
monthly (every 2 months) review to ensure completeness of data collection. Any discrepancies will be 
immediately addressed by the co-PIs.  All adverse events will be recorded and then summarized for 
inclusion in the final manuscript.  
 
Data monitoring will be performed by an individual who is not a study investigator. CRFs and appropriate 
source documents will be made available to this individual for review to ensure completeness of data 
collection. Any discrepancies will be immediately addressed by the co-PIs. 
 
• Verify receipt of all documents and supplies needed to conduct study 
• Informed consent obtained for each participant 
• Source document verification 100% 
• CRF completion 
• Investigational product accountability 
• Check and review of the regulatory binder and all essential documents 
• Clinical supply inventory 
• SAE reporting 
• Protocol amendment and their approval by the IRB 
• Significant protocol deviations 


 
16 
 
• Personnel changes 
• Updated regulatory documentation 
• Any other issue as deemed important to the conduct of the study 
 
 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
9.3 Case Report Forms  
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is 
left blank because the procedure was not done or the question was not asked, write “N/D”.  If the item is 
not applicable to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any 
entry error has been made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents should be retained for a longer 
period if required by an agreement with the sponsor.  In such an instance, it is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be retained.  
 


 
17 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored by an independent monitor from outside of UNC.  The investigator will 
allocate adequate time for such monitoring activities.  The Investigator will also ensure that the monitor or 
other compliance or quality assurance reviewer is given access to all the above noted study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate 
space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of EC/IRB members and their affiliate 
to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. This consent 
form will be submitted with the protocol for review and approval by the EC/IRB for the study.  The formal 
consent of a subject, using the EC/IRB-approved consent form, must be obtained before that subject 
undergoes any study procedure.  The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent.  
12 Study Finances 
12.1 Funding Source 
The radiology department will be using internal funds. Hameln Pharma GmbH will be providing study 
drug. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved by the study sponsor prior to participation in this study.  All University of 
UNC investigators will follow the University conflict of interest policy. 


 
18 
 
13 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the study sponsor.  Any investigator involved with this study is 
obligated to provide the sponsor with complete test results and all data derived from the study. 
14 References 
1. Sieber MA1, Lengsfeld P, Walter J, Schirmer H, Frenzel T, Siegmund F, Weinmann HJ, Pietsch 
H., Gadolinium-based contrast agents and their potential role in the pathogenesis of nephrogenic 
systemic fibrosis: the role of excess ligand. J Magn Reson Imaging. 2008 May;27(5):955-62 doi: 
10.1002/jmri.21368 
. 
15 Appendices  
 
A. Table of Events 
B. Visual Analog Pain Scale 
C. Quality of Life scale 
D. Copy of Consent Form 
 
Time and Events Table: 
 
 
Pre-
treatment 
Visit 0 
 
V 1 
Day 1 
 
V 2 
Day 2 
V 3 
Day 3  
 
V 4 
Day 7 
 
V 5 
Day 1 
Mo 2 
V 6 
Day 2 
Mo 2 
V 7 
Day 3 
Mo 2 
V 8 
Day 7  
Mo 2 
V 9 
Day 1  
Mo 3 
V10 
Day 2 
Mo 3 
V 11 
Day 3 
Mo 3 
V 12 
Day 7 
Mo 3 
V 13-
14 
Mo 6 
& 12 
Physical 
Assessments 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Labs 
X 
Xc 
 
X 
 
Xc 
 
X 
 
Xc 
 
X 
 
 
24 hr urine gd 
X 
Xa 
Xa 
 
 
Xa 
Xa 
 
 
Xa 
Xa 
 
 
 
Pain/QOL 
questionnaire 
X 
 
 
 
Xe 
 
 
 
Xe 
 
 
 
Xe 
 
Xd 
IV Ca-DTPA 
therapy 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
IV Zn-DTPA 
therapy 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
a. Patients will begin 24hr urine collection immediately following therapy 
b. Assessments may be done by phone when patient lives greater than 3 hours away 
c. Urine pregnancy testing will be done on day one of therapy for WCBP 


 
19 
 
d. Patients will be called to collect pain and QOL data at months 6 and 12 
e. Pain/QOL questionnaires will be filled out days 1-6 and returned day 7