Clinical trial NCT03232580
Conditions: Spondyloarthritis
Keywords: Suspicion or confirmed diagnosis of Spondyloarthritis Ankylosing Spondylarthritis Ankylosing Spondylitis Ankylosing Spondyloarthritis Rheumatoid Spondylitis Spondylarthritis Ankylopoietica Spondylitis Ankylopoietica Spondyloarthritis Ankylopoietica Autoimmune systemic rheumatic disease Inflammatory bowel disease Psoriatic arthritis Undifferentiated spondyloarthropathy.
Sponsor: Advanced Accelerator Applications
Start date: 2017-09-18; Completion date: 2018-11-12
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This single center, open-label, proof of concept (PoC) Phase II study aimed to assess the investigational imaging agent 99mTc-rhAnnexin V-128 in detecting spondyloarthritis (SpA) lesions.

Overall, it was planned to recruit 20 adults with suspected or confirmed SpA. First, 5 patients were enrolled into a "proof of concept" phase, to assess the imaging potential of 99mTc-rhAnnexin V-128 in terms of imaging quality, disease-lesion radiotracer uptake and medical relevance. Based on these results the Data Monitoring Committee (DMC) was to decide whether to terminate the study or whether to continue and enroll the next 15 planned patients.

Detailed description:
The study was prematurely terminated by the sponsor after the first 5 patients completed the PoC phase based on strategic considerations.

Novartis acquired Advanced Accelerator Applications SA.

Arms: arm 1: All patients received a single i.v injection of 99mTc-rhAnnexin V-128 at Day 0.
Interventions: intervention 1: rhAnnexin V-128
Intervention descriptions: intervention 1: All patients received a single i.v injection of 99mTc-rhAnnexin V-128 at Day 0.

Protocol documents:
Prot_000.pdf: 
AAA-Annexin-03 
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Study Protocol 
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Study Protocol 
Protocol Number 
AAA-Annexin-03 / NCT03232580 
Investigational Product 
Kit for the preparation of 99mTc-rhAnnexin V-128 
Active substance 
rhAnnexin V-128 
Radiolabeled Imaging Product 
99mTc-rhAnnexin V-128 
Trial Phase 
Proof of Concept and Phase II 
Trial Title 
Phase II Study of 99mTc-rhAnnexin V-128 Radionuclide 
Imaging in Patients with Clinical Suspicion or Confirmed 
Diagnosis of Spondyloarthritis (SpA) 
Short Trial Title 
99mTc-rhAnnexin V-128 in patients with SpA 
Version and Date 
v4.0 – 13 March 2018 
Investigators 
Principal Investigator: 
Dr 
, MD 
Co-Investigators: 
Dr 
, MD 
Trial Sponsor 
Advanced Accelerator Applications USA Inc. 
The concepts and information contained herein or generated during the study 
are considered proprietary and shall not be disclosed in whole or in part without 
the expressed written consent of Advanced Accelerator Applications USA Inc. 
This study is to be completed according to the guidelines of Good Clinical Practice (GCP) and 
conducted in full compliance with the World Medical Association Declaration of Helsinki and its 
most recent amendments. 


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Study Protocol 
 
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CONFIDENTIAL 
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SPONSOR SIGNATORY APPROVAL PAGE 
 
 
Key Personnel - Advanced Accelerator Applications 
Function 
Name and contact 
Date and Signature 
 
 
 
, MD 
Advanced Accelerator Applications SA 
Tel: 
 
E-mail: 
 
 
 
 
, MD, PhD 
Advanced Accelerator Applications SA 
Tel: 
 
E-mail: 
  
 
 
 
 
, PhD 
Advanced Accelerator Applications SA 
Tel:  
 
Fax: 
 
Cell: 
 
E-mail:
 
 
 


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Study Protocol 
 
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INVESTIGATOR ENDORSEMENT PAGE 
 
I agree to conduct the study as outlined in the protocol entitled “Phase II Study of 99mTc-rhAnnexin 
V-128 Radionuclide Imaging in Patients with Clinical Suspicion or Confirmed Diagnosis of 
Spondyloarthritis (SpA)” in accordance with the guidelines and all applicable government 
regulations. These guidelines and regulations include, but are not limited to:  
 
1. Permission to allow the Sponsor and the regulatory agencies to inspect study facilities and 
pertinent records at reasonable times and in a reasonable manner that ensures subject 
confidentiality.  If this study is to be inspected by a regulatory agency, the Sponsor should 
be notified as soon as possible; 
 
2. Submission of the proposed clinical investigation, including the protocol and the consent 
form to a duly constituted Institutional Review Board (IRB) or Ethics Committee (EC) for 
approval and acquisition of written approval for each, prior to the use of the test article; 
 
3. Use of written informed consent that is obtained prior to administration of test article or any 
non-routine procedures that involve risk, and that contains all the elements of consent as 
specified in the federal regulations and has been previously approved by the Sponsor and 
the IRB/EC; 
 
4. Submission of any proposed change in or deviation from the protocol to the IRB/EC using a 
signed formal amendment document approved by the Sponsor.  Any proposed changes or 
deviations from the protocol require that the informed consent also reflect such changes or 
deviations and that the revised informed consent be approved by the IRB/EC; 
 
5. Documentation and explanation of individual protocol deviations on the appropriate case 
report form page or in letters to the Sponsor; 
 
6. Reports of serious adverse events to the Sponsor/CRO within 24 hours by telephone and a 
written report of the serious adverse event within 72 hours after the Investigator’s initial 
receipt of the information; 
 
7. Reporting of Serious Adverse Events (SAEs) according to ICH/GCP and Regulatory 
Standards. SAEs will be reported from the signing of the informed consent and followed 
until resolution or determined to be not clinically significant; 
 
8. Submission of timely progress reports to the IRB/EC and Sponsor at appropriate intervals 
on a schedule determined by the IRB/EC. 
 
Regulations require an Investigator to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data (such as test article accountability) pertinent to 
the investigation on each individual enrolled in the study. These records must be maintained by the 
Investigator for a period of 2 years or a period of time determined by the Sponsor following the date 
a marketing application is approved for the indication for which it is being investigated, or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years or a 
period of time determined by the Sponsor after the investigation is discontinued and the appropriate 
regulatory authorities are notified. 


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In addition, I agree to provide all the information requested in the case report form in a manner to 
assure legibility and accuracy. To this end, I shall carefully follow the instructions for completing 
case report forms. 
 
I also agree that all information provided to me by the Sponsor, including protocols, case report 
forms, and verbal and written information, will be kept strictly confidential and confined to the 
clinical personnel involved in conducting the study. It is recognized that this information may be 
related in confidence to the IRB/EC. I also understand that reports of information about the study or 
its progress will not be provided to anyone who is not involved in the study other than to the 
Principal Investigator, or in confidence to the IRB/EC or to the legally constituted regulatory 
authorities. 
 
 
 
 
Principal Investigator Signature 
 
Date of Signature 
 
 
 
 
 
 
 
 
 
 


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1 SYNOPSIS 
Investigational 
Medicinal 
Product 
Kit for the Preparation of Tc-99m Recombinant Human Annexin V-128 for 
Injection 
Title of the study Phase II Study of 99mTc-rhAnnexin V-128 Radionuclide Imaging in Patients 
with Clinical Suspicion or Confirmed Diagnosis of Spondyloarthritis (SpA). 
Clinical Center 
Cedars-Sinai Medical Center 
8700 Beverly Blvd., 1258 
Los Angeles, CA 90048 
United States 
Investigators 
Dr 
, MD 
Dr 
, MD 
Corporate 
Sponsor 
Advanced Accelerator Applications USA, Inc. 
Subject’s 
Indication 
Patients with Clinical Suspicion or Confirmed Diagnosis of Spondyloarthritis 
(SpA) 
Objectives 
Primary Objective 
- 
To determine the magnitude and dynamic range of 99mTc-rhAnnexin V-128 
uptake in disease affected sacro-iliac or lumbar spine joints, in patients 
with clinical suspicion or confirmed diagnosis of Spondyloarthritis (SpA).  
Secondary Objectives: 
- 
To determine the clinical utility of 99mTc-rhAnnexin V-128 SPECT/CT 
imaging in the identification of chronic osteoarthritic active sites of SpA 
compared with conventional imaging (Magnetic Resonance Imaging), in 
patients with disease affected sacro-iliac, or lumbar spine joints. 
- 
To assess the presence of antibodies against rhAnnexin V-128 at 
baseline and pot-treatment 
- 
To determine the localization pattern and magnitude of focal uptake of 
99mTc-rhAnnexin V-128 within the abdomen in patients with clinical 
suspicion or confirmed diagnosis of Spondyloarthritis (SpA). 
 
 
Rationale 
Annexin V is an endogenous human protein that binds to phosphatidylserine 
(PS), a constitutive anionic phospholipid of the plasma cell membranes in all 


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mammalian cells, that is expressed on the surface of physiologically stressed, 
depolarized, or apoptotic cells only. Technetium-99m (99mTc) is a medical 
isotope widely used in diagnostic imaging. 99mTc-labeled annexin V-128 has 
demonstrated the ability to image cellular stress, apoptosis, and necrosis in a 
variety of diseases with strong inflammatory component including rheumatoid 
arthritis, prosthetic joint infection, myocarditis, acute heart transplant rejection, 
or Crohn’s disease in both, animal models and in humans. 
Planned number 
of patients 
Twenty evaluable patients with clinical suspicion or confirmed diagnosis of 
spondyloarthritis due to ankylosing spondylitis, or associated with other known 
clinical conditions like inflammatory bowel disease, psoriatic arthritis, or 
undifferentiated spondyloarthropathy. 
Five patients will be recruited in the first part of the trial, as a Proof of Concept 
(PoC) phase. The PoC phase will assess the imaging potential of 99mTc-
rhAnnexin V-128 in terms of imaging quality, disease-lesion radiotracer uptake 
and medical relevance to enable the decision-making to terminate or to 
continue the clinical investigation completing the enrollment with the remaining 
15 patients. 
Study design and 
Methodology 
This is a single-centre, open label, PoC, Phase II study. Patients who have 
signed the informed consent and are eligible to participate in the study will 
undergo the following assessments: 
 
At screening visit, eligible and consented patients who have clinical 
suspicion or confirmed diagnosis of SpA will undergo a physical 
examination, vital signs (systolic and diastolic blood pressure, heart 
rate), blood analysis [CBC with automated differential, general 
chemistry panel (SMA-20) including CRP, PT/PTT, INR (international 
normalized ratio for PT values), assessment of anti-annexin V-128 
antibodies] and urinalysis. In addition, disease activity score 
assessments (BASDAI, BASFI, BASMI and MASES) will also be 
performed. Screening laboratory assays, physical examination and 
vital signs will be performed 24 hours to 14 days before 99mTc-
rhAnnexin V-128 imaging. Within 14 days of 99mTc-rhAnnexin V-128 
scanning patients will undergo T1 and STIR without contrast Magnetic 
Resonance Imaging (MRI) of the sacro-iliac and lumbar spine joints.  
 
At Day 0 (the day of intravenous injection and imaging with 99mTc-
rhAnnexin V-128), a dedicated lumbosacral spine and abdomen 
SPECT/CT starting 60 minutes after injection of tracer followed by a 
whole body planar scan and spot views on selected areas will be 
performed. The same SPECT/CT and whole body planar scans will be 
repeated at 2 hrs after injection of tracer except the spot views unless 
they suggest to be repeated. Vital signs assessment will also start 15 
minutes before and for 2 hours after injection of radiotracer.  
 
At Day 1 (one day after the administration of 99mTc-rhAnnexin V-128), 
15\20 patients will be contacted over the phone for assessment of 
possible adverse events (e.g. allergic reaction such as rash, edema). 5 


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patients will return for an optional whole body planar scan at 24hrs post 
injection as well as spot views, if deemed appropriate by the 
investigator. Safety information will be collected at this time for these 5 
patients. 
 
At Day 30 ± 3 days, all patients will return to the clinic for a physical 
examination and a final blood sampling to rule out the development of 
anti-annexin V-128 antibodies and for the following blood analysis and 
urinalysis: CBC with automated differential, general chemistry panel 
(SMA-20) including CRP, PT/PTT, INR (international normalized ratio 
for PT values). 
 
Once the first 5 patients have been administered with 99mTc-rhAnnexin 
V-128 and have performed the imaging at Day 0, a Data Monitoring 
Committee (DMC) will review the images. The visual assessment of the 
scans in these first 5 patients may support the continuation or the 
termination of the Phase II study. In the first case, the enrollment of 15 
additional patients will be required.  
 
Treatment 
The treatment will consist of 
99mTc-rhAnnexin V-128. Following the 
reconstitution and labelling of rhAnnexin V-128, the imaging product will be 
administered as a single intravenous bolus of 350 MBq ± 10% over 10-20 
seconds at Day 0 for the purpose of SPECT/CT imaging. 
 
Inclusion/ 
exclusion criteria 
 
Inclusion criteria 
For the first 5 patients enrolled in the POC part: 
1. Patients with clinical suspicion or confirmed diagnosis of SpA, based on 
the ASA criteria with active symptoms including back, hip or buttock 
pain prior to: 
 
A change in NSAID therapy or 
 
A change in non-biologic DMARD or  
 
A start of non-biologic DMARD. 
 
For the next 15 patients enrolled in the Phase II part: 
1. Patients with clinical suspicion or confirmed diagnosis of  SpA, based 
on the ASAS criteria with active symptoms including back, hip or 
buttock pain prior to:  
 
A change in NSAID therapy or  
 
A change in non-biologic DMARD or  
 
A start of non-biologic DMARD or 
 
A start of biologic DMARD 
 
For all patients: 
2. Age over 18 years old. 
3. Signed Informed Consent Form. 
 


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Exclusion criteria 
1. Pregnancy or lactation 
2. Liver impairment (ALT, AST or Bilirubin > 2 ULN) at screening visit or 
baseline. 
3. Kidney impairment (serum creatinine > 1.5 mg/dL) 
4. History of any disease or relevant physical or psychiatric condition or 
abnormal physical finding which may interfere with the study objectives 
at the investigator judgment. 
5. Know hypersensitivity to the investigational product or any of its 
components. 
6. Contraindication(s) to the MRI procedure (claustrophobia, prosthetic 
valve, pacemaker, inability to lie still in a supine position) 
7. Participation in another clinical trial within 4 weeks before study 
inclusion. 
 
Study duration 
and 
assessments: 
Maximum 7 weeks including the screening period, for an individual patient. 
Safety 
Venous blood samples will be drawn for each patient at screening and at Day 
30 for laboratory analysis (CBC with diff., SMA-20 including CRP, PT/PTT, 
INR).  
To rule out the development of anti-rhAnnexin V-128 antibodies, venous blood 
samples will also be drawn for each patient at screening and Day 30. Assays 
for anti-rhAnnexin V-128 IgG and IgM antibodies will be performed in serum 
samples by ELISA. For this purpose, 10 mL of blood will be collected at 
screening visit and at Day 30.  
24 hours after injection, at Day 1, each patient will be called to check if they 
experienced any Adverse Events.  
All patients will undergo a physical examination at screening and at Day 30.  
Vital signs (systolic and diastolic blood pressure, heart rate) will be performed 
by all patients at screening and Day 0 (before and after injection of the 
radiotracer).  If there is any Adverse Event(s), they will be reported and 
recorded in the Electronic Case Report Form (eCRF). 
Statistics 
The number of patients in this study is not based on statistical power 
considerations. Five patients will be enrolled in the PoC phase, and 15 
additional patients in the second part of the study, which is believed to provide 
sufficient data to demonstrate the potential of 99mTc-rhAnnexin V-128 imaging 
in the assessment of disease severity in SpA patients and plan for future 
clinical studies. 
Adverse events will be listed on an individual basis, including relationship, and 
severity, and will be summarized by System Organ Class (SOC) and Preferred 
Term (PT). Patients with more than one adverse event within a particular SOC 


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and PT will be counted only once for that SOC and PT. The incidence of 
adverse events will also be summarized by severity. 
All other safety variables will be tabulated at each measuring time together 
with descriptive statistics, if appropriate. Hematology, clinical chemistry, 
urinalysis and immunogenicity data will be analyzed. Similarly, descriptive 
statistics will also be provided for vital signs, physical examination, etc. 
Efficacy by 99mTc-rhAnnexin V-128 uptake will be assessed qualitatively and 
semi-quantitatively in sacro-iliac joints and in the lumbar spine of patients with 
clinical suspicion or confirmed diagnosis of SpA. Sensitivity and specificity of 
99mTc-rhAnnexin V-128 SPECT/CT imaging compared to MRI will be evaluated 
based on the clinical follow-up information as the standard of truth for disease 
diagnosis. 
 
 


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Visit schedule – Table 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 24 hours after injection of 99mTc-rh-Annexin V-128, each patient will be called over the phone to assess if   
they experienced any adverse events such as allergic reactions (edema, rash). 
 
2 Anti-rhAnnexin V-128 IgG and IgM antibodies will be quantified in serum samples by ELISA. For this purpose 
10 mL blood samples will be collected at screening and Day 30 post administration of test agent. Serum will 
be prepared, divided into six aliquots and frozen (-80°C). Three out of six serum aliquots will then be shipped 
to the central laboratory at 
. The 3 remaining aliquots will be sent to 
 
with an additional shipment. 
 
Study Procedures 
Screening 
(Within 14 days 
prior to Day 0) 
Day 0  
 
Day 1 
24 hours1 
 
Day 30 
 
Written informed 
consent 
x 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
Medical history 
x 
 
 
 
Concomitant 
medications  
x 
x 
X 
X 
Disease assessment 
(BASDAI, BASFI, 
BASMI, MASES)  
x 
 
 
 
Physical examination 
x 
 
 
x 
Vital signs 
(BP, HR) 
x 
x 
 
 
Lab analysis 
(hematology, 
PT/PTT/INR 
biochemistry; urine) 
x 
 
 
x 
Immunogenicity by 
ELISA2 
x 
 
 
x 
Pregnancy test 
x 
x 
 
 
MRI (within 14 Days 
of rh-Annexin V-128 
scanning) 
x3 
 
 
 
rh-Annexin V-128 
administration and 
scan (SPECT/CT and 
planar imaging)  
 
X4 
 
 
Whole Body Planar 
Imaging + spots 
 
 
X4 
 
High Resolution spot 
images of hands, feet, 
any symptomatic joint 
group  
 
X4 
X4 
 
Adverse Events 
x 
x 
X 
x 


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3 A whole lumbar spine MRI must be performed prior to the enrolment date, or within 14 days of 99mTc-rh-
Annexin V-128 scanning prior to changing NSAID therapy or non-biologic DMARD or starting non-biologic 
DMARD for the first 5 patients and prior to changing NSAID therapy or non-biologic DMARD or starting non-
biologic DMARD or biologic DMARD for the next 15 patients. 
4 First five patients after which the process will be re-evaluated: 
 
All patients will have  whole body planar imaging at 60 minutes post injection. 
 
At two hours post injection do a whole body planar scan and SPECT/CT with onboard isotope with 
no spot views unless initial views suggest otherwise. The whole body planar scan adds 15-20 
minutes; each spot adds 5 minutes 
 
The SPECT/CT and spot imaging will be done for first 5 patients after which the protocol will be re-
adjusted.  
 
An optional whole body planar scan will be done at 24hrs post injection for 5 patients as well as 
spot views, if deemed appropriate by the investigator.  


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2 LIST OF ABBREVIATIONS 
 
AAA 
AE 
ACR 
AS 
ASAS 
BASDAI 
BASFI 
BASMI 
Bi-DMARD 
BUN 
CIA 
CRF 
CRO 
CRP 
CT 
DAS28 
DMARD 
DMC 
ELISA 
FDA 
GCP 
GP 
Hb 
HPLC 
ICF 
ICH 
ICP-MS 
ICP-OES 
ICRP 
Advanced Accelerator Applications 
Adverse Event 
American College of Rheumatology 
Ankylosing Spondylitis 
Assessment of Spondylo-Arthritis Society 
Bath Ankylosing Spondylitis Disease Activity Index 
Bath Ankylosing Spondylitis Functional Index 
Bath Ankylosing Spondylitis Metrology Index 
Biological Disease Modifying Anti-Rheumatic Drug 
Blood Urea Nitrogen 
Collagen Induced Arthritis 
Case Report Form 
Clinical Research Organization 
C-Reactive Protein 
Computed Tomography 
Disease Activity Score 
Disease Modifying Anti-Rheumatic Drug 
Data Monitoring Committee 
Enzyme-Linked Immuno-absorbent Assay 
Food and Drug Administration 
Good Clinical Practice 
General Practitioner 
Hemoglobin 
High-Performance Liquid Chromatography 
Informed Consent Form 
International Conference on Harmonization 
Inductively Coupled Plasma Mass Spectrometry 
Inductively Coupled Plasma Optical Emission Spectrometry 
International Commission on Radiological Protection 


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IEC 
IL-6 
IMP 
INR 
IRB 
ITLC 
MBq 
MIRD 
MCV 
MedDRA 
MRI 
NSAID 
NOAEL 
PBS 
PI 
PoC 
PS 
PT 
PTT 
PV 
QA 
QC 
RA 
RBC 
RCP 
ROI 
SAE 
SAP 
SEC-HPLC  
SI 
SOP 
SpA 
Independent Ethics Committee 
Interleukine-6 
Investigational Medicinal Product 
International Normalized Ratio 
Institutional Review Board 
Instant Thin Layer Chromatography 
Mega Becquerel 
Medical Internal Radiation Dose 
Mean Corpuscular Volume 
Medical Dictionary For Regulatory Activities 
Magnetic Resonance Imaging 
Non-Steroidal Anti-Inflammatory Drug 
No Observed Adverse Effect Level 
Phosphate Buffered Saline 
Principal Investigator 
Proof of Concept 
Phosphatidylserine 
Prothrombin Time 
Partial Thromboplastin Time 
PharmacoVigilance 
Quality Assurance 
Quality Control 
Rheumatoid Arthritis 
Red Blood Cell 
Radiochemical Purity 
Region of Interest 
Serious Adverse Event 
Statistical Analysis Plan 
Size-Exclusion HPLC 
Sacro-Iliac 
Standard Operating Procedure 
Spondyloarthritis 


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SPECT 
TBR 
TLC 
TNF 
US 
UV/Vis 
WBC 
WFI 
WHO 
VOI 
Single-Photon Emission Computed Tomography 
Target to Background Ratio 
Thin Layer Chromatography 
Tumor Necrosis Factor 
United States 
Ultraviolet/Visible 
White Blood Cell 
Water For Injection 
World Health Organization 
Volumes Of Interest 


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TABLE OF CONTENTS 
 
SPONSOR SIGNATORY APPROVAL PAGE ........................................................................................................ 2 
INVESTIGATOR ENDORSEMENT PAGE .............................................................................................................. 3 
1 
SYNOPSIS .......................................................................................................................................................... 5 
2 
LIST OF ABBREVIATIONS ............................................................................................................................ 12 
3 
INTRODUCTION .............................................................................................................................................. 17 
3.1 BACKGROUND AND RATIONALE ........................................................................................................................................ 17 
3.2   99MTC-RHANNEXIN V-128 RISK-BENEFIT ASSESSMENT ....................................................................................................... 20 
4 
STUDY OBJECTIVES AND HYPOTHESES ................................................................................................. 22 
4.1  STUDY OBJECTIVES ........................................................................................................................................................ 23 
4.2  STUDY HYPOTHESES....................................................................................................................................................... 23 
4.3  STUDY JUSTIFICATION .................................................................................................................................................... 24 
5 
STUDY DESIGN ............................................................................................................................................... 24 
5.1  STUDY OUTLINE ........................................................................................................................................................... 24 
5.2  STUDY DURATION AND END OF STUDY .............................................................................................................................. 24 
6  PATIENT SELECTION........................................................................................................................................ 24 
6.1  INCLUSION CRITERIA ...................................................................................................................................................... 24 
6.2  EXCLUSION CRITERIA ..................................................................................................................................................... 25 
6.3  NUMBER OF PATIENTS ................................................................................................................................................... 25 
6.4  PATIENTS IDENTIFICATION .............................................................................................................................................. 25 
6.5  PREMATURE DISCONTINUATION ...................................................................................................................................... 26 
6.6  PROHIBITION AND RESTRICTIONS ..................................................................................................................................... 26 
7  STUDY MEDICATION AND TREATMENT ....................................................................................................... 26 
7.1  PACKAGING AND LABELLING ........................................................................................................................................... 26 
7.2  HANDLING OF STUDY MEDICATION .................................................................................................................................. 27 
7.3  IMP PACKAGING AND STORAGE ...................................................................................................................................... 27 
7.4  PRECAUTIONS AND RECOMMENDATION FOR USE ................................................................................................................. 27 
7.5  STUDY MEDICATION DOSE, MODE OF ADMINISTRATION, BATCH NUMBER .............................................................................. 28 
8  ASSESSMENTS .................................................................................................................................................. 28 
8.1 BASELINE ASSESSMENTS ................................................................................................................................................. 28 
8.2 SAFETY ASSESSMENTS .................................................................................................................................................... 29 
8.3 STANDARD LABORATORY ASSESSMENTS ............................................................................................................................ 29 
8.4  CLINICAL ASSESSMENT ................................................................................................................................................... 30 
8.5  IMAGING ..................................................................................................................................................................... 30 
8.6  IMMUNOGENICITY ASSESSMENTS ..................................................................................................................................... 31 
9  DATA MONITORING COMMITTEE (DMC) ...................................................................................................... 31 
10  STATISTICAL CONSIDERATIONS ................................................................................................................ 31 
10.1  GENERAL STATISTICAL CONSIDERATIONS .......................................................................................................................... 32 
10.2  SAMPLE SIZE .............................................................................................................................................................. 32 
10.3  DEMOGRAPHICS AND OTHER SUBJECT CHARACTERISTICS .................................................................................................... 32 
10.4  CONCOMITANT MEDICATIONS ...................................................................................................................................... 32 


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10.5  LABORATORY TESTS .................................................................................................................................................... 32 
10.6  SAFETY ..................................................................................................................................................................... 33 
10.7  PHYSICAL EXAMINATION .............................................................................................................................................. 33 
10.8  ADVERSE EVENTS ........................................................................................................................................................ 33 
10.9  ANALYSIS OF EFFICACY ................................................................................................................................................. 33 
11  ADVERSE EVENTS AND OTHER SAFETY ASPECTS ............................................................................... 34 
11.1  DEFINITION OF ADVERSE EVENTS ................................................................................................................................... 34 
11.2  DEFINITION OF SERIOUS ADVERSE EVENTS ....................................................................................................................... 34 
11.3  INVESTIGATOR REPORTING REQUIREMENTS ..................................................................................................................... 35 
11.4  REPORTING OF SERIOUS ADVERSE EVENTS ....................................................................................................................... 35 
11.5  FOLLOW-UP OF ADVERSE EVENTS .................................................................................................................................. 36 
11.6  PROCEDURE IN CASE OF PREGNANCY .............................................................................................................................. 36 
12  TERMINATION OF THE STUDY ..................................................................................................................... 36 
13 OPERATIONAL, ETHICAL, AND ADMINISTRATIVE CONSIDERATIONS ................................................ 37 
13.1  STUDY PERSONNEL ...................................................................................................................................................... 37 
13.2  DATA COLLECTION ...................................................................................................................................................... 37 
13.3  DATA REVIEW ............................................................................................................................................................ 37 
13.4  DATA CLARIFICATION .................................................................................................................................................. 38 
13.5  SOURCE DOCUMENTS .................................................................................................................................................. 38 
13.6  CLINICAL STUDY MONITORING ...................................................................................................................................... 39 
13.7  DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................................................................................... 39 
13.8  DATA MANAGEMENT .................................................................................................................................................. 39 
13.9  ETHICAL CONDUCT OF CLINICAL STUDY ........................................................................................................................... 39 
13.10  AUTHORITIES ........................................................................................................................................................... 40 
13.11  PATIENT CONFIDENTIALITY ......................................................................................................................................... 40 
13.12  PATIENT INFORMATION/WRITTEN INFORMED CONSENT .................................................................................................. 40 
13.13  ARRANGEMENT FOR USE OF INFORMATION AND PUBLICATION OF CLINICAL STUDY DATA ....................................................... 41 
13.14  DOCUMENTS AND RECORDS RELATED TO THE CLINICAL STUDY .......................................................................................... 41 
13.15  SAMPLING COLLECTION .............................................................................................................................................. 42 
13.16  PROTOCOL AMENDMENT AND/OR REVISION .................................................................................................................. 42 
13.17  QUALIFICATION OF THE INVESTIGATORS ........................................................................................................................ 42 
13.18  FINANCIAL DISCLOSURE ............................................................................................................................................. 43 
13.19  INSURANCE OF PATIENTS AND OTHERS.......................................................................................................................... 43 
13.20  INVESTIGATOR INDEMNITY .......................................................................................................................................... 43 
14  QUALITY ASSURANCE ................................................................................................................................... 44 
15  REFERENCES .................................................................................................................................................. 44 
APPENDIX I – RADIOLABELING PROCEDURE OF RH-ANNEXIN V-128 AND QUALITY CONTROLS .................................. 48 
APPENDIX II – SPA ASSESSMENTS .................................................................................................................... 51 
APPENDIX III – SAE FORM .......................................................................................................................................... 55 
APPENDIX IV – PREGNANCY FORM........................................................................... ERROR! BOOKMARK NOT DEFINED. 


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3 INTRODUCTION 
3.1 Background and rationale 
Spondyloarthropathy or spondyloarthritis (SpA) represents several types of autoimmune 
inflammatory arthritis which share a number of clinical and genetic features. These include; 
ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis or spondyloarthritis, SpA associated 
with inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis 
(UC), undifferentiated SpA and juvenile-onset spondyloarthritis [Dougados 2011, Ehrenfeld 2012, 
Poddubnyy 2012].  
 
There are certain characteristics linking AS and spondylitis associated CD together based on 
sharing some of the genetic, clinical, immunological, and microbial features [Ebringer A et al 2007]. 
Furthermore, most if not all SpA conditions are thought to have a fundamental link with the gut 
lesions and enterobacterial microbes [Rashid T et al 2011]. For example, around 10 percent of 
patients with AS have overt IBD, whilst 70% of AS patients have subclinical terminal ileitis [Mielants 
H et al 1995]. Axial and peripheral arthritis can occur in up to 30% of patients with CD [Orchard T et 
al 2009], and the prevalence of AS might increase to up to 6% in patients having CD [Palm Ø et al 
2002]. Moreover, HLA-B27 positive patients with IBD were shown to have higher chance of 
developing AS compared to those without IBD [Wright W et al 1978]. 
 
Clinically patients present with sacroilitis and inflammatory back pain, peripheral arthropathy, 
enthesitis, extra-articular or extra-spinal involvement, including of the eye, heart, lung and skin in 
the absence of rheumatoid factor or subcutaneous nodules. SpAs also display a strong hereditary 
tendency and a varying association with HLA-B27 (and other less common genes) suggesting that 
these disorders share patho-physiologies [Wendling 2013, Bleil 2014, Hreggvidsdottir 2014]. 
Overall SpAs have disease prevalence similar to rheumatoid arthritis (RA) in the general population 
[Dougados 2011, Ehrenfeld 2012, Poddubnyy 2012]. 
 
Challenges in the management of SpAs include; the prevention of new and/or progressive bone 
formation/spinal fusion and the lack of robust measures for early diagnosis [Poddubnyy 2012, 
Wendling 2013, Hreggvidsdottir 2014]. The introduction of tumor necrosis factor (TNF)-alfa-blocking 
agents in the past decade has provided the first effective, though imperfect, disease-modifying anti-
rheumatic drug therapy for SpA [Dougados 2011, Ehrenfeld 2012, Poddubnyy 2012]. However, as 
stated above these agents and potential new disease modifying drugs would be best used earlier in 
the disease course. In order to identify and treat patients with SpA early in the disease process, 
prior to radiographic changes of erosion and bony ankyloses of the sacro-iliac joints and spine, T1-
weighted images alone or together with STIR images are considered of most importance for the 
MRI as indicative of SpA by the vast majority of radiologists and rheumatologists. For diagnosing 
SpA by MRI in the inflammatory back pain context, the T1-weighted sequence, either alone or in 
combination with STIR, still is considered as more relevant approach (Weber 2010). 
 


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In this clinical trial, we propose to test the feasibility of 99mTc-annexin V-128, an in vivo marker of 
phosphatidylserine (PS) expression [Blankenberg 1998 & 2009], to detect and assess the severity 
of inflammation at sites of disease in SpA patients. PS is an anionic membrane phospholipid 
present in all mammalian cells which is actively restricted to the inner leaflet of the lipid bilayer by 
ATP dependent pumps within the plasma membrane. However in conditions of severe metabolic 
stress, activation of the apoptotic cell death pathway or persistent or chronic neuronal 
excitation/depolarization PS is selectively exposed on the cell surface [Smith 2009, Kenis 2010]. 
Annexin V, an endogenous human intracellular protein specifically binds to membrane bound PS 
with a high affinity (kd = 1 to 2 nM) permitting its use an imaging agent of cellular stress, 
depolarization and apoptosis both in vitro and in vivo [Tait 2005, 2006].  
 
Preliminary data with 99mTc-annexin V for imaging of acute and chronic inflammation.  
 
Radiolabeled forms of annexin V, including 99mTc-HYNIC-annexin V and 99mTc-annexin V-128 have 
shown the ability to image and monitor sites of autoimmune and infectious inflammation and 
response to treatment in multiple animal models and humans [Vriens1998, Blankenberg 2000, 
Ogura 2000 & 2001, Tokita 2003, Lorberboym 2009, Benali 2014, Hardy 2014]. The ability of 
annexin V to localize sites of inflammation is directly related to its highly specific binding to PS, 
whose exposure on the cell surface is an indicator of cellular stress that if unchecked can lead to 
apoptosis (programmed cell death) and recognition by the immune system for removal. In general 
PS externalization due to ongoing stress (as opposed to apoptosis) demonstrates far lower levels 
of PS exposure as compared with apoptosis and other forms of cell death (Hamill 1999, Geske 
2001). These relatively low levels of PS exposure can be readily counteracted by the prompt 
removal of the offending physiologic stressor and is referred to as “reversible PS expression”. 
However, if the stress(ors) remains uncorrected, a cell may undergo apoptosis. Reversible uptake 
of radiolabeled annexin V has been observed in vitro and in human models of forearm muscle 
exercised induced ischemia (Risken 2005 & 2006, Rongen 2005). The ability of annexin V to bind 
to cells with low but potentially reversible levels of PS exposure may also explain the uptake of 
radiolabeled annexin V outside (contralateral) regions of apoptosis  in patients with hypoxic-
ischemic reperfusion injury in the heart (Thimister 2003, Sarda-Mantel 2006) or brain (Lorberboym 
2006, Blankenberg 2006, Tang 2007). In fact, even in regions with apoptosis/ischemic injury, there 
are far more annexin V–positive cells after the administration of radiolabeled annexin V than 
apoptotic nuclei as seen by TUNEL staining (Tang 2007). These observations suggest that much (if 
not most) uptake of annexin V after ischemic reperfusion injury maybe due to large numbers of 
stressed cells (not necessarily committed to apoptosis) with relatively low levels of PS expression in 
contrast to the relatively fewer cells with high levels of PS exposure that are irreversibly committed 
to apoptosis. The ability of annexin V to localize cells that are stressed but not necessarily 
committed to apoptotic cell death suggests that this radiotracer can be used to identify tissues or 
organs at risk for irreversible injury, such as seen in hypoxic-ischemic injury (Taki 2007) or chronic 
heart failure (Kietselaer 2007), or sites of active disease that are seen in infection (Rouzet 2008, 
Kietselaer 2009), unstable atherosclerotic plaques (Tahara 2009), allograft rejection (Narula 2001), 
or autoimmune disorders such as SpA (Tokita 2003, Perker 2004). Annexin V imaging could 
therefore be useful in the serial assessment of acute and chronic disorders in organs or tissues at 
risk for permanent damage in which prompt treatment with effective drug or surgical intervention 


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Figure 1. Spot views of knees (images on 
left) and hands/wrists (images on right) in 
patient 
with 
RA 
using 
99mTc-HYNIC 
annexin V (first generation form of 
radiolabeled annexin V). Note the marked 
multifocal synovial uptake in knees (and 
linear uptake in the tensor fascia lata of 
the right knee; just above the radionuclide 
marker). Also note the intense carpal 
uptake in the right wrist (side of marker) 
and focal uptake in the right 1st-MCP and 
2nd-MCP joints. Focal uptake in the left 1st 
metacarpal-trapezial and 1st MCP joints is 
also present. Foci of less intense uptake in 
the left 2nd MCP and right 1st PIP joints are 
seen as well. (Courtesy of Theseus 2002). 
Figure 2. Spot views of the hands/wrist of another patient with RA with injection and radionuclide imaging (1 hr 
later) with 99mTc-HYNIC annexin V performed at baseline and at 24 hrs, one week and four weeks after starting 
biologic modifying therapy with chimeric anti-TNF monoclonal antibody (Infliximab™). At baseline intense linear 
focal uptake was noted in the right 2nd and 5th flexor tendon sheaths and left triquetral-pisiform joint space. Less 
intense focal uptake was noted in the 1st PIPs bilaterally and left 2nd DIP, and 3rd MCP joints. There was a prompt 
significant decrease in focal uptake 24 hours after the start of Infliximab treatment (i.e. uptake decreasing to soft 
tissue background) particularly of the tenosynovitis of the right hand. At one week there were no signs of 
tenosynovitis at imaging though there was persistent though decreased uptake within the left triquetral-pisiform 
joint. At four weeks there were no sites of focal increased uptake in either hand or wrist though there was a 
persistent low diffuse uptake of tracer in the region of the left carpus just above soft tissue background. (Courtesy 
of Theseus Corp. 2002). 
may prevent irreversible cellular injury and cell death. 
 
Brief history of 99mTc-HYNIC-annexin V in patients with rheumatoid arthritis or infection 
 
99mTc-HYNIC-annexin V, the first generation form of radiolabeled annexin V to be tested in humans 
starting in 2000, was effective at imaging disease within the knees and wrists/hands of several 
rheumatoid arthritis (RA) patients and was also able to monitor the early effects of biologic 
modifying therapy at one week in a small pilot study performed in Liege, Belgium in 2002 (Figures 1 
& 2). The sensitivity of 99mTc-HYNIC-annexin V for regions of low grade chronic inflammation due to 
subacute bacterial infection of hip and knee prostheses was confirmed in a pilot study in Israel 
(Figure 3). Interestingly reactive bone formation, osteoarthritis and prosthetic joint loosening while 
positive on conventional bone scans with 99mTc-MDP did not result in significant increases in 
annexin V uptake. While effective in human trials 99mTc-HYNIC-annexin V due to the metabolism of 
the HYNIC linker had relatively high nonspecific tracer uptake in bone marrow and renal tubular 
cells prompting the development of the second generation form of self-chelating radiolabeled 
annexin V known as 99mTc-annexin V-128.   
 
 
 
 
 


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3.2   99mTc-rhAnnexin V-128 Risk-Benefit Assessment 
Preclinical characterization of 99mTc-rhAnnexin V-128 safety profile indicated that the product can 
be safely administered, both from the point of view of the proposed radioactive dose (350 ± 10 % 
MBq) and also considering the total drug substance (protein) present in a 350 ± 10 % MBq dose 
(0.4 mg). In particular, the radiation safety assessment performed based on extrapolations from 
animal biodistribution and dosimetry data showed that, for the proposed injected dose of 350 ± 10 
% MBq, the estimated kidney absorbed dose in human is around 60 mGy, which is below the level 
recommended by FDA for the single dose per organ (0.05 Sv), as generally recognized as safe in 
the FDA Guidance for Industry and Researchers (2010) and considerably lower than the threshold 
for nephrotoxicity reported in literature, that is 14 Gy (corresponding to 14 Sv for 99mTc) when 
delivering radiation dose in 2 fractions, as reported by Emami et al., 1991, for tolerance dose 5/5 
(the probability of 5% complications within 5 years of irradiation) reported in literature [30]. These 
estimated kidney absorbed doses are also lower than those achieved with some technetium base 
diagnostics currently used in the nuclear medicine practice (e.g. 99mTc MoAb antiCEA has kidney as 
critical organ with an absorbed dose of 100-400 mGy for an injected dose of 1000 MBq). 
 
The estimation of effective dose for total human body, from an injected dose of 350 ± 10 % MBq, is 
2.2 ± 10 % mSv, that is far below the FDA single-study limit of 30 mSv for research subjects, as per 
FDA Guidance for Industry and Researchers, 2010. 
 
Therefore, animal data from biodistribution/dosimetry studies and extrapolation of human kidney 
absorbed and total body effective dose, along with the current nuclear medicine practice 
concerning technetiated diagnostics, support the proposed single dose of 350 ± 10 % MBq of 99mTc 
Annexin V-128 for the Phase II study. 
 
Regarding the toxicity profile of the non-radiolabeled protein, a package of pre-clinical studies was 
Figure 3. Bone scan of the knees (image on left) and 
corresponding 
99mTc-HYNIC 
annexin 
V 
scan  
(image on the right) several days later in a 76 year 
old man with a painful right knee prosthesis and 
signs of loosening on plain x ray. Arrows on the 
medial side of the femoral portion of the knee 
prosthesis mark intense focal linear uptake both on 
bone scan and on the annexin scan. This region of 
uptake corresponded to the infected portion of the 
prosthesis at surgery. Also note that annexin V 
uptake was highly specific as compared to bone 
scan in which focal non-specific uptake of Tc99m-
MDP was present over the entire femoral portion of 
the 
prosthesis 
as 
well 
as 
the 
osteophytic 
spurring/osteoarthritis of the medial aspect of the 
right 
knee 
(proximal 
tibia) 
as 
indicated 
by 
arrowheads. From: Lorberboym M, et al. J Nucl 
Med 2009; 50:534–537. 


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designed in order to investigate the potential toxicity of rhAnnexin V-128. Preliminary 7-day toxicity 
studies conducted in rats and dogs, showed that rhAnnexin V-128, administered intravenously once 
daily, was well tolerated up to the highest tested dose, that is 450 fold (in rats) and 200 fold (in 
dogs) the proposed dose in humans. 
 
The main repeated-dose toxicity studies were conducted in rats and dogs as well, and consisted of 
2-week daily intravenous administrations of rhAnnexin V-128, at doses that were approximately 25, 
50 and 100 times the intended dose in humans. The toxicity profile was in general favorable, with 
some treatment-related findings in the spleen (germinal centers hyperplasia) and in the liver 
(periportal eosinophilic cell infiltration) of the rats at the intermediate and high dose, and some 
periportal subchronic inflammation in dog liver at the high dose. These signs were in general 
reversible after 2 weeks recovery period. The No-Observed-Adverse-Effect-Level (NOAEL) was 
defined to be 0.2 mg/kg/day in rats (25 fold the intended dose in humans) and 0.4 mg/kg/day in 
dogs (50 fold the intended dose in humans). 
 
These findings meet the safety margins recommended in the relevant guideline, which indicates 
that the dose intended to be used in Phase I studies should be at least 100 times lower than the 
NOAEL found in the acute toxicity studies in the rat and at least 25 times lower than the NOAEL 
found in the repeated toxicity studies in rat and dog. 
 
As described in the Investigator’s Brochure, it is worth noticing that no adverse reaction, including 
any sign of allergic or anaphylactic reaction, was reported in animals during in vivo phase of any of 
the toxicity studies performed in rats and dogs. As a reference the dose range tested in animals 
was within 25 to 450 times the intended human dose). 
 
In addition to the in vivo toxicology studies mentioned above, the safety of rhAnnexin V-128 was 
evaluated in a whole blood cytokine release ex-vivo assay. The results showed that rhAnnexin V-
128 did not induce any cytokine release. 
 
An open label, single dose, Phase I clinical study of safety, tolerability, pharmacokinetics and 
nuclear medicine imaging of 99mTc-rhAnnexin V-128 intravenous administration of 350 MBq single 
intravenous bolus in 12 healthy adult volunteers has been conducted. A series of images for up to 
24 hours from the time of injection and blood samples were obtained from time of screening, dosing 
day and 24 hours after injection, with follow up visits at 72 hrs, 7 days and 30 days post injection.  A 
physical examination was conducted 72 hrs, 7 days and 30 days post administration of 99mTc - 
rhAnnexin V-128. No abnormal findings have been noted after administration of the studied imaging 
product and during the observation period. No immunology response has been reported in the 
immunogenicity assessment 14 and 30 days post administration. 
 
The concentration-time profiles for total radioactivity in blood and serum were similar at the injected 
dose. Concentrations of radioactivity were measurable in blood and serum of all subjects between 
5 min and 24 h, reaching the higher concentration of about 30 ngEq/mL at the first sampling time. 
Blood and serum area under the concentration-time curves (AUC) were highly correlated (Pearson 
r = 0.77; p=0.006), and the blood-to-serum AUC ratio averaged 0.72 (range, 0.65 to 0.82) 


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suggesting moderate distribution of rhAnnexin V-128-related material into blood cells. Mean 
terminal t1/2 of radioactivity averaged 757 min in blood and 766 min in plasma (Pearson r = 0.92; 
p=0.0001), further suggesting that serum is a suitable matrix for the representation of rhAnnexin V-
128 pharmacokinetics in whole blood. 
 
The mean serum concentrations of rhAnnexin V-128 based on ELISA analysis were lower and 
disappeared faster than the mean serum concentrations of total radioactivity. However, the ELISA 
assay was generally not sensitive enough to follow serum concentrations for more than 90-180 min, 
this rapid decay probably approximating an initial phase of the compound distribution to tissues. 
Thus, an elimination phase could not be clearly defined for rhAnnexin V-128 at this intravenous 
dose. Estimates of pharmacokinetic parameters for rhAnnexin V-128 suggest low to moderate 
mean total clearance (Cl; 45.4 mL/min) and moderate to large mean steady-state volume of 
distribution (Vss; 49.8 L) in healthy volunteers. Inter-subject variability of pharmacokinetic 
parameters was moderate to high with coefficients of variation (C.V.) ranging from about 38% for 
systemic Cl to about 70% for Vss. 
 
Around 65% (range, 36 to 81%) of the administered radioactive dose was eliminated within 6 h 
post-dosing, and only about 16% (range, 3% to 22%) and 3% (range,1.4% to 4.5%) were recovered 
during the subsequent 6-18 h and 18-24 h collection periods, respectively, in eleven subjects (one 
subject had incomplete urine collection). The overall dose of administered 99mTc-rhAnnexin V-128 
recovered in urine during the 0-24 h post-dose interval was 85% (61% to 114%), in the eleven 
evaluable subjects. There was negligible excretion of radioactivity in feces during the 0-24 h period, 
which accounted for a mean of only about 1% (range, 0.1% to 3.5%) of the administered dose. 
 
4 STUDY OBJECTIVES AND HYPOTHESES 
 
This Phase II study will be undertaken to determine the presence and degree of 99mTc-rhAnnexin V-
128 uptake at sites of clinical disease in patients with clinical suspicion or confirmed diagnosis of 
SpA. While the majority of these patients will be diagnosed with AS, there will be a substantial 
number of patients diagnosed with other types of disease including IBD related SpA and Psoriatic 
arthritis. We hypothesize that SpA patients with active disease as manifested clinically by dull low 
back, buttock or hip pain will have significant increased 99mTc-rhAnnexin V-128 uptake in the sacro-
iliac joints and/or spine which will correlate with both clinical scoring and changes with T1 and STIR 
without contrast MRI findings. We also hypothesize that we will be able to directly quantify the 
severity of inflammation at sites of disease with a higher degree of specificity and sensitivity than 
MRI, CT and plain film radiography. 
 
Eligible patients after obtaining informed consent, baseline blood labs, and urinalysis, will be injected 
once with 99mTc-rhAnnexin V-128 followed by SPECT/CT imaging of the lumbosacral spine, 
sacroiliac joints and abdomen at 60 min and 2 hrs after injection of the radiotracer. Patients will 
undergo also a whole body planar scan and spot views on specific areas at the same time-points 
(spot views may not be repeated at T+2hrs). An optional whole body planar scan will be done 24hrs 
post injection for 5 patients as well as spot views, if deemed appropriate by the investigator. 


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Knowledge of the expected dynamic range of the disease related changes in 99mTc-rhAnnexin V-128 
uptake in correlation with clinical measured of disease severity within affected joints will be critical for 
the power calculations and sample size estimates as part of the design of a follow up studies in SpA 
patients in order to further demonstrate the benefit of this new imaging procedure versus 
conventional imaging with MRI and plain film radiography. Furthermore, it is expected that the 
quantitative capabilities of SPECT/CT and the inherit sensitivity of 99mTc-rhAnnexin V-128 imaging 
and reduced cost will replace MRI as a screening tool for the work up of patients with SpA. 
 
As secondary goal, we also wish to determine the ability (specificity) of 99mTc-rhAnnexin V-128 to 
distinguish between active autoimmune arthritis versus osteoarthritis particular of the lumbosacral 
spine and SI joints of patients with SpA. We also hypothesize that some of SpA patients with active 
disease have subclinical Crohn’s disease. Therefore, we wish to perform a pilot study on the 
localization of 99mTc-rhAnnexin V-128 in the abdomen. 
4.1  Study objectives 
Primary Objective: 
 
 
To determine the magnitude and dynamic range of 99mTc-rhAnnexin V-128 uptake in disease 
affected sacro-iliac or lumbar spine joints in patients with clinical suspicion or confirmed 
diagnosis of SpA.  
 
Secondary Objectives: 
 
 
To determine clinical utility of 99mTc-rhAnnexin V-128 SPECT imaging in the identification of 
chronic osteoarthritic active sites of SpA patients compared with MRI in patients with disease-
affected sacro-iliac or lumbar spine joints. 
 
To assess the presence of antibodies against rhAnnexin V-128 at baseline and post-treatment 
 
To determine the localization pattern and magnitude of focal uptake of 99mTc-rhAnnexin V-128 
within the abdomen in patients with clinical suspicion or confirmed diagnosis of 
Spondyloarthritis (SpA). 
 
 
4.2  Study hypotheses 
We hypothesize that 99mTc-rhAnnexin V-128; a second generation form of 99mTc radiolabeled 
annexin V with significantly higher PS binding affinity and improved in vivo localization properties, 
will be highly specific in imaging degenerative osteoarthritis particularly of the lumbosacral spine 


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and sacroiliac joints as seen by SPECT/CT in patients with SpA.  We also hypothesize that 99mTc-
rhAnnexin V-128 will be localized within the abdomen of SpA patients with active disease showing 
suspicious Crohn’s disease. 
4.3  Study justification 
At the completion of this study, we will have preliminary data on the expected magnitude and 
dynamic range and specificity of 99mTc-rhAnnexin V-128 uptake at sites of active disease in SpA 
patients at presentation. 
 
5 STUDY DESIGN 
5.1  Study Outline 
This is a monocentric, open label, PoC, Phase II study. Patients who have signed the informed 
consent and are eligible for study participation according to the inclusion and exclusion criteria will 
receive a single intravenous bolus of 99mTc-rhAnnexin V-128 on Day 0 followed by SPECT/CT of the 
sacro-iliac joints, spine and abdomen at 60 min and 2hrs after injection of the radiotracer within 14 
days after screening in order to minimize the potential delay in changing NSAID therapy or non-
biologic DMARD or the start of non-biologic DMARD or biologic DMARD (excepted for the first 5 
enrolled patients who will not be eligible for the start of biologic DMARD). Patients will undergo also 
a whole body planar scan and spot views on specific areas at the same time-points (spot views may 
not be repeated at T+2hrs). We will also perform T1 and STIR without contrast MRI of the sacro-iliac 
joints and lumbar spine within this same time window, 
 
Details on study assessments are provided in Protocol Section 8 and Table1. 
5.2  Study duration and End of Study 
Study duration is maximum 7 weeks (including the screening period) for each patient. The end of 
the study is defined as the moment that the last enrolled patient has completed the planned 
assessments at Day 30. 
6  PATIENT SELECTION 
 
Approval for the study will be obtained from the local IRB of Cedars-Sinai Medical Center Office of 
Research of Compliance. All patients will provide written informed consent prior to the initiation of 
any study procedures. 
6.1  Inclusion Criteria 
For the first 5 patients enrolled in the POC part: 
1. Patients with clinical suspicion or confirmed diagnosis of SpA, based on the ASA criteria with 
active symptoms including back, hip or buttock pain prior to: 


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 
A change in NSAID therapy or 
 
A change in non-biologic DMARD or  
 
A start of non-biologic DMARD. 
 
For the next 15 patients enrolled in the Phase II part: 
1. Patients with clinical suspicion or confirmed diagnosis of SpA, based on the ASAS criteria 
with active symptoms including back, hip or buttock pain prior to: 
 
A change in NSAIDs therapy 
 
A change in non-biologic DMARD 
 
A start of non-biologic DMARD  
 
A start of biologic DMARD 
 
For all patients: 
2. Age over 18 years old. 
3. Signed Informed Consent Form 
6.2  Exclusion Criteria 
1. Pregnancy or lactation 
2. Liver impairment (ALT, AST or Bilirubin > 2 ULN) at screening visit or baseline  
3. Kidney impairment (serum creatinine > 1.5 mg/dL) 
4. History of any disease or relevant physical or psychiatric condition or abnormal physical 
finding which may interfere with the study objectives at the investigator judgment 
5. Known hypersensitivity to the investigational drug or any of its components 
6. Contraindication(s) to the MRI procedure (claustrophobia, prosthetic valve, pacemaker, 
inability to lie still in a supine position) 
7. Participation to another clinical trial within 4 weeks before study inclusion except for patients 
who have participated or who are currently participating in an interventional study without any 
study drug administration. 
 
6.3  Number of patients 
Up to twenty evaluable patients will be recruited. 
6.4  Patients Identification 
Each patient will be anonymized and identified with a patient ID number. A unique patient 
identification number (Patient ID) will be assigned at the start of the screening period to each patient 
who signs the informed consent form until the study termination of the patient. This number will 
identify the subject throughout the study. Patient IDs will include the 2-digit protocol number (03), the 
2-letter country code (US) and a 3-digit patient number (ex: 03-US001 for first subject in). 


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6.5  Premature Discontinuation 
 The withdrawal of a study patient is mandatory in the following cases: 
 
Pregnancy 
 
Protocol violation determined as critical 
 
Lost to follow-up 
 
Serious intercurrent illness or other safety reasons for what the Investigator considers it is in 
the best interest of the participant to withdraw from the study 
 
Screening failure 
 
A “screening failure” is a patient who has signed the informed consent, but who does not meet all 
selection criteria following the screening evaluations. For patients not considered eligible after the 
screening period, the reason for not being eligible must be documented. No additional assessments 
are needed. Patient information collected at the Screening visit will be entered in the e-CRF and will 
be used in the study analysis. 
Patients who will not have received the study product will be replaced. 
 
  
The patient is free to withdraw from the study for any reason and at any time without giving reason 
for doing so and without penalty or prejudice. It is also possible that the Sponsor or the regulatory 
authorities request termination of the study if there are concerns about conduct or safety. 
The primary reason for a patient’s withdrawal from the study should be determined as possible. The 
date and reason for discontinuation must be documented in the e-CRF. 
6.6  Prohibition and Restrictions 
The most important required restriction for study patients is pregnancy. Pregnancy tests will be 
performed for all patients (of child bearing potential) at baseline and prior to the radiotracer 
administration. 
Imaging is performed ambulatory. After imaging, patient may go back home or go back to work 
without particular precaution for him or his relatives. 
Any concomitant medication deemed necessary for the welfare of the subject during the study may 
be given at the discretion of the Investigator.  However, it is the responsibility of the Investigator to 
ensure that details regarding the medication are recorded in full in the case report form, including 
any changes that have occurred during the study. 
 
7  STUDY MEDICATION AND TREATMENT 
7.1  Packaging and Labelling 
The full name of the Investigational New Drug is “Kit for the Preparation of Tc-99m Recombinant 
Human Annexin V-128 for Injection”. The kit will be prepared, packaged and released according to 
Sponsor Standard Operating Procedures (SOPs), and in compliance with the principles of the Good 
Manufacturing Practice (GMP) guidelines, ICH Good Clinical Practice (GCP) guidelines, and 


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applicable federal, state and local laws/regulations. 
The investigational product will be supplied by the Sponsor as a sterile, single vial lyophilized kit for 
reconstitution with 99mTc solution. 
A single dose vial contains an amount of rhAnnexin V-128 and excipients suitable for preparing up to 
740 MBq of injectable 99mTc-rhAnnexin V-128. The excipients in the kit are the following: stannous 
chloride (reducing agent), sodium α-D-Glucoheptonate dihydrate (transchelating agent), gentisic 
acid sodium salt hydrate (radiation stability enhancer), hydroxypropyl-β-cyclodextrin (solubilizer), 
sodium metabisulfite (antioxidant) and trehalose dihydrate (lyoprotectant and cake-forming agent). 
Lactic acid is also present as buffering agent. 
The reconstitution procedure and the specifications of the kit and of the radiolabeled imaging agent 
are described in Appendix I.  
7.2  Handling of Study Medication 
99mTc-rhAnnexin V-128 must be administered at the investigational site. The study medication must 
be stored, handled and administered only by qualified/authorized personnel and must be prepared in 
accordance with pharmaceutical quality requirements, and radiation safety regulations. 
Based on the stability tests performed (Appendix I), the Annexin Kit can be stored upon receipt at  
5°C ± 3°C until the expiry date stated on the labels. 
 
A single dose vial containing 0.4 mg of lyophilized rhAnnexin V-128 will be reconstituted with 2 mL 
± 0.2 mL containing 740 MBq ± 74 MBq (20 mCi ± 2 mCi) of 99mTc from the generator. This amount 
of radioactivity provides a sufficient amount of radioactivity for QC testing and the foreseen 99mTc-
rhAnnexin V-128 dose of 350 ± 10 % MBq for up to 4 h after labelling. The administration volume 
(corresponding to 350 ± 10 % MBq) is calculated according to the estimated time of injection, on 
the basis of the physical decay of the radionuclide (half-life = 6.02 h). Stability studies have 
demonstrated radiochemical purity at 6 h from labelling greater than 90%, which is in line with 
current specifications of the Kit for the preparation of 99mTc-rhAnnexin V-128 for injection. For the 
purpose of this study, it is recommended to administer the reconstituted solution within 4 hours after 
completion of the labelling reaction. It is also required to determine the amount of radioactivity 
injected to the patient by measuring the radioactivity before and after injection with an appropriate 
radioactivity calibration system. 
7.3  IMP Packaging and Storage 
The site personnel will maintain shipping, dispensing, and collection logs.  All investigational 
product will be stored and inventoried according to the protocol instructions and applicable federal, 
state, and local regulations and will be stored in a secure, locked location with limited authorized 
access at the investigational site. 
7.4  Precautions and recommendation for use 
Technetium-99m eluate should be obtained from a commercially available Mo-99/Tc-99m generator, 
approved by regulatory authorities, that has been eluted within the past 24 hrs. The radiopharmacist 
will be directed to use the eluate within one hour of milking the generator. 


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On ongoing basis the Investigator/radiopharmacist agrees to conduct a study medication supply 
inventory and to record the results of this inventory on the IMP Reconciliation Form. It must be 
possible to reconcile delivery records with those of used and unused medication. Any discrepancies 
must be accounted for. Appropriate forms of deliveries and returns must be signed by the 
responsible person. 
 
Unused “Kits for preparation of99mTc-rhAnnexin V-128 for injection” will be locally discarded after 
monitoring by the Clinical Research Associate (CR A).  
 
Refer to Appendix I for detailed instruction on the Radiolabeled Imaging Product 99mTc-rhAnnexin V-
128, Cautionary notes, Analytical and Biological Controls, Stability and Shelf Life. 
7.5  Study Medication Dose, Mode of Administration, Batch Number 
The "Kit for preparation of 99mTc-rhAnnexin V-128 for injection" consists of 1 patient dose. The 
single dose vial (0.40 mg rh-Annexin V-128) will be reconstituted with 2 mL ± 0.2 mL containing 740 
MBq ± 74 MBq (20 mCi ± 2 mCi) of 99mTc. 
 
The labelling reaction requires 90 minutes and the reconstituted radiolabeled product is stable for 6 
h. For the purpose of this study, it is recommended to administer the reconstituted solution within 4 
hours after completion of the labelling reaction. Patients will receive a single administration of 99mTc-
rhAnnexin V-128 on Day 0. When the investigational product is received at the site, the 
investigator, pharmacist or authorized designee shall check for accurate delivery and acknowledge 
receipt by signing and dating the documentation provided by the Sponsor and returning it to the 
Sponsor or designee. A copy of this documentation shall be retained for the Investigator file. 
The dispensing of the investigational product shall be carefully recorded on an investigational 
product accountability form provided and an accurate accounting must be available for verification 
by the CRA at each monitoring visit. 
 
Unused investigational product must not be discarded or used for any purpose other than the 
present study. The CRA will periodically collect the Drug Accountability Forms and will check all 
investigational product (both unused and used) before making arrangements for authorizing their 
destruction at the investigational site. 
 
8  ASSESSMENTS 
Voluntary written informed consent will be obtained prior to the initiation of any study-related 
procedures. Study conduct procedures will include screening, the imaging visit and follow-up visits. 
8.1 
Baseline Assessments 
 
 Each patient’s demography: gender, ethnicity, medical history, and relevant baseline 
characteristics will be recorded at Screening visit.  


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 Inclusion/exclusion criteria will be checked at Screening. 
 Women of childbearing potential must have negative urine pregnancy test at Screening before 
the radiotracer administration and before MRI (in case the MRI is not performed on the same 
day of the screening visit). 
 Vital signs will be taken at Screening. 
 Physical examination will be conducted at Screening. 
 BASDAI, BASFI, BASMI and MASES assessments will be performed. 
 
8.2 
Safety Assessments 
 
 Physical examination will be conducted at D30 
 Measurement of vital signs (systolic and diastolic blood pressure and heart rate) will be 
performed 15 minutes before the radiotracer administration and at the end of the last imaging 
procedure at Day 0.  
 Women of childbearing potential must have negative urine pregnancy test before injection of the 
radiotracer at Day 0. 
 All medications taken from 2 weeks prior to the administration date through the end of study are 
to be recorded as prior and concomitant medications, including therapies for SpA. 
 Any adverse events occurring during the course of the study will be reported and recorded in the 
eCRF. 24 hours after treatment injection (at Day 1), each patient will be called in order to inquire 
if they experienced signs or symptoms such as edema, rash or have any clinical findings. 
 
 
8.3 
Standard Laboratory Assessments 
 
General laboratory analysis will be performed and blood samples will be collected at screening and 
at Day 30. 
Blood sample will be drawn and urine will be collected as mentioned in the study chart. A total 
volume of 50 mL, including blood sample for immunogenicity assessment, will be collected during 
the study for each patient. 
 
 
Hematology 
Coagulation 
Blood Chemistry 
Urinalysis 
 WBC with 
differential 
 RBC  
 Platelets 
 Hb 
 MCV 
 Hematocrit 
 
 PT 
 PTT 
 INR 
 BUN 
 Serum creatinine 
 Uric acid 
 Albumin 
 Total bilirubin 
 Direct bilirubin 
 AP 
 AST/ASAT 
 Dipstick test1 
 Pregnancy test  
(at screening and 
before injection of 
study product) 
 


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 ALT/ALAT 
 Gamma-GT 
 Sodium 
 Potassium 
 LDH 
 CRP 
 Calcium 
 Glucose 
 Chloride 
 Phosphorus 
 Total cholesterol 
 Total protein 
1In case one of the assessments of the dipstick test is positive, a microscopy analysis of the urine must be performed.  
 
8.4  Clinical assessment 
A clinical evaluation including the search for enthesopathy – using the Maastricht Score (MASES) - 
and assessments with BASDAI, BASFI and BASMI will be performed at Screening.  
The clinical assessment will be completed by the measurement of biological markers of inflammation 
(CRP and CBC) at Screening and at Day 30. 
8.5  Imaging 
Patients will be injected intravenously with 350 ± 10 % MBq of 99mTc-rhAnnexin V-128 with an 18 
gauge angiocath IV and saline TKO drip set up placed in the antecubital fossa.   
Bone Lumbar Spine SPECT/CT, SI SPECT/CT and abdomen SPECT/CT will be performed 60 
minutes and 2 hours after injection of radiotracer followed by a whole body planar scan and spot 
views on specific areas at the same timepoints (spot views may not be repeated at T+2 hrs if 
deemed unnecessary) 
 
The Infinia™ Hawkeye 4 SPECT/CT (GE Healthcare) scanner was used for patients with the 
following parameters; start at 0°, 180° rotation/detector, 64 steps, 3° per step, 30 sec per step, 
overall ARC 360°, (scan time = 23 minutes) 128 x 128, multi-purpose collimator (Skylight) in 1 x 
zoom mode. An attenuation and diagnostic CT scan will be performed on the lumbar spine using a 
512 x 512 matrix, 140 keV, 2.5 mA, axial 1 sec, 5 mm slices.  
 
Semi-quantitative assessment of inflammatory joints and abdomen will be performed in terms of 
TBR as well as by calculating the relative uptake in ROI/VOIs.  ROI and VOI defined and use in the 
different scintigraphies will strictly have the same pixel size and localization; and will be measured in 
counts. 
In case a suspected anomaly is found at imaging, it would be reported to the rheumatologist and the 
patient’s general practitioner. 
 
A whole lumbar spine and sacro-iliac joint MRI will be performed within 14 days of 99mTc-annexin V-
128 scanning using the following parameters: SI Joint Sequences /3 plane localizer / Whole pelvis 


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Coronal T1/ Whole pelvis Coronal T2 FS. Small FOV over SI Joints (~20 cm FOV): Sequences /Obl 
Axial T1. Obl Axial T2 FS (May use STIR or IDEAL for poor FS), Obl Coronal T1, Obl Coronal T2, 
FS (May use STIR or IDEAL for poor FS). Following pre/post sequences will be used to help assess 
for subtle sacroilitis: Obl Ax T1 FSE FS Pre / Obl Ax T1 FSE FS Post /Obl Cor T1 FSE FS Post. 
FOV notes: Small FOV width should be approximately from femoral head to femoral head; Oblique 
axial and coronal are prescribed relative to the sacrum. Protocol for Spine: Sag T1, T2 FSE no fat 
sat, STIR, FOV 28 / Ax T1 and T2 FSE (no fat sat), FOV 20. 
8.6  Immunogenicity assessments 
As rhAnnexin-V 128 is anexogenous protein, development of antibodies against the protein must be 
assessed in order to evaluate the risk and consequences of such development. 
 
Assays for anti-rhAnnexin V-128 IgG and IgM antibodies will be performed in serum samples by 
ELISA at screening visit. An additional sample is required at Day 30. 
For this purpose 10 mL blood samples will be collected at screening and Day 30. At each time-point, 
after centrifugation, serum will be divided into six aliquots and frozen (-80°C). Three out of six serum 
aliquots will be then shipped to the central laboratory at 
. 
Remaining samples will be shipped only if required for analysis and destroyed at study end if not 
required. Blood Samples Handling will be detailed in the Laboratory Manual provided by 
. 
 
9  DATA MONITORING COMMITTEE (DMC) 
 
The DMC consists of representatives of investigators and Sponsor representatives and could 
include external person such as independent experts, if judged appropriate by the Sponsor. The 
main function of the committee will be to review the images of the first 5 patients and determine if 
there is a premature high evidence of the presence of inadequate technical performance in this 
patients group. The DMC will also determine if there is a high evidence of an excess of adverse 
events. 
 
The DMC will review and evaluate the images of the first 5 patients in terms of image quality visual 
efficacy (uptake) and clinical relevance of the study product. The DMC will also review the 
examinations of safety data. The DMC will promptly give recommendations to continue or terminate 
the study. The DMC report will be edited by the Sponsor and sent to the ethics committee as well as 
competent authorities. 
 
Preliminary results can be used by the Sponsor for publication purpose, before the end of the main 
trial. 
10  STATISTICAL CONSIDERATIONS 
 
The statistical analysis of the present study will be performed in accordance with the principles 
stated in the Consensus-Guideline E9 (Statistical Principles for Clinical Trials) of the International 


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Conference on Harmonization (ICH). 
Statistical method will be described in details in the statistical analysis plan (SAP). The considered 
approach is summarized here after. 
10.1  General Statistical considerations 
If not stated otherwise, all statistical analyses will be conducted as follows. 
Categorical data will be presented as frequencies, percentages and 95% confidence interval if 
relevant. For continuous data, N, missing, mean, standard deviation, median, quartiles, minimum, 
maximum and if relevant 95% confidence interval will be presented. Graphs such as box plots, 
circular diagrams or histograms can also be computed if relevant. p-values of 0.05 or lower will be 
considered as statistically significant. No adjustment will be made for multiple testing and missing 
data will not be replaced. Considering the small sample size planned in this study, non-parametric 
approach will be favored. 
10.2  Sample size 
The number of patients in this study is not based on statistical power considerations. The planned 
sample includes 20 patients which is the number believed to provide sufficient data to assess the 
potential of 99mTc-rhAnnexin V-128 to image disease severity in SpA patients and provide sufficient 
preliminary data to plan larger pivotal trials focusing on the confirmation of the benefit for this new 
imaging procedure for the early diagnosis of SpA. 
At first, five patients will be recruited and analyzed as a Proof of Concept (PoC). In the PoC part of 
the study, medical images will be reviewed by the DMC in charge of assessing the imaging potential 
of 99mTc-rhAnnexin V-128 in terms of image quality, uptake and medical relevance. After reaching a 
consensus, the committee will decide if the clinical investigation should continue with the remaining 
15 patients. The planned number of patients in the PoC study is not based on statistical 
considerations. However, this number of patients should provide sufficient relevant information for 
the evaluation of the images in terms of quality and medical relevance. 
10.3  Demographics and Other Subject Characteristics 
Demographic and other baseline data will be summarized descriptively. All background and 
demographic/SpA diagnostic data will be listed in detail. 
 
10.4  Concomitant Medications 
Concomitant medications (including treatments for the underline disease) will be coded using World 
Health Organization (WHO) dictionary. Type and incidence of concomitant medications will be 
tabulated (generic terms). 
10.5  Laboratory Tests 
Descriptive statistics including shift tables will be generated for all laboratory tests performed i.e. the 


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actual values by cross-tabulations (with classes for below, within, and above normal range). 
Laboratory data will be analyzed with respect to the normal ranges of values provided by the local 
laboratory and abnormal laboratory test results will be tabulated. 
10.6  Vital Signs 
 The statistical analysis of vital signs measurement will be mainly descriptive in nature. 
10.7  Physical Examination 
Physical examination findings will be listed. 
10.8  Adverse Events 
All original AEs terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
System organ classes and preferred terms will be used in the analyses. 
Type and incidence of AEs, as well as severity and relatedness to the study medication will be 
tabulated. Special attention will be given to those patients who prematurely discontinue the study or 
the study medication due to an AE, or who experience a severe AE or an SAE. 
10.9  Analysis of efficacy 
Primary endpoint: 
In order to asses 99mTc-rhAnnexin V-128 magnitude and dynamic range of uptake within areas 
affected by inflammation, SPECT/CT scans will be interpreted and graded by at least two 
independent experienced nuclear medicine physicians blinded from clinical data and other 
imagings modality results. Briefly, 99mTc-rhAnnexin V-128 uptake compared with background (e.g. 
physiological liver uptake) should be assessed for each affected area by nuclear medicine 
physicians using a 4-grade scoring system (e.g. 0, none; 1, mild or present but < to background 
uptake; 2, moderate or = to background uptake; 3, intense or > to background uptake). In case of 
discrepancies between the different readers, an adjudication process based on consensus should 
be put in place in order to obtain one final outcome for each area. 
 
Secondary endpoints: 
Briefly, for quantifying the radioactivity uptake after injection of 99mTc-rhAnnexin V-128, ROIs will be 
drawn manually on the earliest images, and the shapes and sizes (i.e., number of pixels) will be kept 
constant over all subsequent images. Correction for background counts will be performed using an 
appropriate background region by subtracting the mean counts per pixel in the background region 
from the mean counts per pixel in each ROI to yield net counts. For each ROI, the geometric mean 
of net counts, corrected for physical decay, of total anterior and posterior counts will be calculated. 
 
In order to compare SPECT/CT scans and MRI scans, diagnostic performances will be evaluated in 
terms of sensitivity (i.e., true positive rate), specificity (i.e., true negative rate), positive predictive 
value (i.e., proportion of positive values) and negative predictive value (i.e., proportion of negative 
values). To do this, physical examinations will be necessary to define sites of pain in patients with 


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clinical suspicion or confirmed diagnosis of SpA. When sites of pain will match with abnormalities on 
diagnostic images, this will be regard as true positive.  McNemar test will be used to compare 
diagnostic performances of SPECT/CT and MRI technics.  
The determination of antibodies against rhAnnexin V-128 at baseline and post-treatment will be 
described as present or absent, and if applicable, its presence will be correlated as per the 
 objectives. 
 
11  ADVERSE EVENTS AND OTHER SAFETY ASPECTS 
11.1  Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a patient and which does not necessarily 
have a causal relationship with the study medication. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease, temporally 
associated with the use of a study medication, whether or not causally related to the study 
medication.  
 
AEs will be reported from signing the informed consent onwards until the last study-related 
procedure. If the information of an untoward medical occurrence is collected before starting the 
intake of study medication, this information will be listed as a pre-treatment AE during statistical 
analysis. 
11.2  Definition of Serious Adverse Events 
A SAE is any untoward medical occurrence that at any dose: 
 
Results in death;  
 
Is life-threatening; 
Note: “life-threatening” refers to an event in which the patient is at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
was more severe; 
 
Results in persistent or significant disability/incapacity; 
 
Results in congenital anomaly or birth defect; 
 
Requires in-patient hospitalization or leads to prolongation of hospitalization.  
Hospitalization or prolongation of hospitalization will not be considered as SAE in the 
following cases: 
o Hospitalization planned before the patient inclusion, 
o Hospitalization less than 24 h 
o Hospitalization needed for the routine follow-up of the patient disease. 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These events, 
including those that may result in disability, should also usually be considered serious. Examples of 


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such events are intensive treatment in an emergency room or at home for severe allergic reactions 
that do not result in hospitalization. 
 
The Investigator must report all SAEs by sending a completed SAE Reporting Form (Appendix III) 
to the Safety Officer designee within 24 h of becoming aware of the event. 
 
All SAEs must be addressed to Advanced Accelerator Applications pharmacovigilance dept. with 
the following contact details:   
E-mail: pharmacovigilance@adacap.com  
Fax: +33 450 993 634 
When possible the SAE Form should be sent by e-mail. 
 
 
11.3  Investigator Reporting Requirements 
Throughout the study, the study staff will question the patient in a non-directive way as to the 
occurrence of AEs. The patient will also be instructed, when signing the informed consent, as from 
that moment, to contact the Investigator to report any study medication or non-study medication-
related adverse or unusual event that occurs during participation to the study. 
 
The study staff will record all these events in the patient’s medical records and e-CRF, whether 
observed by the Investigator, the investigational staff, or spontaneously reported by the patient. 
The Investigator will provide a complete description of the event in standard medical terminology, 
the date of onset and termination, severity, relationship to the study medication, action taken 
regarding the study medication, any treatment given, the outcome, and whether or not the event is 
considered as a SAE. If known, the Investigator should report the underlying illness or disorder 
rather than the individual signs and symptoms. 
11.4  Reporting of Serious Adverse Events 
In the case of a SAE, the Investigator must immediately (at the earliest possible time point within 
24h of awareness) complete the SAE section of the e-CRF, reporting all information that is required 
by the Regulatory Authorities and contact the delegated Safety Officer designee, if needed. The 
name and contact details of the delegated Safety Officer designee will be available in the 
Investigator Site File (and will be updated when needed).   
The minimum information required for immediate reporting is the event description, the patient ID, 
the study medication concerned, and the identifiable reporter (Investigator or designee). Even if not 
all the facts are known, an initial report should be made. The Investigator must provide follow-up 
information as soon as possible. If requested by the delegated Safety Officer designee, documents 
relevant to the diagnosis, treatment, and course of the event must be submitted (e.g. technical 
investigation reports, histology findings, hospital discharge documents). All documents must be 
anonymized with respect to the patient’s personal identification data. 
 
When the Investigator determines that there is not more information likely to be available, a final 


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report should be provided. The Sponsor or delegated CRO will assume responsibility for 
appropriate reporting of AEs to the regulatory authorities and the Independent Ethics Committee(s)/ 
Institutional Review Board(s) (IEC/IRB) according to local laws and regulations. 
SAEs will be collected following the patient written consent to participate in the study. The collection 
of SAE information will continue to be reported by the Investigator for each patient until 30 days 
after the last study medication administration. 
11.5  Follow-up of Adverse Events 
All AEs occurring during the study are to be followed up until resolved or judged to be no longer 
clinically significant, or until they become chronic to the extent that they can be fully characterized. 
An assessment should be made at the last study-related visit for each patient. Certain long-term 
AEs cannot be followed until resolution within the settings of this protocol. In these cases follow-up 
will be the responsibility of the treating physician. 
 
Since it is unpredictable how long such a follow-up might take, data from this follow-up generated 
after the patient’s last study-related visit will be recorded by the Investigator. Full details regarding 
this follow-up will be described in the Clinical Study Report, if necessary. 
If during AE follow-up the case has progressed to the level of “SAE”, or if a new SAE whose 
relationship to the study medication could not be ruled out is observed, the situation must be 
reported immediately by the Investigator becoming aware of the information (considering that the 
“date of SAE onset” is the date of the first manifestations of that AE). 
11.6  Procedure in Case of Pregnancy 
Prior to clinical study enrolment, women of childbearing potential must be advised of the 
importance of avoiding pregnancy during clinical study participation and the potential risk factors for 
an unintentional pregnancy. The Investigator must report any pregnancy associated with 
investigational product exposure including conceptions occurring until 30 days after the last 
injection of radiotracer. The report should be carried out within 24 hours of pregnancy confirmation 
by sending a completed Pregnancy Reporting Form to the Safety Officer designee. 
Appropriate pregnancy follow-up procedures should be considered if indicated. The Investigator 
must report follow-ups within 24 hours of the receipt of any new information on the course of the 
pregnancy, including perinatal and neonatal outcome, by sending a completed Pregnancy 
Reporting Form to the Safety Officer designee (Appendix IV). 
12  TERMINATION OF THE STUDY 
 
Early termination of the study can occur in the following cases: 
 
 
When the visual review and analysis of the images of the first 5 patients by the Data 
Monitoring Committee does not enable to demonstrate the potential of the study product in 
terms of quality or efficacy, the Sponsor may discontinue the clinical study and send a 
written notice of the discontinuation along with the reasons to the investigator and 
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 
When the Sponsor is aware of information on matters concerning the safety of the study 
product, as well as other important information that may affect proper conduct of the clinical 
study, the Sponsor may discontinue the clinical study and send a written notice of the 
discontinuation along with the reasons to the investigator and applicable authorities.  
 
If the investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor of the discontinuation and the reason for it. 
 
The Sponsor reserves the right to discontinue the study at any time for failure to meet 
expected enrolment goals. 
13 OPERATIONAL, ETHICAL, AND ADMINISTRATIVE CONSIDERATIONS 
13.1  Study personnel 
All study staff will be informed of the study protocol through meeting and internal study initiation. 
Their task will be supported by internal SOPs specific to the study. The study nurse will be asked to 
collect blood and urine samples and to ship/send them to the appropriate laboratory. 
13.2  Data collection 
The study will be monitored by Advanced Accelerator Applications (AAA) according to the current 
SOP for the monitoring of studies. Shortly before the study starts, the Study Monitor will meet with 
the Investigator and Investigational Staff involved reviewing the procedures regarding study 
conduct and recording of data in the e-CRF. During the study, the Investigator will permit the Study 
Monitor to verify the progress of the study at the center as frequently as necessary. The 
Investigator will make the electronic data screens available, provide missing or corrected data, and 
sign the e-CRFs. Key data transcribed into the e-CRF will be reviewed against the source 
documents. Personal information will be treated as strictly confidential and will not be made publicly 
available. Any inconsistency between the source data and the data recorded in the e-CRF will be 
corrected. 
The Sponsor will ensure that appropriate Quality Control (QC) steps are included into the different 
clinical processes to guarantee adequate protection of the study patients and quality of the data. 
 
An independent Quality Assurance (QA) department, Regulatory Authorities and/or IECs/IRBs may 
review this study. This implies that auditors/inspectors have the right to inspect the study center(s) 
at any time during and/or after completion of the study and have access to source documents, 
including the patient’s file. By participating in this study, the Investigator(s) agree(s) to this 
requirement. 
 
For any data transfer, measures will be undertaken to protect patient data handed over against 
disclosure to unauthorized third parties and patient confidentiality will be maintained at all times. 
13.3  Data Review 
All data relating to the study must be recorded in the e-CRFs provided by the Sponsor. These e-
CRFs should always reflect the latest observations on the patient’s participation in the study. 


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Therefore, e-CRFs are to be completed within 5 days after the patient’s visit. To avoid inter-
observer variability, every effort should be made to ensure that the study determinations are 
completed by the same individual who made the initial ones at baseline. The Investigator must 
verify that all data entries in the e-CRFs are accurate and correct. 
 
The monitor will review the e-CRFs and evaluate them for completeness and consistency. The e-
CRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data. All entries, corrections and alterations are to be made by the responsible 
Investigator or his/her designee. The monitor cannot enter data in the e-CRFs.  
13.4  Data Clarification 
If corrections to an e-CRF are needed, the responsible monitor or data manager will raise a query. 
The appropriate investigational staff will answer queries. 
13.5  Source Documents 
Source data must be available at the study center to document the existence of the study patients 
and substantiate the integrity of the study data collected. They must include the original documents 
related to the study, as well as the medical treatment and medical history documentation of the 
patient. 
 
The source medical records should at least include the following information for each patient: 
 
Patient identification (name, date of birth, gender);  
 
Documentation of eligibility criteria, i.e. medical and medication history, physical 
examination; 
 
Participation in study (including study number); 
 
Study discussed, signed and dated ICF; 
 
Dates of all visits; 
 
Images/scans and reports; 
 
Documentation that protocol-specific procedures were performed; 
 
Study medication administration time and date; 
 
Receipt, dispensation and destruction of used/unused study medication; 
 
Record of all AEs and other safety parameters; 
 
Record of all previous and concomitant therapies; 
 
Date of study completion or reason for early discontinuation (if applicable). 
 
The following documents are considered as source documents as well: nurse records and 
worksheets. 
 
The author of an entry in the source documents must be identifiable. Direct access to source 
documentation (medical records) must be allowed for the purpose of verifying that the data 
recorded on the e-CRF are consistent with the original source data. 


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13.6  Clinical Study Monitoring 
Advanced Accelerator Applications or designee is responsible for periodic monitoring of the study 
to ensure that patients’ rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and ICH GCP, and that the data reported by the 
Investigator or designee are accurate, complete, and verifiable with the source documents. The 
assigned Clinical Study Monitor(s) will monitor the study in accordance with the monitoring 
guidelines. A copy of their Monitoring Log will be obtained at the study close-out visits. 
13.7  Direct Access to Source Data/Documents 
The Investigator and the study center must provide all study-related records, as well as source 
documents in the instances when they are requested to by regulatory agencies including the local 
IRB of Cedars-Sinai Medical Center Office of Research of Compliance and FDA. The confidentiality 
of the patient’s identity shall be well protected and consistent with local and national regulations 
when the source documents are patient to direct access. 
13.8  Data Management 
Data management activities will be coordinated by the Sponsor with the support of a CRO as 
necessary.  
All study-specific processes and definitions will be described in the Data Management Plan. Coding 
of AEs and Medical History terms will be performed using MedDRA; previous and concomitant 
medication will be coded using WHO codes. 
 
13.9  Ethical Conduct of Clinical Study 
The Investigator(s) and all parties involved in this study should conduct the study in adherence to 
the ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines, and the applicable 
laws and regulations. 
 
ICH-GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting study activities that involve the participation of human patients. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
the patients are protected, consistent with the principles that have their origin in the Declaration of 
Helsinki, and that the study data are credible. 
 
The Investigator and all study staff will conduct the study in compliance with the IEC/IRB approved 
version of this protocol. The protocol, ICF, any information provided to the patient, recruitment 
advertisements, and any amendments to these items will have IEC/IRB approval prior to their use 
in the study. Voluntary informed consent will be given by every patient in order to be screened for 
the study and prior to the initiation of any study-related procedures. The consent process must 
meet all applicable local laws. The rights, safety, and well-being of the patients are the most 
important considerations and prevail over the interests of science and society. All personnel 


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involved in the conduct of this study must be qualified by education, training, and experience to 
perform their assigned responsibilities. 
13.10  Authorities 
The protocol, name, and study center of the Investigators, the votes of the IEC(s)/IRB(s), as well as 
other locally required documents will be submitted to the regulatory authorities, according to local 
requirements for review and approval before the beginning of the study. 
13.11  Patient Confidentiality 
Individual patient medical information obtained as a result of this study is considered confidential 
and disclosure to third parties is prohibited. Such information may only be given to a third party 
after approval of the patient, to the patient’s general practitioner or to other appropriate medical 
personnel responsible for the patient’s well-being. 
The Sponsor, its board members, and its personnel shall not disclose any confidential information 
on patients obtained during the performance of their duties in the study without justifiable reasons. 
All individuals and organizations involved in conducting the study and/or processing the study data 
must pay very careful attention to protect the patients’ privacy with appropriate measures, for 
example, by prohibiting the use of any private information that may identify a patient (e.g. name or 
address). These details shall be processed in accordance with the applicable local and regional 
laws. 
13.12  Patient Information/Written Informed Consent 
According to ICH GCP (CPMP/ICH135/95) the patient must give consent to participate in the study, 
only after having been fully informed by the Investigator of the nature, significance, and implications 
of the study, as well as to the associated risks involved. Such meetings must be carried out on an 
individual basis, and adapted to the educational background and previous knowledge of the patient. 
Participation to this meeting will be documented in the patient’s clinical chart. In the present 
protocol, patient will be informed by the rheumatologist about the scope and goals of the study 
based on the patient information sheet. Patient will have at least 24 hours to consider his 
participation to the protocol before signing the informed consent. Any study-related procedure will 
only take place after signed patient informed consent has been collected. 
 
The patient will be instructed by the Investigator that the consent for study participation can be 
withdrawn at any time, without having to justify a reason, and that no disadvantageous 
consequences will follow regarding further medical treatment. The Investigator shall ask for the 
reason of premature termination without violating the patient’s rights (ICH GCP Definition 4.3.4). 
Furthermore, the patient must be informed about insurance coverage and the corresponding patient 
obligations (see Patient Information). The ICF must be personally dated and signed by both the 
Investigator/Delegate and the patient. The patient receives one copy of the original patient 
information and Informed Consent Form signed and dated by both Investigator/Delegate and the 
patient. 
The original of the ICF will be retained by the Investigator in the Investigator’s File, who will confirm 


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the patient’s consent in the e-CRF. The patient will only be included in the study after written 
consent is given. 
 
Furthermore, the Investigator is recommended to inform the patient’s general practitioner of his/her 
participation in the study, provided that the patient has a general practitioner and the patient agrees 
to disclose this information. For this purpose, a copy of the patient information sheet and the 
patient’s signed informed consent will be sent to the GP if the patient agrees with this and has 
ticked the appropriate tickbox on the Patient Information Consent Form. 
13.13  Arrangement for Use of Information and Publication of Clinical 
Study Data 
The present study will be registered on http://clinicaltrials.gov/ and its results will be published. 
 
All information regarding the investigational product under study in the outlined protocol and 
Advanced Accelerator Applications operations, such as patent applications, formulas, 
manufacturing processes, basic scientific data, or formulation information, supplied by AAA and not 
previously published, are considered confidential by AAA and shall remain the sole property of 
AAA. The Investigator agrees to use this information only to perform this study and will not use it for 
other purposes including publications and presentations without AAA’s written consent. 
 
It is understood by the Investigator that the information developed during the conduct of this study 
is considered confidential and will be used by AAA for the development of the specified 
investigational medication. This information may be disclosed as deemed necessary by AAA to 
other Investigators, other pharmaceutical companies, and to governmental agencies. To allow for 
the use of the information derived from this study and to ensure complete and thorough analysis, 
the Investigator is obligated to provide AAA with complete test results and all data developed in this 
study, and to provide direct access to source data/documents for study-related monitoring, audits, 
IEC/IRB review, and regulatory inspection. 
 
Any publication or public presentation of the results of this study must be according to the 
Sponsor’s standards. The first publication is coordinated by the Sponsor. The Investigator agrees 
that before he/she publishes any results of this study, he/she shall send the draft manuscripts and 
copies of the information to be presented to the Sponsor at least 30 working days before 
submission to a publisher or presentation. The Sponsor reserves the right to review these materials 
before submission for publication or presentation. This is not intended to restrict or hinder 
publication or presentation but instead to allow the Sponsor to protect proprietary information and to 
provide comments based on information that may not yet be available to the Investigator(s). 
 
13.14  Documents and Records Related to the Clinical Study 
The Investigator must retain e-CRFs and source documents of all enrolled patients (i.e. all patients 
who gave consent to be screened for the study), study medication disposition, and other 
documents required by regulation, in his/her possession or in an accessible area for at least 10 


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years after the completion of this study. The Investigator should take measures to prevent 
accidental or premature destruction of these documents. Under no circumstance shall the 
Investigator relocate or dispose any study documents before having obtained the Sponsor’s written 
approval. 
If it becomes necessary for the appropriate Regulatory Authority to review any documentation 
relating to this study, the Investigator must permit access to such reports. 
Any difficulty in archiving and storage of clinical study documents must be discussed with the study 
monitor prior to the initiation of the study. The data and information collected during this study will 
be reported in Clinical Study Report(s) by the Sponsor. 
13.15  Sampling collection 
Biological samples collected at site for routine lab analysis (Hematology and Biochemistry) will be 
discarded after study analysis, according to local rules. For samples that are to be sent to a 
centralized foreign laboratory, i.e. for ELISA analysis, the Clinical Trial Agreement will be adapted 
according to local rules. These collected samples will be stored for up to 7 years (counting from 
when the last subject performed the last study visit) and then discarded, unless local rules, 
regulations or guidelines require different timeframes or different procedures, which will then be in 
line with the subject consent. 
In case of patient consent withdrawal to the use of personnel data, biological samples will not be 
analyzed and will be destroyed. Samples collected will only be used for study purposes as per 
protocol. 
13.16  Protocol Amendment and/or Revision 
Any changes to the study, which arise after approval of the protocol, must be documented as 
protocol amendments and/or revisions. Depending on the nature of the amendment and/or revision, 
either IEC/IRB approval or notification is required. The changes will become effective only after the 
approval of the Sponsor, the regulatory authorities and the IEC/IRB (if applicable). 
13.17  Qualification of the Investigators 
The Investigator(s) should be qualified by education, language, training, and experience to assume 
responsibility for the proper conduct of the study. He/she should meet all qualifications specified by 
the applicable regulatory requirements and should provide evidence of such qualifications through 
an up-to-date curriculum vitae (Principal as well as all other Investigators) and/or other relevant 
documentation requested. 
The Investigator should be thoroughly familiar with the appropriate use of the investigational 
product(s), as described in the protocol, the current Investigator’s Brochure, the product 
information, and other information sources provided by the Sponsor. 
The Investigator should be aware of, and should comply with, ICH-GCP and the applicable 
regulatory requirements. The Investigator should maintain a list of appropriately qualified persons to 
whom the Investigator has delegated significant study related duties. 


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13.18  Financial Disclosure 
The disclosed financial interest of the Investigator must be collected prior to enrolment of the first 
patient into the study, following study center completion, and 1 year following study completion. The 
Investigator should promptly update this information if any relevant changes occur during this 
period. Disclosable financial interests will be recorded on the Investigator Financial Disclosure 
Form, US FDA 1572 Form, and communicated to the regulatory authorities. Any Investigator(s) 
added as investigational staff must complete the Investigator Financial Disclosure Form (US FDA 
1572 Form) at the beginning of his/her participation to the study. For any Investigator(s) leaving the 
site prior to study completion, an Investigator Financial Disclosure Form should be obtained at the 
end of his/her participation. 
13.19  Insurance of Patients and Others 
The Sponsor has covered this study by means of insurance for the patient according to national 
requirements. The name and address of the relevant insurance company, the certificate of 
insurance, the policy number, and the sum insured are provided in the Investigator’s File. 
13.20  Investigator Indemnity 
The Sponsor shall be liable towards the patients in accordance with the provisions of the Clinical 
Study Law. Notwithstanding the foregoing; the Sponsor does not, however, agree to indemnify, 
defend, or hold the Investigator harmless against liability, damage, loss, cost or expense (including 
reasonable attorney’s fees and expenses), including liabilities arising out of or in connection with 
claims of any nature by third parties, including, without limitation, in respect of bodily injury or death, 
arising out of or in connection with the negligence, wrongful acts or omissions or willful misconduct 
of the Investigator, the Institution, or its affiliates. 
Including but not limited to: 
 
The making of unauthorized representations and warranties concerning the study 
medication or the study; 
 
The failure to obtain appropriate informed consent; 
 
The non-compliance with applicable rules or regulations; 
 
The failure to conduct the study in accordance with this protocol. 
 
A condition of this indemnity obligation is that, whenever the Investigator has information from 
which it may be reasonably concluded that an incident of bodily injury, sickness, disease, or death 
has occurred, the Investigator must immediately notice the Sponsor of all pertinent data 
surrounding any such incident, and, in the event a claim is made or a suit is brought, the 
Investigator will assist the Sponsor and cooperate in gathering information with respect to the time, 
place, and circumstances, and in obtaining the names and addresses of the injured parties and 
available witnesses. 
The Investigator shall not, except at his/her own cost, voluntarily make any payment or incur any 
expense in connection with any such claim or suit without the prior written consent of the Sponsor. 


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14  QUALITY ASSURANCE 
 
The Sponsor is implementing and maintaining QA and QC systems with written SOPs to ensure 
that studies are conducted and data are generated, documented (record), and reported in 
compliance with the protocol, GCP, and applicable regulatory requirement(s). 
The Sponsor or designee may arrange to inspect or audit the study center. The auditor is 
independent from the clinical monitoring and project management team at the Sponsor’s site. The 
audit may include on-site review of regulatory documents, e-CRFs and source documents. The 
auditors will have direct access to these documents. 
 
Medical imaging is the main research tool used in the present study. These tools are subject to 
strict quality control laws such as regular controls performed by the producer and regular internal 
controls. 
 
 
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 Appendix I – Radiolabeling procedure of rh-Annexin V-128 and quality controls 
 
Radiolabeling procedure 
 
The Technetium solution to be used for the labeling of rh-Annexin V-128 kit is the solution which 
can be obtained by commercially available Tc Generators compliant with the Ph.Eur. Monograph 
“Sodium Pertechnetate (99mTc) Injection (Fission)” and Tc 99m Injection USP. 
During the product development, the following procedures and conditions have been tested and 
confirmed as adequate: 
a) Radioactive concentration of the Pertechnetate solution added for labelling should be 370 
MBq/mL (the reconstitution volume is 2 mL ± 0.2 mL). 
b) Labelling at room temperature under slight rotation by introducing the vial in a shielded roller 
for 90 min: shorter incubation times may result in inadequate labelling. 
c) Stability of the Radiolabelled compound up to 6h at room temperature (RCP ≥ 90 %). 
d) Suitability of the Radio TLC method to determine the radiochemical yield and purity by using 
three different eluents: Acetone 100% (99mTcO4-, Rf=1.0); Anticoagulant Citrate Dextrose 
solution (ACD) (99mTc-rhAnnexin V-128, Rf=0.0); PBS (99mTc-Glucoheptonate, Rf=1.0 and 
99mTcO2,Rf=0.0). 
 
Labelling takes place through an exchange reaction [40, 41] with 99m-Technetium-Glucoheptonate.  
 
 
 
Scheme of the exchange reaction between 99mTc-Glucoheptonate (99mTc-GH) and rhAnnexin V-
128. 
 
The instructions for the preparation of the 99mTc-rhAnnexin V-128 are in accordance with the 
following aseptic procedure: 
1) Remove an rhAnnexin V128 Kit reaction vial from refrigerated storage and allow it to reach 
room temperature (from 5 to 10 minutes). 
2) Waterproof gloves should be worn during the preparation procedure. Flip off cap from the 
rhAnnexin V-128 Kit vial and swab the top of the vial closure with an appropriate antiseptic 
to disinfect the surface, and then allow the stopper to dry. 


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CONFIDENTIAL 
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3) Place the vial in a suitable radiation shield appropriately labelled with date, time of 
preparation, volume and activity. 
4)  Aseptically add 2 mL ± 0.2 mL of Sodium Pertechnetate Tc-99m solution containing 740 
MBq ± 74 MBq (20 mCi ± 2 mCi)  to the vial in the lead shield (Do not shake). 
5) Remove the vial from the lead shield and place it in an appropriately shielded roller. Leave 
the vial under slow rotation for 90 min.   
6) Remove the vial from the shielded roller, inspect visually for the absence of particulate 
matter and discoloration and place it again in a lead shield. 
7) Aseptically withdraw material using a sterile shielded syringe. The so-obtained solution is 
stable for 6 hours after completion of radiolabelling reaction. For the purpose of this study it 
is recommended to use it within 4 hours after preparation. 
8) Perform the quality control according to the recommended methods in order to check the 
compliance to the specifications in table below: 
 
Table 
Specification of 99mTc Annexin V-128 KIT product 
Test 
Acceptance criteria 
Method 
Appearance 
Clear solution, colorless 
and free from visible 
particles 
Visual inspection 
pH 
5.0-5.8 
pH indicator strips 
Radiochemical purity (% 99mTc 
rhAnnexin V-128 species) 
≥ 90% 
Thin layer chromatography 
(iTLC) 
Radiochemical purity (% 99mTc 
Glucoheptonate) 
≤ 10% 
Thin layer chromatography 
(iTLC) 
Radiochemical purity (%99mTcO2 
and 99mTcO4- ) 
≤ 8% 
Thin layer chromatography 
(iTLC) 
 
Cautionary Notes: 
 
Tc-99m pertechnetate eluate should be obtained from a generator which has been eluted 
within the last 24 h 


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CONFIDENTIAL 
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 
Tc-99m pertechnetate eluate which is more than 6 hour old from the time of elution should 
NOT be used. 
 
 
Stability evaluation was performed so far on the lab-scale, engineering and first GMP batches. 
Stability data indicate that the product is stable up to 12 months both at 5°C ± 3°C (long term 
condition) and up to 9 months at 25°C ± 2°C/60% RH ± 5% RH (accelerated conditions), with high 
radiochemical purity (RCP, well above 90%) and good biological activity (Biopotency, higher than 
90%). Since the Drug Product confirmed to be stable after 12 months of storage at the accelerated 
temperature conditions (25°C ± 2°C/60% RH ± 5% RH), the current applied shelf-life is 12 months 
at 5°C ± 3°C. 
 
The stability evaluation will be performed on future GMP batches in order to obtain complete 
stability data on at least three GMP batches of the Drug Product up to 12 months at the intended 
long term storage temperature (5°C ± 3°C).  As mentioned above, the stability assessment is being 
also performed at the accelerated temperature condition (25°C ± 2°C/60% RH ± 5% RH), up to 9 
months. 
  
 
Stability of the Finished Product (99mTc-rhAnnexin V-128 radiolabelled Imaging Agent) 
 
The stability of the Finished Product is 6 h after labeling at room temperature. At this time the 
Radiochemical Purity is still ≥ 90%. For the purpose of this study it is recommended to inject the 
product within 4 h after completion of the radiolabelling reaction. 
 


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CONFIDENTIAL 
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0 
¼ 
½ 
¾ 
1 
1¼ 
1½ 
1¾ 
2 hours or more 
(0) 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
BASDAI 
Bath Ankylosing Spondylitis 
Disease Activity Index 
 
 
Name:     
 
 Date:   
 
 
 
 
 
 
 
             Ankylosing Spondylitis      
International Federation 
Please draw a mark on each line below to 
indicate your situation in the past 7 days:
 
 
n How would you  describe the overall level of fatigue / tiredness you have experienced 
in the past week? 
 
Evaluation by 
the doctor 
 
none  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
very severe 
 
o How would you describe the overall level of AS neck, back or hip pain you have had 
in the past week? 
 
none 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
very severe 
 
 
p How would you describe the overall level of pain / swelling in joints other than neck, 
back or hips you have had in the past week? 
 
none 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
very severe 
 
q How would you describe the overall level of discomfort you have had in the past week 
from any areas tender to touch or pressure? 
 
none 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
very severe 
 
 r How would you describe the overall level of morning stiffness you have had in the 
past week from the time you wake up? 
 
none  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
very severe 
 s How long did your morning stiffness last from the time you wake up? 
 
 
 
 
 
BASDAI = 
BASDAI = (sum of questions 1 to 4 plus mean of questions 5 and 6) 
divided by 5 
 
 
 
 
 
 
 
Ankylosing Spondylitis International Federation 
Appendix II – SpA assessments 


 
 
> 20 
0 
18–20 
1 
15,9–18,9 
2 
13,8–15,8 
3 
11,7–13,79 
4 
9,6–11,6 
5 
7,5–9,5 
6 
5,4–7,4 
7 
3,3–5,3 
8 
1,2–3,2 
9 
< 1,2 
10 
< 10 
0 
10–12 
1 
13–15 
2 
16–18 
3 
19–21 
4 
22–24 
5 
25–27 
6 
28–30 
7 
31–33 
8 
34–36 
9 
> 36 
10 
> 7,0 
0 
6,4–7,0 
1 
5,7–6,3 
2 
5,0–5,6 
3 
4,3–4,9 
4 
3,6–4,2 
5 
2,9–3,5 
6 
2,2–2,8 
7 
1,5–2,1 
8 
0,8–1,4 
9 
< 0,8 
10 
> 119 
0 
110–119 
1 
100–109
2 
90–99 
3 
80–89 
4 
70–79 
5 
60–69 
6 
50–59 
7 
40–49 
8 
30–39 
9 
< 30 
10 
> 85,0 
0 
76,6–85 
1 
68,1–76,5 
2 
59,6–68,0 
3 
51,1–59,5 
4 
42,6–51,0 
5 
34,1–42,5 
6 
25,6–34,0 
7 
17,1–25,5 
8 
8,6–17,0 
9 
< 8,6 
10 
BASMI 
 
Bath Ankylosing Spondylitis Metrology Index, 
a combined index to assess the spinal mobility 
in patients with ankylosing spondylitis *) 
 
 
Name:   
 
 
 
 
Ankylosing Spondylitis 
International Federation 
 
Date:   
 
 
 
 
Lateral lumbar flexion: Patient stands with heels and buttocks touching the wall, knees straight, shoulders 
back, hands by the side. The patient is then asked to bend to the right side as far as possible without lifting the 
left foot/heel or flexing the right knee, and maintaining a straight posture with heels, buttocks, and shoulders 
against the wall. The distance from the third fingertip to the floor when patient bends to the side, is subtracted 
from the distance when patient stands upright. The manoeuvre is repeated on the left side. 
 
Assessment: 
Score: 
 
 
Tragus-to-wall distance: Maintain same starting position as above. Ensure head in as neutral position (ana- 
tomical alignment) as possible, chin drawn in as far as possible. Measure distance between tragus of the ear 
and wall on both sides, using a rigid ruler. Ensure no cervical extension, rotation, flexion or side flexion occurs. 
 
Assessment: 
Score: 
 
 
 
 
 
 
mean of 
right/left 
 
 
 
 
 
 
 
mean of 
right/left 
 
 
Lumbar flexion (modified Schober): With the patient standing upright, place a mark at the lumbosacral 
junction (at the level of the dimples of Venus on both sides). Further marks are placed 5 cm below and 10 cm 
above 1. Measure the distraction of these two marks when the patient bends forward as far as possible, keeping 
the knees traight. 
1) Among the "modified Schober"s published in the literature, the modification recommended by Macrae and Wright is used. 
Assessment: 
Score: 
 
 
Maximal intermalleolar distance: Patient supine on the floor or a wide plinth, with the knees straight and the 
feet pointing straight up. Patient is asked to separate legs along the resting surface as far as possible. Distance 
between medial malleoli is measured. 
 
Assessment: 
Score: 
 
 
Cervical rotation: Patient supine on plinth, head in neutral position, forehead horizontal (if necessary head on 
pillow or foam block to allow this, must be documented for future reassessments). Gravity goniometer placed 
centrally on the forehead. Patient rotates head as far as possible, keeping shoulders still, ensure no neck flexion 
or side flexion occurs. 
 
 
 
 
 
mean of 
right/left 
 
 
 
 
 
*) Remark: 
In the literature (Jenkinson et al: J Rheumatol 1994;21:1694–1698 and Jones et al: J Rheumatol 1995;22:1609) two 
different BASMI definitions have been published where the same measurement results lead to different BASMI values. 
The above is based on the newer definition of1995 with scores 0 to 10 for each component. 
BASMI: 
(mean of 
5 scores) 
 
 
 
Ankylosing Spondylitis International Federation 
World-wide network of societies of patients suffering from ankylosing spondylitis or related diseases 
www.spondylitis-international.org 


World-wide network of societies of patients suffering from ankylosing spondylitis or related diseases 
www.spondylitis-international.org 
 
 
 
 
BASFI 
Bath Ankylosing Spondylitis 
Functional Index 
 
Name:     
 
Date: 
ASIF Ankylosing 
Spondylitis International 
Federation 
 
 
 
 
Please draw a mark on each line below to 
indicate your level of ability with each of 
the following activities in the past 7 days: 
 
 n Putting on your socks or tights without help or aids (e.g. sock aid) 
 
easy 
impossible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Evaluation by 
the doctor 
 
o Bending forward from the waist to pick up a pen from the floor without an aid 
 
easy 
impossible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
p Reaching up to a high shelf without help or aids (e.g. helping hand) 
 
easy 
impossible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
q Getting up out of an armless dining room chair without using your hands or any other help 
 
easy 
impossible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 r Getting up off the floor without help from lying on your back 
 
easy 
impossible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
s Standing unsupported for 10 minutes without discomfort 
 
easy 
impossible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
t Climbing 12–15 steps without using a handrail or walking aid, one foot on each step 
 
easy 
impossible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 u Looking over your shoulder without turning your body 
 
easy 
impossible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 v Doing physically demanding activities (e.g. physiotherapy exercises, gardening or sports) 
 
easy 
impossible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
w  Doing a full day‘s activities whether it be at home or at work 
 
easy 
impossible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
BASFI = 
 
(sum of answers 1 to 10 
divided by 10) 
 
 
 
 
Ankylosing Spondylitis International Federation 


 
 
 
 
Protocol v.4.0 – 13 Mar 2018 
CONFIDENTIAL 
Page 54 of 64 
 
Maastricht Ankylosing Spondylitis Enthesis Score 
 
 
 
 
 
 
 
 
 
 
 


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Page 55 of 64 
Appendix III – SAE form 
 
Serious Adverse Event (SAE) Reporting Form 
 
 
ALL REPORTS MUST BE SIGNED AND DATED BY THE INVESTIGATOR. 
 
Please fax or send by e-mail the form to AAA Global Pharmacovigilance within 24 hours from 
awareness of event. 
 
E-mail: pharmacovigilance@adacap.com; 
 
Fax N°: +33 4 50 99 36 34; 
 
 
Study Name 
EudraCT N° 
Center N° 
Investigator N° 
Country 
 
 
 
 
 
 
 
TYPE OF REPORT 
 
 
 Initial 
 
 
 Completion of data 
 
 
 Follow-up 
 
 
1. PATIENT DATA - DO NOT SEND PATIENT IDENTIFIABLE DATA 
Patient Initials (first 
letter of First Name 
and first letter of Last 
Name): 
Last name    
First name    
Patient N°: 
Sex: 
 
Year of Birth 
(yyyy): 
 
Age at onset of 
event: 
 
 
Weight (kg): 
 
Height (cm): 
 
 
2. EVENT DETAILS 
Date of onset 
(dd/mm/yyyy): 
 
Diagnosis: 
 
 
Description of SAE (please state date of first use): 
 
 
 
 
 
 
 
 
Seriousness Criteria (check all that are relevant to the event): 
 Participant died                          
 Hospitalisation or prolongation of existing hospitalisation 
 
 Life-threatening                          
 Persistent or significant disability or incapacity 
 


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Page 56 of 64 
 Congenital anomaly/                  
 Other significant medical events 
            birth defect 
 
 
Severity of event:                        
 
Mild                            
 Moderate                               
 
Severe 
 
 
 
3. STUDY TREATMENT 
Drug 
Schedule 
Route of 
administration 
Start date 
(dd/mm/yyyy) 
End date 
(dd/mm/yyyy) 
Causally Related to Drug?  
Tick either unrelated or possibly 
related 
Expected  
(Y/N) 
Unrelated 
Possibly 
Related 
1. 
 
 
 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
 
 
 
 
4. NIMPs (Non-investigational medicinal products) 
Are there any additional medications used as part of the protocol?  Such medications are referred to as 
NIMPs 
Yes 
  
 
 
 
 
 
No 
 
If yes, please complete the table below  
NIMP(s) 
Dose/schedule 
Route of 
administration 
Start date 
(dd/mm/yyyy) 
End date 
(dd/mm/yyyy) 
Causally Related to NIMP?  
Tick either unrelated or 
possibly related 
Expected  
(Y/N/NA) 
Unrelated 
Possibly 
Related 
1. 
 
 
 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
 
 
 
 
5. CONCOMITANT DRUGS RELEVANT TO THE SAE (do not include therapy used to treat the 
SAE) 
Tick box if no relevant concomitant medication 
Drug name 
Dose/schedule 
Route of 
administration 
Reason for 
use 
Start date 
(dd/mm/yyyy) 
End date 
(dd/mm/yyyy) 
Continued? 
(Y/N) 
1. 
 
 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
 
 
4. 
 
 
 
 
 
 


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Page 57 of 64 
 
 
5. 
 
 
 
 
 
 
 
 
6. 
 
 
 
 
 
 
 
 
 


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Page 58 of 64 
 
6. MEDICAL HISTORY (list relevant medical history): 
Tick box if no relevant medical history 
Condition 
Start Date 
(dd/mm/yyyy) 
End date 
(dd/mm/yyyy) 
Ongoing 
(Y/N)  
Medication required 
Y/N 
1. 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
 
7. RELEVANT TEST/LABORATORY FINDINGS (include only the results relevant to the SAE 
diagnosis or course of SAE)  
Test/lab 
finding  
Unit  
Date 
(dd/mm/yyyy) 
Value 
Reference range 
1. 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
Comment on test/laboratory findings (if none, mark as NA) 
 
 
 
 
 
 
 
8. ACTION TAKEN (check all that are relevant to the SAE)  
 No action taken  
 
 Drug permanently 
discontinued due to this 
SAE  
 
 
 Concomitant medication 
taken  
 Drug schedule 
adjusted/temporarily 
interrupted  
 
If multiple drugs used, please 
record which drug(s) have been 
adjusted/interrupted: 
 Non-drug therapy given 
 Hospitalisation/prolonged 
hospitalisation  
 


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Page 59 of 64 
9. OUTCOME OF SAE 
 Completely recovered 
Date of recovery (dd/mm/yyyy) 
 
 Condition still present and 
unchanged 
 Recovered with sequelae 
Date (dd/mm/yyyy) 
Describe sequale: 
 
 
 Condition deteriorated 
 
 
 
 Condition improving 
 Death  
Date of death (dd/mm/yyyy) 
 
 
Autopsy:  
Yes 
     No 
     N/A 
 
If Yes, include relevant information: 
 
 
10. ADDITIONAL INFORMATION  
 
 
 
 
 
 
 
11. INFORMATION SOURCE 
Name, address and 
telephone number of PI 
 
 
 
 
 
 
Date of report (dd/mm/yyyy) 
 
 
PI signature 
 
 
 
 
 
 
 
 
 
 
 
 
TO BE COMPLETED BY AAA GLOBAL PV (INTERNAL USE ONLY) 
 


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Page 60 of 64 
DATE OF RECEIPT: 
(dd/mm/yyyy) 
AAA CASE TRACKING NUMBER: 
 
 
INFORMATION COMPLETE: 
 Yes  
 No  
 
 
Name and signature: 
 
 
FOLLOW-UP REQUESTED:  
 YES 
 
 NO  
Details: 
 
 
PREGNANCY REPORTING FORM  
ALL REPORTS MUST BE SIGNED AND DATED BY THE INVESTIGATOR. 
Please fax or send by e-mail the form to AAA Global Pharmacovigilance within 24 hours from 
awareness of event. 
E-mail: pharmacovigilance@adacap.com; 
Fax N° : +33 4 50 99 36 34; 
 
N.B : Fill the applicable fields and refer to Completion Guide of Pregnancy Reporting Form. 
TYPE OF REPORT:      Initial       Completion of data         Follow-up n° ………………       
                                                                       
Study Name 
EudraCT N° 
Center N° 
Investigator N° 
Country 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. PREGNANT WOMAN’S GENERAL MEDICAL HISTORY / BACKGROUND 
BACKGROUND  
PRIOR IMMUNIZATIONS 
Rhesus: 
Smoking: 
Alcohol:  
Drug abuse(s): 
  Unknown    Rh -    Rh + 
  Unknown    No      Yes ….…….……………. (pack-years) 
  Unknown    No      Yes ....….…….…..……. (glasses/day) 
  Unknown    No      Yes ....……….…..…………... (detail) 
Rubella: 
Toxoplasma: 
  Unknown   No    Yes   
  Unknown   No    Yes   
MEDICAL HISTORY 
VIRAL SEROLOGY  
1. PATIENT INFORMATION 
Patient initials (first letter of Last Name and first 
letter of First Name) 
                       Last name   
First name   
Patient N°: 
Birthdate (YYYY): 
        
   Age: ……………… 
Weight (kg): 
  
Height (cm):  


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Hypertension: 
Diabetes mellitus: 
Epilepsy:  
Psychiatric diseases: 
  Unknown    No      Yes   
  Unknown    No      Yes   
  Unknown    No      Yes   
  Unknown    No      Yes   
HIV: 
Hepatitis: 
  Unknown   No    Yes   
  Unknown   No    Yes   
 
3. PREGNANT WOMAN’S GYNECOLOGICAL & OBSTETRICAL HISTORY 
GYNECOLOGICAL HISTORY 
Used contraception: 
Regular menses: 
Infertility treatment: 
  None     Oral    Local    Intra-uterine device    Other   …………………………..…………………………. (detail) 
  No        Yes    
  No        Yes   …………………………..……………………………………………………………………….……… (detail) 
OBSTETRICAL HISTORY 
Gravidity: 
Parity: 
  No    Yes ………………………….. (detail)  
  No    Yes ………………………….. (detail) 
Abortions:  
 
 
 
 
 
  No    Yes 
If yes, please precise: 
  Spontaneous ……………….…………… (detail) 
  Elective …………………….…………….. (detail) 
  Therapeutic ……………….…..…………. (detail) 
In utero demise: 
  No    Yes ………………………….. (detail) 
Number of healthy live offspring:   
Number of death offspring:   
Number of malformated live offspring:   
…………………………   
…………………………   
…………………………   
 
4. MATERNAL & PATERNAL FAMILY HISTORY 
Malformations: 
Prematurely died children: 
Psychomotor retardation: 
Consanguinity: 
Hereditary disease: 
Other: 
  Unknown    No    Yes ……………………………………………………………………..….……… (detail) 
  Unknown    No    Yes ……………………………………………………………………..….……… (detail) 
  Unknown    No    Yes ……………………………………………………………………..….……… (detail) 
  Unknown    No    Yes ……………………………………………………………………..….……… (detail) 
  Unknown    No    Yes ……………………………………………………………………..….……… (detail) 
……………………………………………………………………..….………………………………………...… (detail) 
 
 
5. CURRENT PREGNANCY STATUS AT TIME OF DETECTION 
Last menstrual period: 
    /     /         
 
Gestational age: ……………………. 
Ultrasound-estimated gestational age: …………………… 
 
Polyzygotic pregnancy:  
Ectopic pregnancy :  
 
  No     Yes 
  No     Yes 
Estimated date of delivery: 
    /     /         
 
6. COURSE OF CURRENT PREGNANCY 
DELETERIOUS EXPOSURES DURING PREGNANCY 
PATHOLOGY (IES) DURING PREGNANCY 


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Page 62 of 64 
Smoker: 
Alcohol:  
Drug abuse(s) : 
Other : 
  No     Yes ……...……………………………..  (pack-years) 
  No     Yes ……………………………………….  (glasses/day) 
  No     Yes ……………………………………….........  (detail) 
…………………………………………………………………………. 
Hypertension : 
Diabetes: 
Infection :  
Other : 
  No     Yes  
  No     Yes  
  No     Yes  
……………………………. 
MEDICATION RECEIVED AFTER PREGNANCY DETECTION 
Name 
 
Posology 
(with units) 
Administration 
route 
Indication(s)  
Administration dates (start/end)  
1.  
 
 
 
 
2.  
 
 
 
 
3.  
 
 
 
 
4.  
 
 
 
 
5.  
 
 
 
 
MEDICAL FOLLOW-UP 
Hospitalization during pregnancy:  
Intrauterine growth retardation: 
Prenatal diagnosis:  
  No     Yes    ………………………………………...………………………………………...... (reason) 
  No     Yes    ………………………………………...………………………………………........ (detail) 
  No     Yes     
Ultrasound: 
  No     Yes  
If yes, please precise: 
 
 
Date:     /     /         
Date:     /     /         
Date:     /     /         
Results: ………………………………………... 
Results: ………………………………………... 
Results: ………………………………………... 
Invasive method:  
  No     Yes 
If yes, please precise: ………………………………………... (method) 
 
Date:     /     /         
Results: ………………………………………... 
Toxicology screen:  
  No     Yes 
If yes, please precise: ………………………………………... (drug / body fluid) 
 
Date:     /     /         
Results: ………………………………………... (level) 
 
7. OUTCOME OF CURRENT PREGNANCY 
Live newborn: 
  No     Yes 
If NO, please precise: 
 
  Spontaneous abortion 
  Elective abortion 
  Therapeutic abortion 
  In utero demise 
Date:     /     /          
Date:     /     /         
Date:     /     /         
 
Term: ……………………… (week) 
Term: ……………………… (week) 
Term: ……………………… (week) 
Term: ……………………… (week) 
Malformations: 
Histopathology: 
  No     Yes  
  No     Yes 
……………………………………………………………...  (detail) 
……………………………………………………………...  (detail) 
 
8. DELIVERY 
Delivery date: 
    /     /         
  Normal delivery 
Fetal distress:  
  No     Yes    (If yes)   Chronic    Acute 


AAA-Annexin-03 
 
page 63 of 64 
Study Protocol 
 
Protocol v.4.0  – 13 Mar 2018 
Page 63 of 64 
Gestational age: 
…………………………. (weeks) 
  Induced delivery   
  Caesarean section 
Normal placenta: 
Amniotic fluid:  
  No     Yes    Unknown 
  Clear     Turbid 
Postpartum maternal condition: 
Intrapartum medication: 
  Normal         Abnormal     
  Unknown     No     Yes    
…………………………………………………..…….  (detail) 
…………………………………………………..…….  (if yes, detail) 
 
9. NEWBORN 
Sex :     F     M   
Weight: ………………………..... (unit) 
Length: …………………….….... (unit) 
Cranial perimeter: ………......... (unit) 
Preterm:         No     Yes  
Dysmature:    No     Yes   
Intensive care:    
Malformation :  
Neonatal pathology:  
Breastfeeding: 
  No     Yes    Unknown 
  No     Yes ………………………...  (detail) 
  No     Yes ………………………...  (detail) 
  No     Yes   
APGAR score: ……..…. (1 min)    
                          ……..…. (5 min) 
Transfer to NICU / pediatrics:  
Immediate outcome: 
  No    Yes  ….……..  (duration) 
………………………...................... 
Department address:  
Child’s follow-up performed by: 
………………………...………………… 
………………………...………………… 
 
10. INITIAL REPORTER 
 
Occupation:  
 
Full name:  
 
Organization/Adress:  
 
Telephone:  
Fax:  
Email:  
 
Date & signature  ______________________________________   
 
If the reporter is a patient or not a Healthcare Professional: 
Has the patient given the authorization to AAA to follow up the pregnancy 
with its treating Doctor?    Yes     No   
Date & signature  __________________________________ 
 
Details of the treating Doctor (if different from the reporter): 
Occupation:  
Full name:  
Organization/Address:  
Telephone/Fax:  
Email:  
 
 
 
 
 
 
 
ADMINISTRATIVE INFORMATION (for internal use only) 
AAA Case #: ……………………………………………. 
TYPE DE RAPPORT:      Initial     Follow up n°: ……………… 
Initial reception by: 
NAME:  
OCCUPATION:  
LOCAL AFFILIATE/COUNTRY:  
Reception date by AAA PV department 
    /     /         


AAA-Annexin-03 
 
page 64 of 64 
Study Protocol 
 
Protocol v.4.0  – 13 Mar 2018 
Page 64 of 64 
Reception date by a partner 
    /     /         
DATE:       /     /         
 
 SIGNATURE   _________________________________________ 
 
Data collected during a Pharmacovigilance investigation may be stored in a database according to Regulation (UE) no 520/2012, Regulation (CE) no 
726/2004 and directive 2001/83/CE. 
 
 

SAP_001.pdf: 
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Statistical Analysis Plan 
Version 1 
 
TITLE: Phase II Study of 99mTc-rhAnnexin V-128 Radionuclide Imaging in Patients with Clinical 
Suspicion or Confirmed Diagnosis of Spondyloarthritis (SpA) 
 
PROTOCOL #: AAA-Annexin-03 
 
NCT #: NCT03232580 
 
PHASE: Proof of Concept and Phase II study 
 
DATE: Final version 1.0 dated 06 March 2019 
 
DESIGN: Monocentric, open label, study. 
 
INVESTIGATIONAL PRODUCT: Kit for the Preparation of Tc-99m Recombinant Human Annexin 
V-128 for Injection 


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APPROVAL/REVISION HISTORY 
Autorship/Approval 
Author: 
 
 
 Statistician 
Date 
Reviewed by: 
 
 
 Statistician 
Date 
Approved by: 
 
 
Advanced Accelerator Application S.A. (Sponsor), 
 
Date 
 
Revision history 
Rev. Name 
Date 
Note 
1 
 
 
 
 
Sent to 
Rev. 
Name 
e-mail 
Sent on 
Note 
01 
 
 
 
 
 


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1 Index 
1 
Index 
3 
2 
List of abbreviations ................................................................................................................................... 8 
3 
Protocol title and number ......................................................................................................................... 11 
4 
INFORMATION TAKEN FROM THE PROTOCOL.................................................................................. 12 
4.1 
Study objectives ............................................................................................................................. 12 
 
Primary objective ........................................................................................................................ 12 
 
Secondary objective ................................................................................................................... 12 
12 
 
Study hypoteses and justification ............................................................................................... 13 
4.2 
Study design ................................................................................................................................... 13 
 
Study population ......................................................................................................................... 13 
 
Inclusion criteria ................................................................................................................ 14 
 
Exclusion criteria ............................................................................................................... 14 
 
Study exposure ........................................................................................................................... 15 
 
Termination of the study ............................................................................................................. 15 
4.3 
Methods and procedures................................................................................................................ 16 
 
Source of study population ......................................................................................................... 16 
 
Participant study identification .................................................................................................... 16 
 
Study procedure ......................................................................................................................... 16 
 
Baseline assessments....................................................................................................... 16 
 
Efficacy assessments ........................................................................................................ 17 
4.3.3.2.1 
Imaging ......................................................................................................................... 17 
4.3.3.2.2 
Clinical asessment ....................................................................................................... 18 
 
Safety assessments .......................................................................................................... 18 
4.3.3.3.1 
Adverse events and other safety aspects .................................................................... 18 
4.3.3.3.2 
Standard laboratory assessments................................................................................ 21 
4.3.3.3.3 
Immunogenicity assessments ...................................................................................... 22 
 
Withdrawal/discontinuation ............................................................................................... 22 


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Prohibitions and restrictions .............................................................................................. 23 
 
Schedule of assessments ........................................................................................................... 23 
 
Planned sample size .................................................................................................................. 26 
5 
SUBJECT POPULATIONS (ANALYSIS SETS) ...................................................................................... 27 
5.1 
Efficacy ........................................................................................................................................... 27 
 
Full analysis set (FAS) ................................................................................................................ 27 
 
Per Protocol population (PP) ...................................................................................................... 27 
5.2 
Safety set ....................................................................................................................................... 27 
5.3 
Primary population ......................................................................................................................... 27 
6 
STATISTICAL METHODS ....................................................................................................................... 28 
6.1 
Statistical analysis strategy ............................................................................................................ 28 
 
Efficacy endpoint ........................................................................................................................ 28 
 
Primary endpoint of PoC ................................................................................................... 28 
 
Primary endpoint of Phase II ............................................................................................. 28 
 
Secondary endpoints......................................................................................................... 29 
 30 
 
Safety endpoint(s)....................................................................................................................... 31 
 
Adverse events .................................................................................................................. 31 
 
Clinical laboratory values .................................................................................................. 32 
 
Vital signs and physical examination ................................................................................ 32 
 
Multiplicity ................................................................................................................................... 32 
 
Significance testing and estimation ............................................................................................ 33 
 
Missing data and outliers ............................................................................................................ 33 
 
Missing data ...................................................................................................................... 33 
 
Missing or incomplete dates .............................................................................................. 33 
 
Outliers .............................................................................................................................. 33 
 
Subject disposition ...................................................................................................................... 34 
 
Withdrawals ................................................................................................................................ 34 
 
Demographic and baseline characteristics ................................................................................. 34 
 
Disease assessments ................................................................................................................. 34 
 Medical and surgical history ....................................................................................................... 35 
 Subject compliance .................................................................................................................... 35 


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 Prior and concomitant therapies ................................................................................................. 35 
 Derived data ............................................................................................................................... 35 
 Visit windows .............................................................................................................................. 36 
 Rules and data formats .............................................................................................................. 36 
 Pooling of Centres ...................................................................................................................... 37 
 Interim analysis ........................................................................................................................... 37 
 Role of independent data monitoring committee (DMC) / interim data review committee ......... 37 
 Covariates and analysis of subgroups ....................................................................................... 37 
 Sensitivity analysis...................................................................................................................... 37 
7 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS ........................................ 38 
7.1 
Hardware ........................................................................................................................................ 38 
7.2 
Software ......................................................................................................................................... 38 
7.3 
Validation programs ....................................................................................................................... 38 
8 
CHANGES FROM PROTOCOL .............................................................................................................. 40 
9 
REFERENCES 41 
10 DATA PRESENTATION .......................................................................................................................... 42 
10.1 
Listings index .................................................................................................................................. 42 
10.2 
Listing templates ............................................................................................................................ 44 
10.3 
Tables index ................................................................................................................................... 44 
10.4 
Table templates .............................................................................................................................. 44 
10.5 
Figure templates ............................................................................................................................. 44 
10.6 
Statistical Appendix ........................................................................................................................ 44 
11 APPENDICES 46 
11.1 
Standard listings ............................................................................................................................. 46 
Listing 16.2.1.1: 
Subject Disposition – All subjects ................................................................................. 47 
Listing 16.2.1.2: 
Subject Disposition – Study Withdrawals ..................................................................... 48 
Listing 16.2.1.3: 
Inclusion Criteria ........................................................................................................... 49 
Listing 16.2.1.4: 
Exclusion Criteria .......................................................................................................... 50 


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Listing 16.2.1.5: 
Screening Failures ........................................................................................................ 51 
Listing 16.2.2: 
Protocol Deviations ....................................................................................................... 52 
Listing 16.2.3: 
Subjects Excluded from the Efficacy Analysis .............................................................. 53 
Listing 16.2.4.1: 
Demographics ............................................................................................................... 54 
Listing 16.2.4.2/1: 
Disease Assessment .................................................................................................... 55 
Listing 16.2.4.2/2: 
Disease Assessment .................................................................................................... 56 
Listing 16.2.4.3: 
Significant Medical History and Associated Pathologies .............................................. 57 
Listing 16.2.4.4/1: 
Prior and Concomitant Medications .............................................................................. 58 
Listing 16.2.4.4/2: 
Prior and Concomitant Medications .............................................................................. 59 
Listing 16.2.5.1/1: 
Study Drug Administration and Extent of Subject Exposure ........................................ 60 
Listing 16.2.5.1/2: 
Study Drug Administration and Extent of Subject Exposure ........................................ 61 
Listing 16.2.6.1: 
Imaging Results ............................................................................................................ 62 
Listing 16.2.7.1/1: 
All Adverse Events ........................................................................................................ 63 
Listing 16.2.7.1/2: 
All Adverse Events ........................................................................................................ 64 
Listing 16.2.7.1/3: 
All Adverse Events ........................................................................................................ 65 
Listing 16.2.7.2/1: 
Serious Adverse Events ................................................................................................ 66 
Listing 16.2.7.2/2: 
Serious Adverse Events ................................................................................................ 67 
Listing 16.2.7.2/3: 
Serious Adverse Events ................................................................................................ 68 
Listing 16.2.7.3/1: 
Adverse Events Leading to Withdrawal ........................................................................ 69 
Listing 16.2.7.3/2: 
Adverse Events Leading to Withdrawal ........................................................................ 70 
Listing 16.2.7.3/3: 
Adverse Events Leading to Withdrawal ........................................................................ 71 
Listing 16.2.7.4/1: 
Adverse Events Leading to Deaths .............................................................................. 72 
Listing 16.2.7.4/2: 
Adverse Events Leading to Deaths .............................................................................. 73 


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Listing 16.2.7.4/3: 
Adverse Events Leading to Deaths .............................................................................. 74 
Listing 16.2.8.1/1: 
Hematology ................................................................................................................... 75 
Listing 16.2.8.2/1: 
Blood Chemistry ............................................................................................................ 76 
Listing 16.2.8.3/1: 
Urinalysis....................................................................................................................... 77 
Listing 16.2.8.4: 
Immunogenicity ............................................................................................................. 78 
Listing 16.2.9.1: 
Pregnancy Test ............................................................................................................. 79 
Listing 16.2.9.2/1: 
Physical Examination .................................................................................................... 80 
Listing 16.2.9.3: 
Vital Signs ..................................................................................................................... 81 
11.2 
Standard Tables ............................................................................................................................. 82 
11.3 
Standard Figures ............................................................................................................................ 83 
APPENDICES TO THE SAP TEMPLATE ....................................................................................................... 84 
11.4 
Derived Data .................................................................................................................................. 84 
11.5 
SAS Programs ................................................................................................................................ 85 
 


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2 List of abbreviations 
AAA  
 
Advanced Accelerator Applications 
AE  
 
Adverse Event 
ADR 
 
Adverse Drug Reaction 
ALAT 
 
Alanine Aminotransferase 
ALP  
 
Alkanine Phosphatase 
ALT  
 
Alanine Transaminase 
AS  
 
Ankylosing Spondylitis 
ASAS 
 
Assessment of Spondylo-Arthritis Society 
ASAT 
 
Aspartate Aminotransferase 
AST  
 
Aspartate Transaminase 
ATC  
 
Anatomical Therapeutic Chemical classification system 
BASDAI 
 
Bath Ankylosing Spondylitis Disease Activity Index 
BASFI 
 
Bath Ankylosing Spondylitis Functional Index 
BASMI 
 
Bath Ankylosing Spondylitis Metrology Index 
BMI  
 
Body Mass Index 
BP  
 
Blood Pressure 
BUN 
 
Blood Urea Nitrogen 
CBC 
 
Complete Blood Count 
CRO 
 
Clinical Research Organization 
CRP 
 
C-Reactive Protein 
CT  
 
Computed Tomography 
DMARD 
 
Disease Modifying Anti-Rheumatic Drug 
DMC 
 
Data Monitoring Committee 
eCRF 
 
Electronic Case Report Form 
ELISA 
 
Enzyme-Linked Immuno-absorbent Assay 


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FAS  
 
Full Analysis Set 
GGT 
 
Gamma-Glutamyl Transpeptidase 
Hb  
 
Hemoglobin 
HR  
 
Heart Rate 
ICH  
 
International Conference on Harmonization 
ID 
 
 
Identification 
IEC  
 
Indipendent Ethics Committee 
INR  
 
International Normalized Ratio 
IP 
 
 
Investigational Product 
IQR  
 
Interquartile Range 
IRB  
 
Institutional Review Board 
ITT  
 
Intention To Treat 
LDH  
 
Lactate Dehydrogenase 
LLT  
 
Lowest Level Term 
MASES 
 
Maastricht Ankylosing Spondylitis Enthesis Score 
MBq  
 
Mega Becquerel 
MCV 
 
Mean Corpuscular Volume 
MedDRA   
Medical Dictionary for Regulatory Activities  
MRI  
 
Magnetic Resonance Imaging 
NSAID 
 
Non-Steroidal Anti-Inflammatory Drug 
PoC  
 
Proof of Concept 
PP  
 
Per Protocol 
PS  
 
Phosphatidylserine 
PT  
 
Preferred Term 
PT  
 
Prothrombin Time 
PTT  
 
Partial Thromboplastin Time 
RBC 
 
Red Blood Cell 


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ROI  
 
Region Of Interest 
  
 
 
SAE  
 
Serious Adverse Event 
SAP  
 
Statistical Analysis Plan 
S.D.  
 
Standard Deviation 
SI 
 
 
Sacro-Iliac 
SMA-20 
 
Sequential Multiple Analysis-20 
SpA  
 
Spondyloarthritis 
SPECT 
 
Single Photon Emission Computed Tomography 
SOC 
 
System Organ Class 
TBR  
 
Target to Background Ratio 
TEAE 
 
Treatment Emergent Adverse Event 
US  
 
United States 
VOI  
 
Volume Of Interest 
WBC 
 
White Blood Cell 


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3 Protocol title and number 
Phase II Study of 99mTc-rhAnnexin V-128 Radionuclide Imaging in Patients with Clinical Suspicion or 
Confirmed Diagnosis of Spondyloarthritis (SpA) (Protocol Number AAA-Annexin-03). 


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4 INFORMATION TAKEN FROM THE PROTOCOL 
4.1 
Study objectives 
 Primary objective 
The primary objective of this study is to determine the magnitude and dynamic range of 
99mTc-rhAnnexin V-128 uptake in disease affected sacro-iliac or lumbar spine joints in patients with 
clinical suspicion or confirmed diagnosis of SpA. 
 Secondary objective 
The secondary objectives of this study are: 
 
To determine clinical utility of 99mTc-rhAnnexin V-128 SPECT imaging in the identification of 
chronic osteoarthritic active sites of SpA patients compared with MRI in patients with 
disease-affected sacro-iliac or lumbar spine joints. 
 
To assess the presence of antibodies against rhAnnexin V-128 at baseline and post-
treatment. 
 
To determine the localization pattern and magnitude of focal uptake of 99mTc-rhAnnexin 
V-128 within the abdomen in patients with clinical suspicion or confirmed diagnosis of 
Spondyloarthritis (SpA). 


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 Study hypoteses and justification 
It is hypothesized that 99mTc-rhAnnexin V-128, a second generation form of 99mTc radiolabeled 
annexin V with significantly higher PS binding affinity and improved in vivo localization properties, 
will be highly specific in imaging degenerative osteoarthritis particularly of the lumbosacral spine and 
sacroiliac joints as seen by SPECT/CT in patients with SpA. It is also hypothesized that 
99mTc- rhAnnexin V-128 will be localized within the abdomen of SpA patients with active disease 
showing suspicious Crohn’s disease. 
At the completion of this study, there will be preliminary data on the expected magnitude and dynamic 
range and specificity of 99mTc-rhAnnexin V-128 uptake at sites of active disease in SpA patients at 
presentation. 
4.2 
Study design 
This is a monocentric, open label, PoC, Phase II study. Patients who have signed the informed 
consent and are eligible for study participation according to the inclusion and exclusion criteria will 
receive a single intravenous bolus of 99mTc-rhAnnexin V-128 on Day 0 followed by SPECT/CT of the 
sacro-iliac joints, spine and abdomen at 60 min and 2 hrs after injection of the radiotracer within 14 
days after screening in order to minimize the potential delay in changing NSAID therapy or 
non-biologic DMARD or the start of non-biologic DMARD or biologic DMARD (excepted for the first 
5 enrolled patients who will not be eligible for the start of biologic DMARD). Patients will undergo 
also a whole body scan and spot views on specific areas at the same time-points (spot views may 
not be repeated at T+2 hrs). T1 and STIR without contrast MRI of the sacro-iliac joints and lumbar 
spine will also be performed within this same time window. 
 Study population 
Approval for the study will be obtained from the local IRB of Cedars-Sinai Medical Center Office of 
Research of Compliance. All patients will provide written informed consent prior to the initiation of 
any study procedures. Up to twenty evaluable patients will be recruited. 


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 Inclusion criteria 
For the first 5 patients enrolled in the PoC part: 
1. Patients with clinical suspicion or confirmed diagnosis of SpA, based on the ASAS criteria 
with active symptoms including back, hip or buttock pain prior to: 
 
a change in NSAID therapy or 
 
a change in non-biologic DMARD or 
 
a start of non-biologic DMARD. 
For the next 15 patients enrolled in the Phase II part: 
1. Patients with clinical suspicion or confirmed diagnosis of SpA, based on the ASAS criteria 
with active symptoms including back, hip or buttock pain prior to: 
 
a change in NSAIDs therapy or 
 
a change in non-biologic DMARD or 
 
a start of non-biologic DMARD or 
 
a start of biologic DMARD. 
For all patients: 
2. Age over 18 years old. 
3. Signed Informed Consent Form. 
 Exclusion criteria 
1. Pregnancy or lactation. 
2. Liver impairment (ALT, AST or Bilirubin > 2 ULN) at screening visit or baseline. 
3. Kidney impairment (serum creatinine > 1.5 mg/dL). 
4. History of any disease or relevant physical or psychiatric condition or abnormal physical 
finding which may interfere with the study objectives at the investigator judgment. 
5. Known hypersensitivity to the investigational drug or any of its components. 
6. Contraindication(s) to the MRI procedure (claustrophobia, prosthetic valve, pacemaker, 
inability to lie still in a supine position). 


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7. Participation to another clinical trial within 4 weeks before study inclusion except for patients 
who have participated or who are currently participating in an interventional study without any 
study drug administration. 
 Study exposure 
The “Kit for preparation of 99mTc-rhAnnexin V-128 for injection” consists of 1 dose. Following the 
reconstitution and labelling of rhAnnexin V-128, the imaging product will be administered as a single 
intravenous bolus of 350 MBq ± 10% over 10-20 seconds at Day 0 for the purpose of SPECT/CT 
imaging. 
 Termination of the study 
Early termination of the study can occur in the following cases: 
 
When the visual review and analysis of the images of the first 5 patients by the DMC does 
not enable to demonstrate the potential of the study product in terms of quality or efficacy, 
the Sponsor may discontinue the clinical study by sending a written notice of the 
discontinuation along with the reasons to the investigator and applicable authorities. 
 
When the Sponsor is aware of new information on matters concerning the safety of the study 
product, as well as other important information that may affect proper conduct of the clinical 
study, the Sponsor may discontinue the clinical study and send a written notice of the 
discontinuation along with the reasons to the investigator and applicable authorities. 
 
If the investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor of the discontinuation and the reason for it. 
If none of the previous condition applies, the end of study is defined as the moment that the last 
enrolled patient has completed the planned assessments at Day 3; study duration is maximum 7 
weeks (including the screening period) for each patient. 
The Sponsor reserves the right to discontinue the study at any time for failure to meet expected 
enrolment goals. 


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4.3 
Methods and procedures 
 Source of study population 
Twenty evaluable patients with clinical suspicion or confirmed diagnosis of SpA due to ankylosing 
spondylitis, or associated with other known clinical conditions like inflammatory bowel disease, 
psoriatic arthritis, or undifferentiated spondyloarthropathy will be recruited at Cedars-Sinai Medical 
Center. 
 Participant study identification 
Each patient will be anonymized and identified with a patient ID number. A unique patient 
identification number (Patient ID) will be assigned at the start of the screening period to each patient 
who signs the informed consent form until the study termination of the patient. This number will 
identify the subject throughout the study. Patient IDs will include the 2-digit protocol number (03), 
the 2-letter country code (US) and a 3-digit patient number (ex: 03-US-001 for first subject in). 
 Study procedure 
Voluntary written informed consent will be obtained prior to the initiation of any study-related 
procedures. Study conduct procedures will include screening, the imaging visit and follow-up visits. 
 Baseline assessments 
 
Each patient’s demography, i.e. date of birth, gender, ethnicity, medical history and relevant 
baseline characteristics, will be recorded at Screening visit. 
 
Inclusion/exclusion criteria will be checked at Screening. 
 
Women of childbearing potential must have negative urine pregnancy test at Screening 
before the radiotracer administration and before MRI (in case the MRI is not performed on 
the same day of the screening visit). 
 
Vital signs will be taken at Screening. 
 
Physical examination will be conducted at Screening. 
 
BASDAI, BASFI, BASMI and MASES assessments will be performed. 


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 Efficacy assessments 
4.3.3.2.1 Imaging 
Patients will be injected intravenously with 350 ± 10% MBq of 99mTc-rhAnnexin V-128 with an 18 
gauge angiocath IV and saline TKO drip set up placed in the antecubital fossa. 
Bone Lumbar Spine SPECT/CT, SI SPECT/CT and abdomen SPECT/CT will be performed 60 
minutes and 2 hours after injection of radiotracer followed by a whole body scan and spot views on 
specific areas (spot views may not be repeated at T+2 hrs if deemed unnecessary). 
The Infinia™ Hawkeye 4 SPECT/CT (GE Healthcare) scanner will be used for patients with the 
following parameters; start at 0°, 180° rotation/detector, 64 steps, 3° per step, 30 sec per step, overall 
ARC 360°, (scan time = 23 minutes) 128 x 128, multi-purpose collimator (Skylight) in 1x zoom mode. 
An attenuation and diagnostic CT scan will be performed on the lumbar spine using a 512 x 512 
matrix, 140 keV, 2.5 mA, axial 1 sec, 5 mm slices. 
Semi-quantitative assessment of inflammatory joints and abdomen will be performed in terms of TBR 
as well as by calculating the relative uptake in ROI/VOIs. ROI and VOI defined and used in the 
different scintigraphies will strictly have the same pixel size and localization and will be measured in 
counts. 
In case a suspected anomaly is found at imaging, it would be reported to the rheumatologist and the 
patient’s general practitioner. 
A whole lumbar spine and sacro-iliac joint MRI will be performed within 14 days of 99mTc-rhAnnexin 
V-128 scanning using the following parameters: SI Joint Sequences / 3 plane localizer / Whole 
pelvis Coronal T1 / Whole pelvis Coronal T2 FS. Small FOV over SI Joints (~20 cm FOV): Sequences 
/ Obl Axial T1. Obl Axial T2 FS (May use STIR or IDEAL for poor FS), Obl Coronal T1, Obl Coronal 
T2, FS (May use STIR or IDEAL for poor FS). Following pre/post sequences will be used to help 
assess for subtle sacroilitis: Obl Ax T1 FSE FS Pre / Obl Ax T1 FSE FS Post / Obl Cor T1 FSE FS 
Post. FOV notes: Small FOV width should be approximately from femoral head to femoral head; 
oblique axial and coronal are prescribed relative to the sacrum. Protocol for Spine: Sag T1, T2 FSE 
no fat sat, STIR, FOV 28 / Ax T1 and T2 FSE (no fat sat), FOV 20. 


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4.3.3.2.2 Clinical asessment 
A clinical evaluation including the search for enthesopathy – using the Maastricht Score (MASES) – 
and assessments with BASDAI, BASFI and BASMI will be performed at Screening. 
The clinical assessment will be completed by the measurement of biological markers of inflammation 
(CRP and CBC) at Screening and at Day 30. 
 Safety assessments 
 
Physical examination will be conducted at D30. 
 
Measurement of vital signs (systolic and diastolic blood pressure and heart rate) will be 
performed 15 minutes before the radiotracer administration and at the end of the last imaging 
procedure at Day 0. 
 
Women of childbearing potential must have negative urine pregnancy test before injection of 
the radiotracer at Day 0. 
 
All medications taken from 2 weeks prior to the administration date through the end of study 
are to be recorded as prior and concomitant medications, including therapies for SpA. 
 
Any adverse events occurring during the course of the study will be reported and recorded 
in the eCRF. 24 hours after treatment injection (at Day 1), each patient will be called in order 
to inquire if they experienced signs or symptoms such as edema, rash or have any clinical 
findings. 
4.3.3.3.1 Adverse events and other safety aspects 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a participant and which does not necessarily 
have a causal relationship with the study medication. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal clinically significant laboratory finding), symptom, or disease, 
temporarily associated with the use of a study medication, whether or not causally related to the 
study medication. 
AEs will be reported, if applicable, from the signing of the informed consent onwards until the last 
study-related procedure. If the information of an untoward medical occurrence is collected before 


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starting the intake of study medication, this information will be listed as a pre-treatment AE during 
statistical analysis. 
Throughout the study, the study staff will question the patient in a non-directive way as to the 
occurrence of AEs. The patient will also be instructed, when signing the informed consent, as from 
that moment, to contact the Investigator to report any study medication or non-study medication 
related adverse or unusual event that occurs during participation to the study. 
The study staff will record all these events in the patient’s medical records and eCRF, whether 
observed by the Investigator, the investigational staff, or spontaneously reported by the patient. The 
Investigator will provide a complete description of the event in standard medical terminology, the 
date of onset and termination, severity, relationship to the study medication, action taken regarding 
the study medication, any treatment given, the outcome, and whether or not the event is considered 
as a SAE. If known, the Investigator should report the underlying illness or disorder rather than the 
individual signs and symptoms. 
All AEs occurring during the study are to be followed up until resolved or judged to be no longer 
clinically significant, or until they become chronic to the extent that they can be fully characterized. 
An assessment should be made at the last study-related visit for each patient. Certain long-term AEs 
cannot be followed until resolution within the settings of the protocol. In these cases follow-up will be 
the responsibility of the treating physician. 
Since it is unpredictable how long such a follow-up might take, data from this follow-up generated 
after the patient’s last study-related visit will be recorded by the Investigator. Full details regarding 
this follow-up will be described in the Clinical Study Report, if necessary. If during AE follow-up the 
case has progressed to the level of “SAE”, or if a new SAE whose relationship to the study medication 
could not be ruled out is observed, the situation must be reported immediately by the Investigator 
becoming aware of the information (considering that the “date of SAE onset” is the date of the first 
manifestations of that AE). 


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Definition of Serious Adverse Events 
A SAE is any untoward medical occurrence that at any dose: 
 
results in death; 
 
is life-threatening; 
Note: “life-threatening” refers to an event in which the participant is at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
was more severe; 
 
results in persistent or significant disability/incapacity; 
 
results in congenital anomaly or birth defect; 
 
requires in-patient hospitalization or leads to prolongation of hospitalization. 
Hospitalization or prolongation of hospitalization will not be considered as SAE in the 
following cases: 
o Hospitalization planned before the patient inclusion, 
o Hospitalization les than 24 h 
o Hospitalization needed for the routine follow-up of the patient disease. 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These events, 
including those that may result in disability, should also usually be considered serious. Examples of 
such events are intensive treatment in an emergency room or at home for severe allergic reactions 
that do not result in hospitalization. 
The Investigator must report all SAEs by sending a completed SA Reporting Form (Appendix III of 
study protocol) to the Safety Officer designee within 24 h of becoming aware of the event. All SAEs 
must be addressed to Advanced Accelerator Applications pharmacovigilance department. 
The minimum information required for immediate reporting is the event description, the patient ID, 
the study medication concerned and the identifiable reporter (Investigator or designee). Even if not 
all the facts are known, an initial report should be made. The Investigator must provide follow-up 
information as soon as possible. If requested by the delegated Safety Officer designee, documents 
relevant to the diagnosis, treatment, and course of the event must be submitted (e.g. technical 


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investigation reports, histology findings, hospital discharge documents). All documents must be 
anonymized with respect to the patient’s personal identification data. 
When the Investigator determines that there is not more information likely to be available, a final 
report should be provided. The Sponsor or delegated CRO will assume responsibility for appropriate 
reporting of AEs to the regulatory authorities and the Independent Ethics Committee(s)/Institutional 
Review Board(s) (IEC/IRB) according to local laws and regulations. 
SAEs will be collected following the patient written consent to participate in the study. The collection 
of SAE information will continue to be reported by the Investigator for each patient until 30 days after 
the last study medication administration. 
Procedure in Case of Pregnancy 
Prior to clinical study enrolment, women of childbearing potential must be advised of the importance 
of avoiding pregnancy during clinical study participation and the potential risk factors for an 
unintentional pregnancy. The Investigator must report any pregnancy associated with investigational 
product exposure including conceptions occurring until 30 days after the last injection of radiotracer. 
The report should be carried out within 24 hours of pregnancy confirmation by sending a completed 
Pregnancy Reporting Form to the Safety Officer designee. 
Appropriate pregnancy follow-up procedures should be considered if indicated. The Investigator 
must report follow-ups within 24 hours of the receipt of any new information on the course of the 
pregnancy, including perinatal and neonatal outcome, by sending a completed Pregnancy Reporting 
Form to the Safety Officer designee (Appendix IV of study protocol). 
4.3.3.3.2 Standard laboratory assessments 
General laboratory analysis will be performed and blood samples will be collected at screening and 
at Day 30. 
Blood samples will be drawn and urine will be collected as mentioned in the study chart. A total 
volume of 50 mL, including blood samples for immunogenicity assessments, will be collected during 
the study for each patient. 


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Hematology 
Coagulation 
Blood chemistry 
Urinalysis 
 WBC with 
differential 
 RBC 
 Platelets 
 Hb 
 MCV 
 Hematocrit 
 PT 
 PTT 
 INR 
 BUN 
 Serum creatinine 
 Uric acid 
 Albumin 
 Total bilirubin 
 Direct bilirubin 
 AP 
 AST/ASAT 
 ALT/ALAT 
 Gamma-GT 
 Sodium 
 Potassium 
 Dipstick test1 
 Pregnancy test 
(at screening and 
before injection of 
study product) 
1 In case one of the assessments of the dipstick test is positive, a microscopic analysis of the urine must be performed. 
4.3.3.3.3 Immunogenicity assessments 
As rhAnnexin V-128 is an exogenous protein, development of antibodies against the protein must 
be assessed in order to evaluate the risk and consequences of such a development. 
Assays for anti-rhAnnexin V-128 IgG and IgM antibodies will be performed in serum samples by 
ELISA at screening visit. An additional sample is required at Day 30. 
For this purpose 10 mL blood samples will be collected at screening and Day 30. At each time-point, 
after centrifugation, serum will be divided into six aliquots and frozen (-80°C). Three out of six serum 
aliquots will be then shipped to the central laboratory at 
. 
Remaining samples will be shipped only if required for analysis and destroyed at study end if not 
required. Blood Samples Handling will be detailed in the Laboratory Manual provided by 
. 
 Withdrawal/discontinuation 
The withdrawal of a study participant is mandatory in the following cases: 
 
Pregnancy 
 
Protocol violation determined as critical 
 
Lost to follow-up 
 
Serious intercurrent illness or other safety reasons for what the Investigator considers it is in 
the best interest of the participant to withdraw from the study 
 
Screening failure 


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A “screening failure” is a patient who has signed the informed consent, but who does not meet all 
selection criteria following the screening evaluations. For patients not considered eligible after the 
screening period, the reason for not being eligible must be documented. No additional assessments 
are needed. Patient information collected at the Screening visit will be entered in the eCRF and will 
be used in the study analysis. 
Patients who will not have received the study product will be replaced. 
The patient is free to withdraw from the study for any reason and at any time without giving reason 
for doing so and without penalty or prejudice. It is also possible that the Sponsor or the regulatory 
authorities request termination of the study if there are concerns about conduct or safety. 
The primary reason for a patient’s withdrawal from the study should be determined as possible. The 
date and reason for discontinuation must be documented in the eCRF. 
 Prohibitions and restrictions 
The most important required restriction for study patients is pregnancy. Pregnancy tests will be 
performed for all patients (of child bearing potential) at baseline and prior to the radiotracer 
administration. 
Imaging is performed ambulatory. After imaging, patient may go back home or go back to work 
without particular precaution for him or his relatives. 
Any concomitant medication deemed necessary for the welfare of the subject during the study may 
be given at the discretion of the Investigator. However, it is the responsibility of the Investigator to 
ensure that details regarding the medication are recorded in full in the case report form, including 
any changes that have occurred during the study. 
 Schedule of assessments 
Patients who have signed the informed consent and are eligible to participate in the study will 
undergo the following assessments:  
 
At screening visit, eligible and consented patients who have clinical suspicion or confirmed 
diagnosis of SpA will undergo a physical examination, vital signs (systolic and diastolic blood 
pressure, heart rate), blood analysis, i.e. CBC with automated differential, general chemistry 


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panel (SMA-20) including CRP, PT/PTT, INR (international normalized ratio for PT values), 
assessment of anti-annexin V-128 antibodies, and urinalysis. In addition, disease activity 
score assessments (BASDAI, BASFI, BASMI and MASES) will also be performed. Screening 
laboratory assays, physical examination and vital signs will be performed 24 hours to 14 days 
before 99mTc-rhAnnexin V-128 imaging. Within 14 days of 99mTc-rhAnnexin V-128 scanning 
patients will undergo T1 and STIR without contrast Magnetic Resonance Imaging (MRI) of 
the sacro-iliac and lumbar spine joints. 
 
At Day 0 (the day of intravenous injection and imaging with 99mTc-rhAnnexin V-128), a 
dedicated lumbosacral spine and abdomen SPECT/CT starting 60 minutes after injection of 
tracer followed by a whole body planar scan and spot views on selected areas will be 
performed. The same SPECT/CT and whole body planar X4scans will be repeated at 2 hrs 
after injection of tracer except the spot views unless they suggest to be repeated. Vital signs 
assessment will also start 15 minutes before and for 2 hours after injection of radiotracer. 
 
At Day 1 (one day after the administration of 99mTc-rhAnnexin V-128), 15\20 patients will be 
contacted over the phone for assessment of possible adverse events (e.g. allergic reaction 
such as rash, edema). 5 patients will return for an optional whole body planar scan at 24hrs 
post injection as well as spot views, if deemed appropriate by the investigator. Safety 
information will be collected at this time for these 5 patients. 
 
 
 
At Day 30 ± 3 days, all patients will return to the clinic for a physical examination and a final 
blood sampling to rule out the development of anti-annexin V-128 antibodies and for the 
following blood analysis and urinalysis: CBC with automated differential, general chemistry 
panel (SMA-20) including CRP, PT/PTT, INR (international normalized ratio for PT values). 
 
Once the first 5 patients have been administered with 99mTc-rhAnnexin V-128 and have 
performed the imaging at Day 0, a DMC will review the images. The visual assessment of 
the scans in these first 5 patients may support the continuation or the termination of the 
Phase II study. In the first case, the enrollment of 15 additional patients will be required. 


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The following table summarizes all the procedures and evaluations to be conducted during the study: 
Study Procedures 
Screening 
(within 14 days 
prior to Day 0) 
Visit 1 
(Day 0) 
Visit 2 
(Day 1 
24 hours1) 
Visit 3 
(Day 30) 
Written informed 
consent 
X 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
Medical history 
X 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
Disease assessment 
(BASDAI, BASFI, 
BASMI, MASES) 
X 
 
 
 
Physical examination 
X 
 
 
X 
Vital signs (BP, HR) 
X 
X 
 
 
Lab analysis 
(hematology, 
PT/PTT/INR, 
biochemistry, urine) 
X 
 
 
X 
Immunogenicity by 
ELISA2 
X 
 
 
X 
Pregnancy test 
X 
X 
 
 
MRI (within 14 days of 
rh-Annexin V-128 
scanning) 
X3 
 
 
 
99mTc-rhAnnexin V-128 
administration and scan 
(SPECT/CT and 
planar imaging) 
 
X4 
X4 
 
Whole Body Planar 
Imaging + spots 
 
 
X4 
 
High resolution spot 
images of hands, feet, 
any symptomatic joint 
group 
 
X4 
X4 
 
Adverse Events 
X 
X 
X 
X 


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1 24 hours after injection of 99mTc-rhAnnexin V-128, each patient will be called over the phone to assess if they experienced 
any adverse events such as allergic reactions (edema, rash). 
2 Anti-rhAnnexin V-128 IgG and IgM antibodies will be quantified in serum samples by ELISA. For this purpose 10 mL blood 
samples will be collected at screening and Day 30 post administration of test agent. Serum will be prepared, divided into 
six aliquots and frozen (-80°C). Three out of six serum aliquots will then be shipped to the central laboratory at 
 
. The 3 remaining aliquots will be sent to 
 with an additional shipment. 
3 A whole lumbar spine MRI must be performed prior to the enrolment date, or within 14 days of 99mTc-rhAnnexin V-128 
scanning prior to changing NSAID therapy or non-biologic DMARD or starting non-biologic DMARD for the first 5 patients 
and prior to changing NSAID therapy or non-biologic DMARD or starting non-biologic DMARD or biologic DMARD for the 
next 15 patients. 
4 First five patients after which the process will be re-evaluated: 
 
All patients will have whole body planar imaging at 60 minutes post injection. 
 
At two hours post injection do a whole body scan and SPECT/CT with onboard isotope with no spot views 
unless initial views suggest otherwise. The whole body scan adds 15-20 minutes; each spot adds 5 minutes. 
 
The SPECT/CT and spot imaging will be done for first 5 patients after which the protocol will be re-adjusted. 
 An optional whole body planar scan will be done at 24hrs post injection for 5 patients as well as 
spot views, if deemed appropriate by the investigator.  
 Planned sample size 
The number of patients in this study is not based on statistical power considerations. The planned 
sample includes 20 patients which is the number believed to provide sufficient data to assess the 
potential of 99mTc-rhAnnexin V-128 to image disease severity in SpA patients and provide sufficient 
preliminary data to plan larger pivotal trials focusing on the confirmation of the benefit for this new 
imaging procedure for the early diagnosis of SpA. 
At first, five patients will be recruited and analyzed as a Proof of Concept (PoC). In the PoC part of 
the study, medical images will be reviewed by the DMC in charge of assessing the imaging potential 
of 99mTc-rhAnnexin V-128 in terms of image quality, uptake and medical relevance. After reaching a 
consensus, the committee will decide if the clinical investigation should continue with the remaining 
15 patients. The planned number of patients in the PoC study is not based on statistical 
considerations. However, this number of patients should provide sufficient relevant information for 
the evaluation of the images in terms of quality and medical relevance. 


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5 SUBJECT POPULATIONS (ANALYSIS SETS) 
5.1 
Efficacy 
 Full analysis set (FAS) 
In accordance with the Intention To Treat (ITT) principle the FAS population includes all subjects 
who received the study drug and completed the 99mTc-rhAnnexin V-128 imaging procedure. 
 Per Protocol population (PP) 
All subjects in the FAS population for whom no major protocol violations/deviations occurred. 
Deviations from the protocol including violations of the Inclusion/Exclusion criteria will be assessed 
as minor/major before the data base locking. 
5.2 
Safety set 
The safety population is made up of all subjects who received the administration of 99mTc-rhAnnexin 
V-128. 
5.3 
Primary population 
The primary, secondary 
 efficacy analysis will be based on the FAS population. 
The primary efficacy analysis on the Primary endpoint of Phase II will be also performed on the PP 
population as confirmatory analysis. The analysis on the PP population will be performed if the size 
difference between this population and the FAS population exceeds 2 patients. 
The assessment of safety and tolerability will be based on the Safety population. 


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6 STATISTICAL METHODS 
6.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with the principles of ICH E9 guideline and 
the guideline on clinical evaluation of diagnostic agents and they will be based on data from the 
study site, unless otherwise stated. 
The statistical analysis will be performed by 
. 
 Efficacy endpoint 
Due to the premature stopping of the study, the efficacy endpoints will not be addressed. All available 
efficacy data will be provided in subjects data listings and described in a descriptive manner in an 
abbreviated CSR.  
 Primary endpoint of PoC 
The PoC phase will assess the imaging potential of 99mTc-rhAnnexin V-128 in terms of imaging 
quality, disease-lesion radiotracer uptake and medical relevance to enable the decision-making to 
terminate or to continue the clinical investigation completing the enrollment with the remaining 
patients. 
Parameters used by DMC to assess primary endpoint of PoC will be described in the DMC charter. 
 Primary endpoint of Phase II 
The primary endpoint of Phase II is to determine the magnitude and dynamic range of 
99mTc-rhAnnexin V-128 uptake in disease affected sacro-iliac or lumbar spine joints, in patients with 
clinical suspicion or confirmed diagnosis of Spondyloarthritis (SpA). SPECT/CT scans will be 
interpreted and graded by the P.I. and two independent experienced nuclear medicine physicians 
blinded from clinical data and other imagings modality results. Briefly, 99mTc-rhAnnexin V-128 uptake 
compared with background (e.g. physiological liver uptake) should be assessed for each affected 
area by nuclear medicine physicians using a 4-grade scoring system (0 = none, 1 = mild or present 


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but lower than background uptake; 2, moderate or equal to background uptake; 3, intense or greater 
than background uptake). The assessed uptake will be the score with more adjudications (two or 
more). In case of discrepancies among the three different readers, an adjudication process based 
on consensus should be put in place in order to obtain one final outcome for each area.  
Imaging procedure result, SUV and uptake intensity grades for SPECT/CT of sacro-iliac and lumbar 
spine joints will be summarized in descriptive tables; furthermore, concordance between the raters 
will be assessed with Kendall’s W. For both SPECT/CT, two separate analysis will be conducted: 
one based on values measured 60 min after IP injection and the other on values measured 120 min 
after IP injection. 
 Secondary endpoints 
The secondary endpoints of Phase II and the related statistical analyses are: 
a) Endpoint: to determine the clinical utility of 99mTc-rhAnnexin V-128 SPECT/CT imaging in the 
identification of chronic ostheoarthritic active sites of SpA compared with conventional 
imaging (MRI), in patients with disease affected sacro-iliac or lumbar spine joints. 
Statistical analysis: for quantifying the radioactivity uptake after injection of 99mTc-rhAnnexin 
V-128, ROIs will be drawn manually on the earliest images, and the shapes and sizes (i.e. 
number of pixels) will be kept constant over all subsequent images. Correction for 
background counts will be performed using an appropriate background region by subtracting 
the mean counts per pixel in the background region from the mean counts per pixel in each 
ROI to yield net counts. For each ROI, the geometric mean of net counts, corrected for 
physical decay, of total anterior and posterior counts will be calculated. In order to compare 
SPECT/CT scans and MRI scans, diagnostic performances will be evaluated in terms of 
sensitivity (i.e. true positive rate), specificity (i.e. true negative rate), positive predictive value 
(i.e. proportion of positive values) and negative predictive value (i.e. proportion of negative 
values). This analysis will be performed for both region, sacro-iliac and lumbar spine joints 
To do this, physical examinations will be necessary to define sites of pain in patients with 
clinical suspicion or confirmed diagnosis of SpA. When sites of pain will match with 
abnormalities on diagnostic images, this will be regard as true positive. Furthermore, for all 
the performed statistics, a two sided 95% C.I. will be computed 


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b) Endpoint: to assess the presence of antibodies against rhAnnexin V-128 at baseline and 
post-treatment. 
Statistical analysis: The determination of antibodies against rhAnnexin V-128 at baseline and 
post-treatment will be described as present or absent; these data, related to immunogenicity, 
will be described in contingency tables reporting frequencies and percentages.  
c) Endpoint: to determine the localization pattern and magnitude of focal uptake of 
99mTc-rhAnnexin V-128 within the abdomen in patients with clinical suspicion or confirmed 
diagnosis of Spondyloarthritis (SpA). 
Statistical analysis: Imaging procedure result, SUV and uptake intensity grades for 
SPECT/CT of abdomen and of spot views, and imaging procedure result and uptake intensity 
grades for whole body planar imaging will be summarized in descriptive tables; furthermore, 
concordance between the raters will be assessed with Kendall’s W. For each imaging 
assessment, two separate analysis will be conducted: one based on values measured 60 
min after IP injection and the other on values measured 120 min after IP injection 


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 Safety endpoint(s) 
Safety and tolerability will be primarily evaluated by the incidence of adverse events, clinical 
laboratory values (hematology, blood chemistry and urinalysis), vital signs (blood pressure and heart 
rate) and physical examination findings. 
All safety data will be included in the data listings and summary tables will be based on the safety 
population. The statistical analysis of safety data will be mainly descriptive in nature. 
Categorical data will be presented as frequencies, percentages and 95% confidence interval if 
relevant. For continuous data, N, missing, mean, standard deviation, median, quartiles, minimum, 
maximum and if relevant 95% confidence interval will be presented. Graphs such as box plots, 
circular diagrams or histograms can also be computed if relevant. Considering the small sample size 
planned in this study, non-parametric approach will be favored. 
 Adverse events 
All original AE/SAE terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA v.19.0). 
Adverse events will be listed on an individual basis, including relationship and severity, LLT, LLT 
code and verbatim term. Treatment Emergent Adverse Events (TEAEs) and Adverse Drug Reactions 
will be summarized by System Organ Class (SOC) and Preferred Term (PT). Patients with more 
than one adverse event within a particular SOC and PT will be counted only once for that SOC and 
PT reporting the highest level in severity. The incidence of TEAEs and ADRs will also be summarized 
by severity and relationship to the investigational imaging product. In the case several patients have 
experienced more than one adverse event, detailed descriptive statistics may also be presented on 
patients with 2, 3 or more than 3 AEs, if relevant. 
Adverse drug reactions (ADRs, i.e. all AEs at least possibly related to the study drug according to 
the investigator) will be summarised in a similar way to TEAEs. Listings of serious adverse events 
(SAE), adverse events leading to withdrawal and listings of deaths will also be presented. 
Treatment Emergent Adverse Events and Adverse Drug Reactions will be defined as below: 


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 
Treatment Emergent Adverse Events: Events that emerge after the 99mTc-rhAnnexin V-128 
injection and up to 30 days after the injection that were absent before it or worsen relative to 
the pre-treatment state. 
 
Adverse Drug Reactions: Treatment emergent adverse events possibly or probably related 
to treatment. 
 Clinical laboratory values 
Hematology, blood chemistry, urinalysis and immunogenicity values are recorded at baseline for 
screening and 30 days post IP administration. Descriptive statistics will be tabulated by measuring 
time for raw data and changes from baseline; boxplots will be reported, if appropriate. Data listing 
will be ordered by subject and measuring time. A listing of all the abnormal values (clinically and 
non-clinically relevant) will be reported. 
 Vital signs and physical examination 
Vital signs data are recorded once at screening visit and twice at imaging visit (Day 0), before the 
injection of 99mTc-rhAnnexin V-128 and after the last imaging procedure (within 2 hrs after 
99mTc-rhAnnexin V-128 injection). Physical examination data are recorded at screening visit and at 
Day 30. Descriptive statistics will be tabulated by measuring time for raw data and changes from 
baseline (screening visit); boxplots will be reported, if appropriate. For day 0, post imaging 
procedures values will also be compared with pre injection counterparts (i.e. assessed on the same 
day). If appropriate, comparisons between different measuring times will be performed according to 
appropriate non-parametric paired inferential statistics. Data listing will be ordered by subject and 
measuring time. 
 
 Multiplicity 
Due to the exploratory nature of the study no adjustements will be made for multiplicity. 


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 Significance testing and estimation 
All statistical tests will be two-sided at the 5% level of significance. 
 Missing data and outliers 
 Missing data 
As stated in the protocol, missing data will not be replaced. 
 Missing or incomplete dates 
Incomplete dates due to missing day will be recorded as full dates replacing the missing day with 
the first day of month (01). Incomplete dates due to missing day and month will be recorded as full 
dates replacing the missing day and month with the first day of month and first month of the year 
(01/January). The trial database will record the information about incomplete dates due to missing 
day or due to missing day and month. 
Only the incomplete dates related to date of birth, SpA diagnosis date, medical history (date of 
diagnosis and end date), concomitant medications (start and end date) and AEs (start and end date) 
will be replaced according to the above rule. 
Calculation, sorting or assignation based on dates, in case of incomplete dates, will be performed 
using the related full dates defined by the above rule. 
In all listings, missing and incomplete dates will be reported as full dates. In all listings will be also 
reported the information about incomplete dates according to the following coding: missing value = 
full date, Day = missing day, Day&Month = missing day and month. 
 Outliers 
For categorical or score data, like adverse events, physical exam’s findings and disease assessment 
parameters, outliers are not expected. 


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Demographic, vital signs, and clinical laboratory (haematology, blood chemistry and urinalysis) 
parameters will be checked for outliers according to data plausibility, normal ranges and the range 
between ± 2 S.D. 
For each identified outlier, 
 will inform the Sponsor in order to assess any errors. If data cannot 
be verified or if relevant, the descriptive statistics of the related parameters will be reported with and 
without the outliers. If appropriate, outliers can also be specifically identified in the boxplots. 
 Subject disposition 
A listing of dates of assessments (relative day) and their study exposure will be presented by subject. 
A summary table and a flow chart will be presented for each subject population presenting the 
number of subjects at each assessment procedure and identifying the number of subjects who 
withdrew over time. 
 Withdrawals 
Discontinued subjects will be listed and a summary table of the number and percentage of subjects 
who withdrew from the study and the reasons for withdrawal will be presented for all screened 
subjects. 
 Demographic and baseline characteristics 
All demographic and baseline characteristics will be listed by subject. Summary statistics will be 
provided for demographic and baseline characteristics for the FAS and Safety population. 
 Disease assessments 
Descriptive statistics will be reported for all the parameters related to disease assessments (scores 
of BASDAI, BASFI, BASMI and MASES, MRI results, presence of clinical pain, number of 
inflammatory joints and category of patient treatment) for FAS and Safety population. 


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 Medical and surgical history 
Medical and surgical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Medical and surgical history will be listed on an individual basis, including SOC, preferred term and 
verbatim. A frequency table of the number and percentage of subjects will be provided for all medical 
and surgical history by primary SOC and preferred term for FAS and Safety population. 
 Subject compliance 
A listing will be presented for imaging product administration (dose, quality, date) by subject. 
Deviations from observed and scheduled times will be presented. Summary tables and, eventually, 
boxplots will be presented for all the continuous variables. 
A listing will be presented for important concomitant medication for any subject who has received 
medication which could have an impact on safety assesments. 
All the Protocol deviations will be also listed by subject. 
 Prior and concomitant therapies  
Concomitant therapies will be coded using ATC Drug Dictionary. 
Listings will be presented for active substance, ATC code and verbatim text. The listings will be 
sorted by subject, chronological start date, active substance, ATC code and verbatim text. 
A frequency table of the number and percentage of subjects will be provided for concomitant 
therapies by Anatomical Main Group and Chemical substance for Safety population. Two different 
tables will report Prior Therapies (the drug therapies taken prior to the 99mTc-rhAnnexin V-128 
injection) and Concomitant Therapies (the drug therapies that started after the 99mTc-rhAnnexin 
V-128 injection or that were ongoing at the start of  99mTc-rhAnnexin V-128 injection). 
 Derived data 
The derived data are variables which are calculated from the raw data in the eCRF and could not be 
included in the database (e.g.: Age, BMI, days from 99mTc-rhAnnexin V-128 injection). The formula 
used for derived data and the strategy for missing data are provided in Section 11.4. 


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 Visit windows 
The screening visit can occur anytime within 2 weeks before the injection day. Visit 1 is the day of 
99mTc-rhAnnexin V-128 administration (Day 0). The first follow-up visit (phone call) should occur 
within 24 hours after the injection. The second follow-up visit should occur 30 days after the injection 
with a window of 3 days, i.e. the visit has to be performed between the 27th and the 33rd day from 
the 99mTc-rhAnnexin V-128 administration. 
 Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the number of decimal 
places used does not imply undue precision). Raw data will be presented to the number of decimal 
places collected, and derived data will be presented to an appropriate number of decimal places. 
The appropriate number of decimal places will be determined by general practice, mathematical 
rationale or scientific rationale (e.g. age should be presented in whole numbers). 
For summary statistics, the following will be presented: number of non-missing values (n), number 
of missing values, arithmetic mean, standard deviation, median, the IQR (first quartile, third quartile), 
the range (minimum, maximum) and, only if appropriate, 95% 2-sided confidence interval. 
Mean, standard deviation, first quartile, median, third quartile and confidence interval values will be 
rounded to one more decimal place than the raw data whereas minimum and maximum will be 
reported with the same precision as the raw data. 
Percentages will be reported to one decimal place. Percentages will be calculated using a 
denominator of all subjects in a specified population. The denominator will be specified in the title of 
the tables for clarification if necessary. 
p-values will be reported to four decimal places (e.g.: p=0.0037), after rounding; p-values which are 
less than 0.0001 will be presented as ‘<0.0001’. 
All text fields must be left justified and numeric or numeric with some text specification (e.g. not done, 
unknown, <4.5, …) must be decimal justified. Dates will be presented in the format [dd/mm/yyyy] 
and times in the format [hh:mm] using 24-hour clock scale. 


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 Pooling of Centres 
Not applicable. 
 Interim analysis 
No formal interim analysis will be done; however the DMC will review the images of the first 5 
participants of the study to determine the presence of inadequate technical performance to assess 
disease-lesion radiotracer uptake. 
 Role of independent data monitoring committee (DMC) / interim data review 
committee 
The DMC consists of representatives of investigators and Sponsor representatives and could include 
external person such as independent experts, if judged appropriate by the Sponsor. The main 
function of the committee will be to review the images of the first 5 patients and determine if there is 
a premature high evidence of the presence of inadequate technical performance in this patients 
group. The DMC will also determine if there is a high evidence of an excess of adverse events. 
The DMC will promptly give recommendations to continue or terminate the study. The DMC report 
will be edited by the Sponsor and sent to the ethics committee as well as competent authorities. 
Preliminary results can be used by the Sponsor for publication purpose, before the end of the main 
trial. 
 Covariates and analysis of subgroups 
Not applicable. 
 Sensitivity analysis 
Not applicable. 


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7 COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF 
PROGRAMS 
7.1 
Hardware 
The statistical analysis will be performed using Dell personal computer with Windows 7 professional 
(64 bit) as operating system. 
7.2 
Software 
All tables, listings and figures will be produced and statistical analysis performed using SAS version 
9.4. All outputs will be in word format. 
7.3 
Validation programs 
An Independent Statistician is responsible for reviewing each project program and output associated 
with the deliverable product. Program logs are reviewed for logical, syntax and fatal errors. The 
review in SAS includes, but is not limited to, all ERRORS, WARNINGS, NOTES, and variables 
check. Program logs are also reviewed for accurate and consistent variable and observation counts 
following each procedure and data step. 
The Independent Statistician is also responsible for checking and reviewing the work produced using 
whatever method he/she feels is appropriate (e.g. SAS commands review, hand calculation, etc.) to 
reassure of the quality of the output. 
Outputs are reviewed for typographical errors, misspellings and nonsensical values or results and to 
check the consistency with the reporting and analysis plan. Outputs are cross-checked against each 
other for accuracy and consistency. For statistical tables, listings, and figures, this procedure 
includes comparison of subject group numbers, counts of subjects at each observation point, and 
consistency of results for variables between outputs. 
Findings of the quality control reviews are communicated to the party responsible for making 
necessary changes. The programs will be retested after modifications. 


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After final review, and when no further changes are required to produce the deliverable, the 
Independent Statistician needs to complete and sign the SAS Outputs, to indicate that he has 
successfully performed all of his responsibilities. 


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8 CHANGES FROM PROTOCOL 
As per sponsor decision, it has been decided to close the study after the first 5 patients were enrolled. 
For this reason and due to the small number of patients enrolled, only subjects data listings will be 
produced for this study and the results described in a short close-out CSR. 
 


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9 REFERENCES 
Not applicable. 


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10 DATA PRESENTATION 
Data listings are presented for all screened subjects. 
Footnotes should be used to clarify ambiguities (e.g.: the denominator used to calculate a 
percentage or notes for the programmer). If the number of footnotes is high, they could be presented 
only in the last page, with on each page the following footnote “See last page for listing notes”. The 
order of the footnotes for key symbols (*, ~) will be in the order that they appear in the listing. 
10.1 
Listings index 
16.2 SUBJECT DATA LISTINGS 
16.2.1 Discontinued Subjects 
Listing 
16.2.1.1: 
Subject Disposition – All Subjects 
Listing 
16.2.1.2: 
Subject Disposition – Study Withdrawals 
Listing 
16.2.1.3: 
Inclusion Criteria 
Listing 
16.2.1.4: 
Exclusion Criteria 
Listing 
16.2.1.5: 
Screening Failures 
16.2.2 Protocol deviations 
Listing 
16.2.2: 
Protocol Deviations and Reasons for Exclusion from the Study 
Populations 
16.2.3 Subjects Excluded from the efficacy analysis 
Listing 
16.2.3: 
Subjects Excluded from the Efficacy Analysis 
16.2.4 Demographic data 
Listing 
16.2.4.1: 
Demographics 
Listing 
16.2.4.2: 
Disease Assessment 
Listing 
16.2.4.3: 
Significant Medical History and Associated Pathologies 
Listing 
16.2.4.4: 
Concomitant Medications 


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16.2.5 Compliance and/or drug concentration data 
Listing 
16.2.5.1: 
Study Drug Administration and Extent of Subject Exposure 
16.2.6 Individual efficacy response data 
Listing 
16.2.6.1: 
Whole Body Planar Imaging – 60 min After IP Injection 
Listing 
16.2.6.2: 
Whole Body Planar Imaging – 120 min After IP Injection 
Listing 
16.2.6.3: 
Abdomen SPECT/CT Imaging – 60 min After IP Injection 
Listing 
16.2.6.4: 
Abdomen SPECT/CT Imaging – 120 min After IP Injection 
Listing 
16.2.6.5: 
Lumbosacral SPECT/CT Imaging – 60 min After IP Injection 
Listing 
16.2.6.6: 
Lumbosacral SPECT/CT Imaging – 120 min After IP Injection 
Listing 
16.2.6.7: 
Sacroiliac SPECT/CT Imaging – 60 min After IP Injection 
Listing 
16.2.6.8: 
Sacroiliac SPECT/CT Imaging – 120 min After IP Injection 
Listing 
16.2.6.9: 
Spot SPECT/CT Imagings – 60 min After IP Injection 
Listing 
16.2.6.10: 
Spot SPECT/CT Imagings – 120 min After IP Injection 
16.2.7 Adverse event listings (each subject) 
Listing 
16.2.7.1: 
All Adverse Events 
Listing 
16.2.7.2: 
Serious Adverse Events 
Listing 
16.2.7.3: 
Adverse Events Leading to Withdrawal 
Listing 
16.2.7.4: 
Deaths 
16.2.8 Listing of individual laboratory measurements by subject 
Listing 
16.2.8.1: 
Hematology 
Listing 
16.2.8.2: 
Blood Chemistry 
Listing 
16.2.8.3 
Urinalysis 
Listing 
16.2.8.4 
Immunogenicity 
16.2.9 Listing of other safety data  
Listing 
16.2.9.1: 
Pregnancy test 
Listing 
16.2.9.2: 
Physical Examination 
Listing 
16.2.9.3: 
Vital Signs – Before IP Administration 


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Listing 
16.2.9.4: 
Vital Signs – After Last Imaging Procedure 
10.2 
Listing templates 
Listing templates are provided in Appendix 11.1. The listings will be presented in landscape, in a 
fixed font (Arial) with a minimum size as 8. 
The page number of each listing shell (n of N) represent n=page number of the listing and N=total 
number of pages for that specific listing. 
Each listing must be presented in an independent, separate Word file for each ICH heading (e.g. 
Listings 16.2.9.X combined in one file). 
10.3 
Tables index 
14. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT 
10.4 
Table templates 
Table templates are provided for each unique table in Appendix 11.2. The tables will be presented 
in landscape, in a fixed font (arial) with a minimum size as 8. 
All tables, in table number order, must be presented in a single Word file. 
10.5 
Figure templates 
Figure templates are provided for each unique figure in Appendix 11.3. The figures will be presented 
in landscape, in a fixed font (arial) with a minimum size as 8. 
10.6 
Statistical Appendix 
A Statistical Appendix for inclusion in the study report will be provided. All the methods used in 
checking the assumptions of the analyses and conclusions should be included and explained. 


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Transformation of the data or other methods used for the statistical analysis other than the ones 
detailed in the SAP will be described and the change will be justified. All the SAS output will be 
included without reworking the data (raw output). 
This output should contain the study number, the date, the number of pages printed by SAS and the 
table number to which it refers. Any other relevant information (e.g. statistical references…) will be 
added in the Statistical Appendix. 


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11 APPENDICES 
11.1 
Standard listings 
All listings must contain examples of possible data and be presented in fixed font (arial) with a 
minimum size as 8. 
 


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Listing 16.2.1.1: 
Subject Disposition – All subjects 
 
Subject ID 
Screening date 
Informed consent date 
Visit 1 date 
Phone call 2 date 
Visit 3 date 
Premature study 
discontinuation date 
FAS 
PP 
Safety 
PAT_PATNUMBER 
PAT_FIRSTVISITDATE 
PAT_INFCONS_DATE 
PATV_VISITDATE 
PATV_VISITDATE 
PATV_VISITDATE 
SD_DATE 
[Derived 
Data] 
[Derived 
Data] 
[Derived 
Data] 
03-US-001 
11/03/2011 
11/03/2011 
11/04/2011 
12/04/2011 
11/05/2011 
 
Yes 
Yes 
Yes 
03-US-002 
09/04/2011 
09/04/2011 
09/04/2011 
10/04/2011 
10/05/2011 
 
Yes 
Yes 
Yes 
03-US-003 
10/07/2011 
10/07/2011 
15/07/2011 
16/07/2011 
NA 
10/08/2011 
Yes 
No 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_PATIENTVIS, W_SD. 
Note: NA = Not Available for patient early withdrawal 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Listing 16.2.1.2: 
Subject Disposition – Study Withdrawals 
 
Subject ID 
Screening date 
Informed consent date 
Premature study 
discontinuation date 
Reason for 
withdrawal 
Explanation 
Notes 
FAS 
PP 
Safety 
PAT_PATNUMBER 
PAT_FIRSTVISITDATE 
PAT_INFCONS_DATE 
SD_DATE 
SD_OUTCOME 
SD_OUTCOME_SP 
SD_NOTES 
[Derived 
Data] 
[Derived 
Data] 
[Derived 
Data] 
03-US-001 
11/03/2011 
11/03/2011 
10/05/2012 
XXXXXX 
XXXXXX 
XXXXXX 
Yes 
No 
Yes 
03-US-002 
09/04/2011 
09/04/2011 
10/05/2012 
XXXXXX 
XXXXXX 
XXXXXX 
Yes 
No 
Yes 
03-US-003 
10/07/2011 
10/07/2011 
10/05/2012 
XXXXXX 
XXXXXX 
XXXXXX 
Yes 
No 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_PATIENTVIS, W_SD. 
Note: NA = Not Available for patient early withdrawal 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Listing 16.2.1.3: 
Inclusion Criteria 
 
 
 
 
 
Inclusion criteria 
Subject ID 
Sex 
Age 
Screening date 
First 
(PoC phase) 
First 
(Phase II study) 
Second 
Third 
PAT_PATNUMBER 
PAT_GENDER 
PAT_AGEYEAR 
PAT_FIRSTVISITDATE 
IC_1A 
IC_1B 
IC_2 
IC_3 
03-US-001 
Male 
54 
11/03/2011 
Yes 
Yes 
No 
Yes 
03-US-002 
Female 
68 
09/04/2011 
Yes 
Yes 
Yes 
Yes 
03-US-003 
Female 
59 
10/07/2011 
No 
Yes 
Yes 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_PATIENTVIS, W_IEC. 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Listing 16.2.1.4: 
Exclusion Criteria 
 
 
 
 
 
Exclusion criteria 
Subject ID 
Sex 
Age 
Screening date 
First 
Second 
Third 
Fourth 
Fifth 
Sixth 
Seventh 
PAT_PATNUMBER 
PAT_GENDER 
PAT_AGEYEAR 
PAT_FIRSTVISITDATE 
EC_1 
EC_2 
EC_3 
EC_4 
EC_5 
EC_6 
EC_7 
03-US-001 
Male 
54 
11/03/2011 
Not applicable 
No 
No 
No 
No 
No 
No 
03-US-002 
Female 
68 
09/04/2011 
No 
Yes 
Yes 
No 
No 
No 
No 
03-US-003 
Female 
59 
10/07/2011 
No 
No 
No 
No 
No 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_PATIENTVIS, W_IEC. 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Listing 16.2.1.5: 
Screening Failures 
 
Subject ID 
Screening failure 
Reason for screen failure 
PAT_PATNUMBER 
[Derived Data] 
[Derived Data] 
03-US-001 
Yes 
XXXXX 
03-US-002 
No 
XXXXX 
03-US-003 
No 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_PATIENTVIS, W_IEC, W_SD. 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Listing 16.2.2: 
Protocol Deviations 
 
Subject ID 
Screening date 
Deviation description 
PAT_PATNUMBER 
PAT_FIRSTVISITDATE 
[Derived Data] 
03-US-001 
11/03/2011 
XXXXXX 
03-US-002 
09/04/2011 
XXXXXX 
03-US-003 
10/07/2011 
XXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.3: 
Subjects Excluded from the Efficacy Analysis 
 
Subject ID 
Screening part 1 date 
FAS 
Reason for exclusion 
from the FAS 
PP set 
Reason for exclusion 
from the PP set 
PAT_PATNUMBER 
PAT_FIRSTVISITDATE 
[Derived Data] 
[Derived Data] 
[Derived Data] 
[Derived Data] 
03-US-001 
11/03/2011 
Yes 
 
Yes 
 
03-US-002 
09/04/2011 
No 
XXXXXXXXX 
No 
XXXXXX 
03-US-003 
10/07/2011 
Yes 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_PATIENTVIS, W_SD. 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Listing 16.2.4.1: 
Demographics 
 
Subject ID 
Screening date 
Sex 
Date of birth 
Partial date 
Age 
Ethnicity 
Specify other 
ethnicity 
PAT_PATNUMBER 
PAT_FIRSTVISITDATE 
PAT_GENDER 
PAT_BIRTH_DATE 
PAT_PARTIAL_BIRTH_DATE PAT_AGEYEAR 
PAT_ETHNIC 
PAT_ETHNIC_SP 
03-US-001 
11/03/2011 
Male 
12/03/1959 
Day 
54 
Other 
XXXXXXXX 
03-US-002 
09/04/2011 
Female 
10/09/1945 
Day & Month 
68 
Caucasian 
 
03-US-003 
10/07/2011 
Female 
24/02/1954 
 
59 
Asian 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ANNEXIN 03 
 
 
Listing 16.2.4.2/1: 
Disease Assessment 
 
Subject ID 
SpA diagnosis date 
Partial date 
Score of BASDAI 
Score of BASFI 
Score of BASMI 
Score of MASES 
PAT_PATNUMBER 
DA_DATE 
DA_PARTIAL_DATE 
DA_BASDAI 
DA_BASFI 
DA_BASMI 
DA_MASES 
03-US-001 
11/03/2011 
Day 
9.4 
5.4 
7.7 
12 
03-US-002 
09/04/2011 
Day & Month 
5.2 
6.7 
0.5 
10 
03-US-003 
10/07/2011 
 
8.3 
3.5 
9.9 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ANNEXIN 03 
 
 
Listing 16.2.4.2/2: 
Disease Assessment 
 
 
 
 
 
MRI results in 
Clinical pain in 
 
Subject ID 
Was a MRI 
performed? 
MRI date 
Number of 
inflammatory joints 
lumbar spine 
sacroiliac joints 
lumbar spine 
sacroiliac joints 
Category of 
patient treatment 
PAT_PATNUMBER 
DA_MRI_YN 
DA_MRI_DATE 
DA_MRI_NUM 
DA_MRI_RES_LUM 
DA_MRI_RES_SAC 
DA_CLIN_PAIN_LU
M 
DA_CLIN_PAIN_SA
C 
DA_PAT_TRT 
03-US-001 
Yes 
11/02/2011 
2 
Positive 
Negative 
No 
Yes 
Start of non-biologic 
DMARD 
03-US-002 
Yes 
01/04/2011 
3 
Negative 
Positive 
Yes 
No 
Start of biologic 
DMARD 
03-US-003 
No 
NA 
NA 
NA 
NA 
No 
No 
Change in NSAID 
therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ANNEXIN 03 
 
 
Listing 16.2.4.3: 
Significant Medical History and Associated Pathologies 
 
Subject ID 
Medical condition 
SOC 
PT 
Date of 
diagnosis 
Partial date 
Ongoing? 
Currently 
treated? 
Resolution date 
Partial date 
PAT_PATNUM
BER 
MH_MEDCOND 
MEDDRA_SOC 
MEDDRA_PT 
MH_DIAGN_DA
TE 
MH_PARTIAL_S
TART_DATE 
MH_ONGOING_
YN 
MH_TREATED_
YN 
MH_END_DATE 
MH_PARTIAL_E
ND_DATE 
03-US-001 
XXXXXXXX 
XXXXXX 
XXXXXX 
15/08/1990 
Day 
No 
 
14/04/1994 
Day 
03-US-002 
XXXXXXXX 
XXXXXX 
XXXXXX 
31/12/2007 
Day&Month 
No 
 
15/06/2008 
Day&Month 
03-US-003 
XXXXXXXX 
XXXXXX 
XXXXXX 
05/05/2005 
 
Yes 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ANNEXIN 03 
 
 
Listing 16.2.4.4/1: 
Prior and Concomitant Medications 
 
Subject ID 
Medication 
trade name 
ATC description 
Start date (day) 
Partial date 
Ongoing? 
End date 
Partial date 
PAT_PATNUMBE
R 
CM_NAME 
ATC_DESCR 
CM_START_DATE CM_PARTIAL_STA
RT_DATE 
CM_ONGOING_Y
N 
CM_END_DATE 
CM_PARTIAL_EN
D_DATE 
03-US-001 
XXXXXXXX 
XXXXXX 
15/08/1990 (-1) 
Day 
No 
14/04/1994 
Day 
03-US-002 
XXXXXXXX 
XXXXXX 
31/12/2007 (2) 
Day&Month 
No 
15/06/2008 
Day&Month 
03-US-003 
XXXXXXXX 
XXXXXX 
05/05/2005 (X) 
 
Yes 
Resolution date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.4.4/2: 
Prior and Concomitant Medications 
 
Subject ID 
Medication 
trade name 
Total daily dose 
Unit 
Specify other unit 
Frequency of 
administration 
Specify other 
frequency 
Route of 
administration 
Specify other route 
PAT_PATNUMBE
R 
CM_NAME 
CM_DOSE 
CM_DOSEU 
CM_DOSEU_SP 
CM_FREQ 
CM_FREQ_SP 
CM_ROUTE 
CM_ROUTE_SP 
03-US-001 
XXXXXXXX 
3 
G 
 
BID 
 
Otherl 
XXXXXX 
03-US-002 
XXXXXXXX 
3 
Other 
XXXXXX 
TID 
 
Intramuscolar 
 
03-US-003 
XXXXXXXX 
12 
Mg 
 
Other 
XXXXXX 
Subcutaneous 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ANNEXIN 03 
 
 
Listing 16.2.5.1/1: 
Study Drug Administration and Extent of Subject Exposure 
 
Subject ID 
Has the injection 
been performed? 
Reason for not 
performing the 
injection 
Injection date 
Injection time 
Batch of kit 
Batch of 
99mTc generator 
PAT_PATNUMBER 
ANN_YN 
ANN_YN_SP 
ANN_DATE 
ANN_TIME 
ANN_KIT 
ANN_GEN 
03-US-001 
Yes 
 
11/03/2011 
10:50 
09101-110631 
09101-110631 
03-US-002 
Yes 
 
03/03/2011 
10:00 
09101-110981 
09101-110981 
03-US-003 
No 
XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.5.1/2: 
Study Drug Administration and Extent of Subject Exposure 
 
Subject ID 
Has the injection 
been performed? 
Reason for not 
performing the 
injection 
Radiochemical purity 
Pre injection total 
dose in the syringe 
Post injection residual 
dose in the syringe 
Actual dose injected 
Volume of solution 
PAT_PATNUMBER 
ANN_YN 
ANN_YN_SP 
ANN_TEST1 
ANN_TEST2_PRE 
ANN_TEST2_POST 
ANN_TEST2_EFF 
ANN_TEST2_VOL 
03-US-001 
Yes 
 
98.7% 
123 
123 
123 
123 
03-US-002 
Yes 
 
99.1% 
456 
456 
456 
456 
03-US-003 
No 
XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ANNEXIN 03 
 
 
Listing 16.2.6.1: 
Imaging Results 
 
 
 
 
 
 
 
 
 
 
Grade of uptake 
Subject ID 
Region 
Time point 
Has the imaging 
been completed? 
Reason for not 
performing the 
imaging 
Date 
Time 
Has the image 
been reviewed? 
Result 
PI 
Reviewer 1 
Reviewer 2 
03-US-001 
Whole Body 
Planar 
60 min 
Yes 
 
11/03/2011 
10:50 
Yes 
Positive 
0 
0 
1 
 
 
120 min 
Yes 
 
11/03/2011 
11:50 
Yes 
Positive 
0 
0 
1 
 
Spot SPECT/CT: 
XXXXX 
60 min 
Yes 
 
11/03/2011 
10:50 
Yes 
Positive 
0 
0 
1 
 
 
120 min 
Yes 
 
11/03/2011 
11:50 
Yes 
Positive 
0 
0 
1 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
03-US-002 
 
 
Yes 
 
03/03/2011 
10:00 
Yes 
 
2 
3 
2 
03-US-003 
 
 
No 
XXXXXXX 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.7.1/1: All Adverse Events 
Subject ID 
Event ID 
Event description 
SOC 
PT 
LLT 
Day of onset§ (day) 
Ongoing? 
Duration (days) 
TEAE^ 
PAT_PATNUMBER 
ID_WEB 
AE_NAME 
MEDDRA_SOC 
MEDDRA_PT 
MEDDRA_LLT 
[Derived Data] 
AE_ONGOING_YN 
[Derived Data] 
[Derived 
Data] 
03-US-001 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
 
 
 
03-US-002 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
 
 
 
03-US-003 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
SOC: System Organ Class 
PT: Preferred Term 
LLT: Lowest Level Term 
Dictionary Name: MedDRA 
Version: XX.X 
§ Start day of onset in regarding to the annexin injection
^TEAE: Treatment Emegent Adverse Event 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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ANNEXIN 03 
 
 
Listing 16.2.7.1/2: All Adverse Events 
 
Subject ID 
Event ID 
Event description 
AE caused 
premature 
withdrawal? 
SAE 
SAE seriousness 
Maximal severity 
Causal relationship with 
medication or procedure 
Possible 
cause 
Specify other 
possible cause 
TEAE^ 
PAT_PATNUMBE
R 
ID_WEB 
AE_NAME 
AE_WITHD_YN 
AE_SAE_YN 
[Derived Data] 
AE_MAXSEV 
AE_REL 
AE_CAUSE 
AE_CAUSE_SP 
[Derived Data] 
03-US-001 
XXX 
XXXXXXXX 
Yes 
Yes 
XXXXXX / XXXXX / XX 
Grade 2 (Moderate) 
Possible 
Other 
XXXXXXXXXXX 
Yes 
03-US-002 
XXX 
XXXXXXXX 
No 
No 
XXXXXX / XXXXX / XX 
Grade 1 (Mild) 
Unlikely 
Pre-
existing/unde
rlying disease 
XXXXXXXXXXX 
Yes 
03-US-003 
XXX 
XXXXXXXX 
No 
No 
XXXXXX / XXXXX / XX 
Grade 3 (Severe) 
Unrelated 
Other 
treatment 
XXXXXXXXXXX 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
^TEAE: Treatment Emegent Adverse Event 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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ANNEXIN 03 
 
 
Listing 16.2.7.1/3: All Adverse Events 
 
Subject ID 
Event ID 
Event description 
Action taken 
Other action taken 
Other action taken, specify 
Outcome 
PAT_PATNUMBER 
ID_WEB 
AE_NAME 
AE_ACT 
[Derived Data] 
AE_ACT_OTH_SP 
AE_OUTCOME 
03-US-001 
XXX 
XXXXXXXX 
No action 
XXX/XXXXX/XXX 
 
Resolved 
03-US-002 
XXX 
XXXXXXXX 
Dose modification in next 
treatment 
XXX/XXXXX 
XXXXXX 
Worsened 
03-US-003 
XXX 
XXXXXXXX 
Unknown  
XXX 
 
Persisting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Statistical Analysis Plan 
ANNEXIN 03 
 
 
Listing 16.2.7.2/1: Serious Adverse Events 
 
Subject ID 
Event ID 
Event description 
SOC 
PT 
LLT 
Delay of onset§ (days) 
Ongoing? 
Duration (days) 
TEAE^ 
PAT_PATNUMBER 
ID_WEB 
AE_NAME 
MEDDRA_SOC 
MEDDRA_PT 
MEDDRA_LLT 
[Derived Data] 
AE_ONGOING_YN 
[Derived Data] 
[Derived 
Data] 
03-US-001 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
No 
≥2 
Yes 
03-US-002 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
No 
15 
Yes 
03-US-003 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
Yes 
≥30 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
SOC: System Organ Class 
PT: Preferred Term 
LLT: Lowest Level Term 
Dictionary Name: MedDRA 
Version: XX.X 
§Delay of onset is defined as days from Annexin injection 
^TEAE: Treatment Emegent Adverse Event 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Listing 16.2.7.2/2: Serious Adverse Events 
 
Subject ID 
Event ID 
Event description 
AE caused 
premature 
withdrawal? 
SAE 
SAE seriousness 
Maximal severity 
Causal relationship with 
medication or procedure 
Possible 
cause 
Specify other 
possible cause 
TEAE^ 
PAT_PATNUMBE
R 
ID_WEB 
AE_NAME 
AE_WITHD_YN 
AE_SAE_YN 
[Derived Data] 
AE_MAXSEV 
AE_REL 
AE_CAUSE 
AE_CAUSE_SP 
[Derived Data] 
03-US-001 
XXX 
XXXXXXXX 
Yes 
Yes 
XXXXXX / XXXXX / XX 
Grade 2 (Moderate) 
Possible 
Other 
XXXXXXXXXXX 
Yes 
03-US-002 
XXX 
XXXXXXXX 
No 
No 
XXXXXX / XXXXX / XX 
Grade 1 (Mild) 
Unlikely 
Pre-
existing/unde
rlying disease 
XXXXXXXXXXX 
Yes 
03-US-003 
XXX 
XXXXXXXX 
No 
No 
XXXXXX / XXXXX / XX 
Grade 3 (Severe) 
Unrelated 
Other 
treatment 
XXXXXXXXXXX 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
^TEAE: Treatment Emegent Adverse Event 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Listing 16.2.7.2/3: Serious Adverse Events 
 
Subject ID 
Event ID 
Event description 
Action taken 
Other action taken 
Other action taken, specify 
Outcome 
PAT_PATNUMBER 
ID_WEB 
AE_NAME 
AE_ACT 
[Derived Data] 
AE_ACT_OTH_SP 
AE_OUTCOME 
03-US-001 
XXX 
XXXXXXXX 
No action 
XXX/XXXXX/XXX 
 
Resolved 
03-US-002 
XXX 
XXXXXXXX 
Dose modification in next 
treatment 
XXX/XXXXX 
XXXXXX 
Worsened 
03-US-003 
XXX 
XXXXXXXX 
Unknown  
XXX 
 
Persisting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Statistical Analysis Plan 
ANNEXIN 03 
 
 
Listing 16.2.7.3/1: Adverse Events Leading to Withdrawal 
 
Subject ID 
Event ID 
Event description 
SOC 
PT 
LLT 
Delay of onset§ (days) 
Ongoing? 
Duration (days) 
TEAE^ 
PAT_PATNUMBER 
ID_WEB 
AE_NAME 
MEDDRA_SOC 
MEDDRA_PT 
MEDDRA_LLT 
[Derived Data] 
AE_ONGOING_YN 
[Derived Data] 
[Derived 
Data] 
03-US-001 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
No 
≥2 
Yes 
03-US-002 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
No 
15 
Yes 
03-US-003 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
Yes 
≥30 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
SOC: System Organ Class 
PT: Preferred Term 
LLT: Lowest Level Term 
Dictionary Name: MedDRA 
Version: XX.X 
§Delay of onset is defined as days from Annexin injection 
^TEAE: Treatment Emegent Adverse Event 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Statistical Analysis Plan 
ANNEXIN 03 
 
 
Listing 16.2.7.3/2: Adverse Events Leading to Withdrawal 
 
Subject ID 
Event ID 
Event description 
AE caused 
premature 
withdrawal? 
SAE 
SAE seriousness 
Maximal severity 
Causal relationship with 
medication or procedure 
Possible 
cause 
Specify other 
possible cause 
TEAE^ 
PAT_PATNUMBE
R 
ID_WEB 
AE_NAME 
AE_WITHD_YN 
AE_SAE_YN 
[Derived Data] 
AE_MAXSEV 
AE_REL 
AE_CAUSE 
AE_CAUSE_SP 
[Derived Data] 
03-US-001 
XXX 
XXXXXXXX 
Yes 
Yes 
XXXXXX / XXXXX / XX 
Grade 2 (Moderate) 
Possible 
Other 
XXXXXXXXXXX 
Yes 
03-US-002 
XXX 
XXXXXXXX 
No 
No 
XXXXXX / XXXXX / XX 
Grade 1 (Mild) 
Unlikely 
Pre-
existing/unde
rlying disease 
XXXXXXXXXXX 
Yes 
03-US-003 
XXX 
XXXXXXXX 
No 
No 
XXXXXX / XXXXX / XX 
Grade 3 (Severe) 
Unrelated 
Other 
treatment 
XXXXXXXXXXX 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
^TEAE: Treatment Emegent Adverse Event 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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ANNEXIN 03 
 
 
Listing 16.2.7.3/3: Adverse Events Leading to Withdrawal 
 
Subject ID 
Event ID 
Event description 
Action taken 
Other action taken 
Other action taken, specify 
Outcome 
PAT_PATNUMBER 
ID_WEB 
AE_NAME 
AE_ACT 
[Derived Data] 
AE_ACT_OTH_SP 
AE_OUTCOME 
03-US-001 
XXX 
XXXXXXXX 
No action 
XXX/XXXXX/XXX 
 
Resolved 
03-US-002 
XXX 
XXXXXXXX 
Dose modification in next 
treatment 
XXX/XXXXX 
XXXXXX 
Worsened 
03-US-003 
XXX 
XXXXXXXX 
Unknown  
XXX 
 
Persisting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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ANNEXIN 03 
 
 
Listing 16.2.7.4/1: Adverse Events Leading to Deaths 
 
Subject ID 
Event ID 
Event description 
SOC 
PT 
LLT 
Delay of onset§ (days) 
Ongoing? 
Duration (days) 
TEAE^ 
PAT_PATNUMBER 
ID_WEB 
AE_NAME 
MEDDRA_SOC 
MEDDRA_PT 
MEDDRA_LLT 
[Derived Data] 
AE_ONGOING_YN 
[Derived Data] 
[Derived 
Data] 
03-US-001 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
No 
≥2 
Yes 
03-US-002 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
No 
15 
Yes 
03-US-003 
XXX 
XXXXXXXX 
XXXXXX 
XXXXXXXX 
XXXXXX 
YY 
Yes 
≥30 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
SOC: System Organ Class 
PT: Preferred Term 
LLT: Lowest Level Term 
Dictionary Name: MedDRA 
Version: XX.X 
§Delay of onset is defined as days from Annexin injection 
^TEAE: Treatment Emegent Adverse Event 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Listing 16.2.7.4/2: Adverse Events Leading to Deaths 
Subject ID 
Event ID 
Event description 
AE caused 
premature 
withdrawal? 
SAE 
SAE seriousness 
Maximal severity 
Causal relationship with 
medication or procedure 
Possible 
cause 
Specify other 
possible cause 
TEAE^ 
PAT_PATNUMBE
R 
ID_WEB 
AE_NAME 
AE_WITHD_YN 
AE_SAE_YN 
[Derived Data] 
AE_MAXSEV 
AE_REL 
AE_CAUSE 
AE_CAUSE_SP 
[Derived Data] 
03-US-001 
XXX 
XXXXXXXX 
Yes 
Yes 
XXXXXX / XXXXX / XX 
Grade 2 (Moderate) 
Possible 
Other 
XXXXXXXXXXX 
Yes 
03-US-002 
XXX 
XXXXXXXX 
No 
No 
XXXXXX / XXXXX / XX 
Grade 1 (Mild) 
Unlikely 
Pre-
existing/unde
rlying disease 
XXXXXXXXXXX 
Yes 
03-US-003 
XXX 
XXXXXXXX 
No 
No 
XXXXXX / XXXXX / XX 
Grade 3 (Severe) 
Unrelated 
Other 
treatment 
XXXXXXXXXXX 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
^TEAE: Treatment Emegent Adverse Event 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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ANNEXIN 03 
 
 
Listing 16.2.7.4/3: Adverse Events Leading to Deaths 
 
Subject ID 
Event ID 
Event description 
Action taken 
Other action taken 
Other action taken, specify 
Outcome 
PAT_PATNUMBER 
ID_WEB 
AE_NAME 
AE_ACT 
[Derived Data] 
AE_ACT_OTH_SP 
AE_OUTCOME 
03-US-001 
XXX 
XXXXXXXX 
No action 
XXX/XXXXX/XXX 
 
Resolved 
03-US-002 
XXX 
XXXXXXXX 
Dose modification in next 
treatment 
XXX/XXXXX 
XXXXXX 
Worsened 
03-US-003 
XXX 
XXXXXXXX 
Unknown  
XXX 
 
Persisting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source Table: W_PATIENT, W_AE. 
Note: NA = Not Available 
File directory: path of directory status from study level downwards /XXXXXX.sas 


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Statistical Analysis Plan 
ANNEXIN 03 
 
 
Listing 16.2.8.1/1: Hematology 
 
Subject ID 
Visit 
Have tests 
been done? 
Sample 
collection date 
Sample 
collection time 
Parameter 
Result 
Unit 
Abnormality 
03-US-001 
Screening 
Yes 
11/03/2011 
10:52 
Red Blood Cells 
106/uL 
XX 
Abnormal Non-
Clinical Relevant 
 
 
 
 
 
Hematocrit 
% 
XX 
Abnormal Non-
Clinical Relevant 
 
 
 
 
 
Etc… 
 
 
 
 
 
Visit 3 
Yes 
09/04/2011 
15:00 
 
 
 
 
03-US-002 
Screening 
Yes 
10/07/2011 
09:38 
 
 
 
 
03-US-003 
Visit 3 
No: XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ANNEXIN 03 
 
 
Listing 16.2.8.2/1: Blood Chemistry  
Subject ID 
Visit 
Have tests 
been done? 
Sample 
collection date 
Sample 
collection time 
Parameter 
Result 
Unit 
Abnormality 
03-US-001 
Screening 
Yes 
11/03/2011 
10:52 
ALT 
U/L 
XX 
Abnormal Non-
Clinical Relevant 
 
 
 
 
 
AST 
U/L 
XX 
Abnormal Non-
Clinical Relevant 
 
 
 
 
 
Etc… 
 
 
 
 
 
Visit 3 
Yes 
09/04/2011 
15:00 
 
 
 
 
03-US-002 
Screening 
Yes 
10/07/2011 
09:38 
 
 
 
 
03-US-003 
Visit 3 
No: XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ANNEXIN 03 
 
 
Listing 16.2.8.3/1: Urinalysis  
Subject ID 
Visit 
Have tests 
been done? 
Sample 
collection date 
Sample 
collection time 
Parameter 
Result 
Unit 
Abnormality 
03-US-001 
Screening 
Yes 
11/03/2011 
10:52 
Appearance 
XX 
XX 
Abnormal Non-
Clinical Relevant 
 
 
 
 
 
pH 
XX 
XX 
Abnormal Non-
Clinical Relevant 
 
 
 
 
 
Etc… 
 
 
 
 
 
Visit 3 
Yes 
09/04/2011 
15:00 
 
 
 
 
03-US-002 
Screening 
Yes 
10/07/2011 
09:38 
 
 
 
 
03-US-003 
Visit 3 
No: XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.8.4: 
Immunogenicity 
 
 
 
 
 
 
 
anti-rhAnnexin V-128  
Subject ID 
Visit 
Has venous 
sample been done? 
Reason for non 
performance 
Sample collection date 
Sample collection time 
IgG 
IgM 
PAT_PATNUMBER 
VISIT_NAME 
IM_YN 
IM_YN_SP 
IM_DATE 
IM_TIME 
 
 
 
03-US-001 
Screening 
Yes 
 
11/03/2011 
10:52 
Negative 
Negative 
03-US-001 
Visit 3 
Yes 
 
09/04/2011 
15:00 
 
 
03-US-002 
Screening 
Yes 
 
10/07/2011 
09:38 
 
 
03-US-003 
Visit 3 
No 
XXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.9.1: 
Pregnancy Test 
 
Subject ID 
Sex 
Age 
Visit 
Has the pregnancy test 
been performed? 
Reason for non 
performance 
Specify reason 
Pregnancy 
test date 
Pregnancy 
test time 
Pregnancy 
test result 
PAT_PATNUMBER 
PAT_GENDER 
PAT_AGEYEAR 
VISIT_NAME 
PT_YN 
PT_NOTDONE 
PT_NOTDONE_SP 
PT_DATE 
PT_TIME 
PT_RESULT 
03-US-001 
Male 
54 
Screening 
Not applicable 
 
 
 
 
 
03-US-001 
Male 
54 
Visit 1 
Not applicable 
 
 
 
 
 
03-US-002 
Female 
38 
Screening 
Yes 
 
 
09/04/2011 
12:00 
Negative 
03-US-002 
Female 
38 
Visit 1 
Yes 
 
 
12/04/2011 
11:00 
Negative 
03-US-003 
Female 
59 
Screening 
No 
Menopause 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.9.2/1: Physical Examination 
 
 
 
 
 
 
 
 
Specify 
Subject ID 
Visit 
Has the physical 
examination been done? 
Reason for non 
performance 
Physical 
examination date 
Physical 
examination time 
Any clinically 
relevant finding? 
First finding 
Second finding 
Third finding 
PAT_PATNUM
BER 
VISIT_NAME 
PE_YN 
PE_YN_SP 
PE_DATE 
PE_TIME 
PE_RELFIND_Y
N 
PE_RELFIND
1 
PE_RELFIND
2 
PE_RELFIND
3 
03-US-001 
Screening 
Yes 
 
09/04/2011 
12:00 
No 
 
 
 
03-US-001 
Visit 3 
Yes 
 
09/05/2011 
10:00 
No 
 
 
 
03-US-002 
Screening 
Yes 
 
06/05/2013 
9:45 
Yes 
XXXXXXX 
XXXXXX 
XXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.9.3: 
Vital Signs  
 
Subject ID 
Visit 
Time point 
Have vital signs 
been evaluated? 
Reason for 
non evaluation 
Vital signs 
evaluation date 
Vital signs 
evaluation time 
Systolic BP 
(mmHg) 
Diastolic BP 
(mmHg) 
Pulse rate 
(beats/min) 
PAT_PATNUMBER 
VISIT_NAME 
 
VS_POST_YN 
VS_POST_YN_SP 
VS_POST_DATE 
VS_POST_TIME 
VS_POST_SBP 
VS_POST_DBP 
VS_POST_HR 
03-US-001 
Visit 1 
Before IP admin 
Yes 
 
09/04/2011 
12:00 
165 
99 
77 
 
 
After Last Imaging 
Procedure 
Yes 
 
09/04/2011 
12:00 
165 
99 
77 
03-US-002 
Visit 1 
 
Yes 
 
12/04/2011 
10:00 
129 
93 
60 
03-US-003 
Visit 1 
 
Yes 
 
06/05/2013 
9:45 
147 
68 
76 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.2 
Standard Tables 
 


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11.3  Standard Figures 
The different lines on the figures should look different (e.g. dotted lines) rather than using different 
colours so that the lines can be distinguished when using a non-colour printer. 
 


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APPENDICES TO THE SAP TEMPLATE 
11.4 
Derived Data 
The following derived data will be calculated and included in the listings or in the tables: 
(1) Age 
Subject age (years) will be derived as ([visit date] – [birth date])/365.25 and truncated to the largest 
integer that is less than or equal to the calculated result. If birth date is not a complete date then it 
will be approximated using “01” as value for the day and “01” as value for the month. 
(2) BMI 
BMI (kg/m2) will be automatically derived as [WEIGHT] (kg)/([HEIGHT](cm)/100)2 and rounded to the 
nearest decimal. 
(3) Time from injection 
Time from injection (min) will be derived as the difference between each imaging assessment (i.e. 
whole body planar imaging, abdomen SPECT/CT, lumbosacral SPECT/CT, sacroiliac SPECT/CT 
and spot SPECT/CT) time and injection time [WBPI1_TIME / WBPI2_TIME / ABD1_TIME / 
ABD2_TIME / LUMB1_TIME / LUMB2_TIME / SACRO1_TIME / SACRO2_TIME / SPOT1_TIME / 
SPOT2_TIME - ANN_TIME]. 
(4) Adverse event duration 
If the start and end dates of the adverse event are identical then “<1” day will be presented with the 
duration in hh:mm recorded in the eCRF if it is available. If times are available, the duration will be 
calculated as (end date/time - start date/time) and presented in days hh:mm. If at least one time is 
missing and if the duration is greater than 24 hours then it will be calculated as (end date - start 
date)+1 and presented in days. If the recorded end date is CONT. (for continuing), the end date will 
be listed as “ongoing” and the duration will be approximated as “≥(last attended visit date - start 
date)+1” day(s). If the start date or the end date are partial the duration will be presented as a 
superior inequality “≥xx” day(s) (i.e. “≥2” where start date = 31JAN2004 and end date = FEB2004 or 
start date = JAN2004 and end date = 01FEB2004). 


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(5) Delay of onset 
Delay of onset will be reported as the difference in days from the day of Annexin injection. If the start 
date of the adverse event is identical to the date of injection, then “1” day will be presented with the 
time to onset in hh:mm recorded in the eCRF if it is available. If the time to onset is greater than 24 
hours then it will be calculated as (start date - injection date) and presented in days. If the start date 
is partial, the time since injection will be presented as a superior inequality (i.e. for an AE started in 
FEB2004 after the injection performed on 31JAN2004, the delay of onset will be “≥2” days). 
11.5 
SAS Programs 
This section provides the SAS programs related to the statistical tests specified in the statistical 
analysis section. All computer output from SAS statistical programs used as a basis for extracted 
results should be retained for review by Responsible of statistical analysis. 
1 
Data manipulation 
 
Proc Format 
 
Proc SQL 
 
Proc Transpose 
2 
Descriptive statistics 
 
Proc Freq 
 
Proc Means 
 
Proc Tabulate 
3 
Test statistics 
 
Proc GLM 
 
Proc Mixed 
 
Proc Ttest 
 
Proc Univariate 
 
SAS macro %MAGREE 
4 
Graphs 
 
Proc Boxplot