Registry Protocol
A Registry for Patients with
Hereditary Thrombotic Thrombocytopenic Purpura
(TTP)
(Upshaw-Schulman Syndrome)
10 February 2009
Dr. Johanna A. Kremer Hovinga, MD
Prof. Bernhard Lämmle, MD
Hemostasis Research Laboratory
Division of Hematology & Central Hematology Laboratory
Inselspital
University of Bern
CH - 3010 Bern, Switzerland
TTP Registry Protocol, Inselspital Bern, Switzerland, 2009-02-10
Table of Contents
Principal Physicians of the Registry........................................................................................... 3
Signature Page for Authors ........................................................................................................ 4
List of Abbreviations .................................................................................................................. 5
Protocol Overview...................................................................................................................... 6
1. Introduction ......................................................................................................................... 8
1.1. Background .................................................................................................................. 8
1.2. Hereditary TTP (Upshaw-Schulman syndrome) ......................................................... 9
1.3. Rationale .................................................................................................................... 10
2. Registry Objectives ........................................................................................................... 10
3. Registry Design ................................................................................................................. 11
3.1. Registry Questionnaires ............................................................................................. 11
3.2. Laboratory Investigations .......................................................................................... 11
3.3. Registry Medications ................................................................................................. 11
4. Registry Population ........................................................................................................... 12
4.1. Inclusion Criteria ....................................................................................................... 12
4.2. Exclusion Criteria ...................................................................................................... 13
4.3. Patient Withdrawal .................................................................................................... 13
5. Registry Procedures .......................................................................................................... 13
5.1. Registry Overview ..................................................................................................... 13
5.2. Enrollment Visit ........................................................................................................ 14
5.3. Acute Bout Visits....................................................................................................... 15
5.4. Follow-up Visits ........................................................................................................ 15
5.5. Laboratory Investigations .......................................................................................... 15
5.6. Additional Laboratory Investigations ........................................................................ 16
6. Data Collection and Data Management ............................................................................ 17
7. Data Quality Assurance .................................................................................................... 18
8. Data Analysis .................................................................................................................... 18
9. Ethical Considerations ...................................................................................................... 19
9.1. Ethical Review ........................................................................................................... 19
9.2. Consideration of Patient and their Relative Inconveniences ..................................... 19
10. Safety Considerations .................................................................................................... 20
11. Registry Management ................................................................................................... 20
12. Publications and Use of Information ............................................................................. 20
13. References ..................................................................................................................... 21
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TTP Registry Protocol, Inselspital Bern, Switzerland, 2009-02-10
Principal Physicians of the Registry
Johanna A. Kremer Hovinga, MD
Hemostasis Research Laboratory
Division of Hematology & Central Hematology Laboratory
Inselspital
University of Bern
CH - 3010 Bern
Switzerland
Phone: +41 31 632 90 22
Fax : +41 31 632 18 82
e-mail: johanna.kremer@insel.ch
...................................................................................................
Bernhard Lämmle, MD
Hemostasis Research Laboratory
Division of Hematology & Central Hematology Laboratory
Inselspital
University of Bern
CH - 3010 Bern
Switzerland
.................................................................................................
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Signature Page for Authors
Position
Name
Principal Physician
Johanna A. Kremer Hovinga, MD
……………..
……………..
Signature
Date
Position
Name
Principal Physician
Bernhard Lämmle, MD
……………..
……………..
Signature
Date
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List of Abbreviations
The following is a list of the most commonly used abbreviations; others are expanded at first
use.
Abbreviation
Definition
ADAMTS13
CRF
A Disintegrin-like and Metalloprotease with
Thrombospondin Type 1 Motif, 13
Case report form
DCF
EC
EDC
FDA
ICB
Data Clarification Form
Ethics Committee
Electronic data capture
Food and Drug Administration
International Coordination Board
ICH
IRB
TTP
USS
VWF
International Conference on Harmonisation
Institutional Review Board
Thrombotic Thrombocytopenic Purpura
Upshaw-Schulman syndrome
von Willebrand factor
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Protocol Overview
Full Title of the Registry: A Registry for Hereditary Thrombotic Thrombocytopenic Purpura
(TTP) (Upshaw-Schulman Syndrome, USS).
Background/Rationale: TTP is a rare disorder with an annual incidence of 3.7-4.5 cases per
106 individuals. TTP, which can be hereditary or acquired, is characterized by
thrombocytopenia due to microvascular platelet clumping, microangiopathic hemolytic
anemia, often accompanied by organ dysfunctions such as neurological abnormalities, renal
insufficiency, and fever. Currently, the clinical symptoms and laboratory values on which
treatment regimens for hereditary TTP can be based are unclear. There is also very little
known on side effects of long standing plasma substitution, the only treatment for hereditary
TTP today. The registry will gather information from patients with hereditary TTP in order to
establish recommendations for the treatment and management of the disorder.
Primary objective: To collect as much information as possible on the clinical presentation,
disease course, disease-modifying factors, and treatment modalities of patients suffering from
hereditary TTP.
Secondary objective: To document potential adversary effects of (long-term) plasma
treatment in patients with hereditary TTP.
Registry Design: The TTP Registry is designed to collect both retrospective and prospective
clinical, molecular, and observational data on patients with confirmed or suspected hereditary
TTP. Additionally, the registry will collect data from family members of the registry TTP
patients. The registry will enroll as many confirmed or suspected hereditary TTP patients and
their family members as possible; there is no cap on enrollment. The registry enrollment and
follow-up periods are open-ended. The endpoints for patients with confirmed or suspected
hereditary TTP and family members are death or withdrawal of consent.
Registry Population: Patients with either confirmed or with suspected hereditary TTP and
their family members will be eligible for inclusion.
Data Collection: Data from TTP patients will be collected at an enrollment visit and at
follow-up visits scheduled for at least once per year. Data from the family members in the
study will be collected only at study enrollment (i.e. no longitudinal follow-up). Data will be
collected either on paper CRFs, which will be sent to study center in Bern and from there to
the Clinical Trials Unit (CTU), Inselspital, Bern University Hospital, CH-3010 Bern,
Switzerland or by Electronic data capture (EDC). The CTU is responsible for data entry
into the registry database,
Data Analysis: Summary descriptive statistics including univariate and bivariate analyses
will be performed for patients with a confirmed hereditary TTP only to describe demographic,
clinical, and laboratory parameters.
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Ethical and Regulatory Considerations: Central or local Research Ethics Committee or
Institutional Review Board approval of registry documents will be obtained, per requirements
at each site. The registry will be conducted in compliance with the International Conference
on Harmonisation (ICH) GCP guidelines (May 9, 1997); the Declaration of Helsinki, as
amended in South Africa (1996); and any applicable local regulatory requirements.
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1.
Introduction
1.1.
Background
TTP is a rare disorder with an annual incidence of 3.7-4.5 cases per 106 individuals.1,2 TTP is
characterized by thrombocytopenia due to micro-vascular platelet clumping, microangiopathic
hemolytic anemia, often accompanied by organ dysfunctions such as neurological
abnormalities, renal insufficiency, and fever. In 1924, Moschcowitz first described TTP in a
16-year-old girl who died within a fortnight after abrupt onset of petechiae, anemia, microhematuria, fever, and coma.3 Acute TTP remained an almost universally fatal disorder until
the 1970s when the empirical introduction of plasma therapy dramatically improved survival
from <10% to about 80-90%.4,5
During the last decade, remarkable advances in understanding the pathogenesis of TTP have
been achieved. The condition is often associated with a severe deficiency of the von
Willebrand factor-cleaving protease (<5% of normal plasma), now denoted as ADAMTS13.
Deficiency of ADAMTS13 prevents normal processing of unusually large von Willebrand
factor (VWF) multimers, which are synthesized and secreted into the circulation by
endothelial cells. It is assumed that these unusually large VWF multimers are responsible for
the formation of platelet thrombi in the microvasculature, the pathophysiologic hallmark of
acute TTP.
Today two forms of classical TTP are distinguished. The acquired form is caused by
circulating autoantibodies, mainly IgG, inhibiting ADAMTS13 activity.6-8 In the majority of
patients with this form, a normalization of ADAMTS13 activity as well as disappearance of
the inhibiting antibodies is observed upon remission. In contrast, hereditary TTP (also known
as Upshaw-Schulman Syndrome, USS) is the result of severe constitutional deficiency of
ADAMTS13 due to compound heterozygous or homozygous mutations in the ADAMTS13
gene.
Figure 1: Protein domain structure of ADAMTS13
The ADAMTS13 gene is located on chromosome 9q34, spans ~37kb and contains 29 exons.
The primary translation product consists of 1427 amino acid residues and is composed of a
signal peptide (S) and a propeptide (P), followed by the motifs defining the ADAMTS family:
a reprolysine-like metalloprotease domain, a disintegrin-like domain, a thrombospondin type
1 (TSP1) repeat, a characteristic cysteine-rich domain, a spacer domain followed by an unique
combination of seven TSP1 repeats, and two CUB domains (Figure 1).9
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1.2.
Hereditary TTP (Upshaw-Schulman syndrome)
The discovery of two brothers with chronic relapsing TTP, the linkage of their disease to the
complete deficiency of ADAMTS13 activity at the Hemostasis Research Laboratory,
Inselspital, Bern, Switzerland, and the subsequent identification of the underlying
ADAMTS13 mutations prompted many clinicians to refer plasma and whole blood samples of
similar cases to the Hemostasis Research Laboratory.10,11 Today, the laboratory has identified
63 patients from 53 families in 18 countries with a severe constitutional ADAMTS13
deficiency. More than 100 different mutations, which are distributed throughout the whole
ADAMTS13 gene and thus not restricted to a specific protein domain, have been reported or
identified in patients diagnose in Bern.
Analysis of patient histories revealed a striking age-dependent clustering of the first TTP
attack. Half of the patients suffered from a first acute bout of TTP between their first day of
life and the age of ~5 years (early onset), while the other half remained asymptomatic into
early adulthood and suffered from a first acute TTP episode at the age of 20 - 40 years (late
onset). Six female patients from four families who had their first attack during a first
pregnancy were identified. Regardless of the age at disease onset, once affected individuals
had developed a first bout of TTP, they usually had a chronic relapsing course.12 So far, no
correlation between genotype and phenotype (i.e., disease severity, organ tropism, and age at
disease onset) is evident. However, in many of the families with two or more affected
siblings, the age of initial disease presentation was comparable. Apparently, additional,
hitherto unidentified disease-modifying genetic or environmental triggering factors may be
needed to result in clinically apparent disease.
Hereditary TTP (OMIM #274150) is considered an extremely rare disorder, but observations
suggest that the prevalence of the disorder may have been greatly underestimated.13,14 Several
siblings of patients diagnosed in our laboratory had died without an established diagnosis, a
substantial proportion had been misdiagnosed as Evans’ syndrome or ITP resulting in idle
immunosuppressive treatment, and in others diagnosis was greatly delayed and made only
after irreversible organ damage had occurred, such as ischemic neurological deficits or
permanent renal insufficiency, or even postmortem.15
The principal physicians are regularly contacted by clinicians treating patients with hereditary
TTP requesting recommendations concerning treatment strategies to prevent relapses.
Generally, patients with hereditary TTP respond dramatically to simple FFP infusion10,12,16-20
and can be maintained for many years in good health by regular FFP infusion every 2-3
weeks.12,19,20 From the observations in the first two brothers with chronic relapsing TTP as a
consequence of complete ADAMTS13 deficiency, we tend to recommend regular plasma
infusion, as the index-patient experienced a number of ischemic strokes and TIAs resulting in
mental alteration and dementia before diagnosis of hereditary TTP. Regular plasma infusion
was not possible due to his mental state. His brother, who is on regular plasma infusion every
3 weeks, is doing well. However, probably not all patients need regular plasma infusions, as
they present with rather mild courses only requiring plasma treatment in special situations
(i.e., pregnancy).
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1.3.
Rationale
At present, the clinical symptoms and laboratory values on which to base treatment regimens
for hereditary TTP are poorly understood. Furthermore, increasing awareness of hereditary
TTP, results in rising numbers of patients in need of treatment and/or prophylaxis. However,
currently very little is known on side effects of long standing plasma substitution. Alloimmunization, with the formation of antibodies acting as inhibitors of treatment, are well
known in other congenital coagulation factor deficiencies (e.g. hemophilia A), but so far no
case of treated hereditary TTP with subsequent antibody formation has been reported.
The hereditary TTP registry will provide information on the clinical course of the disease in
as many patients as possible and therefore help to provide recommendations on the necessity,
modalities, and risks of prophylactic plasma therapy in patients with hereditary TTP. Furthermore, the objective is to gain detailed insight into triggers of acute bouts of TTP and to
identify additional risk factors. The information gathered will be made available on the
website of our institution and help clinicians who treat such patients. Certainly, broad
communication concerning hereditary TTP will make this often unrecognized but treatable
condition known to more clinicians, especially pediatricians, thereby preventing delayed
diagnosis and fatal courses in patients or their siblings.
2.
Registry Objectives
The ultimate goal of the registry is to develop evidence-based recommendations for treatment
and surveillance of patients suffering from hereditary TTP and to provide a platform for the
debate and exchange of experiences between clinicians treating patients diagnosed with
hereditary TTP. The registry will also seek to address difficult questions such as care during
pregnancies and management of terminal renal insufficiency.
In pursuit of this goal, the primary objective of this registry is to collect as much information
as possible on the clinical presentation, disease course, disease-modifying factors, and
treatment modalities used in patients suffering from hereditary TTP.
The secondary objective of the registry is to document potential adversary effects of longterm plasma treatment in patients with hereditary TTP.
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3.
Registry Design
The TTP Registry is designed to collect both retrospective and prospective clinical,
molecular, and observational data on patients with confirmed or suspected hereditary TTP.
Additionally, the registry will collect data from family members of the registry TTP patients.
The registry will prospectively enroll as many confirmed and suspected hereditary TTP
patients as possible with no cap on enrollment. The registry enrollment and follow-up periods
are open-ended. Patient participation is anticipated to extend until death, withdrawal of
consent, loss to follow-up, or close out of the registry.
3.1.
Registry Questionnaires
Confirmed or suspected hereditary TTP Patients: At enrollment, physicians will work
with patients with either confirmed or with suspected hereditary TTP to complete a
questionnaire documenting their clinical history. For each post-enrollment acute bout of TTP,
the physician will complete a follow-up questionnaire. A follow-up visit will be scheduled for
at least once every 12 months, at which time the physician will complete the follow-up form.
Family Members: Family members of relevance to the purpose of the registry are parents,
children, and siblings of patients. At enrollment family members of patients with hereditary
TTP will complete a questionnaire documenting their demographics, relation to the TTP
patient, and clinical characteristics. No follow-up encounters will be scheduled with the
family members.
3.2.
Laboratory Investigations
Confirmed or suspected hereditary TTP Patients: At registry enrollment, blood samples
will be taken and several laboratory investigations will be done including genetic testing to
confirm the diagnosis. At each post-enrollment acute bout of TTP and at every follow-up
visit, blood samples will be taken and several laboratory investigations will be done. Results
of the laboratory investigations will be added to the registry.
Family Members: At enrollment, blood samples will be taken from family members for the
same laboratory investigations as for TTP patients, including relevant genetic testing. Results
of the laboratory investigations will be added to the Registry. No follow-up blood samples
will be taken.
3.3.
Registry Medications
The Hereditary TTP Registry does not provide or require any treatments. Any treatments
provided will be determined by the treating physician.
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4.
Registry Population
Clinicians who have referred suitable patients for diagnostic purposes to the Hemostasis
Research Laboratory, University of Bern, will be contacted and invited to include their
patients. In addition, corresponding authors of several research publications on hereditary
TTP will be invited to enroll their patients into the registry.13,14,17-19,21-33
The registry will include TTP patients in, but not limited to, Europe, Japan and Northern
America. The registry will enroll as many confirmed or suspected hereditary TTP patients as
possible. Because the disease is extremely rare, the expected patient population is small.
Parents, children and siblings of participating TTP patients will also be invited for enrollment.
4.1.
Inclusion Criteria
All patients with a confirmed diagnosis of hereditary TTP (Upshaw-Schulman syndrome,
USS) or with suspected hereditary TTP are eligible for the registry. Patients, or their
appropriate proxy if pediatric, must provide informed consent to participate.
Retrospective de-identified data will be sought for patients with a confirmed or suspected case
of hereditary TTP who have been seen by participating physicians in the past but are not
expected to return to the practice, including those who are deceased.
The registry will collect data on both confirmed and suspected cases of hereditary TTP, but
only confirmed cases will be included in the analyses. The confirmation of a diagnosis of
hereditary TTP depends on the concurrent presence of:
1.) A suitable patient and family history.
2.) A severe ADAMTS13 deficiency (<5% of the normal) in the absence of an
ADAMTS13 inhibitor, documented at two different time points at an interval of more
than 14 days.
3.) Identified homozygous or compound heterozygous ADAMTS13 gene mutations.
4.) An additional optional criterion is a plasma infusion trial with a documented
ADAMTS13 recovery and half-life time compatible with results in the literature in the
absence of an ADAMTS13 inhibitor (recovery of all infused ADAMTS13 and
ADAMTS13 plasma half-life time of 2-4 days).
A patient full-filling criterion 1, 2 and 4 with no or only one ADAMTS13 mutations identified
are eligible but are coded as suspected hereditary TTP patient.
Therefore, ADAMTS13 activity and antigen as well as a molecular analysis of the
ADAMTS13 gene have to be performed to confirm a diagnosis of hereditary TTP.
Family members of patients with confirmed or suspected hereditary TTP will be included if
possible.
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4.2.
Exclusion Criteria
There are no exclusion criteria.
4.3.
Patient Withdrawal
Patients may withdraw from the registry at any time at their own, or their proxy’s, request. If
the patient withdraws from the registry, no further assessments will be taken and no additional
data will be collected. The registry may retain and continue to use any data collected before
such withdrawal of consent.
5.
Registry Procedures
5.1.
Registry Overview
Figure 2: Flow chart of registry procedures
Registry Population
Registry Population
Patients with a diagnosis of hereditary
TTP or
patients with suspected
hereditary TTP
Family members of patients with a
diagnosis of hereditary TTP or of
patients with suspected hereditary TTP
Enrollment
Enrollment
 Completion of enrollment questionnaire
 Collection of blood samples
 Collection of additional laboratory data (if available)
 Completion of enrollment questionnaire
 Collection of blood samples
 Routine and molecular analyses to confirm
ADAMTS13 status (local/central/other approved lab)
 Collection of additional laboratory data (if available)
Routine and molecular analyses of ADAMTS13 to
confirm diagnosis (local/central/other approved lab)
Patients with confirmed
hereditary TTP
Patients with suspected,
hereditary TTP
Acute bout / Follow-up
 Completion of questionnaire
 Collection of blood samples
 Laboratory investigations (local/central/other
approved lab)
 Collection of additional laboratory data (if available)
Data entry into registry database
Analyses will focus, but not
limited to, on patients with
confirmed hereditary TTP
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Table 1: Assessment schedule for patients with confirmed or suspected hereditary TTP
Assessments
Enrollment Form
Blood sample collection
Enrollment Laboratory Investigations
Acute bout Form
Acute bout Laboratory Investigations
Follow-Up Form
Follow-Up Laboratory Investigations
Additional Laboratory Investigations
(if available)
Enrollment
Acute bout
Follow-up
X
X
X
X
X
X
X
X
X
X
X
X
Table 2: Assessment schedule for family members of patients with confirmed or suspected
hereditary TTP
Assessments
Enrollment Form
Blood sample collection
Enrollment Laboratory Investigations
Acute bout Form
Acute bout Laboratory Investigations
Follow-Up Form
Follow-Up Laboratory Investigations
Additional Laboratory Investigations
(if available)
5.2.
Enrollment
Follow-up
X
X
X
X
-
Enrollment Visit
Patients with confirmed or suspected hereditary TTP: At enrollment, physicians will
complete the enrollment form detailing the patient’s name, date of birth, gender, family
history, disease course, pregnancies, and acute episodes, including clinical presentation, lab
results, and treatments.
The following laboratory investigations will be performed at the enrollment:






ADAMTS13 activity; ADAMTS13 antigen (ELISA, SDS-PAGE)
ADAMTS13 Inhibitor
ADAMTS13 genetic analysis
VWF ristocetin cofactor activity; VWF antigen
Blood group
Additional laboratory investigations may be performed at the discretion of the
responsible physician
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Family members: At enrollment, physicians will complete the enrollment form detailing the
individual the name, date of birth, gender, relation to the TTP patient, and additional clinical
data.
The following laboratory investigations will be performed at the enrollment:




5.3.
ADAMTS13 activity; ADAMTS13 antigen (ELISA, SDS-PAGE)
ADAMTS13 Inhibitor
ADAMTS13 genetic analysis
VWF ristocetin cofactor activity; VWF antigen
Acute Bout Visits
Only for patients with confirmed or suspected hereditary TTP: For each post-enrollment
acute bout of TTP, the physician will complete a follow-up form.
The laboratory investigations listed below will be performed:


5.4.
ADAMTS13 activity; ADAMTS13 antigen (ELISA, SDS-PAGE)
ADAMTS13 Inhibitor
Follow-up Visits
Only for patients with confirmed or suspected hereditary TTP: In the absence of acute
TTP bouts post-enrollment, follow-up visits are scheduled at least once per year.
At the follow-up visit, the physician will complete the follow-up questionnaire to gather data
on the physical exam, treatments, and laboratory results. The laboratory investigations listed
below will be performed:


5.5.
ADAMTS13 activity; ADAMTS13 antigen (ELISA, SDS-PAGE)
ADAMTS13 Inhibitor
Laboratory Investigations
For all of these investigations except for blood group, five (children aged 0-7 years) to 10ml
of citrated venous blood and 2 ml of EDTA venous blood will be withdrawn from the patients
and family members at the appropriate visits.
As per instructions by the principal physicians and the International Coordination Board
(ICB), EDTA whole blood, citrated plasma, and serum (“blood samples”) could be shipped
frozen to the principal physicians in Bern (“Central laboratory”) or other specialized
laboratories approved by the principal physicians and ICB ("other approved laboratories") for
laboratory investigations relevant to the diagnosis of hereditary TTP, including, but not
limited to genetic testing, ADAMTS13 activity and antigen determination, ADAMTS13
inhibitor screening; and measurement of VWF:RCo and VWF:Ag. Results of the laboratory
investigations will be added to the registry.
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After analysis the blood samples will be stored for an undetermined time period, possibly for
several years, at the site’s laboratory, the Central laboratory or other approved laboratories.
Samples will be stored at –70°C for possible investigation of new, hitherto unknown factors
involved in the pathogenesis of hereditary TTP.
5.6.
Additional Laboratory Investigations
The laboratory tests listed below are not required for the registry, but the registry will collect
data on these tests when they are performed. The decision to perform these tests will be made
by the treating physician. The tests will be performed locally and not at the Central laboratory
or other approved laboratories.













Hemoglobin
Reticulocytes
Platelet count
Peripheral blood smear (e.g. Schistocytes)
Aspartate aminotransferase (AST/SGOT)
Alanine aminotranseferase (ALT /SGPT)
Bilirubin
Creatinine
Blood urea nitrogen (BUN)
Lactate dehydrogenase (LDH)
Hydroxybuterate dehydrogenase (HBDH)
Haptoglobin
HCV, HBV, HIV status
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6.
Data Collection and Data Management
Data collection will be accomplished by the physicians by either data capture through paper
case reports forms (CRFs) or by EDC. CRFs will be posted online so physicians can
download and print them or physicians will have access to EDC for data entry.
A data management manual will be provided as part of the initial registry materials along with
the CRF-EDC completion guidelines. Physicians should follow the CRF-EDC completion
guidelines when filling out the paper CRFs or EDC.
Paper CRF: If physicians complete CRFs, completed CRFs will be sent to the principal
physicians in Bern. The principal physicians send the CRF pages with the exception of the
front CRF page containing the patient or family member name (see below “Prevention of
enrollment of duplicates”) to the Clinical Trials Unit (CTU), Inselspital, Bern University
Hospital, CH-3010 Bern, Switzerland. CTU will be responsible for data entry and data
management activities for the registry. CTU will enter the paper CRFs into a secure internetbased EDC system. All of the data on the CRF will be entered into the system except for the
patient or family member name. CTU will issue data clarification forms (DCFs) to physicians
to resolve any questions or data issues.
EDC: If physicians enter data directly into the secure internet-based EDC system using their
assigned account with a CTU-assigned username and password, all of the data will be entered
into the system except for the patient or family member name. Correct data entry has to be
confirmed by the physician by electronic signature. The CTU will issue data clarification
forms to physicians to resolve any questions or data issues.
Physicians will also complete the front page of the paper CRF in addition and send it to the
principal physicians (see below “Prevention of enrollment of duplicates”).
Once the data are entered into the database, physicians will be able to access their account
with a CTU-assigned username and password. Physicians will be able to view data from their
patients and their family members only online, access reports of patient characteristics, and
participate in discussion forums.
Prevention of enrollment of duplicates: The principal physicians will cross-check new
patients and family members against existing patients and family members using the
individual’s name which is collected on the CRF front page. If a duplicate patient or family
member is suspected, the principal physicians will contact the treating physician and CTU for
further clarification.
In addition, CTU will cross-check new patients and family members against existing patients
and family members using the individual’s date of birth, gender, and blood group. If a
duplicate individual is suspected, CTU will contact the principal physicians for further
investigations to determine if the patient or family member is a duplicate.
Duplicate patients and family members will not be entered into the database or, in case
duplicate enrollment is confirmed only after data entry, removed from the database.
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Storage of documents: All CRFs, DCFs and original informed consent forms will be
maintained at the participating physician’s site for an undetermined time period, possibly for
several years, but for at least five years after registry closure.
CRF’s will be maintained at the study center in Bern, in a secure location to protect patient
privacy, for an undetermined time period, possibly for several years, but for at least five years
after registry closure.
CTU will also retain CRFs and DCFs for an undetermined time period, possibly for several
years, but for at least five years after registry closure in a secure location to protect patient
privacy.
7.
Data Quality Assurance
The registry database, including data from the TTP patients and their relatives, will be housed
at CTU in a physically and logically secure computer system maintained by CTU in
accordance with a written security policy. The system meets approved established standards
for the security of health information and is validated. The system also meets the standards of
the International Committee on Harmonisation (ICH) guideline E6R1 regarding electronic
registry data handling and is available for audit upon request. Patient confidentiality will be
strictly maintained.
CTU maintains high data quality standards and utilizes processes and procedures to
repeatedly ensure that the data are as clean and accurate as possible when presented for
analysis. Data quality is enhanced through a series of programmed data quality checks that
automatically detect and prevent the entry out-of-range or anomalous data.
8.
Data Analysis
Summary descriptive statistics including univariate and bivariate analyses will be performed
for patients with confirmed hereditary TTP only to describe demographic, clinical, and
laboratory parameters. Statistical analyses will be performed by the principal physicians.
CTU will provide data to the principal physicians in SAS format for analysis.
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9.
Ethical Considerations
9.1.
Ethical Review
The registry will be conducted in accordance the International Conference on Harmonization
(ICH) GCP guidelines (May 9, 1997); the Declaration of Helsinki, as amended in South
Africa (1996); and any applicable local regulatory requirements.
Before the start of the registry and prior to the enrollment of patients into the registry at every
participating site, documents submitted to the appropriate Institutional Review
Board/Independent Ethnics Committee for review and approval must include, but are not
limited to:





Current version of registry protocol approved by the principal physicians
Case report forms
Patient information forms
Informed consent
Site principal physician’s current curriculum vitae
Informed consent must take place prior to the initiation of the registry data collection. An
informed consent will be obtained (signed and dated) from each patient (or his/her legally
acceptable representative) and each participating family member (or his/her legally acceptable
representative) in accordance with local regulatory and legal requirements. The completed
informed consent form must be retained by the physician as part of registry records.
Prior to initiation of this registry, the Kantonale Ethikkommission (KEK) Bern, Switzerland,
as the responsible local ethics committee at the study center in Bern has approved the registry
protocol, the questionnaires, the patient information forms and informed consent forms. Reapproval of the protocol and informed consent will be necessary if the principal physicians
amend the protocol or informed consent at any time during the course of the registry.
Amendments to the protocol may only be made by the principal physicians.
9.2.
Consideration of Patient and their Relative Inconveniences
The main inconvenience to the patient in context of this registry is the venipunctures at
enrollment and during follow-up visits for blood sample withdrawal. Since surveillance of
patients with hereditary TTP generally requires regular monitoring of laboratory parameters
such as hemoglobin, platelet count, and creatinine, no additional venipuncture is necessary in
the majority of patients. In addition, physicians may complete a more thorough medical and
family history of the patient in order to complete the questionnaires.
Family members of TTP patients will be investigated at one single point in time and therefore
will experience only one venipuncture at study enrollment.
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10.
Safety Considerations
There is no administration of any medication as part of this registry. All medication usage is
solely at the discretion of the physicians in accordance with their usual patient care. Should a
patient experience a serious, unexpected adverse event resulting from one of his/her
medications, the reporting should follow the customary procedures for reporting adverse
events to the appropriate regulatory authority and a copy of the report should be sent to the
principal physicians’ attention.
11.
Registry Management
The registry will be overseen by the principal physicians, Drs. Kremer Hovinga and Lämmle,
Hemostasis Research Laboratory, Division of Hematology & Central Hematology
Laboratory, Inselspital, University of Bern, CH - 3010 Bern, Switzerland, who are the owners
of the data. The principal physicians will be responsible for the administration and quality
assurance of the registry. All contracts with sites will be addressed by the University of Bern,
including each participating physician’s right to access data from the registry.
CTU will be responsible for management of the database, data entry, and data management
activities. In addition, CTU will provide training and ongoing support to physicians.
Clinical guidance for the registry will be provided by the ICB, which will be chaired by Drs.
Lämmle and Kremer Hovinga. The members of the ICB will be specified on the registry
website. Members will have full access to the registry data.
Funding of the registry is provided by third party funds (Swiss National Research Foundation;
Mach-Gaensslen Foundation, Switzerland). Additional funding for the registry is obtained
from Baxter BioScience through a research grant.
12.
Publications and Use of Information
The principal physicians will publish the insights gained and the results of this registry on the
registry website to make this information available for treating clinicians as well as patients
and their family members.
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13.
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