Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01565239 |
| Other study ID # |
Landspitali-1 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
March 22, 2012 |
| Last updated |
September 8, 2014 |
| Start date |
March 2012 |
| Est. completion date |
February 2014 |
Study information
| Verified date |
September 2014 |
| Source |
Landspitali University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Iceland: Ministry of Health and Social Security |
| Study type |
Interventional
|
Clinical Trial Summary
Experiments suggest that during treatment with vitamin K antagonists (VKA) the activity of
coagulation factors (F) II and X better reflect anticoagulation than does FVII. Based on
this a new prothrombin time based monitoring test (Fiix-PT) has been invented which is only
sensitive to FII and FX. The Fiix-PT can be converted to INR ("Fiix-INR").
The investigators hypothesize that the Fiix-PT may reflect anticoagulation and the
antithrombotic effect of VKA as accurately or better than the current PT based tests do (INR
based on PT or P&P). The protocol describes a prospective randomized double-blind trial that
will be conducted at the Landspitali Anticoagulation Management Center (AMC).
The objective of the protocol is to evaluate the efficacy and safety of Fiix-INR as a
monitoring test compared to the current PT based assays (INR) used to monitor patients
treated with VKA to prevent thromboembolism. The investigators will randomize 1200 clients
of the AMC into two identically sized monitoring groups, Fiix-INR (test group) and INR
(control group).
The clinical endpoints to be studied include efficacy (arterial and venous thromboembolic
event rate) and safety (bleeding events). Additionally, surrogate convenience endpoints will
be studied such as test frequency and time within target range.
Description:
Clinical outcome during warfarin anticoagulation to prevent thromboembolism monitored with
"Fiix-INR" compared to standard monitoring with INR.
A prospective randomized double-blinded trial. Study protocol Abbreviated Version Jan 25
2012 Corresponding author: Pall T. Onundarson, M.D., Department of Laboratory Hematology and
Hemostasis Center, K-building, Landspitali Hringbraut, 101 Reykjavik, Iceland, Phone: +354
543 1000/5010, Fax +354 543 5539, email: pallt@landspitali.is.
1. STUDY SYNOPSIS Experiments suggest that during treatment with vitamin K antagonists
(VKA) the activity of coagulation factors (F) II and X better reflect anticoagulation
than does FVII. Based on this a new monitoring prothrombin time base test (Fiix-PT) has
been invented which is only sensitive to FII and FX. The Fiix-PT can be converted to
INR ("Fiix-INR").We hypothesize that the Fiix-PT may reflect anticoagulation and the
antithrombotic effect of VKA as accurately or better than the current PT based tests do
(INR based on PT or P&P). The protocol describes a prospective randomized double-blind
trial that will be conducted at the Landspitali Anticoagulation Management Center
(AMC). The objective of the protocol is to evaluate the efficacy and safety of Fiix-INR
as a monitoring test compared to the current PT based assays (INR) used to monitor
patients treated with VKA in order to prevent thromboembolism. We will randomize 1200
clients of the AMC into two identically sized monitoring groups, Fiix-INR (test group)
and INR (control group). Each individual will be assessed monthly for up to 24 months
(an expected average of 18 months) until a total of 600 patients years of observation
has been reached in each group. The clinical endpoints to be studied include efficacy
(arterial and venous thromboembolic event rate) and safety (bleeding events). Also,
surrogate convenience endpoints will be studied such as test frequency and time within
target range.
2. INTRODUCTION AND RATIONALE 2.1 Background Vitamin K antagonists (VKA, coumarins) are
orally active anticoagulants that prevent normal gamma carboxylation of the vitamin K
dependent coagulation factors (FII, FVII, FIX, FX). The consequence is a reduction in
the clotability of the blood, ie an anticoagulant effect that can be used
therapeutically for the purpose of preventing thromboembolism. In order to assure
efficacy and safety, the dose of VKA needs to be adjusted to maintain the normalized
prothrombin time ratio (international normalized ratio, INR) within a safe therapeutic
range (most often with INR target 2.5, range 2.0-3.0). The clotting times obtained with
PT based tests have in practice for over 50 years been presumed to directly reflect the
antithrombotic effect of VKA in patients (Loeliger 1984). The PT (or P&P-test) are used
all over the world for the purpose of monitoring anticoagulation and to make
dose-adjustments in patients taking VKA. Their results have been standardized by
calculating the International Normalized Ratio (INR) which takes into account the
sensitivity (strength) of the thromboplastin used by different reagents.
However, inherent problems exist with the PT. Due to the VKD factors´ significantly
different half-lifes (above), the PT clotting time obtained early after initiation or
dose change may mainly reflect the concentration of factor VII since FVII has the
notably shortest half-life (about 4-8 hours). If the concentration of factor VII has
little influence on the antithrombotic effect of VKA (see below), it is possible that
unnecessary and too frequent dose adjustments are made based on the use of the PT.
This, could potentially be harmful to the patient.
Prior studies by others have indicated that the thrombin generation(Xi, Beguin et al.
1989; Brummel, Paradis et al. 2001) and antithrombotic influence of factor VII in
rabbits (Zivelin, Rao et al. 1993) may be less important than that of prothrombin or
factor X. Based on those observations, it is possible that monitoring VKA and their
safety could be improved by measuring either coagulation factor II or coagulation
factor X. Measuring and monitoring coagulation factor II alone (native prothrombin
antigen) has been shown to be very successful and more accurate than PT in clinical
studies (Furie, Liebman et al. 1984; Xi, Beguin et al. 1989; Furie, Diuguid et al.
1990; Kornberg, Francis et al. 1993). The native prothrombin antigen assay, however, is
not as convenient for laboratories as the PT or P&P. Monitoring coagulation factor X
alone has not been tested in patients to our knowledge.
We have investigated (Thrombosis Research 2012, in press.) the influence of each of the
VKD factors on coagulation induced by dilute (trace amount) thromboplastin using
rotational thromboelastometry (ROTEM). The dilute thromboplastin is by some scientists
considered to reflect physiological clotting better than the 17,000 fold stronger
thromboplastin used in the current PT assays. ROTEM measures coagulation in more detail
than the traditional clotting times, i.e. initiation phase (clotting time), propagation
phase (bulk clot formation) and stabilization phase. Taken together, these experiments
using ROTEM show that the ROTEM clotting time (CT, initiation phase), ROTEM maximum
velocity of clot formation (Max Vel, propagation phase) and the ROTEM MCF
(stabilization phase) were affected much more by mildly and moderately low
concentrations of factors II or X (at activity levels that are present during ideal
anticoagulation) than by identical FVII or factor IX activity levels. Factors VII and
IX mainly influenced the ROTEM parameters at very low concentrations (< 5%) which only
occur during marked over anticoagulation. We conclude from these experiments that when
coagulation is initiated with trace amount thromboplastin (physiological coagulation),
reduction in concentration of coagulation factors II or X has much more effect on the
development of a clot than do the concentrations of factors VII or IX except at
extremely low activity levels of the latter two factors. Our experimental results may
indicate that in patients anticoagulated with warfarin, the factor VII activity is a
confounding source of variation in INR (PT) results. Hence, measuring the influence of
factor II or X or both II and X simultaneously on fibrin formation might reduce INR
fluctuation. Possibly, this could better predict the antithrombotic effect than the
current tests do. Thus, measuring II or X or both simultaneously could possibly improve
monitoring and dosing during VKA therapy. This has led to our invention of a new test,
"Fiix-PT" (or Stuart-Prothrombin time) , which measures the combined action of factor
II and factor X activity on clotting induced by tissue thromboplastin in PPP. We are
not aware of any other scientists investigating this method and a local patent has been
granted with international patent applications in process (March 2012). The Fiix-PT is
not affected by reduced activity of any other coagulation factors. In comparison, the
traditional test method (Quick PT or Owren´s PT) measures the combined effect of
factors II, VII and X on fibrin formation in patients taking VKA.
2.2 Hypothesis: Based on our experimental results as well as the results of others(Xi,
Beguin et al. 1989; Zivelin, Rao et al. 1993; Brummel, Paradis et al. 2001), we
hypothesize that the Fiix-PT may reflect anticoagulation and the antithrombotic effect
of VKA at least as accurately as than the current PT based tests do (PT, P&P).
3. STUDY OBJECTIVE The objective of the study is to evaluate the efficacy and safety of
Fiix-INR as a monitoring test compared to the current PT based assays used to monitor
patients treated with VKA to prevent thromboembolism.
4. STUDY OVERVIEW This is a prospective, single-center, randomized, double-blinded,
non-inferiority study(D'Agostino, Massaro et al. 2003; Scott 2009) for the efficacy and
safety of Fiix-PT as a monitoring method in VKA treated patients involving 1200 patient
years of observation.
4.1 Participants: All ambulatory patients 18 years or older currently on or starting on
warfarin to treat and prevent thromboembolism during the study period at the
anticoagulation management center (AMC) at the Landspitali University Hospital in
Reykjavik, Iceland with a treatment goal of INR 2-3 will be eligible for participation
and randomization irrespective of indication for anticoagulation, age or concurrent
medication use. Thus, the study population will have various (or mixed) indications for
OA but the majority likely will have atrial fibrillation. Both current patients and new
patients will be randomized over a 3-6 month period until adequate number of patients
have entered the study. After patients sign informed consent they will be randomized
(see METHOD of randomization in chapter 7) to either Fiix-PT (test method, Fiix INR) or
PT (PT-INR based on Quick PT method as a control method). We will measure the PT- INR
as well as the Fiix - INR in the test group for the sake of safety.
4.2 Randomization standard (PT-INR) vs. new test (Fiix-INR). The aim is to randomize
1200 clients of the AMC into two identically sized monitoring groups, Fiix-INR (test
group) and INR (control group). Each individual will be assessed monthly for up to 24
months (an expected average of 18 months) until a total of 600 patients years of
observation has been reached in each group.
4.3 Time frame: The clinical observation period for each participant will be 18 months
on average.
4.4 Endpoints to be recorded: see Chapter 7 for details A.Clinical endpoints. Rate of
all TE or major bleeding. The major efficacy endpoint is symptomatic diagnosed TE
events or death from TE and the major safety endpoint, is major bleeding, including
death from major bleeding (Palareti 1996; Abdelhafiz and Wheeldon 2004). TE and major
bleeding as a combined endpoint. Death and causes of death from natural causes. All
bleeding (major and any other reported bleeding) B. Convenience/surrogate endpoints,
eg. time within target range, number of tests within target range, number of tests
during study period, number of tests needed to achieve stable anticoagulation.
4.5 Study management: The study will be managed from day to day by an Executive
Committee (EXC) . All clinical diagnoses will be reviewed by a blinded Independent
Adjudication Committee (IAC) and Data Safety Monitoring Board (DSMB). The IAC and DSMB
will be blinded to which test group the patient with event for review belongs. All
suspected recurrent TEs, deaths, as well as all episodes of bleeding and other possible
vascular events will be evaluated by the IAC. The patent holders (PTÖ, BRG) will not be
on the IAC due to potential bias. Only adjudicated results will be the basis for the
final analyses. The DSMB will also monitor the study progress and patients' safety
during the study and give recommendations to the EXC.
Every time a patient has a contact (eg INR measurement or dosing instructions), the
dosing staff or study nurse will ask questions by exactly following the case review
form (CRF, 14.2). If the questions are answered with a "yes", the study nurse will
without delay contact that particular patient for more detailed information (i.e. HCRU
form see: Event report form / Health Care resource utilization (HCRU)), and, as
appropriate, will also collect necessary case record documents for the IAC.
5. STUDY POPULATION, RANDOMIZATION AND BLINDING
5.1 Planned number of patients. See 11.3.1 5.2 Inclusion criteria
1. Current or new patients 18 years or older currently on or starting VKA with INR
treatment target of 2-3
2. Willingness to participate as volunteers and to signing an informed consent 5.3
Exclusion criteria
1. Age under 18 years 2. Patients unable to sign informed consent
5.4 Randomization and blinding 5.4.1 Random allocation to experimental testing (Fiix-PT,
Fiix-INR) group and standard testing (PT, PT-INR) group will be done by the study nurse or
coagulation laboratory staff member in the outpatient phlebotomy ward when patients come for
scheduled visits or in hospital inpatient wards;
1. In current stable patients: at time of signing informed consent. Stable patients have
had at least two INR´s within the target range.
2. In new patients: no later than on the 4th day of warfarin administration, i.e. prior to
the first dose adjustment as above.
Note that the first dose change/first dose adjustment decision of warfarin must be based on
post-randomization Fiix-PT or PT result.
5.4.2 Randomization After patients sign informed consent they will be randomized to either
Fiix-PT (test method, Fiix INR) or PT (PT-INR based on Quick PT method as a control method).
Randomization will be done manually at time of signing the informed consent, ie the
participants will draw a labeled color card with an assigned study number (CRF number) which
will randomize them to either the test group or the control group. The coagulation
laboratory (supervised by BRG) will maintain a list of study participants during the study.
They will be responsible for randomization (color assignment) following the signing of
informed consent. Following randomization, each patient will be assigned a study participant
number. The laboratory will based on this participant number and color code as appropriate
direct each patient´s sample to test A (Fiix-INR) or test B (PT-INR) which will be measured
in the Landspitali coagulation laboratory using the STA-R instrument (Stago).
5.4.3 Blinding. The study will be double-blinded, i.e. all assessors of clinical effect and
dosing staff as well as patients will be blinded to the monitoring test-method. Blinded test
results (INR) will be administered by the coagulation laboratory staff which cannot be
blinded since they do the laboratory testing. The coagulation laboratory will measure INR
(PT) on one STA-R instrument and Fiix-INR (Fiix-PT) on another STA-R instrument. All
results, however will be reported out as "INR". The patients will not be informed on which
test is used to monitor their anticoagulation and only a value ("INR") will be reported to
patients. The test results will also be reported electronically as "INR" to the dosing staff
(nurses, biomedical scientists, physicians) and study nurse who will not have knowledge on
which test is used to monitor each patient. The data will be managed by the study nurse who
will not have access to monitoring test allocation. All formal assessors of clinical events
and secondary endpoints will also be blinded to test allocation. The dosing staff will dose
patients based on INR, i.e. using the DAWN anticoagulation management software (Onundarson,
Einarsdottir et al. 2008).
5.5 Prior and concomitant anticoagulant medication 5.5.1 Anticoagulant medication prior to
randomization Therapeutic dosages of (LMW)heparin/fondaparinux are allowed concomitantly
with warfarin in new patients or during bridging therapy in association with procedures.
6 STUDY TESTS 6.1 INR and Fiix-INR Current patients on stable warfarin therapy (see 5.4.1)
can be included. In new patients, no later than after the first dose of warfarin should the
dosing be managed by the AMC staff at Landspitali. The VKA dosage will be adjusted to
maintain the Fiix-INR or the INR (PT-INR) with the therapeutic target of 2.5 (range
2.0-3.0).
6.1.1 PT-INR The INR is calculated by the following formula: INR= (Patient PT/mean normal
PT)ISI .
6.1.2 Fiix-INR Fiix-PT will be measured using Neoplastin CI plus® and Fiix depleted plasma
as described in patent application P8151IS00, March, 8th 2011. Fiix-INR will be calculated
in the same manner as the PT-INR is calculated. ISI is calculated from DEKS calibrators as
in 6.1.1.
6.2 Packaging, labeling, and storage The test reagents will be stored according to their
package inserts and the Fiix deficient plasma will be stored in aliquots at -70°C.
6.3 Accountability and study compliance All testing, dosing and follow-up must be done in
accordance with the protocol and group assignment. During emergency testing both tests
should be measured on all patients. When the laboratory is not sure both tests should be
measured. All samples drawn during weekend and holidays should be kept until coagulation
laboratory staff has decided that they can be discarded.
6.3.1 VKA treatment monitoring The INR and Fiix-INR should initially be measured every 2 to
4 days and when stable (at least two consecutive tests within target range) no less that
every 8 weeks.
7 STUDY PROCEDURES 7.1 Study period This is the period between randomization (first testing
with assigned test = Day 1) and final assessment of each individual. Data will be retrieved
continuously as described above. After 3, 6, 9 and 12 months "interim" (safety, efficacy)
analyzes will be performed (see Chapter 11). We will randomize 1200 clients of the AMC into
two identically sized monitoring groups, Fiix-INR (test group) and INR (control group). Each
individual will be assessed monthly for up to 24 months (an expected average of 18 months)
until a total of 600 patients years of observation has been reached in each group. The study
may also be stopped by the recommendation of the DSMB if a clinically significant difference
in outcome becomes evident at an earlier time-point indicating inferiority of the new
method.
7.1.1 Patient written information Prior to enrollment potential study participants will
receive an introductory information letter as well as informed consent form detailing the
study and symptoms suggestive of new or recurrent thromboembolism or major bleeding.
7.1.2 Patient contacts Data will be retrieved continuously and each patient will be
contacted on a monthly basis. As described in detail in the protocol, in the case of
suspected bleeding or thrombotic events or death data will be retrieved from case records,
hospital summaries, autopsy reports or other records from physicians. When suspected serious
events occur, the patients will be immediately referred to appropriate level care in the
hospital.
7.1.2.1 Initial CRF form (see: Initial Case Report Form (Initial CRF) form) When the patient
has signed an informed consent, an initial CRF form (ICRF) will be filled in.
7.1.2.2 Follow-up CRF form (see: Follow-up Contact Case report (review) form (Follow-up
CRF)) Every time a patient has a contact with the AMC (e.g. INR measurement or dosing
instructions), the dosing staff or study nurse will ask questions by exactly following the
case review form (CRF, 14.2). If the questions are answered with a "yes", the study nurse
will without delay contact that particular patient for more detailed information (ie HCRU
form, see: Event report form / Health Care resource utilization (HCRU)). The study nurse
will then, as appropriate, collect necessary documents for the independent adjudication
committee (IAC), see chapter 9.3.3. During each patient event, the following will be
systematically checked by interviewing patients and reviewing the hospital chart for
thromboembolism, bleeding events, concomitant medication, in particular antiplatelet agents
such as aspirin or clopidogrel and NSAID use and compliance with monitoring 7.1.2.3
Observational period All patients will have a 5 day observational period after discontinuing
from study.
7.2 Efficacy and safety outcome criteria for the IAC 7.2.1 Assessment of clinical outcomes
All suspected clinical outcomes i.e. recurrent TE, bleeding, death and vascular events, will
be notified expedited to the IAC in a manner blinded to which test was applied. Blinded
review of the event by the IAC should be completed within 2-4 weeks after occurrence of the
event. The primary efficacy outcome is symptomatic or fatal recurrent arterial or venous TE
event during the study period. The primary safety outcome is bleeding. Prespecified criteria
for these events are excluded from this abbreviated protocol version.
7.3 Surrogate endpoints/Convenience endpoints
1. During initiation of VKA therapy: i. Number of tests needed to reach stable INR, i.e.
until the first of two consecutive INR values are obtained within the target range. ii.
Time until stable INR within target range
2. During stable phase: i. Total number of tests per treatment year ii. Dose adjustment
frequency (interval or number of dose adjustments during observation period) iii.
Percent tests within treatment range over observation period iv. Percent time within
target range (TTR) over observation period
7.4 Measures to minimize bias A series of measures will be implemented to minimize the
potential for bias in this study as detailed in the full protocol.
7.5 Approach to the bleeding patient If a patient has a serious bleed during study, the
following routine measures should be considered.
Refer the patient immediately to the emergency department Delay or discontinue the next
anticoagulant dose and consider vitamin K administration and usual treatment for bleeding,
including blood transfusion, prothrombin complex concentrate administration, recombinant
factor VIIa (NovoSeven and fresh frozen plasma
8 PREMATURE DISCONTINUATION OR TEMPORARY DISRUPTION
Subjects may be withdrawn from the study for the following reasons:
At their own request or at the request of their legally acceptable guardian. If, in the
investigator's opinion, continuation on anticoagulation would be detrimental to the
subject's well-being.
This is further detailed in the full protocol 9 DATA QUALITY ASSURANCE 9.1 Data quality The
monitoring and auditing procedures defined below will be followed.
9.2 Documentation Entries made in the CRF must be either verifiable against source
documents, or have been directly entered into the CRF, in which case the entry in the CRF
will be considered as the source data. The source data parameter to be verified and the
identification of the source document must be documented. The study file and all source data
will be retained for 5 years following final publication of study results when source data
can be destroyed. No published result will be traceable to particular persons.
9.3 Study administration/committees 9.3.1 Executive committee (EXC) The EXC has the overall
scientific responsibility of the study. Its tasks and responsibilities are to create and
approve the final protocol, co-author protocol amendments whenever necessary, ensure a
scientifically sound and safe conduct of the study, including by abiding to DSMB
recommendations, decide on the DSMB recommendations, review and approve the statistical
analysis plan, guarantee the integrity of data collection and analyses and to decide on the
publication- and presentation policy of the final results and ancillary studies 9.3.2 Study
management and coordination committee (SMCC) The SMCC has the overall clinical
responsibility of the study. Its tasks and responsibilities are to review the protocol,
review the CRF, support the EXC by advice, monitor progress of study enrollment,
address/resolve study management problems and participate in the analysis and presentation
of the results.
Member (author group):
The Independent adjudication committee (IAC) has the following roles: A. Blinded review of
clinical events (IAC- function), i.e. all suspected recurrent thromboembolic events,
bleeding of any kind, any vascular events and all deaths during the study period and the
observational period will be evaluated by IAC .The study nurse will provide the IAC with all
relevant documentation related to the events but the IAC will be blinded as to the
monitoring method of each patient while evaluating events. Adjudication results will be the
basis for the final analyses. and B. Data safety and monitoring (DSMB-function), i.e. this
committee also has the responsibility to provide the EXC with recommendations related to the
protection of the patients' safety, including stopping recruitment and stopping the study.
For this purpose, the DSMB will review all incidences of recurrent thromboembolism and
bleeding every 3 months, see Chapter 11.
9.3.4 External monitoring of study Adherence to study protocol will be monitored by an
external agency. 10 ETHICAL AND LEGAL ASPECTS 10.1 Ethical committees (EC) The study will we
conducted in accordance with the Helsinki declaration. Documented approval from appropriate
ethical committees (EC) (applications will be sent to National Bioethics Committee (NBC)
("Vísindasiðanefnd"), The Data Protection Authority ("Persónuvernd") and from the
Landspitali Medical Director will be obtained prior to the start of the study, according to
good clinical practice (GCP), local laws, regulations and organizations. Regulatory
authority approvals/authorizations notifications will be in place and fully documented prior
to study start.
10.2 Ethical conduct of the study The procedures set out in this protocol, pertaining to the
conduct, evaluation, and documentation of this study, are designed to ensure that the
investigators abide by GCP Guidelines and under the guiding principles detailed in the
declaration of Helsinki. The study will also be carried out in keeping with applicable local
law(s) and regulation(s). This may include an inspection by regulatory authority
representatives at any time, including allowing direct access of source documents to the
regulatory authority.
10.3 Subject information and consent A core information and informed consent form will be
provided. Written informed consent must be obtained before any study specific procedure
takes place. Participation in the study and date of informed consent given by the subject
should be documented appropriately in the subject's files.
10.4 Insurance All subjects participating in the study will be covered by the Landspitali
Hospital patient insurance in line with applicable laws and/or regulations.
10.5 Confidentiality All records identifying the subject will be kept confidential and, to
the extent permitted by the applicable laws and/or regulations, will not be made publicly
available. Only the subject number will be recorded in the CRF. A list with names and
subjects numbers will be kept separately by the EXC and its employees. If the results of the
study are published, the subject's identity will remain totally confidential. The
investigator will, however, maintain a list to enable subjects' records to be identified.
10.6 Archiving of data The investigator will arrange for the retention of the study
documentation file for 5 years. All data and documents should be made available if requested
11 STATISTICAL AND ANALYTICAL METHODS 11.1 Statistical analysis plan (SAP) The plan is
described in the following sections. However, the SAPs will allow protocol amendments or
unexpected issues in study execution or data that affect planned analyses.
11.2 Analysis populations The intention-to-monitor ("ITM") population will consist of all
patients who have been randomized, i.e., when the patient number and allocated monitoring
method are recorded in study-data base.
Patients will be analyzed by the monitoring method assigned. Patients will contribute to
patient years during the time they are in the study For patient year analysis the following
patients will be censored at the last day the patient had a complete assessment for study
outcomes within the intended treatment duration. Patients who did not have a thromboembolic
or bleeding event during the time of the predefined randomized test duration, patients lost
to follow-up patients who died because of other reasons than thromboembolic events patients
who withdrew informed consent before the end of the predefined treatment duration and who
did not have an efficacy or safety outcome. The per-protocol-population (PPP) will consist
of all randomized patients without any major deviation from the protocol. The following
deviations will lead to exclusion from the PP population: Patients not tested according to
allocation or no VKA treatment received at all 11.3 Study population/sample size and power/
demographics and patient characteristics Baseline characteristics: Demographic
characteristics (including age, sex, indications for anticoagulation, concomitant drug use)
will be summarized by treatment group using descriptive statistics and the groups will be
compared with regard to baseline characteristics using traditional statistical methods. As,
all major clinical events are likely to be admitted to Landspitali, the only acute care
hospital in the Reykjavik area, loss to follow-up is expected to be negligible. Therefore,
no adjustment of sample size is considered necessary. Patients excluded from the analysis
population in the per protocol analysis will be listed by test method and reason for
exclusion. The number and percentage of randomized patients who discontinued from the study
prematurely will be tabulated by main reason for discontinuation and treatment group.
11.3.1 Non-inferiority margin estimation This study is powered for analysis of successful
anticoagulation treatment and monitoring. For this calculation we have used data from
studies on the clinical outcome of patients with mixed indications for anticoagulation,
monitored and dosed by anticoagulation management centers (Palareti, Leali et al. 1996;
Wilson, Wells et al. 2003; Abdelhafiz and Wheeldon 2004; Menendez-Jandula, Souto et al.
2005). In these studies the combined endpoints of major bleeding and thromboembolic events
ranged from 2.7 to 7.3 per 100 patients years and event rate for thromboembolic events was
0.9 to 5.4 per 100 patient years (0.9-5.4%) with the lower margin of the 95% CI ranging form
2.9 to 8.2%. The largest observational study (Palareti, Leali et al. 1996; Wilson, Wells et
al. 2003; Abdelhafiz and Wheeldon 2004; Menendez-Jandula, Souto et al. 2005) and the only
randomized study (Palareti, Leali et al. 1996; Wilson, Wells et al. 2003; Abdelhafiz and
Wheeldon 2004; Menendez-Jandula, Souto et al. 2005) had an TE event rate of 3.5 and 5.4%
respectively. We therefore chose to use 3% TE-event rate as our expected TE-event rate (97%
success rate) and the non-inferiority of 5.5% (94.5% success rate for efficacy). We consider
this 2.5% difference one that is clinically significant, yet within the 95% CI for event
rate in some prior studies. Based on these considerations, the appropriate number of
participants needed to demonstrate statistical non-inferiority of clinically important
events for the test method with an 80% certainty after one year of observation are about 600
(576) patients in each group, i.e. 600 (576) patient years in each group.
11.4 Major event analysis (Efficacy and safety analysis) Major events analyses, primarily
the TE event rate (efficacy) but also the secondary end points of the rate of bleeding and
major bleeding (safety) as well as the combined endpoint of TE events and major bleeding
events will be based on the ITT population. For the primary and secondary endpoints, event
free survival will be compared in the two groups using Kaplan-Meier curves. Optionally, the
time to the first events will be analyzed using Cox's proportional hazard models.
11.5 Interim analysis 11.5.1 Study monitoring The study progress will be monitored
continuously. Interim analysis for safety purposes is planned at 3, 6, 9 and 12 months.
Based on this, risk-benefit will be evaluated by the DSMB.
11.6 Surrogate endpoint analysis Median time within target range, time until stable INR as
well as other surrogate parameters will be evaluated using the Mann-Whitney test for numeric
rows or other appropriate statistical tests.
