Hemophilia A Clinical Trial
Official title:
Calibrated Automated Thrombogram: A Scandinavian Multicenter Study
This study is aims at determining the inter laboratory variation when using the thrombin generation assay calibrated automated thrombogram (TGA CAT). It is thus, not a clinical trial in its usual meaning. However, to achieve relevant test samples one patient will be treated with two different study drugs as part of the trial and therefore, approval by Läkemedelsverket is needed. Test plasma samples will be sent out to five participating centers in the Scandinavian countries (Gothenburg and Stockholm, Sweden, Århus Denmark, Oslo Norway and Helsinki Finland) and coefficients of variance (CV) and level of agreement will be analyzed. To obtain representative plasma samples with a wide range of thrombin generation capacity (TGC), blood samples will be collected from research persons that has given informed consent to participate in the study. To obtain plasma with low TGC, blood samples will be drawn from patients with severe hemophilia (n=4)(study group 1), to obtain plasma with normal TGC, blood samples will be drawn from healthy volunteers (n=3)(study group 2) and to obtain plasma with high TGC, plasma will be collected from healthy volunteers (n=3)(study group 3) that at previous measurements have been shown to have a TGC>2SD of the median of the control population. Moreover, one patient with severe hemophilia A (HA) will be treated with two factor FVIII concentrates, one with standard half- life (Advate™) and one with a pro-longed half-life (Adynovate™) at two separate occasions (Treated HA person). By taking repeated blood samples after administration, samples with a wide range of FVIII levels and TGC:s will be obtained. Moreover, the effect of using plasmas with low, normal and high TGC for normalization will be investigated. Plasma samples will be collected as soon as approval from the Swedish medical agency (SMA) has been obtained, we count on sending them to participating centers March 2017. All laboratory measurements, data analysis and report writing will be concluded before December 31 2017.
Main goal The aim is to further improve the inter-laboratory variability for the TGA-CAT
(Thrombin generation assay-calibrated automated thrombogram) method by using an elaborate
standardization protocol and in extension making the use of large prospective multi-center
studies a reality.
Goals of the project are:
- To determine the inter-laboratory variability by evaluating an enhanced standardized
TGA-CAT protocol.
- To evaluate if the inter-laboratory variability of the TGA-CAT method is effected by
administration of a recombinant FVIII product (Advate) in a person with severe
hemophilia A
- To evaluate if the inter-laboratory variability of the TGA-CAT method is effected by
administration of a long acting FVIII product (Adynovate) in a person with severe
hemophilia A
- To evaluate three reference plasma´s ability, through normalization of data, to improve
the lab-to-lab variability.
Introduction The TGA CAT method has proved its usefulness for multiple purposes including
diagnosis and management of bleeding disorders (1, 2), detecting hyper coagulability (3, 4),
and monitoring and characterization of oral anticoagulant drugs (5, 6). Most of these studies
are single-center studies and large prospective multi-center studies are needed to further
validate the results. These multi-center studies have proved to be hard to produce due to
lack of standardization of the method. In the last couple of years several articles have
addressed the problem with large inter-laboratory variability for the TGA-CAT method by
presenting thoroughly worked-out standardization protocols. Focus has been put both on the
method itself and its pre-analytical factors as well as the usage of reference plasmas (RP)
for normalization of results. One article showed that the choice of RP for the normalization
of results could greatly reduce the inter-lab variability and that certain RP have a better
ability to do so (7).
Lately a number of recombinant Factor VIII (rFVIII) and IX (rFIX) drugs with prolonged
half-life have been developed and are about to or even have reached the market. The length of
the pro-longed activity of the drug differs between patients and a need for individual
tailoring of the patient´s drug administration is obvious. Thrombin generation could prove to
be an excellent tool in tailoring the optimal drug administration and monitoring the effect
of the drug for each individual.
Methods and materials Thrombin generation Thrombin generation will be measured according to
the method described by Hemker et al.(8): calibrated automated thrombogram (CAT,
Thrombinoscope BV, Maastricht, the Netherlands).
Reagents PPP-reagent LOW (1 pM), PPP-reagent (5 pM), Thrombin Calibrator and FluCa-kit
(TS31.00, TS30.00, TS20.00 and TS50.00, Thrombinoscope BV, Maastricht, The Netherlands) will
be used in the test.
Samples Three different plasmas will be tested, normal plasma, hypo- and hypercoagulable
plasma. Normal and hypercoagulable plasma will be pooled from 3 donors and hypocoagulable
plasma will be collected from 4 donors. Hypocoagulable plasma will be collected from five
haemophilia A (HA) patients regularly treated at the Malmö Coagulation Unit by taking 10 4.5
mL tubes of citrated blood at one occasion. Normal plasma will be collected from 3 co-workers
at the same unit, each person donating 13 tubes of 4.5 mL citrated blood. Hypercoaguable
plasma will be prepared from 3 healthy volunteers, shown to have TGA CAT parameter values >2
SD of median by taking 13 tubes of 4.5 mL citrated blood. Plasma from one patient with severe
HA patient that have been given FVIII-concentrates, Advate™ respectively the long-acting
Adynovate™ at two separate occasions will also be tested. After informed consent the patient
will be asked not to take his regular profylaxis dose for 72 hours. The patient will be given
Advate™ and Adynovate™ respectively at 30 U/kg. The monitoring samples will be taken 1h, 8h,
24h, 36h and 48h (Advate™) and 1h, 24h, 36h, 48h and 72h (Adynovate™) after injection. At
each time point 3 tubes of 4.5 mL blood will be taken.
Reference plasmas Siemens Control Plasma P diluted 1:5 will be used as hypocoaguable RP,
HemosIL calibration plasma (Instrumentation Laboratory, Bedford, Ma, USA) will be used as
Standard RP and as hypercoagable plasma PS-DP (protein S-deficiency plasma)(Enzyme research
laboratories, South Bend, In, USA) will be used.
Statistical analysis Raw data will be collected and analyzed at the Coagulation Unit, Skåne
University Hospital, Malmö. Each participating center will be matched with Malmö Coagulation
unit in a test of agreement where Bland-Altman bias plot will be used. The mean, standard
deviation (SD) and coefficient of variation (CV%) will be calculated for each center with and
without normalization and displayed in a table. The Advate/ Adynovate elimination profiles
will be plotted and multivariate repeated measurements analyses of variance including a
general test for parallel curves, will be applied to evaluate differences between Centers in
the elimination profiles.
Study design The study aims to evaluate the inter-laboratory variability of TGA-CAT performed
TGT with a highly standardized protocol, how the use of RFs for normalization of data impact
on variability of results and to evaluate the usefulness of TGA-CAT in monitoring prolonged
FVIII drug administration. All Fluorometers of the participating center´s should be serviced
and have temperature calibrated to 37 C prior start of the study. The latest software version
must be installed (Thromboscope BV, Maastricht, The Netherlands, version V5.0.0.742). All
laboratory equipment, pipettes, water baths, water purifiers, etc., needs to be calibrated.
All plasmas, TGA-CAT reagents needed for the study will be administered and distributed to
all participating centers by the Coagulation Unit, Malmö. An USB-memory stick containing a
plate set-up scheme file and a video file covering critical pre-analytical and analytical
steps will also be provided alongside the samples and reagents. Three pooled plasmas (normal,
hypo- and hypercoaguable), three RF, five Adynovate and five Advate monitoring samples will
be run five times on five different days by each participating center, following a scheme
provided in the USB-memory stick, with two different triggers, PPP-reagent LOW (1 pM) and
PPP-reagent (5 pM). Two test runs are scheduled each day to maximize RF and reagent usage.
The reason for testing three different types of RF is the fact an earlier study results
implied a better reduction of variability when using, for an example a hypocoaguable RF to
hypocoaguable plasmas (9).
;
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT03834727 -
Characterizing the Impact and Treatment of Reproductive Tract Bleeding on Women and Post-menarchal Girls With Bleeding Disorders
|
||
Completed |
NCT03191799 -
A Study to Evaluate the Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A Patients With Inhibitors
|
Phase 3 | |
Completed |
NCT01599819 -
BAX 855 Dose-Escalation Safety Study
|
Phase 1 | |
Terminated |
NCT04541628 -
Safety & Efficacy of Encapsulated Allogeneic FVIII Cell Therapy in Haemophilia A
|
Phase 1/Phase 2 | |
Completed |
NCT02847637 -
A Clinical Trial to Evaluate Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants Without Inhibitors
|
Phase 3 | |
Completed |
NCT04072237 -
Study of Coagulation Faction VIIa Variant Marzeptacog Alfa (Activated) in Adult Subjects With Hemophilia
|
Phase 1 | |
Completed |
NCT04085458 -
Study to Gain More Information on How Safe and Effective Jivi Works in Patients With Severe Hemophilia A (Post-marketing Investigation)
|
Phase 4 | |
Completed |
NCT04565236 -
A Post Approval Commitment Study to Gain More Information on How Safe and Effective KOVALTRY is in Chinese Children, Adolescents /Adults With Severe Hemophilia A
|
Phase 4 | |
Recruiting |
NCT05987449 -
A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of NXT007 in Persons With Severe or Moderate Hemophilia A
|
Phase 1/Phase 2 | |
Active, not recruiting |
NCT04621916 -
Preventing Inhibitor Recurrence Indefinitely
|
Phase 4 | |
Not yet recruiting |
NCT02888223 -
Pharmacokinetic Study of SCT800 in Previously Treated Patients With Hemophilia A
|
Phase 1 | |
Completed |
NCT02528968 -
National Study of a Pharmacokinetic-Focused Educational Package for Patients With Severe Haemophilia A
|
N/A | |
Completed |
NCT02225483 -
Phenotypic Heterogeneity in Hemophilia A: An Investigation of the Role of Platelet Function
|
N/A | |
Completed |
NCT02199717 -
An Institutional Pilot Study to Investigate Physical Activity Patterns in Boys With Hemophilia
|
N/A | |
Completed |
NCT01217255 -
Comparing the Burden of Illness of Hemophilia in the Developing and the Developed World
|
||
Terminated |
NCT00995046 -
Individually Tailored Prophylaxis in Patients With Severe Hemophilia A
|
N/A | |
Completed |
NCT00969319 -
Effekt-2 - Efficacy and Safety of Long-term Treatment With KOGENATE® FS in Latin America
|
N/A | |
Completed |
NCT00868530 -
Study Evaluating On-Demand Treatment Of Xyntha In Chinese Subjects
|
Phase 3 | |
Completed |
NCT00839202 -
Activity and Content of Factor VIII (FVIII) in Human Plasma: The Assessment of a Novel Immunoassay
|
N/A | |
Completed |
NCT00629837 -
Pharmacokinetics and Safety of a Single Intravenous Infusion of BAY 79-4980
|
Phase 1 |