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Protocol - Population-based Pharmacokinetic Study Using One-stage Clotting Factor Assay - Extended Half-life Factor IX Products

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Description:

This protocol provides instructions and guidance for collecting and processing samples for coagulation testing, performing a population-based pharmacokinetic study using the one-stage clotting factor assay, and interpreting pharmacokinetic results in response to infusion of extended half-life Factor IX products. Because there are many comparable assays for performing the one-stage assay, the protocol also provides basic guidelines to aid comparability among different studies.

Specific Instructions:

The PhenX Hemophilia Inhibitor Research Working Group (WG) notes that these measures are intended for use in observational and interventional trials but are not sufficient to define hemophilia phenotypes when used in isolation.

The WG recommends that when measuring inhibitor recovery in non-severe patients, endogenous factor should be measured by the same assay that was optimized prior to inhibitor development.

The WG recommends that Factor VIII and IX assays, either by one-stage clotting factor or chromogenic substrate methodology, should be performed by a laboratory that is College American Pathologists (CAP) accredited or Clinical Laboratory Improvement Amendments of 1998 (CLIA) certified. For multi-center clinical trials, the use of a central laboratory is strongly encouraged.

The WG notes that certain one-stage assays are not suitable to monitor specific extended half-life products (see General References). Investigators should select an assay that aligns with the one used to determine the potency of the extended half-life product. Additionally, investigators should record the make and manufacturer of equipment, the repeatability and coefficients of variation for the assay, and the reagents used.

Protocol:

Extended Half-life Factor IX Products: Population-based Pharmacokinetic Study Using One-stage Clotting Factor Assay

Sample Collection

The PhenX Hemophilia Inhibitors Working Group (WG) recommends that investigators follow the sample collection procedures outlined in Lippi et al. (2012) to ensure quality specimens for coagulation testing. These recommendations include basic criteria for venipuncture (e.g., proper patient identification, use of correct techniques, appropriate devices and needles) as well as additional guidance for critical parameters which can affect the outcome of clot-based tests. These critical parameters include prevention of prolonged venous stasis, collection of nonhemolyzed samples, order of blood draw, and appropriate filling and mixing of collection tubes.

Additionally, the WG highlights that blood should be collected by direct venipuncture into 3.2% sodium citrate tubes and filled within 11% of fill line. A second tube should be collected. A discard tube should be drawn if using a winged butterfly collection system.

Sample Processing

The WG recommends that investigators follow the sample collection procedures outlined in Adcock Funk et al. (2012). The procedures include that:

  • unprocessed or processed sodium citrate samples remain capped and at room temperature until testing,
  • samples should not be refrigerated or stored on ice or in an ice bath,
  • samples should be transported vertically, and
  • processed samples should not be agitated during transportation to avoid remixing of components.

Additionally, samples can be transported and stored as:

  • unprocessed sodium citrate whole blood samples,
  • whole blood samples centrifuged and maintained in sodium citrate tubes, or
  • plasma processed by centrifugation and aliquoted into a second tube.

Ideally, whole blood samples should be processed to platelet-poor plasma (PPP) within 1 hour of collection and assayed within 4 hours of collection.

If centrifuging samples, the centrifuge should be validated so that post-centrifuged samples contain less than 10,000 platelets/microliter. Centrifuged samples should be frozen immediately and can be stored at -20o C for 2 weeks. Samples should be transferred to < -70o C for longer storage, including shipment.

Extended Half-life Factor IX Products: One-stage Clotting Factor Assay

There are a number of different assays and instruments that are appropriate to perform the one-stage clotting factor assay. However, the WG notes the activity of Factor IX extended half-life products in plasma determined by the one-stage clotting factor assay can vary according to the reagents and instrumentation used. Some one-stage assays are not suitable to monitor specific extended half-life products (see General References). Investigators should select an assay that aligns with the one used to determine the potency of the extended half-life product.

Once an assay is chosen for a particular study, the WG recommends that no changes in the protocol be made over the course of the study. Additionally, the WG recommends that the investigator record the make and manufacturer of equipment, the repeatability and coefficients of variation for the assay, and the reagents used.

Extended Half-life Factor IX Products: Population-based Pharmacokinetic Study

The WG recommends that investigators follow parameters outlined by the International Society on Thrombosis and Haemostasis Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders (Iorio et al., 2017). These parameters include taking three measurements at least 24 hours apart after a routine dose of the extended half-life product (i.e., no washout period and no standardized dose) at the following timepoints:

  • 24-36 hours after infusion;
  • 48-60 hours after infusion; and
  • 5-14 days after infusion.

Extended Half-life Factor IX Products: Population-based Pharmacokinetics Model

Investigators should use a "robust" population pharmacokinetics model, such as WAPPS-Hemo or PKFit

Protocol Name from Source:

N/A; see source.

Availability:

Publicly available

Personnel and Training Required

Phlebotomist

Equipment Needs
Laboratory with the ability to perform the one-stage clotting factor assay.
Requirements
Requirement CategoryRequired
Major equipment No
Specialized training No
Specialized requirements for biospecimen collection Yes
Average time of greater than 15 minutes in an unaffected individual Yes
Mode of Administration

Bioassay

Life Stage:

Toddler, Child, Adolescent, Adult

Participants:

Any age

Selection Rationale

The PhenX Hemophilia Inhibitors Working Group selected the recommendations from Lippi et al. (2012) and Adcock Funk et al. (2012) as the best standardized methodology for collecting and processing samples for coagulation testing. The International Society on Thrombosis and Haemostasis (Iorio et al., 2017) provides recommended parameters for consistent implementation of the pharmacokinetic study.

Language

English

Standards
StandardNameIDSource
Common Data Elements (CDE) Individual Pharmacokinetic Study Coagulation Factor IX Extended Half Life Chromogenic Substrate Clotting Factor Assay 6706635 CDE Browser
Derived Variables

None

Process and Review

Not applicable.

Source

Adcock Funk, D. M., Lippi, G., & Favaloro, E. J. (2012). Quality standards for sample processing, transportation, and storage in hemostasis testing. Seminars in Thrombosis and Hemostasis, 38(6), 576-585.

Iorio, A., Blanchette, V., Blatny, J., Collins, P., Fischer, K., & Neufeld, E. (2017). Estimating and interpreting the pharmacokinetic profiles of individual patients with hemophilia A or B using a population pharmacokinetic approach: Communication from the SSC of the ISTH. Journal of Thrombosis and Haemostasis, 15(12), 2461-2465.

Lippi, G., Salvagno, G. L., Montagnana, M., Lima-Oliveira, G., Guidi, G. C., & Favaloro, E. J. (2012). Quality standards for sample collection in coagulation testing. Seminars in Thrombosis and Hemostasis, 38(6), 565-575.

General References

lvarez-Romn, M. T., Fernandez-Bello, I., de la Corte-Rodrguez, H., Hernndez-Moreno, A. L., Martn-Salces, M., Butta-Coll, N., Rivas-Pollmar, M. I., Rivas-Muoz, S., & Jimnez-Yuste, V. (2017). Experience of tailoring prophylaxis using factor VIII pharmacokinetic parameters estimated with myPKFiT in patients with severe haemophilia A without inhibitors. Haemophilia, 23(1), e50-e54.

Blanchette, V. S., Key, N. S., Ljung, L. R., Manco-Johnson, M. J., van den Berg, H. M., & Srivastava, A.; Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. (2014). Definitions in hemophilia: Communication from the SSC of the ISTH. Journal of Thrombosis and Haemostasis, 12(11), 1935-1939.

Hay, C. R., & DiMichele, D. M.; International Immune Tolerance Study. (2012). The principal results of the International Immune Tolerance Study: A randomized dose comparison. Blood, 119(6), 1335-1344.

Iorio, A., Keepanasseril, A., Foster, G., Navarro-Ruan, T., McEneny-King, A., Edginton, A. N., & Thabane, L.; WAPPS-Hemo co-investigator network. (2016). Development of a Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Study protocol. JMIR Research Protocols, 5(4), e239.

Iorio, A., Edginton, A.N., Blanchette, V., Blatny, J., Boban, A., Cnossen, M., Collins, P., Croteau, S.E., Fischer, K., Hart, D.P., Ito, S., Korth-Bradley, J., Lethagen, S., Lillicrap, D., Makris, M., Matht, R., Morfini, M., Neufeld, E.J., Spears, J. (2018). Performing and interpreting individual pharmacokinetic profiles in patients with Hemophilia A or B: Rationale and general considerations. Research and Practice in Thrombosis and Haemostasis, 2(3), 535-548.

Kershaw, G. W., Dissanayake, K., Chen, V. M., & Khoo, T. L. (2018). Evaluation of chromogenic factor IX assays by automated protocols. Haemophilia, 24(3), 492-501.

Kitchen, S., Kershaw, G., & Tiefenbacher, S. (2016). Recombinant to modified factor VIII and factor IX Chromogenic and one-stage assays issues. Haemophilia, 22(Suppl. 5), 72-77.

Kitchen, S., Tiefenbacher, S., & Gosselin, R. (2017). Factor activity assays for monitoring extended half-life FVIII and factor IX replacement therapies. Seminars in Thrombosis and Haemostasis, 43(3), 331-337.

Lee, M., Morfini, M., Schulman, S., & Ingerslev, J.; Factor VIII/Factor IX Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis. (2001). Scientific and Standardization Committee communication. The design and analysis of pharmacokinetic studies of coagulation factors. https://www.isth.org/members/group_content_view.asp?group=100348&id=159244. Retrieved August 30, 2018.

Peyvandi, F., Oldenburg, J., & Friedman, K. D. (2006). A critical appraisal of one-stage and chromogenic assays of factor VIII activity. Journal of Thrombosis and Haemostasis, 14(2), 248-261.

Teichman, J., Chaudhry, H. R., & Sholzberg, M. (2018). Novel assays in the coagulation laboratory: A clinical and laboratory perspective. Transfusion and Apheresis Science, 57(4), 480-484.

Protocol ID:

911002

Variables:
Export Variables
Variable Name Variable IDVariable DescriptiondbGaP Mapping
PX911002_Factor_Nine_Population_Clotting_Extended_One_Stage_Clotting_Factor_Assay_Changes
PX911002030100 Were any changes made in the protocol over more
the course of the study? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_One_Stage_Clotting_Factor_Assay_Record
PX911002030200 Were the make and manufacturer of equipment, more
repeatability and coefficients of variation for the assay, and the reagents used recorded? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Pharmacokinetic_Model
PX911002040500 Was a "robust" population pharmacokinetics more
model, such as WAPPS-Hemo or PKFit, used? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Pharmacokinetic_Study
PX911002040100 Were the parameters outlined by the more
International Society on Thrombosis and Haemostatis Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders (Iorio et al., 2917) followed? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Pharmacokinetic_Study_After_Infusion_Days
PX911002040400 Was a measurement taken 5-14 days after more
infusion with a routine dose of the extended half-life product? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Pharmacokinetic_Study_After_Infusion_Hours_24
PX911002040200 Was a measurement taken 24-36 hours after more
infusion with a routine dose of the extended half-life product? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Pharmacokinetic_Study_After_Infusion_Hours_48
PX911002040300 Was a measurement taken 48-60 hours after more
infusion with a routine dose of the extended half-life product? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Collection
PX911002010100 Were the sample collection procedures more
outlined in Lippi et al. (2012) followed? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Collection_Blood_Draw
PX911002010400 Was the order of blood draw recorded? N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Collection_Nonhemolyzed
PX911002010300 Were nonhemolyzed samples collected? N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Collection_Tubes
PX911002010500 Were collection tubes filled and mixed? N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Collection_Tubes_Discard
PX911002011000 Was a discard tube drawn? N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Collection_Tubes_Filled
PX911002010700 Were the tubes filled within 11% of the fill line? N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Collection_Tubes_Second
PX911002010800 Was a second tube collected? N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Collection_Tubes_Winged
PX911002010900 Was a winged butterfly collection system used? N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Collection_Venipuncture
PX911002010600 Was blood collected by direct venipuncture more
into 3.2% sodium citrate tubes? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Collection_Venous_Statsis
PX911002010200 Were steps taken to prevent prolonged venous more
stasis? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing
PX911002020100 Were the sample collection and processing more
procedures outlined in Adcock Funk et al. (2012) followed? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Agitation
PX911002020500 Were samples agitated during transportation? N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Assayed
PX911002021000 Were samples assayed within 4 hours of collection? N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Centrifuge_Validated
PX911002021100 Was the centrifuge validated so that process more
results in less than 10,000 platelets/microliter show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Deep_Freeze
PX911002021300 Was the sample transferred to <= -70 C, more
including shipment? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Frozen
PX911002021200 Was the sample frozen immediately and stored more
at -20 C for at most 2 weeks? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Platelet_Poor_Plasma
PX911002020900 Were samples processed to platelet poor more
plasma (PPP) within 1 hour of collection? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Refrigerated
PX911002020300 Were samples refrigerated or stored on ice more
or in an ice bath? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Sodium_Citrate
PX911002020200 Did unprocessed or processed sodium citrate more
samples remain capped and at room temperature until testing? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Storage_Plasma
PX911002020800 Were samples stored as plasma processed by more
centrifugation and aliquoting into a second tube? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Storage_Unprocessed
PX911002020600 Were samples stored as unprocessed sodium more
citrate whole blood samples? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Storage_Whole_Blood
PX911002020700 Were samples stored as whole blood samples more
centrifuged and maintained in sodium citrate tubes? show less
N/A
PX911002_Factor_Nine_Population_Clotting_Extended_Sample_Processing_Transportation
PX911002020400 Were samples transported vertically? N/A
Hemophilia Inhibitor Research
Measure Name:

Response to Factor IX Infusion - Population-based Pharmacokinetic Study

Release Date:

May 7, 2019

Definition

A series of plasma Factor IX activity determinations in blood samples are obtained immediately prior to, and at timepoints after, infusion of Factor IX concentrate.

Purpose

The results of the population-based pharmacokinetic study (i.e., initial recovery and half-life) can be used to guide prophylactic dosage of standard and extended half-life Factor IX products in hemophiliacs who do not have FIX inhibitors.

Keywords

Hemophilia inhibitors, Factor IX, FIX, hemophilia B, pharmacokinetic study, population pharmacokinetic study, popPK, prophylaxis, half-life, recovery