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Protocol - Individual Pharmacokinetic Study Using One-stage Clotting Factor Assay - Extended Half-life Factor VIII Products

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Description:

This protocol provides instructions and guidance for collecting and processing samples for coagulation testing, performing an individual pharmacokinetic study using the one-stage clotting factor assay, and interpreting pharmacokinetic results in response to infusion of extended half-life Factor VIII products. Because there are many comparable assays for performing the one-stage clotting factor 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.

If a washout is not performed, comparison of pharmacokinetic data between studies should be conducted under steady-state conditions. Steady-state is defined as a patient-specific condition during which a pharmacokinetic assessment remains valid over a clinically useful period of time. Examples of non-steady state conditions include:

  • Bleeding state
  • Peri- and immediate post-surgical states in which patients are receiving continuous or regular high (non-routine prophylactic) doses of Factor VIII
  • Immune tolerance induction during which inhibiter titers are in flux
  • Children in whom age- and weight-based clearance is still developing toward adult physiologic states.
Protocol:

Individual Pharmacokinetic Study Using One-stage Clotting Factor Assay - Extended Half-life Factor VIII Products

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 VIII Products: One-stage Clotting Factor Assay

There are a number of different assays and instruments that are available to perform the one-stage clotting factor assay. However, the WG notes the activity of Factor VIII extended half-life products measured by the one-stage clotting factor assay can vary according to the reagents and instrumentation. Some one-stage assays are not suitable to monitor specific extended half-life products (see "General References"). Therefore, 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. Because results can vary with the instrumentation and reagents, 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 VIII Products: Individual Pharmacokinetic Study

Prior to pharmacokinetic evaluations, participants should undergo a treatment-free washout period lasting longer than five half-lives. Samples should be taken before infusion (baseline), 10-15 minutes after infusion, and then up to eight other time points that cover 2.5 half-lives of the extended half-life Factor VIII products. The Hemophilia Inhibitors WG notes that the timepoints necessary for the pharmacokinetic study to cover 2.5 half-lives will depend on the specific extended half-life Factor VIII product being used and can be identified in relevant pre-licensure studies. Investigators should report which timepoints were used.

Extended Half-life Factor VIII Products: Interpretation of Individual Pharmacokinetic Study Results

The half-life of extended half-life Factor VIII products is highly variable and the level at which an inhibitor is suggested has not been established.

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 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.

Language

English

Standards
StandardNameIDSource
Common Data Elements (CDE) Population Pharmacokinetic Study Coagulation Factor IX Extended Half Life One-stage Clotting Factor Assay Ê 6706642 CDE Browser
Derived Variables

The results of this protocol can be combined with the results of Determination of Factor VIII Inhibitors: Bethesda Assay with Nijmegen Modification Using Chromogenic Substrate Assay or Determination of Factor VIII Inhibitors: Bethesda Assay with Nijmegen Modification Using One-Stage Clotting Factor Assay to document:

Presence of an Inhibitor

The presence of an inhibitor is indicated by:

  • lack of response (cessation of bleeding) to factor infusion for treatment of bleeding in a clinical setting,
  • less than expected (< 66%) of Factor VIII levels after infusion (Response to Factor VIII Infusion - Individual Pharmacokinetic Study) and positive inhibitor titer (Quantitative Measure of Factor VIII Inhibitor Activity) in routine surveillance.

Evolution of an Inhibitor

Inhibitor evolution is indicated by:

  • change in inhibitor titer over time (Quantitative Measure of Factor VIII Inhibitor Activity), with or without immune tolerance induction;
  • change in clinical response (i.e., bleeding) to Factor VIII infusion;
  • change in Factor VIII activity after factor infusion (Response to Factor VIII Infusion - Individual Pharmacokinetic Study).

Resolution of an Inhibitor

Inhibitor resolution is indicated by the following:

  • for patients receiving immune tolerance therapy for eradication of an Factor VIII inhibitor, success is defined as a negative inhibitor titer (Quantitative Measure of Factor VIII Inhibitor Activity), a normal recovery (>= 66% of expected) and a normal half-life of infused Factor VIII concentrate (Response to Factor VIII Infusion- Individual Pharmacokinetic Study).

Persistence of an Inhibitor

A persistent inhibitor is indicated by a decrease response to Factor VIII concentrate infusion (Response to Factor VIII Infusion - Individual Pharmacokinetic Study) with or without a persistently positive inhibitor titer (Quantitative Measure of Factor VIII Inhibitor Activity).

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.

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.

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

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 VIII 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., 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.

Kitchen, S., Kershaw, G., & Tiefenbacher, S. (2016). Recombinant to modified factor VIII and factor VIII 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 VIII 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.

Morfini, M., Lee, M., Messori, A. and the Factor VIII/Factor IX Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis. (1991). The design and analysis of half-life and recovery studies for factor VIII and factor IX. Thrombosis and Haemostasis, 66(3), 384-386.

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:

911102

Variables:
Export Variables
Variable NameVariable IDVariable DescriptionVersiondbGaP Mapping
PX911102_Factor_Eight_Individual_Clotting_Extended_One_Stage_Clotting_Factor_Assay_Changes PX911102030200 Were any changes made in the protocol over more
the course of the study? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_One_Stage_Clotting_Factor_Assay_Record PX911102030300 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
PX911102_Factor_Eight_Individual_Clotting_Extended_One_Stage_Clotting_Factor_Assay_Selection PX911102030100 Does the assay selected align with the one more
used to determine the potency of the extended half-life product? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Pharmacokinetic_Interpretation PX911102050100 During interpretations of the results, was more
it taken into account that the half-life of extended half-life Factr VIII products is highly variable and the level at which an inhibitor is suggested has not be established? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Pharmacokinetic_Study PX911102040100 Were the parameters outlined by the more
Subcommittee on Factor VIII and Factor VIII of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (Lee et al., 2001) followed? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Pharmacokinetic_Study_After_Infusion PX911102040400 Was a sample collected 10-15 minutes after more
infusion? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Pharmacokinetic_Study_After_Infusion PX911102040500 Were samples collected at up to eight other more
time points that cover 2.5 half-lives of the extended half-life Factor VIII products? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Pharmacokinetic_Study_After_Infusion_Baseline PX911102040300 Was a sample collected before infusion (baseline)? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Pharmacokinetic_Study_Timepoints PX911102040600 Was it taken into account that the more
timepoints necessary for the pharmacokinetic study to cover 2.5 half-lives depend on the specific extended half-life Factor VIII product being used? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Pharmacokinetic_Study_Timepoints_Record PX911102040700 Were sample collection timepoints recorded? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Pharmacokinetic_Study_Washout PX911102040200 Did the patient undergo a treatment-free more
washout period lasting longer than file half-lives? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Collection PX911102010100 Were the sample collection procedures more
outlined in Lippi et al. (2012) followed? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Collection_Blood_Draw PX911102010400 Was the order of blood draw recorded? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Collection_Nonhemolyzed PX911102010300 Were nonhemolyzed samples collected? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Collection_Tubes PX911102010500 Were collection tubes filled and mixed? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Collection_Tubes_Discard PX911102011000 Was a discard tube drawn? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Collection_Tubes_Filled PX911102010700 Were the tubes filled within 11% of the fill line? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Collection_Tubes_Second PX911102010800 Was a second tube collected? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Collection_Tubes_Winged PX911102010900 Was a winged butterfly collection system used? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Collection_Venipuncture PX911102010600 Was blood collected by direct venipuncture more
into 3.2% sodium citrate tubes? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Collection_Venous_Statsis PX911102010200 Were steps taken to prevent prolonged venous more
statsis? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing PX911102020100 Were the sample collection and processing more
procedures outlined in Adcock Funk et al. (2012) followed? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Agitation PX911102020500 Were samples agitated during transportation? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Assayed PX911102021000 Were samples assayed within 4 hours of collection? N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Centrifuge_Validated PX911102021100 Was the centrifuge validated so that process more
results in less than 10,000 platelets/microliter show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Deep_Freeze PX911102021300 Was the sample transferred to <= -70 C, more
including shipment? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Frozen PX911102021200 Was the sample frozen immediately and stored more
at -20 C for at most 2 weeks? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Platelet_Poor_Plasma PX911102020900 Were samples processed to platelet poor more
plasma (PPP) within 1 hour of collection? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Refrigerated PX911102020300 Were samples refrigerated or stored on ice more
or in an ice bath? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Sodium_Citrate PX911102020200 Did unprocessed or processed sodium citrate more
samples remain capped and at room temperature until testing? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Storage_Plasma PX911102020800 Were samples stored as plasma processed by more
centrifugation and aliquoting into a second tube? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Storage_Unprocessed PX911102020600 Were samples stored as unprocessed sodium more
citrate whole blood samples? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Storage_Whole_Blood PX911102020700 Were samples stored as whole blood samples more
centrifuged and maintained in sodium citrate tubes? show less
N/A
PX911102_Factor_Eight_Individual_Clotting_Extended_Sample_Processing_Transportation PX911102020400 Were samples transported vertically? N/A
Hemophilia Inhibitor Research
Measure Name:

Response to Factor VIII Infusion - Individual Pharmacokinetic Study

Release Date:

May 7, 2019

Definition

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

Purpose

The results of an individual pharmacokinetic study (i.e., initial recovery and half-life) of infused Factor VIII concentrate can characterize an individual’s response to a new drug or can confirm the success of immune tolerance induction (ITI).

Keywords

Hemophilia inhibitors, Factor VIII, FVIII, hemophilia A, inhibitors, pharmacokinetic study, immune tolerance induction, prophylaxis, half-life, recovery