Personalized Prophylactic Treatment With Advate® in Severe or Moderate Haemophilia A Patients

NCT02622646 | Unknown

• 1 other identifier: HUF-OCT-2015-01
• Study Type: observational
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

Haemophilia A is an inherited bleeding disorder caused by a deficiency of factor VIII (FVIII). Patients with severe hemophilia A have a FVIII plasma concentration less than1 IU/dL and experience spontaneous and trauma-induced bleeds. Joint bleeds lead to hemophilic arthropathy resulting in progressive disability. Patients with moderate hemophilia (FVIII level between 1-5 IU/dL) are characterized by fewer hemarthroses, usually trauma-induced, and a decreased likelihood of developing arthropathy. This clinical observation led to the use of prophylactic FVIII infusions to convert patient´s bleeding phenotype from severe to moderate with the result of decreasing or preventing arthropathy. Prophylactic regimens may be effective when based on standard fixed-dose protocols (that assumes one approach fits all patients) or phenotypic dosing determined by bleeding patterns, but do not protect all patients with severe haemophilia from joint damage caused by spontaneous or activity-triggered bleeding. Individualized treatment in haemophilia A takes into consideration all available information about the patient, not only his phenotypic bleeding pattern. Some of the factors that contribute to the observed interpatient variability include baseline or residual FVIII activity, the pharmacokinetic (PK) profile of the replacement factor, the individual's level of physical activity and perceived risk of traumatic bleeding, the presence or absence of joint disease, presence of comorbidities and adherence to the dosing regimen. Objectives: Identify and analyze cause(s) of poor bleeding control in patients on prophylaxis treatment and study the clinical impact of a "personalized pilot program" with a 1 year follow up to act on the specific causes.

1. 1.Describe PK parameters in patients on prophylaxis treatment with Advate®.
2. 2.Analyze differences in PK parameters in non-controlled vs well controlled patients.
3. 3.Identify causes of poor clinical outcome in non-controlled patients. Patients' individual variables that influence bleeding risk will be studied (individual PK, bleeding pattern, joint status, physical activity, life style and patient's adherence).
4. 4.Study the improvement in clinical outcomes (ABR and Joint status) of a 1 year Personalized Prophylaxis Program that acts specifically on the previously identified causes of bleeding in non-controlled patients (named: short half-life, high bleeding pattern, joint damage, high risk physical activity, active life style and poor patient's adherence).

Conditions

Hemophilia A; Factor VIII

Outcome Measures

Primary Outcomes (13)

• Steady state volume (Vss)

  This PK parameter of FVIII will be evaluated for each patient using the Bayesian pharmacokinetic 2-compartment model described by Björkman (MyPkFit ®). This model needs at least two samples: * First sample: at 3 hours of the administration. * Second sample: between 24-32 hours post-infusion. FVIII is measured by the one-stage assay in a central laboratory. PK monitoring will be performed in all the routine medical visits, at least two visits per year.

  At baseline and at 12 months

• Clearance (Cl)

  This PK parameter of FVIII will be evaluated for each patient using the Bayesian pharmacokinetic 2-compartment model described by Björkman (MyPkFit ®). This model needs at least two samples: * First sample: at 3 hours of the administration. * Second sample: between 24-32 hours post-infusion. FVIII is measured by the one-stage assay in a central laboratory. PK monitoring will be performed in all the routine medical visits, at least two visits per year.

  At baseline and at 12 months

• Half-life of FVIII (t½)

  This PK parameter of FVIII will be evaluated for each patient using the Bayesian pharmacokinetic 2-compartment model described by Björkman (MyPkFit ®). This model needs at least two samples: * First sample: at 3 hours of the administration. * Second sample: between 24-32 hours post-infusion. FVIII is measured by the one-stage assay in a central laboratory. PK monitoring will be performed in all the routine medical visits, at least two visits per year.

  At baseline and at 12 months

• Time to 1% FVIII activity above

  This PK parameter of FVIII will be evaluated for each patient using the Bayesian pharmacokinetic 2-compartment model described by Björkman (MyPkFit ®). This model needs at least two samples: * First sample: at 3 hours of the administration. * Second sample: between 24-32 hours post-infusion. FVIII is measured by the one-stage assay in a central laboratory. PK monitoring will be performed in all the routine medical visits, at least two visits per year.

  At baseline and at 12 months

• Annualized bleeding rate (ABR)

  To measure the bleeding pattern of each patient the annualized bleeding rate (ABR) will be employed. A subgroup analysis will be performed by bleeding type to determine numbers of traumas and spontaneous bleeds.

  At baseline, at 6 months and at 12 months

• Annualized joint bleeding rate (AJBR)

  To measure the bleeding pattern of each patient the annualized joint bleeding rate (AJBR) will be employed. A subgroup analysis will be performed by bleeding type to determine numbers of traumas and spontaneous bleeds.

  At baseline, at 6 months and at 12 months

• Gilbert joint score

  To measure the joint status of each patient the Gilbert joint score will be employed.

  At baseline and at 12 months

• HJHS score

  To measure the joint status of each patient the HJHS score will be employed..

  At baseline and at 12 months

• Physical activity

  The physical activity will be broadly categorized using a modification of the taxonomy devised by the American National Hemophilia Foundation (Broderick et al. JAMA 2012, Fischer et al. Haemophilia 2014). * Category 1 activities: are activities in which significant collisions are not expected (eg, swimming). * Category 2 activities: are those in which significant collisions might occur (eg, basketball). * Category 3 activities: are those in which significant collisions are inevitable (eg, wrestling).

  At baseline, at 6 months and at 12 months

• Adherence

  To quantify the adherence, adherence index (AI) will be calculated as the units administered divided by the units prescribed, multiplied by one hundred. Then the difference between this value and the perfect percentage of adhesion (100%) will be calculated. The result is the difference in percentage points the patient moves away from ideal adhesion. Adherence is based on data recorded in medical history of the patients and in their pharmacy dispensation records (García-Dasí et al. Haemophilia 2015).

  At baseline and at 12 months

• Quality of life

  The A36 Hemofilia-QoL questionnaire will be used to measure quality of life perceived by patients at the beginning and end of the study.

  At baseline and at 12 months

• FVIII consumption

  The amount of FVIII concentrate used and the corresponding cost will be calculated at the beginning and end of the study.

  At baseline and at 12 months

• FVIII inhibitors

  Assessment of FVIII inhibitor development is included in the safety analyses (and exclusion criteria) and will be performed at baseline and in all the routine medical visits, using the Bethesda Assay.

  At baseline and at 12 months

Study Arms (2)

Well controlled patients

Patients with an adequate disease control with the routine clinical practice (AJBR≤2, non-severe ABR≤5 and severe ABR≤2) (Ministerio de Sanidad, Servicios Sociales e Igualdad. Gobierno de España; 2012)

Drug: Recombinant VIII factor

Poor controlled patients

Patients with poor disease control, based on the international guidelines: AJBR\>2, ABR\>2 for severe BE or ABR \>5 for non-severe BE

Drug: Recombinant VIII factor

Interventions

Recombinant VIII factor DRUG

Identify and analyze cause(s) of poor bleeding control in patients on prophylaxis treatment and study the clinical impact of a "personalized pilot program" with a 1 year follow up to act on the specific causes. 1. Describe PK parameters in patients on prophylaxis treatment with Advate® 2. Analyze differences in PK parameters in non-controlled vs well controlled patients 3. Identify causes of poor clinical outcome in non-controlled patients. Patients' individual variables that influence bleeding risk will be studied (individual PK, bleeding pattern, joint status, physical activity, life style and patient's adherence). 4. Study the improvement in clinical outcomes (ABR and Joint status) of a 1 year Personalized Prophylaxis Program that acts specifically on the previously identified causes of bleeding in non-controlled patients (named: short half-life, high bleeding pattern, joint damage, high risk physical activity, active life style and poor patient's adherence).

Poor controlled patients; Well controlled patients

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Haemophilia A severe (FVIII \< 1 IU/dL) or moderate (FVIII 1 ≤5 IU/dL) in adult or adolescent patients in prophylactic treatment with Advate®.

You may qualify if:

• Adults or adolescents older than 12 years
• Patients under Prophylactic treatment with Advate® for at least 1 year
• Written informed consent.

You may not qualify if:

• History of FVIII inhibitor (titre ≥ 0.6 BU \[Bethesda unit\]) or detectable FVIII inhibitors at screening (titre ≥ 0.4 BU),
• Another haemostatic defect
• Need for major surgery.
• Withdrawal of informed consent

Sponsors & Collaborators

• Hospital Universitario La Fe: lead

Study Sites (1)

Hemostasis and Thrombosis Department, Hospital Universitari i Politecnic La Fe, Valencia, Spain.

Valencia, Valencia, 46026, Spain

RECRUITING

Related Publications (20)

• Berntorp E, Spotts G, Patrone L, Ewenstein BM. Advancing personalized care in hemophilia A: ten years' experience with an advanced category antihemophilic factor prepared using a plasma/albumin-free method. Biologics. 2014 Apr 5;8:115-27. doi: 10.2147/BTT.S53456. eCollection 2014.

  PMID: 24741292 RESULT

• Bjorkman S. Limited blood sampling for pharmacokinetic dose tailoring of FVIII in the prophylactic treatment of haemophilia A. Haemophilia. 2010 Jul 1;16(4):597-605. doi: 10.1111/j.1365-2516.2009.02191.x. Epub 2010 Feb 9.

  PMID: 20148977 RESULT

• Bjorkman S. Evaluation of the TCIWorks Bayesian computer program for estimation of individual pharmacokinetics of FVIII. Haemophilia. 2011 Jan;17(1):e239-40. doi: 10.1111/j.1365-2516.2010.02372.x. Epub 2010 Aug 22. No abstract available.

  PMID: 20731725 RESULT

• Bjorkman S, Oh M, Spotts G, Schroth P, Fritsch S, Ewenstein BM, Casey K, Fischer K, Blanchette VS, Collins PW. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood. 2012 Jan 12;119(2):612-8. doi: 10.1182/blood-2011-07-360594. Epub 2011 Oct 31.

  PMID: 22042695 RESULT

• Bolon-Larger M, Chamouard V, Bressolle F, Boulieu R. A limited sampling strategy for estimating individual pharmacokinetic parameters of coagulation factor VIII in patients with hemophilia A. Ther Drug Monit. 2007 Feb;29(1):20-6. doi: 10.1097/FTD.0b013e3180311384.

  PMID: 17304146 RESULT

• Broderick CR, Herbert RD, Latimer J, Barnes C, Curtin JA, Mathieu E, Monagle P, Brown SA. Association between physical activity and risk of bleeding in children with hemophilia. JAMA. 2012 Oct 10;308(14):1452-9. doi: 10.1001/jama.2012.12727.

  PMID: 23047359 RESULT

• Collins PW, Blanchette VS, Fischer K, Bjorkman S, Oh M, Fritsch S, Schroth P, Spotts G, Astermark J, Ewenstein B; rAHF-PFM Study Group. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost. 2009 Mar;7(3):413-20. doi: 10.1111/j.1538-7836.2008.03270.x. Epub 2008 Dec 20.

  PMID: 19143924 RESULT

• Collins P, Faradji A, Morfini M, Enriquez MM, Schwartz L. Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover study. J Thromb Haemost. 2010 Jan;8(1):83-9. doi: 10.1111/j.1538-7836.2009.03650.x. Epub 2009 Oct 11.

  PMID: 19817995 RESULT

• Collins PW, Fischer K, Morfini M, Blanchette VS, Bjorkman S; International Prophylaxis Study Group Pharmacokinetics Expert Working Group. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. Haemophilia. 2011 Jan;17(1):2-10. doi: 10.1111/j.1365-2516.2010.02370.x. Epub 2010 Aug 22.

  PMID: 20731726 RESULT

• Fischer K, Konkle B, Broderick C, Kessler CM. Prophylaxis in real life scenarios. Haemophilia. 2014 May;20 Suppl 4:106-13. doi: 10.1111/hae.12425.

  PMID: 24762285 RESULT

• Garcia-Dasi M, Aznar JA, Jimenez-Yuste V, Altisent C, Bonanad S, Mingot E, Lucia F, Gimenez F, Lopez MF, Marco P, Perez R, Fernandez MA, Paloma MJ, Galmes B, Herrero S, Garcia-Talavera JA. Adherence to prophylaxis and quality of life in children and adolescents with severe haemophilia A. Haemophilia. 2015 Jul;21(4):458-64. doi: 10.1111/hae.12618. Epub 2015 Feb 4.

  PMID: 25649244 RESULT

• Morfini M, Lee M, Messori A. The design and analysis of half-life and recovery studies for factor VIII and factor IX. Factor VIII/Factor IX Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis. Thromb Haemost. 1991 Sep 2;66(3):384-6. No abstract available.

  PMID: 1746011 RESULT

• Rodriguez-Merchan EC, Jimenez-Yuste V, Aznar JA, Hedner U, Knobe K, Lee CA, Ljung R, Querol F, Santagostino E, Valentino LA, Caffarini A. Joint protection in haemophilia. Haemophilia. 2011 Sep;17 Suppl 2:1-23. doi: 10.1111/j.1365-2516.2011.02615.x.

  PMID: 21819491 RESULT

• Ruffo S, Messori A, Grasela TH, Longo G, Donati-Cori G, Matucci M, Morfini M, Tendi E. A calculator program for clinical application of the Bayesian method of predicting plasma drug levels. Comput Programs Biomed. 1985;19(2-3):167-77. doi: 10.1016/0010-468x(85)90008-x.

  PMID: 3928243 RESULT

• Schulman S, Eelde A, Holmstrom M, Stahlberg G, Odeberg J, Blomback M. Validation of a composite score for clinical severity of hemophilia. J Thromb Haemost. 2008 Jul;6(7):1113-21. doi: 10.1111/j.1538-7836.2008.03001.x. Epub 2008 Jul 1.

  PMID: 18466317 RESULT

• Tarantino MD, Collins PW, Hay CR, Shapiro AD, Gruppo RA, Berntorp E, Bray GL, Tonetta SA, Schroth PC, Retzios AD, Rogy SS, Sensel MG, Ewenstein BM; RAHF-PFM Clinical Study Group. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia. 2004 Sep;10(5):428-37. doi: 10.1111/j.1365-2516.2004.00932.x.

  PMID: 15357767 RESULT

• Valentino LA, Mamonov V, Hellmann A, Quon DV, Chybicka A, Schroth P, Patrone L, Wong WY; Prophylaxis Study Group. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost. 2012 Mar;10(3):359-67. doi: 10.1111/j.1538-7836.2011.04611.x.

  PMID: 22212248 RESULT

• Valentino LA. Considerations in individualizing prophylaxis in patients with haemophilia A. Haemophilia. 2014 Sep;20(5):607-15. doi: 10.1111/hae.12438. Epub 2014 Apr 8.

  PMID: 24712891 RESULT

• Vyas S, Enockson C, Hernandez L, Valentino LA. Towards personalizing haemophilia care: using the Haemophilia Severity Score to assess 178 patients in a single institution. Haemophilia. 2014 Jan;20(1):9-14. doi: 10.1111/hae.12227. Epub 2013 Jul 16.

  PMID: 23855877 RESULT

• Carlsson M, Berntorp E, Bjorkman S, Lethagen S, Ljung R. Improved cost-effectiveness by pharmacokinetic dosing of factor VIII in prophylactic treatment of haemophilia A. Haemophilia. 1997 Apr;3(2):96-101. doi: 10.1046/j.1365-2516.1997.00091.x.

  PMID: 27214717 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

FVIII is measured by the one-stage assay in a central laboratory in complete blood samples

MeSH Terms

Conditions

Hemophilia A

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Design

• Study Type: observational
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Drug Clinical Area, Hospital Universitari i Politecnic La Fe, Valencia, Spain.

Study Record Dates

• First Submitted: December 1, 2015
• First Posted: December 4, 2015
• Study Start: August 1, 2016
• Primary Completion: February 1, 2018
• Study Completion: February 1, 2018
• Last Updated: August 17, 2016

Record last verified: 2016-08

Locations

ES (1)