Personalized Prophylactic Treatment With Advate® in Severe or Moderate Haemophilia A Patients
试验速览
- 阶段
- 不适用
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Steady state volume (Vss)
研究概览
简要总结
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.
- Describe PK parameters in patients on prophylaxis treatment with Advate®.
- Analyze differences in PK parameters in non-controlled vs well controlled patients.
- 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).
- 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).
详细描述
Research Question:
- Is standard prophylaxis effective for all hemophilia A patient?
- Which are the causes for poor clinical response in some patients on prophylactic treatment?
- Can differences in PK impact the clinical outcome and effectiveness of prophylaxis?
- For a given group of poor controlled patients in standard prophylaxis, may personalized prophylaxis improve clinical outcome when acting on the specific cause(s)?
Study Background & Rationale:
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.
研究设计
- 研究类型
- Observational
- 时间视角
- Prospective
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults or adolescents older than 12 years
- •Patients under Prophylactic treatment with Advate® for at least 1 year
- •Written informed consent.
排除标准
- •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
研究组 & 干预措施
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)
干预措施: Recombinant VIII factor (Drug)
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
干预措施: Recombinant VIII factor (Drug)
结局指标
主要结局
Steady state volume (Vss)
时间窗: At baseline and at 12 months
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.
Gilbert joint score
时间窗: At baseline and at 12 months
To measure the joint status of each patient the Gilbert joint score will be employed.
HJHS score
时间窗: At baseline and at 12 months
To measure the joint status of each patient the HJHS score will be employed..
Adherence
时间窗: At baseline and at 12 months
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).
FVIII consumption
时间窗: At baseline and at 12 months
The amount of FVIII concentrate used and the corresponding cost will be calculated at the beginning and end of the study.
FVIII inhibitors
时间窗: At baseline and at 12 months
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.
Quality of life
时间窗: At baseline and at 12 months
The A36 Hemofilia-QoL questionnaire will be used to measure quality of life perceived by patients at the beginning and end of the study.
Clearance (Cl)
时间窗: At baseline and at 12 months
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.
Half-life of FVIII (t½)
时间窗: At baseline and at 12 months
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.
Physical activity
时间窗: At baseline, at 6 months and at 12 months
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).
Time to 1% FVIII activity above
时间窗: At baseline and at 12 months
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.
Annualized bleeding rate (ABR)
时间窗: At baseline, at 6 months and at 12 months
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.
Annualized joint bleeding rate (AJBR)
时间窗: At baseline, at 6 months and at 12 months
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.
次要结局
未报告次要终点
研究者
José Luis Poveda Andrés
Director of Drug Clinical Area, Hospital Universitari i Politecnic La Fe, Valencia, Spain.
Hospital Universitario La Fe