E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe, inherited von Willebrand disease (VWD) and frequent bleedings |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10047715 |
E.1.2 | Term | Von Willebrand's disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate if long term, secondary prophylaxis with highly purified FVIII/VWF concentrates, with respect to on demand treatment with the same pharmacological agent, prevents spontaneous bleedings onset in patients with severe inherited VWD unresponsive to DDAVP and with frequent bleedings. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of prophylaxis versus on demand therapy in the following:
- safety, with particular reference to the likelihood of thrombotic complications occurrence
- patient compliance
- possible impact on the global costs of care and on patients’ quality of life, describing and evaluating:
a) incremental cost per unit of effect
b) the Health Related Quality of Life (HRQoL) of adult and paediatric patients and their caregivers |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Documented unresponsiveness to DDAVP. All the patients, excluding type 3 and type 2B, should have been exposed to a documented infusion trial with DDAVP. Responsiveness to DDAVP is defined as an increase in plasma FVIII:C and VWF:RCo levels of at least three fold over baseline and in absolute reaching at least 30 IU/dl for both values and a BT of 12 minutes or less after 2 hours from administration of 0,3 mcg/kg of DDAVP
OR
contraindication to DDAVP (namely type 2B VWD patients or other patients who display significant side effects to DDAVP)
2. Frequent, spontaneous bleedings i.e. at least 5 episodes in whatever anatomical site in the last 12 months, severe enough to require treatment with FVIII/VWF concentrates
Prolonged or excess bleeding during menses will be allowed only when:
i. No other medication can control frequent bleeds
ii. Bleeding exceeds 10 consecutive days
OR
Recurrent spontaneous bleedings, severe enough to require treatment with FVIII/VWF concentrates of the following types:
- Epistaxes (at least 5 episodes in the last 12 months)
- Haemarthroses (at least 3 episodes at the same joint in the last 12 months)
- Gastrointestinal bleeding (at least 2 episodes in the last 12 months, with a drop ≥ 2 g/dl of haemoglobin in 24-48 hours) due to unexplained reason or in association with underlying gastrointestinal angiodysplasia
3. Willingness to participate in the study, expressed by signed, written informed consent
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E.4 | Principal exclusion criteria |
1. a life expectancy < 1 year
2. presence of allo-antibodies to VWF or FVIII
3. acquired Von Willebrand’s syndrome (AVWS)
4. co-morbidity with other haemorrhagic diathesis, excluded those linked to VWD as the complication of treatment (for instance thrombocytopenia in Type 2B VWD)
5. advanced liver cirrhosis with:
- cirrhosis related coagulation abnormalities (thrombocytopenia, defined as platelet count < 50.000/mm3, INR >1,7, prolonged prothrombin time > 4 seconds versus normal)
- portal hypertension with history of variceal bleeding
6. pregnancy and lactation
7. any known need for invasive procedures or elective surgery scheduled in the following 3 months (recruitment in these cases should be postponed)
8. proven co-morbidity for other causes of gastrointestinal bleeding not related to the studied disease (as drug induced haemorrhagic gastropathy, upper GI tract ulcers or cancer, or operable conditions, e.g. haemorrhoids) with the exception of concomitant angiodysplasia which meets the inclusion criteria
9. gastrointestinal bleeding due to trauma, invasive diagnostic or surgical procedures
10. concomitant autoimmune anaemia and/or autoimmune thrombocytopenia |
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E.5 End points |
E.5.1 | Primary end point(s) |
Prevention of spontaneous bleeding onset, expressed as the proportion of patients who do not present any spontaneous bleeding episode during the study period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Incidence rate of spontaneous bleedings (episodes/patient*time)
- Incidence rate of all bleedings (episodes/patient*time)
- Total number of bleedings (either spontaneous and all bleedings)
- Mean duration of spontaneous bleeding episode (days)
- Mean number of infusions per spontaneous bleeding episode
- Mean dose of concentrate per spontaneous bleeding episode (expressed in FVIII:C and in VWF:RCo)
- Transfusional needs*, expressed either as:
Proportion of patients who need a transfusion
Incidence rate of transfusions (events/patient*time)
- Mean level of VWF:Rco (IU/dl) and Factor VIII (IU/dl) attained before infusion (trough levels) for patients in prophylaxis
- Petterssen score, for patients with recurrent joint bleedings
- Disease related days of in-hospitalisation in the period of interest. Hospitalisation in these patients reflects the need to control bleeding, or to transfuse blood components
- Reduction of disease related in-hospital admissions and disease-related days of inhospitalisation in the period of interest. Hospitalisation in these patients reflects the need to control bleeding, or to transfuse blood components
- Time free from event, the interval between randomization and the first bleeding episode after randomization. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
on demand treatment with the same product |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |