E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
male or female patients with confirmed diagnosis of Essential Thrombocythemia |
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E.1.1.1 | Medical condition in easily understood language |
male or femal patients with confirmed diagnosis of Essential Thrombocythemia |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015494 |
E.1.2 | Term | Essential thrombocythemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether Anagrelide Retard is non-inferior to Thromboreductin® in terms of mean platelet count measured by a central laboratory/centralized method at 3 time points during the maintenance phase. |
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E.2.2 | Secondary objectives of the trial |
To compare the effects of Anagrelide Retard and Thromboreductin® on the following:
- platelet response status
- tolerability and safety
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Willing and able to give written informed consent prior to any study specific procedures and able to comply with this protocol.
• Male / female
• Age ≥18 years
• Confirmed diagnosis of ET according to 2008 World Health Organization (WHO) diagnostic criteria*, defined as meeting all four criteria as follows:
a. Sustained platelet count ≥450 G/L.
b. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes. No significant increase or left shift of neutrophil granulopoiesis or erythropoiesis. (Bone marrow examination should be available as source data and based on existing biopsies – no screening assessment.)
c. Not meeting WHO criteria for polycythemia vera, primary myelofibrosis, BCR-ABL1-positive chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid neoplasm.
d. Demonstration of JAK2V617F or other clonal marker, or in the absence of JAK2V617F, no evidence for reactive thrombocytosis.
* If the diagnosis was made according to earlier criteria (for example, Polycythemia Vera Study Group [PVSG]), re-examination and confirmation of diagnosis according to 2008 WHO criteria must be done. In the source data a notice by investigator should be made: ‘Reclassified according to WHO 2008 criteria for ET’.
AND:
• at high risk of experiencing ET-related events, indicated for Thromboreductin® treatment as defined by one or more of the following criteria:
o Age ≥ 60 years
o Platelet counts ≥ 1000 G/L
o Increase of platelet count ≥ 300 G/L within 3 months
o Severe thrombohemorrhagic or ischemic symptoms in anamnesis
EITHER:
• Currently treated with anagrelide (Thromboreductin® or other locally available anagrelide formulations), meeting the definition of well controlled disease. Well controlled disease is defined as the absence at screening of any acute disease related symptoms, as well as the achievement of stable platelet counts (<600 G/L AND fluctuation of these values of not more than +/- 30 %, confirmed at the Screening Visit and one previous measurement within 3 months before Screening).
OR:
• Naive:
a. ET treatment naive: no cytoreductive treatment received yet
b. Anagrelide naive, defined as meeting ALL of the below mentioned criteria:
o Treatment received has to be another cytoreductive treatment than anagrelide (e.g. Hydroxyurea, Busulfan, Interferons).
o This cytoreductive treatment had to be terminated either due to intolerance or lack of reduction of the elevated platelet counts. Intolerance to hydroxyurea is defined according to LeukemiaNet European Collaboration (see Appendix 5). Intolerance to busulfan, interferon (IFN) or another cytoreductive treatment than anagrelide is defined as any NCI CTCAE 4.0 toxicity of ≥ grade 2 (see Appendix 7).
o Termination of treatment has to be at least four weeks before start of study medication/randomization.
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E.4 | Principal exclusion criteria |
• Diagnosis of any other myeloproliferative disorder
• Any known cause for a secondary thrombocytosis, e.g. thrombocytosis due to iron deficiency
• ET currently well controlled by another cytoreductive treatment than Anagrelide (e.g. hydroxyurea, busulfan, IFN) AND the opportunity to continue to receive this treatment
• ET currently treated with combination of any two of the following agents: anagrelide, hydroxyurea, interferons, busulfan
• Hypersensitivity to either active or non-active ingredients of anagrelide or to any other excipients of the investigational products
• Known hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
• Cardiovascular disease grade 3 with a negative benefit/risk assessment or grade 4 (South West Oncology Group, see Appendix 6)
• Clinically significant abnormal laboratory values (excluding markers for ET) in investigator’s opinion, including electrolyte imbalance
• Severe renal insufficiency (creatinine clearance <30 ml/min)
• Moderate to severe hepatic insufficiency (ALT or AST > 5 times upper normal limit [UNL])
• White blood count (WBC) ≥ 15 G/L at screening
• Diagnosis of any malignancy, other than ET (except basal cell and squamous cell carcinomas of the skin and carcinoma in situ of the cervix that have been completely excised and are considered cured), within the last 3 years, or coexisting, malignant, systemic disease
• Poorly controlled diabetes mellitus
• Known infection with hepatitis B, hepatitis C or HIV
• Pregnant or lactating women (pregnancy test to be performed within 7 days prior study treatment start)
• Women of childbearing potential or male patients, who have sexual intercourse with females of childbearing potential, not willing to use an effective method of contraception during the study. Effective methods for women are hormonal contraceptives, intrauterine devices (IUDs), surgical intervention, and sexual abstinence. Female patients with childbearing potential receiving oral hormonal contraception will have to apply an additional effective method of contraception during the study period. Effective methods for men are condoms and sexual abstinence.
• History of drug/alcohol abuse within the previous 2 years
• Participation in another investigational study within 4 weeks prior to informed consent signed or for a longer duration if specified in local regulations
• Any significant psychiatric disorder that, in the opinion of the investigator, might prohibit the understanding and giving of informed consent, or that might prevent the patient from completing the trial.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Mean platelet count based on three measurements during the maintenance phase.
Optimal dosing (increase to achieve the target platelet level, decrease in case of toxicity, following the SmPC specifications of Thromboreductin® and the dosing rules for Anagrelide Retard) should be applied to each patient to reduce (for anagrelide naive patients) or maintain (for anagrelide pre-treated patients) the platelet count ≤400 G/L or, in cases in which further dose up-titration is not possible due to poor tolerability, at least below 600 G/L.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Mean platelet count based on three measurements during the maintenance phase; Visit 14, Visit 16 & Visit 18 |
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E.5.2 | Secondary end point(s) |
Efficacy
• Platelet response status:
Responder: Response is defined as the attainment of platelet levels <600 G/L (response will be evaluated by taking the mean of three platelet counts from the central laboratory) during the maintenance treatment period.
Non responder: If platelet levels do not remain <600 G/L or missing values (e.g. drop-outs during titration and maintenance phase).
• Time from randomization to entering maintenance phase
• Study drug administration (the maintenance dose and the number of titrations)
• Change in platelet counts in the titration phase
• Time from randomization until withdrawal
Safety
• Incidence, causality and intensity of adverse events (AEs) according to common terminology criteria for adverse events (CTCAE 4.0), with additional special focus on cardiovascular, neurological and general disorders (adverse events of special interest, AESI: palpitation, tachycardia, headache, dizziness, nausea, vomiting, diarrhea, abdominal pain)
• Incidence, intensity and outcomes of events leading to dose reduction or temporary or permanent treatment discontinuation
• Need of medications (dose and duration) to treat AEs
• Electrocardiogram (ECG) abnormalities
• Ejection fraction and echocardiography (ECHO) overall conclusion (normal/abnormal)
Patient reported outcomes
• Quality of Life (EQ-5D-3L)
Pharmacokinetic measurements
There will be a mandatory PK sampling (at three visits during the maintenance period: Visits M1, M3 and M5) and an optional PK sampling (at the second visit in the maintenance period: Visit M2) to determine the concentration of anagrelide in plasma.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
Evaluation of platelet status will be done throughout the Titration Period and the Maintainance Phase
Safety:
Evaluation of safety aspects status will be done throughout the complete study
Patient reported outcomes:
Evaluation of Quality of Life Questionnaire will be done throughout the Titration Period at Visit 2 and the Maintainance Phase at Visit 14 and at Visit 18.
Pharmacokinetic measurements:
There will be a mandatory PK sampling (at three visits during the maintenance period: Visits M1, M3 and M5) and an optional PK sampling (at the second visit in the maintenance period: Visit M2) to determine the concentration of anagrelide in plasma.
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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 | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Bulgaria |
Lithuania |
Poland |
Russian Federation |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |