E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Polycythemia Vera, a myeloproliferative disease of blood forming cells |
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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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036061 |
E.1.2 | Term | Polycythemia vera |
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 demonstrate non-inferiority of AOP2014 vs. HU in terms of disease response rate in both HU naïve and currently treated patients, diagnosed with Polycythemia Vera. |
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E.2.2 | Secondary objectives of the trial |
Efficacy in the two treatment arms, safety, QoL and change of JAK-2 allelic burden will be analyzed, using the secondary endpoints outlined, to provide a more comprehensive picture on AOP2014 compared to HU in patients with PV. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional bone marrow samplings (one at screening prior the first study drug dose, and another one after completion of the 12 month period) taken and sent for central evaluation will be setup within the PROUD-PV study. Patients may decline participation in the bone marrow sub study, while remaining on the main study protocol |
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E.3 | Principal inclusion criteria |
1. 18 years or older
2. Diagnosis of Polycythemia Vera according to the WHO 2008 criteria (Barbui et al, 2011 - Appendix 1) with the mandatory presence of JAK2V617F mutation as the major disease criterion.
3. For previously cytoreduction untreated patients – documented need of cytoreductive treatment (any of the following criteria):
- age >60 years at the planned day of the first drug administration
- at least one previous well documented major cardiovascular PV-related event (see appendix 6 for definitions), except bleeding and PV-related thromboembolic complications in the abdominal area, see excl. criterion 7) in the medical history
- poor tolerance (defined as a phlebotomy/ procedure-related adverse event causing significant adverse impact on the patient and limiting ability to apply phlebotomy with the intention to keep Hct <45%) or frequent need of phlebotomy (more than one phlebotomy within last three months prior entering the study, while each of these phlebotomies was performed to reduce Hct level from >45%, or if one phlebotomy was not able to reduce Hct level to <45% for the next three months following phlebotomy)
- progressive splenomegaly (de novo appearance of a palpable spleen, or appearance of the symptoms, related to the enlarged spleen, e.g. pain, early satiety etc., with confirmed size increase)
- platelet counts greater than 1000 x 10 9/L (for two measurements within one week)
- leukocytosis (WBC>10 x 10 9/L for two measurements within one week)
4. For patients currently treated or pre-treated with HU, all of the following criteria:
- being non-responders (as defined by the response criteria for primary endpoint in this protocol, see section 3.1.1)
- total HU treatment duration shorter than three years
- no documented resistance or intolerance as defined by modified Barosi et al, 2009 criteria(Appendix 2)
5. Hospital Anxiety and Depression Scale (HADS) score 0-7 on both subscales
6. Patients with a HADS score of 8-10 inclusive on either or both of the subscales may be eligible following psychiatric assessment
7. Signed written informed consent
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E.4 | Principal exclusion criteria |
1. Any systemic cytoreduction for PV in the medical history prior to study entry with the exception of HU for shorter than 3 years (see respective inclusion criterion)
2. Any contraindication to any of the IMPs (pegylated interferon or hydroxyurea) or their excipients
3. Any systemic exposure to a non-pegylated or pegylated interferon alpha in the medical history
4. Documented autoimmune disease at screening or in the medical history
5. Clinically relevant pulmonary infiltrates, pneumonia, and pneumonitis at screening
6. Infections with systemic manifestations, e.g., hepatitis B, hepatitis C, or HIV at screening
7. Known, PV-related thromboembolic complications in the abdominal area (e.g. portal vein thrombosis, Budd-chiari syndrome)
8. Any investigational drug less than 6 weeks prior to the first dose of study drug or not recovered from effects of prior administration of any investigational agent
9. History or presence of depression requiring treatment with antidepressant
10. HADS score equal to or above 11 on either or both of the subscales
11. Any risk of suicide at screening or previous suicide attempts
12. Any significant morbidity or abnormality which may interfere with the study participation
13. Pregnancy and breast-feeding females of reproductive potential and males not using effective means of contraception
14. History of active substance or alcohol abuse within the last year
15. Evidence of severe retinopathy (e.g. cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension)
16. Thyroid dysfunction (clinical symptoms of thyroid hyper- or hypofunction) not adequately controlled
17. Patients tested positively with TgAb (autoantibodies to thyroglobulin) and/ or TPOAb (autoantibodies to thyroid peroxidase) at screening
18. History of major organ transplantation
19. History of uncontrolled severe seizure disorder
20. Leukocytopenia at the time of screening
21. Thrombocytopenia at the time of screening
22. History of malignant disease, including solid tumours and hematological malignancies (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
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
- Disease response rate at 12 months defined as hematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets <400 x 10 9/L, leukocytes <10 x 10 9/L (all three lab parameters measured by blinded central lab), and normal spleen size (by imaging, central, blinded assessment) |
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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) |
• Secondary efficacy endpoints
- Durable disease response rate as per the following definition of durable responder:
Durable responder is
o a responder at 12 months, i.e., the following criteria have to be met: hematocrit <45% without phlebotomy between 9 month visit to 12 month visit, platelets <400 x 10 9/L, leukocytes <10 x 10 9/L, normal spleen size),
and
o a responder at 9 months as measured by blood parameters, i.e. the following criteria have to be met: hematocrit <45% without phlebotomy in the past three months (i.e. visits at 6-9 months according to study schedule), platelets <400 x 10 9/L, leukocytes <10 x 10 9/L.
For all parameters mentioned above, central lab blinded assessments and assessment of spleen size at 12 months according to blinded central imaging will be used for determination of durable responders. Following discussions with the U.S. FDA, this endpoint will be analyzed as the primary one for study submission in the U.S. (Pre-IND meeting minutes with FDA, Sep 26, 2013).
- Disease response rate at 6 months, based on hematological parameters only, defined as hematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets <400 x 10 9/L, leukocytes <10 x 10 9/L (all three lab parameters measured by blinded central lab) for the formal interim analysis,
- Disease response rate at 6 months, defined as hematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets <400 x 10 9/L, leukocytes <10 x 109/L (all three lab parameters measured by blinded central lab), and normal spleen size (by imaging, local ultrasonography measurement).
- Disease response rates at 3 months and 9 months (spleen size measurements and hematological parameters coming from local measurements)
- Time to first disease response
- Disease response duration
- Number of phlebotomies performed (per protocol, a phlebotomy has to be performed any time the patient’s hematocrit is higher than 45%)
- Hematocrit change from baseline to last patient visit
- Leukocytes change from baseline to last patient visit
- Platelets change from baseline to last patient visit
- Erythrocytes change from baseline to last patient visit
- Spleen size from baseline to last patient visit
- Disease-related symptoms (microvascular disturbances, pruritus, headache)
• Safety evaluation
- Incidence, causality and intensity of adverse events according to common terminology criteria for adverse events (CTCAE 4.0)
- Events leading to dose reduction or permanent treatment discontinuation. Adverse events of special interest (see section 7.3.9)
• Quality of Life (EQ-5D)
• Change of JAK-2 allelic burden over time |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Months 3,6,9
and change over time as well as time to response |
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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 | 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 | 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 | 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) | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Poland |
Romania |
Russian Federation |
Slovakia |
Spain |
Ukraine |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |