| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Polycythemia Vera, a myeloproliferative disease of blood forming cells |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036061 |
| E.1.2 | Term | Polycythemia vera |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 assess the long-term efficacy of AOP2014 or BAT in terms of disease response rate in patients diagnosed with PV, who were previously treated with AOP2014 or HU in the PROUD-PV Study and who completed this study.
•To assess the long-term efficacy including changes in disease burden
present during PROUD-PV Study in patients diagnosed with PV, who
were previously treated with AOP2014 or HU in the PROUD-PV Study.
Disease burden is defined as disease-related signs (clinically significant
splenomegaly) and disease-related symptoms (microvascular
disturbances, pruritus, headache), assessed by investigator. |
|
| E.2.2 | Secondary objectives of the trial |
•To further assess the long-term efficacy, safety, quality of life (QoL),
and change of JAK2 allelic burden in patients diagnosed with PV and
previously enrolled in the PROUD-PV Study.
•Additionally, for patients using the pre-filled injection pen, to collect
information on self-administration of AOP2014.
*Sub-study 1 (completed): AOP2014 administration with the pre-filled
500 μg pen
*Sub-study 2 (ongoing): Evaluation of PK of AOP2014 within the
CONTINUATION-PV Study
The PK evaluation will include
•The AOP2014 PK characterization in steady state for the evaluation of
AOP2014 exposure during the 2-weekly (PK group 1) or 4-weekly (PK
group 2) interval between two AOP2014 administrations.
•The estimation of the AOP2014 terminal elimination half-life with
sampling for at least 5 times the claimed half-life of 10 days from a
sufficient number of patients who discontinued AOP2014 treatment (PK
group 3).
|
|
| 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 |
•Genetic sample testing
Gentetic testing is optional. Patients may decline participation in the
genetic testing sub study, while remaining on the main study protocol.
Genetic testing should be performed during visit 1, the assessment visits
(6-monthly intervals) and the EoT visit/premature discontinuation visit.
Detailed instructions for sample handling, labelling and storage will be
provided in the laboratory manual. Samples will be stored at the central
laboratory (Covance, Switzerland) under AOP Orphans responsibility for
up to 5 years to allow thorough analysis and reanalysis, if needed.
Afterwards samples will be discarded. All these analyses will be
performed in a fully anonymous way. The optional genetic samples may
also be collected to assess disease status following discontinuation of
AOP2014 administration or BAT treatment after 2 and 3 years, if genetic
ICF is signed.
• Bone marrow assessment
Bone marrow assessment is optional. Patients may decline participation
in the bone marrow sub-study, while remaining on the main study
protocol. An independent bone marrow pathology board will be in charge
of bone marrow assessment in this study. Bone marrow assessments
should occur on visit 1 and at the EoT visit/premature discontinuation
visit. Samples may be kept up to 5 years. All these analyses will be
performed in a fully anonymous way.
• Sub-study 1 (completed): AOP2014 administration with the 500 μg
pre-filled pen
Patients who receive a total dose of >300 μg AOP2014 per
administration require two 250 μg pens on the same date and the same
time in the CONTINUATION-PV Study. Those patients were invited to
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participate in a sub-study for the administration of AOP2014 via the 500
μg pen. The use of the 500 μg pre-filled pen was intended to allow for
one single administration of the total dose in these patients. The 500 μg
is no longer in use in the CONTINUATION-PV study; AOP2014 will be
supplied as 250 μg pens only.
• Sub-study 2(ongoing): Evaluation of PK of AOP2014 within the
CONTINUATION-PV Study
Patients who are receiving AOP2014 are invited to participate in the PK
sub-study.
The PK evaluation will include
-The AOP2014 PK characterization in steady state for the evaluation of
AOP2014 exposure during the 2-weekly (PK group 1) or 4-weekly (PK
group 2) interval between two AOP2014 administrations.
- The estimation of the AOP2014 terminal elimination half-life with
sampling for at least 5 times the claimed half-life of 10 days from a
sufficient number of patients who discontinued AOP2014 treatment (PK
group 3). |
|
| E.3 | Principal inclusion criteria |
1. Patients who completed PROUD-PV Study:
a. normalization of at least two out of three main blood parameters (Hct, PLTs and WBCs) if these parameters were moderately increased (Hct<50%, WBC<20 x 109/L, PLTs<600 x 109/L) at baseline of the PROUD-PV Study, OR
b. >35% decrease of at least two out of three main blood parameters (Hct, PLTs and WBCs) if these parameters were massively increased (Hct>50%, WBCs>20 x 109/L, PLTs>600 x 109/L), at baseline of the PROUD-PV Study, OR
c. normalization of spleen size, if spleen was enlarged at baseline of the PROUD-PV Study, OR
d. otherwise a clear, medically verified benefit from treatment (e.g. normalization of disease-related micro-vasculatory symptoms, substantial decrease of JAK2 allelic burden).
2. Signed written ICF. |
|
| E.4 | Principal exclusion criteria |
Withdrawal criteria, as specified in the PROUD-PV (and PEN-PV study), which mandate treatment discontinuation:
1. Non-recovery from the treatment related toxicities to the grade (usually, Grade I) which allows continuation of the treatment.
2. HADS score of 11 or higher on either or both of the subscales, and /or development or worsening of the clinically significant depression or suicidal thoughts.
3. Progressive and clinically significant increase of liver enzyme levels despite dose reduction, or if such increase is accompanied by increased bilirubin level, any signs or symptoms of a clinically significant autoimmune disease.
4. Clinically significant development of a new ophthalmologic disorder, or worsening of a pre-existing one, during the study.
5. AOP2014 arm only: Loss of efficacy of study treatment or any comparable situation where no further benefits of treatment continuation are expected by the investigator.
Sub-study 2 (ongoing): Evaluation of PK of AOP2014 within the
CONTINUATION-PV Study
a)AOP2014 PK characterisation in steady state (PK group 1 and 2)
For the estimation of the systemic exposure of AOP2014, blood samples will be collected in the dosing interval between two AOP2014
administrations (i.e. 2-weekly and 4-weekly). Patients within the CONTINUATION-PV Study are eligible for blood sampling who
• are treated with AOP2014 with the pre-filled pen (applicable for all dose levels), and
• are receiving AOP2014 in a 2-weekly (PK group 1) or 4-weekly interval PK group 2), and
• having received at least 4 stable and consecutive (no dose interruption within 2 months prior entry in sub-study) AOP2014 doses with the same type of pen (250 μg or 500 μg) and
• are giving consent.
b) Estimation of the AOP2014 terminal elimination half-life (PK group 3)
Patients within the CONTINUATION-PV Study are eligible for blood sampling at the last AOP2014 administration until elimination to unquantifiable levels who
• have a temporally interruption of the AOP2014 treatment long enough to participate in the PK sub-study (up to 56 days [+/- 2 days])
• do not directly continue with AOP2014 (or another interferon) therapy after study end, or
• drop-out from the study due to reasons not related to safety and who decided to not continue with AOP2014/IFN therapy, or
• drop-out from the study due to safety reasons where the treating physician decided that blood sampling is feasible and where the patients
decided to not continue with AOP2014/interferon therapy, and
5.• are giving consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the rate of disease response at
assessment visits (every 6 months).
The co-primary efficacy evaluation criterion will be (1) disease response
defined as hematologic response: Hct<45% without phlebotomy (at
least 3 months since the last phlebotomy), PLTs<400 x 109/L, WBCs<10
x 109/L, and normal spleen size, and (2) disease response defined as
hematologic response (Hct<45% without phlebotomy (at least 3 months
since the last phlebotomy), PLTs<400 x 109/L, WBCs<10 x 109/L),
resolution and/or clinically improvement of disease-related signs
(clinical significant splenomegaly) and disease-related symptoms
(microvascular disturbances, pruritus, headache). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy evaluation:
1. Change in hematological parameters, Hct, WBCs, PLTs and erythrocytes (RBC), from CONTINUATION-PV baseline (i.e. "End of Treatment (EoT) visit" in the PROUD-PV Study) over time up to last patient visit.
2. Change in spleen size from baseline (i.e. "EoT visit" in the PROUD-PV Study) over time up to last patient visit, including change in clinical assessment of asymptomatic to symptomatic /progressive splenomegaly.
3. Maintenance rate of disease response at assessment visits.
4. Duration of response maintenance/further improvement in response.
5. Time to disease response.
6. Progression free time.
7. Phlebotomy need.
8. Change of disease related signs and disease-related symptoms (microvascular disturbances, pruritus, headache).
9. Change in QoL (EQ-5D-3L) from baseline ("EoT visit" of the PROUD-PV Study) over time up to last patient visit.
10. Change in JAK2 allelic burden from baseline ("EoT visit" of the PROUD-PV Study) over time up to last patient visit.
Safety evaluation:
11. Incidence, causality and intensity of adverse events (AEs) according to common terminology criteria for adverse events (CTCAE 4.0).
12. Events leading to dose reduction or permanent treatment discontinuation.
13. AEs of special interest (AESI).
Data collected during the PROUD-PV or PEN-PV study may also be included in further analyses for exploratory purposes, to compare longterm
changes in efficacy and safety parameters (i.e. to PROUD-PV baseline values). These additional endpoints including data collected
during PROUD-PV or PEN-PV Study will be defined in the Statistical Analysis Plan (SAP) of this study.
Sub-study 1 (completed): AOP2014 administration with the pre-filled 500 μg pen
Safety evaluation:
• To assess the local tolerability of the 500 μg pen in comparison with the previous used 250 μg pen
• To assess the patient satisfaction with the application of one 500 μg pen in comparison with the application of two 250 μg pens
Sub-study 2 (ongoing): Evaluation of PK of AOP2014 within the CONTINUATION-PV Study
• for the PK characterisation of AOP2014 in steady state conditions)
• for the estimation of the AOP2014 terminal elimination half-life. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Russian Federation |
| Ukraine |
| Austria |
| Bulgaria |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Romania |
| Slovakia |
| Spain |
|
| 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
|
| Study participation will be as long as the treatment is effective and tolerable/safe and/or until AOP2014 becomes otherwise available. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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