An open-label, multicenter, phase IIIb study assessing the long-term efficacy and safety of AOP2014 and standard first line treatment (BAT) in patients with Polycythemia Vera who previously participated in the PROUD-PV Study

• Register: EUCTR
• Last refreshed on: 7 June 2021
• Main ID: EUCTR2014-001357-17-AT
• Date of registration: 25/08/2014
• Prospective Registration: Yes
• Primary sponsor: AOP Orphan Pharmaceuticals AG
• Public title: An open-label, multicenter, phase IIIb study assessing the long-term efficacy and safety of AOP2014 and standard first line treatment (BAT) in patients with Polycythemia Vera who previously participated in the PROUD-PV Study
• Scientific title: An open-label, multicenter, phase IIIb study assessing the long-term efficacy and safety of AOP2014 and standard first line treatment (BAT) in patients with Polycythemia Vera who previously participated in the PROUD-PV Study - CONTINUATION-PV
• Date of first enrolment: 23/10/2014
• Target sample size: 200
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-001357-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Bulgaria, Czech Republic, France, Germany, Hungary, Italy, Poland, Romania, Russian Federation, Slovakia, Spain, Ukraine

Contacts

• Name: Clinical Project Manager
• Affiliation: AOP Orphan Pharmaceuticals AG

• Name: Clinical Project Manager
• Affiliation: AOP Orphan Pharmaceuticals AG

Key inclusion & exclusion criteria

Inclusion criteria:
1. Patients who completed the 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 140
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 60

Exclusion criteria:
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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Polycythemia Vera
MedDRA version: 21.1 Level: LLT Classification code 10036061 Term: Polycythemia vera System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: Pegylated proline-interferon alpha-2b
Product Code: AOP2014
Pharmaceutical Form: Solution for injection in pre-filled pen
INN or Proposed INN: PEGylated Proline-interferone alpha-2b recombinant
CAS Number: 1335098-50-4
Current Sponsor code: PEG-P-INFa-2b; P1101
Other descriptive name: PEGINTERFERON ALFA-2B
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 0.5-

Primary Outcome(s)

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 10 9/L, WBCs<10 x 10 9/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 10 9/L, WBCs<10 x 10 9/L), resolution and/or clinically improvement of disease-related signs (clinical significant splenomegaly) and disease-related symptoms (microvascular disturbances, pruritus, headache).

Secondary Objective: • To further assess the long-term efficacy, safety, quality of life, 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 250 µg 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).

Main Objective: • 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.

Timepoint(s) of evaluation of this end point: every three months

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: every three months

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 splenomegalie.
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 the PROUD-PV or PEN-PV Study will be defined in the 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 pre-filled 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 with the 250 µg pen 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

Secondary ID(s)

CONTINUATION-PV

2014-001357-17-HU

Source(s) of Monetary Support

AOP Orphan Pharmaceuticals AG

Ethics review

Status: Approved
Approval date: 09/10/2014
Contact: