Ignite Creation Date:
2025-12-25 @ 3:13 AM
Ignite Modification Date:
2026-03-05 @ 10:45 AM
Study NCT ID:
NCT01949805
Status:
COMPLETED
Last Update Posted:
2016-11-28
First Post:
2013-09-06
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Pegylated Interferon Alpha-2b Versus Hydroxyurea in Polycythemia Vera
Sponsor:
AOP Orphan Pharmaceuticals AG
Organization:
Study Overview
Official Title:
A Randomized, Open-label, Multicenter, Controlled, Parallel Arm, Phase III Study Assessing the Efficacy and Safety of AOP2014 vs. Hydroxyurea in Patients With Polycythemia Vera
Status:
COMPLETED
Status Verified Date:
2016-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PROUD-PV
Brief Summary:
Phase III study to compare the efficacy and safety of the novel monopegylated interferon alpha 2b AOP2014 versus Hydroxyurea (the current licensed therapy for this disease). One year treatment of patients with polycythemia vera. Objective is 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. Response is measured as normalisation of key lab parameters as well as normalized spleen size.
Detailed Description:
Hydroxyurea is an established first-line treatment option currently approved in several European countries for Polycythemia Vera (PV) patients requiring a cytoreductive therapy (Barbui et al, 2011). Clinical trials have shown that HU is an effective drug for preventing thrombosis in PV compared to phlebotomy (Michiels et al, 1999).
The main concern of a long term treatment with HU is its potential leukaemogenicity: based on the mechanism of action, HU can potentially accelerate the accumulation of mutations in DNA and increase the risk of leukaemic transformation (Dingli et Tefferi, 2006). However, there is currently no clear clinical data to confirm leukaemogenicity of HU in patients with PV (Tefferi, 2012).
Even though IFN-alpha has shown its activity in PV in the 1980s, it is still considered as an experimental treatment in Europe due to pending approval in this indication (Barbui et al, 2011). It induces major or complete molecular remissions in patients with PV accompanied by a reduction in the risk of thrombosis and bleeding - the major determinants of morbidity in this indication (Hasselbalch, 2011). However, only low doses are tolerated and significant adverse effects from long-term use may limit its usefulness.
Pegylated interferons are better tolerated and are the preferred options of treatment in PV patients (Kiladjian et al, 2008) despite the lack of evidences based on well-designed randomized controlled clinical studies.
AOP2014 is a next generation pegylated interferon (Peg-P-IFN-alpha-2b), with the addition of proline in the N-terminal end.
AOP2014 like all interferon suppresses the malignant clone causing PV and subsequently is expected to possibly defer the onset of or avoid long term sequelae of PV. In addition, a reduction in the frequency of phlebotomies should be achieved. The peg-P-IFN-alpha-2b might potentially have a positive impact on reducing the drop-out rate compared to conventional IFNs. It is expected that the reduced frequency of administration of AOP2014 will contribute to higher compliance rates.
The maximum tolerated dose as well as the safety, efficacy and pharmacokinetics of AOP2014 were assessed in a phase I/II study in patients with PV. After 24 evaluable patients had entered the Phase I dose finding part, the MTD was defined at the level of 540 µg administered every two weeks. Another 27 patients were recruited in order to further investigate the drug efficacy and safety in PV. Efficacy results of AOP2014 were promising. By visit 18, 53.0% of the patients had reached complete response (12 evaluable patients). Adverse events were manageable and rarely necessitated treatment discontinuation.
AOP2014 was shown to have a prolonged plasma half-life with a concomitant increase in AUC. This is expected to enhance the therapeutic window of peg-IFN-alpha-2b.
The safety profile of type I interferons alpha is believed to be well characterized after clinical experience for nearly 20 years. Since the dose is carefully titrated to the optimal effective dose no additional risks for the patients are expected. HU, the IMP-comparator in the study, is the standard reference treatment in PV.
This phase III study was designed to compare, for the first time, the efficacy and safety of HU with a pegylated prolin-interferon alpha-2b (AOP2014) in patients with PV. Two populations will be assessed: HU naïve patients and patients currently treated or pre-treated with HU for less than 3 years, not responding to HU treatment (according to criteria in this protocol).
The main concern of a long term treatment with HU is its potential leukaemogenicity: based on the mechanism of action, HU can potentially accelerate the accumulation of mutations in DNA and increase the risk of leukaemic transformation (Dingli et Tefferi, 2006). However, there is currently no clear clinical data to confirm leukaemogenicity of HU in patients with PV (Tefferi, 2012).
Even though IFN-alpha has shown its activity in PV in the 1980s, it is still considered as an experimental treatment in Europe due to pending approval in this indication (Barbui et al, 2011). It induces major or complete molecular remissions in patients with PV accompanied by a reduction in the risk of thrombosis and bleeding - the major determinants of morbidity in this indication (Hasselbalch, 2011). However, only low doses are tolerated and significant adverse effects from long-term use may limit its usefulness.
Pegylated interferons are better tolerated and are the preferred options of treatment in PV patients (Kiladjian et al, 2008) despite the lack of evidences based on well-designed randomized controlled clinical studies.
AOP2014 is a next generation pegylated interferon (Peg-P-IFN-alpha-2b), with the addition of proline in the N-terminal end.
AOP2014 like all interferon suppresses the malignant clone causing PV and subsequently is expected to possibly defer the onset of or avoid long term sequelae of PV. In addition, a reduction in the frequency of phlebotomies should be achieved. The peg-P-IFN-alpha-2b might potentially have a positive impact on reducing the drop-out rate compared to conventional IFNs. It is expected that the reduced frequency of administration of AOP2014 will contribute to higher compliance rates.
The maximum tolerated dose as well as the safety, efficacy and pharmacokinetics of AOP2014 were assessed in a phase I/II study in patients with PV. After 24 evaluable patients had entered the Phase I dose finding part, the MTD was defined at the level of 540 µg administered every two weeks. Another 27 patients were recruited in order to further investigate the drug efficacy and safety in PV. Efficacy results of AOP2014 were promising. By visit 18, 53.0% of the patients had reached complete response (12 evaluable patients). Adverse events were manageable and rarely necessitated treatment discontinuation.
AOP2014 was shown to have a prolonged plasma half-life with a concomitant increase in AUC. This is expected to enhance the therapeutic window of peg-IFN-alpha-2b.
The safety profile of type I interferons alpha is believed to be well characterized after clinical experience for nearly 20 years. Since the dose is carefully titrated to the optimal effective dose no additional risks for the patients are expected. HU, the IMP-comparator in the study, is the standard reference treatment in PV.
This phase III study was designed to compare, for the first time, the efficacy and safety of HU with a pegylated prolin-interferon alpha-2b (AOP2014) in patients with PV. Two populations will be assessed: HU naïve patients and patients currently treated or pre-treated with HU for less than 3 years, not responding to HU treatment (according to criteria in this protocol).
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| 2012-005259-18 | EUDRACT_NUMBER | None | View |