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Pegylated Interferon Alpha-2b Versus Hydroxyurea in Polycythemia Vera (PROUD-PV)

This study has been completed.
Sponsor:
Collaborator:
PharmaEssentia (Co-Sponsor for USA)
Information provided by (Responsible Party):
AOP Orphan Pharmaceuticals AG
ClinicalTrials.gov Identifier:
NCT01949805
First received: September 6, 2013
Last updated: November 24, 2016
Last verified: November 2016
  Purpose
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.

Condition Intervention Phase
Polycythemia Vera
Drug: Peg-P-IFN-alpha-2b (AOP2014)
Drug: Hydroxyurea
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by AOP Orphan Pharmaceuticals AG:

Primary Outcome Measures:
  • Disease response rate [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    Disease response rate is defined as hematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets <400 G/L, leukocytes <10 G/L , and normal spleen size


Secondary Outcome Measures:
  • Disease response [ Time Frame: at month 3, 6 and 9 ] [ Designated as safety issue: No ]
  • JAK2 allelic burden changes [ Time Frame: at month 6 and 12 ] [ Designated as safety issue: No ]
  • time to response [ Time Frame: from inclusion until first response confirmation ] [ Designated as safety issue: No ]
    will be measured during the study period of 12 months

  • duration of response [ Time Frame: during the 12 months of study duration ] [ Designated as safety issue: No ]
    from the first documented response on study

  • number of phlebotomies [ Time Frame: from inclusion until month 12 ] [ Designated as safety issue: No ]
  • blood parameters [ Time Frame: from inclusion until month 12 ] [ Designated as safety issue: No ]
    biweekly

  • spleen size [ Time Frame: at month 3, 6, 9 and 12 ] [ Designated as safety issue: No ]
    both centrally (blinded assessment) and locally

  • disease related symptoms [ Time Frame: from inclusion until month 12 ] [ Designated as safety issue: No ]
    biweekly

  • adverse events [ Time Frame: from inclusion until month 12 ] [ Designated as safety issue: Yes ]
    biweekly

  • protocol-specific adverse events of special interest [ Time Frame: from inclusion until month 12 ] [ Designated as safety issue: Yes ]
    biweekly


Enrollment: 257
Study Start Date: September 2013
Study Completion Date: July 2016
Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Hydroxyurea
Hydroxyurea capsules (500 mg each). Daily intake of doses from 500 mg Q2D to 3000 mg QD
Drug: Hydroxyurea
Hydroyurea capsules taken daily po
Other Names:
  • HU
  • Hydroxycarbamide
  • brand name Litalir (or other)
Experimental: Peg-P-IFN-alpha-2b (AOP2014)
Peg-P-IFN-alpha-2b at 50mcg to max 500 mcg, given every other week as one subcutanous injection
Drug: Peg-P-IFN-alpha-2b (AOP2014)
Pegylated interferon alpha 2b given Q2W as SC injection
Other Names:
  • AOP2014
  • P1101

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).

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 18 years or older
  2. Diagnosis of Polycythemia Vera according to the WHO 2008 criteria (Barbui et al, 2011) with the mandatory presence of JAK2V617F mutation as the major disease criterion.
  3. For previously cytoreduction untreated patients - documented need of cytoreductive treatment

    - leukocytosis (WBC>10G/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)
    • total HU treatment duration shorter than three years
    • no documented resistance or intolerance as defined by modified Barosi et al, 2009 criteria
  5. Hospital Anxiety and Depression Scale (HADS) score 0-7 on both subscales
  6. Patients with HADS score of 8-10 inclusive on either or both of the subscales may be eligible following psychiatric assessment that excludes clinical significance of the observed symptoms in the context of potential treatment with an interferon alpha
  7. Signed written informed consent

Exclusion Criteria:

  1. Any systematic cytoreduction for PV prior study entry with 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
  4. Documented autoimmune disease at screening or in the medical history
  5. Clinically relevant pulmonary infiltrates, pneumonia, and pneumonitis at screening
  6. Systemic infections, 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) and/or splenectomy in the medical history
  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 not adequately controlled
  17. Patients tested positively with TgAb and / or TPOAb 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01949805

  Show 58 Study Locations
Sponsors and Collaborators
AOP Orphan Pharmaceuticals AG
PharmaEssentia (Co-Sponsor for USA)
Investigators
Principal Investigator: Heinz Gisslinger, MD Medical University of Vienna
  More Information

Responsible Party: AOP Orphan Pharmaceuticals AG
ClinicalTrials.gov Identifier: NCT01949805     History of Changes
Other Study ID Numbers: PROUD-PV  2012-005259-18 
Study First Received: September 6, 2013
Last Updated: November 24, 2016
Health Authority: Austria: Austrian Medicines and Medical Devices Agency
Bulgaria: Ministry of Health
Czech Republic: State Institute for Drug Control
France: Agence Nationale de Sécurité du Médicament et des produits de santé
Germany: Federal Institute for Drugs and Medical Devices
Hungary: Ministry of Health, Social and Family Affairs
Italy: Ministry of Health
Poland: Ministry of Health
Romania: National Agency for Medicines and Medical Devices
Russia: Ministry of Health of the Russian Federation
Slovakia: State Institute for Drug Control
Spain: Ministry of Health
Ukraine: Ministry of Health
Individual Participant Data  
Plan to Share IPD: No

Additional relevant MeSH terms:
Polycythemia
Polycythemia Vera
Hematologic Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Interferons
Hydroxyurea
Interferon-alpha
Peginterferon alfa-2b
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on December 09, 2016