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NCT01949805 · CITED IN SOURCE DOCUMENTS

Pegylated Interferon Alpha-2b Versus Hydroxyurea in Polycythemia Vera

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2016-11-28

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
eligibility 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
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Hydroxyurea capsules (500 mg each). Daily intake of doses from 500 mg Q2D to 3000 mg QD
    intervention Names
    1. Drug: Hydroxyurea
    label
    Hydroxyurea
    type
    ACTIVE_COMPARATOR
  2. description
    Peg-P-IFN-alpha-2b at 50mcg to max 500 mcg, given every other week as one subcutanous injection
    intervention Names
    1. Drug: Peg-P-IFN-alpha-2b (AOP2014)
    label
    Peg-P-IFN-alpha-2b (AOP2014)
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Peg-P-IFN-alpha-2b (AOP2014)
    description
    Pegylated interferon alpha 2b given Q2W as SC injection
    name
    Peg-P-IFN-alpha-2b (AOP2014)
    other Names
    1. AOP2014
    2. P1101
    type
    DRUG
  2. arm Group Labels
    1. Hydroxyurea
    description
    Hydroyurea capsules taken daily po
    name
    Hydroxyurea
    other Names
    1. HU
    2. Hydroxycarbamide
    3. brand name Litalir (or other)
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
257
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    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
    measure
    Disease response rate
    time Frame
    Month 12
secondary Outcomes
  1. measure
    Disease response
    time Frame
    at month 3, 6 and 9
  2. measure
    JAK2 allelic burden changes
    time Frame
    at month 6 and 12
  3. description
    will be measured during the study period of 12 months
    measure
    time to response
    time Frame
    from inclusion until first response confirmation
  4. description
    from the first documented response on study
    measure
    duration of response
    time Frame
    during the 12 months of study duration
  5. measure
    number of phlebotomies
    time Frame
    from inclusion until month 12
  6. description
    biweekly
    measure
    blood parameters
    time Frame
    from inclusion until month 12
  7. description
    both centrally (blinded assessment) and locally
    measure
    spleen size
    time Frame
    at month 3, 6, 9 and 12
  8. description
    biweekly
    measure
    disease related symptoms
    time Frame
    from inclusion until month 12
  9. description
    biweekly
    measure
    adverse events
    time Frame
    from inclusion until month 12
  10. description
    biweekly
    measure
    protocol-specific adverse events of special interest
    time Frame
    from inclusion until month 12
Full study description
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).
Source references
references
  1. citation
    Verger E, Soret-Dulphy J, Maslah N, Roy L, Rey J, Ghrieb Z, Kralovics R, Gisslinger H, Grohmann-Izay B, Klade C, Chomienne C, Giraudier S, Cassinat B, Kiladjian JJ. Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo. Blood Cancer J. 2018 Oct 4;8(10):94. doi: 10.1038/s41408-018-0133-0.
    pmid
    30287855
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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        quent for patients who received pegylated interferon alfa (46% vs. 28%).</li></ul></div></li><li>The <a href="/clinicaltrials/NCT01949805">PROUD-PV</a> study (NCT01949805) randomly assigned 257 patients with an indication for cytoreduction to receive either ropeginterferon alfa-2B or hydroxyurea. Patients could have previously r
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    Preserved source evidence · Not medical advice