The Benefit/Risk Profile of AOP2014 in Low-risk Patients With PV
Condition: Polycythemia Vera
MeSH terms: Polycythemia Vera; Polycythemia
Study type: Interventional
Phase: Phase 2

Summary: 
      The Low-PV study is a multicenter, phase II, randomized trial aimed to assess whether the
      addition of Pegylated Proline-interferon-alpha-2b to the best therapeutic current strategy
      available based on phlebotomies and low dose acetylsalicylic acid (ASA) could improve the
      efficacy of treatment of patients with PV at low risk of thrombosis (younger than 60 years
      and without prior vascular events), in term of control of recommended level of hematocrit <
      45%, over a period of 12 months.
    

Detailed description: 
      It is an independent, investigator-generated, pragmatic trial including adult PV patients
      (aged 18-60) diagnosed according to World Health Organization 2008 criteria within the last 3
      years before inclusion, without history of thrombosis and younger than 60 years ('low risk'
      patients).

      Eligible patients are randomized to be treated with the best available therapy (recommended
      for this risk class, standard arm) based on phlebotomy including administration of low-dose
      (100 mg/daily) of acetylsalicylic acid (ASA, when there are not contraindications) OR
      Pegylated Proline-Interferon alpha-2b (AOP2014) every 2 weeks in addition to the recommended
      available regimen (experimental arm), for up to 12 months. The allocation of patients to
      study arms is 1:1 and stratification at randomization will be performed according to age
      category (< 50 years old or > 50 years old) and time from diagnosis (naϊve or non-naϊve).
      Naive patients are defined as new cases coming to observation, diagnosed for the first time
      just before study entry and never treated; non-naive patients are old cases (diagnosis not
      older than 3 years before study entry) undergoing therapy with phlebotomy and/or low doses of
      ASA.

      Primary endpoint (PEp) is defined by the proportion (%) of patients who maintain the median
      value of hematocrit (HCT) below 45% during 12 months of treatment in each arm, without
      progression of disease and no need of any extra-protocol cytoreductive drug (responder
      patients).

      Secondary endpoints include evaluation of hematological and molecular response, histological
      remission and safety profile of the protocol therapy.

      Before randomization all patients undergo phlebotomies in order to reach an HCT below 45%.

      After randomization, according to current common clinical practice the regimen of
      phlebotomies must be selected accordingly to maintain the recommended level of HCT< 45%. Once
      normalization of the HCT has been achieved, blood counts at regular intervals (every 4 weeks)
      will establish the frequency of future phlebotomies. Sufficient blood is recommended to be
      removed in order maintain the hematocrit below 45%. Supplemental iron therapy should not be
      administered.

      All patients receive low-dose of ASA (100 mg/daily) as recommended by the current guidelines
      for low-risk subjects with PV.

      Patients allocated in the experimental group receive in addition a pre-filled auto-injection
      pen for the subcutaneous auto-administration (into the abdominal skin or the thigh) of 100 µg
      of Pegylated Proline-Interferon alpha-2b (AOP2014) once every 14 days.

      Patient visits are scheduled every month (4 weeks) for 12 months to assess and perform a
      reliable calculation of the primary end-point (% of patients with median HCT levels <45%).

      At each monthly visit a pre-filled auto-injection pen is delivered to the patients who have
      been randomized in the experimental arm.

      Assuming an expected drop-out rate of 12%, a total sample size of 150 patients (75 randomized
      in each group) will be randomized to reject the null hypothesis that the proportion of
      patients achieving the primary endpoint is 50% in favor of the alternative hypothesis that
      this proportion is 75% when AOP2014 is added to the phlebotomy based- therapy, with a power
      of 80% and an alpha error of 0.05 (two-tailed).

      Two interim-analysis are planned when 50 and 100 of randomized patients have completed the 12
      months study, respectively, in order to evaluate and supervise both safety and primary
      endpoint. The Lan and DeMets (1983) spending function with O'Brien-Fleming type boundaries
      will be employed to preserve the overall two-sided type I error rate for effectiveness at the
      0.05 level, regardless of the timing of the analysis.

      The results of the second interim analysis carried out at in April 2020 indicated a
      significant higher efficacy of the experimental arm than standard arm. The composite primary
      end-point was reached in 84% in patients of Ropeginterferon arm vs. 60% in standard arm
      (p=0.008, Odds Ratio=3.5, 95% CI: 1.3-10.4). This result, according to the statistical
      evaluation for futility and efficacy, reveals that , the null hypothesis is already been
      proven with first 100 patients randomized and cannot change in the future when 150 patients
      will enter the study. Therefore the data safety monitoring board and the steering committee
      agree that the accrual of new patients can be interrupted with 127 patients included.

      The primary endpoint assessment is performed after the completion of the first 12 months of
      therapy for all subjects enrolled ('core study').

      A period of 12 months is expected for completion of the enrolment / randomization phase. The
      'core study' itself will take 12 months of treatment per patient.

      Based on results from the 'core study' the extension phase will continue as follows:

        1. After 12 month patients who meet the primary endpoint following either conventional or
           experimental therapy will enter the extension phase and remain on their current regimen.

        2. non-responders, not meeting the primary endpoint after 12 months of conventional therapy
           will be switched to the experimental treatment.

        3. non-responder, not meeting the primary endpoint after 12 months of experimental therapy
           will be switched to conventional treatment.

      This extension phase will last for another 12 months from the Last Visit Last Patient
      included (LVLP) into the core study (matching cases 1 and 2 as defined above). Based on this,
      the overall length of the study is expected to cover a period of 36 months from the First
      Patient Included (FPI).
    

Intervention name(s): AOP2014; Phlebotomies; ASA
Intervention type(s): Drug; Procedure; Drug
Intervention description(s): AOP2014 will be supplied to the patients as pre-filled auto-injection pens, containing 250 µg of active drug (0.5 ml solution for injection). One pen may be used twice within a time period of 4 weeks. Hence investigators will provide one prefilled pen at every monthly visit. AOP2014 will be self-injected subcutaneously by patients once every 14 days at the single doses of 100 µg (0.2 ml).; According to current common clinical practice the regimen must be selected accordingly to maintain the recommended level of HCT< 45%. Once normalization of the hematocrit has been achieved, blood counts at regular intervals (every 4 weeks) will establish the frequency of future phlebotomies. Sufficient blood should be removed to maintain the hematocrit below 45%.; 100 mg/daily of ASA is recommended (when there are not contraindications) according with current guidelines for this risk class of patients
Other intervention name(s): Pegylated-Proline-Interferon α-2b, P1101; blood removing; Acetylsalicylic Acid
Intervention MeSH terms: Aspirin; Interferons
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: low risk of thrombosis; Interferon