Polycythemia VeraPhase 2Low-PVNCT03003325
The Benefit/Risk Profile of AOP2014 in Low-risk Patients With PV
A Phase 2 study testing AOP2014, Phlebotomies and ASA in people with Polycythemia Vera, run by FROM- Fondazione per la Ricerca Ospedale di Bergamo- ETS at 23 sites in Italy.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Polycythemia Vera
- What is being tested?
- AOP2014, Phlebotomies and ASA
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 127 participants
- Where
- 23 sitesItaly
- Study dates
- 2 Feb 2017to 31 Mar 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Age 18-60 years
- Diagnosis of Polycythemia Vera according to World Health Organization 2016 criteria
- Diagnosis of Polycythemia Vera including a recent bone marrow (BM) biopsy (performed within 3 years prior randomization in the study) and never treated with cytoreductive drugs
- HCT<45%
- Ability and willingness to comply with all study requirements
- Signed written informed consent.
Who cannot join
- Any previous well documented cardiovascular PV-related events (see Appendix 1 for description)
- Previous cytoreductive drugs
- Known hypersensitivity or contraindications to the Investigational Medicinal Product (Pegylated Proline-Interferon alpha-2b) including:
- evidence of severe retinopathy (e.g. cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension); thyroid dysfunction not adequately controlled; patients tested positively with Thyroglobulin antibody and / or TPOAb at screening; documented autoimmune disease at screening or in the medical history; history or presence of depression requiring treatment with antidepressant; any risk of suicide at screening or previous suicide attempts;
- Previous exposure to a non-pegylated or pegylated interferon α
- Clinically relevant pulmonary infiltrates, pneumonia, and pneumonitis
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- Systemic infections, e.g. hepatitis B, hepatitis C, or HIV at screening
- Significant liver (AST or alanine aminotransferase > 2.5 times ULN) or renal disease (creatinine > 2 mg/ml)
- Presence of any life-threatening condition or of any disease (e.g. cancer) that is likely to significantly shorten life expectancy
- History of active substance or alcohol abuse within the last year
- Any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety or be associated with poor adherence to the protocol
- Pregnant or lactating women and women*/men of childbearing potential who are not using or are not willing to use any effective means of contraception (i.e. sexual abstinence, hormonal contraceptive, intra-uterine device, barrier method such as diaphragms or condoms, surgical methods).
- Pregnancy test will be performed in order to ascertain negativity of human chorionic gonadotropin (β-hCG) test and confirm that childbearing women are not pregnant.
Trial locations and contacts
23 sites in 1 country.
23 sites in 1 country
Italy23 sites
U.O. Ematologia con Trapianto, Azienda Universitaria Ospedaliera Consorziale - Policlinico Bari
Bari, Apulia, 70120
UOC Ematologia, ASST Papa Giovanni XXIII
Bergamo, Lombardy, 24127
Divisione Ematologia Policlinico S. Orsola - Malpighi
Bologna, Emilia-Romagna, 40138
Unità Operativa Complessa di Emostasi Azienda Ospedaliero-Universitario "Policlinico Vittorio-Emanuele - Presidio Ospedaliero Ferrarotto
Catania, Sicily, 95124
S.C. Ematologia Azienda Ospedaliera S. Croce e Carle Cuneo
Cuneo, Piedmont, 12100
SOD Ematologia AUOC Azienda Ospedaliero-Universitaria "Careggi"
Florence, Tuscany, 50134
UOC Ematologia, Azienda Ospedaliera Universitaria Policlinico "G. Martino"
Messina, Sicily, 98100
Divisione Oncoematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Milan, Lombardy, 20122
Divisione Ematologia ASST, Grande Ospedale Metropolitano Niguarda
Milan, Lombardy, 20162
IRCCS Ospedale San Raffaele
Milan, 20132
Divisione Ematologia, ASST di MONZA - Ospedale San Gerardo di Monza
Monza, Lombardy, 20900
Azienda Ospedaliera Universitaria Federico II di Napoli
Naples, Campania, 80131
SCDU Ematologia, A.O.U. Maggiore della Carità
Novara, Piedmont, 28100
Clinica Medica I Azienda Ospedaliera di Padova
Padova, Veneto, 35128
Divisione Ematologia Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone" Palermo
Palermo, Sicily, 90127
Divisione Ematologia, Fondazione IRCCS Policlinico San Matteo
Pavia, Lombardy, 27100
UCSC Ematologia, Fondazione Policlinico Universitario "Agostino Gemelli"Università Cattolica del Sacro Cuore
Rome, Lazio, 00168
U.O. Ematologia, Ospedale Casa Sollievo della Sofferenza Istituto di Ricovero e Cura a Carattere Scientifico
San Giovanni Rotondo, (FG) Puglia, 71013
S.C. Ematologia, AOU- Presidio Ospedaliero Molinette
Turin, Piedmont, 10126
Clinica Ematologica, Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia"
Udine, Friuli Venezia Giulia, 33100
U.O. Ematologia, Ospedale di Circolo e Fondazione Macchi Varese
Varese, Lombardy, 21100
Divisione Ematologia, Ospedale Borgo Roma
Verona, Veneto, 37134
Divisione Ematologia, Ospedale San Bortolo
Vicenza, Veneto
About this study
Official title: The Benefit/Risk Profile of Pegylated Proline-Interferon Alpha-2b (AOP2014) Added to the Best Available Strategy Based on Phlebotomies in Low-risk Patients With Polycythemia Vera (PV). The Low-PV Randomized Trial
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.
Read the 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:
- 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.
- non-responders, not meeting the primary endpoint after 12 months of conventional therapy will be switched to the experimental treatment.
- 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).
- Conditions
- Polycythemia Vera
- Being tested
- AOP2014, Phlebotomies, ASA
- Keywords
- low risk of thrombosis, Interferon
- Medical subject headings
- Polycythemia Vera
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AOP2014Drug
Also called Pegylated-Proline-Interferon α-2b, P1101
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).
PhlebotomiesProcedure or surgery
Also called blood removing
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%.
ASADrug
Also called Acetylsalicylic Acid
100 mg/daily of ASA is recommended (when there are not contraindications) according with current guidelines for this risk class of patients
| Study group | Role | What they receive |
|---|---|---|
| Phlebotomies + ASA | Active comparator | Conventional treatment based on phlebotomies and low dose (100 mg) of acetylsalicylic acid (ASA) Receives: Procedure: Phlebotomies; Drug: ASA |
| Phlebotomies + ASA + AOP2014 | Experimental | Conventional treatment based on phlebotomies, low dose (100 mg) of acetylsalicylic acid (ASA) plus the addition of 100 µg of Pegylated Proline-Interferon alpha-2b (AOP2014) once every 14 days (subcutaneously). Receives: Drug: AOP2014; Procedure: Phlebotomies; Drug: ASA |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of patients who maintains the median value of HCT< 45%, along 12 months, on number of patients randomized in each arm, per cent
For each patient the median value of HCT percentage will be calculated from all measurements detected and reported every month (from baseline to 12-month visit or study end). A patient will be defined as responder (achieving PEp) when he maintains the median value of HCT < 45%, after undergoing treatments according to this protocol, for up 12 months.
A patient will be defined as non-responder (not achieving PEp) when
- Does not maintain the median value of HCT < 45%, after undergoing treatments according to this protocol, for up 12 months, or
- Is in need of any additional chemotherapeutic and/or cytoreductive treatment aimed to manage disease due to disease progression.
Measured: 12 months
Secondary outcomes (7)
Median number of phlebotomies performed
- The total number of phlebotomies will be calculated for each patients during 12 months of therapy (and then 24 months);
- Based on values obtained from point (1) in each arm-group of patients, the median number of phlebotomies performed in each therapy group will be calculated (and compared) after 12 and 24 months of therapy (or completion of the study)
Measured: 12 months, 24 months
Number of patients achieving hematological response (as defined below in 'Description') on number of patients randomized in each arm, per cent,
For each patient the median value of HCT (%), absolute white blood cells (WBCs) count and absolute platelets (PLTs) count will be calculated from all measurements detected and reported at least every month (from baseline to 12-month visit and then to 24-month visit/study completion). A patient will be defined as achieving hematological response when the median values of HCT < 45%, WBCs count < 10 x10*9/L and PLTs count < 400 x10*9/L is observed after 12 months of therapy (or 24 months). The proportion of patients who maintains this response after 24 months (or study completion) will be calculated (and compared) in each arm.
Measured: 12 months, 24 months
Proportion (rate per cent) of patients with not palpable spleen
The proportion (rate per cent) of patients with not palpable spleen will be calculated in each arm as the ratio of number of patients with resolution of splenomegaly or persistence of not palpable spleen at palpation with respect to baseline, on number of patients randomized in each arm, after 12 and 24 months (study completion) of therapy, per cent.
Measured: 12 months, 24 months
Janus kinase-2 allele burden reduction or complete molecular remission
Quantitative Janus kinase-2 measurements (central lab facility) will be performed at baseline and after 12 months of therapy for all patients; Janus kinase-2 assessment will be performed also after 24 months for patients receiving interferon (experimental therapy). Reduction of allele burden in each patient (with respect to baseline) will be assessed according to Jovanovic et al, Leukemia 2013.
The proportion (rate per cent) of patients with Janus kinase-2 allele burden reduction or remission will be calculated in each arm (and compared).
Measured: 12 months, 24 months
Bone marrow histological remission
Defined as presence of age-adjusted normocellularity and disappearance of trilinear hyperplasia, and absence of >grade 1 reticulin fibrosis. It will be assessed in each patient and then the proportion (rate per cent) of patients with bone marrow histological remission will be calculated in each arm (and compared).
Measured: 24 months
Incidence and frequence of thrombotic and hemorrhagic events occurred
The number of events will be recorded any time during the study in order to assess the frequency ,every 12 months and at completion of the study, and their incidence in each arm and whole population. Comparison between arms will be performed.
Measured: 12 months, 24 months
Number of adverse events occurred
Incidence, causality and intensity of clinical relevant adverse events will be assessed in each arm and compared all over the study.
The rate of assigned treatment withdrawal due to any protocol drug-related toxicity occurred any time will be compared. Number of adverse events, expressed as frequency in each arm, will be calculated (as ratio of number of patient experiencing adverse on the the number of patients randomized in each arm) and compared
Measured: 12 months, 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Dec 2016 (estimated)
- Study start2 Feb 2017
- Primary completion31 Mar 2022
- Study completion31 Mar 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (22)Papers the sponsor has linked to this study.
- Other trials for Polycythemia VeraStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 127 participants (actual)
Sponsor and investigators
- Lead sponsor
- FROM- Fondazione per la Ricerca Ospedale di Bergamo- ETS
- Sponsor type
- University, hospital or other
- Collaborators
- AOP Orphan Pharmaceuticals AG
- Responsible party
- Sponsor
- Investigators
- Tiziano Barbui, Professor, Study chair, Fondazione per la Ricerca Ospedale Maggiore di Bergamo (FROM)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03003325
- Sponsor's protocol ID
- Low-PV
- Acronym
- Low-PV
- Status last verified
- Sep 2024
- First submitted
- 3 Nov 2016
- Last updated
- 19 Sep 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: No plan has been defined yet about sharing of IPD
Publications
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90. doi: 10.1056/NEJMoa051113.
PubMed 15858187Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish HF, Green AR. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007 Feb 1;356(5):459-68. doi: 10.1056/NEJMoa065202.
PubMed 17267906Passamonti F, Elena C, Schnittger S, Skoda RC, Green AR, Girodon F, Kiladjian JJ, McMullin MF, Ruggeri M, Besses C, Vannucchi AM, Lippert E, Gisslinger H, Rumi E, Lehmann T, Ortmann CA, Pietra D, Pascutto C, Haferlach T, Cazzola M. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011 Mar 10;117(10):2813-6. doi: 10.1182/blood-2010-11-316810. Epub 2011 Jan 11.
PubMed 21224469Vannucchi AM, Rotunno G, Bartalucci N, Raugei G, Carrai V, Balliu M, Mannarelli C, Pacilli A, Calabresi L, Fjerza R, Pieri L, Bosi A, Manfredini R, Guglielmelli P. Calreticulin mutation-specific immunostaining in myeloproliferative neoplasms: pathogenetic insight and diagnostic value. Leukemia. 2014 Sep;28(9):1811-8. doi: 10.1038/leu.2014.100. Epub 2014 Mar 12.
PubMed 24618731Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, Hehlmann R, Hoffman R, Kiladjian JJ, Kroger N, Mesa R, McMullin MF, Pardanani A, Passamonti F, Vannucchi AM, Reiter A, Silver RT, Verstovsek S, Tefferi A; European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011 Feb 20;29(6):761-70. doi: 10.1200/JCO.2010.31.8436. Epub 2011 Jan 4.
PubMed 21205761Najean Y, Rain JD. The very long-term evolution of polycythemia vera: an analysis of 318 patients initially treated by phlebotomy or 32P between 1969 and 1981. Semin Hematol. 1997 Jan;34(1):6-16. No abstract available.
PubMed 9025157Treatment of polycythaemia vera by radiophosphorus or busulphan: a randomized trial. "Leukemia and Hematosarcoma" Cooperative Group, European Organization for Research on Treatment of Cancer (E.O.R.T.C.). Br J Cancer. 1981 Jul;44(1):75-80. doi: 10.1038/bjc.1981.150.
PubMed 7020738Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C, Marilus R, Villegas A, Tognoni G, Barbui T. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005 Apr 1;23(10):2224-32. doi: 10.1200/JCO.2005.07.062. Epub 2005 Feb 14.
PubMed 15710945Barosi G, Vannucchi AM, De Stefano V, Pane F, Passamonti F, Rambaldi A, Saglio G, Barbui T, Tura S. Identifying and addressing unmet clinical needs in Ph-neg classical myeloproliferative neoplasms: a consensus-based SIE, SIES, GITMO position paper. Leuk Res. 2014 Feb;38(2):155-60. doi: 10.1016/j.leukres.2013.09.008. Epub 2013 Sep 19.
PubMed 24378116Barosi G, Mesa R, Finazzi G, Harrison C, Kiladjian JJ, Lengfelder E, McMullin MF, Passamonti F, Vannucchi AM, Besses C, Gisslinger H, Samuelsson J, Verstovsek S, Hoffman R, Pardanani A, Cervantes F, Tefferi A, Barbui T. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013 Jun 6;121(23):4778-81. doi: 10.1182/blood-2013-01-478891. Epub 2013 Apr 16.
PubMed 23591792Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, De Stefano V, Elli E, Iurlo A, Latagliata R, Lunghi F, Lunghi M, Marfisi RM, Musto P, Masciulli A, Musolino C, Cascavilla N, Quarta G, Randi ML, Rapezzi D, Ruggeri M, Rumi E, Scortechini AR, Santini S, Scarano M, Siragusa S, Spadea A, Tieghi A, Angelucci E, Visani G, Vannucchi AM, Barbui T; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013 Jan 3;368(1):22-33. doi: 10.1056/NEJMoa1208500. Epub 2012 Dec 8.
PubMed 23216616Gisslinger H, Ludwig H, Linkesch W, Chott A, Fritz E, Radaszkiewicz T. Long-term interferon therapy for thrombocytosis in myeloproliferative diseases. Lancet. 1989 Mar 25;1(8639):634-7. doi: 10.1016/s0140-6736(89)92142-9.
PubMed 2564458Tefferi A, Hudgens S, Mesa R, Gale RP, Verstovsek S, Passamonti F, Cervantes F, Rivera C, Tencer T, Khan ZM. Use of the Functional Assessment of Cancer Therapy--anemia in persons with myeloproliferative neoplasm-associated myelofibrosis and anemia. Clin Ther. 2014 Apr 1;36(4):560-6. doi: 10.1016/j.clinthera.2014.02.016. Epub 2014 Mar 14.
PubMed 24636526Emanuel RM, Dueck AC, Geyer HL, Kiladjian JJ, Slot S, Zweegman S, te Boekhorst PA, Commandeur S, Schouten HC, Sackmann F, Kerguelen Fuentes A, Hernandez-Maraver D, Pahl HL, Griesshammer M, Stegelmann F, Doehner K, Lehmann T, Bonatz K, Reiter A, Boyer F, Etienne G, Ianotto JC, Ranta D, Roy L, Cahn JY, Harrison CN, Radia D, Muxi P, Maldonado N, Besses C, Cervantes F, Johansson PL, Barbui T, Barosi G, Vannucchi AM, Passamonti F, Andreasson B, Ferrari ML, Rambaldi A, Samuelsson J, Birgegard G, Tefferi A, Mesa RA. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012 Nov 20;30(33):4098-103. doi: 10.1200/JCO.2012.42.3863. Epub 2012 Oct 15.
PubMed 23071245Barbui T, Carobbio A, Rambaldi A, Finazzi G. Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood. 2009 Jul 23;114(4):759-63. doi: 10.1182/blood-2009-02-206797. Epub 2009 Apr 16.
PubMed 19372254
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Benefit/Risk Profile of Pegylated Proline-Interferon Alpha-2b (AOP2014) Added to the Best Available Strategy Based on Phlebotomies in Low-risk Patients With Polycythemia Vera (PV). The Low-PV Randomized Trial
- ClinicalTrials.gov ID
- NCT03003325
- Acronym / sponsor ID
- Low-PV / Low-PV
- Conditions
- Polycythemia Vera
- Keywords
- low risk of thrombosis, Interferon
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 127 participants (actual)
- Lead sponsor
- FROM- Fondazione per la Ricerca Ospedale di Bergamo- ETSUniversity, hospital or other
- Collaborators
- AOP Orphan Pharmaceuticals AG
- Study start
- 2 Feb 2017 (actual)
- Primary completion
- 31 Mar 2022 (actual)
- Study completion
- 31 Mar 2023 (actual)
- First posted
- 28 Dec 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
- non-responders, not meeting the primary endpoint after 12 months of conventional therapy will be switched to the experimental treatment.
- 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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Phlebotomies + ASA | Active comparator | Procedure: Phlebotomies, Drug: ASAConventional treatment based on phlebotomies and low dose (100 mg) of acetylsalicylic acid (ASA) |
| Phlebotomies + ASA + AOP2014 | Experimental | Drug: AOP2014, Procedure: Phlebotomies, Drug: ASAConventional treatment based on phlebotomies, low dose (100 mg) of acetylsalicylic acid (ASA) plus the addition of 100 µg of Pegylated Proline-Interferon alpha-2b (AOP2014) once every 14 days (subcutaneously). |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Age 18-60 years
- Diagnosis of Polycythemia Vera according to World Health Organization 2016 criteria
- Diagnosis of Polycythemia Vera including a recent bone marrow (BM) biopsy (performed within 3 years prior randomization in the study) and never treated with cytoreductive drugs
- HCT<45%
- Ability and willingness to comply with all study requirements
Key exclusion criteria (13 listed)
- Any previous well documented cardiovascular PV-related events (see Appendix 1 for description)
- Previous cytoreductive drugs
- Known hypersensitivity or contraindications to the Investigational Medicinal Product (Pegylated Proline-Interferon alpha-2b) including:
- evidence of severe retinopathy (e.g. cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension); thyroid dysfunction not adequately controlled; patients tested positively with Thyroglobulin antibody and / or TPOAb at screening; documented autoimmune disease at screening or in the medical history; history or presence of depression requiring treatment with antidepressant; any risk of suicide at screening or previous suicide attempts;
- Previous exposure to a non-pegylated or pegylated interferon α
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AOP2014Also: Pegylated-Proline-Interferon α-2b, P1101AOP2014 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). | Drug | Phlebotomies + ASA + AOP2014 |
| PhlebotomiesAlso: blood removingAccording 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%. | Procedure or surgery | Phlebotomies + ASA, Phlebotomies + ASA + AOP2014 |
| ASAAlso: Acetylsalicylic Acid100 mg/daily of ASA is recommended (when there are not contraindications) according with current guidelines for this risk class of patients | Drug | Phlebotomies + ASA, Phlebotomies + ASA + AOP2014 |
Primary outcome
Number of patients who maintains the median value of HCT< 45%, along 12 months, on number of patients randomized in each arm, per cent
Time frame: 12 months
For each patient the median value of HCT percentage will be calculated from all measurements detected and reported every month (from baseline to 12-month visit or study end). A patient will be defined as responder (achieving PEp) when he maintains the median value of HCT < 45%, after undergoing treatments according to this protocol, for up 12 months. A patient will be defined as non-responder (not achieving PEp) when 1. Does not maintain the median value of HCT < 45%, after undergoing treatments according to this protocol, for up 12 months, or 2. Is in need of any additional chemotherapeutic and/or cytoreductive treatment aimed to manage disease due to disease progression.
7 secondary outcomes
Median number of phlebotomies performed
Time frame: 12 months, 24 months
Number of patients achieving hematological response (as defined below in 'Description') on number of patients randomized in each arm, per cent,
Time frame: 12 months, 24 months
Proportion (rate per cent) of patients with not palpable spleen
Time frame: 12 months, 24 months
Janus kinase-2 allele burden reduction or complete molecular remission
Time frame: 12 months, 24 months
Bone marrow histological remission
Time frame: 24 months
Incidence and frequence of thrombotic and hemorrhagic events occurred
Time frame: 12 months, 24 months
Number of adverse events occurred
Time frame: 12 months, 24 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2024.
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- Individual participant dataSharing planned: No. No plan has been defined yet about sharing of IPD
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tiziano Barbui, Professor study chair
Fondazione per la Ricerca Ospedale Maggiore di Bergamo (FROM)
23 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing AOP2014, Phlebotomies and ASA in people with Polycythemia Vera, run by FROM- Fondazione per la Ricerca Ospedale di Bergamo- ETS at 23 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 23 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of patients who maintains the median value of HCT< 45%, along 12 months, on number of patients randomized in each arm, per cent (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03003325, which also lists 22 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2024.