E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036061 |
E.1.2 | Term | Polycythemia vera |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy of INC424 to Best Available Therapy (BAT) as assessed by both the absence of phlebotomy eligibility and reduction in spleen volume. |
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E.2.2 | Secondary objectives of the trial |
• To compare the proportion of subjects randomized to INC424 vs Best Available Therapy achieving both durable absence of phlebotomy eligibility and durable spleen volume reduction
• To compare the proportion of subjects randomized to INC424 vs Best Available Therapy achieving complete hematologic remission
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects 18 years of age or older.
2. Subjects must be diagnosed with PV for at least 24 weeks prior to Screening according to the 2008 World Health Organization criteria (Table 2 in Tefferi and Vardiman, 2008; Appendix 1).
3. Subjects must have a treatment history for PV that meets the definition of resistance or intolerance to hydroxyurea (HU) by exhibiting at least one of the following five criteria (modified from Barosi et al, 2009A; Appendix 2):
• HU Resistance, defined after 12 weeks into a course of HU therapy at a dose of at least 2 grams/day OR at the subject’s maximally tolerated dose if that dose is less than 2 grams/day:
a.Need for phlebotomy to keep hematocrit < 45%, OR
b. Platelet count > 400 x 109/L AND white blood cell count > 10 x 109/L, OR
c. Failure to reduce splenomegaly extending greater than 10 cm below the costal margin by more than 50%, as measured by palpation.
•HU Intolerance:
a. Absolute neutrophil count < 1.0 x 109/L OR platelet count < 100 x 109/L OR hemoglobin < 100 g/L (i.e. 10 g/dL) at the lowest dose of HU required to achieve a response (with response modified from Barosi et al, 2009B: hematocrit < 45% without phlebotomy AND/OR all of the following three items: platelet count ≤ 400 x 109/L, white blood cell count ≤ 10 x 109/L, and non-palpable spleen), OR
b. Presence of leg ulcers or other unacceptable HU-related non-hematological toxicities (such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis or fever at any dose of HU), defined as
- CTCAE version 3.0 Grade 3-4, OR
- more than 1 week of CTCAE version 3.0 Grade 2, OR
- permanent discontinuation of HU, OR
- interruption of HU until toxicity resolved, OR
- hospitalization due to HU toxicity.
4. Subjects must have required
a. at least 2 phlebotomies within the 24 weeks prior to Screening, AND
b. at least one phlebotomy within the 16 weeks prior to Screening, AND
c. The most distant and the most recent phlebotomy within the 24 weeks prior to Screening must be at least 4 weeks apart
OR subjects will be considered to have met this criterion if they have required a phlebotomy within the 16 weeks prior to Screening AND they exhibit a hematocrit > 45% at Screening
5. Patients with splenomegaly, defined as
a. Spleen palpable below the costal margin, provided that MRI (or CT in applicable patients) spleen assessment during Screening confirms that the spleen is enlarged, defined with a volume of ≥ 450 cm3, OR
b. Spleen non palpable below the costal margin due to body habitus (e.g., in obese subjects), provided that MRI (or CT in applicable patients) spleen assessment during Screening confirms that the spleen is enlarged, defined with a volume of ≥ 450 cm3
6. Subjects with ANC ≥ 1.5 x 109/L and PLT ≥ 100 x 109/L at Screening.
7. Subjects with peripheral blood blast count of 0% at Screening
8. Subjects with an ECOG performance status of 0, 1 or 2 (Appendix 5) at Screening and Baseline.
9. Subjects on a therapeutic regimen for PV must have been on a stable dose and schedule for at least 2 weeks prior to Screening and no less than 4 weeks prior to randomization (Study Day 1).
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E.4 | Principal exclusion criteria |
Subjects eligible for this study must not meet any of the following criteria:
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception (confirmed by a positive hCG laboratory test > 5 mIU/mL) and until the termination of gestation.
2. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method.
• Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide (Appendix 3).
• Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.
• Reliable contraception should be maintained throughout the study and for 5-half lives of study drug after study treatment discontinuation.
• Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
• Sexually active males must use a condom during intercourse while taking the drug and for five half-lives after stopping treatment and should not father a child in this period.
3. Subjects with inadequate liver or renal function at Screening as demonstrated by:
a. Encephalopathy Grade 2 or more as per Child-Pugh System. (Appendix 12)
b. Known hepatocellular disease (for example, hepatitis B or C, cirrhosis or other hepatocellular disease)
c. Direct bilirubin ≥ 2 X upper limit of laboratory normal (ULN).
d. Alanine aminotransferase (ALT) > 2.5x ULN.
e. MDRD-eGFR < 30 mL/min/1.73m2 or on dialysis.
4. Subjects with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral INC424 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
5. Subjects with clinically significant bacterial, fungal, parasitic or viral infection which requires therapy:
• Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
• Subjects with known active hepatitis A, B or C at Screening or with known HIV positivity.
6.Subjects with diagnosed primary immunodeficiency syndromes such as X-Linked Agammaglobulinemia and Common Variable Immune Deficiency
7. Subjects with an active malignancy over the previous 5 years except treated cervical intraepithelial neoplasia, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin, with no evidence for recurrence in the past 3 years.
8. Subjects with clinically significant cardiac disease (NYHA Class III or IV; Appendix 6).
9. Subjects receiving PEG-IFN-alpha-2a within 5 weeks of Screening or having a prior history of 32P therapy.
10. Subjects being treated concurrently with a potent systemic inhibitor of CYP3A4 at the time of Screening (ketoconazole, clarithromycin, itraconazole, nefazodone or telithromycin, see Appendix 13).
11. Subjects being treated concurrently with any prohibited medications (see Section 5.1.11 for specific prohibited medications and the associated timeframe over which they are prohibited).
12. Subjects who have previously received treatment with a JAK inhibitor.
13. Subjects being treated concurrently with any investigational agent or prior participation in an investigational study within 30 days prior to the first dose of study drug or within 5-half lives of the investigational product, whichever is longer.
14. Subjects who are unable to comprehend or are unwilling to sign an informed consent form (ICF).
15. Subjects with active alcohol or drug addiction that would interfere with their ability to comply with the study requirements.
16. Subjects with an uncontrolled intercurrent illness or any concurrent condition that, in the investigator’s opinion, would jeopardize the safety of the subject or compliance with the protocol.
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects achieving a response at Week 32, with response defined as having achieved both of the following:
• The absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32, with no more than one phlebotomy eligibility occurring post-randomization and prior to the Week 8 visit;
• A reduction in spleen volume as assessed by Imaging (see Section 6.2.1) ≥ 35% from baseline at Week 32.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
proportion of all randomized subjects who achieve the primary endpoint and wh remain free from progression 48 weeks after randomization. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
refer to protcol section 9.5 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Best available therapy as selected by Investigator |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 48 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Belgium |
Egypt |
France |
Germany |
Hungary |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Russian Federation |
Spain |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study (last patient last visit) will occur after all subjects in the study have completed their last assessment as per protocol. Efficacy and safety analyses will be conducted after all subjects remaining in the study have completed 256 weeks of follow-up. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |