E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Persistent and Chronic Immune Thrombocytopenia (ITP) |
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E.1.1.1 | Medical condition in easily understood language |
Immune thrombocytopenia despite prior therapy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066667 |
E.1.2 | Term | Chronic thrombocytopenia |
E.1.2 | System Organ Class | 100000004851 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and efficacy on the primary endpoint (platelet response) of select (200 mg BID and 400 mg BID) doses of SKI-O-703 compared to placebo in patients with persistent and chronic ITP, with a platelet count <30,000/μL on 2 occasions at least 7 days apart with the confirmatory count on the first day of treatment. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy on the secondary endpoints of select (200 mg BID and 400 mg BID) doses of SKI-O-703 compared to placebo in patients with persistent and chronic ITP To investigate the PK profile of SKI-O-592 (the free base of SKI-O-703) and its metabolites (M2 and M4) in patients with persistent and chronic ITP To evaluate the effects of SKI-O-703 on PD biomarkers in patients with persistent and chronic ITP |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Able to provide written informed consent and agreeable to the schedule of assessments 2. Male or female subjects, aged 18 years or older 3. Diagnosis of primary ITP (persistent or chronic) made according to the American Society of Hematology 2011 evidence-based guideline 4. Failed to respond or relapsed after at least 1 prior therapy, with a platelet count of <30,000/μL on 2 occasions at least 7 days apart with the confirmatory count on the first day of treatment. Response to such prior therapy is defined as platelet count of ≥30,000/µL and >2 times increase from baseline in the absence of bleeding. Failure to respond and relapse to such prior therapy are defined as failure to achieve and/or failure to maintain response on a tolerable regiment of prior therapy. 5. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥ 1.5 X 109/L, hemoglobin [Hgb] ≥ 10.0 g/dL, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≤ 2.0 x ULN, bilirubin <1.5 x ULN, albumin ≥ 3 g/dL, estimated glomerular filtration rate [eGFR] ≥40 mL/min/1.73m2, and creatinine ≤ 1.5 x ULN) 6. ECOG performance status of 0, 1, or 2 7. Both male and female subjects must agree to take the following steps to reduce the potential for transmission of genetic material containing the investigational product a. Both male and female subjects, the subject and their partners of childbearing potential must agree to use 2 of the following medically acceptable methods of contraception from the time of randomization, during the study, and for 6 months following discontinuation of study drug, of which: o One must be a highly reliable method of contraception, such as: An intrauterine device or intrauterine system implanted for at least 30 days prior to Day 1 Surgical sterilization of one of the partners for at least 6 months prior to the date of informed consent (assuming this will be the only partner for the whole duration of the clinical trial) Consistent and correct use of hormonal contraceptives (hormonal implants, injectables, contraception pills, transdermal patches, or contraceptive rings) for at least 30 days prior to Day 1 o One supplementary barrier method, such as: Male or female condom always with spermicide (a spermicidal foam/gel/film/cream) Diaphragm or cervical/vault caps always with spermicide (a spermicidal foam/gel/film/cream) Double-barrier methods (which means a barrier method used by both partners at the same time), even when used with spermicide, are not considered to be highly reliable contraception methods, and as such, may not be the only forms of contraception used One of the other listed highly reliable methods must be used in conjunction with a barrier method. b. Female subjects must agree not to breastfeed starting from the time of Screening, throughout the study, and until after 6 months following the last dose of study drug. c. Male subjects must agree not to donate sperm starting from the time of randomization, throughout the study, and until after 6 months following the last dose of study drug d. For subjects and partners considered not of childbearing potential, the following conditions apply: a. Menopausal females must have experienced their last period more than 12 months prior to the date of informed consent to be classified as not of childbearing potential. b. Male and female subjects are in a situation of abstinence from heterosexual intercourse from Screening until after 6 months following the last dose of study drug when this is in line with the preferred lifestyle of the subject (eg, homosexual women and men or a member of a religious order such as nuns and priests). |
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E.4 | Principal exclusion criteria |
1. History of any clinically significant disease or disorder that in the opinion of the investigator or the sponsor may put the subject at risk due to study participation, impact the subject’s ability to participate in the study, or influence the study results 2. History of current, active malignancy requiring or likely to require chemotherapeutic or surgical treatment during the study, with the exception of non-melanoma skin cancer, carcinoma in situ of the cervix, and localized prostate cancer managed by active surveillance 3. Transfusion with blood or blood products or plasmapheresis within 2 weeks before the first administration of study drug (Day 1) 4. PT INR > 1.5 5. History of known inherited coagulopathy (including prothrombotic conditions such as Factor V Leiden, APC resistance, AT-III deficiency, and lupus anticoagulant), or recent arterial or deep venous thrombosis within the preceding 6 months 6. Change in corticosteroid or immunosuppressant (azathioprine, mycophenolate mofetil, cyclosporine) dose within 2 weeks prior to Day 1 (more than 10% variation from Day 1 daily doses) 7. Treatment with thrombopoietin (TPO) receptor agonists within 2 weeks before Day 1 8. Treatment with rituximab or splenectomy within the 8 weeks prior to Day 1 9. Treatment with IVIGs within 4 weeks prior to Day 1 10. Infections requiring intravenous antibiotics or hospitalization within 3 months prior to Day 1 11. Subject had positive test results at Screening for human immunodeficiency virus, hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody Subjects with past or resolved hepatitis B infection (defined as having a negative HBsAg test and a positive IgG antibody to hepatitis B core antigen [anti-HBc]) are eligible but hepatitis B virus (HBV) DNA must be obtained in these patients prior to Cycle 1, Day 1, and must demonstrate no active infection. Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA 12. Live vaccine within 28 days prior to Day 1 or plan to receive one during the study 13. History or presence of any gastrointestinal, hepatic, or renal disease or any other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs 14. Subject has not recovered from a recent medical/surgical procedure or trauma by Day 1 as determined by the investigator 15. Uncontrolled hypertension (as defined by systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) 16. Subject had ECG findings of corrected QT interval by Fridericia formula (QTcF) > 480 msec, cardiac arrhythmias, or clinically significant cardiac or ECG abnormalities 17. Subject have received any investigational medication within 30 days or 5 half lives prior to Day 1, whichever was longer 18. Concomitant use of any anticoagulants and platelet aggregation inhibiting drugs including aspirin (within 14 days of planned dosing through end of follow-up) 19. Female subject who is currently pregnant or breastfeeding 20. Prior treatment with a SYK inhibitor 21. Planned surgery in the time frame of the dosing period. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Patient platelet response is defined as platelet count ≥ 30,000/μL and doubling the baseline (average of 2 previous counts), at any visit during the treatment period and without the use of rescue medication |
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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) |
Subjects able to achieve 2 or more consecutive platelet counts of ≥ 30,000/μL separated by at least 5 days and without use of rescue medication Subjects able to achieve 2 or more consecutive platelet counts of ≥ 30,000/μL with an increase of platelet count of ≥20,000/μL from baseline separated by at least 5 days and without use of rescue medication Subjects able to achieve 2 or more consecutive platelet counts of ≥ 50,000/μL separated by at least 5 days and without use of rescue medication Subjects able to achieve 2 or more consecutive platelet counts of ≥ 100,000/μL during the treatment period, separated by at least 5 days and without use of rescue medication Subjects able to achieve platelet counts of ≥ 50,000/μL at 3 of the last 4 visits Change from baseline in the average of the last 2 platelet counts during the treatment period Time to first platelet response (>30,000/μL and 2 x baseline) Number of subjects receiving rescue medication at least once during treatment period Subjects with at least one Grade 2 or higher non-skin bleeding event during treatment period. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
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 |
Korea, Republic of |
United States |
Poland |
Spain |
Greece |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |