| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Thrombocytopenia associated with chronic hepatitis C virus |
|
| E.1.1.1 | Medical condition in easily understood language |
| Reduced platelet (thrombocyte) count in blood which is associated with hepatitis C virus infection. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10035534 |
| E.1.2 | Term | Platelet disorders |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10043554 |
| E.1.2 | Term | Thrombocytopenia |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10005329 |
| E.1.2 | Term | Blood and lymphatic system disorders |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039884 |
| E.1.2 | Term | Secondary thrombocytopenia |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 efficacy of E5501 by measuring platelet response in subjects with chronic hepatitis C virus (HCV)-related thrombocytopenia who require antiviral treatment
|
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of E5501
• To evaluate the pharmacokinetics (PK) of E5501
• To evaluate the ability of subjects to initiate and maintain antiviral treatment for 12 weeks, while treated with E5501
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Core Study (Part A) Entry Criteria (for Double-blind Treatment Periods)
• Males or females ≥ 18 years of age
• Subjects with chronic HCV-related thrombocytopenia (defined as a platelet count ≥ 20 x 109/L to ≤ 70 x 109/L) who require antiviral treatment
• Chronic HCV infection (defined as the presence of anti-HCV antibodiesand detectable serum HCV RNA levels)
• Model for End-stage Liver Disease (MELD) score ≤ 20, Child-Pugh score ≥ 6
• Adequate renal function as evidenced by a calculated creatinine
clearance ≥ 50 mL/minute per the Cockcroft and Gault formula
• Life expectancy ≥ 3 months
• Females must not be pregnant at Screening or Baseline (as
documented by a negative serum beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity 25 IU/L or equivalent units of β-hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
• All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
• Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (e.g., abstinence, an intrauterine device, a double-barrier method such as condom + spermicide or condom + diaphragm with spermicide, a progesterone only contraceptive implant/injection, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double-barrier method as described above if
they become sexually active during the study period or for 30 days after study drug discontinuation. All women who are of reproductive potential and who have been using estrogen-containing oral contraceptives must have discontinued the contraceptive product for at least 30 days before dosing, throughout the entire study period, and for 30 days after study
drug discontinuation. All female subjects of childbearing potential who receive ribavirin (antiviral treatment) must agree to use one of the aforementioned methods for 6 months (4 months for subjects enrolled in Israel or the European Union [EU]) (added per Amendment 01) after antiviral treatment discontinuation.
• Male subjects must either have had a successful vasectomy (confirmed azoospermia) or they and their female partner meet the criteria above (not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation or 6 months [7 months for subjects enrolled in Israel or the EU] (added per Amendment 01) after antiviral treatment discontinuation). In addition, sperm donation cannot take place for 7 months after discontinuation of antiviral treatment.
• Provision of written informed consent
• Are willing and able to comply with all aspects of the protocol
Entry Criteria for Treatment Periods A2, B1, B2, or B3.
Treatment Period A2
• Subjects who achive sufficient increase in platelet counts (≥100 x 109/L)
Treatment Period B1
• Subjects who fail to obtain a sufficient increase in platelet counts (≥ 100 x 109/L) during Treatment Period A1 to initiate antiviral treatment by 21 days
Treatment Period B2
• Subjects who fail to maintain sufficient platelet counts (≥75 x 109/L) to continue antiviral treatment during Treatment Period A2, or
• Subjects whose platelet counts increase to ≥150 x 109/L during Treatment Period A1 or A2, or
• Subjects who successfully completed Treatment Period B1
Treatment Period B3
Subjects not on telaprevir who achieved antiviral response defined as a ≥ 2-log reduction in HCV viral RNA on completion of 12 weeks of antiviral treatment during Treatment Periods A2 or B2
• Subjects on telaprevir who achieve < 1000 IU/mL HCV viral RNA on completion of 12 weeks of antiviral treatment during Treatment Periods
A2 or B2
• Subjects who achieved EVR (≥2 log reduction [compared with
Baseline] and undetectable [<50 IU/mL] HCV viral RNA) on completion of 12 weeks of antiviral treatment during Treatment Periods A2 or B2 |
|
| E.4 | Principal exclusion criteria |
• Any history of arterial or venous thrombosis, including partial or
complete thromboses (e.g., stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis or pulmonary embolism), thrombosis (partial or complete) in the main portal vein and portal vein branches, and thrombosis of any part of the splenic-mesenteric system
• Any evidence of current PVT as detected by Doppler sonography and portal vein flow rate <15 cm/second at Screening or within 30 days prior to Screening
• Any known family history of hereditary thrombophilic disorders (e.g., Factor V Leiden, antithrombin III deficiency)
• Evidence of myocardial infarction in the last 6 months or
uncompensated congestive heart failure (New York Heart Association Class III or IV)
• Co-infection with human immunodeficiency virus (HIV) or hepatitis B or acute hepatitis C
• Any prohibited concomitant medications or therapy that cannot be discontinued by Visit 1, e.g., subjects currently receiving interferon who cannot undergo a 4-week washout period prior to Screening, or subjects who receive blood products that may affect platelet count within 1 week prior to Screening
• Weekly alcohol intake > 21 units (168 g) [male] and >14 units (112 g) [female]
• Any known medical condition, other than chronic liver disease, that can lead to thrombocytopenia
• History of hepatocellular carcinoma, metastatic liver cancer, or liver transplantation
• History of immune thrombocytopenic purpura
• History of myelodysplastic syndrome
• History of pernicious anemia or subjects with vitamin B12 deficiency (defined as less than the lower limit of normal) who have not had pernicious anemia excluded as a cause
• Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that, in the opinion of the investigator, could affect the subject's safety or study conduct
• Subjects with a history of suicide attempts
• Subjects with a history of hospitalization for depression within the past 5 years
• Subjects with any current severe or poorly controlled psychiatric or seizure disorder
• Current use of recreational drugs
• Subjects who have participated in another investigational study within 30 days prior to Visit 1
• Subjects with hypersensitivity, intolerance, or allergy to E5501 or any anti-HCV therapies or their ingredients
• Any past or current medical condition that, in the opinion of the
investigator, would compromise the subject's ability to safely complete the study
• Scheduled for surgery during the projected course of the study
• Subjects who have any medical conditions or diseases that would contraindicate treatment with anti-HCV therapy
• Subjects who are currently treated with proton pump inhibitors (PPIs) or H2-antagonist therapy but have not been receiving a stable dose for at least 6 weeks prior to randomization or have not completed these therapies more than 2 weeks prior to randomization
• Fasting gastrin-17 blood levels exceeding 1.5 times the upper limit of normal (ULN) (including subjects on PPIs or H2 antagonists) at Screening
• Subjects with a history of gastric atrophy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is the proportion of responders. A responder is defined as a subject having a platelet count of ≥ 100 x 109/L by Day 21 starting from an average baseline platelet count of ≥ 20 x 109/L to ≤ 70 x 109/L. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| By Day 21 of Treatment period A1 |
|
| E.5.2 | Secondary end point(s) |
• Change in platelet count from baseline on Day 7 and Day 14
• Proportion of subjects who achieve a platelet count >30 x 109/L above baseline by Day 21
• Proportion of subjects who initiate antiviral treatment
• Proportion of subjects who initiate antiviral treatment and who achieve 12 weeks of antiviral treatment
• Proportion of subjects who maintain platelet count ≥ 50 x 109/L for
12 weeks of antiviral treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
21 Days (Treatment period A1)
12 Weeks (Treatment period A2) |
|
| 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 | No |
| 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 | Yes |
| 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 | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Bulgaria |
| France |
| Germany |
| Israel |
| Romania |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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