| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Immune Thrombocytopenic Purpura (ITP) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Immune Thrombocytopenic Purpura (ITP), a chronic, autoimmune disease that is associated with bleeding risk due to low platelet levels in the blood. |
|
| 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 | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10074667 |
| E.1.2 | Term | Immune thrombocytopenic purpura |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 |
Safety:
• To characterize the safety and tolerability of up to four dose levels of PRN1008 in patients with ITP
Efficacy:
• To explore the clinical activity of up to four dose levels of PRN1008 in relapsed/refractory patients with ITP
• To identify a potential dose regimen to use in future studies of PRN1008 in patients with ITP
Pharmacokinetics:
• To characterize the pharmacokinetics of PRN1008 in patients with ITP
|
|
| E.2.2 | Secondary objectives of the trial |
Exploratory:
• To explore effect of PRN1008 on platelet autoantibody levels
• To explore effect of PRN1008 on markers of hemolysis
• To explore effect of PRN1008 on thrombopoietin (TPO) levels
• To explore effect of PRN1008 on quality of life (QOL) using the Euro-QoL 5-Dimension Visual Analog Scale (EQ-5D VAS)
• To characterize plasma metabolites of PRN1008 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria:
1. Male or female patients, aged 18 to 80 years old (Czech Republic only: 18 to 65 years old)
2. Immune-related ITP (both primary and secondary)
3. Refractory or relapsed patients with no available and approved therapeutic options with a platelet count of <30,000/μL on two occasions no less than 7 days apart in the 15 days prior to beginning study treatment.
4. A history of response (two or more platelet counts ≥ 50,000 μL with an increase of at least 20,000 μL) to at least one prior line of therapy (with splenectomy being considered a line of therapy)
5. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥ 1.5 X 109/L, Hgb > 9 g/dL, AST/ALT ≤ 1.5 x ULN, albumin ≥ 3 g/dL, total bilirubin ≤ 1.5 x ULN, estimated
GFR > 60 (Cockcroft and Gault method) (C1D1 pre dose may be checked up to Day -3 prior to C1D1)
6. Female patients who are of reproductive potential must agree for the duration of active treatment in the study to use a highly effective means of contraception (hormonal contraception methods that inhibits ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner or true abstinence; when it is in line with the preferred and usual lifestyle or the patient). Unless surgically sterile, postmenopausal females should have menopause confirmed by FSH testing.
7. Able to provide written informed consent and agreeable to the schedule of assessments |
|
| E.4 | Principal exclusion criteria |
1. Pregnant or lactating women
2. ECG findings of QTcF > 450 msec (males) or > 470 msec (females), poorly controlled atrial fibrillation (i.e., symptomatic patients or a ventricular rate above 100 beats/min on ECG), or other
clinically significant abnormalities
3. History of current, active malignancy requiring or likely to require chemotherapeutic or surgical treatment during the trial, with the exception of non-melanoma skin cancer
4. Transfusion with blood or blood products or plasmapheresis within 2 weeks before Day 1
5. Change in corticosteroid and/or TPO agonist dose within 2 weeks prior to Day 1 (more than 10% variation from Day 1 daily doses)
6. Use of rescue medications other than corticosteroids or TPO in exclusion #5 in the two weeks before Day 1
7. Immunosuppressant drugs other than corticosteroids – these drugs should be discontinued for at least 14 days before Day 1
8. Treatment with rituximab or splenectomy within the 3 months prior to Day 1
9. Ongoing need for the use of proton pump inhibitor drugs such as omeprazole and esomeprazole (it is acceptable to change patient to H2 receptor blocking drugs prior to Day 1)
10. Concomitant use of known strong-to-moderate inducers or inhibitors of CYP3A within 3 days or 5 half-lives (whichever is longer) of Day 1
11. Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index within 3 days or 5 half-lives (whichever is longer) of study drug dosing including, but not limited to, alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or terfenadine
12. Planned or concomitant use of any anticoagulants and platelet aggregation inhibiting drugs such as aspirin, NSAIDs, thienopyridenes (within 14 days of planned dosing through end of
follow-up), fish oil supplements (within 30 days of planned dosing through end of follow-up)
13. Has received any investigational drug within the 30 days before receiving the first dose of study medication, or at least 5 times elimination half-life of the drug (whichever is longer); patient
should not be using an investigational device at the time of dosing
14. Current drug or alcohol abuse
15. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate study drug absorption
16. History of solid organ transplant
17. Positive for screening for HIV, hepatitis B (surface and core antibodies unrelated to vaccination), or hepatitis C (anti-HCV antibody confirmed with Hep C RNA)
18. History of serious infections requiring intravenous therapy within the last 3 months before Day 1
19. Clinically significant cognitive dysfunction (≥ Grade 1) or medical history suggestive of increased risk for cognitive dysfunction during the study
20. Live vaccine within 28 days prior to Day 1 or plan to receive one during the study
21. Planned surgery in the time frame of the dosing period
22. Any other clinically significant disease, condition, or medical history that, in the opinion of the Investigator, would interfere with subject safety, study evaluations, and/or study procedures |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Safety will be assessed by the incidence, severity and relationship of TEAEs, including clinically significant changes in physical examination, laboratory tests, and vital signs. TEAEs in the post treatment follow-up period will also be assessed and examined for possible relationship to the prior PRN1008 treatment. Adverse events will be categorized as treatment emergent after the first dose of PRN1008 has been received.
2. The Primary Efficacy Endpoint is the proportion of patients able to achieve two or more consecutive platelet counts, separated by at least 5 days, of ≥ 50,000/μL AND an increase of platelet count of ≥20,000/μL from baseline, by dose level, without use of rescue medication in the 4 weeks prior to the latest elevated platelet count. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 1, Day 15, haematology weekly visits between clinical visits of each cycle; Day 169 (last day of active treatment); Day 197 (FUV end of study) |
|
| E.5.2 | Secondary end point(s) |
- Proportion of patients able to achieve two or more platelet counts of ≥ 50,000/μL AND increase of platelet count of ≥20,000/μL from baseline at any time (on treatment or during follow up) without use of rescue medication in the 4 weeks prior to the latest elevated platelet count
- Proportion of patients able to achieve two or more platelet counts, separated by at least 5 days, representing an increase of platelet count of ≥20,000/μL from baseline, by dose level, without use of rescue medication in the 4 weeks prior to the latest elevated platelet count
-Proportion of patients able to achieve two or more platelet counts, separated by at least 5 days, of ≥ 100,000/μL, by dose level, without use of rescue medication in the 4 weeks prior to the latest elevated platelet count
- Change from baseline to the average of the last two platelet counts at each dosing level
- Time to first platelet response (as defined in the primary endpoint)
- Proportion of partients receiving rescue medication at each dosing level and overall
- Proportion of patients with a Grade 2 or higher bleeding event at each dosing level and overall
-Bleeding scale (ITP-BAT scale) at the end of treatment period for each dosing level
- Proportion of patients that completed 24 weeks of treatment and demonstrated a platelet response defined as platelet counts ≥50,000/μL at ≥ 50% of the visits during the last 8 weeks of the active treatment period |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 1, Day 15, haematology weekly visits between clinical visits of each cycle; Day 169 (last day of active treatment); Day 197 (FUV end of study) |
|
| 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 | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 12 |
| 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 |
| Australia |
| Bulgaria |
| Canada |
| Czech Republic |
| Netherlands |
| Norway |
| United Kingdom |
| 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
|
| The end of the study is defined as the date of the final safety follow-up visit after the last participant’s last visit (LPLV). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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