E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
β-Thalassemia Subjects with Chronic Anemia (transfusion and non transfusion dependent) |
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E.1.1.1 | Medical condition in easily understood language |
Blood disease that reduces the production of hemoglobin (protein needed to carry oxygen in the red blood cells) causing anemia. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10043391 |
E.1.2 | Term | Thalassaemia beta |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
1. To evaluate the safety and tolerability of PTG-300 in subjects with NTD and TD β-thalassemia.
2. To obtain preliminary evidence of PTG-300’s efficacy for treating chronic anemia in subjects with β-thalassemia.
3. To identify the optimal starting dose, titration algorithm, dose range and dose regimen to be used in Phase 3 studies. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the pharmacokinetics (PK) of PTG-300.
2. To evaluate the pharmacodynamic (PD) effects of PTG-300.
3. To evaluate the immunogenicity of PTG-300. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female subjects aged 18 to 65 years, inclusive (Cohorts 1-4b).
2. Male and female subjects aged 12-<18 years, with a minimum weight of 30 kg (Cohorts 5 and 6).
3. Documented diagnosis of β-thalassemia.
4. Women of childbearing potential (WOCBP) and men agree to use a highly effective contraceptive measure (based on the Clinical Trial Facilitation Group [CTFG]) during the duration of the study and for 28 days after the last dose of study drug in the case of women and 90 days after the last dose of study drug in the case of men, as described in Appendix 1.
5. For WOCBP, a negative serum pregnancy test at screening and a negative urine pregnancy test within 24 hours prior to the first dose of study medication.
6. Subjects or legal guardians (in the case of minors) understand the study procedures and agree to participate in the study by giving written informed consent.
7. Subjects, or legal representative (in the case of minors), are willing and able to adhere to the study visit schedule and other protocol requirements.
8. Subjects between 12-<18 years of age understand and provide the assent to participate in the study, according to local guidelines.
Inclusion criteria applicable only for NTD β-thalassemia subjects:
1. Mean Hgb < 10.0 g/dL of two measurements (one performed 7–28 days prior to dosing and the other performed within 7 days prior to dosing).
2. Requirement of < 6 units RBC transfusion in a 24 week period with the last transfusion at least 8 weeks before screening.
Inclusion criteria applicable only for TD β-thalassemia subjects:
1. Transfusion requirement of at least 6 units of RBC in the 24 weeks prior to screening with no transfusion free period > 45 days.
2. Last RBC transfusion 5–15 days prior to dosing. |
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E.4 | Principal exclusion criteria |
1. Subjects with Sickle Cell disease, HgB H, Hb Bart's hydrops foetalis or hemoglobin S.
2. Infection requiring hospitalization or IV antimicrobial therapy, or opportunistic infection within 6 months of dosing, any infection requiring antimicrobial therapy within 2 weeks of dosing; history of infection with human immunodeficiency virus (HIV).
3. Subject has a concurrent clinically significant, unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic or other medical disorder that, in the opinion of the Investigator, might confound the results of the study or pose additional risk to the subject by their participation in the study.
4. Known primary or secondary immunodeficiency.
5. History within 6 months of screening of any of the following: myocardial infarction, unstable angina, transient ischemic attack, decompensated heart failure requiring hospitalization, congestive heart failure (New York Heart Association Class 3 or 4), uncontrolled arrhythmias, cardiac revascularization, stroke, uncontrolled hypertension (resting systolic blood pressure [BP] > 160mmHg or resting diastolic BP > 100mmHg on more than one occasion) or uncontrolled diabetes (Hgb A1c > 9% or > one episode of severe hypoglycemia).
6. Clinically meaningful laboratory abnormalities at screening including, but not limited to, the ranges below:
1. Absolute neutrophil count < 1000/μL
2. Platelet count < 100,000/μL
3. Estimated glomerular filtration rate (eGFR) < 60
4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 x upper limit of normal (ULN) 4
7. Treatment with hydroxyurea ≤ 24 weeks prior to screening (unless approved by the Medical Monitor).
8. Use of erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to screening.
9. Chronic use of systemic glucocorticoids (anti-inflammatory dose for more than 14 days) ≤ 12 weeks prior to screening (physiologic replacement therapy for adrenal insufficiency is allowed).
10. Pregnant or lactating females.
11. Any surgical procedure requiring general anesthesia within 1 month prior to screening or planned elective surgery during the study.
12. History of malignant neoplasms within 5 years prior to screening. Subjects who are cancer-free for the 5 years before screening may be enrolled. Subjects with carcinoma in situ, adequately treated non-metastatic basal cell skin cancer, or squamous cell skin cancer that has not recurred for at least 1 year prior to screening, may be enrolled.
13. Current or recent history of alcohol dependence or illicit drug use within 1 year prior to screening.
14. Subject is mentally or legally incapacitated at the time of screening visit or has a history of clinically significant psychiatric disorders that would impact the subject’s ability to participate in the trial according to the Investigator. Note: Subjects who have had situational depression or adjustment disorder or treated depression may be enrolled at the discretion of the Investigator.
15. Concurrent participation in any other interventional study.
16. Having undergone splenectomy ≤24 weeks prior to screening.
17. NTD subjects receiving iron chelation therapy (unless approved by the Medical Monitor).
18. TD subjects who started regular transfusions before age 2 years
19. TD subjects who required more that 140 mL pure RBC/kg in the year prior to screening. |
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E.5 End points |
E.5.1 | Primary end point(s) |
NTD:
•Proportion of responders, where responders are defined as
- Subjects who achieve an increase in Hgb ≥ 1.0 g/dL without transfusion, confirmed by a successive measurement at least 1 week later
• Hgb change from baseline
TD:
•Proportion of responders, where responders are defined as:
− Subjects who achieve ≥ 20% reduction in the RBC units required over an 8-week period
• Change from baseline in the number of units of RBC required |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
NTD: Every Visit.
TD: over an 8-week period under the same dose. |
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E.5.2 | Secondary end point(s) |
NTD:
• Hgb level
•Proportion of subjects who achieve an increase in Hgb ≥ 1.5 g/dL without transfusion, confirmed by a successive measurement at least 1 week later
• Duration of Hgb change of ≥1.0 g/dL from baseline without transfusion
• Duration of Hgb change of ≥1.5 g/dL from baseline without transfusion
• Change from baseline in the following PD parameters: serum iron, ferritin, transferrin, transferrin saturation (TSAT).
TD:
•Proportion of subjects who achieve ≥ 33% reduction in the RBC units required over an 8-week period.
•Duration of response (defined as ≥ 20% reduction in the RBC units required over an 8-week period).
• Percent change from baseline in the RBC units required
• Best percent change from baseline in the RBC units required over an 8-week period
•Number of RBC units required.
• Change from baseline in the following PD parameters: serum iron, ferritin, transferrin, TSAT
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
NTD:
Every Visit
TD:
Over an 8 week period
under the same dose |
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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 | 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 | 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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
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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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 17 |
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 |
Greece |
Italy |
Lebanon |
Malaysia |
Thailand |
Tunisia |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 study will be considered completed when all subjects have either completed all study assessments or have withdrawn early. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 27 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 27 |