E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paroxysmal Nocturnal Hemoglobinuria (PNH) |
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E.1.1.1 | Medical condition in easily understood language |
Paroxysmal Nocturnal Hemoglobinuria (PNH) |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10034042 |
E.1.2 | Term | Paroxysmal nocturnal haemoglobinuria |
E.1.2 | System Organ Class | 10038359 - Renal and urinary 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 |
To evaluate the efficacy of ACH-0145228 based on improvement hemoglobin (Hgb) relative to baseline at Week 12 of treatment |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of ACH-0145228 based on reduction in transfusion requirements • To evaluate the efficacy of ACH-0145228 on lactate dehydrogenase (LDH) relative to baseline at Week 12 of treatment • To assess laboratory markers of hemolysis and other markers relevant in patients with paroxysmal nocturnal hemoglobinuria (PNH) • To evaluate the safety and tolerability of 12 weeks of treatment with ACH-0145228 with or without the use of background therapy with an approved C5 inhibitor, based on treatment-emergent adverse events, (TEAEs), serious adverse events (SAEs), and events leading to discontinuation of study medication |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Male or female greater than or equal to 18 years of age, female subjects of child-bearing potential
For newly identified PNH patients must meet one of the following conditions: 1. PNH patients not currently receiving an approved C5 inhibitor must have: - PNH Type III erythrocyte and/or granulocyte clone size ≥10% with adequate reticulocytosis (absolute reticulocyte count ≥100×10⁹/L). - Anemia (Hgb <10.5 g/dL). - LDH ≥1.5× upper limit of normal (ULN). - Platelet count ≥30,000/µL without the need for platelet transfusions. - Absolute neutrophil count (ANC) ≥750/ µL.
2. PNH patients with a sub-optimal response to background therapy with an approved C5 inhibitor must have: - Stable background regimen of an approved C5 inhibitor (at least 24 weeks for eculizumab, or at least 2 doses for ravulizumab), without change in dose or interval for at least the past 8 weeks. - Anemia (Hgb <10 g/dL). - Adequate reticulocytosis (absolute reticulocyte count ≥100×109/L). Platelet count ≥30,000/µL without the need for platelet transfusions. - Absolute neutrophil count (ANC) ≥750/ µL. |
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E.4 | Principal exclusion criteria |
- Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 and/or are on dialysis. - History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant ([HSCT] unless HSCT engraftment has failed). - History of dosing with an investigational agent other than danicopan within 30 days or 5 half-lives of the investigational agent prior to ACH 0145228 administration, whichever is greater. - New patients in the monotherapy group with a history of dosing with eculizumab at any dose or interval within the past 75 days before study medication administration or 300 days for ravulizumab. - Known or suspected complement deficiency. - Contraindication to one or more of the required vaccinations that may be used in the study. - History of seizure disorder unless seizure free without the use of antiepileptic medications for the past 5 years prior to screening. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in Hgb relative to baseline at Week 12 |
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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) |
1.Transfusion requirements: Change in transfusion requirements during the treatment compared to 12 weeks of historical transfusion requirements 2. Lactate dehydrogenase (LDH): Change in LDH relative to baseline at Week 12 3. Reticulocyte count: Change from baseline in absolute reticulocyte count 4. Direct Bilirubin: Change from baseline in direct bilirubin 5. Total Bilirubin: Change from baseline total bilirubin 6. PNH red blood cell (RBC) clone size: Change from baseline in PNH red blood cell (RBC) clone size 7. C3 complement protein (C3) fragment deposition on PNH RBCs: Change from baseline in C3 complement protein (C3) fragment deposition on PNH RBCs at week 12 8. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]: Number of TEAEs recorded 9. Incidence of Serious Adverse events [Safety and Tolerability]: Number of SAEs recorded 10. Incidence of adverse events leading to discontinuation [Safety and Tolerability]: Number of events leading to discontinuation of study medication recorded
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 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.8.2.4 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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 |
Italy |
Korea, Republic of |
New Zealand |
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 end of the study is defined as the date of the last visit of the last patient remaining in the study. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 9 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 9 |