E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
PNH is an acquired, rare, clonal, non-malignant hematologic disease characterized by complement-mediated RBC hemolysis with or without hemoglobinuria, an increased susceptibility to thrombotic episodes, and/or some degree of bone marrow dysfunction. PNH is caused by complement-mediated lysis of erythrocyte clones lacking functional CD55 and CD59 on their surface. These RBCs are particularly susceptible to the MAC and have been shown to lyse readily in the presence of complement activation. |
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E.1.1.1 | Medical condition in easily understood language |
PNH is a rare disorder causing red blood cells to break down too early. Patients may still suffer from anemia even when treated with standard of care. |
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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 | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055629 |
E.1.2 | Term | Paroxysmal nocturnal hemoglobinuria |
E.1.2 | System Organ Class | 100000004857 |
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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 |
The primary objectives of this study are to establish the efficacy and safety of APL-2 compared to eculizumab in patients with PNH who continue to have Hb levels <10.5 g/dL despite treatment with eculizumab. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.At least 18 years of age 2.Primary diagnosis of PNH confirmed by high-sensitivity flow cytometry 3.On treatment with eculizumab. Dose of eculizumab must have been stable for at least 3 months prior to the Screening Visit 4.Hb <10.5 g/dL at the Screening Visit 5.Absolute reticulocyte count > 1.5x ULN at the Screening Visit 6.Platelet count of >50,000/mm3 at the Screening Visit 7.Absolute neutrophil count >500/mm3 at the Screening Visit 8.Vaccination against Neisseria meningitides types A, C, W, Y and B, Streptococcus pneumoniae and Haemophilus influenzae Type B (Hib) either within 2 years prior to Day 1 dosing, or within 14 days after starting treatment with APL-2. Unless documented evidence exists that subjects are non-responders to vaccination as evidenced by titers or display titer levels within acceptable local limits 9.Women of child-bearing potential (WOCBP) must have a negative pregnancy test at the Screening and Day -28 Visit (Run-in Period) and must agree to use protocol defined methods of contraception for the duration of the study and 60 days after their last dose of study drug 10.Males must agree to use protocol defined methods of contraception and agree to refrain from donating sperm for the duration of the study and 60 days after their last dose of study drug 11.Willing and able to give informed consent 12.Willing and able to self-administer APL-2 (administration by caregiver will be allowed)
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E.4 | Principal exclusion criteria |
1.Active bacterial infection within 4 weeks prior to Day -28 (Run-in Period) 2.Receiving iron, folic acid, vitamin B12 and EPO, unless the dose is stable, in the 4 weeks prior to Screening 3.Hereditary complement deficiency 4.History of bone marrow transplantation 5.History or presence of hypersensitivity or idiosyncratic reaction to compounds related to the investigational product of SC administration 6.Participation in any other investigational drug trial or exposure to other investigational agent within 30 days or 5 half-lives (whichever is longer) 7.Currently breast-feeding women 8.Inability to cooperate or any condition that, in the opinion of the investigator, could increase the subject's risk of participating in the study or confound the outcome of the study 9.History or family history of Long QT Syndrome or torsade de pointes, unexplained syncope, syncope from an uncorrected cardiac etiology, or family history of sudden death 10.Myocardial infarction, CABG, coronary or cerebral artery stenting and /or angioplasty, stroke, cardiac surgery, or hospitalization for congestive heart failure within 3 months or > Class 2 Angina Pectoris or NYHA Heart Failure Class >2 11.QTcF > 470 ms, PR > 280 ms 12.Mobitz II 2nd degree AV Block, 2:1 AV Block, High Grade AV Block, or Complete Heart Block unless the patient has an implanted pacemaker or implantable cardiac defibrillator (ICD) with backup pacing capabilities 13.Receiving Class 1 or Class 3 antiarrhythmic agents, or arsenic, methadone, ondansetron or pentamidine at screening 14.Receiving any other QTc-prolonging drugs, at a stable dose for less than 3 weeks prior to dosing 15.Receiving prophylactic ciprofloxacin, erythromycin or azithromycin for less than one week prior to the first dose of study medication (must have a repeat screening ECG after one week of prophylactic antibiotics with QTcF < 470 ms)
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E.5 End points |
E.5.1 | Primary end point(s) |
Week 16 change from baseline in hemoglobin level |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 16 of randomized controlled treatment |
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E.5.2 | Secondary end point(s) |
•Week 16 change from baseline in reticulocyte count •Week 16 change from baseline in lactate dehydrogenase (LDH) level •Week 16 change from baseline in FACIT-fatigue scale score •Number of PRBC units transfused from Week 4 to Week 16 (Day 28 to Day 112) •Hemoglobin response in the absence of transfusions (Yes/No). Hemoglobin response is defined as a 1g/dL increase in hemoglobin from Baseline at Week 16 •Reticulocyte normalization in the absence of transfusions at Week 16 (Yes/No). Reticulocyte normalization is defined as the reticulocyte count being below the upper limit of the normal range
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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 | 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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Consecutively run-in period, randomized comparator controlled period, and one-arm open-label period. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Canada |
Japan |
Korea, Republic of |
Russian Federation |
United States |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |