| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Paroxysmal Nocturnal Hemoglobinuria (PNH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Paroxysmal Nocturnal Hemoglobinuria (PNH) |
|
| 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 | 21.1 |
| 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 |
|
| 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 objective for this study is to evaluate the efficacy of ABP 959 compared with that of eculizumab based on control of intravascular hemolysis. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the safety, pharmacokinetics (PK),
and immunogenicity of ABP 959 compared with that of eculizumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The study will enroll subjects with PNH who are stable on eculizumab treatment. Subjects cannot be enrolled or randomized before all inclusion criteria (including test results) are confirmed:
1. Men and women ≥ 18 years of age
2. Historical diagnosis of PNH by documented flow cytometry
3. Administration of eculizumab for ≥ 6 months and currently receiving 900 mg of eculizumab every 14 ± 2 days
4. Hemoglobin ≥ 9.0 g/dL for at least 6 weeks prior to randomization
5. Lactate dehydrogenase (LDH) < 1.5 × the upper limit of normal at screening
6. Platelet count ≥ 50 × 10^9/L
7. Absolute neutrophil count ≥ 0.5 x 10^9/L (500/μL)
8. Subjects must be vaccinated against Neisseria meningitidis. Subjects must have been vaccinated or revaccinated according to current national guidelines for vaccination use.
9. Subjects must sign an institutional review board/independent ethics committee-approved informed consent form before participation in any procedures. |
|
| E.4 | Principal exclusion criteria |
If any of the following apply, the subject MUST NOT enter the study:
1. Known or suspected hereditary complement deficiency
2. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure [New York Heart Association ≥ Class III], serious uncontrolled cardiac arrhythmia), peripheral vascular disease, cerebrovascular accident, or transient ischemic attack in the previous 6 months
3. Evidence of acute thrombosis (liver Doppler ultrasound of hepatic and portal veins)
4. Known to be positive for human immunodeficiency virus
5. Woman who is pregnant or breastfeeding
6. Woman of childbearing potential who does not consent to use a highly effective method of birth control (e.g., true abstinence, sterilization, birth control pills, Depo Provera injections, or contraceptive implants) during treatment and for an additional 5 months after the last administration of protocol-specified treatment
7. Man with a partner of childbearing potential who does not consent to use a highly effective method of birth control (eg, true abstinence, vasectomy, or a condom in combination with hormonal birth control or barrier methods used by the woman) during treatment and for an additional 5 months after the last administration of protocol-specified treatment
8. Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or subject is receiving other investigational agent(s).
9. Subject has known sensitivity to any constituent of the products to be administered during the study, including mammalian cell-derived drug products.
10. History or evidence of clinically significant disorder, infection, condition, or disease that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
11. History of meningococcal infection
12. Presence or suspicion of active bacterial infection, or recurrent bacterial infection.
13. History of bone marrow transplantation
14. Red blood cell transfusion required within 12 weeks before randomization
15. Subject experienced ≥ 2 breakthrough events, (ie, signs and symptoms of intravascular hemolysis, that require dose and/or schedule adjustments of eculizumab) in the previous 12 months before screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint for Parallel Comparison:
• Hemolysis, as measured by LDH at week 27
Primary Endpoint for Crossover Comparison:
• Hemolysis, as measured by the time-adjusted AUEC of LDH from week 13 to week 27, from week 39 to week 53 and from week 65 to week 79 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of the primary endpoint of week 27 LDH for the parallel comparison will be conducted on the Full Analysis Set (FAS), consisting of all randomized subjects, with treatment as randomized in Period 1 regardless of treatment actually received.
The primary analysis of the primary endpoint of time-adjusted AUEC of LDH for the crossover comparison will be conducted on the Modified Full Analysis Set (mFAS), consisting of all randomized subjects who have an LDH-time profile evaluable for the time-adjusted AUEC within at least one of the following 14-week assessment: week 13 to week 27, week 39 to week 53 and week 65 to week 79, according to treatment per the randomized sequence regardless of treatment actually received. |
|
| E.5.2 | Secondary end point(s) |
• Total complement (CH50), total hemoglobin, serum-free hemoglobin, haptoglobin, bilirubin, degree of hemoglobinuria, and type III erythrocytes at week 27, week 39, week 53, and post-crossover week 65 and week 79
• Crossover comparison of hemolysis as measured by LDH at week 53 and week 79
• Lactate dehydrogenase-time profile
• Red blood cell transfusion
• Pharmacokinetic area under the curve (AUC) of ABP 959 and eculizumab from week 13 to week 15, and trough PK |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The analysis of secondary endpoints (except for PK) will be conducted on the FAS. Total complement, total hemoglobin, serum-free hemoglobin, haptoglobin, bilirubin, degree of hemoglobinuria, and type III erythrocytes (%) at weeks 27, 39, 53, 65, and 79 will be summarized descriptively. For the endpoint of RBC transfusions, summary statistics for the number of packed red cells transfused per month after week 13 will be presented. A descriptive summary of LDH at each time point through the end of the study (EOS) visit will be presented. Individual and mean LDH-time profile through EOS visit will also be presented graphically.
The secondary endpoint of crossover comparison of LDH at week 53 and week 79 will be evaluated descriptively. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Anti-drug Antibody testing |
|
| 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 | 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 | Yes |
| E.8.1.7 | Other | No |
| 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 | 22 |
| 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 |
| Brazil |
| Czechia |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Portugal |
| Slovenia |
| Spain |
| Taiwan |
| Turkey |
| 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
|
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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