|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Paroxysmal Nocturnal Hemoglobinuria
|Medical condition in easily understood language
|PNH is a rare disorder causing red blood cells to break down too early
|Diseases [C] - Blood and lymphatic diseases [C15]
|E.1.2 Medical condition or disease under investigation
|Paroxysmal nocturnal hemoglobinuria
|System Organ Class
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The objectives of this study are to:
1. Establish the long-term safety of Pegcetacoplan (APL-2) in PNH subjects
2. Establish the long-term efficacy of Pegcetacoplan (APL-2) in PNH subjects
|Secondary objectives of the trial
|Trial contains a sub-study
|Full title, date and version of each sub-study and their related objectives
|Subjects enrolled in Study APL2-307 who experience acute hemolysis (AH) will be offered the opportunity to enter a substudy in which they receive either intensive SC or intravenous pegcetacoplan as an acute treatment for AH. In order to qualify for participation in the substudy, subjects must have LDH >2 × the ULN and the presence of at least one new or worsening sign or symptom of hemolysis (eg, decrease in Hb, hemoglobinuria, fatigue, etc), warranting acute intervention in the opinion of the investigator.
|Principal inclusion criteria
|1. Subjects at least 18 years of age with PNH who have participated in an antecedent Pegcetacoplan (APL-2) clinical trial. Subjects who received treatment with Pegcetacoplan (APL-2) must have experienced clinical benefit and adequate tolerability in the opinion of the Investigator.
Note: Subjects with PNH who completed an antecedent Pegcetacoplan (APL-2) clinical trial without receiving Pegcetacoplan (APL-2) (or without receiving Pegcetacoplan (APL-2) for long enough to demonstrate clinical benefit) may be enrolled in this study if, in the opinion of the Investigator, the subject is expected to demonstrate clinical benefit upon the initiation or continuation of Pegcetacoplan (APL-2) therapy.
2.Vaccination against Neisseria meningitidis 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 Pegcetacoplan (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. Immunization status checks will be performed to determine whether subjects require primary or booster vaccinations.
3. Willing and able to give written informed consent.
4. Willing and able to self-administer Pegcetacoplan (APL-2) (administration by caregiver will be allowed).
5. Women of child-bearing potential, defined as any females who
have experienced menarche and who are NOT permanently sterile or
postmenopausal, must have a negative pregnancy test and must agree to continue to use an approved method of contraception for the duration of the study and 90 days after their last dose of study drug. Note: Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause.
6. Males must agree to continue to use an approved method of
contraception and must agree to refrain from donating sperm for the duration of the study and 90 days after their last dose of study drug.
|Principal exclusion criteria
|1. Subjects who have withdrawn from an Pegcetacoplan (APL-2) clinical study and/or subjects who met study drug discontinuation criteria during a pegcetacoplan clinical study.
2. Any condition that could increase the subject’s risk by participating in the study
3. Any comorbidity or condition (such as malignancy) that, in the opinion of the Investigator, could put the subject at increased risk or potentially confound study data.
4. History or presence of hypersensitivity or idiosyncratic reaction to compounds related to the investigational product or SC administration.
5. Acute or active infection with hepatitis B, hepatitis C, or HIV infection.
6. Hereditary complement deficiency.
7. History of bone marrow transplant.
8. Concurrent severe aplastic anemia (defined by bone marrow cellularity <25% [or 25% to 50% if less than 30% of residual cells are hematopoietic] and at least 2 of the following values: peripheral blood absolute neutrophil count <500/μL [<0.5 × 109/L], peripheral blood platelet count <20,000/μL, peripheral blood reticulocyte count <20,000/μL).
9. History of meningococcal disease.
10. Concomitant treatment with any complement inhibitor (eg, eculizumab, ravulizumab).
11. Pregnancy, breastfeeding, or positive pregnancy test.
|E.5 End points
|Primary end point(s)
• Incidence and severity of Treatment Emergent Adverse Events (TEAE)
• Incidence of thromboembolic events
• Laboratory parameters
• ECG parameters
• Lactate dehydrogenase level
• Indirect bilirubin level
• Absolute Reticulocyte count
• Hemoglobin level
• Red blood cell (RBC) transfusions
• Functional Assessment of Chronic Illness Therapy–Fatigue scale score
|Timepoint(s) of evaluation of this end point
• Incidence and severity of Treatment Emergent Adverse Events : after dosing begins, or worsen of severity, for up to 30 days after the last dose of Pegcetacoplan (APL-2)
• Incidence of thromboembolic events:
after dosing begins for up to 30 days after the last dose of Pegcetacoplan (APL-2)
• Laboratory parameters: Please refer to Schedule Events in Protocol
• ECG parameters: Please refer to Schedule Events in Protocol
Please Refer to Schedule Events in Protocol
|Secondary end point(s)
• Pegcetacoplan (APL-2) pharmacokinetic concentrations
• Complement (eg, classical pathway hemolytic activity [CH50], alternative pathway hemolytic activity [AH50], and C3) levels
• C3 deposition on RBC cells
• Clonal distribution of PNH RBCs
• Incidence of anti-pegcetacoplan peptide and anti-polyethylene glycol antibodies
|Timepoint(s) of evaluation of this end point
Blood samples will be collected at the time points delineated in the Schedule of Events in Section 3 of Protocol
Pharmacodynamic Endpoints: Blood samples will be collected at the time points delineated in the Schedule of Events in Section 3 of Protocol
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Korea, Republic of
|Trial has a data monitoring committee
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
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days