|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
|• To define the pharmacokinetics of pegcetacoplan in adolescents with PNH
• To evaluate the efficacy of pegcetacoplan based on Hb level, LDH level, and ARC
• To assess the safety of pegcetacoplan as measured by the incidence and severity of treatment-emergent adverse events (TEAEs), including bacterial infections
|Secondary objectives of the trial
|• To assess the pharmacodynamics and biological activity of pegcetacoplan as measured by effects on complement levels, C3 deposition on RBCs, and clonal distribution of PNH RBCs
• To evaluate the efficacy of pegcetacoplan as assessed by effects on transfusion requirements and episodes of breakthrough hemolysis
• To assess the effect of pegcetacoplan on health-related quality of life (HRQOL) as measured by FACIT-Fatigue and PedsQL General Well-Being Scale
• To assess the long-term safety and efficacy of pegcetacoplan
• To assess the safety of pegcetacoplan as measured by the occurrence of thromboembolic events
|Trial contains a sub-study
|Principal inclusion criteria
|1. Between the ages of 12 and 17, inclusive, at time of study entry.
2. A diagnosis of PNH, confirmed by high-sensitivity flow cytometry (granulocyte or monocyte clone >10%).
3. Be either a naïve patient or a switch patient, as defined below.
a. A naïve patient must:
i. Not be currently receiving an approved complement inhibitor, and must not have received a complement inhibitor within at least 5 half-lives of that drug prior to starting pegcetacoplan
ii. Have evidence of a hemolytic anemia based on a hemoglobin less than the lower limit of the normal range (LLN), and LDH >1.5 × ULN.
b. A switch patient must:
i. Be currently receiving treatment with an approved complement inhibitor, and the dose of that inhibitor must have been stable for at least 5 half-lives of that drug
ii. Have evidence of anemia based on a hemoglobin less than the LLN.
iii. Have ARC > ULN.
4. Platelet count >75,000/mm3.
5. Absolute neutrophil count >1000/mm3.
6. Weigh at least 20 kg.
7. Have a body mass index (BMI) that is less than the 95th percentile for their age.
8. Either not receiving the following medications, or on a stable regimen for at least the minimum time period indicated below, prior to the first screening visit, with no anticipated changes to the regimen over the course of the study:
a. Erythropoietin: 8 weeks
b. Systemic corticosteroids: 4 weeks
c. Immunosuppressants (other than steroids): 8 weeks
d. Vitamin K antagonists (eg, warfarin): 4 weeks, with a stable international normalized ratio (INR) over that period
e. Iron supplements, vitamin B12, or folic acid: 4 weeks
f. Low-molecular weight heparin or direct oral anticoagulants (DOACs): 4 weeks
9. Have received vaccinations against Neisseria meningitidis (types A, C, W, Y, and B), Streptococcus pneumoniae, and Haemophilus influenzae (type B) prior to dosing on Day 1, or agree to receive vaccinations within 14 days after starting treatment with pegcetacoplan. Vaccination is mandatory, unless there is documented evidence of titers within acceptable local limits, or documented evidence of nonresponse to vaccination based on titers. Subjects receiving vaccinations after starting pegcetacoplan must be willing to take prophylactic antibiotics from the first day of treatment with pegcetacoplan until at least 2 weeks after vaccination as described in Section 8.2.1.
10. Female subjects of childbearing potential must have a negative blood pregnancy test at screening (and negative urine pregnancy test on Day 1) and must agree to practice abstinence or to use another protocol-defined method of contraception, as described in Section 10.3.5.1, from screening through at least 90 days after receiving the last dose of pegcetacoplan.
11. Male subjects who have reached sexual maturity must agree to practice abstinence or to use another protocol-defined method of contraception, as described in Section 10.3.5.1, and agree to refrain from donating semen from screening through at least 90 days after receiving the last dose of pegcetacoplan.
12. Willing and able to self-administer pegcetacoplan or has a caregiver who is willing and able to do so.
13. The subject or their legally authorized representative must be willing and able to provide written informed consent as described in Section 12.1.2, including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Where appropriate, the subject must also give their assent to participation in the study.
|Principal exclusion criteria
|1. Known or suspected hereditary fructose intolerance (HFI).
2. Active bacterial infection that has not resolved within at least 1 week before the first dose of pegcetacoplan.
3. Hereditary complement deficiency.
4. History of bone marrow transplantation.
5. History or presence of hypersensitivity or idiosyncratic reaction to compounds related to the formulation or SC administration of pegcetacoplan.
6. Participation in another investigational drug trial or exposure to another investigational agent, device, or procedure within 30 days or 5 half-lives (whichever is longer) from the last dose of investigational agent prior to screening period.
7. Planning to become pregnant during study participation, or currently breastfeeding.
8. History of meningococcal disease.
9. Inability to cooperate, or any condition that, in the opinion of the investigator makes the subject inappropriate for the study or could confound the outcome of the study.
|E.5 End points
|Primary end point(s)
• Pegcetacoplan concentrations and PK parameters over the course of the 16-week treatment period
• Change from baseline to Week 16 in Hb level
• Change from baseline to Week 16 in LDH level
• Change from baseline to Week 16 in ARC
• Incidence and severity of TEAEs over the course of the 16-week treatment period, including bacterial infections
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|Efficacy and Pharmacodynamics
• Change from baseline to Week 16 and Week 52 in:
− Complement levels (eg, total complement hemolytic activity [CH50], alternative complement pathway hemolytic activity [AH50], and C3 level)
− C3 deposition on RBCs
− Clonal distribution of PNH RBCs
• Number of transfusions, number of packed RBC units, and total units (mL/kg) transfused over 16 and 52 weeks of treatment with pegcetacoplan
• Occurrence of breakthrough hemolysis over 16 and 52 weeks of treatment with pegcetacoplan
• Change from baseline to Week 52, and from Week 16 to Week 52, in hemoglobin, LDH, and ARC
• Change from baseline to Week 16 and to Week 52 in Health-Related Quality of Life assessments (FACIT-Fatigue and PedsQL General Well-Being Scale)
• Incidence of thromboembolic events (major adverse vascular events [MAVE]) over the course of the 16-week treatment period and over 52 weeks of treatment with pegcetacoplan
|Timepoint(s) of evaluation of this end point
|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
|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