The objectives of the study are to assess safety and tolerability, pharmacokinetics (PK), and biological activity (including efficacy and pharmacodynamics [PD]) of multiple subcutaneous doses of pegcetacoplan in pediatric patients with paroxysmal…
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Brief title
Condition
- Haemolyses and related conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objectives of this study are:
• 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 outcome
The secondary objectives of this study are:
• 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
Background summary
Paroxysmal nocturnal hemoglobinuria is an acquired, rare, clonal, nonmalignant
hematologic disease characterized by complement-mediated red blood cell (RBC)
hemolysis, with or without hemoglobinuria, an increased susceptibility to
thrombotic episodes, and/or some degree of bone marrow dysfunction. The onset
of PNH is often insidious. Although there have been reports of spontaneous
remission, the course of the disease is generally chronically progressive.
It has been known for many years that PNH is caused by complement-mediated
lysis of erythrocyte clones lacking functional CD55 and CD59 on their surface
to protect them against this process. As such, these erythrocytes are
particularly susceptible to the membrane attack complex (MAC) and have been
shown to lyse readily in the presence of complement activation.
Any therapy that effectively inhibits MAC formation and the resulting
intravascular hemolysis (IVH) is anticipated to be a plausible
candidate-treatment for PNH. Eculizumab is a monoclonal anti-C5 antibody that
inhibits the formation of the MAC, and eculizumab treatment has been approved
for the treatment of this serious condition. However, inhibition of MAC
formation does not appear to be sufficient to fully control the disease, as
many PNH patients receiving eculizumab treatment still suffer from anemia, with
only roughly 13% of patients being classified as complete responders (ie,
achieving transfusion independence and normal hemoglobin [Hb] levels). Most of
the patients (53%) were classified as partial responders with decreased
transfusion needs and reduced lactate dehydrogenase (LDH), and 33% of patients
were poor responders, with unchanged transfusion needs and persistent symptoms
(DeZern et al. 2013). Pegcetacoplan is being developed to address this unmet
need.
Recent studies have suggested that significant opsonization of PNH erythrocytes
by C3 fragments is observed in patients receiving eculizumab treatment. This
opsonization is believed to cause the removal of erythrocytes by the spleen and
the liver, resulting in extravascular hemolysis (EVH). Evidence for
C3b-mediated EVH was observed in 3 patients exhibiting a *suboptimal
hematologic response [to eculizumab] and massive C3 RBC binding* using
51Cr-labeled RBCs. Although these subjects were still receiving eculizumab and
had normal
LDH levels, they demonstrated markedly reduced RBC half-lives (10, 11, and 13
days, with a normal range of 25 to 35 days) and excess counts on images of the
spleen and liver (Risitano et al. 2009). In contrast, C3b opsonization of RBCs
is not observed in PNH patients who have not been treated with eculizumab,
presumably because RBCs in these patients are rapidly lysed by MAC (Risitano et
al. 2009). EVH can be significant in a subset of eculizumab-treated PNH
patients and is considered to be the principal contributor to the lack of
complete eculizumab response in most patients.
Study objective
The objectives of the study are to assess safety and tolerability,
pharmacokinetics (PK), and biological activity (including efficacy and
pharmacodynamics [PD]) of multiple subcutaneous doses of pegcetacoplan in
pediatric patients with paroxysmal nocturnal hemoglobinuria (PNH).
Study design
This is an open-label, single-arm, multicenter study of pegcetacoplan in
pediatric PNH patients who are between the ages of 12 and 17 years, inclusive.
Patients must have anemia due to PNH and may be either not receiving complement
inhibitor treatment (nai*ve patients) or receiving an approved complement
inhibitor (switch patients), as described below. At least 12 patients will be
enrolled, at least 6 of whom will be nai*ve patients. The study will consist of
a 4-week screening period followed by a 16-week treatment period. Switch
patients will have an additional 4-week run-in period between the screening and
treatment periods, during which they will receive both their current complement
inhibitor and pegcetacoplan. The timing of the last dose of their current
complement inhibitor will depend on the complement inhibitor they are
receiving. Subjects who discontinue pegcetacoplan at any time during the study,
including after completion of the 16-week treatment period, will enter an
8-week safety follow-up period. The dose will be 1080 mg twice weekly for
subjects weighing at least 50 kg. Subjects weighing at least 35 kg but less
than 50 kg will receive pegcetacoplan twice weekly, with a first dose of 648 mg
and then 810 mg for each dose thereafter. Subjects weighing at least 20 kg but
less than 35 kg will receive pegcetacoplan twice weekly, with the first 2 doses
of 540 mg and then 648 mg for each dose thereafter. Following commencement of
monotherapy with pegcetacoplan, LDH will be monitored as part of the scheduled
assessments at the planned clinic visits. If LDH is >2 × the upper limit of
normal (ULN), a dose increase should be initiated. In order to confirm or
adjust the dosing regimen for future subjects, the observed exposure and PD
data will be evaluated against the adult-based model-based predictions once at
least 1 month of data are available for at least 3 subjects. In addition, the
model will be updated to include the new pediatric data. If the observed
exposures in the first 3 subjects are not consistent with the adult-based model
predictions, then the updated model, with combined pediatric and adult data,
will be used to determine a new dosing regimen. The model will continue to be
updated as additional data become available and will be used to continue to
confirm or adjust the dosing regimen for future subjects. Safety (adverse
events [AEs] including bacterial infections) will be assessed throughout the
study. Blood and urine samples will be collected for safety assessments and for
the assessment of pegcetacoplan PK and PD.
Intervention
See protocol schedule of assessments, table 1 (switch patient) and table 2
(naieve patient)
Study burden and risks
See ICF and D10
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Listed location countries
Age
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 nai*ve patient or a switch patient, as
defined below. a. A nai*ve 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.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-001350-21-NL |
| ClinicalTrials.gov | NCT04901936 |
| CCMO | NL78739.091.22 |