Primary objective:- To demonstrate the efficacy of twice-weekly s.c. 1080-mg infusions of pegcetacoplan compared with that of placebo in patients with CAD.Secondary objectives:- To demonstrate the effect of pegcetacoplan on the number of PRBC…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Response to treatment at Week 24. Response is defined as:
• An increase in hemoglobin (Hb) of >= 1.5 g/dL from Baseline or Hb
normalization at Week 16; AND
• Maintenance of this effect from Week 16 to Week 24; AND
• The absence of PRBC transfusions (between Week 5 and Week 24).
Note: Hb normalization is defined as within normal range (between the defined
upper and lower limits of normal [ULN and LLN]), as set by the testing
laboratory.
Secondary outcome
Key secondary endpoints:
• Change from Baseline to Week 24 in Hb level.
• Transfusion avoidance (Yes/No) from Week 5 to Week 24.
• Change from Baseline to Week 24 in the Functional Assessment of Cancer
Therapy-Anemia/Fatigue (FACT-An) score.
Background summary
AIHA is defined as the increased destruction of RBCs in the presence of
anti-RBC autoantibodies, with or without complement activation. Autoantibodies
are produced by both tissue and circulating self-reactive B lymphocytes,
following cooperation with T-helper
lymphocytes. A third key player in anti-RBC autoimmunity is the complement
system, which can induce a direct erythrocyte osmotic lysis through the
sequential activation of the membrane attack complex or an extravascular
hemolysis through Ab-dependent cellular cytotoxicity and phagocytosis occurring
preferentially in the spleen and lymphoid organs.
AIHA occurs uncommonly with estimates of 1 to 3 in 100 000 population annually.
The ability
of the autoantibody to bind to the erythrocyte antigen at specific temperatures
is fundamental to the diagnosis in terms of whether it is designated as warm
(reacts maximally at 37 °C) or cold (reacts maximally at 4 °C) AIHA. The
pathologic and clinical features of AIHA relate to the autoantibody class,
thermal amplitude and their efficiency in activating complement.
AIHAs consist of warm-, cold-, and mixed-reactive Ab types that are directed
against antigens on the RBC surface. The autoantibodies may be idiopathic
(primary) or related to an underlying condition such as infection, malignancy,
or immune disease (secondary). Cold-antibody
AIHAs are further characterized into CAD, whose patients will be focused on
this study.
Primary chronic CAD is an uncommon form of AIHA in which hemolysis is thought
to be entirely complement-dependent. CAD accounts for about 15 % of AIHAs and
is defined as an AIHA mediated by cold agglutinins, without any obvious
underlying disease such as aggressive lymphoma, other overt malignancies or
specific infections. Cold agglutinins are autoantibodies that can agglutinate
RBCs at an optimum temperature of 3 to 4 ºC.
Cold antibodies (IgM) temporarily bind to the RBC membrane, which in turn
activates complement, and leads to the deposition of C3b on the cell surface.
These C3b-coated RBCs are cleared slowly by the macrophages of the liver
through extravascular hemolysis. To a lesser extent, the complete complement
cascade may be activated at the cell surface, ultimately resulting in the
insertion of membrane attack complex C5b to C9 and intravascular hemolysis.
Clinical data from studies with pegcetacoplan in patients with PNH indicate
that pegcetacoplan is an effective complement modulating agent resulting in
broad control of intravascular and extravascular hemolysis.
To date, pegcetacoplan, at doses of <= 360 mg/day, has been well tolerated when
administered via
s.c. infusion, including to patients with warm AIHA and CAD (Study
APL2-CP-AIHA-208). This study also demonstrated that pegcetacoplan rapidly
increased Hb values, an effect that persisted for 48 weeks. This result was
more prominent in patients with CAD (Cohort 2). In
addition, transfusion avoidance during the 12 months of the core study phase
was observed in Cohort 2 in 77% of patients after treatment with pegcetacoplan.
Improvements in hemolysis by reduction in ARCs, LDH and indirect bilirubin were
observed in both cohorts.
Persistent inhibition of the alternative complement pathway was demonstrated
without affecting classical complement activation. Increases in C3 levels were
also observed in both dosage groups (270 mg/day and 360 mg/day). There was also
a trend of reduction of C3 deposition on RBCs (% Type I) in both cohorts, which
suggests that pegcetacoplan protects RBCs from complement-mediated attack.
Study objective
Primary objective:
- To demonstrate the efficacy of twice-weekly s.c. 1080-mg infusions of
pegcetacoplan compared with that of placebo in patients with CAD.
Secondary objectives:
- To demonstrate the effect of pegcetacoplan on the number of PRBC transfusions
in patients with CAD.
- To demonstrate the effect of pegcetacoplan on health-related quality of life
in patients with CAD.
Other secondary objectives:
- To assess the effect of pegcetacoplan on clinical laboratory markers of
hemolysis and transfusion dependence in patients with CAD.
- To determine the durability of response in patients with CAD receiving
pegcetacoplan.
- To assess tolerability, safety and immunogenicity of pegcetacoplan in
patients with CAD.
- To describe long-term effect of pegcetacoplan in patients with CAD.
Exploratory objectives:
- To evaluate the PK of pegcetacoplan following twice-weekly s.c. infusions.
- To evaluate the effect of pegcetacoplan in complement biomarkers.
Study design
This is a phase 3, randomized, double-blind, placebo-controlled multicenter
study of pegcetacoplan (1080 mg) or placebo, administered twice weekly by s.c.
infusion in patients with CAD.
A total of 57 patients with CAD will be enrolled in this study. Patients will
be randomized in a ratio of 2:1 to receive either pegcetacoplan or placebo,
respectively. The randomization will be stratified by transfusion history
(number of transfusions during the 6-month period prior to randomization >= 1;
0). Every effort should be made to enroll patients in both subgroups.
The planned length of participation in the study for each patient is a maximum
of 110 weeks. This study will consist of 5 periods:
• Screening period: up to 4 weeks (may be extended up to 2 additional weeks).
• Double-blind treatment period: 24 weeks (Part A).
• Open-label treatment period: 24 weeks (Part B).
• Open-label maintenance period: up to additional 48 weeks or until the product
becomes commercially available (Part C).
• Follow-up period: 8 weeks.
Intervention
Part A
Double-blind treatment period (24 weeks):
Patients randomized into the study will receive s.c. IMP (pegcetacoplan or
placebo) twice weekly for 24 weeks.
Part B
Open-label treatment period (24 weeks):
All patients who complete the 24-week double-blind treatment will be eligible
to enter the open-label treatment period, in which they will receive
pegcetacoplan 1080 mg s.c. twice weekly for up to 24 weeks (Week 48).
Part C
Open-label maintenance period (up to additional maximum 48 weeks or until the
product becomes commercially available):
After completion of the open-label treatment period, patients who benefit from
therapy without significant side effects will continue receiving pegcetacoplan
1080 mg s.c. twice weekly for a maximum of 48 additional weeks or until the
product is commercially available, whichever occurs first. In the event that
the commercial product is not yet available at the end of Part C, patients will
be managed outside of the current study on a case-by-case basis, in accordance
with applicable laws and regulations.
Study burden and risks
Procedures with Associated Risks:
- Blood collection (between 15 and 25 mL in total, at each visit) - drawing
blood can cause local irritation, pain, bruising, or
infection, bleeding where the needle is inserted. Some people experience
dizziness, fainting, or upset stomach when their blood is drawn.
- Bone marrow biopsy (at screening (only if not previously taken within 1 year)
- bone marrow biopsy can cause pain, a small amount of bleeding, bruising,
infection, or scarring where the biopsy is taken.
- Vaccination (per prescribed schedule) - like any medication, vaccines can
cause side effects. Most commonly, vaccinations cause local reaction (pain,
swelling, or redness) where the shot was given.
- Preventive antibiotics (according to local guidelines in your country) -
these are given to prevent infections, but there is a possibility some side
effects from the anti-infective treatment.
- Electrocardiogram (ECG) - skin irritation caused by electrodes or gel are
rare but could occur during this procedure.
- Infusion site reactions - there is a possibility of redness, swelling and
pain or tenderness at the site of infusion. There is also a slight possibility
of infection.
Health related questionnaires - patients will be asked to complete three
different questionnaires the day of treatment initiation (or the day before),
every 4 weeks until Week 24, then every 8 weeks, and at End of Treatment and
End of Study.
Tomtebodavägen 23A
Solna SE-112-76
SE
Tomtebodavägen 23A
Solna SE-112-76
SE
Listed location countries
Age
Inclusion criteria
1. Age18 years or older.
2. Diagnosis of primary CAD on the basis of the presence of all the following
criteria at screening:
a. Signs of hemolysis with abnormal values by at least 2 of the following
hemolytic markers:
i. Reduced haptoglobin level (< LLN).
ii. Elevated LDH level (> ULN).
iii. Elevated indirect bilirubin level (> ULN; > 3 x ULN for patients with
Gilbert-Meulengracht Syndrome).
iv. Increased ARC (above the ULN).
b. Monospecific direct antiglobulin test strongly positive for C3d.
c. Cold agglutinin titer >= 64 at 4 °C.
3. Hb level <= 9 g/dL at screening.
4. An absolute neutrophil count >= 1500 cells/mm3 at screening.
5. Documented results from bone marrow biopsy within 1 year of screening with
lymphoproliferative infiltration <= 20 %. Patients who have not received a bone
marrow biopsy within 1 year of their screening visit or those patients for whom
bone marrow biopsy reports are incomplete or unavailable will be required to
receive a bone marrow biopsy to determine eligibility.
6. Body weight <= 100 kg.
7. Either have vaccination against Streptococcus pneumoniae, Neisseria
meningitidis (Types A, C, W, Y, and B), and Haemophilus influenzae (Type B)
within 2 years prior to screening or agree to receive vaccination during
screening as follows:
a. First dose of vaccine against N. meningitidis Types A, C, W, and Y at least
2 weeks prior to start of study drug with second dose 2 months later (Study Day
57), and then boosters every 5 years.
b. First dose of the vaccine against N. meningitidis Type B at least 2 weeks
prior to start of study drug with a second dose after at least 1 month (Study
Day 29). First booster dose 1 year later, and then additional booster doses
every 2 to 3 years.
c. S. pneumoniae: pneumococcal conjugate vaccine 23 (PCV13) and/or pneumococcal
polysaccharide vaccine 23 (PPSV23) as per Advisory Committee on Immunization
Practices (ACIP) guidelines for adults or children with immunocompromising
conditions.
d. H. influenzae Type B: 1 dose at least 2 weeks prior to start of study drug.
Vaccination is mandatory, unless documented evidence exists that patients are
nonresponders to vaccination. Vaccinations should be administered following the
ACIP recommendations for adults or children with complement deficiencies and/or
immunocompromising conditions.
8. Women of childbearing potential (WOCBP), defined as any women who have
experienced menarche and who are NOT permanently sterile or postmenopausal,
must have a negative pregnancy test at screening and agree to use
protocol-defined methods of contraception for the duration of the study and 8
weeks after their last IMP dose.
Note: Postmenopausal is defined as having had 12 consecutive months with no
menses without an alternative medical cause.
9. Men must agree to the following for the duration of the study and 8 weeks
after their last IMP dose:
a. Avoid fathering a child.
b. Use protocol-defined methods of contraception.
c. Refrain from donating sperm.
10. Willing and able to give written informed consent.
Exclusion criteria
1. Have received other anticomplement therapies (approved or investigational)
within 5 half-lives of the agent prior to randomization (e.g., eculizumab
within 10 weeks, ravulizumab within 36 weeks or sutimlimab within 15 weeks) and
are not able or willing to refrain from using them during the study. Patients
previously treated with > 1 dose of sutimlimab will be excluded if they have
not experienced a documented increase in Hb >= 1.0 g/dL during sutimlimab
treatment.
2. Treatment with belimumab, rituximab or other anti-CD20 antibody (such as
obinutuzumab or ocrelizumab), or with bendamustine, fludarabine, other
cytotoxic drugs, or Bruton tyrosine kinase inhibitors such as ibrutinib,
acalabrutinib and zanubrutinib, alone or in combination with rituximab within
16 weeks prior to randomization.
3. Use of prohibited medications as described in the protocol. The list of
acceptable medications and required stable regimen periods are outlined in the
study protocol.
4. Diagnosis of systemic lupus erythematosus or other autoimmune diseases with
antinuclear antibodies (antinuclear antibodies of long-standing duration
without associated clinical symptoms will be adjudicated on a case-by-case
basis by the investigator after discussion with the medical monitor).
5. History of an aggressive lymphoma or presence of a lymphoma requiring
therapy.
6. Have received an organ transplant.
7. Cold agglutinin syndrome secondary to Mycoplasma pneumoniae, Epstein-Barr
virus or other specific causative infection. In patients with long history of
CAD, positive IgM titer and IgG titer without associated clinical symptoms will
be adjudicated on a case-by-case basis by the investigator after discussion
with the medical monitor.
8. HIV or hepatitis C virus detectable by polymerase chain reaction at
screening or documented in the patient*s medical record.
9. Chronic hepatitis B virus carriers with viral loads > 1000 IU/mL (> 5000
copies/mL) at screening or documented in the patient*s medical record. Eligible
patients who are chronic inactive carriers (<= 1000 IU/mL) must receive
prophylactic antiviral treatment (e.g., entecavir, tenofovir, lamivudine)
according to local country guidelines.
10. Presence of an active malignant disease within the last 12 months other
than skin basal cell carcinoma or in situ carcinoma of the
cervix. A low-grade lymphoproliferative bone marrow disorder not requiring
therapy by itself is not defined as a malignant disease in this context.
11. A monospecific direct antiglobulin test result of IgG > 1+.
12. Presence or suspicion of liver dysfunction as indicated by elevated alanine
aminotransferase (ALT) > 2.5 x ULN, or direct bilirubin levels > 2 x ULN. For
any patient with increased direct bilirubin, the investigator should exercise
medical judgement to ensure that the increased direct bilirubin value is due to
hemolysis and discuss inclusion with the medical monitor. If the direct
bilirubin is higher than the indirect bilirubin, in addition a thorough search
for exclusion of underlying liver or cholestatic disease, including but not
necessarily limited to abdominal ultrasound, is warranted to exclude liver
and/or cholestatic disorders.
13. Hypersensitivity to pegcetacoplan or to any of the excipients or placebo
compounds.
14. Known or suspected hereditary fructose intolerance.
15. Unresolved infection caused by encapsulated bacteria including N.
meningitidis, S. pneumoniae and H. influenzae.
16. Presence or suspicion of severe recurrent or chronic infections that, in
the opinion of the investigator, increase the patient*s risk by participating
in the study.
17. Participation in any other investigational drug trial or exposure to other
investigational agent, device or procedure within 30 days prior to screening
period.
18. If breastfeeding, is unwilling to discontinue for the duration of study and
for at least 8 weeks after the final IMP dose.
19. Inability to cooperate with study procedures.
20. Any disease(s), psychiatric condition, metabolic dysfunction, or findings
from a physical examination or clinical laboratory test result that would cause
reasonable suspicion of a disease or condition that may jeopardize the
patient*s wellbeing, that may
increase the risk associated with study participation, that may affect the
interpretation of the results, or that would make the patient unsuitable for
this study.
21. Protected adults (guardianship, trusteeship) who are unable to express
their consent and persons under court protection.
22. Any infection (including COVID-19) requiring hospitalization or treatment
with intravenous anti-infectives not resolved within 2 weeks prior to the first
dose of the IMP.
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 | EUCTR2021-003160-27-NL |
| CCMO | NL80480.018.22 |