A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients with Cold Agglutinin Disease (CAD)
1. Age18 years or older.
2. Diagnosis of primary CAD on the basis of the presence of all the following criteria:
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.
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 13 (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. Patients who were not previously vaccinated should not receive multiple vaccines on the same day.
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.
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 4 weeks) and are not able or willing to refrain from using them during the study.
2. Treatment with rituximab monotherapy within 12 weeks prior to randomization, or rituximab combination therapies (e.g., with bendamustine, fludarabine, other cytotoxic drugs or ibrutinib) 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.
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.
8. HIV or hepatitis C virus detectable by polymerase chain reaction at screening or documented in the patient’s medical record.
9. Chronic inactive hepatitis B virus with viral loads > 1000 IU/mL (> 5000 copies/mL) at screening or documented in the patient’s medical record. Eligible patients who are chronic active 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.
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.
To demonstrate the efficacy of twice-weekly subcutaneous (s.c.) 1080-mg infusions of pegcetacoplan compared with that of placebo in patients with CAD.