This study has been transitioned to CTIS with ID 2023-506498-36-00 check the CTIS register for the current data. To evaluate the efficacy of crovalimab compared to eculizumab
ID
Source
Brief title
Condition
- Red blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Proportion of patients who achieve transfusion avoidance
2. Proportion of patients with hemolysis control, measured by LDH <=1.5×ULN
Secondary outcome
1. Proportion of patients with breakthrough hemolysis
2. Proportion of patients with stabilization of hemoglobin
3. Mean change in fatigue as assessed through use of the Functional Assessment
of Chronic Illness Therapy (FACIT)-Fatigue scale
4. Incidence and severity of adverse events
5. Change from baseline in targeted vital signs
6. Change from baseline in targeted clinical laboratory test results
7. Incidence and severity of injection-site reactions, infusion-related
reactions, hypersensitivity, and infections
8. Incidence of adverse events leading to study drug discontinuation
9. Incidence and severity of clinical manifestations of drug-target-drug
complex formation in patients who switched to crovalimab treatment from
eculizumab or ravulizumab treatment
10. Serum concentration of crovalimab or eculizumab
11. Prevalence and incidence of anti-drug antibodies (ADAs) to crovalimab
12. Change over time in pharmacodynamic biomarkers
13. Change over time in free C5 concentration in crovalimab-treated patients
14. Observed value and absolute change in parameters reflecting hemolysis
Background summary
Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired, clonal,
hematopoietic stem cell disorder. Due to a somatic mutation, hematopoietic
cells (and progeny of affect stem cells) are deficient in proteins involved in
complement regulation. This deficiency leads to inadequate blocking of the
membrane attack complex (MAC), subsequently resulting in intravascular
hemolysis.
Current treatment (with ravulizumab or eculizumab) for PNH is based on
inhibition of C5, however about 35-50% of the patients treated with eculizumab
still require regular transfusions. Therefore, there is still an unmet medical
need.
Based on clinical data, nonclinical pharmacology, and pharmacodynamic (PD)
data, crovalimab is expected to lead to consistent and complete complement
protein C5 inhibition resulting in suppression of intravascular hemolysis at
the targeted dosing regimens. Compared to ravulizumab and eculizumab,
crovalimab binds to a different part of C5.
Study objective
This study has been transitioned to CTIS with ID 2023-506498-36-00 check the CTIS register for the current data.
To evaluate the efficacy of crovalimab compared to eculizumab
Study design
A Phase III, randomized, open-label, active-controlled, multicenter study of
crovalimab in adult and adolescent patients with paroxysmal nocturnal
hemoglobinuria (PNH).
Intervention
Subjects will be randomized 2:1 to crovalimab versus eculizumab.
For participants in the crovalimab group weighing 40-100 kg: Crovalimab will be
administered intravenously on Day 1 (at 1000 mg) and during week 1-4 will be
injected subcutaneously (at 340 mg) weekly. In week 5 and later, participants
will receive 680 mg crovalimab subcutaneously every 4 weeks.
For participants in the crovalimab group weighing 100 kg or more: Crovalimab
will be administered intravenously on Day 1 (at 1500 mg) and at Day 2 will be
injected subcutaneously (at 340 mg). In weeks 2, 3 and 4, participants will
receive 340 mg crovalimab weekly. Starting Week 5 and later, participants will
receive 1020 mg crovalimab subcutaneously every 4 weeks.
For participants in the eculizumab group: participants will receive eculizumab
as intravenous infusion weekly (600 mg) during weeks 1-4. Starting week 5 and
up until week 25, participations will receive eculizumab through an IV every 2
weeks (at 900 mg).
Study burden and risks
The minimum duration of subject*s participation in this study:
- 52 weeks for those randomized to receive crovalimab
- 38 weeks for those randomized to receive eculizumab.
During the treatment period the subject in the crovalimab group, will have to
visit the hospital weekly for the first 4 weeks. From week 5-25, the subject
will have a visit every 2 weeks. After week 25, the subject will have a
hospital visit every 8 weeks, and subsequently every 12 weeks for as long as
they remain on the study.
For subjects randomized to the eculizumab group, weekly visits are scheduled
for the first 4 weeks. Then every 2 weeks during weeks 5-25. Subsequently they
can switch to receive crovalimab and will have visits as described for the
crovalimab group.
Risks associated with crovalimab treatment include, but are not limited to,
meningococcal infection, type III hypersensitivity reactions and infusion
related reactions.
These side effects can be symptomatically treated.
For PNH patients, lifelong therapy is needed. Considering this, treatment with
crovalimab can (potentially) reduce the treatment burden with optimal disease
control, compared to treatment with eculizumab and ravulizumab. Current
clinical experience indicates that the drug is well tolerated in naïve PNH
patients. Therefore, there is a positive overall risk-benefit for treatment
with crovalimab.
Grenzacherstrasse 124
Basel 4070
CH
Grenzacherstrasse 124
Basel 4070
CH
Listed location countries
Age
Inclusion criteria
- Body weight >= 40 kg
- Documented diagnosis of PNH, confirmed by high sensitivity flow
cytometry evaluation of WBCs
- LDH level >=2 x ULN at screening (as per local assessment)
- Vaccination against Neisseria meningitidis serotypes A, C, W, and Y < 3
years prior to initiation of study treatment. Vaccination against serotype
B should be administered in accordance with the most current local
guidelines or SOC, as applicable in patients with complement deficiency.
If not previously administered or no longer current, vaccination must be
completed no later than one week after the first study drug
administration. Vaccination currency with vaccination against serotypes
A, C, W, Y and B should be maintained throughout the study, according
to local guidelines or standard-of-care as applicable in patients with
complement deficiency. In the absence of clear local guidelines for
Neisseria meningitidis, the Advisory Committee on Immunization
Practices 2020 Guidelines are recommended.
- Platelet count >= 30,000/mm*3 at screening without transfusion
support within 7 days of lab testing.
- ANC > 500/micro L at screening
- For female patients of childbearing potential: agreement to remain
abstinent or use contraception
Additional Inclusion Criteria for Patients in the Randomized Arms
-Age >=18 years
Additional Inclusion Criteria for Patients in the Descriptive Arm
- Age < 18 years
Exclusion criteria
- Current or previous treatment with a complement inhibitor
- History of allogeneic bone marrow transplantation
- History of Neisseria meningitidis infection within 6 months prior to
screening and up to first study drug administration
- History of myelodysplastic syndrome with Revised International Prognostic
Scoring System (IPSS-R) prognostic risk categories of intermediate, high and
very high
- Pregnant or breastfeeding, or intending to become pregnant during the study
or within 46 weeks (approximately 10.5 months) after the final dose of
crovalimab, or 3 months after final dose of eculizumab (or longer if required
by the local product label)
- Concurrent disease, treatment, procedure, or surgery or abnormality in
clinical laboratory tests that could interfere with the conduct of the study,
may pose any additional risk for the patient, or would, in the opinion of the
Investigator, preclude the patient's safe participation in and completion of
the study
- Splenectomy <= 6 months prior to screening
- Positive for hepatitis B surface antigen at screening
- Positive for hepatitis C virus antibody at screening (confirmed by detectable
viral RNA)
- History of or ongoing cryoglobulinemia at screening
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 |
|---|---|
| EU-CTR | CTIS2023-506498-36-00 |
| EudraCT | EUCTR2019-004931-21-NL |
| CCMO | NL74837.056.20 |