This study has been transitioned to CTIS with ID 2023-506526-37-00 check the CTIS register for the current data. To evaluate the safety and tolerability of crovalimab compared witheculizumab
ID
Source
Brief title
Condition
- Red blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Incidence and severity of adverse events
2. Change from baseline in targeted vital signs
3. Change from baseline in targeted clinical laboratory test results
4. Incidence and severity of injection-site reactions, infusion-related
reactions, hypersensitivity, and infections
5. Incidence of adverse events leading to study drug discontinuation
6. Incidence and severity of clinical manifestations of drug-target-drug
complex formation in patients who switched to crovalimab treatment
from eculizumab or ravulizumab treatment
Secondary outcome
1. Serum concentration of crovalimab or eculizumab
2. Serum concentration of ravulizumab
3. Prevalence and incidence of anti-drug antibodies (ADAs) to
crovalimab
4. Change over time in pharmacodynamic biomarkers
5. Change over time in free C5 concentration in crovalimab-treated
patients
6. Observed value and absolute change in parameters reflecting
hemolysis
7. Percent change from baseline in LDH level averaged over Weeks 21,
23, and 25 LDH measurements
8. Proportion of patients with transfusion avoidance
9. Proportion of patients with breakthrough hemolysis
10. Proportion of patients with stabilization of hemoglobin
11. Mean change in fatigue as assessed through use of the Functional
Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale
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 2023-506526-37-00 check the CTIS register for the current data.
To evaluate the safety and tolerability of crovalimab compared with
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 1:1 to crovalimab (Arm A) versus eculizumab (Arm B)
or will be assigned to Arm C if younger than 18 or if they meet specific
criteria.
For participants in Arm A and C 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 Arm A and C 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 Arm B: participants will receive eculizumab at the same
dose and schedule as they were on before the study (IV infusion, every 2
weeks).
Study burden and risks
The minimum duration of subject*s participation in this study:
- 52 weeks for those randomized/enrolled to receive crovalimab
- 38 weeks for those randomized to receive eculizumab.
During the treatment period the subject in Arms A and C, 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 Arm B, weekly visits are scheduled for the first 4
weeks. Then every 2 weeks during weeks 5-9, and after week 9, they will have a
visit every 4 weeks until week 25. Subsequently they will have visits every 12
weeks.
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. 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,
- Vaccination against Neisseria meningitidis serotypes A, C, W, and Y <
3 years prior to initiation of study treatment, or, if not previously done,
vaccination administered no later than one week after the first drug
administration. Vaccination currency should be maintained throughout
the study in accordance with most current local guidelines or
standardofcare
as applicable in patients with complement deficiency
- Vaccination against Haemophilus influenzae type B and Streptococcus
pneumoniae according to national vaccination recommendations
- 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
For Patients in Randomized Arms (Arm A and B)
- Age >= 18 years
- Documented treatment with eculizumab according to the approved
dosing recommended for PNH and completion of a minimum of 24 weeks
of treatment prior to Day 1
- Lactate dehydrogenase (LDH) <= 1.5 × ULN at screening
For Patients in Non Randomized Arm (Arm C)
- Age <18 old, currently treated with eculizumab OR
- Currently treated with ravulizumab OR
- Currently treated with eculizumab at higher-than-approved doses OR
- Patients with known C5 polymorphism and poorly controlled hemolysis
by eculizumab or ravulizumab
-Adult patients currently treated with approved doses of eculizumab
LDH <= 1.5 × ULN at screening
Exclusion criteria
- Major Adverse Vascular Event within 6 months prior to first drug
administration (Day 1)
- History of allogeneic bone marrow transplantation,
- 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) prognosticrisk 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 the 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
HCV 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 | CTIS2023-506526-37-00 |
| EudraCT | EUCTR2020-000597-26-NL |
| CCMO | NL74836.056.20 |