This study has been transitioned to CTIS with ID 2022-502546-26-00 check the CTIS register for the current data. This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of crovalimab compared with placebo for the…
ID
Source
Brief title
Condition
- Red blood cell disorders
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome = safety:
- Incidence and severity of adverse events
- Change from baseline in targeted vital signs and clinical laboratory test
results
- Incidence and severity of infusion-related reactions and hypersensitivity
Secondary outcome
Pharmacokinetics (PK)
Serum concentrations of crovalimab over time
Pharmacodynamics (PD)
Change over time in PD biomarkers
Exploratory Biomarker
Change over time in exploratory biomarkers
Efficacy:
-Time to VOE improvement
-Time to readiness for discharge
-Time to hospital discharge
-Total cumulative opioid dose (MEU/kg)
-Time to discontinuation of all parenteral opioids
-Change in pain score at hospital discharge (NRS: 0-10)
-Time to confirmed decrease in pain score of at least 2 points sustained for a
minimum of 6 hours
-Proportion of patients requiring intensive care unit (ICU)
-Proportion of patients requiring blood transfusion
-Proportion of patients who develop ACS up to Day 28
-Re-admission within 28 days of discharge of the primary hospitalization
Background summary
Refer to chapter 1.1, 1.2 and 1.3.1 of the protocol
The available data from patients with SCD, in vitro and in vivo nonclinical
models indicate that complement is activated in patients with SCD and suggest a
role in its pathophysiology in multiple domains. Complement activation is
detected in patients at steady state in SCD and has also been described in
association with VOE. In vitro and in vivo models of complement inhibition
suggest multiple potential downstream effects of C5 inhibition in patients
with SCD that include prevention of endothelial activation by free heme,
reduction in rate of hemolysis, reduction in vaso-occlusion,
improvement in chronic inflammation, and reduction in end-organ damage.
Published evidence supports exploratory trials of complement inhibition in
patients with SCD, which may address the unmet medical need in this disease,
employing a mechanism that does not overlap with current therapies.
Crovalimab induces rapid and complete inhibition of the terminal complement
pathway by targeting C5, making it a suitable candidate for exploration of the
role of targeting complement in treatment for SCD.
Study objective
This study has been transitioned to CTIS with ID 2022-502546-26-00 check the CTIS register for the current data.
This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and
efficacy of crovalimab compared with placebo for the management of acute
uncomplicated vaso-occlusive episodes (VOE) in patients with sickle cell
disease (SCD).
Study design
This randomized, multicenter, placebo-controlled, double-blinded Phase Ib study
is designed to evaluate the safety (primary study objective),
pharmacokinetics, pharmacodynamics, and efficacy of crovalimab compared with
placebo for the management of an acute uncomplicated VOE in adult and
adolescent patients with SCD.
Ratio crovalimab : placebo = 2:1
This study has three parts:
1. Screening #1 (initial outpatient clinic) and screening #2 (VOE presentation)
to assess the eligibility for the study
2. Treatment/Hospitalization for pain attack (crisis): one single dose at day
1, and hospitalization period
3. Follow-up (check after discharge from the hospital) D28 and D84 on site and
phone calls on D14, D46, D64, D168 and D322
Intervention
The investigational medicinal products for this study are crovalimab IV and
placebo IV (2:1). Patients in this study will receive a single IV dose of
crovalimab or placebo according to a weight-based dosing approach:
>= 40 kg to < 100 kg 1000 mg IV( 60 ± 10 minutes)
>= 100 kg 1500 mg IV (90 ± 10 minutes)
Study burden and risks
Chapter 1.3.1 en 1.3.2. protocol: Study rational and benefit-risk assessment
Published evidence supports exploratory trials of complement inhibition in
patients with SCD, which may address the unmet medical need in this disease,
employing a mechanism that does not overlap with current therapies.
Crovalimab induces rapid and complete inhibition of the terminal complement
pathway by targeting C5, making it a suitable candidate for exploration of the
role of targeting complement in treatment for SCD.
Preclinical findings support the use of crovalimab in patients with SCD, with
a preliminary safety profile of crovalimab assessed in the Phase I/II clinical
study in PNH. Additionally, this Phase Ib study in SCD includes only a single
dose of crovalimab and short duration of exposure; the safety risk is
considered to be manageable with patient selection, prevention by immunization
and use of prophylactic antibiotics where indicated, safety monitoring, strict
guidance for early evaluation and intervention, and ongoing patient education
measures. In addition, early mandatory reporting of sentinel events and ongoing
safety assessments will provide an ongoing assessment of the risk and allow
for optimization of the risk minimization approach where, or if needed.
Beneluxlaan 2A
Woerden 3446AA
NL
Beneluxlaan 2A
Woerden 3446AA
NL
Listed location countries
Age
Inclusion criteria
-Age 12-55 years; >=40 kg at screening
-Confirmed diagnosis of SCD (HbSS or HbSβ0)
-Diagnosis of an acute uncomplicated VOE defined as an acute episode of pain
with no other medically determined cause, requiring admission to a hospital and
treatment with parenteral opioids
-Ability to receive the first dose of study drug within 12 hours from initial
evaluation in the ER/ED
-Vaccinations against Neisseria meningitidis, Haemophilus influenzae type B,
and Streptococcus pneumoniae
-Adequate hepatic and renal function
-Hemoglobin >= 5 g/dL; Platelet count >= 100,000/µL
-Patients receiving sickle cell therapies must be on a stable dose for 28 days
prior to VOE presentation
-For women of childbearing potential: agreement to remain abstinent or use
contraception
Eligibility criteria are split between an Initial Screening (#1) and VOE
Screening (#2) in the protocol. If an initial screening is not completed, all
criteria listed must be assessed at VOE presentation.
Exclusion criteria
- >10 VOE events in the past 12 months requiring a medical facility/ healthcare
provider visit
- VOE ongoing for >48 hours prior to presenting to the ER/ED or acute care
facility
- Pain atypical of an acute uncomplicated VOE or other alternative cause or
explanation for pain
Evidence of ACS; Acute pain related to avascular necrosis, hepatic or splenic
sequestration, or priapism
- Evidence or high suspicion of a severe systemic infection; Presence of fever
>= 38 °C (100.4 °F)
- Transfusion within 3 months or as part of BSC regimen for the current VOE, or
participation in a chronic transfusion protocol
- Presentation with a critical illness necessitating ICU or critical care
admission
- History of N. meningitidis infection within 6 months prior to VOE presentation
- Major surgery and/or hospitalization for any reason within 30 days prior to
VOE presentation
- Pregnant or breastfeeding, or intending to become pregnant during the study
or within 10.5 months after the study drug administration
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 | CTIS2022-502546-26-00 |
| EudraCT | EUCTR2020-004840-27-NL |
| ClinicalTrials.gov | NCT04912869 |
| CCMO | NL83161.056.23 |