To study the effect of crizanlizumab on the hemodynamics of the cerebral vasculature (CBF and CVR)
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
To assess the effect of crizanlizumab on the cerebral vascular reserve capacity
(CVR)
Secondary outcome
Secondary outcome:
1. To assess the effect of crizanlizumab on cerebral blood flow (CBF).
2. To determine the effect of crizanlizumab on neurocognitive function
(processing speed).
3. To determine the effect of crizanlizumab on the Quality of Life.
Exploratory outcomes:
1. To determine the effect of crizanlizumab on cerebral oxygen utilization and
oxygen extraction fraction (CMRO2 and OEF).
2. To determine the effect of crizanlizumab on cardiovascular biomarkers
(NTproBNP and TRV).
3. To determine the effect of crizanlizumab on biomarkers of oxidative stress
and endothelial damage (AGE*s, VWFag and VCAM-1).
4. To determine the effect of crizanlizumab on neutrophil activity,
pro-inflammatory properties and oxidative burst capacity.
5. To determine the effect of crizanlizumab on neutrophil-platelet adhesion as
measure of neutrophil adhesiveness.
Background summary
In sickle cell disease (SCD), acute anemia increases the risk for silent
cerebral infarcts (SCI), despite having elevated cerebral blood flow (CBF) to
compensate anemia. In previous research, we showed that patients with SCD have
an increased resting CBF due to chronic vasodilatation, to compensate for the
reduced oxygen availability caused by anemia, vaso-occlusion and chronic
inflammation. As a result of this already dilated intracerebral vasculature,
there is a diminished capacity to further enhance CBF during episodes of
decreased oxygen delivery due to hypoxia, pneumonia or reduced blood pressure,
resulting in cerebral ischemia.
By the use of Diamox we are able to temporary increase the cerebral blood flow,
as a result of maximal vasodilatation of the cerebral vasculature. The rate of
increase in cerebral blood flow is called vascular reserve capacity. In a
previous trial with a cohort of adult sickle cell patients, we demonstrated
that the vascular reserve capacity is strongly reduced in patients with sickle
cell disease confirming their vulnerable state with respect to cerebral
ischemia.
Crizanlizumab is a new drug that is has been studied in a large international
placebo-controlled trial, that has demonstrated to prevent vaso-occlusion in
several preclinical models by preventing cellular adhesion to the activated
endothelial surface. Recurrent vaso-occlusion of the microvasculature is
responsible for tissue ischemia and reperfusion injury, resulting in organ
damage.
Organs that have demonstrated to be typically vulnerable to recurrent ischemia
are the brain, kidneys, spleen and the bones. Since crizanlizumab is
specifically targeting the enhanced cellular adhesion in the microvasculature,
thereby preventing vaso-occlusion, tissue ischemia and reperfusion injury, we
hypothesize that crizanlizumab may improve cerebral perfusion.
Given the slow progression rate of silent strokes in patients with SCD only a
large placebo-controlled trial with a long follow up would be needed to
elucidate whether crizanlizumab can prevent silent infarcts. Therefore robust
surrogate markers of cerebrovascular perfusion/oxygenation are needed to be
able to evaluate the ameliorating effect of crizanlizumab on cerebral perfusion
in a small group of patients in a limited time period.
Study objective
To study the effect of crizanlizumab on the hemodynamics of the cerebral
vasculature (CBF and CVR)
Study design
Single center, open label intervention study with crizanlizumab. In this study,
20 adult patients with SCD (HbSS or HbSβ0-thalassemia) will be treated with
crizanlizumab for 12 months. The study procedures consist of echo, MRI and
laboratory assessments that will be performed at baseline, 3 months 6, months
(no MRI and no echo) and 12 months upon crizanlizumab administration.
Neurocognitive performance will be assessed at baseline and 12 months following
crizanlizumab administration.
Intervention
Crizanlizumab infusion over 30 minutes, every 4 weeks for a period of 12 months
Study burden and risks
Potential risk of adverse events due to treatment with crizanlizumab. MRI is
harmless, Diamox infusion has proven to be save in patients with SCD and
venipuncture is routine in patients with SCD. Parameters obtained by blood
drawn in this study will be used clinically as well. Presumably, participation
is associated with minimal burden and risks. As cranial MRI is not routinely
performed in adults with SCD, coincidental findings are potentially beneficial.
The studied population represents the group of patients with the highest
disease severity, and is, thus, representable.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
1. Documented SCD genotype (HbSS, HbSβ0-thalassemia) which may be based on
history of laboratory testing or must be confirmed by laboratory testing during
screening.
2. Age 18 and above
3. For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be
stable for at
least 90 days prior to participation and with no anticipated need for dose
adjustments
4. Participants, who if female and of child bearing potential, are using
highly effective
methods of contraception from study start to 30 days after the last dose of
study drug, and who if male are willing to use barrier methods of
contraception, from study start to 30
days after the last dose of study drug.
5. Participant has provided documented informed consent or assent (the
informed consent
form [ICF] must be reviewed and signed by each participant; the participant*s
legal representative or legal guardian, and the participant*s assent must be
obtained).
Exclusion criteria
1. No informed consent has been given
2. Contra-indication for MRI or acetazolamide
3. Female who is breast feeding or pregnant.
4. Patients who are receiving regularly scheduled blood (RBC) transfusion
therapy (also
termed chronic, prophylactic, or preventive transfusion) or have received a RBC
transfusion for any reason within 90 days before participation.
5. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14
days prior participation.
6. History of overt stroke (defined as a symptomatic stroke confirmed by CT or
MRI).
7. Hypertension or uncontrolled diabetes mellitus
8. Hepatic dysfunction characterized by alanine aminotransferase (ALT) >4 ×
ULN.
9. Participants with clinically significant bacterial, fungal, parasitic or
viral infection which
require therapy:
• Participants with acute bacterial infection requiring antibiotic use should
delay
screening/enrollment until the course of antibiotic therapy has been
completed.
• Participants with known active hepatitis A, B, or C
10. Severe renal dysfunction (estimated glomerular filtration rate <30mL/min).
11. History of malignancy within the past 2 years prior to participation
requiring chemotherapy and/or radiation (with the exception of local therapy
for non-melanoma
skin malignancy).
12. History of unstable or deteriorating cardiac or pulmonary disease within 6
months prior
to consent including but not limited to the following:
• Unstable angina pectoris or myocardial infarction or elective coronary
intervention.
• Congestive heart failure requiring hospitalization.
• Uncontrolled clinically significant arrhythmias.
13. Any condition affecting drug absorption, such as major surgery involving
the stomach or
small intestine (prior cholecystectomy is acceptable).
14. Participated in another clinical trial of an investigational agent (or
medical device) within
30 days or 5 half-lives of date of informed consent, whichever is longer, or is
currently
participating in another trial of an investigational agent (or medical device)
15. Medical, psychological, or behavioral conditions, which, in the opinion of
the
Investigator, may preclude safe participation, confound study interpretation,
interfere
with compliance, or preclude informed consent.
16. Receipt of erythropoietin or other hematopoietic growth factors within 28
days of signing
ICF or anticipated need for such agents during the study.
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 | EUCTR2020-003601-66-NL |
| CCMO | NL74869.018.20 |