Primary Objective:To assess the safety and tolerability of single doses of CSL889 administered by IV infusion in subjects with stable SCD and in subjects with SCD in VOCSecondary Objectives:1. To characterize the PK profile of CSL889 after single IV…
ID
Source
Brief title
Condition
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoints:
Frequency, nature and severity of TEAEs from start of infusion until 32 days
after infusion in subjects with stable SCD and in subjects with SCD in VOC
Secondary outcome
Secondary Endpoints:
1. Serum PK parameters of CSL889, with and without adjustment for baseline
hemopexin: Cmax, AUC from time 0 to the last measurable concentration
(AUC0-last), AUC0-inf, time of maximum concentration (tmax), terminal half-life
(t1/2), clearance (CL), volume of distribution during the elimination phase (Vz)
2. Anti-CSL889 antibodies
Background summary
The study drug CSL889 is being developed for the treatment of vaso-occlusive
crisis (also known as pain crisis) that occurs in patients with severe sickle
cell disease. CSL889 is a human protein called hemopexin. All humans have
hemopexin. However, patients with sickle cell disease may have very little
hemopexin. A main job of hemopexin is to combine with a substance in blood
called heme and to clear heme from the blood. The heme comes from red blood
cells when red blood cells die. Research suggests that heme may play a role in
pain crisis. If CSL889 combines with heme, similar to the way hemopexin found
in the body does, it may help clear heme from the blood.
Study objective
Primary Objective:
To assess the safety and tolerability of single doses of CSL889 administered by
IV infusion in subjects with stable SCD and in subjects with SCD in VOC
Secondary Objectives:
1. To characterize the PK profile of CSL889 after single IV doses of CSL889 in
subjects with stable SCD and in subjects with SCD in VOC
2. To assess immunogenicity of CSL889 after single IV doses of CSL889 in
subjects with stable SCD and in subjects with SCD in VOC
Study design
his is a 2-part phase 1, first-in-human, multicenter, open label, cohort study
to evaluate the safety and tolerability, pharmacokinetics (PK), exploratory
pharmacodynamics (PD), and biomarkers of target engagement of CSL889 following
single intravenous (IV) doses of CSL889 in subjects with stable SCD and in
subjects with SCD in vaso-occlusive crisis (VOC), requiring parenteral opioids
and admission to hospital for management. The study includes 2 parts.
Part A: To evaluate single dose administration of CSL889 in subjects with
stable SCD
Part B: To evaluate single dose administration of CSL889 in subjects with SCD
in VOC.
This study will be conducted in the United States, the United Kingdom, The
Netherlands, and possibly other countries.
TStudy Part A involves sequential dose escalation of cohorts with between group
assessments of safety, PK, exploratory PD, and biomarkers of target engagement,
and consists of a 21-day Screening Period, CSL889 administration on Day 1, and
a Safety Follow-up Period of 32 days after CSL889 administration for each
subject. The study includes an inpatient period and outpatient visits, some of
which may be performed as home care visits.
DIn Part A, eligible subjects receive a single IV dose of CSL889 in an open
label manner at the study site on Day 1 and remain in the clinic for inpatient
monitoring until approximately 24 hours after end of CSL889 infusion, during
which blood samples for scheduled assessments of safety, PK, exploratory PD,
and biomarkers of target engagement will be obtained. Subjects will be followed
up in scheduled study site and home care visits for 32 days for safety, PK,
exploratory PD, and biomarkers of target engagement.
In Part A, it is planned to assess 6 ascending single doses at 3, 10, 30, 60,
120, and 200 mg/kg CSL889 in 4 subjects per dose cohort. These doses are
putative, and based on emerging safety and PK data, dose levels by cohort may
be adjusted, and intermediate dose cohorts may be added. Sentinel dosing will
be used for the first subject of each dose cohort (sentinel subject), with a
24-hour monitoring period for the sentinel subject and dosing of the remaining
subjects >= 72 hours after the start of CSL889 infusion in the sentinel subject.
Study Part B assesses safety, PK, exploratory PD, and biomarkers of target
engagement in subjects with SCD in VOC, and will enroll 1 cohort of 4 subjects
in VOC to receive a single IV dose of CSL889 at a dose selected based on
emerging safety and PK data from Part A. An additional cohort of up to 4
subjects may be included if necessary to adequately characterize safety and /
or PK and / or exploratory PD and biomarkers of target engagement.
In Part B, informed consent and Screening will be conducted only in the context
of a hospital admission for VOC. The process of obtaining informed consent may
be initiated once the decision has been made to admit the subject for ongoing
treatment of VOC per local standard of care (eg, in the Emergency Department),
even if the subject has not yet been admitted to an inpatient facility.
Potential subjects for Part B may be preidentified while in stable SCD, based
on their medical history.
The duration of the study for an individual subject is expected to be
approximately 8 weeks in Part A and approximately 5 weeks in Part B. The
overall study duration globally (first subject*s first visit to last subject*s
last visit) will be approximately 17 months.
Intervention
Study product:
CSL889 is a human 60 kilodalton glycoprotein that is purified from human plasma
using a Kistler Cohn Fraction IV-4 as the starting material for the
manufacturing process. CSL889 will be supplied as a sterile liquid formulation
at a concentration of 100 mg/mL in 50 mL vials, formulated with commonly used
stabilizers including citric acid, sodium phosphate dihydrate, and sodium
chloride, pH 6.9 to 7.5.
Dose:
Part A: It is planned to assess 6 ascending single doses at 3, 10, 30, 60, 120,
and 200 mg/kg CSL889 in 4 subjects per dose cohort. These doses are putative,
and based on emerging safety and PK data, dose levels by cohort may be
adjusted, and intermediate dose cohorts may be added.
Part B: The proposed dose for Cohort B1 is 60 mg/kg, provided it has been shown
to be safe and well tolerated in subjects with stable SCD in Part A. The dose
level may be adjusted based on emerging safety and PK data from Part A. The
decision to study a second dose level in Part B will be determined based on
emerging data from Cohort B1. The dose would be selected from those studied in
Part A.
Dosing regimen:
Single dose administration.
Administration:
IV infusion at a constant rate into the left or right arm contralateral to the
blood sampling site.
Study burden and risks
Please refer to section 6. 'Possible side effects and discomforts' in the
subject information sheet for an overview of the risks and side effects.
First Avenue 1020
King of Prussia PA19406
US
First Avenue 1020
King of Prussia PA19406
US
Listed location countries
Age
Inclusion criteria
• Diagnosis of SCD as documented in the subject's medical record
• Aged 18 to 60 years, inclusive
• Stable SCD for at least 30 days before Day 1. Stable SCD is defined as the
subject being at his or her medical baseline, with no evidence of worsening of
disease over the last 30 days (including VOC, recent major surgery,
hospitalization, serious infection, significant bleeding, cerebrovascular
accident, seizures, or IV opioids)(Part A)
• Uncomplicated VOC requiring parenteral opioid treatment and admission to
hospital for management
Uncomplicated VOC is defined as sickle cell pain without the following
associated clinical features (Part B):
o Fever (> 38.5 °C)
o Hypotension (< 90/60 mmHg)
o Hypoxia (< 90% oxygen saturation on room air, or requiring oxygen therapy to
maintain oxygen saturation above 90%)
o New neurological signs and / or symptoms clinically suggestive of stroke or
transient ischemic attack
o Signs and / or symptoms of Acute Chest Syndrome, accompanied by any new
pulmonary infiltrate on chest radiography (chest X-ray to be performed if
clinically indicated and according to local clinical guidelines)
•Subject is either not taking one of the study permitted SCD therapies
(hydroxyurea, L-glutamine, L-glutaminecrizanlizumab, and/or voxelotor) or
subject has been taking one or more of those for at least 30 days before Day 1
and is on a stable, well tolerated regimen that is planned to continue without
change throughout the study
Exclusion criteria
• History of primary hemorrhagic stroke
• History or evidence of inherited bleeding diathesis or significant
coagulopathy at risk for bleeding
• Hospitalization for vaso-occlusive crisis (VOC) or treated with parenteral
pain medications in other medical settings such as the emergency department or
day hospital for VOC during the past 30 days before Day 1
• Blood transfusion within the 90 days before Day 1, or expecting blood
transfusion during the study
• Weight >110 kg (242 lbs)
• Surgery within 30 days before Day 1 or any preplanned surgeries during the
study (minor surgeries may be permitted under local anesthesia before
screening, with permission of the medical monitor)
• Female subjects who are pregnant or breastfeeding
• Female subject of childbearing potential or fertile male subject either not
using or not willing to use an acceptable method of contraception to avoid
pregnancy during the study and for 30 days after receipt of CSL889.
• Treatment with any other drug / biologic that is newly approved for SCD
during the conduct of this study within 90 days before Day 1.
Exceptions: crizanlizumab [Adakveo®] and voxelotor [Oxbryta®] are permitted
(where prescribed).
• Treatment with another investigational product within 30 days or within 5
half-lives of the product (whichever is greater) before Day 1
• Vaccination within 30 days before Day 1, or planned vaccination during the
study
• Body-mass index < 16 kg/m2 or weight < 50 kg (110 lbs)
• History of anaphylactic-type reactions, transfusion related reaction, asthma,
or autoimmune disease
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
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 | EUCTR2019-001870-27-NL |
| ClinicalTrials.gov | NCT04285827 |
| CCMO | NL74968.018.20 |