Hemorrhagic Stroke, Intracerebral Hemorrhage (ICH)
Conditions
Keywords
stroke, intracerebral hemorrhage, ICH, BAF312, siponimod, sphingosine-1-phosphate receptor, adult
Brief summary
This is a randomized, placebo-controlled, subject and investigator-blinded study to evaluate efficacy, safety and tolerability of BAF312 in participants with intracerebral hemorrhage (ICH)
Detailed description
This was the first trial of BAF312 in ICH patients to evaluate if BAF312 had the potential to limit brain inflammation after ICH, and thereby improve neurological outcome for stroke patients when administered in addition to standard of care. ICH patients meeting study criteria were randomized at 1:1 ratio into either active or placebo group. Patients received an intravenous infusion (i.v.) treatment within 24 hours of an ICH event and were up titrated for 7 days. Following the i.v. treatment, participants received 10 mg BAF312 or placebo in tablet form (taken daily orally) for an additional 7 days. Participants were followed for an additional 76 days after treatment for neurological and safety conditions during three clinic visits. Recruitment for the trial was put on hold due to the COVID-19 pandemic. Thirty-two patients had been enrolled in the trial and completed the protocol as planned. After seven months of the trial being on hold, an Interim analysis was conducted and reviewed by the Data Monitoring Committee. Novartis terminated the trial due to lack of potential efficacy.
Interventions
DRUGBAF312 solution
Solution for intravenous (IV) infusion - 4.5mg/4.5mL
DRUGMatching Placebo for BAF312 solution
Solution for intravenous (IV) infusion - 0mg/4.5mL matching placebo
DRUGBAF312 tablet
2 mg film-coated tablet
DRUGMatching Placebo for BAF312 tablet
0 mg film-coated tablet matching placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
This is a randomized, patient- and investigator-blinded, placebo-controlled, parallel group study of BAF312 on top of standard-of-care for ICH, consisting of 3 epochs: Screening/Baseline, Treatment (Day 1-14), and Follow-Up (to Day 90)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
ICH patients eligible for inclusion in this study must fulfill all of the following criteria: 1. Male or female patients aged 18 to 85 years (inclusive). 2. Written informed consent obtained before any study assessment is performed. If the patient is not able to give the informed consent personally, consent by a relative or legal representative is acceptable. 3. Spontaneous, supratentorial intracerebral hemorrhage in cerebral cortex or deep brain structures (putamen, thalamus, caudate, and associated deep white matter tracts) with a volume ≥ 10 mL but ≤ 60 mL (calculated by the ABC/2 method, after Kothari et al 1996) determined by routine clinical MRI or CT. 4. Patients with the onset of ICH witnessed and/or last seen healthy no longer than 24 hrs previously. 5. Patients with Glasgow Coma Scale (GCS) best motor score no less than 5 (brings hands above clavicle on stimulus to head or neck).
Exclusion criteria
ICH patients fulfilling any of the following criteria are not eligible for inclusion in this study: 1. Use of other investigational drugs within 5 half-lives of enrollment, or until the expected pharmacodynamic effect has returned to baseline (for biologics), whichever is longer. 2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes (e.g., fingolimod). 3. Current use of concomitant medications with potent CYP2C9/3A4 inhibitory or induction potential. 4. Infratentorial (midbrain, pons, medulla, or cerebellum) ICH. 5. Candidates for surgical hematoma evacuation or other urgent surgical intervention (i.e., surgical relief of increased intracranial pressure) on initial presentation. If during the treatment period surgical hematoma evacuation or surgical intervention to lower intracranial pressure becomes indicated, the investigational treatment should be stopped. 6. Patients with intraventricular hemorrhage (IVH) having a Graeb score of \>3 on initial presentation. Patients must not have blood in the 4th ventricle and may only have blood in the 3rd ventricle in the absence of ventricular expansion. Trace or mild hemorrhage in either or both lateral ventricles is permitted. Patients with hydrocephalus determined radiologically on initial presentation are excluded regardless of Graeb score. 7. Secondary ICH due to: * aneurysm * brain tumor * arteriovenous malformation * thrombocytopenia, defined as platelet count of \<150,000/µl * known history of coagulopathy * acute sepsis * traumatic brain injury (TBI) * disseminated intravascular coagulation (DIC) 8. Prior disability due to other disease compromising mRS evaluation, thereby interfering with the primary outcome, operationally defined as an estimated mRS score (by history) of ≥ 3 before ICH for patients less than or equal to 80 years of age. For ICH patients 81-85 years of age, estimated mRS by history prior to ICH must be less than or equal to 1 (no significant disability despite symptoms). 9. Preexisting unstable epilepsy. 10. Patients with active systemic bacterial, viral or fungal infections. 11. Concomitant drug-related
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Perihematoma Edema (aPHE) Volume Measured by Computed Tomography (CT) Scan After Intracerebral Hemorrhage (ICH) | On Day 14 following ICH | Following the initial diagnostic CT, repeat CT images were obtained between 24-48 h after the diagnostic scan, and on Day 7 and Day 14 to capture the trajectory of PHE increase and plateau after ICH. Only non-contrast study CT scans were obtained on Day 7 and Day 14. The non-contrast scan acquired on each patient at first follow-up (i.e. 24-48 h after the diagnostic scan) served as the baseline for our analysis. All CT scans were uploaded through a secure server, and edema and hematoma volumes were measured in a semi-automated manner by one Central Reader. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma BAF312 Concentrations | Days 1, 8, and 14 | Blood samples will be collected to assess plasma concentrations. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BAF312 Days 1 - 7, IV up titration; days 8 - 14, 10 mg (5 x 2 mg tablets) taken daily orally | 16 |
| Placebo Days 1 - 7, IV up titration; days 8 - 14, 10 mg (5 x 2 mg tablets) taken daily orally - matching placebo | 13 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Safety Follow-Up Period | Adverse Event | 0 | 1 |
| Safety Follow-Up Period | Lost to Follow-up | 1 | 0 |
| Safety Follow-Up Period | Protocol deviation | 1 | 0 |
| Treatment Period | Adverse Event | 0 | 2 |
| Treatment Period | Physician Decision | 2 | 0 |
| Treatment Period | Protocol deviation | 1 | 0 |
| Treatment Period | Subject failed swallow test | 4 | 0 |
| Treatment Period | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | BAF312 |
|---|---|---|---|
| Absolute perihematoma edema (aPHE) volume | 28.237 mL STANDARD_DEVIATION 24.7188 | 22.825 mL STANDARD_DEVIATION 9.8617 | 32.927 mL STANDARD_DEVIATION 32.3153 |
| Age, Continuous | 60.8 years STANDARD_DEVIATION 11.66 | 63.8 years STANDARD_DEVIATION 9.06 | 58.3 years STANDARD_DEVIATION 13.6 |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 5 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Caucasian | 19 Participants | 11 Participants | 8 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 16 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 13 Participants | 7 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 13 | 0 / 29 |
| other Total, other adverse events | 14 / 16 | 11 / 13 | 25 / 29 |
| serious Total, serious adverse events | 2 / 16 | 2 / 13 | 4 / 29 |
Outcome results
Primary
Absolute Perihematoma Edema (aPHE) Volume Measured by Computed Tomography (CT) Scan After Intracerebral Hemorrhage (ICH)
Following the initial diagnostic CT, repeat CT images were obtained between 24-48 h after the diagnostic scan, and on Day 7 and Day 14 to capture the trajectory of PHE increase and plateau after ICH. Only non-contrast study CT scans were obtained on Day 7 and Day 14. The non-contrast scan acquired on each patient at first follow-up (i.e. 24-48 h after the diagnostic scan) served as the baseline for our analysis. All CT scans were uploaded through a secure server, and edema and hematoma volumes were measured in a semi-automated manner by one Central Reader.
Time frame: On Day 14 following ICH
Population: Per protocol analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| BAF312 | Absolute Perihematoma Edema (aPHE) Volume Measured by Computed Tomography (CT) Scan After Intracerebral Hemorrhage (ICH) | 55.09 mL |
| Placebo | Absolute Perihematoma Edema (aPHE) Volume Measured by Computed Tomography (CT) Scan After Intracerebral Hemorrhage (ICH) | 52.50 mL |
p-value: 0.58590% CI: [0.717, 1.535]ANCOVA
Secondary
Plasma BAF312 Concentrations
Blood samples will be collected to assess plasma concentrations.
Time frame: Days 1, 8, and 14
Population: Pharmacokinetics analysis set that included participants with at least one blood sample available
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312 | Plasma BAF312 Concentrations | Day 1 - 0.1 Hours Post I.V. Dose n=11 | 0.1658 ng/mL | Geometric Coefficient of Variation 85.6 |
| BAF312 | Plasma BAF312 Concentrations | Day 1 - 2 Hours Post I.V. Dose n=11 | 0.5663 ng/mL | Geometric Coefficient of Variation 78.7 |
| BAF312 | Plasma BAF312 Concentrations | Day 1 - 6 Hours Post I.V. Dose n=10 | 2.4313 ng/mL | Geometric Coefficient of Variation 30.5 |
| BAF312 | Plasma BAF312 Concentrations | Day 8 - 0 Hours Pre Oral Dose n=11 | 81.9423 ng/mL | Geometric Coefficient of Variation 55.9 |
| BAF312 | Plasma BAF312 Concentrations | Day 14 - 0 Hours Pre Oral Dose n=11 | 36.4460 ng/mL | Geometric Coefficient of Variation 550.8 |