Clinical trial NCT03338998: Efficacy, Safety and Tolerability of BAF312 Compared to Placebo in Patients With Intracerebral Hemorrhage (ICH).
Official title: A Phase II, Patient- and Investigator-blinded, Randomized, Placebo-controlled Study to Evaluate Efficacy, Safety and Tolerability of BAF312 (Siponimod) in Patients With Stroke Due to Intracerebral Hemorrhage (ICH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hemorrhagic Stroke
Intracerebral Hemorrhage (ICH)
Keywords: stroke
intracerebral hemorrhage
ICH
BAF312
siponimod
sphingosine-1-phosphate receptor
adult
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-11-09
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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)
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 exclusion criteria:

    * Intravenous immunoglobulin, immunosuppressive and/or chemotherapeutic medications.
    * Moderate immunosuppressives (e.g. azathioprine, methotrexate) and/or fingolimod within 2 months prior to randomization.
    * Stronger immunosuppressives (e.g. cyclophosphamide, immunosuppressive mAb) within (minimally) 6 months prior to randomization, or longer with long-lasting immunosuppressive medications as determined by the investigator.
12. Cardiovascular exclusion criteria:

    * Cardiac conduction or rhythm disorders including sinus arrest or sino-atrial block, heart rate \<50 bpm, sick-sinus syndrome, Mobitz Type II second degree AV block or higher grade AV block, or preexisting atrial fibrillation (either by history or observed at screening).
    * PR interval \>220 msec. Long QT syndrome or QTcF prolongation \>450 msec in males or \>470 msec in females on screening electrocardiogram (ECG).
    * Patients receiving treatment with QT-prolonging drugs having a long half-life (e.g., amiodarone).
13. Any of the following abnormal laboratory values prior to randomization:

    * White blood cell (WBC) count \< 2,000/μl (\< 2.0 x 109/L)
    * Lymphocyte count \< 800/μl (\< 0.8 x 109/L)
14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
15. Patients with any other medically unstable condition or serious laboratory abnormality as determined by the investigator.

Primary outcomes:
measure: Absolute Perihematoma Edema (aPHE) Volume Measured by Computed Tomography (CT) Scan After Intracerebral Hemorrhage (ICH)
timeFrame: On Day 14 following ICH
Secondary outcomes:
measure: Plasma BAF312 Concentrations
timeFrame: Days 1, 8, and 14
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Novartis Investigative Site
state: California
city: New Haven
country: United States
facility: Novartis Investigative Site
state: Connecticut
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Detroit
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Portland
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Charlottesville
country: United States
facility: Novartis Investigative Site
state: Virginia
Study officials:
affiliation: Yale University
name: Kevin N. Sheth, MD
role: PRINCIPAL_INVESTIGATOR
References: