Efficacy, Safety and Tolerability of BAF312 Compared to Placebo in Patients With Intracerebral Hemorrhage (ICH).
Condition: Hemorrhagic Stroke; Intracerebral Hemorrhage (ICH)
MeSH terms: Stroke; Cerebral Hemorrhage; Hemorrhagic Stroke; Hemorrhage
Intervention: BAF312 solution; Matching Placebo for BAF312 solution; BAF312 tablet; Matching Placebo for BAF312 tablet
Intervention description: Solution for intravenous (IV) infusion - 4.5mg/4.5mL; Solution for intravenous (IV) infusion - 0mg/4.5mL matching placebo; 2 mg film-coated tablet; 0 mg film-coated tablet matching placebo
Intervention MeSH terms: Pharmaceutical Solutions; Siponimod
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
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)
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: stroke; intracerebral hemorrhage; ICH; BAF312; siponimod; sphingosine-1-phosphate receptor; adult

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)
    

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.