Tocilizumab-aazg for Hemorrhage: Reduction of Ischemic Vascular Events

Inclusion Criteria:

• Adult patients (aged ≥18 years) with Hunt Hess Grade 1-3, Fisher score 3 or 3 and 4,aneurysmal subarachnoid hemorrhage within 24 hours of symptom onset (rupturedaneurysm confirmed by CTA, MRA or DSA)

• Must have external ventricular drain or lumbar drain, or plan to place an externalventricular drain or lumbar drain.

• Female subjects of child-bearing potential must have negative pregnancy test

• Signed informed consent from subject or legally authorized representative

• Able and willing to comply with followup visits

• For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraception, as defined below:

Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate of 1% per year during the treatment period and for 2 months after the final dose of TYENNE. Women must refrain from donating or storing eggs during the same time period. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized acceptable methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

The following are examples of adequate non-hormonal contraceptive methods: bilateral tubal ligation; male sterilization; copper intrauterine devices; male or female condom with or without spermicide; and cap, diaphragm, or sponge with spermicide.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 2 months after the dose of TYENNE to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.

Exclusion Criteria:

• Evidence for vasospasm or DCI prior to study enrollment

• Hemodynamically unstable pre-enrollment

• Severe or unstable concomitant condition or disease (e.g., known significantneurological deficit, cancer, hematologic or coronary disease), or chronic condition (e.g., liver disease, kidney disease, or psychiatric disorder), that may increasethe risk associated with study participation, or may interfere with theinterpretation of study results

• Subjects who have received an investigational product or participated in anotherinterventional clinical study within 30 days prior to enrollment.

• Known hypersensitivity or severe allergic reaction to tocilizumab and/or otherbiologics agents (i.e. shock, anaphylactic reactions)

• Serious infection defined as pneumonia, sepsis/septic shock, and neutropenic feverprior to enrollment

• Any previous treatment with IL-6 inhibitory therapy (e.g. satralizumab),alemtuzumab, etc.

• Total body irradiation or bone marrow transplantation within 6 months prior tobaseline.

• Any previous treatment with anti-CD20, anti-CD19, eculizumab, belimumab, interferon,natalizumab, glatiramer acetate, fingolimod, teriflunomide or dimethyl fumaratewithin 6 months prior to baseline.

• Any previous treatment with anti-CD4, cladribine or mitoxantrone within 2 yearsprior to baseline

• Pregnant or breastfeeding, or intending to become pregnant during the study orwithin 2 months after TYENNE administration

• Women of childbearing potential must have a negative serum pregnancy test resultprior to initiation of study drug.

• Any surgical procedure (except for minor surgeries) within 4 weeks prior tobaseline.

• Evidence of serious uncontrolled concomitant diseases that may preclude patientparticipation, such as: other nervous system disease, cardiovascular disease,hematologic/hematopoiesis disease, respiratory disease, muscular disease, endocrinedisease, renal/urologic disease, digestive system disease, congenital or acquiredsevere immunodeficiency.

• Known active infection (excluding fungal infections of nail beds or caries dentium)within 4 weeks prior to baseline.

• History of diverticulitis that, in the principal investigator's opinion, may lead toincreased risk of complications such as lower gastrointestinal perforation.

• Evidence of active or untreated latent tuberculosis (TB; excluding patientsreceiving chemoprophylaxis for latent TB infection).

• Evidence of active interstitial lung disease

• Receipt of any live or live attenuated vaccine within 6 weeks prior to baseline andthroughout the duration of the study.

• History of malignancy within the last 5 years, including solid tumors, hematologicmalignancies and in situ carcinoma (except basal cell and squamous cell carcinomasof the skin, or in situ carcinoma of the cervix uteri that have been completelyexcised and cured).

• Laboratory exclusion criteria (at screening):

• White blood cells (WBC) <3.0 x103/μL

• Absolute neutrophil count (ANC) <2.0 x103/μL

• Absolute lymphocyte count <0.5 x103/μL

• Platelet count <100 x 103/μL

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times theupper limit of normal (ULN).

• Patient with known medical history at screening listed for the following must beexcluded from this trial:

• Evidence of chronic active hepatitis B (HBV)

• Evidence of chronic active hepatitis C (HCV)

• Positive for hepatitis C virus (HCV) antigen

• Positive for hepatitis B surface antigen (HBsAg)

• Known HIV infection.

• Illicit drug or alcohol abuse within 12 months prior to screening, in theinvestigator's judgment

• Poor peripheral venous access

• Serious infection requiring oral or IV antibiotics prior to screening

• Any serious medical condition or abnormality in clinical laboratory tests that, inthe investigator's judgment, precludes the patient's safe participation in andcompletion of the study

• History or presence of an abnormal ECG that is clinically significant in theinvestigator's opinion, including complete left bundle branch block, second- orthird-degree atrioventricular heart block, or evidence of prior myocardialinfarction