Ensayos clínicos

Inclusion Criteria:

• Male or female.
• 12 years or older.
• Within 72 hours before randomization, blood culture positive for S. aureus determined by rapid diagnostic test or conventional method, or Gram stain showing Gram-positive cocci in clusters and either positive tube coagulase test or positive latex slide agglutination test from blood culture specimens.
  • Note: The 72-hour time period starts at the time the specimen is collected for blood culture. Any S. aureus-positive blood culture collected within the 72 hours before randomization can be used to support enrollment of the patient.
• At least two of the following signs or symptoms attributable to S. aureus BSI/IE within approximately 24 hours before randomization. If more than one measurement is taken within approximately 24 hours before randomization, the most abnormal value is used for inclusion:
  • Shortness of breath;
  • Sweating;
  • Chills and/or rigors;
  • Fatigue;
  • Confusion;
  • Pain associated with metastatic foci;
  • Fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) or hypothermia (oral temperature equivalent 10,000/µL) [CTCAE 2017], leukopenia (WBC 10% immature neutrophils [bands] regardless of total peripheral WBC);
  • Tachycardia (heart rate >100 bpm)
  • Tachypnea (respiratory rate >20 breaths/min);
  • Hypotension (systolic blood pressure < 90 mmHg).
• Patient must have:
  • Known or suspected R-IE (involvement of pulmonic and/or tricuspid valve[s]) based on Modified Duke Criteria (defined in protocol); or
  • Known or suspected complicated S. aureus BSI, demonstrated as one or more of the following:
  • Blood culture positive for S. aureus on more than one day;
  • Clots in the vein at the catheter site seen on ultrasound;
  • Signs or symptoms of metastatic foci of S. aureus infection (e.g., splenic abscess, deep tissue abscess not associated with open wound or other local source of infection, septic pulmonary emboli) or hematogenous seeding (e.g., of the renal system evidenced by S. aureus bacteriuria [in absence of other source such as indwelling ureteral catheter], septic arthritis, osteomyelitis) confirmed by physical examination, imaging, and/or culture (as described in the study procedures sections of the protocol);
  • Persistent fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) for 72 hours or more;
  • Met criteria for sepsis or septic shock using the Sequential (sepsis-related) Organ Failure Assessment (SOFA) score (definition in protocol [adapted from Singer 2016]) during the time of diagnosis/presumptive diagnosis of BSI. If the SOFA score is the only criteria for complicated S. aureus BSI that is met, contact the Medical Monitor prior to randomization;
  • Significantly immunocompromised:
  • AIDS (HIV positive with an AIDS-defining condition or a CD4 count < 200 cells/mm³);
  • Severe leukopenia defined as absolute neutrophil count (ANC)  < 500 cells/mL for ≥ 3 days in the 7 days prior to the qualifying blood culture;
  • Post organ-transplantation including autologous bone marrow transplantation;
  • On treatment for active graft vs. host disease;
  • On immunosuppressive therapy (e.g., ≥15 mg of prednisone or equivalent for more than 5 days, biologics such as infliximab, monoclonal antibodies such as daclizumab, methotrexate, cyclophosphamide, or similar agents);
  • On myelosuppressive chemotherapy; or
  • At least one of the following risk factors for complicated S. aureus BSI:
  • Preexisting right-sided valvular heart disease;
  • Surgery (e.g., orthopedic, cardiothoracic, or intraabdominal surgery) within the previous 30 days that puts the patient at risk for nosocomial bacteremia;
  • Extravascular foreign material.
  • Note: Catheters including ports, AV fistulas and related dialysis access points are considered intravascular foreign material;
  • Hemodialysis.
• Patient is not pregnant or breastfeeding and meets one of the following criteria:
  • A female patient who is not of childbearing potential is eligible without requiring the use of contraception. This includes female patients who have not undergone menarche or who are documented to be surgically sterile (e.g., hysterectomy, or removal of both ovaries, or tubal ligation) or postmenopausal (i.e., amenorrhea >1 year and follicle stimulating hormone [FSH] >40 mIU/mL) with a negative pregnancy test. FSH and pregnancy testing is not required in postmenopausal females with amenorrhea for > 2 years;
  • Female patients of childbearing potential and male patients with partners of childbearing potential must agree to remain abstinent* or use 2 methods of contraception and refrain from donating sperm (male patients) from screening through 30 days after receiving the study drug.
  • *Abstinence is defined as refraining from heterosexual intercourse from screening through 30 days after receiving the study drug; the Investigator will consider whether abstinence is consistent with the preferred and usual lifestyle of the patient. Acceptable methods of contraception include either:
  • Hormonal contraception (injection, implant, pill, patch, or vaginal ring) and a condom or diaphragm with spermicide; or
  • Intrauterine device (IUD) and a condom or diaphragm;
  • A male patient who is not of reproductive potential is eligible without requiring the use of contraception. This includes males who have undergone a successful vasectomy, defined as (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post vasectomy.
• Willing and able to provide written informed consent or assent. If the patient is not able to provide written informed consent or assent, written informed consent may be provided by the patient’s legally acceptable representative as permissible based on local laws and regulations. For patients 12 to < 18 years of age, written informed consent from the patient’s parent/guardian or other legally acceptable representative will be obtained according to the site’s IRB requirements. For emancipated minors, written informed consent will be obtained according to the site’s IRB requirements.

Exclusion Criteria:

• Previously received exebacase.
• Known or suspected left-sided IE (involvement of mitral and/or aortic valve[s]) based on Modified Duke Criteria (defined in protocol). Note: In patients that have clinical findings suggestive of L-IE (new murmur, worsening cardiac function, and/or peripheral or central nervous embolic phenomenon), a TEE will be performed before randomization to rule out mitral and/or aortic valve vegetation(s) or the patient will be excluded from the study.
• Treatment with any potentially effective systemic anti-staphylococcal antibiotic for more than 72 hours within 7 days before randomization.
• Exception:  Documented S. aureus resistance to the prior systemic antibiotics and/or persistent S. aureus-positive blood cultures while on the systemic antibiotics.
• Current or planned treatment within the 14 days after randomization with dalbavancin or oritavancin.
  • Note:  Patients who are receiving teicoplanin, linezolid, telavancin, beta-lactam/beta-lactam inhibitors (e.g., piperacillin-tazobactam), carbapenems, fourth- or fifth-generation cephalosporins (e.g., cefepime, ceftaroline fosamil), and/or sulfamethoxazole/ trimethoprim are eligible for the study provided that treatment is switched to a protocol-specified appropriate SoCA (appropriate SoCA includes daptomycin and vancomycin for MRSA and semi-synthetic penicillins [e.g., nafcillin, oxacillin, cloxacillin, flucloxacillin] and first-generation cephalosporins [e.g., cefazolin] for MSSA;
  • Daptomycin or vancomycin may be used for patients with MSSA with a known history of beta-lactam allergy or other reason that beta-lactam cannot be used);
  • Patients with persistent S. aureus bacteremia for which ceftaroline fosamil or other nonprotocol recommended antibiotic (e.g., rifampin, gentamicin, other beta lactam) has already been added to a protocol-recommended SoCA prior to randomization, the patient may remain on the non-protocol recommended antibiotic (plus SoCA) after randomization, if approved by the Medical Monitor;
  • Vancomycin or daptomycin used in combination with beta-lactams has not been shown to offer benefit and may increase the risk of kidney injury [Tong 2020]; therefore, this combination should not be used.
• Presence of any removable or surgically managed infection source (e.g., intravascular catheter, abscess) that will not be removed or debrided based upon standard medical practice within approximately 72 hours after randomization.
  • Note: Other hemodialysis access types (i.e., AV fistulas or AV grafts) and surgically managed infection sources that are known or suspected to be infected will be evaluated for removal/replacement, if clinically feasible. If removable/ debridement is not feasible based on standard medical practice, the patient should be discussed with the Medical Monitor.
• Presence of prosthetic valve or cardiac valve support ring, or presence of known or suspected infected orthopedic hardware, prosthetic joint, or cardiac device (e.g., implantable cardioverter defibrillator [ICD], permanent pacemaker).
  • Note: Patients who have S. aureus bacteremia after the removal of infected hardware or cardiac device may be included in the study.
• Known or suspected brain abscess or meningitis.
• Patient with BOTH asplenia and creatinine clearance (CrCl) < 60 mL/min including those on dialysis (risk for reduced ability to catabolize exebacase).
  • Note: CrCl will be calculated by Cockcroft-Gault formula (provided in protocol) using ideal body weight in patients with BMI ≥ 30 kg/m^2 and serum creatinine result obtained locally.
• Patient receiving continuous renal replacement therapy (CRRT) within 4 hours prior toat the time of dosing and/or within 248 hours after dosing.
• Known polymicrobial BSI (i.e., more than one pathogen in the blood).
  • Note: Culture results that include organisms that are considered contaminants do not exclude the patient.
• Patient with known, ongoing systemic infection caused by other bacterial pathogen(s) (i.e., other than S. aureus) and/or fungal pathogen(s) and/or patient who has a known positive coronavirus disease 2019 (COVID-19) diagnostic test at the time of screening. Patients who previously had COVID-19 and are COVID-19-negative by diagnostic test are eligible for enrollment. Note: COVID-19 testing should be performed as clinically indicated in accordance with local standard medical practice.
• Patient is not expected to survive through Day 14 of the study due to underlying comorbidity (e.g., terminal end-stage cancer) and/or patient has an Acute Physiology and Chronic Health Evaluation II (APACHE II) score of > 2530.
• Patient participated or plans to participate in another interventional investigational drug, device, or diagnostic trial involving administration of an investigational agent within 30 days or 5 half-lives of investigational drug, whichever is longer, prior to or during the study.
• Other comorbid condition or laboratory abnormality that would, in the opinion of the Investigator, pose a safety risk for the patient to participate or pose a risk to the patient’s ability to complete the study.
• Patient is employed by the Sponsor or a member of the investigational site study team (i.e., on the Delegation of Authority Log) or is a first degree relative of a person employed by the Sponsor or a member of the investigational site study team (i.e., on the Delegation of Authority Log). Patient is institutionalized by administrative or court order.
• Patient is not willing or able to comply with the protocol requirements.

Eligibility last updated 10/20/21. Questions regarding updates should be directed to the study team contact.