Primary:- To evaluate the effect of suvratoxumab on reducing the incidence of nosocomial all-cause pneumonia.Secondary:- To evaluate the safety of a single IV dose of suvratoxumab.- To evaluate the effect of suvratoxumab on reducing the incidence of…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Incidence of nosocomial all-cause pneumonia through 30 days post dose.
Secondary outcome
- Treatment emergent adverse events (TEAE) and clinical laboratory assessments
through 30 days post dose, and treatment emergent serious adverse events
(TESAE) and TEAE of special interest (TEAESI) through 90 days, and for a subset
of subjects through 180 days post dose.
- Incidence of nosocomial all-cause pneumonia or death through 30 days post
dose.
- Incidence of nosocomial S. aureus pneumonia through 30 days post dose.
- Incidence of nosocomial pneumonia caused by S. aureus through 90 days post
dose.
- Magnitude of healthcare utilization (e.g., duration of mechanical
ventilation, duration of ICU stay, duration of hospital stay, number of and
days of systemic antibiotic use) through 90 days post dose in all subjects and
in a subset of subjects through 180 days post dose.
- Suvratoxumab serum concentration and PK parameters through 30 days post dose,
and in a subset of subjects through 90 days post dose.
- Suvratoxumab ADA response in serum through 30 days post dose, and in a subset
of subjects through 90 days post dose.
Background summary
Bacterial pneumonia, especially an event occurring within the hospitalized or
intensive care unit (ICU) population, is a clinically significant and serious
disease that contributes significantly to morbidity and mortality. These
events constitute the second most common nosocomial infection and the leading
cause of death from nosocomial infection in critically ill patients in Europe
(Torres et a, 2017), in the United States (US; Spellberg and Talbot, 2010,
Elliot et al, 2018), and worldwide (de Carvalho Baptista et al, 2018). In the
European Union (EU), the mortality varies widely between European Countries
with rates between 1% and 48% (Peyrani et al, 2019). Staphylococcus aureus (S.
aureus) is a primary cause of nosocomial pneumonia. In both European and US
ICUs, investigators found that 20% to 22% of their mechanically ventilated ICU
patients developed pneumonia caused by S. aureus (Esperatti et al, 2010, Hurley
2018).
S. aureus pneumonia among mechanically ventilated ICU patients is associated
with significant healthcare-associated costs (Paling et al, 2017). In a study
conducted from 2002 to 2006, mean incremental costs of S. aureus pneumonia
compared to non-pneumonia controls was reported to be $101,660 (Restrepo et al,
2010). Similarly, an analysis of privately insured patients admitted to an ICU
between 2006 and 2012 suggests that S. aureus pneumonia was associated with a
mean excess or incremental cost of $100,000 compared to the intubated (control)
ICU patients (Kyaw et al, 2015).
There is limited data available for the incidence and prevalence of S. aureus
pneumonia occurring in each specific patient population subgroup (Gaensbauer
2017). Estimates indicate that S. aureus pneumonia occurs most frequently in
adults (83.2 to 84.3% of all cases in years 2012, 2009, 2006) followed by
neonates/infants (birth up to 1 year) (11.2 to 12.5% of reported cases) and
adolescents (12 years up to 17 years) (4.0 to 4.3% of all cases; HCUP 2017).
Older pediatric patients (especially adolescents) are at risk for developing S.
aureus pneumonia and ventilator associated pneumonia (VAP), which results in
experiencing head and neck trauma, such as traumatic brain injury (Hamele et
al, 2016).
During infection, S. aureus releases a number of toxins, and S. aureus alpha
toxin (AT) is a key virulence factor leading to immune evasion, tissue invasion
and necrosis (Wilke and Bubeck Wardenburg, 2010, Wu et al, 2019). The pivotal
role of AT in S. aureus pathogenesis is supported by animal models
(dermonecrosis, pneumonia, sepsis, endocarditis, and mastitis) (Bramley et al,
1989; Bayer et al, 1997; Bubeck Wardenburg et al, 2008; Kobayashi et al, 2011;
Powers et al, 2012) and by observational studies in humans in which the
presence of anti-AT antibodies during severe infections was associated with
improved outcome (Adhikari et al, 2012; Jacobsson et al, 2010; Ruotsalainen et
al, 2008, Wu et al, 2018). AT expression level by colonizing methicillin
susceptible S. aureus (MSSA) has been reported to be a marker for progression
to VAP, thereby implicating a role for AT in VAP.
Antibiotics are the only intervention available for treating S. aureus
diseases. Despite the introduction of new antibiotics against S. aureus,
emergence of resistance requires new approaches for combatting S. aureus
diseases. While prevention of healthcare-associated infections caused by S.
aureus is an important public health goal, no vaccines or passive immunization
therapies are commercially available (Argondizzo et al, 2021). Prevention
currently focuses on infection control practices and limited prophylactic use
of antibiotics (e.g., pre-surgery). Indeed, antimicrobial prophylaxis should
be limited to specific, well-accepted indications to avoid excess cost,
toxicity, and antimicrobial resistance (Enzler et al, 2011). In a recent
study, systemic antibiotics were determined to be ineffective in patients
colonized with S. aureus to reduce colonization burden and prevent S. aureus
VAP (Stulik et al. 2017). Topical decolonization regimens have been proposed
for S. aureus carriers based on anecdotal data, given that nasal carriage is a
risk factor for hospital-acquired infection (Muñoz et al, 2008; Bode et al,
2010, Hantisch et al, 2020). However, decolonization efforts have not been
consistently effective and are not universally implemented (Kluytmans et al,
1996; Perl et al, 2002; Kalmeijer et al, 2002, Kuraitis and Williams 2018).
Several antibiotic prophylactic treatment options are shown to be ineffective
in preventing S. aureus VAP, which underscores the urgent need for better
therapeutic alternatives for the prevention of S. aureus pneumonia (Burnham
2017; Stulik et al 2017).
Study objective
Primary:
- To evaluate the effect of suvratoxumab on reducing the incidence of
nosocomial all-cause pneumonia.
Secondary:
- To evaluate the safety of a single IV dose of suvratoxumab.
- To evaluate the effect of suvratoxumab on reducing the incidence of
nosocomial all-cause pneumonia or death.
- To evaluate the effect of suvratoxumab on reducing the incidence of
nosocomial S. aureus pneumonia.
- To evaluate the effect of suvratoxumab on reducing the incidence of long-term
nosocomial pneumonia caused by S. aureus.
- To measure the effect of suvratoxumab on the magnitude of healthcare
utilization.
- To evaluate the serum PK of suvratoxumab.
- To evaluate the serum ADA responses to suvratoxumab.
Study design
This is a Phase 3, randomized, double-blind, placebo-controlled study
evaluating the efficacy of a single IV dose of suvratoxumab (5000 mg) in
mechanically ventilated subjects in the ICU who are at high risk for S. aureus
infections and who are currently free of active S. aureus-related disease but
are colonized with S. aureus in the LRT. Approximately 564 subjects will be
enrolled and randomized at about 200 centers worldwide. Subjects in this study
will be adult (18 to 65 years of age) and adolescent subjects (12 to < 18 years
of age) in the ICU, who require mechanical ventilation for * 3 days and who are
colonized with S. aureus in the LRT, but currently free of active S.
aureus-related disease. Subjects will be randomly assigned in a 1:1 ratio
(282:282) to receive a single IV dose of suvratoxumab (5000 mg) or placebo.
Randomization will be stratified by whether or not subjects received systemic
anti-S. aureus systemic antibiotic treatment, and by geographic region.
Following investigational product administration on Day 0, subjects will be
followed through Day 90 (and for a subset of approximately 100 subjects for PK
and ADA through Day 90 and followed for safety through Day 180).
Intervention
Single-dose of 5000 mg suvratoxumab or placebo intravenously administered at D0
of V2.
Study burden and risks
Potential benefits from participating to the trial:
- Suvratoxumab may prevent development of pneumonia, but that is not certain.
- In this study the participant can also get a placebo. In case the participant
is getting a placebo no preventative treatment will be given (prevention
currently focuses on infection control practices, however, there are no
preventive treatments that prove to be effective).
- Research will help doctors to learn more about the study drug. This may help
others with a similar health problem in the future.
Potential disadvantages from participating to the trial:
- Possible side effects of suvratoxumab
- Possible discomfort from the measurements during the study
- Participant can lose additional time
- (additional) testing
- Appointment that the participant need to attend
Conclusion:
Antibiotics are the only intervention available for treating S. aureus
diseases. Despite the introduction of new antibiotics against S. aureus,
emergence of resistance requires new approaches for combatting S. aureus
diseases. While prevention of healthcare-associated infections caused by S.
aureus is an important public health goal, no vaccines or passive immunization
therapies are commercially available (Argondizzo et al, 2021). Prevention
currently focuses on infection control practices and limited prophylactic use
of antibiotics (e.g., pre-surgery). Indeed, antimicrobial prophylaxis should
be limited to specific, well-accepted indications to avoid excess cost,
toxicity, and antimicrobial resistance (Enzler et al, 2011). In a recent
study, systemic antibiotics were determined to be ineffective in patients
colonized with S. aureus to reduce colonization burden and prevent S. aureus
VAP (Stulik et al. 2017).
University Avenue, Building B 983
Los Gatos CA 95032-7637
US
University Avenue, Building B 983
Los Gatos CA 95032-7637
US
Listed location countries
Age
Inclusion criteria
1. Adult (18 [unless otherwise specified by local Country laws] to 65 years of
age) or Adolescent (12 to < 18 years of age [unless otherwise specified by
local Country laws]) at the time of screening.
2. Written informed consent and written informed assent and any locally
required authorization (e.g., Health Insurance Portability and Accountability
Act [HIPPA] in the United States [US], European Union [EU] Data Privacy
Directive in the EU) obtained from the subject/legally acceptable
representative (LAR) prior to performing any protocol-related procedures,
including screening evaluations.
3. Females of childbearing potential (inclusive of adolescents) who are
sexually active with a non-sterilized male partner must have evidence of not
being pregnant upon enrolment and have a negative pregnancy test prior to
administration of investigational product.
- Females of childbearing potential are defined as those who are not surgically
sterile (i.e., bilateral oophorectomy, or complete hysterectomy), premenarchal
or postmenopausal (defined as 12 months with no menses without an alternative
medical cause).
4. Tracheal or bronchial sample positive by polymerase chain reaction (PCR) for
S. aureus within 36 hours prior to randomization. Note: the 36-hour window
will be determined by the time of sample collection.
5. Currently intubated and on mechanical ventilation in the ICU.
6. Expected to remain intubated and mechanically ventilated for * 3 days based
on investigator estimate.
7. No diagnosis of new-onset pneumonia within 72 hours prior to randomization
(subjects with evidence of resolved pneumonia will be eligible).
Exclusion criteria
1. The study subject is moribund or unlikely to survive for a week post
randomization despite delivery of adequate antibiotics and supportive care
based on clinical judgement by the Principal Investigator (PI).
2. Acute confirmed or suspected active S. aureus disease at study enrolment and
investigational product dosing (colonization is acceptable as per inclusion
criterion #4).
3. Active pulmonary disease that would impair the ability to diagnose
pneumonia, such as active tuberculosis or fungal disease, obstructing lung
cancer, large empyema, cystic fibrosis, or acute respiratory distress syndrome
with lung "white out".
4. Receipt of anti- S. aureus systemic antibiotics for > 48 hours within 72
hours prior to randomization that are considered active against the S. aureus
strain with which the subject is colonized or anticipated ongoing receipt of
anti- S. aureus systemic antibiotics.
5. Acute Physiology and Chronic Health Evaluation (APACHE)-II score >= 25 (if
Glasgow Coma Scale [GCS] score is > 5) or >= 30 (if GCS score is <= 5), or SOFA
score >= 9 at time of randomization.
- Note: Vasopressors only used to improve cerebral perfusion pressure (e.g.,
subarachnoid hemorrhage) will not be entered in the calculation of the
cardiovascular component of the SOFA score.
6. Receipt of any investigational drug therapy within 30 days prior to
randomization.
7. Previous receipt of a mAb within 60 days prior to randomization.
8. Subjects with a CD4 count of < 200 due to advanced human immunodeficiency
virus (HIV) infection. Subjects with a history of HIV infection who have been
on highly active antiretroviral therapy and asymptomatic from HIV infection for
at least 6 months may be enrolled.
9. History of allergic disease or reactions likely to be exacerbated by any
component of the investigational product.
10. Not able to complete long-term follow-up for at least 90 days post dose
based on investigator judgment.
11. Pregnant female or nursing mother.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 5331885 |
| EudraCT | EUCTR2021-004979-14-NL |
| CCMO | NL81137.028.22 |