Safety and Efficacy of Mupirocin in Eradicating Colonization With S. Aureus in Critically Ill Infants

Study Overview
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Brief Summary
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The objective of this trial is 1) to evaluate the safety and clinical acceptability of a 5-day course of mupirocin applied every 8 hours (± 2 hours) to the nares, umbilical and perianal areas of infants residing in the ICU. 2) to examine the efficacy of mupirocin in eradicating SA colonization of infants in the ICU, defined as the absence of SA in cultures of the nares, umbilical, and perianal areas on day 8 (± 2) (primary decolonization) 3) to examine the efficacy of mupirocin in achieving persistent eradication of SA colonization among infants residing in the ICU,defined as the absence of SA in cultures of the nares, umbilical, and perianal areas. Duration is 36 months. Enrolled infants will continue to receive medical care as they otherwise would if they were not enrolled in the trial. The study will be powered with a primary endpoint with 126 participants. Enrollment may continue to 500 participants to power secondary and exploratory endpoints and assist design subsequent studies.

Detailed Description
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This is a Phase 2, open label, multi-center, randomized trial to determine the safety and efficacy of mupirocin in eradicating colonization with Staphylococcus aureus (SA) and preventing the occurrence of invasive and other clinically significant SA infections among critically ill infants in the ICU. Infants hospitalized in an ICU at any one of the 6 participating centers with a positive nasal culture for SA will be eligible to enroll. Infants will be stratified by birth gestational age (< 28 weeks and <8 weeks of post-natal life or > /= 28 weeks / < 28 weeks and > /=8 weeks of post-natal life) and colonizing strain methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-sensitive Staphylococcus aureus (MSSA) and then randomized 1:1 to receive a 5 day course of mupirocin applied to the nares, umbilicus and perianal (NUP) areas every 8 hours (± 2 hours) vs. no treatment. (Stratification by birth gestational age is performed to minimize bias that could result from a higher risk for developing infection due to prematurity or prolonged length of stay due to prematurity.) The primary objectives of this study are to 1) evaluate the safety and clinical acceptability of a 5-day course of mupirocin applied every 8 hours (± 2 hours) to the nares, umbilical and perianal areas of infants residing in the ICU 2) to examine the efficacy of mupirocin in eradicating SA colonization of infants in the ICU, defined as the absence of SA in cultures of the nares, umbilical, and perianal areas on day 8 (± 2) (primary decolonization) 3) to examine the efficacy of mupirocin in achieving persistent eradication of SA colonization among infants residing in the ICU, defined as the absence of SA in cultures of the nares, umbilical, and perianal areas on days 8 (±2) and 22 (±2) (persistent decolonization). The secondary objectives of this study are to 1) To examine the efficacy of mupirocin in preventing clinical SA infection during days 1-22 or until discharge, whichever occurs first, among SA colonized infants who are residing in the ICU 2) To compare time until SA decolonization between the mupirocin and placebo groups: Time from Day 1 until the first NUP collection with no SA is detected in the nares, umbilical, and perianal areas 3) To examine whether mupirocin affects the frequency of non-SA clinical infections by comparing the frequency of these infections in the treatment and control groups during the 85 day observation period 4) To examine whether mupirocin affects the frequency of severe (stage II-III) necrotizing enterocolitis by comparing the frequency of occurrence in the treatment and control groups during the 85 day observation period. Each participant will be enrolled for up to 12 weeks (Day 85) or until the time of discharge from the hospital, death or withdrawal from further participation, whichever occurs first. It is anticipated that it will take at least 2 years to enroll all participants. Study duration is 36 months. Enrolled infants will continue to receive medical care as they otherwise would if they were not enrolled in the trial. The study will be powered toward the primary endpoint with 126 participants. Enrollment may continue up to a maximum of 500 participants to inform the secondary and exploratory endpoints and to help design any subsequent study.

Official Title
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Safety and Efficacy of Intranasal and Topical Mupirocin in Eradicating Colonization With Staphylococcus Aureus (SA) in Critically Ill Infants - a Phase 2, Multi-Center, Open Label, Randomized Trial

Conditions
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Staphylococcal Infection

Intervention / Treatment
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* Drug: Mupirocin calcium
* Drug: Mupirocin calcium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Currently admitted to a NICU or ICU at a participating site 2. Chronological age less than 24 months 3. Evidence of colonization with SA (MRSA or MSSA) based on a positive nasal surveillance culture. Randomization must occur within 7 days (168 hours) of when the site's laboratory reports the first SA positive nasal surveillance swab 4. The attending neonatologist/ intensivist anticipates that the infant will remain in the ICU for a minimum of 14 days after enrollment 5. Parent or legal guardian agrees that the infant will not participate in a research trial involving the administration of an investigational drug for 14 days following enrollment Exclusion Criteria: 1. Receipt of an investigational drug as part of a research trial within the past 14 days 2. Previously enrolled and participated in this trial 3. Has an active or previous SA infection 4. Currently receiving topical or intranasal mupirocin 5. Has a rash in an area to which mupirocin will be directly applied 6. Has any of the following congenital abnormalities: --A congenital skin disorder (i.e. - epidermolysis bullosa, icthyosis) --An opened neural tube defect --Confirmed or suspected choanal atresia --Any of the following abdominal wall defects: wound dehiscence, gastroschisis, open abdominal wound (small abdominal wall defects such as ostomy sites or peritoneal drain sites are not exclusionary) 7. Is nasally intubated 8. Known hypersensitivity to the trial product or its constituents 9. Known or suspected immune deficiency. Infants born to HIV-seropositive mothers with the following risk factors for intrapartum transmission will not be eligible to participate: --Mother's most recent viral load within the past 3 months was > 1,000 copies/ml or --Mother's viral load is not known or has has not been measured in the past 3 months. 10. Any other condition(s) that in the opinion of the investigator would jeopardize the safety or rights of a participant or would render the participant unable to comply with the protocol

Ages Eligible for Study
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Maximum Age: 24 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Subjects receive a 5-day course of mupirocin calcium ointment 2 % 20 mg intranasally applied every 8 hours and a topical skin application (umbilical and perianal area) of mupirocin calcium cream 2% 20 mg applied every 8 hours for a total of 15 doses | Drug: Mupirocin calcium<br>* Mupirocin calcium cream 2% applied topically to umbilicus and perianal area every 8 hours for 5 days, for a total of 15 applications<br>Drug: Mupirocin calcium<br>* Mupirocin calcium ointment 2% will be applied intranasally every 8 hours for 5 days, for a total of 15 applications<br>|
| No Intervention: Group 2<br>No treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Solicited Adverse Events (AEs) During Days 1-7 | Participants were evaluated for solicited adverse events while in the NICU/ICU on days 1-7. Participants were counted if they experienced the symptom at any severity during the reporting period. Although participants received only 5 days of mupirocin, solicited events were collected through day 7. | Days 1 through 7 | 
| Number of Participants With Moderate and Severe Unsolicited Adverse Events; During Days 1-7 | Participants were evaluated for moderate and severe unsolicited adverse events (that were not otherwise considered pre-defined trial endpoints) while in the NICU/ICU on days 1-7. Although participants received 5 days of mupirocin, unsolicited events were collected until day 7. Moderate events were defined as those that may cause some interference with functioning and daily activities. Severe events were defined as those that interrupt the participant's usual daily activities and may require systemic drug therapy or other treatment. Severe events were usually incapacitating. | Days 1 through 7 | 
| Number of Participants With Serious Adverse Events (SAEs) During Days 1-7 | Participants were evaluated for Serious Adverse Events (SAEs) while in the NICU/ICU on days 1-7. Although participants received only 5 days of mupirocin, SAEs were collected through day 7. An adverse event or suspected adverse reaction was considered serious if, in the view of either the investigator or sponsor, it resulted in any of the following outcomes: death; a life-threatening adverse event (an event that places the participant at immediate risk of death; it doesn't include an adverse event, had it occurred in a more severe form, might have caused death); inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or any other event that when based upon appropriate medical judgement may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed in this definition. | Days 1 through 7 | 
| Primary Decolonization Efficacy- Number of Participants in the Treatment and Control Groups Who Have no Detectable S. Aureus (SA) on Direct Nasal, Umbilical, and Perianal (NUP) Cultures Obtained on Day 8. | Colonization was defined as the presence of SA identified by NUP culture without signs of illness or infection. On day 8, participants were swabbed in each of three areas: nasal, umbilical, and perianal. These swabs were cultured by direct plating. If SA did not grow on any of these cultures the infant was considered to be decolonized. If SA grew on any one of these cultures the infant was considered to be colonized with SA. | Day 8 | 
| Persistent Decolonization Efficacy- Number of Participants in the Treatment and Control Groups Who Have no Detectable S. Aureus (SA) on Direct Nasal, Umbilical, and Perianal (NUP) Cultures on Days 8 and 22. | Participants were admitted into the study based on being colonized with SA. Participants who were decolonized both on day 8 and day 22, as determined by NUP cultures were considered to have persistent decolonization. Colonization was defined as the presence of SA identified by NUP culture without signs of illness or infection. NUP swabs were collected on day 8 and on day 22 and cultured by direct plating. If the cultures were negative for SA at both day 8 and day 22 the participant was considered to have persistent decolonization. Colonization with SA was a prerequisite for enrollment, because of this there was no baseline measure. | Day 8 and Day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Risk of Occurrence of Non-SA Clinical Infection in the Treatment Compared to Control Group in the Intent To Treat Cohort | Relative risk of occurrence of non-SA clinical infection in the treatment compared to the control group using the intent to treat (ITT) cohort for analysis. The time periods in the table correspond to the study days having scheduled collection of nasal, umbilical, and perianal (NUP) cultures. At risk participants were eligible for the non-SA clinical infection to occur at the start of the interval, were still on study and had not yet had a non-SA clinical infection but were still being watched for the event. Non-SA clinical infection was the development of a non-SA clinical infection due to an identifiable organism as evidenced by culture of an organism other than SA from a normally sterile body site or an infant who met the clinical diagnosis of localized infection as defined in the protocol. Censored participants were at risk for some of the interval, did not have a non-SA clinical infection but were removed from eligibility for the event at some point after the interval started. | Day 1 through 85 | 
| Relative Risk of Occurrence of Non-SA Clinical Infection in the Treatment Compared to Control Group in the According to Protocol Cohort. | Relative risk of occurrence of non-SA clinical infection in the treatment compared to control groups using the according to protocol (ATP) cohort. The time periods in the table correspond to the study days having scheduled collection of nasal, umbilical, and perianal (NUP) cultures. At risk participants were eligible for the non-SA clinical infection to occur at the start of the interval, were still on study and had not yet had a non-SA clinical infection but were still being watched for the event. Non-SA clinical infection was the development of a non-SA clinical infection due to an identifiable organism as evidenced by culture of an organism other than SA from a normally sterile body site or an infant who met the clinical diagnosis of localized infection as defined in the protocol. Censored participants were at risk for some of the interval, did not have a non-SA clinical infection but were removed from eligibility for the event at some point after the interval started. | Day 1 through 85 | 
| Median Time to Occurrence of Severe (Stage II-III) Necrotizing Enterocolitis (NEC) in the Treatment Compared to Control Group. | Median time to occurrence of severe (stage II-III) NEC in the treatment compared to control group as estimated using Kaplan-Meier estimates of the survival curves. | Day 1 through 85 | 
| Protective Efficacy of Clinical S. Aureus (SA) Infection in the Treatment Compared to the Control Group During Days 1-22 or Until Discharge, Whichever Occurs First, Using the Intent to Treat Cohort. | Protective efficacy of clinical SA infection in the treatment compared to the control group during days 1-22 or until discharge, whichever occurs first using the intent to treat (ITT) cohort. The time periods in the table correspond to the study days having scheduled collection of nasal, umbilical, and perianal (NUP) cultures. At risk participants were eligible for the SA clinical infection to occur at the start of the interval, were still on study and had not yet had a SA clinical infection but were still being watched for the event. SA clinical infection was the development of a SA clinical infection due to an identifiable organism as evidenced by culture of an organism from a normally sterile body site or an infant who met the clinical diagnosis of localized infection as defined in the protocol. Censored participants were at risk for some of the interval, did not have a SA clinical infection but were removed from eligibility for the event at some point after the interval started. | Day 1 through 22 | 
| Protective Efficacy of Clinical SA Infection in the Treatment Compared to the Control Group During Days 1-22 or Until Discharge, Whichever Occurs First, Using the According to Protocol (ATP) Cohort. | Protective efficacy of clinical SA infection in the treatment compared to the control group during days 1-22 or until discharge, whichever occurs first using the ATP cohort. The time periods in the table correspond to the study days having scheduled collection of nasal, umbilical, and perianal (NUP) cultures. At risk participants were eligible for the SA clinical infection to occur at the start of the interval, were still on study and had not yet had a SA clinical infection but were still being watched for the event. SA clinical infection was the development of a SA clinical infection due to an identifiable organism as evidenced by culture of an organism from a normally sterile body site or an infant who met the clinical diagnosis of localized infection as defined in the protocol. Censored participants were at risk for some of the interval, did not have a SA clinical infection but were removed from eligibility for the event at some point after the interval started. | Day 1 through 22 | 
| Median Time to Occurrence of Non-S. Aureus (SA) Clinical Infection in the Treatment Compared to Control Group | Median time to occurrence of non-SA clinical infection in the treatment compared to control group as estimated using Kaplan-Meier estimates of the survival curves. | Day 1 through 85 | 
| Relative Risk of Severe (Stage II-III) Necrotizing Enterocolitis (NEC) in the Treatment Compared to Control Group | The association between mupirocin treatment and severe (stage II-III) NEC on or before Day 85 was to be assessed via Cox Proportional Hazards Model. | Day 1 through 85 | 
| Time Until Decolonization: Count of Participants From Day 1 Until the First NUP Collection With no S. Aureus (SA) Detected in the Nares, Umbilical, and Perianal Areas Using the Modified Intent to Treat Day 8 Cohort (mITT-8). | Time until decolonization: Count of participants from Day 1 until the first NUP collection with no SA is detected in the nares, umbilical, and perianal areas using the modified intent to treat (mITT-8) cohort. The time periods in the table correspond to the study days having collection of nasal, umbilical, and perianal (NUP) cultures. At risk participants were eligible for the SA decolonization to occur at the start of the interval, were still on study and had not yet had SA decolonization but were still being watched for the event. SA decolonization was the absence of SA detected from the NUP cultures through direct plating. Censored participants were at risk for some of the interval, did not have SA decolonization but were removed from eligibility for the event at some point after the interval started. | Day 1 through 85 | 
| Time Until Decolonization: Count of Participants From Day 1 Until the First NUP Collection With no SA is Detected in the Nares, Umbilical, and Perianal Areas Using the According to Protocol Day 8 (ATP-8) Cohort. | Time until decolonization: Count of participants from Day 1 until the first NUP collection with no SA is detected in the nares, umbilical, and perianal areas using the according to protocol day 8 (ATP-8) cohort. The time periods in the table correspond to the study days having scheduled collection of nasal, umbilical, and perianal (NUP) cultures. At risk participants were eligible for the SA decolonization to occur at the start of the interval, were still on study and had not yet had SA decolonization but were still being watched for the event. SA decolonization was the absence of SA detected from the NUP cultures through direct plating. Censored participants were at risk for some of the interval, did not have SA decolonization but were removed from eligibility for the event at some point after the interval started. | Day 1 through 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antibacterial agent, children, colonisation, critically ill, infants, mupirocin, prevention, Staphylococcus aureus