Clinical trial NCT06306001: Intravenous Methylene Blue for Treating Refractory Neonatal Septic Shock
Official title: Intravenous Methylene Blue for Treating Fluid-refractory, Catecholamine-resistant, Neonatal Septic Shock: a Randomized, Placebo-controlled, Superiority Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Neonatal Sepsis
Shock, Septic
Keywords: Methylene blue
Neonate
Septic shock
Clinical trial
Lead sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh
Sponsor class: OTHER
First posted: 2024-03-12
Enrollment: 130
Sex: ALL
Minimum age (years): 0
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects will be randomly allocated to an intervention arm and a placebo arm. The 2 arms of the trial will run concurrently.
Primary purpose: TREATMENT

Brief summary: Preterm infants (born at less than 37 weeks of pregnancy) sometimes develop a serious blood infection leading to low blood pressure, which does not respond to saline or to the standard medicines for increasing blood pressure, such as dopamine and epinephrine. The goal of this research study is to compare the effect of giving an injectable medicine called Methylene blue (MB) versus not giving MB to such preterm infants who are unresponsive to standard treatment. The main questions that this study aims to answer is:

1. Whether MB treatment reduces death to any cause as compared to no MB treatment.
2. Whether treatment with MB reduces the time to achieve normal blood pressure
3. Whether treatment with MB reduces the time to stoppage of all blood pressure medications, steroids and normal saline.
4. Whether treatment with MB improves heart function as measured by echocardiography at 24 and 48 hours.

Detailed description: Preterm infants with definite or probable sepsis and fluid-refractory, catecholamine-resistant septic shock will be eligible for enrolment if they have no contraindication to receive MB. After obtaining parental consent, they will be stratified as per the first-line catecholamine used and randomly allocated to receive MB (bolus followed by infusion) or no MB for 24 hours. They will be observed for all-cause mortality (primary outcome), cause-specific mortality, time to achieve hemodynamic stability and adverse effects (secondary outcomes) over a 7-day period, all-cause mortality and cause-specific mortality hospital stay and duration of hospital stay.

The main questions it aims to answer are

1. To determine whether treatment with intravenous MB therapy reduces all-cause mortality when compared to no MB treatment, among preterm neonates with catecholamine-resistant septic shock
2. To compare the time to achieve therapeutic endpoints among preterm neonates with catecholamine-resistant septic shock treated with intravenous MB versus no MB
3. To compare time to stoppage of all inotrope/vasopressor treatment among preterm neonates with catecholamine-resistant septic shock treated with intravenous MB versus no MB
4. To compare echocardiographic parameters (at 24 hours after randomization) among preterm neonates with catecholamine-resistant septic shock treated with intravenous MB versus no MB

Eligibility criteria: Screening Criteria: preterm infants (\<37 weeks, \<28 days) clinically diagnosed to have septic shock will be screened for inclusion Inclusion criteria: Subjects must fulfill all the following

1. Definite/probable sepsis :Clinical syndrome of sepsis for which bedside neonatologist starts intravenous antibiotics AND either a positive culture of otherwise sterile body fluid OR presence of any 2 or more of the following five markers of sepsis: (a) C-reactive protein \>10 mg/dL; (b) procalcitonin as per age-appropriate cut-off (c) total leukocyte count and absolute neutrophilic count beyond acceptable range (d) chest X-ray adjudged as pneumonia by two independent Neonatologists.
2. Shock: adapted from the definition given by Davis et al 2017

   1. Either SBP \< age and gestation appropriate cut-off OR
   2. Presence of any 2 of the following 6 parameters i. HR \>205/min ii. Central pulses either week OR bounding iii. CRT \>3 sec OR flash refill (\<1 sec) iv. skin mottled/cool OR flushed v. urine output \<0.5 ml/kg/h in the preceding 6 hours vi. DBP \< age and gestation appropriate cut-off
3. Fluid and catecholamine-resistant shock: received fluid boluses up to a maximum of 40 ml/kg followed by catecholamine infusion titrated up to the maximum dose. The catecholamine infusion could be either dopamine (maximum dose 20 µg/kg/min) or epinephrine (maximum dose 0.4 µg/kg/min) or norepinephrine (maximum dose 0.4 µg/kg/min).

Exclusion Criteria:

excluded if ≥1 criterion positive:

1. G6PD deficient or family history of G6PD deficiency
2. Potentially lethal malformation
3. Congenital heart disease
4. Severe acute kidney injury
5. Family history of allergy to methylene blue or food dyes

Primary outcomes:
measure: All-cause mortality within 7 days after randomization
timeFrame: 7 days
Secondary outcomes:
measure: Time taken to achieve therapeutic end-points within 7 days after randomization
timeFrame: 7 days
measure: Time taken to stop all inotrope/vasopressor treatment within 7 days after randomisation
timeFrame: 7 days
measure: Echocardiographic fractional shortening at 24 hour after randomization
timeFrame: 24 hour
measure: Left ventricular end-diastolic diameter (LVEDD) by echocardiography at 24 hour after randomization
timeFrame: 24 hour
measure: Left ventricular end-systolic diameter (LVESD) by echocardiography at 24 hour after randomization
timeFrame: 24 hour
measure: Aortic diameter by echocardiography at 24 hour after randomization
timeFrame: 24 hour
measure: Velocity time integral (LVI) by echocardiography at 24 hours after randomization
timeFrame: 24 hour
measure: Echocardiographic fractional shortening at 48 hour after randomization
timeFrame: 48 hour
measure: Left ventricular end-diastolic diameter (LVEDD) on echocardiography at 48 hour after randomization
timeFrame: 48 hour
measure: Left ventricular end-systolic diameter (LVESD) by echocardiography at 48 hour after randomization
timeFrame: 48 hour
measure: Aortic diameter by echocardiography at 48 hour after randomization
timeFrame: 48 hour
measure: Velocity time integral (LVI) by echocardiography at 48 hours after randomization
timeFrame: 48 hour
measure: Time taken to stop vasopressor treatment
timeFrame: 100 days
measure: Mortality during hospital stay
timeFrame: 100 days
measure: Serious adverse effects
timeFrame: 100 days
measure: Septic shock-related mortality
timeFrame: 7 days
Other outcomes:
Locations:
city: Chandigarh
country: India
facility: Post Graduate Institute of Medical Education and Research (PGIMER)
Study officials:
affiliation: Post Graduate Institute of Medical Education and Research, Chandigarh
name: Sourabh Dutta, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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