Trial Outcomes & Findings for Steroid Use in Pediatric Fluid and Vasoactive Infusion Dependent Shock - Pilot Study (NCT NCT02044159)

NCT ID: NCT02044159

Last Updated: 2019-03-26

Results Overview

The total number of participants recruited over the recruitment period to both arms (this was a feasibility outcome that was analyzed for the full cohort and, as stated a priori in the study protocol was not compared between study arms). Our goal is to recruit 72 patients over one year . However, we will consider patient accrual rate to be adequate if we recruit 60 patients from seven sites within this time period.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 57 participants
• Primary outcome timeframe: 1 year
• Results posted on: 2019-03-26

Participant Flow

Participant milestones

Measure	Hydrocortisone Patients randomized to the hydrocortisone arm will receive a 2 mg/kg hydrocortisone IV bolus on enrolment followed by 1 mg/kg of hydrocortisone IV q6h until the patient has not had an escalation in therapy for at least 12 hours. If the patient meets these criteria their hydrocortisone will be weaned to 1 mg/kg every 8 hours which will be continued until they are off all vasoactive infusions for 12 hours. If following the initial hydrocortisone wean, the patient requires fluid boluses and/or an increase in their vasoactive infusion(s), their hydrocortisone will be increased back to 1 mg/kg of hydrocortisone IV q6h until they meet stability criteria again. Duration of treatment will range from a minimum of 20 hours to a maximum of 7 days of study drug. Hydrocortisone: Hydrocortisone will be made up as a 10 mg/ml solution so the volume of added fluid will be very small (2 to 10 mls even for the initial dose of 2 mg/kg).	Placebo Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
Overall Study STARTED	27	30
Overall Study COMPLETED	23	26
Overall Study NOT COMPLETED	4	4

Reasons for withdrawal

Measure	Hydrocortisone Patients randomized to the hydrocortisone arm will receive a 2 mg/kg hydrocortisone IV bolus on enrolment followed by 1 mg/kg of hydrocortisone IV q6h until the patient has not had an escalation in therapy for at least 12 hours. If the patient meets these criteria their hydrocortisone will be weaned to 1 mg/kg every 8 hours which will be continued until they are off all vasoactive infusions for 12 hours. If following the initial hydrocortisone wean, the patient requires fluid boluses and/or an increase in their vasoactive infusion(s), their hydrocortisone will be increased back to 1 mg/kg of hydrocortisone IV q6h until they meet stability criteria again. Duration of treatment will range from a minimum of 20 hours to a maximum of 7 days of study drug. Hydrocortisone: Hydrocortisone will be made up as a 10 mg/ml solution so the volume of added fluid will be very small (2 to 10 mls even for the initial dose of 2 mg/kg).	Placebo Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
Overall Study Consent declined (deferred consent)	2	4
Overall Study No longer eligible, drug not given	1	0
Overall Study Nurse declined to give study drug	1	0

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	Hydrocortisone n=23 Participants Patients randomized to the hydrocortisone arm will receive a 2 mg/kg hydrocortisone IV bolus on enrolment followed by 1 mg/kg of hydrocortisone IV q6h until the patient has not had an escalation in therapy for at least 12 hours. If the patient meets these criteria their hydrocortisone will be weaned to 1 mg/kg every 8 hours which will be continued until they are off all vasoactive infusions for 12 hours. If following the initial hydrocortisone wean, the patient requires fluid boluses and/or an increase in their vasoactive infusion(s), their hydrocortisone will be increased back to 1 mg/kg of hydrocortisone IV q6h until they meet stability criteria again. Duration of treatment will range from a minimum of 20 hours to a maximum of 7 days of study drug. Hydrocortisone: Hydrocortisone will be made up as a 10 mg/ml solution so the volume of added fluid will be very small (2 to 10 mls even for the initial dose of 2 mg/kg).	Placebo n=26 Participants Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).	Total n=49 Participants Total of all reporting groups
Age, Continuous	90.0 Months n=23 Participants	108.0 Months n=26 Participants	92.0 Months n=49 Participants
Sex: Female, Male Female	11 Participants n=23 Participants	13 Participants n=26 Participants	24 Participants n=49 Participants
Sex: Female, Male Male	12 Participants n=23 Participants	13 Participants n=26 Participants	25 Participants n=49 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.

PRIMARY outcome

Timeframe: 1 year

Population: This feasibility objective, as stated a priori in the protocol, was analyzed for the full study cohort and was not compared between arms. The primary objective was the patient accrual rate over one year (percentage of for the target sample size for the full cohort that was achieved).

The total number of participants recruited over the recruitment period to both arms (this was a feasibility outcome that was analyzed for the full cohort and, as stated a priori in the study protocol was not compared between study arms). Our goal is to recruit 72 patients over one year . However, we will consider patient accrual rate to be adequate if we recruit 60 patients from seven sites within this time period.

Outcome measures

Measure	Full Cohort n=57 Participants Feasibility outcomes were analyzed for the full cohort, and not compared between groups	Placebo Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
Patient Accrual Rate Over One Year (% of Target Sample Size Achieved)	82 percentage of target sample size	—

SECONDARY outcome

Timeframe: 8 hours from starting vasoactive medication

Population: This feasibility objective, as stated a priori in the protocol, was analyzed for the full study cohort and was not compared between arms. Objective 1a was to determine the time to administration of the first dose of study drug for the full cohort.

This objective is a measure of protocol adherence. The goal is to have patients randomized within 6 hours, and study drug administration completed within 8 hours of starting a vasoactive medication. We will consider adherence to our protocol to be adequate if secondary outcomes 1a to 1c are met in 80% of enrolled patients.

Outcome measures

Measure	Full Cohort n=49 Participants Feasibility outcomes were analyzed for the full cohort, and not compared between groups	Placebo Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
1a. Time to Administration of the First Dose of Study Drug	3.8 hours Standard Deviation 2.6	—

SECONDARY outcome

Timeframe: 7 days

Population: The percentage of study drug doses administered correctly was calculated for the full cohort.This feasibility objective was analyzed for the full cohort, and as stated a prior in our protocol, was not compared between study arms.

This objective is a measure of protocol adherence. The goal is weaning of study drug to q8h within 12 hours of no escalation of therapy. We will consider adherence to our protocol to be adequate if secondary outcomes 1a to 1c are met in 80% of enrolled patients.

Outcome measures

Measure	Full Cohort n=49 Participants Feasibility outcomes were analyzed for the full cohort, and not compared between groups	Placebo Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
1b. Weaning of Study Drug to q8h When Patient is Hemodynamically Stable	97.6 % of doses administered correctly	—

SECONDARY outcome

Timeframe: 7 days

Population: The percentage of study drug doses that were administered correctly for the full cohort.This feasibility objective, as stated a priori in the protocol, was analyzed for the full study cohort and was not compared between arms.

This objective is a measure of protocol adherence. The goal is to discontinue study drug within 12 to 18 hours of vasoactive medications being stopped. We will consider adherence to the protocol adequate if secondary outcomes 1a to 1c are met in 80% of enrolled patients.

Outcome measures

Measure	Full Cohort n=49 Participants Feasibility outcomes were analyzed for the full cohort, and not compared between groups	Placebo Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
1c. Discontinuation of Study Drug When Off All Vasoactive Medications	97.6 % of doses administered correctly	—

SECONDARY outcome

Timeframe: 7 days

Population: The total number (and %) of patients in the full cohort who were administered open-label steroids by the treating physician.This feasibility objective, as stated a priori in the protocol, was not compared or reported separately by study arm.

We will consider the number of patients started on open label steroids by the treating physician to be acceptable if it occurs in less than 10% of patients. We will also collect information on the clinical parameters of patients when open label steroids are given.

Outcome measures

Measure	Full Cohort n=49 Participants Feasibility outcomes were analyzed for the full cohort, and not compared between groups	Placebo Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
Number of Patients Started on Open Label Steroids by the Treating Physician	6 Participants	—

SECONDARY outcome

Timeframe: Daily during hospital admission (up to 28 days)

The time to discontinuation of vasoactive agents will be used to better estimate the sample size for the full study.

Outcome measures

Measure	Full Cohort n=23 Participants Feasibility outcomes were analyzed for the full cohort, and not compared between groups	Placebo n=26 Participants Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
Time to Discontinuation of Vasoactive Infusions	38.2 hours Interval 13.2 to 71.3	33.1 hours Interval 19.4 to 59.1

SECONDARY outcome

Timeframe: Daily during hospital admission (up to 28 days)

Population: The number of participants with incidence of adverse events and mortality rate in the full cohort in order to provide a better baseline estimate of these outcomes in our study population.

The specific adverse events that will be measured include: severe bleeding, secondary infections and the use of insulin infusions. The incidence of adverse events and mortality rate was measured in aggregate (i.e. the whole cohort) in order to provide a better baseline estimate of these outcomes in our study population.

Outcome measures

Measure	Full Cohort n=49 Participants Feasibility outcomes were analyzed for the full cohort, and not compared between groups	Placebo Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
Number of Participants With Incidence of Adverse Events and Mortality in the Full Cohort	24 Participants	—

SECONDARY outcome

Timeframe: End of the study recruitment phase (up to 1.5 years)

Population: The total number of patients in the full cohort for whom a study blod sample was collected, received and analyzed. This feasibility outcome, as stated a priori in the study protocol, was analyzed for the full cohort and was not compared between arms.

A total of 3 ml of blood in a red top tube will be collected within 24 hours of hospital admission. Patients with access for blood sampling and for whom consent has been obtained will have blood samples collected. The samples will be separated at each centre, stored until the end of the recruitment period, and then shipped to the principal investigators's centre as per the specific test requirements. The free cortisol and stratification biomarker samples will be batched and then shipped to Cincinnati for analysis at the end of the study. The number of samples collected, and the number of samples successfully received and analyzed at the principal investigator's site and at the Cincinnati lab will be determined at the end of the recruitment phase.

Outcome measures

Measure	Full Cohort n=49 Participants Feasibility outcomes were analyzed for the full cohort, and not compared between groups	Placebo Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
Percentage of Patients for Whom Blood Samples Are Sent, and Successfully Received and Analyzed in Their Respective Labs	44 Participants	—

Adverse Events

Hydrocortisone

Serious events: 0 serious events

Other events: 12 other events

Deaths: 1 deaths

Placebo

Serious events: 0 serious events

Other events: 8 other events

Deaths: 3 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Hydrocortisone n=23 participants at risk Patients randomized to the hydrocortisone arm will receive a 2 mg/kg hydrocortisone IV bolus on enrolment followed by 1 mg/kg of hydrocortisone IV q6h until the patient has not had an escalation in therapy for at least 12 hours. If the patient meets these criteria their hydrocortisone will be weaned to 1 mg/kg every 8 hours which will be continued until they are off all vasoactive infusions for 12 hours. If following the initial hydrocortisone wean, the patient requires fluid boluses and/or an increase in their vasoactive infusion(s), their hydrocortisone will be increased back to 1 mg/kg of hydrocortisone IV q6h until they meet stability criteria again. Duration of treatment will range from a minimum of 20 hours to a maximum of 7 days of study drug. Hydrocortisone: Hydrocortisone will be made up as a 10 mg/ml solution so the volume of added fluid will be very small (2 to 10 mls even for the initial dose of 2 mg/kg).	Placebo n=26 participants at risk Patients randomized to the placebo arm will receive a placebo solution consisting of normal saline equivalent in volume to the appropriate dose of hydrocortisone. Hydrocortisone and placebo will be identical in appearance, volume and smell as hydrocortisone is made up in normal saline and dissolves completely with no visible precipitate. The dosing regimen will be identical to the hydrocortisone arm. Placebo: The placebo (normal saline) will be identical in appearance, volume and smell to the active study drug (hydrocortisone).
Gastrointestinal disorders Gastrointestinal bleeding	8.7% 2/23 • Number of events 2	7.7% 2/26 • Number of events 2
Infections and infestations New infection	26.1% 6/23 • Number of events 6	19.2% 5/26 • Number of events 5
Endocrine disorders Insulin infusion	17.4% 4/23 • Number of events 4	3.8% 1/26 • Number of events 1

Additional Information

Katie O'Hearn, Research Coordinator

Children's Hospital of Eastern Ontario

Phone: 613-737-7600

Email: kohearn@cheo.on.ca

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place