Severe Sepsis, Septic Shock
Conditions
Brief summary
The purpose of this study is to evaluate the pharmacokinetics of pioglitazone and to determine the effect on inflammatory biomarkers for pioglitazone in patients with severe sepsis and septic shock.
Detailed description
Severe sepsis is a major cause of morbidity and mortality among adults and children. Few clinical trials have demonstrated clinical benefit in sepsis. Severe sepsis is a systemic inflammatory syndrome in response to infection that is associated with acute organ dysfunction. The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARg) is involved in the regulation of the sepsis-induced inflammatory response. The central hypothesis is that pioglitazone reduces the inflammatory responses in children with severe sepsis and septic shock.
Interventions
Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Weight range between 30 to less than or equal to 90kg * Have a known or suspected infection and meet criteria for severe sepsis or septic shock as defined according to the International Pediatric Sepsis Consensus Conference guidelines
Exclusion criteria
* Are in a moribund state in which death is perceived as imminent * Have an advanced directive or do not resuscitate order to withhold life-sustaining * Have a history of cyanotic heart disease or congestive heart failure * Have a serum transaminase level (ALT) that exceeds about 2.5 times the upper limit of normal (\>112 unit/L) * Are or become pregnant * Are already on or have a history of taking pioglitazone or rosiglitazone * Have type 1 or 2 diabetes * Have total body weight below 30 kg or above 90 kg * Have a serious condition, in addition to sepsis, which in the opinion of the investigator would compromise the participant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Labs - Creatinine | Final day of study | Creatinine levels in blood from subject on the final day of enrollment |
| Safety Labs - Alanine Aminotransferase (ALT) | Final day of study | ALT levels in blood from subject on the final day of enrollment |
| Evaluate the Safety Profile of Pioglitazone in Patients With Severe Sepsis and Septic Shock as the Number of Hypoglycemic Events | Assessement over five days | The number of hypoglycemic events in pioglitazone vs standard care. Hypoglycemia was defined as blood glucose level that remains \<40mg/dl despite dextrose bolus treatment. |
| Safety Labs - Blood Urea Nitrogen (BUN) | Final day of study | BUN levels in blood from subject on the final day of enrollment |
| Pioglitazone Area Under Curve Estimates by Treatment Group and Route of Administration | five days | Pioglitazone concentration as the total area under curve divided by the number of days receiving the drug in subjects who took the drug by mouth versus by naso-gastric tube |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Pioglitazone Area Under the Curve on Changes in IL-6 | Evaluation of inflammatory biomarkers will be obtained prior to dosing for the first five days of the study | We examined the effect of pioglitazone Area under the curve on IL-6 in patients receiving pioglitazone only. (Control subjects did not receive pioglitazone). The pharmacokinetic endpoint was area under the curve (AUC) total/days of pioglitazone administration |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Hydrochloride Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days. | 8 |
| Normal Standard Care Routine normal standard care | 4 |
| Total | 12 |
Baseline characteristics
| Characteristic | Pioglitazone Hydrochloride | Total | Normal Standard Care |
|---|---|---|---|
| Age, Continuous | 13.8 years STANDARD_DEVIATION 3.5 | 16.083 years STANDARD_DEVIATION 6.721 | 20.8 years STANDARD_DEVIATION 9.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 12 Participants | 4 Participants |
| Region of Enrollment United States | 8 Participants | 12 Participants | 4 Participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 8 | 0 / 4 |
| other Total, other adverse events | 5 / 8 | 2 / 4 |
| serious Total, serious adverse events | 2 / 8 | 0 / 4 |
Outcome results
Primary
Evaluate the Safety Profile of Pioglitazone in Patients With Severe Sepsis and Septic Shock as the Number of Hypoglycemic Events
The number of hypoglycemic events in pioglitazone vs standard care. Hypoglycemia was defined as blood glucose level that remains \<40mg/dl despite dextrose bolus treatment.
Time frame: Assessement over five days
Population: Hypoglycemia episodes
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone Hydrochloride | Evaluate the Safety Profile of Pioglitazone in Patients With Severe Sepsis and Septic Shock as the Number of Hypoglycemic Events | 0 events |
| Normal Standard Care | Evaluate the Safety Profile of Pioglitazone in Patients With Severe Sepsis and Septic Shock as the Number of Hypoglycemic Events | 0 events |
p-value: 1Wilcoxon (Mann-Whitney)
Primary
Pioglitazone Area Under Curve Estimates by Treatment Group and Route of Administration
Pioglitazone concentration as the total area under curve divided by the number of days receiving the drug in subjects who took the drug by mouth versus by naso-gastric tube
Time frame: five days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone Hydrochloride | Pioglitazone Area Under Curve Estimates by Treatment Group and Route of Administration | 5363 ng*h/ml | Standard Deviation 2362 |
| Normal Standard Care | Pioglitazone Area Under Curve Estimates by Treatment Group and Route of Administration | 1052 ng*h/ml | Standard Deviation 942 |
p-value: 0.08t-test, 2 sided
Primary
Safety Labs - Alanine Aminotransferase (ALT)
ALT levels in blood from subject on the final day of enrollment
Time frame: Final day of study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pioglitazone Hydrochloride | Safety Labs - Alanine Aminotransferase (ALT) | 21.5 U/L |
| Normal Standard Care | Safety Labs - Alanine Aminotransferase (ALT) | 24.5 U/L |
p-value: 0.683Wilcoxon (Mann-Whitney)
Primary
Safety Labs - Blood Urea Nitrogen (BUN)
BUN levels in blood from subject on the final day of enrollment
Time frame: Final day of study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pioglitazone Hydrochloride | Safety Labs - Blood Urea Nitrogen (BUN) | 7.5 mg/dl |
| Normal Standard Care | Safety Labs - Blood Urea Nitrogen (BUN) | 10 mg/dl |
p-value: 1Wilcoxon (Mann-Whitney)
Primary
Safety Labs - Creatinine
Creatinine levels in blood from subject on the final day of enrollment
Time frame: Final day of study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pioglitazone Hydrochloride | Safety Labs - Creatinine | 0.72 mg/dl |
| Normal Standard Care | Safety Labs - Creatinine | 0.415 mg/dl |
p-value: 0.154Wilcoxon (Mann-Whitney)
Secondary
Effect of Pioglitazone Area Under the Curve on Changes in IL-6
We examined the effect of pioglitazone Area under the curve on IL-6 in patients receiving pioglitazone only. (Control subjects did not receive pioglitazone). The pharmacokinetic endpoint was area under the curve (AUC) total/days of pioglitazone administration
Time frame: Evaluation of inflammatory biomarkers will be obtained prior to dosing for the first five days of the study
Population: Log interleukin (IL)-6. The pharmacokinetic endpoint was area under the curve (AUC) total/days of pioglitazone administration
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone Hydrochloride | Effect of Pioglitazone Area Under the Curve on Changes in IL-6 | -1.4425 ng/ml | Standard Error 0.3741 |
| Normal Standard Care | Effect of Pioglitazone Area Under the Curve on Changes in IL-6 | NA ng/ml | — |
p-value: 0.003Regression, Linear