Trial Outcomes & Findings for Pharmacokinetic and Biomarker Study of Pioglitazone in Adolescents With Severe Sepsis and Septic Shock (NCT NCT01352182)

Last Updated: 2020-09-02

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

12 participants

Primary outcome timeframe

Assessement over five days

Results posted on

2020-09-02

Participant Flow

Participant milestones

Participant milestones
Measure	Pioglitazone Hydrochloride Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.	Normal Standard Care Received normal routine standard care
Overall Study STARTED	8	4
Overall Study COMPLETED	8	4
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pharmacokinetic and Biomarker Study of Pioglitazone in Adolescents With Severe Sepsis and Septic Shock

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pioglitazone Hydrochloride n=8 Participants Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.	Normal Standard Care n=4 Participants Routine normal standard care	Total n=12 Participants Total of all reporting groups
Age, Continuous	13.8 years STANDARD_DEVIATION 3.5 • n=5 Participants	20.8 years STANDARD_DEVIATION 9.7 • n=7 Participants	16.083 years STANDARD_DEVIATION 6.721 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	1 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	8 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants

PRIMARY outcome

Timeframe: Assessement over five days

Population: Hypoglycemia episodes

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.

Outcome measures

Outcome measures
Measure	Pioglitazone Hydrochloride n=8 Participants Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.	Normal Standard Care n=4 Participants Routine 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	0 events

PRIMARY outcome

Timeframe: Final day of study

BUN levels in blood from subject on the final day of enrollment

Outcome measures

Outcome measures
Measure	Pioglitazone Hydrochloride n=8 Participants Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.	Normal Standard Care n=4 Participants Routine normal standard care
Safety Labs - Blood Urea Nitrogen (BUN)	7.5 mg/dl Interval 6.0 to 18.75	10 mg/dl Interval 5.25 to 15.5

PRIMARY outcome

Timeframe: Final day of study

Creatinine levels in blood from subject on the final day of enrollment

Outcome measures

Outcome measures
Measure	Pioglitazone Hydrochloride n=8 Participants Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.	Normal Standard Care n=4 Participants Routine normal standard care
Safety Labs - Creatinine	0.72 mg/dl Interval 0.39 to 0.778	0.415 mg/dl Interval 0.305 to 0.593

PRIMARY outcome

Timeframe: Final day of study

ALT levels in blood from subject on the final day of enrollment

Outcome measures

Outcome measures
Measure	Pioglitazone Hydrochloride n=8 Participants Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.	Normal Standard Care n=4 Participants Routine normal standard care
Safety Labs - Alanine Aminotransferase (ALT)	21.5 U/L Interval 13.5 to 25.25	24.5 U/L Interval 11.0 to 27.5

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Pioglitazone Hydrochloride n=5 Participants Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.	Normal Standard Care n=3 Participants Routine normal standard care
Pioglitazone Area Under Curve Estimates by Treatment Group and Route of Administration	5363 ng*h/ml Standard Deviation 2362	1052 ng*h/ml Standard Deviation 942

SECONDARY outcome

Timeframe: 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

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

Outcome measures

Outcome measures
Measure	Pioglitazone Hydrochloride n=8 Participants Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.	Normal Standard Care n=4 Participants Routine normal standard care
Effect of Pioglitazone Area Under the Curve on Changes in IL-6	-1.4425 ng/ml Standard Error 0.3741	NA ng/ml Standard Error NA patient in the normal standard care group did not receive pioglitazone

Adverse Events

Pioglitazone Hydrochloride

Serious events: 2 serious events

Other events: 5 other events

Deaths: 2 deaths

Normal Standard Care

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Pioglitazone Hydrochloride n=8 participants at risk Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.	Normal Standard Care n=4 participants at risk Routine normal standard care
Renal and urinary disorders Acute kidney injury	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Cardiac disorders Severe biventricular dysfunction	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Respiratory, thoracic and mediastinal disorders mediastinal hemorrhage	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Surgical and medical procedures Surgical and medical procedures - Other	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Cardiac disorders ventricular tachycardia	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Cardiac disorders ventricular fibrillation	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Blood and lymphatic system disorders hemolysis	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Nervous system disorders intracranial hemorrhage	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Respiratory, thoracic and mediastinal disorders Respiratory failure	25.0% 2/8 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.

Other adverse events

Additional Information

Jennifer Kaplan

Cincinnati Children's Hospital Medical Center

Phone: 513-636-4259

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Pioglitazone Hydrochloride n=8 participants at risk Pioglitazone hydrochloride: Participants will receive a daily dose of pioglitazone at 0.5 mg/kg/dose for 5 days.	Normal Standard Care n=4 participants at risk Routine normal standard care
Blood and lymphatic system disorders Anemia	37.5% 3/8 • Number of events 3 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	50.0% 2/4 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Cardiac disorders Complaint of chest pain	0.00% 0/8 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Blood and lymphatic system disorders Leukocytosis	12.5% 1/8 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Cardiac disorders Sinus tachycardia	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Endocrine disorders Adrenal insufficiency	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Eye disorders Conjunctivitis	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Gastrointestinal disorders Pancreatitis	0.00% 0/8 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Gastrointestinal disorders Abdominal distension	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
General disorders Edema	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
General disorders Fever	62.5% 5/8 • Number of events 5 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Infections and infestations Lung infection	0.00% 0/8 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Investigations Blood bilirubin increased	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Investigations INR increased	0.00% 0/8 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Investigations Lipase increased	25.0% 2/8 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Investigations Platelet count decreased	0.00% 0/8 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Investigations Weight gain	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Metabolism and nutrition disorders Acidosis	25.0% 2/8 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Metabolism and nutrition disorders Alkalosis	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Metabolism and nutrition disorders Hyperglycemia	25.0% 2/8 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Metabolism and nutrition disorders Hypoalbuminemia	50.0% 4/8 • Number of events 4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	50.0% 2/4 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Metabolism and nutrition disorders Hypokalemia	25.0% 2/8 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	50.0% 2/4 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Metabolism and nutrition disorders Hypomagnesemia	25.0% 2/8 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Metabolism and nutrition disorders Hypophosphatemia	37.5% 3/8 • Number of events 3 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Metabolism and nutrition disorders Hypernatremia	0.00% 0/8 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Nervous system disorders Headache	25.0% 2/8 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Renal and urinary disorders Renal and urinary disorders - other, increased BUN	0.00% 0/8 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Respiratory, thoracic and mediastinal disorders Atelectasis	25.0% 2/8 • Number of events 2 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Respiratory, thoracic and mediastinal disorders Dyspnea	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Respiratory, thoracic and mediastinal disorders Hpoxia	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Respiratory, thoracic and mediastinal disorders Mild pulmonary edema	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Respiratory, thoracic and mediastinal disorders Pleural effusion	37.5% 3/8 • Number of events 3 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Respiratory, thoracic and mediastinal disorders Respiratory failure	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - Other, pneumomediastinum	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Skin and subcutaneous tissue disorders Edema	0.00% 0/8 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	25.0% 1/4 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Skin and subcutaneous tissue disorders Pain of skin	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Skin and subcutaneous tissue disorders Rash maculo-papular	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - other, skin breakdown and oozing	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Vascular disorders Hypotension	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.
Vascular disorders Peripheral ischemia	12.5% 1/8 • Number of events 1 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.	0.00% 0/4 • Adverse events were monitored for each subject throughout each subject's hospitalization which ranged from 4 days to 30 days for control subjects and 4 days to 23 days for pioglitazone subjects.