Trial Outcomes & Findings for The MENDS2 Study, Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients With Acute Respiratory Failure (NCT NCT01739933)
NCT ID: NCT01739933
Last Updated: 2021-06-07
Results Overview
The analysis of DCFDs will be conducted using Intention-to-Treat (ITT) population, defined as all patients who were randomized and received study drug. We chose a 14 day evaluation period for delirium, because it represents the best balance of gaining valuable clinical information, while maximizing resource utilization, given the average study drug infusion to be 7 days and maximum duration to be 14 days. Thus our follow-up period will cover 7 additional days of delirium monitoring after the study drug is stopped in the majority of our patients.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
438 participants
Primary outcome timeframe
14 days
Results posted on
2021-06-07
Participant Flow
438 participants signed consent and were enrolled in the clinical trial. 16 participants screen-failed and were ineligible for randomization. 422 participants were randomized and assigned to an arm/treatment group
Participant milestones
| Measure |
Dexmedetomidine
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 5 mcg/mL dexmedetomidine. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr.
Dexmedetomidine: For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 0.75 mcg/kg/hr of dexmedetomidine. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
Propofol
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 10 mg/mL propofol. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the propofol group, dose will range from 5-50 mcg/kg/min.
Propofol: For patients in the propofol group, dose will range from 5-50 mcg/kg/min. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 25 mcg/kg/min of propofol. This dose range has been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
|---|---|---|
|
Overall Study
STARTED
|
214
|
208
|
|
Overall Study
Discharged From Hospital and Eligible for Follow-up
|
140
|
147
|
|
Overall Study
COMPLETED
|
108
|
101
|
|
Overall Study
NOT COMPLETED
|
106
|
107
|
Reasons for withdrawal
| Measure |
Dexmedetomidine
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 5 mcg/mL dexmedetomidine. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr.
Dexmedetomidine: For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 0.75 mcg/kg/hr of dexmedetomidine. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
Propofol
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 10 mg/mL propofol. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the propofol group, dose will range from 5-50 mcg/kg/min.
Propofol: For patients in the propofol group, dose will range from 5-50 mcg/kg/min. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 25 mcg/kg/min of propofol. This dose range has been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
|---|---|---|
|
Overall Study
Death
|
89
|
86
|
|
Overall Study
Withdrawal by Subject
|
10
|
8
|
|
Overall Study
Lost to Follow-up
|
3
|
10
|
|
Overall Study
Did not speak English required for neurospychological testing
|
4
|
3
|
Baseline Characteristics
The MENDS2 Study, Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients With Acute Respiratory Failure
Baseline characteristics by cohort
| Measure |
Dexmedetomidine
n=214 Participants
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 5 mcg/mL dexmedetomidine. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr.
Dexmedetomidine: For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 0.75 mcg/kg/hr of dexmedetomidine. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
Propofol
n=208 Participants
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 10 mg/mL propofol. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the propofol group, dose will range from 5-50 mcg/kg/min.
Propofol: For patients in the propofol group, dose will range from 5-50 mcg/kg/min. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 25 mcg/kg/min of propofol. This dose range has been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
Total
n=422 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
59 years
n=5 Participants
|
60 years
n=7 Participants
|
60 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
93 Participants
n=5 Participants
|
88 Participants
n=7 Participants
|
181 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
121 Participants
n=5 Participants
|
120 Participants
n=7 Participants
|
241 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
12 Participants
n=5 Participants
|
18 Participants
n=7 Participants
|
30 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
202 Participants
n=5 Participants
|
190 Participants
n=7 Participants
|
392 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 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
|
15 Participants
n=5 Participants
|
23 Participants
n=7 Participants
|
38 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
188 Participants
n=5 Participants
|
177 Participants
n=7 Participants
|
365 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
11 Participants
n=5 Participants
|
8 Participants
n=7 Participants
|
19 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
|
214 participants
n=5 Participants
|
208 participants
n=7 Participants
|
422 participants
n=5 Participants
|
|
Informant Questionnaire on Cognitive Decline (IQCODE) Short Form
|
3.06 units on a scale
n=5 Participants
|
3 units on a scale
n=7 Participants
|
3 units on a scale
n=5 Participants
|
|
Charlson Comorbities index score
|
2 units on a scale
n=5 Participants
|
2 units on a scale
n=7 Participants
|
2 units on a scale
n=5 Participants
|
|
Sequential Organ Failure Assessment (SOFA) score at enrollment
|
10 units on a scale
n=5 Participants
|
10 units on a scale
n=7 Participants
|
10 units on a scale
n=5 Participants
|
|
Infection confirmed by culture
|
146 Participants
n=5 Participants
|
132 Participants
n=7 Participants
|
278 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 14 daysThe analysis of DCFDs will be conducted using Intention-to-Treat (ITT) population, defined as all patients who were randomized and received study drug. We chose a 14 day evaluation period for delirium, because it represents the best balance of gaining valuable clinical information, while maximizing resource utilization, given the average study drug infusion to be 7 days and maximum duration to be 14 days. Thus our follow-up period will cover 7 additional days of delirium monitoring after the study drug is stopped in the majority of our patients.
Outcome measures
| Measure |
Dexmedetomidine
n=214 Participants
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 5 mcg/mL dexmedetomidine. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr.
Dexmedetomidine: For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 0.75 mcg/kg/hr of dexmedetomidine. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
Propofol
n=208 Participants
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 10 mg/mL propofol. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the propofol group, dose will range from 5-50 mcg/kg/min.
Propofol: For patients in the propofol group, dose will range from 5-50 mcg/kg/min. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 25 mcg/kg/min of propofol. This dose range has been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
|---|---|---|
|
Delirium/Coma Free Days (DCFDs)
|
8 days
Interval 1.0 to 12.8
|
7.5 days
Interval 1.8 to 11.2
|
SECONDARY outcome
Timeframe: 28 DaysVentilator-free days (VFDs), i.e., days alive and free of mechanical ventilation (MV) at 28 days. This endpoint has been used by the National Heart, Lung, and Blood Institute (NHLBI) ARDSNet in numerous critical care trials examining ICU populations.
Outcome measures
| Measure |
Dexmedetomidine
n=214 Participants
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 5 mcg/mL dexmedetomidine. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr.
Dexmedetomidine: For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 0.75 mcg/kg/hr of dexmedetomidine. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
Propofol
n=208 Participants
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 10 mg/mL propofol. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the propofol group, dose will range from 5-50 mcg/kg/min.
Propofol: For patients in the propofol group, dose will range from 5-50 mcg/kg/min. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 25 mcg/kg/min of propofol. This dose range has been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
|---|---|---|
|
Ventilator-free Days (VFDs)
|
20.9 days
Interval 0.0 to 26.1
|
19.9 days
Interval 4.2 to 24.9
|
SECONDARY outcome
Timeframe: 1 through 90 daysThat sedation of mechanically ventilated severely septic patients with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will improve 90-day survival of ICU patients.
Outcome measures
| Measure |
Dexmedetomidine
n=214 Participants
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 5 mcg/mL dexmedetomidine. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr.
Dexmedetomidine: For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 0.75 mcg/kg/hr of dexmedetomidine. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
Propofol
n=208 Participants
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 10 mg/mL propofol. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the propofol group, dose will range from 5-50 mcg/kg/min.
Propofol: For patients in the propofol group, dose will range from 5-50 mcg/kg/min. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 25 mcg/kg/min of propofol. This dose range has been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
|---|---|---|
|
Death at 90 Days
|
81 Participants
|
82 Participants
|
SECONDARY outcome
Timeframe: 6 months after randomizationThe Telephone Interview for Cognitive Status is a standardized test of cognitive functioning that monitors changes in cognitive functioning over time. The TICS-T consists 11 items including wordlist memory, orientation, attention, repetition, conceptual knowledge and nonverbal praxis. Age-adjusted total scores on the TICS-T range from 0 to 100 with a mean of 50+/-10; lower scores indicate worse cognition, and a score of 35 or less indicates cognitive impairment.
Outcome measures
| Measure |
Dexmedetomidine
n=214 Participants
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 5 mcg/mL dexmedetomidine. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr.
Dexmedetomidine: For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 0.75 mcg/kg/hr of dexmedetomidine. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
Propofol
n=208 Participants
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 10 mg/mL propofol. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the propofol group, dose will range from 5-50 mcg/kg/min.
Propofol: For patients in the propofol group, dose will range from 5-50 mcg/kg/min. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 25 mcg/kg/min of propofol. This dose range has been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
|
|---|---|---|
|
Cognitive Function Utilizing the Telephone Interview for Cognitive Status Total (TICS-T)
|
39 score on a scale
Interval 28.0 to 48.0
|
38 score on a scale
Interval 30.0 to 46.0
|
Adverse Events
Dexmedetomidine
Serious events: 0 serious events
Other events: 0 other events
Deaths: 89 deaths
Propofol
Serious events: 0 serious events
Other events: 0 other events
Deaths: 86 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
Adverse event data not reported
Additional Information
Dr. Pratik Pandharipande, Vice Chair Faculty Affairs, PI
Vanderbilt University Medical Center
Phone: 6153436268
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place