Septic Shock
Conditions
Brief summary
The investigators aim to perform a randomized, double-blind, placebo-controlled trial to investigate the efficacy of midodrine in decreasing time to IV vasopressor liberation in patients with septic shock.
Detailed description
A growing body of literature comprising largely retrospective data seems to support the safety and efficacy of midodrine in the intensive care unit for decreasing IV vasopressor use. The investigators hypothesize that administration of midodrine in the early phase of septic shock in patients with adequate enteral access will result in a significant decrease in time to IV vasopressor liberation (increase in vasopressor-free days), secondarily resulting in decreased central venous catheter dwell times and intensive care unit length of stay.
Interventions
Midodrine Hydrochloride, enteral, 10 or 20 mg
OTHERplacebo
investigational pharmacy formulated placebo comparator
Sponsors
University of Virginia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Patients will be randomized to intervention or placebo by the investigational pharmacy. Care providers, investigators and participants will be blinded to study arm.
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
Yes
Inclusion criteria
* Patients aged ≥18-89 years old * Admitted to UVA medical ICU with diagnosis of septic shock. * Patients requiring at least 5 mcg/min norepinephrine infusion (or equivalent) for blood pressure support for at least 3 hours * Patients with enteral access established within 12 hours of admission (either able to swallow, or feeding tube in place)
Exclusion criteria
* Pregnant females; (due to the potential adverse effects to an unborn child); patients with childbearing potential will have results of pregnancy test checked (which is routinely performed on admission); should the patient have child-bearing potential and the pregnancy status is not checked as part of routine care, such patients will be excluded from the study (i.e. pregnancy testing will not be performed for research purposes) * Patients \< 18 years * Prisoners * Patients already taking midodrine * Patients with cirrhosis of the liver as defined by either biopsy, imaging findings of cirrhosis AND thrombocytopenia or patients otherwise undergoing liver transplant evaluation * Patients with Increased intraocular pressure and glaucoma * Patients with allergy to midodrine * Non-English speaking patients, due to the narrow time-frame for study enrollment and execution of study protocol, employing interpreters is deemed to be a significant burden on the investigators with potential to hamper study enrollment. Non-english speaking patients are not deemed to be adversely affected by exclusion from study as there is no clear a priori reason why study results would not also apply to non-English speakers. * Patients without enteral access within 12 hours of initiation of IV vasopressors * Patients where the attending physician does not clinically intend to target a mean arterial pressure of \> 65 mmHg * Patients with pheochromocytoma or thyrotoxicosis * Patients with active bowel ischemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days Free of Vasopressors (Days) | 90 days from enrollment | days without vasopressor adjusted with mortality |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intensive Care Unit Length of Stay (ICU LOS; Days) | 90 days from enrollment | — |
| Hospital Length of Stay (Hospital LOS; Days) | 90 days from enrollment | — |
| 30-day Mortality | 30 days from enrollment | — |
| Central Venous Catheter Free Days | 90 days from enrollment | — |
| In-hospital Mortality | From randomization until date of death if occurred prior to discharge from sentinel hospitalization, assessed up to 52 weeks | Mortality during sentinel admission |
| Intensive Care Unit Mortality | From randomization until date of death if occurred prior to discharge from the sentinel intensive care unit admission, assessed up to 52 weeks | Mortality during intensive care unit stay during sentinel admission |
| Need to Re-initiate IV Vasopressors 2 or More Hours After Discontinuation | From randomization until date of discharge from the sentinel intensive care unit admission, assessed up to 52 weeks | — |
| 90-day Mortality | 90 days from enrollment | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Investigational pharmacy formulated placebo. In early phase patients will be randomized to placebo, 10mg TID midodrine or 20 mg TID midodrine. (15 per group)
placebo: investigational pharmacy formulated placebo comparator | 3 |
| Midodrine Hydrochloride 10 mg TID In early phase patients will be randomized to placebo, 10mg TID midodrine or 20 mg TID midodrine. (15 per group). After the first 45 patients are enrolled, interim safety and efficacy analysis will dictate which experimental group is continued/open to further enrollment (either 10 mg midodrine TID or 20 mg midodrine TID).
Midodrine Hydrochloride: Midodrine Hydrochloride, enteral, 10 or 20 mg | 4 |
| Midodrine Hydrochloride 20 mg TID In early phase patients will be randomized to placebo, 10mg TID midodrine or 20 mg TID midodrine. (15 per group). After the first 45 patients are enrolled, interim safety and efficacy analysis will dictate which experimental group is continued/open to further enrollment (either 10 mg midodrine TID or 20 mg midodrine TID).
Midodrine Hydrochloride: Midodrine Hydrochloride, enteral, 10 or 20 mg | 3 |
| Total | 10 |
Baseline characteristics
| Characteristic | Placebo | Midodrine Hydrochloride 10 mg TID | Midodrine Hydrochloride 20 mg TID | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Age, Continuous | 65 years | 65.5 years | 62.33 years | 65.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 3 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Region of Enrollment United States | 3 participants | 4 participants | 3 participants | 10 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 1 / 4 | 0 / 3 |
| other Total, other adverse events | 0 / 3 | 0 / 4 | 0 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 | 0 / 3 |
Outcome results
Primary
Days Free of Vasopressors (Days)
days without vasopressor adjusted with mortality
Time frame: 90 days from enrollment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Days Free of Vasopressors (Days) | 24.3 days |
| Midodrine Hydrochloride 10 mg TID | Days Free of Vasopressors (Days) | 7.5 days |
| Midodrine Hydrochloride 20 mg TID | Days Free of Vasopressors (Days) | 25.6 days |
Secondary
30-day Mortality
Time frame: 30 days from enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 30-day Mortality | 2 Participants |
| Midodrine Hydrochloride 10 mg TID | 30-day Mortality | 1 Participants |
| Midodrine Hydrochloride 20 mg TID | 30-day Mortality | 0 Participants |
Secondary
90-day Mortality
Time frame: 90 days from enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 90-day Mortality | 2 Participants |
| Midodrine Hydrochloride 10 mg TID | 90-day Mortality | 1 Participants |
| Midodrine Hydrochloride 20 mg TID | 90-day Mortality | 0 Participants |
Secondary
Central Venous Catheter Free Days
Time frame: 90 days from enrollment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Central Venous Catheter Free Days | 15.3 days |
| Midodrine Hydrochloride 10 mg TID | Central Venous Catheter Free Days | 7.25 days |
| Midodrine Hydrochloride 20 mg TID | Central Venous Catheter Free Days | 25 days |
Secondary
Hospital Length of Stay (Hospital LOS; Days)
Time frame: 90 days from enrollment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Hospital Length of Stay (Hospital LOS; Days) | 11.3 days |
| Midodrine Hydrochloride 10 mg TID | Hospital Length of Stay (Hospital LOS; Days) | 11 days |
| Midodrine Hydrochloride 20 mg TID | Hospital Length of Stay (Hospital LOS; Days) | 15.7 days |
Secondary
In-hospital Mortality
Mortality during sentinel admission
Time frame: From randomization until date of death if occurred prior to discharge from sentinel hospitalization, assessed up to 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | In-hospital Mortality | 1 Participants |
| Midodrine Hydrochloride 10 mg TID | In-hospital Mortality | 1 Participants |
| Midodrine Hydrochloride 20 mg TID | In-hospital Mortality | 0 Participants |
Secondary
Intensive Care Unit Length of Stay (ICU LOS; Days)
Time frame: 90 days from enrollment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Intensive Care Unit Length of Stay (ICU LOS; Days) | 6 days |
| Midodrine Hydrochloride 10 mg TID | Intensive Care Unit Length of Stay (ICU LOS; Days) | 10 days |
| Midodrine Hydrochloride 20 mg TID | Intensive Care Unit Length of Stay (ICU LOS; Days) | 7.6 days |
Secondary
Intensive Care Unit Mortality
Mortality during intensive care unit stay during sentinel admission
Time frame: From randomization until date of death if occurred prior to discharge from the sentinel intensive care unit admission, assessed up to 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Intensive Care Unit Mortality | 1 Participants |
| Midodrine Hydrochloride 10 mg TID | Intensive Care Unit Mortality | 1 Participants |
| Midodrine Hydrochloride 20 mg TID | Intensive Care Unit Mortality | 0 Participants |
Secondary
Need to Re-initiate IV Vasopressors 2 or More Hours After Discontinuation
Time frame: From randomization until date of discharge from the sentinel intensive care unit admission, assessed up to 52 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Need to Re-initiate IV Vasopressors 2 or More Hours After Discontinuation | 2 participants |
| Midodrine Hydrochloride 10 mg TID | Need to Re-initiate IV Vasopressors 2 or More Hours After Discontinuation | 0 participants |
| Midodrine Hydrochloride 20 mg TID | Need to Re-initiate IV Vasopressors 2 or More Hours After Discontinuation | 0 participants |