Conditions: Hypotension Critical Illness
Keywords: Midodrine Hypotension Intensive care unit IV vasopressors ICU discharge
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 139
Healthy volunteers: no

Brief summary:
We hypothesize that midodrine treatment of refractory hypotension in patients otherwise ready for discharge from the ICU shortens duration of receiving IV vasopressors and SICU length of stay without increasing MGH length of stay or putting the patient at risk of being readmitted to an ICU.

Detailed description:
Persistent hypotension in critically ill patients remains a major barrier to discharging patients from the intensive care unit (ICU). In our hospital, in patients with adequate tissue perfusion, midodrine has been observed to treat hypotension in order to wean continuous intravenous (IV) vasopressors and therefore promote ICU discharge. There are several possible etiologies of hypotension in the ICU. The most frequently seen causes include septic shock, hypovolemia, adrenal insufficiency, and idiosyncratic reactions from medications. For patients whose reversible causes of hypotension have been addressed but still require vasopressors, midodrine may prove to be a useful adjunctive medication to successfully increase blood pressure. No previous studies have examined the use of midodrine for the treatment of hypotension in an ICU setting. Therefore, we are investigating a new indication for midodrine as the treatment of hypotension in critically ill patients.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Midodrine intervention 2: Placebo
Intervention descriptions: intervention 1: Patients will be randomized to blinded to 20 mg of midodrine intervention 2: Patients will be randomized to blinded placebo control

Protocol document:
Prot_SAP_000.pdf: 
 
 
1 
 
 
 
 
 
Midodrine for the Treatment of Refractory Hypotension 
 
NCT01531959 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document date: March 27, 2020 
 
 


 
 
2 
 
 
STUDY PROTOCOL 
 
PURPOSE 
We hypothesise that midodrine treatment of refractory hypotension in patients otherwise ready for discharge from 
the ICU shortens duration of receiving IV vasopressors and ICU length of stay without increasing hospital length of 
stay or putting the patient at risk of being readmitted to an ICU. 
SIGNIFICANCE AND BACKGROUND  
Midodrine is an orally available alpha-1 agonist, which is currently FDA approved for the treatment of symptomatic 
orthostatic hypotension. This indication is generally reserved for patients with chronic orthostatic hypotension that 
significantly impairs their daily activities of living despite standard care because midodrine carries the risk of supine 
hypertension. However, in patients without orthostatic hypotension, this adverse reaction is theoretically less 
prevalent due to preserved baroreflex buffering that maintains blood pressure homeostasis.1 Midodrine has several 
unique pharmacological properties compared to other medications in its class: it exerts significantly less 
gastrointestinal effects, has minimal central nervous system side effects, and demonstrates excellent bioavailability 
following oral administration.2 These desirable pharmacological properties lead to midodrine’s potential application 
for new indications. 
One of the most frequently prescribed off-label indications for midodrine is prevention of intradialytic hypotension. 
A systematic review was conducted evaluating the use of midodrine for the prevention of intradialytic hypotension.3 
56 patients received a one-time dose of 2.5 to 10 mg of midodrine 15–30 minutes prior to each dialysis session 
compared to a placebo-control group. The midodrine group’s mean pre- and post- dialysis systolic blood pressure 
(SBP) was 128.1 (90.5–138.7) mmHg and 115.5 (81.5–129.9) mmHg and pre- and post-dialysis diastolic blood 
pressure (DBP) was 72.4 (55.4–81.4) mmHg and 58.9 (50.2–72.5) mmHg. The control group’s mean pre- and post-
dialysis SBP was 123.2 (73–135.2) mmHg and 103.1 (64.9–116.5) mmHg and pre- and post-dialysis DBP was 58.1 
(44–76.2) mmHg and 52.5 (32.6–66.8) mmHg. The midodrine group demonstrated a statistically significant greater 
post dialysis and nadir SBP with a mean difference of 12.4 mmHg (7.1–17.7; p<0.0001) and 13.3 mmHg (8.6–18; 
p<0.0001) and post dialysis and nadir DBP with a mean difference of 7.3 mmHg (3.7–10.9; p=0.0001) and 5.9 
mmHg (2.7–9.1; p=0.0004) vs. the placebo control group.3 
Although frequently prescribed as an off-label indication, the optimal dosing range for midodrine in the treatment of 
hypotension unrelated to orthostasis has yet to be fully determined. Our proposed study will use the maximum dose 
that has been previously shown to have a strong correlation with effect on systolic blood pressure. This dosing is 
based on a recently published randomised, two-centre, double-blind, four-way complete crossover, single dose study 
in patients with neurogenic orthostatic hypotension. This study demonstrated that there was a linear relationship 
between dose and change in systolic blood pressure when administering a single dose of midodrine from 2.5 mg to 
20 mg. These doses also produced a predictable blood pressure response and blood concentrations. The time to 
maximum concentration of midodrine was 15 to 30 minutes with an elimination half-life equal to 30 minutes, and 
active metabolite, dysglymidodrine, equal to 4 hours.4 There are limited efficacy and safety data supporting off-label 
use. Based on billing records, a total of 6,443 patients were prescribed midodrine as an inpatient at MGH since 
1998. Utilisation of midodrine has steadily increased over the last decade with 1,200 patients being prescribed in 
2010. Given that midodrine is only indicated to treat rare diseases, it is likely that the majority of these patients were 
prescribed midodrine as an off-label indication. 
The only information available for off-label treatment of hypotension unrelated to orthostatic dysregulation is based 
on observational data. Midodrine was successfully used as an alternative to intravenous vasopressors in the 
treatment of hypotension related to carotid artery stenting. Eleven patients received intravenous dopamine infusion 
in an intensive care setting whereas 4 patients received midodrine in a regular telemetry floor to treat hypotension. 
The cost of hospitalisation was significantly higher in the dopamine group due to the need for ICU admission and no 
major side effects were noted in either group.5 In another study, midodrine was used as an alternative to intravenous 
inotropic therapy in patients with hypotension associated with stunned myocardium. The authors concluded that 
midodrine can shorten the duration of intensive care unit and hospital stay in this setting.6 At MGH’s ICUs, 


 
 
3 
 
midodrine has been observed to effectively wean patients off continuous IV vasopressors. For patients whose only 
barrier to discharge from the ICU was administration of continuous medications, midodrine also appeared to 
decrease ICU length of stay. However, it is unknown if midodrine shortened their total hospital LOS or put the 
patient at risk of being readmitted back to an ICU. Additionally, midodrine appears to be well tolerated by patients 
when prescribed at MGH because there have been no safety reports submitted due to an adverse reaction. 
No previous studies have examined the use of midodrine for the treatment of hypotension in an ICU setting. We are 
investigating a new indication for midodrine as the treatment for hypotension in critically ill patients. We expect that 
midodrine will decrease the time of patients being administered continuous vasopressors by 6 hours and therefore 
accelerate their readiness for ICU discharge. This has potential to have a significant impact on healthcare costs by 
reducing ICU and hospital LOS. 
DESCRIPTION OF RESEARCH PROTOCOL 
Study Design 
The study is a randomised, double-blind, placebo-controlled, multi-centric trial expected to enrol 120 subjects in 
order to detect an expected statistically significant difference of 6 hours (from initiation of drug until discontinuation 
of IV vasopressors) between the two groups.  
 
Subjects are being enrolled at: 
1. 
Massachusetts General Hospital, Boston (MGH)  
o 
Local IRB: Partners Human Research Committee, protocol number:  2016P002045 
2. 
Sir Charles Gairdner Hospital, Australia (SCGH) 
o 
Local IRB: Sir Charles Gairdner Hospital HREC, protocol Number: 2015-098 
3. 
Beth Israel Deaconess Medical Center, Boston (BIDMC) 
o 
Local IRB: Committee on Clinical Investigations, protocol number: 2018P000162 
 
Recruitment 
Subjects will be identified from the ICU census on a daily basis by study personnel and identified by other ICU 
clinicians. If identified subjects meet inclusion/exclusion criteria they will then be approached by a specialised 
health care provider. The specialised health care provider will be a physician that is part of the clinical staff in the 
ICU who has first-hand knowledge of the subject’s medical history. This physician will approach potentially eligible 
subjects to introduce them to the research study. If both the specialised health care provider approves his or her 
subject to be contacted for research purposes and the subject agrees to be contacted by study staff discussed verbally 
during the course of providing medical care, a study physician will then approach the subject to obtain informed 
consent. 
Subject Selection  
Inclusion criteria: 
 
At least 18 years of age 
 
Admitted to the intensive care services at MGH, SCGH, or BIDMC 
 
Requiring IV vasopressors at a rate of less than 100 mcg/min of phenylephrine, or 8 mcg/min of 
norepinephrine, or metaraminol 60mcg/min and unable to wean for more than 24 hours while still 
maintaining desired blood pressure goals. 
Exclusion criteria: 
 
Clinical evidence of inadequate tissue oxygenation 
 
Clinical evidence of liver failure 
 
Hypovolemic shock or hypotension due to adrenal insufficiency (based on clinical suspicion or available 
routine testing) 
 
Pregnancy confirmed with a pregnancy test. Women between the ages of 18–55 who have not had a 
surgical hysterectomy will only be eligible for inclusion if they have a negative urine pregnancy test. 
Pregnancy testing will not need to be repeated if there is a documented negative urine pregnancy test that 
was obtained within 7 days prior to starting study drug, provided the woman was an ICU inpatient 
throughout that period of time. 


 
 
4 
 
 
Chronic renal failure (serum creatinine >2mg/dL or 180 µmol/L) 
 
Severe organic heart disease (ejection fraction less than 30%) 
 
Acute urinary retention 
 
Pheochromocytoma (based on clinical suspicion) 
 
Thyrotoxicosis (based on clinical suspicion) 
 
Enrolment in another clinical trial 
 
Midodrine as pre-admission medication 
 
Any known allergies to midodrine 
 
Bradycardia (HR <50/min) 
 
No enteral route available 
Consent 
Informed consent will be obtained from the participant by a study physician. If the subject lacks mental competency 
based on the mini mental status exam to provide informed consent, the subject’s designated surrogate will be explained 
their responsibility as a LAR to make decisions on the patient’s behalf, and will be asked to provide consent. The LAR 
will also be explained that should the participant re-gain mental capacity, he/she will be formally consented. As part of 
this, the study physician will address the patient explaining what procedures have been held so far, the purpose, risks 
and benefits of the study. The study physician will then explain the patient’s right to decide as to whether they wish to 
continue being a participant in the study. Based on the patient’s decision, study procedures will be continued or 
withheld immediately. The following categories of surrogates (listed in general order of preference) may provide 
consent in writing on behalf of potential subjects incapable of providing informed consent: 
 
Health Care Proxy, a court appointed guardian of the person with specific authority to consent to participation 
in the research study, but also next-of-kin in the following order of priority unless otherwise specified by law: 
spouse, adult child (18 years of age or older), parent, adult sibling (18 years of age or older), grandparent, or 
adult grandchild (18 years of age or older). 
Assent of subjects is required for participation in the research unless the subject is incapable of giving assent due to 
his/her medical condition. If the individual objects to participation, s/he will not be enrolled. The Investigator will 
document the relationship of the surrogate to the subject in the research record. 
Study Procedures 
Prior to randomisation, if subjects are eligible based on inclusion/exclusion criteria, informed consent will be obtained 
from participants. Once informed consent is obtained, the following information will be collected from the subject’s 
medical record: demographics, past medical/surgical history, preadmission medication list, severity of illness at time of 
admission, blood pressure, aspartate aminotransferase, alanine aminotransferase creatinine, troponin, cortisol level.   
 
The study drug or placebo will be selected based on the randomisation scheme and prepared by investigational 
pharmacists. All study personnel will be blinded, except the investigational pharmacist, to the treatment group of the 
subject. Subjects will be randomised to receive either 20 mg PO every 8 hours of midodrine, or placebo PO every 8 
hours. 
 
The study drug will be delivered in a double-blinded manner until:  
 
ICU discharge 
 
Rate of phenylephrine exceeds 100 mcg/min, or rate of norepinephrine exceeds 8 mcg/min, or rate of 
metaraminol exceeds 60mcg/min 
 
Subject exhibits signs and symptoms of organ failure or hypoperfusion 
 
Serious allergic adverse event related to midodrine 
 
Epinephrine requirement 
 
Death 
 
If the blood pressure goal is met for more than 24 hours without IV vasopressors and the attending physician determines 
that the study drug is no longer required, the study drug may be discontinued at the discretion of the treating physician.  
 
 


 
 
5 
 
Outcomes 
Study endpoints include the following: 
 
Primary endpoint:  
o 
Hours from initiation of midodrine until discontinuation of IV vasopressors 
 
Secondary endpoints:  
o 
ICU length of stay (LOS), hospital LOS, rates of ICU readmission 
 
Safety endpoints:  
o 
hypertension (increase in blood pressure to a systolic blood pressure (SBP) 20 percent higher than the 
predefined goal set by the primary team), bradycardia (decrease in heart rate 20 percent lower than the 
predefined goal set by the primary team), hemodynamically significant tachyarrhythmia (>20 percent 
decrease in systolic blood pressure). 
 
Adverse Event Reporting 
Our patient population is by definition critically ill in the ICU.  It is expected that they will have a number of unrelated 
adverse health events (AE) during the course of their hospital stay.  Therefore, we will limit the scope of our AE 
monitoring and recording to the following: 
 
Serious Adverse Events, defined as 
o 
Death, believed to be related to the study drug, or a death that is unexpected considering the 
acuity of a patient 
o 
A life-threatening experience believed to be related to the study drug 
o 
Persistent or significant disability or incapacity that is of greater frequency or severity than 
what would be normally expected in the course of critical illness   
o 
An event that jeopardises the Human Subject and may require medical or surgical treatment to 
prevent one of the preceding outcomes and is not expected in the course of critical illness 
 
Adverse Events possibly related to the study procedures are pre-specified in the list below:  
o 
Hypertension  
o 
Bradycardia  
o 
Hemodynamically significant tachyarrhythmia 
o 
New organ failure 
 
Evidence for adverse events related to midodrine will be assessed until completion of all study measurements. They 
will also be included in the FDA Annual Progress Report. 
Statistical Analysis 
Please refer to the Statistical Analysis Plan (SAP). 
POSSIBLE BENEFITS 
We cannot guarantee any personal benefits from participating in this study. However, potential benefits to the 
subject may include shorter duration of receiving IV vasopressors, and shorter length of stay in the ICU and 
hospital. Earlier discharge from the ICU and hospital reduces the risk of developing nosocomial infections and 
reduces the total cost of the hospital admission. Information gathered from this study will help researchers determine 
if midodrine is safe and effective at decreasing duration of IV vasopressors and shortening ICU length of stay 
without increasing the risk of ICU readmission or increasing hospital length of stay. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
The very common side effects of midodrine reported in previous studies include pilomotor-like reactions, 
paraesthesia, pruritus, and dysuria.  The most common side effects are headache, supine hypertension, flushing, 
rash, nausea, dyspepsia, stomatitis, chills, and pain. Less common side effects comprise sleep disorders, insomnia, 
restlessness, excitability, irritability, and reflex bradycardia. Rare side effects are tachycardia, palpitations, abnormal 
hepatic function, raised liver enzymes. 
These reactions rarely resulted in discontinuation of medication. These side effects may make the subject 
uncomfortable but do not pose any immediate harm. The subject will be assessed daily by study personnel and all 
efforts will be made to minimise discomfort from these side effects. Other risks that the subject may be exposed to 


 
 
6 
 
as a result of midodrine include hypertension, bradycardia, and tachyarrhythmias.  
Patients enrolled in the study will have the same safeguards as non-study patients in an ICU setting. For patients 
who have stable blood pressure and adequate tissue perfusion, midodrine has been used off-label frequently to treat 
hypotension in our ICU. Therefore, the risks and benefits of the study drug are similar to the risks and benefits of the 
current standard for treating this indication in ICU patients. 
Midodrine is a pregnancy category C medication. Pregnant subjects will be excluded from the study because the 
exposure risks of midodrine to a developing fetus are unknown. Women between the ages of 18–55, who have not 
had a surgical hysterectomy, will only be eligible for inclusion if they have a negative urine pregnancy test. 
Pregnancy testing will not need to be repeated if there is a documented negative urine pregnancy test that was 
obtained within 7 days prior to starting study drug, provided the woman was an ICU inpatient throughout that period 
of time. 
SUBJECT PROTECTION 
Potential coercion of subjects will be avoided by obtaining informed consent by a physician who is involved in the 
study and is listed on the Research Staffing Form. Subjects or designated surrogate will have adequate time to decide to 
participate in the study. Fluctuation in a subject’s mental competency is expected due to presence of sedatives or 
delirium. Therefore, if the subject’s surrogate provides consent, a physician independent of the study will reassess the 
subject’s mental competency using the MMSE once their Richmond Agitation Sedation Score returns to 0 or -1 or their 
Confusion Assessment Method for the ICU is negative. If the subject regains decision-making capacity, a study 
physician will obtain informed consent from the subject. 
Privacy  
The screening of patients, discussions with family/proxy/legally authorised representatives, and the consent process 
will occur in private settings with curtains/doors closed so as to provide privacy and comfort.   
DATA SECURITY 
Data Monitoring 
The following areas will be reviewed by the monitor for completeness and accuracy: study binders, screening log, and 
eligibility adherence, consent forms, data retrieved from each patient during the study, adverse event reports, and 
pharmacy-related study contributions. Monitoring procedures will take place on-site, at close-out. A monitoring report 
will be completed to verify that the monitoring plan was followed. This will be presented to the lead PI and placed in 
the regulatory binder. This will also be included in the FDA Annual Progress Report to ensure compliance with the 
FDA Code of Federal Regulations Title 21, section 312, subpart D. A Data Safety Monitoring Board is in place, which 
will review the data collected, as well as adverse event reports and minor deviations logs. 
Confidentiality and Security 
General Protections: All study staff undergo ongoing training in proper research procedures, Good Clinical Practice, 
and the application of HIPAA privacy laws. 
Data collection: Case report forms will be completed on site by study team members. Medical record numbers, 
names, dates or other identifiers will not be entered on REDCap. This platform will be used for storage and 
manipulation of all our de-identified data. For the different study centres, individual access groups will be formed 
and only the coordinating site will have access to all data.  
Study file storage: All data obtained with subject identifiers will be kept in password-protected computer files 
behind the institutions’ firewall. A crosswalk linking patient identifiers to study ID number will be maintained 
indefinitely by the principal investigator. Limited data will be retained on screened patients who do not meet entry 
criteria or who decline to participate. We will retain only the minimum data required to adequately summarise subject 
selection per CONSORT guidelines in the study publications. Paper records will be kept in locked filing cabinets 
within locked and secured offices to ensure confidentiality. All paper file contents will be shredded before disposal. 


 
 
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DISSEMINATION OF RESEARCH RESULTS 
Patients will be thanked for their time throughout the study. There is no plan to share the data at the conclusion of 
the trial. Because study results are likely to be published a few years after a given subject’s participation, it is not 
feasible to send subjects follow-up with the published results. The study investigators are concerned that mailing the 
published manuscript and an additional thank-you note years after participation risks violating subject privacy, as 
mailing addresses are increasingly likely to change with passing time. 
 


 
 
8 
 
STATISTICAL ANALYSIS PLAN  
 
Study aims 
This randomised, controlled clinical trial evaluates the effect of oral midodrine versus placebo on time to liberation 
from intravenous vasopressors in ICU patients with refractory hypotension. The aim of this study is to assess the 
effects of midodrine treatment in patients otherwise ready for discharge from the ICU. The primary hypothesis is 
that midodrine treatment shortens the duration of receiving IV vasopressors compared to placebo. 
Study design 
Prospective multi-centre randomised placebo-controlled trial. 
Study population and study sites 
The study will enrol patients admitted to an intensive care or high-dependency unit (ICU/HDU) and meeting all 
eligibility criteria detailed in the study protocol. Study sites include Massachusetts General Hospital (Boston, MA, 
USA), Sir Charles Gairdner Hospital (Perth, Australia), and Beth Israel Deaconess Medical Center (Boston, MA, 
USA).  
Randomisation 
Patients will be randomly allocated in a 1:1 ratio to receive either midodrine or placebo. Randomisation will be 
performed using a computer-generated randomisation list and will be stratified by study site. Randomisation lists 
will be created by an independent, unblended study team member, under the supervision of an independent 
statistician. The randomisation list will be provided directly to the research pharmacy, which will be responsible for 
preparing and dispensing the study medications following an active order for study medications.  This includes 
preparation and blinding of the placebo in accordance with the study randomisation schema. 
Study groups 
1. Midodrine, 20 mg PO every 8 hours 
2. Placebo (matched in appearance), PO every 8 hours 
Outcomes 
 
Primary endpoint:  
o 
Time until discontinuation of IV vasopressors, measured in hours from initiation of midodrine until 
discontinuation of IV vasopressors 
 
Secondary endpoints:  
o 
Time to ICU discharge readiness, defined as the number of days from study drug initiation to meeting 
discharge criteria 
o 
ICU length of stay, defined as the number of days in the ICU prior to transfer to the general floor 
o 
Hospital length of stay, defined as the total number of days in the hospital after first study drug 
administration 
o 
Rates of ICU readmission, defined as the number of patients readmitted back to the ICU after prior 
discharge to the general floor 
 
Safety endpoints:  
o 
Hypertension (increase in blood pressure to a systolic blood pressure (SBP) 20 percent higher than the 
predefined goal set by the primary team), bradycardia (decrease in heart rate 20 percent lower than the 
predefined goal set by the primary team), hemodynamically significant tachyarrhythmia (>20 percent 
decrease in systolic blood pressure). 
 
Data Collection 
Baseline descriptive data collection will occur on day of enrolment and includes age, sex, ethnicity, APACHE II 
score, admission diagnosis, pre-existing co-morbidities (diabetes, coronary artery disease, asthma, peripheral 
vascular disease, renal failure, psychiatric disease, musculoskeletal disease, and others) obtained from the subject, 
the subject’s family, and the subject’s medical chart. Baseline laboratory data will be recorded (haemoglobin, white 
cell count, alanine aminotransferase (ALT), international normalised ratio (INR), bilirubin, urea, creatinine, 
troponin, lactate). During the study daily SOFA scores, blood pressure goals, total fluid balances, transfused red 
blood cell units, administered corticosteroids, use of epidural analgesia, vasopressor and study drug start and end 


 
 
9 
 
times will be recorded. Days between admission and discharge from the ICU and hospital will be recorded. 
Readmissions to the ICU during the hospital stay will be identified through daily medical record review. 
Sample size estimation 
The sample size estimation is informed by the previous observational study by Levine et al.7 In this study, the rates 
of vasopressor administration decreased by 38% from −0.62 ± 1.40 mcg/min per hour to −2.20 ± 2.45 mcg/min per 
hour after addition of midodrine. Based on a median time of 17 h from midodrine initiation to discontinuation of IV 
vasopressors, the 38% reduction translates to an estimated 6 h difference. 6 h is also thought to be a meaningful time 
frame in terms of reduction in duration of vasopressor treatment. Accordingly, we expect that a sample size of 50 
subjects per group will provide us with >80% probability (power) to detect a difference of 6 h in the primary 
outcome. Allowing for drop-out, our target sample size is 120.  
Statistical analysis 
The study analysis will be performed on a modified intention-to-treat basis: All patients who were randomised and 
received at least 1 dose of the study medication will be included in the analysis. 
Baseline and demographic characteristics will be presented using descriptive statistics. Continuous data will be 
expressed as means and standard deviations, or medians and interquartile ranges (IQR), depending on variable 
distribution. The normality of variable distribution will be assessed by exploratory data analysis, including 
histograms and boxplots. Differences in continuous data between groups will be assessed using a parametric t-test or 
Mann-Whitney U test, as appropriate. Categorical data will be presented as frequencies and proportions and 
analysed using a Chi-square test. If expected cell counts are small (less than 5), Fisher’s exact test will be used 
instead. For all analyses, a two-sided p-value of less than 0.05 will be considered statistically significant. All 
analyses will be conducted under the supervision of a statistician blinded to intervention group assignment. 
Experienced study staff will perform data analysis in collaboration with biostatisticians using statistical Stata version 
13 (StataCorp LLC, College Station, TX) or later. 
Analysis of primary and secondary outcomes 
A parametric t-test or Mann-Whitney U test will be used, as appropriate, to determine whether time from initiation 
of midodrine until discontinuation of IV vasopressors, time from ICU admission to ICU discharge readiness, and 
ICU and hospital LOS differ between groups.  
A Chi-Square or Fisher’s exact test will be used to test whether rates of ICU readmission and incidence of adverse 
events are different between treatment groups.  
Missing data 
The frequency of missing values for each variable will be collected and reported as necessary. If there are missing 
values for the primary or secondary outcome variables, individual patients will be excluded from the analysis of the 
respective outcome and results will be reported for cases with available outcome information. 
Interim Analyses  
There will be no interim analysis. 
Statistical Analytical Issues   
Multiple Comparisons: There will be no adjustment for multiple testing. Results of secondary outcomes and post 
hoc analyses will therefore be considered exploratory.    
Post-hoc analyses  
Post-hoc data-driven analyses are allowed after the following are undertaken:  
1. Document which analyses were conducted after the results for the primary and secondary outcomes are 
analysed. 
2. Document the rationale for these analyses. 
3. Pre-specify their interpretation in the context of the primary and secondary results and their impact on the 
overall trial conclusions. 
 
 


 
 
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Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine vs placebo in 
neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study 
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3. 
Prakash S, Garg AX, Heidenheim AP, House AA. Midodrine appears to be safe and effective for dialysis-
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Wright RA, Kaufmann HC, Perera R, et al. A double-blind, dose-response study of midodrine in 
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Sharma S, Lardizabal JA, Bhambi B. Oral midodrine is effective for the treatment of hypotension 
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6. 
Sharma S, Bhambi B. Successful treatment of hypotension associated with stunned myocardium with oral 
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7. 
Levine AR, Meyer MJ, Bittner EA, et al. Oral midodrine treatment accelerates the liberation of intensive 
care unit patients from intravenous vasopressor infusions. J Crit Care. 2013;28(5):756-762. 
8. 
Ngan Kee WD. A Random-allocation Graded Dose-Response Study of Norepinephrine and Phenylephrine 
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Moyer JH, Beazley HL. Effectiveness of aramine in the treatment of shock. Am Heart J. 1955;50(1):136-
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