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Trial registered on ANZCTR


Registration number
ACTRN12624000342516p
Ethics application status
Submitted, not yet approved
Date submitted
28/02/2024
Date registered
26/03/2024
Date last updated
26/03/2024
Date data sharing statement initially provided
26/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial of the effectiveness of tablet medication to prevent low blood pressure after surgery
Scientific title
A pilot trial of the effectiveness of midodrine, atomoxetine or placebo to prevent ward hypotension in adults who are hypotensive in the Post Anaesthesia Care Unit after major surgery.
Secondary ID [1] 310199 0
Nil
Universal Trial Number (UTN)
U1111-1295-8008
Trial acronym
The FAME trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Postoperative hypotension 330865 0
Condition category
Condition code
Surgery 327664 327664 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The trial involves two intervention groups:
1. Midodrine 10mg oral tablet (as encapsulated GMP-certified product) every eight hours over the first 24 hours post-operatively, the first dose being administered within 4 hours of surgery.
2. Atomoxetine 18mg oral tablet (as encapsulated GMP-certified product) once, followed by placebo partially pregelatinized starch filled capsules at 8 and 16 hours after the first administration of investigational product, the first dose being administered within 4 hours of surgery..

Adherence to the allocated intervention will be checked via the electronic medical record.
Intervention code [1] 326594 0
Prevention
Comparator / control treatment
Placebo partially pregelatinized starch filled capsule (encapsulated GMP-certified product) administered every eight hours for the first 24 hours post-operatively, the first dose being administered within 4 hours of surgery..

Adherence to the allocated intervention will be checked via the electronic medical record.
Control group
Placebo

Outcomes
Primary outcome [1] 337231 0
Minimum recruitment rate per week established via review of trial screening and recruitment logs.
Timepoint [1] 337231 0
Over duration of trial
Secondary outcome [1] 431133 0
The proportion of patients who received the randomised intervention in its entirety via review of the electronic medical record medication administration records.
Timepoint [1] 431133 0
Over duration of trial
Secondary outcome [2] 431134 0
The rate of “unknown” response to the blinding questionnaire. The blinding questionnaire has been specifically developed for this study and is assessed via review of study records.
Timepoint [2] 431134 0
Over the duration of the trial
Secondary outcome [3] 431135 0
The acceptability of the interventions, including whether the intervention is acceptable to anaesthetists and research staff using the Acceptability of Intervention Measure.
Timepoint [3] 431135 0
At end of enrolment
Secondary outcome [4] 431136 0
The proportion of participants who decline to provide continuation of participation/retention of data when approached assessed via review of study records.
Timepoint [4] 431136 0
Over the duration of the trial
Secondary outcome [5] 431137 0
The proportion of case report forms correctly completed assessed via audit of study records.
Timepoint [5] 431137 0
Over the duration of the trial
Secondary outcome [6] 431138 0
The time required to complete all trial procedures in minutes per patient as assessed by the trial invetigators noting the time between the start and end of the relevant procedures.
Timepoint [6] 431138 0
At end of enrolment
Secondary outcome [7] 431139 0
An estimate of the risk of hypotension (defined as any systolic blood pressure (SBP) measurement less than 90 mmHg or any new vasoactive medication requirement) assessed from the electronic medical record.
Timepoint [7] 431139 0
Within 24 hours of discharge from the Post Anaesthesia Care Unit (PACU)
Secondary outcome [8] 431140 0
The absolute efficacy of the medications, including SBP at each time point assessed via the electronic medical record.
Timepoint [8] 431140 0
At 8, 16 and 24 hours after discharge from the PACU
Secondary outcome [9] 431141 0
The risk of hypotension after study product discontinuation assessed from the electronic medical record.
Timepoint [9] 431141 0
At between 24 and 48 hours after surgery, and between 48 and 72 hours after surgery.
Secondary outcome [10] 431142 0
The risk of in-hospital mortality recorded in the electronic medical record.
Timepoint [10] 431142 0
From the time of enrolment and each of discharge from hospital for the index admission (in-hospital mortality), and 30 days and 90 days after enrolment.
Secondary outcome [11] 431143 0
An estimate of health economic effects, including modelling of cost savings based on changes to need for MET calls, ICU admission, and mortality in each group.
Timepoint [11] 431143 0
At the conclusion of study.
Secondary outcome [12] 432858 0
The relative efficacy of the medications, including SBP at each time point assessed via the electronic medical record.
Timepoint [12] 432858 0
At enrolment, 8 hours and 16 hours after enrolment.
Secondary outcome [13] 432859 0
The risk of myocardial injury noted in the electronic medical record notes.
Timepoint [13] 432859 0
From the time of enrolment until discharge from hospital for the index admission.
Secondary outcome [14] 432860 0
The risk of acute kidney injury noted in the electronic medical record notes.
Timepoint [14] 432860 0
From the time of enrolment until discharge from hospital for the index admission.
Secondary outcome [15] 432861 0
The risk of delirium noted in the electronic medical record notes.
Timepoint [15] 432861 0
Between enrolment and discharge from hospital for the index admission.
Secondary outcome [16] 432862 0
The risk of headache noted in the electronic medical record notes.
Timepoint [16] 432862 0
Between enrolment and discharge from hospital for the index admission.
Secondary outcome [17] 432863 0
The risk of hypertension (Systolic BP greater than 180 mmHg) noted in the electronic medical record notes.
Timepoint [17] 432863 0
Between enrolment and discharge from hospital for the index admission.
Secondary outcome [18] 432864 0
The risk of heart failure noted in the electronic medical record notes.
Timepoint [18] 432864 0
Between enrolment and discharge from hospital for the index admission.
Secondary outcome [19] 432865 0
The risk of arrythmias noted in the electronic medical record notes.
Timepoint [19] 432865 0
Between enrolment and discharge from hospital for the index admission.
Secondary outcome [20] 432866 0
The risk of stroke noted in the electronic medical record notes.
Timepoint [20] 432866 0
Between enrolment and 30 days after surgery.
Secondary outcome [21] 432867 0
The risk of clinically significant bleeding (defined as bleeding requiring and of surgical or interventional radiology intervention, blood transfusion or the development of a new permanent disability due to bleeding) noted in the electronic medical record notes.
Timepoint [21] 432867 0
Between enrolment and discharge from hospital for the index admission.
Secondary outcome [22] 432868 0
The risk of psychiatric disturbance noted in the electronic medical record notes.
Timepoint [22] 432868 0
Between enrolment and discharge from hospital for the index admission.
Secondary outcome [23] 432869 0
The number of days alive and at home assessed via the electronic medical record.
Timepoint [23] 432869 0
Between enrolment and both 30 and 90 days after enrolment.
Secondary outcome [24] 432870 0
The risk of intensive care unit admission assessed via the electronic medical record.
Timepoint [24] 432870 0
Between enrolment and 14 days after enrolment.
Secondary outcome [25] 432873 0
The number of Medical Emergency Team calls assessed via the electronic medical record.
Timepoint [25] 432873 0
Between enrolment and discharge from hospital for the index admission.
Secondary outcome [26] 432874 0
The number of changes to Medical Emergency Team calling criteria as assessed via the electronic medical record.
Timepoint [26] 432874 0
Between enrolment and discharge from hospital for the index admission.
Secondary outcome [27] 432875 0
The number of alterations to the patient's usual (at home) medication regime required, as noted in the electronic medical record notes.
Timepoint [27] 432875 0
Between enrolment and discharge from hospital for the index admission as noted in the electronic medical record notes.
Secondary outcome [28] 432876 0
The risk of readmission to hospital (at the index hospital) for surgical complications,
Timepoint [28] 432876 0
Between enrolment and discharge from hospital for the index admission as noted in the electronic medical record notes.
Secondary outcome [29] 432877 0
The length of hospital stay for the index surgery as noted in the electronic medical record notes.
Timepoint [29] 432877 0
Between enrolment and discharge from hospital for the index admission.
Secondary outcome [30] 432878 0
The rate of incorrect guesses by the treating anaesthetist to which product the participant has been allocated to in each investigational product group via a study-specific questionnaire.
Timepoint [30] 432878 0
At the time of enrolment.

Eligibility
Key inclusion criteria
The study will include patients:
• aged equal to or greater than 18 years, and
• who have had major non-cardiac, non-obstetric surgery, under general anaesthesia who are expected to stay at least two postoperative nights in hospital, and
• who are hypotensive (SBP <90 mmHg) for at least 10 minutes in the PACU or who are administered vasoactive medication in PACU,
• who are assessed as suitable for discharge to the ward, and
• who are able to communicate in English, including with the support of an interpreter.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
The study will exclude potential participants where:
• age is less than 18 years old
• hypotension was present before surgery
• there is a clear cause of hypotension not related to vasodilation as assessed by the treating anaesthetist, including:
o arrhythmia
o bleeding requiring intervention
o acute reduction in cardiac output
o anaphylaxis
o other clinical explanation requiring specified treatment
• the patient is in cardiac arrest,
• they are receiving intravenous vasopressor infusions and are planned for admission to the intensive care unit,
• they are unable to safely swallow capsules,
• there is a surgical necessity to avoid vasopressors
o Intracranial neurosurgery
o Renal transplant
o Bowel anastomosis
o Reconstructive flap surgery (inc. DIEP, limb or head and neck free flap)
• they are receiving dialysis,
• they are pregnant or breastfeeding,
• they are unable to communicate at all in English,
• There is a known contraindication to a study medication:
o Hypersensitivity to the active substance or to any of the excipients
o Hypersensitivity to atomoxetine or any excipients in this product.
o Severe organic heart disease (e.g., bradycardia, recent heart attack, congestive heart failure, cardiac conduction disturbances or aortic aneurysm).
o Hypertension (current and severe – e.g., SBP > 160 mmHg)
o Serious obliterative blood vessel disease, cerebrovascular occlusions and vessel spasms.
o Acute kidney disease or severe renal impairment (creatinine clearance of less than 30 ml/min).
o Serious prostate disorder
o Urinary retention
o Proliferative diabetic retinopathy
o Phaeochromocytoma.
o Hyperthyroidism or thyrotoxicosis.
o Narrow angle glaucoma.
o Uncontrolled hyperthyroidism
o Use of Monoamine Oxidase Inhibitors with other drugs that affect brain monoamine concentrations
• Are previously enrolled in the FAME study
• Or are prescribed medications that inhibit cytochrome CYP2D6

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Preparation of the investigational products (including placebos) for this trial will be handled by a Good Manufacturing Practice (GMP) licensed manufacturer (OptimaOvest), with all agents encapsulated in identical AAA DB capsules and delivered to RMH ready for clinical use in identical patient packaging labelled “FAME trial study drug”, including labelling indicating which are the first, second and third doses of investigational product. There will be no markings on the capsules or blister pack to indicate the investigational product contained within the capsules. As all three investigational products will be encapsulated in identical capsules, the allocation of the patient will be blinded to the investigators, treating anaesthetist, patient, recovery and ward nurses. Allocation concealment of treatment group for the outcome assessors will be maintained until the data analysis is complete.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation of eligible patients to the control group, midodrine or atomoxetine group will occur using permuted block randomisation in a 1:1:1 ratio, with a variable block size of three, six and nine, stratified by risk of 30-day mortality using the National Safety and Quality Improvement Program mortality calculator (with strata of <1%, 1-5% and >5%). The randomisation list will be computer-generated by an independent statistician and carried out centrally to ensure concealment.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2024
Actual
Date of last participant enrolment
Anticipated
28/03/2025
Actual
Date of last data collection
Anticipated
30/06/2025
Actual
Sample size
Target
90
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26083 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 41938 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 314367 0
Charities/Societies/Foundations
Name [1] 314367 0
The Australian and New Zealand College of Anaesthetists
Country [1] 314367 0
Australia
Primary sponsor type
Hospital
Name
The Royal Melbourne Hospital
Address
Country
Australia
Secondary sponsor category [1] 316317 0
None
Name [1] 316317 0
Address [1] 316317 0
Country [1] 316317 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 313460 0
The Royal Melbourne Hospital Human Research Ethics Committee
Ethics committee address [1] 313460 0
https://www.thermh.org.au/research/researchers/ethics
Ethics committee country [1] 313460 0
Australia
Date submitted for ethics approval [1] 313460 0
16/11/2023
Approval date [1] 313460 0
Ethics approval number [1] 313460 0

Summary
Brief summary
Patients often experience low blood pressure following major surgery, which may be an emergency situation that could compromise organ function and lead to complications and even death. The trial is a pilot trial of tablet-based therapies that increase the blood pressure and see if they would be useful to prevent low blood pressure after surgery in preparation for a large definitive study in the future. The pilot trial will examine how many patients can be enrolled, as well as how acceptable the trial is to patients, clinicians and researchers, whether there are any problems in the design or execution of the trial and whether the consent procedures which have had to be specially designed for the complex situation after surgery are acceptable. The two medications being tested are widely used in clinical practice to treat low blood pressure that occurs when part of the nervous system does not regulate blood pressure properly called orthostatic hypotension, which the researchers believe there is a mechanism linking this problem to low blood pressure after surgery. Any treatment that could prevent this complication of surgery while being simpler than current options like admission to intensive care would be an important development. This pilot trial will establish the groundwork for a definitive clinical trial in the future that would aim to help reduce the risk of complications and promote recovery after surgery while using health resources efficiently.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128238 0
Dr Ned Douglas
Address 128238 0
The Royal Melbourne Hospital, 300 Grattan St, Parkville, Victoria, Australia, 3050
Country 128238 0
Australia
Phone 128238 0
+61 3 93427136
Fax 128238 0
Email 128238 0
[email protected]
Contact person for public queries
Name 128239 0
Ned Douglas
Address 128239 0
The Royal Melbourne Hospital, 300 Grattan St, Parkville, Victoria, Australia, 3050
Country 128239 0
Australia
Phone 128239 0
+61 3 93427000
Fax 128239 0
Email 128239 0
[email protected]
Contact person for scientific queries
Name 128240 0
Ned Douglas
Address 128240 0
The Royal Melbourne Hospital, 300 Grattan St, Parkville, Victoria, Australia, 3050
Country 128240 0
Australia
Phone 128240 0
+61 3 93427000
Fax 128240 0
Email 128240 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.