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Trial registered on ANZCTR


Registration number
ACTRN12618000064202
Ethics application status
Approved
Date submitted
3/12/2017
Date registered
17/01/2018
Date last updated
18/02/2019
Date data sharing statement initially provided
23/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparison of standard current anaesthetics with Phaxan™, a new intravenous anaesthetic, for efficacy, safety profile and preservation of brain function after hip replacement surgery.
Scientific title
A Pivotal Phase III trial of Phaxan™, a new formulation of alphaxalone dissolved in sulfobutyl ether beta cyclodextrin, for anaesthesia in patients undergoing hip joint replacement; stage 1, the pilot study
Secondary ID [1] 293522 0
Sponsor trial number (Drawbridge Pharmaceuticals): PHAX002
Universal Trial Number (UTN)
U1111-1198-0412
Trial acronym
PHAXTIVA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiovascular complications of anaesthetics
305708 0
Decreased cognitive function after anaesthesia and hip surgery 305709 0
Condition category
Condition code
Anaesthesiology 304924 304924 0 0
Anaesthetics
Cardiovascular 304925 304925 0 0
Other cardiovascular diseases
Surgery 304926 304926 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
PHAXTIVA: a prospective randomised blinded comparison of alphaxalone given intravenously by bolus (0.5mg/kg) for induction and by continuous infusion (rate adjusted between 1.0 and 5.0 mg/kg/hr) for maintenance of anaesthesia, for hip replacement surgery. The maintenance infusion will be started at 2mg/kg/hr immediately after induction of anaesthesia, and thereafter titrated to keep a constant anaesthetic depth (BIS between 40 and 60) from the time of induction until surgery is completed and the skin closed, at which time point the infusion will be stopped. Criteria for infusion rate adjustment:
if the BIS < 40, the anaesthetic dose will be decreased by 10%;
if BIS > 60, the anaesthetic dose will be increased by 10%
Intervention code [1] 299755 0
Treatment: Drugs
Comparator / control treatment
COMPARATOR GROUP 1
intravenous propofol injections given by bolus (1.5mg/kg) for induction and by continuous infusion (rate adjusted between 4.0 and 10.0 mg/kg/hr) for maintenance of anaesthesia for hip replacement surgery. The maintenance infusion will be started immediately after induction of anaesthesia at 6mg/kg/hr, and thereafter titrated to keep a constant anaesthetic depth (BIS between 40 and 60) from the time of induction until surgery is completed and the skin closed, at which time point the infusion will be stopped. Criteria for infusion rate adjustment:
if the BIS < 40, the anaesthetic dose will be decreased by 10%;
if BIS > 60, the anaesthetic dose will be increased by 10%.

COMPARATOR GROUP 2
intravenous propofol injection given by bolus (1.5mg/kg) for induction followed by sevoflurane inhalation (between 0.5 and 3% end-tidal concentration) for maintenance of anaesthesia for hip replacement surgery. At the start of the maintenance phase of anaesthesia, the vapouriser will be set to achieve an initial end-tidal sevoflurane concentration of 1.4%. Thereafter the end-tidal concentration will be titrated to keep a constant anaesthetic depth (BIS between 40 and 60) from the time of induction until surgery is completed and the skin closed, at which time point the vapouriser will be switched off. Criteria for vapouriser adjustment:
if the BIS < 40, the vapouriser setting will be decreased by 10%;
if BIS > 60, the vapouriser setting will be increased by 10%
Control group
Active

Outcomes
Primary outcome [1] 304122 0
The incidence of falls in blood pressure greater than 20% of preanaesthesia levels assessed by invasive monitoring (intra-arterial cannula) associated with use of alphaxalone and comparator groups; all doses having been titrated to the same depth of anaesthesia (bispectral index between 40 and 60).
Timepoint [1] 304122 0
From time of induction of anaesthesia to recovery from anaesthesia in the postoperative care unit
Secondary outcome [1] 341031 0
Speed of recovery from anaesthesia will be compared between treatments with respect to the time from terminating anaesthesia to the following:
time to extubation of the trachea;
Timepoint [1] 341031 0
From end of surgery to 4 hours post op.
Secondary outcome [2] 341033 0
The treatment groups will be compared using integrated pharmacokinetic/pharmacodynamic modelling of drug levels of alphaxalone and propofol and bispectral index measurements.
Plasma drug concentrations (alphaxalone and propofol) and bispectral index (BIS) values will be analyzed with an integrated PKPD model using non linear mixed effects models. Allometry, scaled to a 70-kg person, will be used for PK size standardisation. Effect (BIS) will be described using a fractional sigmoidal EMAX model. A 3-compartment model to fit PK data with an additional effect compartment, linked by an equilibration half-time (t1/2keo), will be applied to generate alphaxalone and propofol PK parameter estimates:
clearance (CL) L/min; central volume of distribution (V1) L; inter-compartment clearances (Q2) and (Q3) L/min; and peripheral volumes of distribution (V2) and (V3) L. PD interrogation of this model will be used to reveal baseline BIS, a fractional maximum effect (EMAX), alphaxalone and propofol concentrations that cause 50% maximal effect (C50) mg/L, a Hill coefficient (?), and the effect site equilibration constant (t1/2keo).

Timepoint [2] 341033 0
Blood samples will be taken for analysis of alphaxalone and propofol drug concentrations and also simultaneous bispectral index measurements will be recorded at the following time points:

at the start of drug administration (time zero) and at 30, 60 and 90 seconds, 2, 5, 10, 15, 30, 60, 90 minutes from time zero and every 30 mins thereafter until the surgical incision is closed

further blood samples will be withdrawn at the completion of skin closure at which time anaesthetic agents will be switched off and more samples collected at 30, 60 and 90 seconds, 2, 5, 10, 15, 30, 60, 90, 120, 180, 240 and 360 minutes after that

BIS measurements will be recorded every 30 seconds until 15 minutes after the start of study drug administration (time zero) and then 5 minutely until the time surgery finished and anaesthetic medication is stopped

more BIS values will be recorded every 30 seconds until 15 minutes after the completion of skin closure and then 5 minutely (including PACU) until the BIS reaches 95 or greater.
Secondary outcome [3] 341034 0
Serum samples will be taken for analysis of levels of brain derived neurotrophic factor (BDNF) for comparison with delirium and cognitive assessments and the differential effects of the anaesthetic treatments with respect to these measurements
Timepoint [3] 341034 0
Blood will be taken for measurement of BDNF levels in serum of all subjects in each of the three treatment groups at the following times:
within 15 minutes prior to induction
30 minutes after start of surgery
at completion of surgery (skin closure)
at 10 am on each postoperative day 1 to 7
Secondary outcome [4] 341683 0
Speed of recovery from anaesthesia will be compared between treatments with respect to the time from terminating anaesthesia to the following:
time to opening eyes to command.
Timepoint [4] 341683 0
From end of surgery to 4 hours post op.
Secondary outcome [5] 341684 0
Speed of recovery from anaesthesia will be compared between treatments with respect to the time from terminating anaesthesia to the following:
time to return of bispectral index of 90 or above.
Timepoint [5] 341684 0
From end of surgery to 4 hours post op.
Secondary outcome [6] 341685 0
Speed of recovery from anaesthesia will be compared between treatments with respect to the time from terminating anaesthesia to the following:
time to recover score of 0 on the Richmond agitation and sedation scale in the post anaesthesia care unit (upto 4 hours after surgery).
Timepoint [6] 341685 0
From end of surgery to 4 hours post op.
Secondary outcome [7] 341686 0
The treatment groups will be compared for the incidence and severity of postoperative delirium using the Richmond Agitation and Sedation Scale (RASS).
30 minutes, 60 minutes, 90 minutes and 120 minutes post surgery and also daily from 1 to 7 days postoperatively.
Timepoint [7] 341686 0
30 minutes, 60 minutes, 90 minutes and 120 minutes post surgery and also daily from 1 to 7 days postoperatively

.
Secondary outcome [8] 341687 0
The treatment groups will be compared for the incidence and severity of postoperative delirium using the Mini Mental State Examination (MMSE).
Timepoint [8] 341687 0
120 minutes post surgery and also daily from 1 to 7 days postoperatively.
Secondary outcome [9] 341688 0
The treatment groups will be compared for the incidence and severity of postoperative delirium using the Attention Screening Examination.
Timepoint [9] 341688 0
120 minutes post surgery and also daily from 1 to 7 days postoperatively.
Secondary outcome [10] 341689 0
The treatment groups will be compared for the incidence and severity of postoperative delirium using the CAM-ICU form.
Timepoint [10] 341689 0
120 minutes post surgery and also daily from 1 to 7 days postoperatively.
Secondary outcome [11] 341690 0
The treatment groups will be compared for the incidence and severity of postoperative delirium using the Quality of Recovery Scale (QoR-15).
Timepoint [11] 341690 0
120 minutes post surgery and also daily from 1 to 7 days postoperatively.
Secondary outcome [12] 341691 0
The treatment groups will be compared for cognitive performance using the difference between preoperative and postoperative scores in the Mini Mental State Examination (MMSE).
Timepoint [12] 341691 0
7 days and 3 months postoperatively
Secondary outcome [13] 341692 0
The treatment groups will be compared for cognitive performance using the difference between preoperative and postoperative scores in the Auditory Verbal Learning Test (AVLT).
Timepoint [13] 341692 0
7 days and 3 months postoperatively
Secondary outcome [14] 341693 0
The treatment groups will be compared for cognitive performance using the difference between preoperative and postoperative scores in the Trail making Test A and B.
Timepoint [14] 341693 0
7 days and 3 months postoperatively
Secondary outcome [15] 341694 0
The treatment groups will be compared for cognitive performance using the difference between preoperative and postoperative scores in the Digit Symbol Substitution Test (DSST).
Timepoint [15] 341694 0
7 days and 3 months postoperatively
Secondary outcome [16] 341695 0
The treatment groups will be compared for cognitive performance using the difference between preoperative and postoperative scores in the Controlled Oral Word Association Test (COWAT).
Timepoint [16] 341695 0
7 days and 3 months postoperatively
Secondary outcome [17] 341696 0
The treatment groups will be compared for cognitive performance using the difference between preoperative and postoperative scores in the Semantic Fluency Test.
Timepoint [17] 341696 0
7 days and 3 months postoperatively
Secondary outcome [18] 341697 0
The treatment groups will be compared for cognitive performance using the difference between preoperative and postoperative scores in the Grooved Pegboard Test.
Timepoint [18] 341697 0
7 days and 3 months postoperatively

Eligibility
Key inclusion criteria
Patients of both genders scheduled for elective single or bilateral hip joint replacements or revisions.

American Society of Anaesthesia fitness grades 1 to 3

BMI 20-40

Score on Mini Mental State Examination greater than 23

Fluency in English as first language

If female, the participant must be (i) of non-childbearing potential, defined as surgically sterile (i.e., hysterectomy or tubal ligation) or at least 2 years post-menopausal); or (ii) [either] practicing [abstinence or] a medically acceptable form of contraception (i.e., hormonal birth control, IUD, double barrier [male condom, diaphragm] or a barrier method plus a spermicidal agent [contraceptive foam or jelly]) which in the opinion of the Investigator is deemed effective. Male participants must agree to use a condom if engaging in sexual intercourse at any time during the duration of the study

If female, the participant must have a negative urine pregnancy test result at the Screening Visit, and be non-lactating
Minimum age
40 Years
Maximum age
95 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• The participant must not have been diagnosed with a stroke in the past year
• The participant must not have drunk alcohol for 24 hours prior to the surgery
• The participant must not have a diagnosis or a history of muscular dystrophy
• The participant must not have a diagnosis of Porphyria or a family history of the disease
• The participant must not have allergies to any drug to be used in the study
• The participant must not have a medical condition, other than a hip joint condition, that is not well controlled with treatment or the participant has any clinically significant condition that would, in the Investigator’s opinion, preclude study participation or would interfere with the study assessments
• The participant must not be involved in an active or pending workers compensation or insurance claim or disability claim or litigation related to hip pain, have settled such claims, or have received payments for such claims;
• The participant must not have used any illicit drugs of abuse, abused opioids or exhibited drug seeking behavior within 5 years prior to the screening visit;
• The participant must not have abused prescription medication or alcohol within 5 years prior to the screening visit.
• The participant must not have a positive alcohol or non-prescribed/ over the counter drugs of abuse test at Screening Visit
• The participant must not have a major psychiatric condition (e.g., major depression, schizophrenia)
• The participant must not have any clinically significant disease or abnormal surgical or medical condition which might compromise, hepatic, or renal function and alter the absorption, distribution, metabolism or excretion of the study drug;
• The participant must not have levels of Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 times the upper limits of normal (ULN) at Screening, or any laboratory abnormality which, in the opinion of the Investigator, would contraindicate study participation;
• The participant must have a creatinine clearance of at least 60 mL/min during the Pretreatment Screening Period, as determined by the Cockcroft-Gault equation:
eCCr = Gender * ((140 - Age) / (Cr)) * (Weight in kg/ 72)
Gender = 1 for males and 0.85 for females
eCCr = estimate of creatinine clearance
Cr = serum creatinine
• The participant must not be unwilling or unable to comply with the protocol or to cooperate fully with the Investigator and site personnel;
• The participant must not be unable to understand verbal or written English;
• The participant must not have a mini mental state examination score less than or equal to 23
• The participant must not have a clinically significant abnormal 12-lead ECG at the Screening Visit
• The participant must not be currently participating in another investigational drug study or have participated in an investigational drug study within the past 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to study drug administration;
• The participant must not have previously received study drug under this protocol.
• The participant must not have had surgery or been under anaesthetic within the last 3 months.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation to treatment group will be performed by pharmacy staff who will dispense the anaesthetic drugs for a patient known by a unique study identifier number. That number and the details of randomised treatment associated with that number plus patient details will be kept in a sealed opaque envelope attached to the clinical record form. The pharmacy staff will not be involved with direct patient care or in contact with blinded study staff. The drugs dispensed will be placed in a sealed box labelled with the subject study number and delivered to the anaesthetist in the operating room.

The anaesthetist administering the drug in the operating room and staff performing measurements in the operating room will be aware of the nature of the treatment; however the subject and all staff performing assessments of recovery will be unaware of which anaesthetic the subject has received.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is the pilot phase to determine the numbers needed for adequate power of a larger phase 3 study using a same or similar protocol.
All data will be listed. In general, data will be summarized using either descriptive statistics (number of non-missing observations, mean, median, standard deviation (SD), minimum and maximum for continuous data) or frequency counts and percentages for categorical data.
Baseline will be defined for each subject and will be defined as the last available, valid, non-missing assessment prior to the start of first Investigational Product administration. Unknown, Not Done, Not Applicable and other classifications of missing data will not be considered when calculating baseline observations. However, valid categorical observations will be considered for baseline calculations.
Hypothesis testing will be performed to compare the effects of the three anaesthetic regimens with respect to:
• Incidence of hypotension and use of metaraminol and ephedrine to treat
• Time to awaken to BIS 95 and RASS 0
• Incidence and severity of delirium
• Levels of BDNF
• Levels of measures of delirium and cognition
Plasma alphaxalone concentrations and bispectral index (BIS) values will be analysed using an integrated PKPD model using non-linear mixed effects models. Allometry, scaled to a 70-kg person, will be used for PK size standardisation. Effect (BIS) will be described using a sigmoidal EMAX model.
A 3-compartment model to fit PK data with an additional compartment, linked by an equilibration half-time (t1/2keo) to describe the effect compartment will be used. PK parameters will be presented using the mean, standard deviation, and number of subjects for each cohort.



Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 9480 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 18216 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 298134 0
Commercial sector/Industry
Name [1] 298134 0
Drawbridge Pharmaceuticals Pty Ltd
Address [1] 298134 0
23 Milton Parade,
Malvern
VIC 3144
Country [1] 298134 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Drawbridge Pharmaceuticals Pty Ltd
Address
23 Milton Parade,
Malvern,
VIC 3144
Country
Australia
Secondary sponsor category [1] 297217 0
None
Name [1] 297217 0
Address [1] 297217 0
Country [1] 297217 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299154 0
Research Ethics Committee, Royal Adelaide Hospital
Ethics committee address [1] 299154 0
CALHN Ethics Office,
Ground Floor, Basil Hetzel Institute,
TQEH,
37a Woodville Rd,
WOODVILLE
SA 5011
Ethics committee country [1] 299154 0
Australia
Date submitted for ethics approval [1] 299154 0
23/11/2017
Approval date [1] 299154 0
08/01/2018
Ethics approval number [1] 299154 0
PHAX002, HREC/17/RAH/523, R20171123

Summary
Brief summary
The purpose of this study is to find out if a new formulation of a previously used anaesthetic medication has clinical advantages over the currently used anaesthetic agents.
The anaesthetic agent alphaxalone was previously dissolved in a derivative of castor oil called CremophorEL, and included a similar drug alphadolone. This medication was called Althesin or Alfathesin and given to tens of thousands of patients for surgical anaesthesia between 1970 and 1983. It was regarded to be one of the safest intravenous anaesthetics because of a minimal effect on lowering blood pressure and suppressing breathing, both of which can be dangerous during and after surgery. However, it occasionally caused a serious allergic reaction and so was withdrawn from use. Investigations have since proved that the rare but serious allergic reactions were related to CremophorEL and not to alphaxalone.
The drugs currently used in most anaesthetics in Australia are propofol, which is a drug given by intravenous injection, and sevoflurane, an anaesthetic gas. Both of these medications have several disadvantages including a drop in blood pressure and depression of breathing. Further, propofol can cause severe pain on injection. Propofol solution also supports bacterial growth and, especially with long term use, requires careful handling to prevent infections such as septicaemia.
It has also become apparent in recent years that postoperative confusion, memory and thinking problems in older subjects occur frequently after some surgery. It has become clear in recent years that our current anaesthetic agents are not adequately protecting the brain against these conditions.
Drawbridge Pharmaceuticals has developed Phaxan, a water based formulation of alphaxalone which does not need the use of CremophorEL to be dissolved. Preclinical studies have shown that alphaxalone given as Phaxan™ requires the same dose needed to induce anaesthesia as the previous drug, Althesin. Further, it produces the same speed of onset and offset of sedation (or ‘sleep’), the same minimal effect on blood pressure and breathing, and the same fast clear-headed recovery. It is also possible that it has a protective effect against confusion and changes in thinking after surgery, and that patients will be awake and clear headed faster.

For the first time during the development process of a new anaesthetic preparation, the quality of recovery of brain function (cognition and memory) will be assessed before and for several months after surgery and anaesthesia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 79478 0
Prof Guy Ludbrook
Address 79478 0
Professor of Anaesthesia,
University of Adelaide and Royal Adelaide Hospital,
North Terrace,
Adelaide South,
South Australia 5000
Country 79478 0
Australia
Phone 79478 0
+61 8 8222 5421
Fax 79478 0
+61 8 8222 5887
Email 79478 0
Guy.Ludbrook@sa.gov.au
Contact person for public queries
Name 79479 0
Dr Colin Goodchild
Address 79479 0
Drawbridge Pharmaceuticals Pty Ltd
23 Milton Pde,
Malvern,
VIC 3144
Country 79479 0
Australia
Phone 79479 0
+61 3 9832 0733
Fax 79479 0
+61 3 9832 0610
Email 79479 0
colin@drawbridgepharmaceuticals.com.au
Contact person for scientific queries
Name 79480 0
Dr Colin Goodchild
Address 79480 0
Drawbridge Pharmaceuticals Pty Ltd
23 Milton Pde,
Malvern,
VIC 3144
Country 79480 0
Australia
Phone 79480 0
+61 3 9832 0733
Fax 79480 0
+61 3 9832 0610
Email 79480 0
colin@drawbridgepharmaceuticals.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
A) Full data set for every subject collected during the trial will be made available to the FDA and other regulatory authorities at the time of application for marketing.
B) Prior to that abbreviated data sets for each subject tabulated in a de-identified form will be made available to readers of resulting publications in scientific journals.
When will data be available (start and end dates)?
A) Full data with the regulatory authorities is uncertain, but estimated 2022.
B) Journal publication and accompanying data expected end 2019/beginning 2020.
Available to whom?
A) Regulatory authorities eg FDA, TGA
B) Scientific journals and all readers thereof
Available for what types of analyses?
Raw data than can be subjected to any analysis the reader wishes
By what mechanism will data be made available?
Paper form and electronic. A) will be restricted to the regulator but B) will be open to web access by scientific journal readership.
What supporting documents are/will be available?
Study protocol
Informed consent form
Clinical study report
Ethical approval
Summary results
Not applicable