Comparison of standard current anaesthetics with Phaxan™, a new intravenous anaesthetic, for efficacy, safety profile and preservation of brain function after hip replacement surgery.
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
Drawbridge Pharmaceuticals Pty Ltd
40 participants
Apr 12, 2018
Interventional
Conditions
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 However, it occasionally caused a serious allergic reaction and so was withdrawn from use.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.
Eligibility
Inclusion Criteria7
- 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
Exclusion Criteria25
- 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.
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Interventions
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%
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ACTRN12618000064202