A phase 3 double-blind placebo-controlled randomized trial of methoxyflurane with periprostatic local anaesthesia to reduce the discomfort of transrectal ultrasound-guided prostate biopsy (Pain-Free TRUS B).

Background Transrectal ultrasound-guided (TRUS) prostate biopsy is associated with significant discomfort, despite the use of periprostatic infiltration of local anaesthetic (PILA).

General aim To determine the efficacy and safety of inhaled methoxyflurane plus PILA versus PILA alone in men undergoing TRUS biopsy of the prostate.

Objectives (endpoints)

To determine the effects of inhaled methoxyflurane on:

Primary

1. Pain-rated by participants 15 minutes after biopsy.

   Secondary

2. Other aspects of the biopsy experience rated by participants 15 minutes and 7-35 days after the biopsy

3. Willingness to undergo a biopsy in the future

4. Urologist's ratings of the participant's biopsy experience (study specific questionnaire completed after the biopsy)

5. Biopsy completion (80% or more of the planned number of biopsies being taken)

6. Frequency of specified adverse events (CTC AE v4.03 and Clavien-Dindo Classification).

7. Frequency of hospitalisation

Design Multi-centre, placebo-controlled, double-blinded, centrally randomised (1:1), stratified, phase 3 trial.

Target population Men scheduled to undergo their first TRUS biopsy of the prostate for a raised PSA or abnormal digital rectal examination (DRE).

Study treatments

Participants randomised to inhaled:

Methoxyflurane (Penthrox®, experimental group). OR Placebo (0.9% saline, control group

All participants are subsequently treated with PILA (2% lignocaine), injected into and around the prostate about 5 minutes before the biopsy.

Assessments Participants will be assessed at time of scheduling of the TRUS prostate biopsy (up to 84 days prior to randomisation), on the day of biopsy, and at the post biopsy clinic (7-35 days after the biopsy). Assessments comprise of medical history and standard blood tests at baseline, patient questionnaire on the day of biopsy and post(7-35 days) biopsy and safety assessments on the day of biopsy and post (7--35 days) biopsy.

Statistical considerations 420 participants provides over 85% power at the two-sided 5% level of significance to detect a 0.80 point difference in mean pain scores (on scale from 0-10) assuming a standard deviation of 2.5 whilst allowing for missing data. A 0.80 point shift in mean pain scores should correspond to a reduction of more than 1/3 in the proportion of men reporting troublesome levels of pain.

Inclusion Criteria:

1. Males older than 18 years scheduled to undergo a TRUS biopsy of the prostate.
2. Adequate liver function: ALT, AST, or bilirubin ≤ 2 x ULN
3. Adequate renal function: serum eGFR> 30 ml/min/1.73m2
4. Willing and able to complete questionnaires in English
5. Willing and able to undergo TRUS biopsy within 7 days of randomisation
6. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
7. Signed, written informed consent

Exclusion Criteria:

1. Previous TRUS biopsy of the prostate
2. Personal or family history of malignant hyperthermia
3. History of significant liver disease
4. Hypersensitivity to fluorinated anaesthetics or other inhalational anaesthetics
5. Concurrent use of barbiturates or tetracycline antibiotics
6. Concurrent illness that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
7. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse.