The ROCKet trial, a large-scale, multi-center study, is currently underway to determine whether perioperative intravenous ketamine can reduce the incidence of chronic post-surgical pain (CPSP). The trial is actively recruiting over 4800 adult patients undergoing a variety of major surgeries associated with a risk of CPSP across Australia, New Zealand, and Hong Kong.
The primary objective of the ROCKet trial is to assess whether IV ketamine, administered immediately prior to and for up to 72 hours following surgical incision, reduces the incidence of CPSP at 3 months after surgery, compared to placebo. Secondary objectives include measuring the effect of perioperative ketamine on indices of acute postoperative pain severity, side effects, and quality of recovery. Ketamine effect on CPSP incidence at 12 months is also being measured.
Trial Design and Methodology
The ROCKet trial is a randomized, double-blind, placebo-controlled trial. Patients are randomized to receive either ketamine or a saline placebo. Those in the ketamine arm receive an intraoperative loading dose of 0.5 mg/kg (capped at 100 kg body weight) after anesthesia induction and prior to surgical incision, followed by an infusion of 0.125 mg/kg/h until wound closure. The infusion is recommenced in the post-anesthesia care unit (PACU) at the same rate and continued for up to 72 hours. The placebo arm receives a loading and infusion of the placebo solution at an identical volume and infusion rate.
Randomization is stratified by hospital and the presence or absence of preoperative pain in the area of surgery (Numerical Rating Scale [NRS] score for average pain in last 24 hours of ≥ 3/10). The trial is being conducted in metropolitan and regional acute care hospitals in Australia, New Zealand, and Hong Kong. Participating sites have access to an acute pain service within their hospital and the equipment available to administer trial drug intraoperatively and postoperatively.
Inclusion and Exclusion Criteria
Inclusion criteria include consenting adult patients (18 years or more) presenting for elective or expedited surgery under anesthesia for a variety of major surgeries associated with CPSP. Exclusion criteria cover a range of relative or absolute contraindications to ketamine administration or to participation in the trial.
Data Collection and Endpoints
Preoperative data relevant to the risk of CPSP, including demographics, major co-morbidities, preoperative medications, and perioperative data, are collected. The primary endpoint is the incidence of CPSP at 3 months post-surgery. CPSP is defined as pain in the area of the index surgery in the previous week which either was not present preoperatively or is different in site, nature, or intensity (NRS score ≥ 2/10 difference) to any pain present at the site prior to surgery.
Secondary endpoints include the effect of ketamine on indices of acute postoperative pain severity (opioid consumption measured as oral morphine equivalents, and NRS pain scores) on the first three postoperative days (or until hospital discharge) and quality of recovery in the two trial treatment arms will be compared using the QoR-15 on day 1 post-surgery.
Statistical Analysis and Power
Trial sample size was initially calculated using CPSP incidence data at 12 months post-surgery, collected from a broad sample of patients who underwent major surgery and were recruited to the ENIGMA II trial and the ROCKet pilot study. Following alignment of the timing of the trial primary endpoint with the new ICD-11 definition of CPSP in 2022, the sample size was not changed. The observed pooled incidence (95% CI) of CPSP at 3 months post-surgery based on blinded EAC-adjudicated CPSP data from the first 1500 recruited patients included in the planned interim analysis is 24 (22–27)%. Assuming the final sample size of 4884 patients is achieved and using 22% as a conservative estimate of the overall incidence of CPSP at 3 months, the study has at least 80% power to detect a clinically significant reduction of at least 15% in incidence of CPSP at 3 months by ketamine (a decrease from 23.75% to 20.25%, or RR of 0.85).
Safety and Monitoring
Data on a range of adverse events among recruited patients is recorded during admission, at discharge from hospital, and at 3 months post-surgery, with complications classified according to body system. Serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) are reported for events that are unexpected given the participant’s underlying condition, and in the opinion of the investigator, the event is possibly related to the ROCKet trial solution infusion. SAEs and SUSARs are reported to the trial coordinating center who are responsible for informing the relevant ethics committees and the administering institution for the trial, within 24 hours of the site investigators becoming aware of the event, using a dedicated reporting form. These reports are reviewed by the DSMC.
