Preventing pAIn With NMDA Antagonists - Steroids in Thoracoscopic lObectomy Procedures (PAIN-STOP) Pilot Trial

Phase 3

Terminated

• Conditions: Pain, Postoperative
• Interventions: Drug: Steroid active; Drug: NMDA active; Drug: Steroid placebo; Drug: NMDA placebo

• Registration Number: NCT02950233
• Lead Sponsor: Population Health Research Institute

Brief Summary

The objective of the PAIN-STOP trial is to assess the feasibility of a larger randomized controlled trial (RCT) evaluating NMDA antagonists and IV steroids, as compared to placebo, in decreasing the chances of clinically significant persistent post-surgical pain (PPSP) after video assisted thoracoscopic surgeries (VATS). This is a multi-centre randomized, controlled clinical trial with a 2 x 2 factorial design. The pilot phase of the trial will recruit 48 patients and follow them for 3 months. Patients will be randomized to one of four groups: 1) NMDA active + Steroid placebo; 2) Steroid active + NMDA placebo; 3) NMDA active + Steroid active; 4) NMDA placebo + Steroid placebo.

Detailed Description

Persistent Post-Surgical Pain (PPSP) after Video Assisted Thoracic Surgery (VATS) lobectomy procedures is an important health problem for which there is no effective method of prevention. NMDA antagonists and steroids can modify pain signaling-sensitization pathways, and inflammatory-immune pathways, and hence can potentially prevent the development of PPSP. These agents have been safely used in thoracic surgeries to obtain many perioperative benefits, without increasing the harmful effects. Since these agents act by different biological mechanisms, it is appropriate to study their effects in a factorial design to increase the trial efficiency. Before conducting a large multicenter trial, we propose to establish the feasibility by carrying out this feasibility trial.

The objective of the PAIN-STOP trial is to assess the feasibility of a larger randomized controlled trial (RCT) evaluating NMDA antagonists and IV steroids, as compared to placebo, in decreasing the chances of clinically significant persistent post-surgical pain (PPSP) after video assisted thoracoscopic surgeries (VATS). This is a multi-centre randomized, controlled clinical trial with a 2 x 2 factorial design. The pilot phase of the trial will recruit 48 patients and follow them for 3 months. Patients will be randomized to one of four groups: 1) NMDA active + Steroid placebo; 2) Steroid active + NMDA placebo; 3) NMDA active + Steroid active; 4) NMDA placebo + Steroid placebo. Follow-up visit will be conducted in hospital; day 8 and month 2 by a phone call; and in person follow-up visits at 30 days and 3 months post-randomization; for patients who cannot attend in person, a telephone follow up will be done.

Study Timeline

• Study First Submitted: 2016-10-28
• Study First Submitted QC: 2016-10-31
• Study First Posted: 2016-11-01
• Study Start: 2017-05-04
• Primary Completion: 2018-12-31
• Study Completion: 2019-03-31
• Status Verified: 2020-01
• Last Update Submitted: 2020-01-13
• Last Update Posted: 2020-01-18

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 27

Inclusion Criteria

• 18-75 years of age,
• Planned elective VATS pulmonary lobectomy,
• Provide written informed consent to participate.

Exclusion Criteria

• Current pain on the same side of the chest of moderate to severe intensity (>3/10 in 0-10 numerical rating scale (NRS) - where 0=no pain, 10=maximum pain),
• Known intracranial mass or cerebral aneurysm or raised intraocular pressure,
• Severe renal impairment (creatinine clearance based GFR of <30ml/min),
• Allergies to one or more of the study medications,
• Steroid treatment > 10mg/day of Prednisolone or its equivalent for > 3 weeks within the last 3 months,
• History of schizophrenia or bipolar disorder,
• History of drug addiction (prescription or non-prescription drug addiction diagnosed by a physician, excluding alcohol),
• Current diagnosis of Cushing's syndrome,
• Pregnancy,
• Previous participation in the PAIN-STOP trial.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
NMDA active + Steroid placebo	Steroid placebo	NMDA active: ketamine (0.5 mg/kg IV bolus pre-incision and 0.1 mg/kg/hr infusion postoperatively up to 24 hours) and oral memantine (5 mg BID \[first week\]; 10 mg BID \[following three weeks\]). Steroid placebo: two doses of normal saline; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.
Steroid active + NMDA placebo	Steroid active	NMDA placebo: normal saline (IV bolus pre-incision and infusion postoperatively up to 24 hours) and oral matching placebo to memantine (one capsule BID \[first week\]; one capsule BID \[following three weeks\]). Steroid active: two doses of dexamethasone; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.
NMDA active + Steroid active	Steroid active	NMDA active: ketamine (0.5 mg/kg IV bolus pre-incision and 0.1 mg/kg/hr infusion postoperatively up to 24 hours) and oral memantine (5 mg BID \[first week\]; 10 mg BID \[following three weeks\]). Steroid active: two doses of dexamethasone; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.
NMDA placebo + Steroid placebo	Steroid placebo	NMDA placebo: normal saline (IV bolus pre-incision and infusion postoperatively up to 24 hours) and oral matching placebo to memantine (one capsule BID \[first week\]; one capsule BID \[following three weeks\]). Steroid placebo: two doses of normal saline; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.
Steroid active + NMDA placebo	NMDA placebo	NMDA placebo: normal saline (IV bolus pre-incision and infusion postoperatively up to 24 hours) and oral matching placebo to memantine (one capsule BID \[first week\]; one capsule BID \[following three weeks\]). Steroid active: two doses of dexamethasone; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.
NMDA active + Steroid active	NMDA active	NMDA active: ketamine (0.5 mg/kg IV bolus pre-incision and 0.1 mg/kg/hr infusion postoperatively up to 24 hours) and oral memantine (5 mg BID \[first week\]; 10 mg BID \[following three weeks\]). Steroid active: two doses of dexamethasone; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.
NMDA placebo + Steroid placebo	NMDA placebo	NMDA placebo: normal saline (IV bolus pre-incision and infusion postoperatively up to 24 hours) and oral matching placebo to memantine (one capsule BID \[first week\]; one capsule BID \[following three weeks\]). Steroid placebo: two doses of normal saline; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.
NMDA active + Steroid placebo	NMDA active	NMDA active: ketamine (0.5 mg/kg IV bolus pre-incision and 0.1 mg/kg/hr infusion postoperatively up to 24 hours) and oral memantine (5 mg BID \[first week\]; 10 mg BID \[following three weeks\]). Steroid placebo: two doses of normal saline; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.

Primary Outcome Measures

Name	Time	Method
Follow-up	9 months	Ability to obtain follow-up in \>90% of enrolled patients, at three months.
Recruitment	6 months	Ability to recruit at least 4 patients per month per site, and complete the recruitment over a 6-month period.

Secondary Outcome Measures

Name	Time	Method
NRS - Incidence of PPSP	3 months	Intensity of PPSP on a scale of 0-10, at 3 months after randomization \[0-10 numerical rating scale (NRS) - where 0=no pain, 10=maximum pain\].
Use of narcotic analgesic medication	3 months	Use of narcotic analgesic medication \> 3 days/week beyond 4 weeks and up to 3 months after randomization.
Difference in Quality of Life	3 months	Difference in Quality of Life (QoL) using European Organization for Research and Treatment of Cancer (EORTC) QoL-30 at 3 months after randomization.
Thoracic surgery specific activity limitations	3 months	Difference in thoracic surgery specific activity limitations, measured at 3 months after randomization.
Change in global health status	3 months	Change in global health status measured using global impression of change (GIC) scale at 3 months after randomization.
NRS - Incidence of PPSP with movement evoked	3 months	Incidence of PPSP (in and/or around the surgical scar) at 3 months after randomization, as the presence of movement evoked pain \> 3/10 in 0-10 NRS.
Presence of NP	3 months	Presence of NP as \> 3 out 7 items using DN4 scale, at measured at 3 months after randomization.
BPI score	3 months	Difference in interference with activities of daily living measured using Brief Pain Inventory interference score, measured at 3 months after randomization.
Rate of change of postoperative pain intensity	3 months	The rate of change of postoperative pain intensity measured over time (pain trajectory).

Trial Locations

Locations (2)

St. Joseph's Healthcare; 🇨🇦 Hamilton, Ontario, Canada

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States