Perioperative Vitamin C to Reduce Persistent Pain After Total Knee Arthroplasty (PROVISION)

PeRiOperative VItamin C to Reduce perSistent paIn After tOtal kNee Arthroplasty (PROVISION): a Pilot Multicentre Randomized Controlled Trial

Phase II Multicentre, pilot, parallel-group, blinded, 1:1 randomized controlled trial to determine the feasibility of conducting a larger definitive trail of using vitamin C to reduce persistent pain in patients undergoing total knee arthroplasty surgery.

Study Overview

• Status: Recruiting
• Conditions: Chronic Pain; Post Operative Pain; Knee Pain Chronic
• Intervention / Treatment: Drug: Vitamin C; Drug: Placebo

Detailed Description

PROVISION is a multicentre, pilot, parallel-group, blinded, randomized controlled trial of 100 patients undergoing total knee arthroplasty surgery. Consented eligible patients will be randomized to receive vitamin C: 2000 mg taken orally within 4 hours of the start of surgery, followed by 500 mg of vitamin C taken twice daily from post-operative day 1 to day 56 (8 weeks). Patient in the control group will receive placebo lactose monohydrate capsules. Study medications will be prepared to look similar and labelled as per regulatory requirements. Patients will follow up on post-operative days 1-3, weeks 2,4,6, and 8 post-operatively, and at 3- and 12-months post-operatively to report on pain, opioid and analgesic consumption, medication adherence, adverse events, functional, mood, and quality of life outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: James Khan, MD; Phone Number: 3243 416-340-4800; Email: James.Khan@medportal.ca
• Study Contact Backup: Name: Nour Ayach; Phone Number: 4221 (416) 340 4800; Email: Nour.Ayach@uhn.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • Recruiting
      • Toronto Western Hospital
      • Contact: Anuj Bhatia, MD; Email: Anuj.Bhatia@uhn.ca
    • Toronto, Ontario, Canada, M5G 1X5
      • Not yet recruiting
      • Mount Sinai Hospital
      • Contact: James Khan, MD; Email: James.Khan@medportal.ca
    • Toronto, Ontario, Canada, M4Y 1H1
      • Not yet recruiting
      • Sunnybrook - Holland Centre
      • Contact: Raman Mundi, MD; Email: Raman.Mundi@medportal.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients >18 years old
• Undergoing a unilateral or bilateral primary total knee arthroplasty for advanced osteoarthritis of the knee

Exclusion Criteria:

• TKA for infection (septic joint), fracture, ankylosing spondylitis, lupus, or psoriatic arthritis
• History of kidney stones, acute or chronic renal failure, hemochromatosis, or glucose-6-phosphate deficiency
• Unlikely to comply with follow-up (e.g., no fixed address, plans to move out of town)
• Language difficulties that would impede valid completion of questionnaires
• Planned staged bilateral TKA
• Treating surgeon deems patient inappropriate for inclusion in trial
• Any allergy or sensitivity to milk
• Pregnant or planning to become pregnant during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; Preoperative Vitamin C capsules	Drug: Vitamin C; Drug: Patients in the intervention group will receive 2g Vitamin C orally within 4 hours of the start of the surgery followed by 500 mg of Vitamin C to be taken orally twice a day from post-op day1 to day 56.; Other Names: Ascorbic Acid
Placebo Comparator: Placebo; Preoperative placebo capsules	Drug: Placebo; Drug: Patients in the placebo group will receive identical placebo capsules taken orally within 4 hours of the start of the surgery followed by placebo capsules taken orally twice a day from post-op day 1 to day 56.; Other Names: Lactose (Monohydrate)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study will determine feasibility of enrolling, recruiting, and follow-up with patients.	The study will assess the feasibility of enrolling, recruiting, and following-up with patients undergoing a primary total knee arthroplasty (TKA) through active monitoring of recruitment/enrollment rates on a monthly basis for a total of one year using excel trackers. The follow-up rate of patients will be assessed at 12 months based on completion of all 12 month questionnaires.	12 months
Clinical site compliance	Clinical site compliance with trial protocol will be determined based on number of protocol deviations at each site as logged on the deviation logs. This will be assessed on a monthly basis for a full year to maintain active monitoring of compliance.	12 months
Resource Assessment	This pilot study will help determine the resources required for larger definitive trial based on critical analysis of recruitment trackers to assess time spent on recruitment/enrollment.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of persistent pain	Pain intensity measured using 0-10 Numeric Rating Scale (NRS) scale at rest and movement	3 months and 12 months
Qualities and characteristics of persistent pain	Pain qualities measured using the 0-10 scale of the Short Form McGill Pain Questionnaire 2 (SF-MPQ-2)	3 months and 12 months
Persistent Neuropathic Pain	Neuropathic pain assessed on a binary scale of Yes or No using the Douleur Neuropathique 4 (DN4) symptoms interview	3 months and 12 months
Acute and chronic analgesic consumption	Analgesic and oral morphine-equivalent opioid consumption	Day of surgery, post-operative day 1-3, 3 months, and 12 months
Development of Complex Regional Pain Syndrome (CRPS)	Presence of CRPS measured by a physical assessment of sensory, vasomotor, sudomotor/edema, and motor/tropic categories using the Budapest Criteria	3 months and 12 months
Physical function	Patient reported outcome measure to assess level of function, daily living activities and their affect on pain measured by answering 12 questions using the Oxford Knee Score (OKS)	3 months and 12 months
Emotional functioning	Patients emotional functioning measured on a scale of 1-5 using the Profile of Mood States (POMS)	3 months and 12 months
Postoperative cognitive impairment	Assessment of different cognitive domains such as attention, concentration, memory, language, conceptual thinking, calculations, and orientation out of a total score of 22 using Montreal Cognitive Assessment - Blind (MoCA-BLIND)	3 months
Patient Satisfaction	Assessment of patient satisfaction with surgery on scale of 0-100	3 months and 12 months
Quality of life assessment	Patient reported assessment of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression on a scale of level 1 - level 5 using the EuroQol 5-dimension 5-level (EQ-5D-5L)	3 months and 12 months
Adverse events	Monitored as a secondary safety outcome using an assessment of follow-up visits for drug related adverse events and passive surveillance of clinical notes	3 months and 12 months

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: Canadian Institutes of Health Research (CIHR); The Arthritis Society, Canada
• Investigators: Principal Investigator: Raman Mundi, MD, Holland Orthopedic and Arthritic Centre; Principal Investigator: Harman Chaudhry, MD, Holland Orthopedic and Arthritic Centre; Principal Investigator: Jesse Wolfstadt, MD, Mount Sinai Hospital; Department of Surgery; Principal Investigator: James Khan, MD, University Health Network; Department of Anesthesia and Pain Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): April 4, 2024
• Primary Completion (Estimated): February 28, 2025
• Study Completion (Estimated): February 28, 2026

Study Registration Dates

• First Submitted: October 10, 2023
• First Submitted That Met QC Criteria: November 7, 2023
• First Posted (Actual): November 9, 2023

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Chronic Pain; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: 23-5642

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No