Multimodal Prehabilitation for Lung Cancer Surgery (MMP-LUNG)

A Novel Multimodal Intervention for Surgical Prehabilitation of Patients With Lung Cancer: the MMP-LUNG Trial

The main objective of this randomized controlled trial (RCT) is to investigate whether a multimodal prehabilitation intervention combining a mixed-nutrient supplement with structured exercise training (MM) or the supplement alone (NUT), against a placebo (CTRL), leads to improvement in functional capacity and postoperative outcomes in surgical patients with lung cancer, at nutritional risk. This will be tested in a single centre RCT of 3 parallel arms, double-blinded for the supplement. Female and male participants (n=168, >=45 y) will be randomized to a 10-week intervention spanning 4 weeks pre-surgery and 6 weeks post-hospital discharge. The primary outcome is functional capacity as measured by the 6-minute walk test. Secondary outcomes include muscle mass, quality and strength, quality of life, length of hospital stay, and postoperative complications.

Study Overview

• Status: Recruiting
• Conditions: Lung Cancer; Surgery
• Intervention / Treatment: Dietary supplement: Placebo Control (CTRL); Dietary supplement: Mixed-nutriend supplement (NUT); Other: Multimodal Prehabilitation (MM)

Detailed Description

RATIONALE: The preoperative period is an opportune time to actively engage and empower patients in improving their functional, nutritional and mental status in anticipation of the surgical stress. Considering that lung cancer patients often present with poor nutritional status and physical function prior to surgery, providing a nutritional supplement to increase protein, leucine, vitamin D and omega-3 fatty acid FA intake with a structured exercise program and relaxation techniques should improve muscle mass, strength and physical performance.

MAIN OBJECTIVE: to test the effect of a multimodal RCT prehabilitation intervention (MM) combining a mixed-nutrient supplement with structured exercise training or the supplement alone (NUT) against a placebo (CTRL), on functional pre- and postoperative outcomes in surgical patients with lung cancer at nutritional risk.

STUDY DESIGN: 10-week randomized controlled trial of 3 parallel arms, double-blinded for supplement: control (CTRL), multi-nutrient supplement (NUT) and multimodal intervention (MM). After baseline assessment, patients will be randomized to either group in a 1:1:1 CTRL:NUT:MM ratio using a computer-generated randomization scheme by permuted block sizes, with stratification by sex and functional capacity (< or > 450 m on the 6-minute walk test (6MWT). Consecutive adult patients = or > 45 years scheduled for elective video-assisted thoracic surgery or open thoracotomy surgery of non-small cell lung cancer (NSCLC) stages I, II or IIIa and a Patient-Generated Subjective Global Assessment (PG-SGA) score = or > 3, will be approached following their first appointment with their surgeon at the McGill University Health Centre (MUHC)-Montreal General Hospital.

INTERVENTION: The NUT arm will ingest a multi-nutrient supplement consisting of whey protein + leucine + viatmin D, and fish oil. The CTRL participants will receive placebo supplements with the same physical aspect, flavor and packaging as the active supplement.The MM arm will receive the NUT intervention in addition to performing structured exercise and relaxation techniques for 4 weeks prior to surgery and 6 weeks after hospital discharge.

OUTCOMES: Primary: physical capacity measured by the 6MWT; Secondary: physical function, muscle strength, total skeletal muscle mass, leg muscle volume and density, body composition, quality of life, length of stay and post-operative complications; Other: dietary intake, physical activity, exercise tolerance, pulmonary function, clinical markers.

STATISTICAL ANALYSIS: Intention-to-treat analysis will be performed in the primary analyses. For preoperative data, analysis of covariance (ANCOVA) will compare between-group differences at 4-week preoperative time, conditioned for baseline data, including predefined covariates in the model (age, sex, BMI). The hypothesis of full recovery from the intervention at 6 weeks postoperative (i.e. 6MWT returning back to or exceeding baseline) will be tested by logistic regression (yes/no). Between-group changes in other outcomes will be evaluated as differences in mean or proportions, as appropriate, with 95% CIs.

• Study Type: Interventional
• Enrollment (Estimated): 168
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stéphanie Chevalier, PhD; Phone Number: 35019 (514) 934-1934; Email: stephanie.chevalier@mcgill.ca

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Recruiting
      • Research Institute of the McGill University Health Centre
      • Contact: Stéphanie Chevalier, PhD; Phone Number: 35019 (514) 934-1934; Email: stephanie.chevalier@mcgill.ca

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Adults aged 45 years and over
• Diagnosed with NSCLC stages I, II or IIIa and scheduled for video-assisted thoracic surgery (VATS) or open thoracotomy surgery for cancer resection
• At nutritional risk (defined as Patient Generated-Subjective Global Assessment score = or >3)

Exclusion Criteria:

• Prior recent (<2 months) adjuvant therapy (chemo- or radio-therapy)
• Inability to perform, or comorbidities contraindicating, exercise (defined as CPET <10 mL O2/kg/min)
• Unable to walk (uses a wheelchair)
• Allergy to milk or seafood
• Hypercalcemia (total serum Ca >2.60 mmol/L or ionized Ca >1.30 mmol/L)
• Hypervitaminosis D (serum 25(OH)D >375 nmol/L)
• Glomerular filtration rate (<30 mL/min/1.73m2)
• Insufficient understanding of English or French to provide informed consent

Patients taking omega-3 FA supplements will be asked to withhold them during the study; those taking vitamin D will continue unless baseline serum 25(OH)D >80 nmol/L.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control (CTRL); Participants will be treated following Enhanced Recovery After Surgery (ERAS) protocols + placebo supplements containing maltodextrin and sunflower oil	Dietary supplement: Placebo Control (CTRL); Participants will follow ERAS protocol and will receive dietary counselling and anxiety management counselling as needed. They will receive a placebo dietary supplement made of maltodextrin and sunflower oil.
Active Comparator: Mixed-nutriend supplement (NUT); Mixed nutrient supplement containing whey protein, leucine, vitamin D and omega 3 fatty acids	Dietary supplement: Mixed-nutriend supplement (NUT); Participants will follow ERAS protocol and will receive dietary counselling and anxiety management counselling as needed. They will receive the active multi-nutrient supplement made of whey protein + leucine + vitamin D doses pre-mixed in unlabeled packets prepared by Gruppo Nutrition to dilute in a cup (250 mL) of water. In addition, participants will ingest 15 mL of fruit-flavored fish oil, provided as a liquid oil. They will receive a dosing cup, pre-marked to 15 mL, for a total dose providing 2120 mg eicosapentaenoic acid (EPA) and 1320 mg docosahexaenoic acid (DHA).
Active Comparator: Multi-modal intervention (MM); Multimodal prehabilitation including structured exercise (1 supervised exercise session per week + home-based exercise program), nutritional optimization with dietician, NUT intervention, and relaxation strategies.	Dietary supplement: Mixed-nutriend supplement (NUT); Participants will follow ERAS protocol and will receive dietary counselling and anxiety management counselling as needed. They will receive the active multi-nutrient supplement made of whey protein + leucine + vitamin D doses pre-mixed in unlabeled packets prepared by Gruppo Nutrition to dilute in a cup (250 mL) of water. In addition, participants will ingest 15 mL of fruit-flavored fish oil, provided as a liquid oil. They will receive a dosing cup, pre-marked to 15 mL, for a total dose providing 2120 mg eicosapentaenoic acid (EPA) and 1320 mg docosahexaenoic acid (DHA).; Other: Multimodal Prehabilitation (MM); Participants will follow ERAS protocol and will receive dietary counselling and anxiety management counselling as needed. They will receive the NUT intervention + structured exercise training prescribed by a kinesiologist (1. 30 min of aerobic exercise per day of their preferred type (ex. walking) and 2. 30 min of resistance exercise targeting major muscle groups, every second day for 2 sets of 8-12 reps). Training will be performed for 4 weeks prior to surgery (1x/week supervised by kinesiologist at hospital, 2x/week at alone at home)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in preoperative functional walking capacity	6-Minute walking test (6MWT): measured as the distance walked during 6 minutes, along a 20-m corridor, expressed in meters	From baseline (4 weeks pre-surgery) to surgery
Postoperative functional walking capacity	6-Minute walking test (6MWT): measured as the distance walked during 6 minutes, along a 20-m corridor, expressed in meters	6 weeks after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in handgrip strength	Handgrip strength using hand-held Jamar dynamometer, measured in kg	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in total skeletal muscle mass	Estimated using deuterium-labeled creatine (D3-creatine), measured in kg	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in foreleg muscle surface area	Skeletal muscle surface area will be measured in the dominant foreleg, using peripheral quantitative computerized tomography (pQCT, Stratec XCT2000), measured in cm2.	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in foreleg myosteatosis (radiodensity)	Skeletal muscle radiodensity will be measured in the dominant foreleg, using peripheral quantitative computerized tomography (pQCT, Stratec XCT2000), measured in mg/cm3.	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in body weight and composition	Soft lean and fat mass measured by bioelectrical impedance (seca mBCA 515)	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in self-reported quality of life	Measured by the 36-item Short Form Survey (SF36, score 0-100; higher means better quality of life)	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in self-reported functional assessment	Measured by the Functional Assessment of Cancer Therapy - Lung questionnaire (FACT-L score 0-136, higher means better quality of life)	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Length of hospital stay	Recorded from medical charts, expressed in days	6 weeks after surgery
Number and severity of postoperative complications	Recorded from medical charts and graded by severity following the Clavien-Dindo classification	6 weeks after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in dietary intake	Collected from 3-day food diaries, using a mobile application (Keenoa)	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in plasma phospholipid fatty acid profile	Plasma lipids will be extracted with organic solvents, phospholipids isolated on thin-layer chromatography, and FAs methylated for determination by gas chromatography-flame-ionization analysis. Change in long-chain omega-3 fatty acids will be used as an objective measure of adherence to fish oil supplement.	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in serum vitamin D 25(OH)D concentrations	Concentrations will be measured by the MUHC-Central Lab. Used as an objective measure of adherence to the supplement.	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in serum C-Reactive Protein (CRP)	Measured as high-sensitive CRP by the MUHC-Central Lab.	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in serum albumin	Analyzed by standard procedures at the MUHC-Central Lab	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in serum pre-albumin	Analyzed by standard procedures at the MUHC-Central Lab	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in serum hemoglobin	Analyzed by standard procedures at the MUHC-Central Lab	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in complete blood count	Analyzed by standard procedures at the MUHC-Central Lab	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in preoperative exercise tolerance	Assessed as oxygen consumption during cardiopulmonary exercise testing (CPET) at anaerobic threshold and peak exercise, in mL O2/kg/min	From baseline (4 weeks pre-surgery) to surgery
Change in forced expiratory volume (FEV1)	Spirometry standard methods to measure the forced expiratory volume (FEV1)	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in forced vital capacity (FVC)	Spirometry standard methods to measure the forced vital capacity (FVC) and calculate FEV1/FVC ratio.	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in self-reported physical activity level score	Measured with the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire, score 0 - x (no maximum score), higher mean more activity.	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in physical activity	Measured by accelerometry (Actigraph wGT3X-BT) during the intervention. Step count and time spent at sedentary, light, moderate/ vigorous activity, and sleeping time will be recorded.	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in anxiety/depression score	Hospital Anxiety and Depression Scale (questionnaire). Scoring for each item ranges from zero to three. A subscale score >8 denotes anxiety or depression.	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Change in Patient-Generated Subjective Global Assessment (PG-SGA) score	PG-SGA questionnaire, total score. A higher score indicates higher nutritional risk or malnutrition.	From baseline (4 weeks pre-surgery) to 6 weeks after surgery
Number of adverse events	Any adverse event, related or not to the intervention	Through study completion, an average of 10 weeks

Collaborators and Investigators

• Sponsor: Stéphanie Chevalier
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Principal Investigator: Stéphanie Chevalier, PhD, McGill University

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2023
• Primary Completion (Estimated): September 20, 2025
• Study Completion (Estimated): March 20, 2026

Study Registration Dates

• First Submitted: June 22, 2023
• First Submitted That Met QC Criteria: July 12, 2023
• First Posted (Actual): July 21, 2023

Study Record Updates

• Last Update Posted (Actual): July 21, 2023
• Last Update Submitted That Met QC Criteria: July 12, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Prehabilitation; Nutritional Supplement
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms
• Other Study ID Numbers: MUHC REB 2022-7782

Drug and device information, study documents

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