Non Small Cell Lung Cancer
Conditions
Keywords
melatonin, natural health product (NHP), lung cancer, complementary and alternative medicine (CAM), randomized clinical trial
Brief summary
There is evidence to support the use of melatonin, a natural health product, as an additional treatment aid for cancer patients. This study is designed to see if the daily ingestion of 20 milligrams of melatonin for one year can lower the incidence of developing lung cancer recurrence and/or death. Only patients with a diagnosis of non small cell lung cancer who are eligible for surgical resection can participate in the trial. The study will also be assessing for changes in quality of life, pain, fatigue, anxiety, sleep, and depression amongst the participants.
Detailed description
The trial employs a two-armed parallel placebo controlled trial design whereby patients with a diagnosis of non small cell lung cancer are randomized to receive either 20 mg of melatonin nightly or an identically matched placebo. All patients will be followed for two years with primary outcomes assessed at a two year time point and secondary outcomes evaluated throughout the course of the trial.
Interventions
DIETARY_SUPPLEMENTmelatonin
20 mgs ingested nightly
DIETARY_SUPPLEMENTplacebo
similar to experimental in all ways except for lack of active ingredient
Sponsors
The Ottawa Hospital
Lotte & John Hecht Memorial Foundation
Gateway for Cancer Research
The Canadian College of Naturopathic Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of non small cell lung cancer * Eligible for surgical resection * Willingness to adhere to randomized treatment * Availability for follow-up schedule of visits
Exclusion criteria
* Taking exogenous melatonin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lung Cancer Recurrence or Mortality - 2 Years | 2 years | Disease-Free survival (DFS) at 2 years post-surgery. DFS is measured by the number of participants in both arms who have experienced a recurrence OR mortality at 2 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fatigue | 2 years | Measured using the Multidimensional Fatigue Inventory 20 (MFI-20) questionnaire. Scores are on a scale of 0-100, where 100 is the best health and 0 is the worst health. |
| Sleep | 2 years | Measured using the Medical Outcomes Study (MOS) Sleep Survey. Scales used were Sleep Adequacy and Sleep problems Index II. Scores are on a scale of 0-100. Sleep Adequacy: 100 represents best health; 0 represents worst health. Problems index: 0 represents best health; 100 represents worst health. |
| Pain Levels | 3 months | Calculated using the Brief Pain Inventory. Each scale ranges from 0-10, where 0 is no pain and 10 is the worst possible pain. |
| Anxiety | 2 years | Measured using the Beck Anxiety Inventory. Scored range from 0-63, where 0 is no anxiety and 63 is the worst possible anxiety. |
| Depression | 2 years | Measured using the Beck Depression Inventory II. Scores range from 0-63, where 0 is no depression and 63 is the worst possible depression. |
| Quality of Life | 2 years | Participant-reported quality of life using the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire C-30 (EORTC QLQ C-30) and Lung Cancer 13 (EORTC QLQ LC13) questionnaires. Scores represent a value from 0-100. Symptom and LC13 scale: 0 represents best health, 100 worst health. Global and functional scales: 100 represents best health, 0 represents worst health. Full scoring algorithms available here: https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf |
| Lung Cancer Recurrence or Mortality - 5 Years | up to 5 years | Measured as disease-free survival (DFS) at 5 years. DFS was measured by the incidence of a recurrence OR mortality up to 5 years post-surgery. |
| Blood Tests to Examine the Effects of Melatonin on the Immune System (Raw Values) | 6 months | NK cell cytotoxicity changes from baseline to 6 months |
| Adverse Events (Radiation) | 2 years | Number of participants who experienced an adverse event related to their adjuvant radiation therapy |
| Blood Tests to Examine the Effects of Melatonin on the Immune System (Comparison Between Groups) | 6 months | Differences in NK cell cytotoxicity between both arms |
| Adverse Events (Chemotherapy) | 2 years | Number of participants who experienced an adverse event related to their adjuvant chemotherapy |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment To receive 20 mg of melatonin nightly for 1 year
melatonin: 20 mgs ingested nightly | 356 |
| Placebo To receive matched supplement to the experimental arm in same schedule
placebo: similar to experimental in all ways except for lack of active ingredient | 353 |
| Total | 709 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Cancer Recurrence | 58 | 58 |
| Overall Study | Death | 11 | 4 |
| Overall Study | Lost to Follow-up | 3 | 6 |
| Overall Study | Protocol Violation | 10 | 12 |
| Overall Study | Withdrawal by Subject | 117 | 100 |
Baseline characteristics
| Characteristic | Treatment | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 67.2 Years STANDARD_DEVIATION 8.5 | 67.2 Years STANDARD_DEVIATION 8.5 | 67.2 Years STANDARD_DEVIATION 8.6 |
| Histological Subtype Adenocarcinoma | 229 Participants | 468 Participants | 239 Participants |
| Histological Subtype Bronchoalveolar | 10 Participants | 18 Participants | 8 Participants |
| Histological Subtype Large Cell | 7 Participants | 22 Participants | 15 Participants |
| Histological Subtype Non-Surgical | 1 Participants | 3 Participants | 2 Participants |
| Histological Subtype Other | 14 Participants | 28 Participants | 14 Participants |
| Histological Subtype Squamous Cell | 93 Participants | 165 Participants | 72 Participants |
| Histological Subtype Undifferentiated | 2 Participants | 5 Participants | 3 Participants |
| Incision Type Minimally Invasive Surgery (MIS) | 213 Participants | 425 Participants | 212 Participants |
| Incision Type MIS Converted to Open | 27 Participants | 46 Participants | 19 Participants |
| Incision Type Non-Surgical | 1 Participants | 3 Participants | 2 Participants |
| Incision Type Open | 114 Participants | 236 Participants | 122 Participants |
| Pathological Cancer Stage Non-Surgical | 1 Participants | 3 Participants | 2 Participants |
| Pathological Cancer Stage Stage I | 245 Participants | 462 Participants | 217 Participants |
| Pathological Cancer Stage Stage II | 75 Participants | 167 Participants | 92 Participants |
| Pathological Cancer Stage Stage III | 32 Participants | 70 Participants | 38 Participants |
| Pathological Cancer Stage Stage IV | 2 Participants | 5 Participants | 3 Participants |
| Pre-Operative Chemotherapy or Radiation | 8 Participants | 22 Participants | 14 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Sex: Female, Male Female | 190 Participants | 398 Participants | 208 Participants |
| Sex: Female, Male Male | 166 Participants | 311 Participants | 145 Participants |
| Smoking History Current Smoker | 47 Participants | 99 Participants | 52 Participants |
| Smoking History Never Smoked | 25 Participants | 56 Participants | 31 Participants |
| Smoking History Past Smoker | 279 Participants | 542 Participants | 263 Participants |
| Smoking History Unknown | 5 Participants | 12 Participants | 7 Participants |
| Surgery Type Lobectomy | 290 Participants | 574 Participants | 284 Participants |
| Surgery Type No Operation | 1 Participants | 4 Participants | 3 Participants |
| Surgery Type Pneumonectomy | 16 Participants | 37 Participants | 21 Participants |
| Surgery Type Segmentectomy | 18 Participants | 34 Participants | 16 Participants |
| Surgery Type Wedge Resection | 31 Participants | 60 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 95 / 356 | 91 / 353 |
| other Total, other adverse events | 184 / 356 | 166 / 353 |
| serious Total, serious adverse events | 84 / 356 | 89 / 353 |
Outcome results
Primary
Lung Cancer Recurrence or Mortality - 2 Years
Disease-Free survival (DFS) at 2 years post-surgery. DFS is measured by the number of participants in both arms who have experienced a recurrence OR mortality at 2 years.
Time frame: 2 years
Population: Intention to treat - all participants analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Melatonin | Lung Cancer Recurrence or Mortality - 2 Years | 80 Participants |
| Placebo | Lung Cancer Recurrence or Mortality - 2 Years | 85 Participants |
Comparison: Analysis conducted was an adjusted logistic regression (adjuvant chemotherapy, adjuvant radiation, smoking history). Results were presented as a relative risk. Based on an estimated 30% outcome rate of recurrence or mortality in the control arm, 294 participants per arm provided 80% power to detect a relative risk of one third at an alpha of 0.05. We inflated this sample size to 346 per arm to account for 15% lost to follow-up.p-value: 0.9495% CI: [0.83, 1.22]Regression, Logistic
Secondary
Adverse Events (Chemotherapy)
Number of participants who experienced an adverse event related to their adjuvant chemotherapy
Time frame: 2 years
Population: Only those who received adjuvant chemotherapy were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Melatonin | Adverse Events (Chemotherapy) | 44 Participants |
| Placebo | Adverse Events (Chemotherapy) | 48 Participants |
p-value: 0.62Chi-squared
Secondary
Adverse Events (Radiation)
Number of participants who experienced an adverse event related to their adjuvant radiation therapy
Time frame: 2 years
Population: Only those who received adjuvant radiation were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Melatonin | Adverse Events (Radiation) | 8 Participants |
| Placebo | Adverse Events (Radiation) | 5 Participants |
p-value: 0.37Chi-squared
Secondary
Anxiety
Measured using the Beck Anxiety Inventory. Scored range from 0-63, where 0 is no anxiety and 63 is the worst possible anxiety.
Time frame: 2 years
Population: Only participants recruited from The Ottawa Hospital were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Melatonin | Anxiety | Baseline | 8.2 Score on a scale of 0-63 | Standard Deviation 8.5 |
| Melatonin | Anxiety | 2Y | 6.2 Score on a scale of 0-63 | Standard Deviation 6.9 |
| Placebo | Anxiety | Baseline | 8.3 Score on a scale of 0-63 | Standard Deviation 8.4 |
| Placebo | Anxiety | 2Y | 6.4 Score on a scale of 0-63 | Standard Deviation 7.6 |
Secondary
Blood Tests to Examine the Effects of Melatonin on the Immune System (Comparison Between Groups)
Differences in NK cell cytotoxicity between both arms
Time frame: 6 months
Population: Only those who were enrolled in the sub study and qualified for analysis were included.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Melatonin | Blood Tests to Examine the Effects of Melatonin on the Immune System (Comparison Between Groups) | 1.1 Ratio of percent cytotoxicity |
| Placebo | Blood Tests to Examine the Effects of Melatonin on the Immune System (Comparison Between Groups) | 1.16 Ratio of percent cytotoxicity |
Comparison: This analysis compares the mean ratios of 6 month cytotoxicity and baseline cytotoxicity between arms.p-value: 0.34Wilcoxon (Mann-Whitney)
Secondary
Blood Tests to Examine the Effects of Melatonin on the Immune System (Raw Values)
NK cell cytotoxicity changes from baseline to 6 months
Time frame: 6 months
Population: Participants who qualified for the sub-study only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Melatonin | Blood Tests to Examine the Effects of Melatonin on the Immune System (Raw Values) | Cytotoxicity (baseline) | 49.8 Percent killing of K62 cells | Standard Error 3.6 |
| Melatonin | Blood Tests to Examine the Effects of Melatonin on the Immune System (Raw Values) | Cytotoxicity (6 months) | 49.2 Percent killing of K62 cells | Standard Error 3 |
| Placebo | Blood Tests to Examine the Effects of Melatonin on the Immune System (Raw Values) | Cytotoxicity (baseline) | 42.7 Percent killing of K62 cells | Standard Error 3.3 |
| Placebo | Blood Tests to Examine the Effects of Melatonin on the Immune System (Raw Values) | Cytotoxicity (6 months) | 46.4 Percent killing of K62 cells | Standard Error 3.8 |
Comparison: Analysis of melatonin changesp-value: 0.9595% CI: [-3.21, 4.56]Wilcoxon (Mann-Whitney)
Comparison: Analysis of placebo changesp-value: 0.0295% CI: [-0.15, 7.42]Wilcoxon (Mann-Whitney)
Secondary
Depression
Measured using the Beck Depression Inventory II. Scores range from 0-63, where 0 is no depression and 63 is the worst possible depression.
Time frame: 2 years
Population: Only participants recruited from The Ottawa Hospital were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Melatonin | Depression | Baseline | 8.1 Score on a scale of 0-63 | Standard Deviation 7.2 |
| Melatonin | Depression | 2Y | 6.6 Score on a scale of 0-63 | Standard Deviation 5.9 |
| Placebo | Depression | Baseline | 8.6 Score on a scale of 0-63 | Standard Deviation 8.5 |
| Placebo | Depression | 2Y | 7.7 Score on a scale of 0-63 | Standard Deviation 8 |
Secondary
Fatigue
Measured using the Multidimensional Fatigue Inventory 20 (MFI-20) questionnaire. Scores are on a scale of 0-100, where 100 is the best health and 0 is the worst health.
Time frame: 2 years
Population: Intention to Treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Melatonin | Fatigue | 1Y | 61.4 Score on a scale of 0-100 |
| Melatonin | Fatigue | 2Y | 62.7 Score on a scale of 0-100 |
| Melatonin | Fatigue | Baseline | 59.8 Score on a scale of 0-100 |
| Placebo | Fatigue | Baseline | 57.0 Score on a scale of 0-100 |
| Placebo | Fatigue | 1Y | 62.4 Score on a scale of 0-100 |
| Placebo | Fatigue | 2Y | 63.1 Score on a scale of 0-100 |
Comparison: Between-arm least squares mean difference in change from randomization to 24 months post-surgery represented the effect of the intervention.p-value: 0.1395% CI: [-7.2, 0.9]Mixed Models Analysis
Secondary
Lung Cancer Recurrence or Mortality - 5 Years
Measured as disease-free survival (DFS) at 5 years. DFS was measured by the incidence of a recurrence OR mortality up to 5 years post-surgery.
Time frame: up to 5 years
Population: Intention to treat - all participants analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Melatonin | Lung Cancer Recurrence or Mortality - 5 Years | All participants | 133 Participants |
| Melatonin | Lung Cancer Recurrence or Mortality - 5 Years | Early Stage Cancer | 109 Participants |
| Melatonin | Lung Cancer Recurrence or Mortality - 5 Years | Late Stage Cancer | 23 Participants |
| Placebo | Lung Cancer Recurrence or Mortality - 5 Years | All participants | 130 Participants |
| Placebo | Lung Cancer Recurrence or Mortality - 5 Years | Early Stage Cancer | 99 Participants |
| Placebo | Lung Cancer Recurrence or Mortality - 5 Years | Late Stage Cancer | 31 Participants |
Comparison: DFS up to five years post-surgery was compared using Kaplan-Meier curves and the log rank test, followed by a hazard ratio calculated using the Cox proportional hazard model adjusting for adjuvant chemotherapy, adjuvant radiation, and smoking history.p-value: 0.4195% CI: [0.85, 1.07]Log Rank
Comparison: This analysis included only those with stage I or II cancer (pathologic stage). DFS up to five years post-surgery was compared using Kaplan-Meier curves and the log rank test, followed by a hazard ratio calculated using the Cox proportional hazard model adjusting for adjuvant chemotherapy, adjuvant radiation, and smoking history.p-value: 0.6695% CI: [0.85, 1.11]Log Rank
Comparison: This analysis included only those participants who had stage III or IV cancer (pathologic stage). DFS up to five years post-surgery was compared using Kaplan-Meier curves and the log rank test, followed by a hazard ratio calculated using the Cox proportional hazard model adjusting for adjuvant chemotherapy, adjuvant radiation, and smoking history.p-value: 0.00495% CI: [0.61, 0.92]Log Rank
Secondary
Pain Levels
Calculated using the Brief Pain Inventory. Each scale ranges from 0-10, where 0 is no pain and 10 is the worst possible pain.
Time frame: 3 months
Population: Only those recruited from the Ottawa Hospital were included in this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Melatonin | Pain Levels | Baseline | 2.4 Score on a scale of 0-10 | Standard Deviation 2.4 |
| Melatonin | Pain Levels | 3 months | 2.3 Score on a scale of 0-10 | Standard Deviation 2.1 |
| Placebo | Pain Levels | Baseline | 2.3 Score on a scale of 0-10 | Standard Deviation 2.2 |
| Placebo | Pain Levels | 3 months | 2.4 Score on a scale of 0-10 | Standard Deviation 2.2 |
Secondary
Quality of Life
Participant-reported quality of life using the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire C-30 (EORTC QLQ C-30) and Lung Cancer 13 (EORTC QLQ LC13) questionnaires. Scores represent a value from 0-100. Symptom and LC13 scale: 0 represents best health, 100 worst health. Global and functional scales: 100 represents best health, 0 represents worst health. Full scoring algorithms available here: https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf
Time frame: 2 years
Population: Intention to Treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Melatonin | Quality of Life | Functional Scale (Baseline) | 75.8 Score on a scale of 0-100 |
| Melatonin | Quality of Life | Global Scale (1Y) | 69.6 Score on a scale of 0-100 |
| Melatonin | Quality of Life | Symptom Scale (Baseline) | 21.4 Score on a scale of 0-100 |
| Melatonin | Quality of Life | Global Scale (2Y) | 70.7 Score on a scale of 0-100 |
| Melatonin | Quality of Life | Symptom Scale (2Y) | 17.3 Score on a scale of 0-100 |
| Melatonin | Quality of Life | LC13 Scale (Baseline) | 17.4 Score on a scale of 0-100 |
| Melatonin | Quality of Life | Symptom Scale (1Y) | 18.2 Score on a scale of 0-100 |
| Melatonin | Quality of Life | LC13 Scale (1Y) | 17.8 Score on a scale of 0-100 |
| Melatonin | Quality of Life | Global Scale (Baseline) | 64.5 Score on a scale of 0-100 |
| Melatonin | Quality of Life | LC13 Scale (2Y) | 17.1 Score on a scale of 0-100 |
| Melatonin | Quality of Life | Functional Scale (1Y) | 79.9 Score on a scale of 0-100 |
| Melatonin | Quality of Life | Functional Scale (2Y) | 80.2 Score on a scale of 0-100 |
| Placebo | Quality of Life | Global Scale (Baseline) | 62.7 Score on a scale of 0-100 |
| Placebo | Quality of Life | Symptom Scale (Baseline) | 20.3 Score on a scale of 0-100 |
| Placebo | Quality of Life | Symptom Scale (1Y) | 17.0 Score on a scale of 0-100 |
| Placebo | Quality of Life | Symptom Scale (2Y) | 15.8 Score on a scale of 0-100 |
| Placebo | Quality of Life | Functional Scale (Baseline) | 75.5 Score on a scale of 0-100 |
| Placebo | Quality of Life | Functional Scale (1Y) | 81.1 Score on a scale of 0-100 |
| Placebo | Quality of Life | Functional Scale (2Y) | 80.5 Score on a scale of 0-100 |
| Placebo | Quality of Life | LC13 Scale (2Y) | 17.5 Score on a scale of 0-100 |
| Placebo | Quality of Life | Global Scale (1Y) | 71.6 Score on a scale of 0-100 |
| Placebo | Quality of Life | Global Scale (2Y) | 72.7 Score on a scale of 0-100 |
| Placebo | Quality of Life | LC13 Scale (Baseline) | 19.0 Score on a scale of 0-100 |
| Placebo | Quality of Life | LC13 Scale (1Y) | 18.1 Score on a scale of 0-100 |
Comparison: Analysis for the LC-13 scale.p-value: 0.3695% CI: [-1.3, 3.7]Mixed Models Analysis
Comparison: Analysis for Symptom Scale.p-value: 0.895% CI: [-2.5, 3.3]Mixed Models Analysis
Comparison: Analysis for Functional Scale.p-value: 0.6995% CI: [-4.1, 2.7]Mixed Models Analysis
Comparison: Analysis for Global Scale.p-value: 0.1195% CI: [-8.5, 0.9]Mixed Models Analysis
Secondary
Sleep
Measured using the Medical Outcomes Study (MOS) Sleep Survey. Scales used were Sleep Adequacy and Sleep problems Index II. Scores are on a scale of 0-100. Sleep Adequacy: 100 represents best health; 0 represents worst health. Problems index: 0 represents best health; 100 represents worst health.
Time frame: 2 years
Population: Intention to Treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Melatonin | Sleep | Sleep Problems Index II (1Y) | 28.0 Score on a scale of 0-100 |
| Melatonin | Sleep | Sleep Adequacy (1Y) | 60.9 Score on a scale of 0-100 |
| Melatonin | Sleep | Sleep Adequacy (2Y) | 59.4 Score on a scale of 0-100 |
| Melatonin | Sleep | Sleep Problems Index II (baseline) | 32.7 Score on a scale of 0-100 |
| Melatonin | Sleep | Sleep Problems Index II (2Y) | 27.5 Score on a scale of 0-100 |
| Melatonin | Sleep | Sleep Adequacy (Baseline) | 56.7 Score on a scale of 0-100 |
| Placebo | Sleep | Sleep Problems Index II (2Y) | 26.9 Score on a scale of 0-100 |
| Placebo | Sleep | Sleep Adequacy (Baseline) | 53.8 Score on a scale of 0-100 |
| Placebo | Sleep | Sleep Problems Index II (baseline) | 33.6 Score on a scale of 0-100 |
| Placebo | Sleep | Sleep Adequacy (1Y) | 61.5 Score on a scale of 0-100 |
| Placebo | Sleep | Sleep Problems Index II (1Y) | 27.7 Score on a scale of 0-100 |
| Placebo | Sleep | Sleep Adequacy (2Y) | 60.5 Score on a scale of 0-100 |
Comparison: Sleep Adequacy Analysis.p-value: 0.1895% CI: [-10, 1.9]Mixed Models Analysis
Comparison: Sleep problems index II analysis.p-value: 0.4195% CI: [-2, 4.8]Mixed Models Analysis