Fatigue, Unspecified Adult Solid Tumor, Protocol Specific
Conditions
Keywords
fatigue, unspecified adult solid tumor, protocol specific, levocarnitine, depression, pain, carnitine deficiency
Brief summary
RATIONALE: Levocarnitine may help improve energy levels in cancer patients. PURPOSE: This randomized phase III trial is studying how well levocarnitine works compared to a placebo in treating fatigue in cancer patients.
Detailed description
OBJECTIVES: Primary Objective: * Compare the efficacy of levocarnitine (L-carnitine) supplementation vs placebo for the management of fatigue in patients with cancer. Secondary Objectives: * Assess the effect of levocarnitine on pain, depression and performance status at 4 and 8 weeks of follow-up. * Determine the prevalence of serum carnitine deficiency in patients treated with these regimens. * Explore the association between carnitine deficiency and fatigue. * Present the toxicity profiles of all patients. Correlative Objective: * Measure serum levels of the pro-inflammatory cytokines and growth factors and correlate with fatigue and other onco-behavioral symptoms. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to gender, ECOG performance status (0-1 vs 2-3), and concurrent chemotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms in a 1:1 ratio. * Arm I (levocarnitine): Patients receive oral levocarnitine (L-carnitine) twice daily (2000 mg/day) on weeks 1-4. * Arm II (placebo): Patients receive oral placebo twice daily (2000 mg/day) on weeks 1-4. The dose was titrated over a 2-day period (i.e. two 500 mg doses the first day and two 1000 mg doses the second day) to avoid gastrointestinal side effects. Patients then continued to receive two daily doses of 1000 mg on days 3 to 28. After week 4, all patients (on both arms) receive open-label oral L-carnitine twice daily on weeks 5-8 (extension phase) administered in the same fashion as during the first 4 weeks. For patients who had received a dose modification during weeks 1 to 4, they received the same reduced dose during the extension phase (without titration) Fatigue, pain, and depression are assessed at baseline and then at weeks 4 and 8. PROJECTED ACCRUAL: A total of 352 patients will be accrued for this study.
Interventions
DIETARY_SUPPLEMENTlevocarnitine
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
ECOG-ACRIN Cancer Research Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of an invasive malignant disorder * Moderate to severe fatigue within the past 4 weeks, defined as a score of ≥ 2 (on a scale of 0-4) on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) question I feel fatigued * Age 18 and over * Eastern Cooperative Oncology Group (ECOG) Performance status of 0-3 * Negative pregnancy test * Fertile patients must use effective contraception during and for 3 months after study participation
Exclusion criteria
* Brain metastases * Hemoglobin \< 9 g/dL, taken \<=4 weeks prior to registration * Severe, uncontrolled liver disease * Evidence of severely compromised renal function including any 1 of the following: * Renal failure * End stage renal disease * Ongoing renal dialysis * Severe, uncontrolled cardiovascular disease * Severe, uncontrolled pulmonary disease * Pregnant or nursing * History of seizures * Known sensitivity to carnitine * Delirium * Nausea \> grade 1 * Taking any form of levocarnitine (L-carnitine) supplementation or nutritional supplements containing carnitine within 2 months prior to registration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Score Change in Fatigue Measured With Brief Fatigue Inventory From Baseline to 4 Weeks | assessed at baseline and 4 weeks after randomization | Fatigue was measured using Brief Fatigue Inventory (BFI). The average of all 9 items included in the scale (range: 0-10) was used to measure fatigue level, and a higher average represented worse fatigue. Score change= BFI score at 4 weeks - BFI score at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Score Change in Fatigue Measured With FACIT-F From Baseline to 4 Weeks | assessed at baseline and 4 weeks after randomization | Fatigue was measured using Functional Assessment of Cancer Therapy- Fatigue subscale (FACIT-F). The sum of the scores for all 13 items (range: 0-52) included in the scale was used to measure fatigue level, and lower score represented worse fatigue. Score change= FACIT-F score at 4 weeks - FACIT-F score at baseline. |
| Mean Score Change in Depression Measured With CES-D Between 4 Weeks and Baseline | assessed at baseline and 4 weeks after randomization | Depression was measured using Center for Epidemiologic Studies Depression Scale (CES-D). The sum of the scores for all 20 items (range: 0-60) was used to assess depression level, and higher scores indicated a higher level of depression. Score change= CES-D score at 4 weeks - CES-D score at baseline. |
| Mean Score Change in Pain Measured With Brief Pain Inventory From Baseline to 4 Weeks | assessed at baseline and 4 weeks after randomization | Pain was measured using Brief Pain Inventory (BPI). The mean of the 4 severity items (range: 0-10 with 0 representing no pain and 10 representing pain as bad as you can imagine) was used to measure pain severity. Score change= BPI score at 4 weeks - BPI score at baseline. |
| Prevalence of Carnitine Deficiency at 4 Weeks | assessed at 4 weeks after randomization | Carnitine deficiency is defined as a ratio of acylcarnitine (total-free) to free carnitine \> 0.4 μmol/L or free carnitine \< 35 μmol/L for males and \< 25 μmol/L for females. |
| Proportion of Patients With Stable or Improving Performance Status at 4 Weeks | assessed at baseline and 4 weeks after randomization | Performance status (PS) was measured using Eastern Cooperative Oncology Group performance status scale. Lower score represents better PS. Change in PS was calculated by PS at week 4- PS at baseline. Patients with negative value for change in PS were considered to have stable or improving PS. |
Countries
United States
Participant flow
Recruitment details
This study was activated on 11/3/2005, accrued its first patient 12/16/2005, suspended on 5/4/2006 after reaching its original accrual goal (160 eligible patients), reactivated on 9/6/2006 after the accrual target amendment (286 eligible patients) was approved, and closed on 1/23/2007 with a total accrual of 376 patients.
Participants by arm
| Arm | Count |
|---|---|
| Levocarnitine Patients receive oral levocarnitine (L-carnitine) twice daily on weeks 1-4.
levocarnitine: Given orally | 189 |
| Placebo Patients receive oral placebo twice daily on weeks 1-4.
placebo: Given orally | 187 |
| Total | 376 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 17 |
| Overall Study | Death | 4 | 1 |
| Overall Study | Disease progression | 3 | 1 |
| Overall Study | Not start protocol therapy | 26 | 17 |
| Overall Study | Other | 3 | 4 |
| Overall Study | Withdrawal by Subject | 10 | 13 |
Baseline characteristics
| Characteristic | Levocarnitine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64 years | 62 years | 63 years |
| Sex: Female, Male Female | 111 Participants | 79 Participants | 190 Participants |
| Sex: Female, Male Male | 78 Participants | 108 Participants | 186 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 166 | 9 / 171 |
| serious Total, serious adverse events | 8 / 166 | 8 / 171 |
Outcome results
Primary
Mean Score Change in Fatigue Measured With Brief Fatigue Inventory From Baseline to 4 Weeks
Fatigue was measured using Brief Fatigue Inventory (BFI). The average of all 9 items included in the scale (range: 0-10) was used to measure fatigue level, and a higher average represented worse fatigue. Score change= BFI score at 4 weeks - BFI score at baseline.
Time frame: assessed at baseline and 4 weeks after randomization
Population: All randomized patients
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levocarnitine | Mean Score Change in Fatigue Measured With Brief Fatigue Inventory From Baseline to 4 Weeks | -0.96 units on a scale |
| Placebo | Mean Score Change in Fatigue Measured With Brief Fatigue Inventory From Baseline to 4 Weeks | -1.11 units on a scale |
p-value: 0.57Wilcoxon (Mann-Whitney)
Secondary
Mean Score Change in Depression Measured With CES-D Between 4 Weeks and Baseline
Depression was measured using Center for Epidemiologic Studies Depression Scale (CES-D). The sum of the scores for all 20 items (range: 0-60) was used to assess depression level, and higher scores indicated a higher level of depression. Score change= CES-D score at 4 weeks - CES-D score at baseline.
Time frame: assessed at baseline and 4 weeks after randomization
Population: All randomized patients who reported CES-D score at both baseline and 4 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levocarnitine | Mean Score Change in Depression Measured With CES-D Between 4 Weeks and Baseline | -3.05 units on a scale |
| Placebo | Mean Score Change in Depression Measured With CES-D Between 4 Weeks and Baseline | -2.91 units on a scale |
p-value: 0.93Wilcoxon (Mann-Whitney)
Secondary
Mean Score Change in Fatigue Measured With FACIT-F From Baseline to 4 Weeks
Fatigue was measured using Functional Assessment of Cancer Therapy- Fatigue subscale (FACIT-F). The sum of the scores for all 13 items (range: 0-52) included in the scale was used to measure fatigue level, and lower score represented worse fatigue. Score change= FACIT-F score at 4 weeks - FACIT-F score at baseline.
Time frame: assessed at baseline and 4 weeks after randomization
Population: All randomized patients who reported FACIT-F score at both baseline and 4 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levocarnitine | Mean Score Change in Fatigue Measured With FACIT-F From Baseline to 4 Weeks | 5.36 units on a scale |
| Placebo | Mean Score Change in Fatigue Measured With FACIT-F From Baseline to 4 Weeks | 4.04 units on a scale |
p-value: 0.64Wilcoxon (Mann-Whitney)
Secondary
Mean Score Change in Pain Measured With Brief Pain Inventory From Baseline to 4 Weeks
Pain was measured using Brief Pain Inventory (BPI). The mean of the 4 severity items (range: 0-10 with 0 representing no pain and 10 representing pain as bad as you can imagine) was used to measure pain severity. Score change= BPI score at 4 weeks - BPI score at baseline.
Time frame: assessed at baseline and 4 weeks after randomization
Population: All randomized patients who reported BPI score at both baseline and 4 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levocarnitine | Mean Score Change in Pain Measured With Brief Pain Inventory From Baseline to 4 Weeks | -0.19 units on a scale |
| Placebo | Mean Score Change in Pain Measured With Brief Pain Inventory From Baseline to 4 Weeks | -0.08 units on a scale |
p-value: 0.61Wilcoxon (Mann-Whitney)
Secondary
Prevalence of Carnitine Deficiency at 4 Weeks
Carnitine deficiency is defined as a ratio of acylcarnitine (total-free) to free carnitine \> 0.4 μmol/L or free carnitine \< 35 μmol/L for males and \< 25 μmol/L for females.
Time frame: assessed at 4 weeks after randomization
Population: All randomized patients who had carnitine data at 4 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levocarnitine | Prevalence of Carnitine Deficiency at 4 Weeks | 0.113 proportion of participants |
| Placebo | Prevalence of Carnitine Deficiency at 4 Weeks | 0.333 proportion of participants |
p-value: 0.00001Fisher Exact
Secondary
Proportion of Patients With Stable or Improving Performance Status at 4 Weeks
Performance status (PS) was measured using Eastern Cooperative Oncology Group performance status scale. Lower score represents better PS. Change in PS was calculated by PS at week 4- PS at baseline. Patients with negative value for change in PS were considered to have stable or improving PS.
Time frame: assessed at baseline and 4 weeks after randomization
Population: All randomized patients who had performance status data at baseline and 4 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levocarnitine | Proportion of Patients With Stable or Improving Performance Status at 4 Weeks | 0.806 proportion of participants |
| Placebo | Proportion of Patients With Stable or Improving Performance Status at 4 Weeks | 0.875 proportion of participants |
p-value: 0.677Fisher Exact