Levocarnitine in Treating Fatigue in Cancer Patients

Phase III Randomized Placebo-Controlled Trial to Determine Efficacy of Levocarnitine for Fatigue in Patients With Cancer

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.

Study Overview

• Status: Completed
• Conditions: Fatigue; Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Other: placebo; Dietary supplement: levocarnitine

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.

• Study Type: Interventional
• Enrollment (Actual): 376
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Veterans Affairs Medical Center - Palo Alto
    • Stanford, California, United States, 94305
      • Stanford Comprehensive Cancer Center - Stanford
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Praxair Cancer Center at Danbury Hospital
    • Manchester, Connecticut, United States, 06040
      • Manchester Memorial Hospital
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Lynn Regional Cancer Center at Boca Raton Community Hospital - Main Center
    • Jacksonville, Florida, United States, 32207
      • Baptist Cancer Institute - Jacksonville
  • Illinois
    • Aurora, Illinois, United States, 60507
      • Rush-Copley Cancer Care Center
    • Bloomington, Illinois, United States, 61701
      • St. Joseph Medical Center
    • Canton, Illinois, United States, 61520
      • Graham Hospital
    • Carthage, Illinois, United States, 62321
      • Memorial Hospital
    • Eureka, Illinois, United States, 61530
      • Eureka Community Hospital
    • Evanston, Illinois, United States, 60201-1781
      • Evanston Northwestern Healthcare - Evanston Hospital
    • Galesburg, Illinois, United States, 61401
      • Galesburg Cottage Hospital
    • Galesburg, Illinois, United States, 61401
      • Galesburg Clinic, PC
    • Havana, Illinois, United States, 62644
      • Mason District Hospital
    • Hopedale, Illinois, United States, 61747
      • Hopedale Medical Complex
    • Joliet, Illinois, United States, 60435
      • Joliet Oncology-Hematology Associates, Limited - West
    • Macomb, Illinois, United States, 61455
      • Mcdonough District Hospital
    • Normal, Illinois, United States, 61761
      • Bromenn Regional Medical Center
    • Normal, Illinois, United States, 61761
      • Community Cancer Center
    • Ottawa, Illinois, United States, 61350
      • Community Hospital of Ottawa
    • Ottawa, Illinois, United States, 61350
      • Oncology Hematology Associates of Central Illinois, PC - Ottawa
    • Pekin, Illinois, United States, 61554
      • Cancer Treatment Center at Pekin Hospital
    • Peoria, Illinois, United States, 61636
      • Methodist Medical Center of Illinois
    • Peoria, Illinois, United States, 61614
      • Proctor Hospital
    • Peoria, Illinois, United States, 61637
      • OSF St. Francis Medical Center
    • Peoria, Illinois, United States, 61615
      • CCOP - Illinois Oncology Research Association
    • Peoria, Illinois, United States, 61615
      • Oncology Hematology Associates of Central Illinois, PC - Peoria
    • Peru, Illinois, United States, 61354
      • Illinois Valley Community Hospital
    • Princeton, Illinois, United States, 61356
      • Perry Memorial Hospital
    • Spring Valley, Illinois, United States, 61362
      • St. Margaret's Hospital
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center at Carle Foundation Hospital
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Indiana
    • Elkhart, Indiana, United States, 46515
      • Elkhart General Hospital
    • Kokomo, Indiana, United States, 46904
      • Howard Community Hospital
    • La Porte, Indiana, United States, 46350
      • Center for Cancer Therapy at LaPorte Hospital and Health Services
    • Michigan City, Indiana, United States, 46360
      • Saint Anthony Memorial Health Centers
    • South Bend, Indiana, United States, 46601
      • Memorial Hospital of South Bend
    • South Bend, Indiana, United States, 46601
      • CCOP - Northern Indiana CR Consortium
    • South Bend, Indiana, United States, 46617
      • Saint Joseph Regional Medical Center
  • Iowa
    • Ottumwa, Iowa, United States, 52501
      • McCreery Cancer Center at Ottumwa Regional
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates, LLP
    • Sioux City, Iowa, United States, 51104
      • St. Luke's Regional Medical Center
    • Sioux City, Iowa, United States, 51104
      • Mercy Medical Center - Sioux City
  • Michigan
    • Ann Arbor, Michigan, United States, 48106-0995
      • Saint Joseph Mercy Cancer Center
    • Ann Arbor, Michigan, United States, 48106
      • CCOP - Michigan Cancer Research Consortium
    • Dearborn, Michigan, United States, 48123-2500
      • Oakwood Cancer Center at Oakwood Hospital and Medical Center
    • Escanaba, Michigan, United States, 49431
      • Green Bay Oncology, Limited - Escanaba
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Flint, Michigan, United States, 48503
      • Genesys Hurley Cancer Institute
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
    • Iron Mountain, Michigan, United States, 49801
      • Dickinson County Healthcare System
    • Jackson, Michigan, United States, 49201
      • Foote Hospital
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • West Michigan Cancer Center
    • Lansing, Michigan, United States, 48912-1811
      • Sparrow Regional Cancer Center
    • Saginaw, Michigan, United States, 48601
      • Seton Cancer Institute - Saginaw
    • Saint Joseph, Michigan, United States, 49085
      • Lakeland Regional Cancer Care Center - St. Joseph
    • Warren, Michigan, United States, 48093
      • St. John Macomb Hospital
  • Minnesota
    • Burnsville, Minnesota, United States, 55337
      • Fairview Ridges Hospital
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy and Unity Cancer Center at Mercy Hospital
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Fridley, Minnesota, United States, 55432
      • Mercy and Unity Cancer Center at Unity Hospital
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
    • Robbinsdale, Minnesota, United States, 55422-2900
      • Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center
    • Saint Louis Park, Minnesota, United States, 55416
      • CCOP - Metro-Minnesota
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Cancer Center
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Waconia, Minnesota, United States, 55387
      • Ridgeview Medical Center
  • New Jersey
    • East Orange, New Jersey, United States, 07018-1095
      • Veterans Affairs Medical Center - East Orange
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein Cancer Center at Albert Einstein College of Medicine
    • Brooklyn, New York, United States, 11209
      • Veterans Affairs Medical Center - Brooklyn
    • New York, New York, United States, 10003-3803
      • Beth Israel Medical Center - Petrie Division
  • Ohio
    • Canton, Ohio, United States, 44708
      • Mercy Cancer Center at Mercy Medical Center
    • Chillicothe, Ohio, United States, 45601
      • Adena Regional Medical Center
    • Columbus, Ohio, United States, 43214-3998
      • Riverside Methodist Hospital Cancer Care
    • Columbus, Ohio, United States, 43222
      • Mount Carmel Health - West Hospital
    • Columbus, Ohio, United States, 43215
      • CCOP - Columbus
    • Columbus, Ohio, United States, 43215
      • Grant Medical Center Cancer Care
    • Columbus, Ohio, United States, 43228
      • Doctors Hospital at Ohio Health
    • Delaware, Ohio, United States, 43015
      • Grady Memorial Hospital
    • Lancaster, Ohio, United States, 43130
      • Fairfield Medical Center
    • Lima, Ohio, United States, 45801
      • St. Rita's Medical Center
    • Marietta, Ohio, United States, 45750
      • Strecker Cancer Center at Marietta Memorial Hospital
    • Newark, Ohio, United States, 43055
      • Licking Memorial Cancer Care Program at Licking Memorial Hospital
    • Springfield, Ohio, United States, 45505
      • Community Hospital of Springfield and Clark County
    • Springfield, Ohio, United States, 45504
      • Mercy Medical Center
    • Westerville, Ohio, United States, 43081
      • Mount Carmel St. Ann's Cancer Center
    • Zanesville, Ohio, United States, 43701
      • Genesis - Good Samaritan Hospital
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Natalie Warren Bryant Cancer Center at St. Francis Hospital
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Rosenfeld Cancer Center at Abington Memorial Hospital
    • Bryn Mawr, Pennsylvania, United States, 19010
      • Bryn Mawr Hospital
    • Danville, Pennsylvania, United States, 17822-0001
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Lewistown, Pennsylvania, United States, 17044
      • Lewistown Hospital
    • Paoli, Pennsylvania, United States, 19301-1792
      • Cancer Center of Paoli Memorial Hospital
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Cancer Center
    • State College, Pennsylvania, United States, 16803
      • Mount Nittany Medical Center
    • State College, Pennsylvania, United States, 16801
      • Geisinger Medical Group - Scenery Park
    • West Grove, Pennsylvania, United States, 19390-9499
      • Jennersville Regional Hospital
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center
    • Wynnewood, Pennsylvania, United States, 19096
      • CCOP - MainLine Health
    • Wynnewood, Pennsylvania, United States, 19096
      • Lankenau Cancer Center at Lankenau Hospital
    • York, Pennsylvania, United States, 17405
      • York Cancer Center at Apple Hill Medical Center
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital Regional Cancer Center
    • Green Bay, Wisconsin, United States, 54301-3526
      • Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center
    • Green Bay, Wisconsin, United States, 54303
      • Green Bay Oncology, Limited at St. Mary's Hospital
    • Green Bay, Wisconsin, United States, 54303
      • St. Mary's Hospital Medical Center - Green Bay
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
    • Madison, Wisconsin, United States, 53717
      • Dean Medical Center - Madison
    • Marinette, Wisconsin, United States, 54143
      • Bay Area Cancer Care Center at Bay Area Medical Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Oconto Falls, Wisconsin, United States, 54154
      • Green Bay Oncology, Limited - Oconto Falls
    • Rice Lake, Wisconsin, United States, 54868
      • Marshfield Clinic - Indianhead Center
    • Sturgeon Bay, Wisconsin, United States, 54235
      • Green Bay Oncology, Limited - Sturgeon Bay

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive oral levocarnitine (L-carnitine) twice daily on weeks 1-4.	Dietary supplement: levocarnitine; Given orally
Placebo Comparator: Arm II; Patients receive oral placebo twice daily on weeks 1-4.	Other: placebo; Given orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	assessed at baseline and 4 weeks after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	assessed at baseline and 4 weeks after randomization
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.	assessed at baseline and 4 weeks after randomization
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.	assessed at baseline and 4 weeks after randomization
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.	assessed at 4 weeks after randomization
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.	assessed at baseline and 4 weeks after randomization

Collaborators and Investigators

• Sponsor: ECOG-ACRIN Cancer Research Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Ricardo Cruciani, MD, PhD, Beth Israel Medical Center - Petrie Division; Study Chair: Russell K. Portenoy, MD, Beth Israel Medical Center - Petrie Division

Publications and helpful links

General Publications

• Cruciani RA, Zhang JJ, Manola J, Cella D, Ansari B, Fisch MJ. L-carnitine supplementation for the management of fatigue in patients with cancer: an eastern cooperative oncology group phase III, randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2012 Nov 1;30(31):3864-9. doi: 10.1200/JCO.2011.40.2180. Epub 2012 Sep 17.
• Rich TA, Manola J, Cella D, et al.: An evaluation of serum cytokine levels and fatigue and depression in ECOG E4Z02. [Abstract] J Clin Oncol 29 (Suppl 15): A-9046, 2011.
• Rich TA, Fisch MJ, Manola J, et al.: Analysis of cytokines in ECOG E4Z02: A phase III randomized study of l-carnitine supplementation for fatigue in patients with cancer. [Abstract] J Clin Oncol 27 (Suppl 15): A-9635, 2009.

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2005
• Primary Completion (Actual): March 1, 2008
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: September 7, 2004
• First Submitted That Met QC Criteria: September 7, 2004
• First Posted (Estimated): September 8, 2004

Study Record Updates

• Last Update Posted (Actual): July 5, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific; pain; fatigue; depression; levocarnitine; carnitine deficiency
• Additional Relevant MeSH Terms: Fatigue
• Other Study ID Numbers: E4Z02 (Other Identifier: Eastern Cooperative Oncology Group); U10CA023318 (U.S. NIH Grant/Contract); CDR0000384087 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.