Reference ↗
Title	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
Topic	Carnitine
Author	Cruciani, RA, Zhang, JJ, Manola, J, Cella, D, Ansari, B, Fisch, MJ
Year	2012
Journal	Journal of clinical oncology: official journal of the American Society of Clinical Oncology
DOI	https://doi.org/10.1200/JCO.2011.40.2180

Study Note

Brief summary

376 patients with different types of cancer took part in this study to investigate carnitine on tiredness/fatigue caused by cancer or the associated chemotherapy and medication. They were randomly assigned to 2 groups, one of which received 2g of carnitine daily for 2 months, while the other initially received a placebo and only after 1 month of the study did they receive carnitine like the other group. The results show no differences between the arms after 1 month in terms of improvement/worsening of fatigue. This can be explained by the fact that both arms showed improvement over time, regardless of whether they received carnitine or a placebo. Other measurements on the improvement/deterioration of the patients' mood after 4 weeks or their physical functionality after 8 weeks with carnitine also remained inconclusive. Overall, the study impresses with a large number of patients in the two arms and a detailed analysis of the data. However, important key data on the patients such as age or type/distribution of cancer are missing. The exact procedure and time points for data collection are also not clear from the study.

An dieser zur Untersuchung von Carnitin auf Müdigkeit/Erschöpfung, verursacht durch eine Krebserkrankung bzw. die damit verbundene Chemotherapie und Medikation, nahmen 376 Patienten mit unterschiedlichen Krebserkrankungen teil. Sie wurden zufällig 2 Gruppen zugeteilt, von der eine Gruppe 2 Monate lang täglich 2g Carnitin erhielt, während die andere zunächst ein Placebo erhielt und erst nach 1 Monat Studienlaufzeit wie die andere Gruppe Carnitin erhielt. Die Ergebnisse zeigen keine Unterschiede zwischen den Gruppen nach 1 Monat bezüglich der Besserung/Verschlechterung der Fatigue. Dies ist dadurch zu begründen, dass bei beiden Gruppen eine Besserung über die Zeit auftritt, unabhängig davon, ob sie Carnitin oder ein Placebo erhalten haben. Andere Messungen über die Besserung/ Verschlechterung der Stimmung der Patienten nach 4 Wochen oder deren körperliche Funktionalität nach 8 Wochen durch Carnitin blieben ebenfalls ergebnislos. Insgesamt beeindruckt die Studie mit einer großen Anzahl an Patienten in den beiden Gruppen und einer ausführlichen Analyse der Daten. Allerdings fehlen wichtige Eckdaten zu den Patienten wie Alter oder Art/ Verteilung der Krebserkrankung. Auch der genaue Ablauf und Zeitpunkte für die Datenerhebung sind nicht klar aus der Studie raus zu lesen.

Study Design

1st phase of the study (1 month): double-blind

2nd phase of the study (1 month): open

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	Yes
Number of arms	2

Study characteristics

Inclusion criteria	Hemoglobin ≥ 9 g/dL taken ≤ 4 weeks before registration
Exclusion criteria	Intake of carnitine, history of seizures, brain metastasis, nausea more than grade 1, and severely compromised renal, liver, or respiratory function
N randomized	376
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis
Specifications on analyses	Included were n=376, but n=43 patients left study before start of intervention.
Countries of data collection	United States
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: after 4 weeks (first phase) T2: after 8 weeks (second phase)

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	NI
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	NI
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Advanced Stage
Specifications on cancer stages	Invasive cancer
Comorbidities	Carnitine deficiency (free carnitine < 35 µmol/L for men or < 25 µmol/L for women or acyl/free carnitine ratio > 0.4; Baseline: intervention arm: 34% and placebo arm: 32%) Medication (intervention/placebo arm) Psychostimulants 2.1/ 3.2% Analgesics 44.4/ 33.7% Antidepressants 28.6/ 27.8%
Current cancer therapies	Chemotherapy, Radiation therapy, No therapy
Specifications on cancer therapies	NI
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Female Intervention arm 58.2% and placebo arm 57.7%
Age groups	NI
Age groups specification	NI

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	189
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	First phase n=62 Second phase n=56
Drop-out reasons	First phase: Revocation: 31x, Side effects: 11x, Treatment refused: 10x, Deceased: 4x, Disease progression: 3x, Other: 3x Second phase: Treatment ended early: 28x, Side effects: 11x, Treatment refused: 9x, Deceased: 2x, Disease progression: 2x, Other: 4x
Intervention	L-Carnitin
Dosage and regime	L-carnitine was a standardized commercial preparation of 10 g of levocarnitine inert salt in 100-mL solution 2g (2x 1g) daily oral Duration: 8 weeks
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	56
Side effects / Interactions	No group differences between side effect grade 5 (Fisher's exact p=0.64) One death possibly caused by treatment (arm unclear). Otherwise possibly/probably/definitely treatment related: Hemoglobin: 10x, Fatigue: 2x, Itching: 1x, Rash: 1x, Constipation: 1x, Diarrhea: 1x, Dizziness: 4x, Vomiting: 1x, Infection reason unknown: 1x, Genitourinary tract: 1x, Abdominal pain: 1x, Dyspnea: 2x By “treatment associated”, probably chemo-/radiotherapy meant. However, description not clear.

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	187
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	First phase n=72 Second phase n=57
Drop-out reasons	First phase: Revocation: 36x, Side effects: 17x, Treatment refused: 13x, Deceased: 1x, Disease progression: 1x, Other: 4x Second phase: Treatment ended early: 29x, Side effects: 11x, Treatment refused: 5x, Deceased: 5x, Disease progression: 3x, Other: 4x
Intervention	Placebo
Dosage and regime	2g (2x 1g) daily oral Duration: 8 weeks
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	56
Side effects / Interactions	No group differences between side effect grade 5 (Fisher's exact p=0.64) One death possibly caused by treatment (arm unclear). Otherwise possibly/probably/definitely treatment related: Hemoglobin: 9x, Platelets: 2x, Death due to disease progression: 2x, Anorexia: 1x, Diarrhea: 4x, Dizziness: 4x, Vomiting: 2x, Abdominal pain: 2x, Atrial fibrillation: 1x, Stench: 1x, Extrapyramidal symptoms: 1x By “treatment associated”, probably chemo-/radiotherapy meant. However, description not clear.

Outcomes

Fatigue

Outcome type As specificed by the authors	Primary
Outcome specification	NA
Type of measurement	BFI (Brief Fatigue Inventory)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	From Baseline to 8 weeks: improvement in fatigue in intervention arm: Mean difference= -0.96; 95% CI: -1.32,-0.60 and placebo arm: Mean difference= -1.11; 95% CI: -1.44,-0.78; no group difference (z-transformed difference= -0.58; p=0.57)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Fatigue

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	FACIT (Functional Assessment of Chronic Illness Therapy)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 4 weeks: no difference between arms (p=0.61)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Depression

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	CES-D (Center for Epidemiologic Studies - Depression Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 4 weeks: no difference between arms (p=0.93)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Pain

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	BPI-SF (Brief Pain Inventory - Short Form)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 4 weeks: no difference between arms for pain intensity: p=0.61, disturbance due to pain: p=0.75
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Performance Status

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	ECOG Performance Status Scale (Eastern Cooperative Oncology Group)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 4 and 8 weeks: no difference between arms (p=0.13, p=0.63)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No difference between arms for grade 5 side effect (Fisher's exact p=0.64)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Carnitine level

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	Blood Test
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 4 weeks: significant difference between arms, with higher proportion of carnitine deficit in placebo arm (intervention arm: 11%, placebo arm: 33%; p≤.001)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	L-carnitine was a standardized commercial preparation of 10 g of levocarnitine inert salt in 100-mL solution, provided by Sigma Tau Pharmaceuticals, Gaithersburg, MD.
Conflicts of Interest	According to authors no conflict of interest.

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis
- Reasons for insufficient sample size based on power analysis
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

PRO:

Ethics approval available.
Balanced by gender, PS (0-1 vs. 2-3), and CTX.
Control for current carnitine intake.
High Cronbach's alpha for BFI at all times.
Subgroup analysis to exclude or identify moderator effects.
Detailed collection of adverse events and tabular representation.

CONTRA:

Placebo arm had higher pain with BPI or analgesic use compared to intervention arm (intervention: 61% vs. placebo: 49.7%; p = 0.04).
Attrition and reporting of remaining group sizes not accurate.
Timing of results for secondary endpoints unclear.
High drop-out/attrition (44% attrition, over 60 refused treatment, unclear why).
No intention-to-treat analysis.
No report of individual p-values for comparisons (e.g., baseline values).
No information on patient age, cancer diagnoses, and data collection period.
Unclear from appendix which AEs are “definitely therapy-associated.”
Death possibly therapy-associated; unclear in which arm, cause of death, and what about NOS deaths (2x).
Representation of side effects not clear.
Discrepancies between text and table (number); also, description of reasons for deaths inconsistent between text and table.