Cruciani et al. (2009): L-Carnitine Supplementation in Patients with Advanced Cancer and Carnitine Deficiency: A Double-Blind, Placebo-Controlled Study

Reference ↗
Title	L-Carnitine Supplementation in Patients with Advanced Cancer and Carnitine Deficiency: A Double-Blind, Placebo-Controlled Study
Topic	Carnitine
Author	Cruciani, RA, Dvorkin, ED, Homel, P, Culliney, B, Malamud, S, Lapin, J, Portenoy, RK, Esteban-Cruciani, N
Year	2009
Journal	Journal of pain and symptom management
DOI	https://doi.org/10.1016/j.jpainsymman.2008.03.021

Brief summary

The study investigated the impact of carnitine on fatigue/exhaustion caused by cancer and the associated chemotherapy and medication. A total of 33 patients with various cancers and a carnitine deficiency caused by the treatment were randomly assigned to two groups. One group received 2g of carnitine daily for 4 weeks, while the other group received a placebo for 2 weeks and then 2g of carnitine daily for the next 2 weeks. At the beginning of the study, none of the participants knew whether they were receiving carnitine or a placebo. After 2 weeks, this information was disclosed, so both groups knew they were either receiving carnitine or had previously received a placebo and were now also receiving carnitine. The resutls of the analysis after 2 weeks showed no significant results. After 4 weeks, the results of an exploratory analysis showed a greater improvement in fatigue in the group that received carnitine from the start. Additionally, it showed a deterioration in quality of life in terms of functionality for the initial placebo group and a general improvement in physical functionality in the group that received carnitine from the beginning. In summary, the improvement in fatigue is not interpretable as the effect only occurred when the participants knew which group they were originally assigned to. Similarly, the effect of better physical functionality or worse functional quality of life only appeared after 4 weeks, and thus under the knowledge of group assignment.

Die Studie untersuchte den Einfluss von Carnitin auf Müdigkeit/ Erschöpfung verursacht durch eine Krebserkrankung bzw. die damit verbundene Chemotherapie und Medikation. Insgesamt 33 Patienten mit verschiedenen Krebserkrankungen und einem Carnitindefizit, verursacht durch die Behandlung wurden zufällig 2 Gruppen zugeordnet. Die eine Gruppe erhielt über 4 Wochen 2g Carnitin täglich, während die andere Gruppe 2 Wochen ein Placebo erhielt und erst dann für die nächsten 2 Wochen auch 2g Carnitin täglich. Zu Beginn der Studie wusste keiner der Probanden ob er Carnitin oder ein Placebo erhielt, nach 2 Wochen wurde dies offen gelegt, sodass beide Gruppen wussten, dass sie Carnitin erhielten oder zuvor ein Placebo erhielten und nun aber auch Carnitin bekommen. In den Auswertungen nach 2 Wochen zeigten sich keine bedeutsamen Effekte. In einer explorativen Analyse zeigte sich nach 4 Wochen eine stärkere Besserung der Müdigkeit in der Gruppe, die von Anfang an Carnitin erhielt. Zudem zeigten die Ergebnisse eine Verschlechterung der Lebensqualität im Sinne der Funktionalität für die anfängliche Placebogruppe und eine generelle bessere körperliche Funktionalität in der Gruppe, die von Anfang an Carnitin erhielt. Zusammenfassend ist das Ergebnis der Besserung der Müdigkeit allerdings nicht interpretierbar, da der Effekt erst auftrat, als die Probanden wussten, welcher Gruppe sie ursprünglich zugeordnet waren. Auch der Effekt der besseren körperlichen Funktionalität bzw. schlechteren funktionalen Lebensqualität tritt erst nach 4 Wochen und damit unter dem Wissen der Gruppenzugehörigkeit auf.

Study Design

1. Phase of the study: double-blind (randomized)

2. Phase of the study: open-label (both arms received carnitine)

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	Moderate to severe fatigue, a Karnofsky Performance Status (KPS) score 14 of 50 or more, and carnitine deficiency; carnitine deficiency was defined as free carnitine less than 35 µmol/L for males or less than 25 µmol/L for females (normal range 35-67 and 25-55, respectively), or an acyl-carnitine ratio of more than 0.4 (acylcarnitine ratio 0.4 total acyl-carnitine - free acyl-carnitine/free acyl-carnitine)
Exclusion criteria	Uncontrolled or severe cardiovascular, pulmonary, or renal disease; current treatment with either chemotherapy or radiation therapy; encephalopathy or psychiatric disorder sufficient to compromise adherence to study methods or data collection; history of stroke, seizure, or primary or metastatic brain tumor; fewer than 60 days of concurrent use of recombinant erythropoietin, and known sensitivity to carnitine
N randomized	29
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, ITT Analysis
Specifications on analyses	ITT-Analyse n=29 Per Protocol Analyse n= 27 An exploratory analysis was performed in which the data (all 17 patients who started on L-carnitine plus 10 patients who started on placebo, inkluding two protocol violators) was supplemented by the scores recorded at the end of the open-label phase. The pattern mixture analysis used three measurements over time and accounted for missing data.
Countries of data collection	United States
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: before intervention (baseline) T1: 2 weeks (end of phase 1) T2: 1 week after the start of the intervention T3: 4 weeks (end of phase 2)

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.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Colorectal Cancer - Colon Cancer, Colorectal Cancer - Rectal Cancer, Gastrointestinal Cancers - Esophageal Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Gastrointestinal Cancers - Liver Cancer, Genitourinary Cancers - Bladder Cancer, Genitourinary Cancers - Kidney (Renal) Cancer, Head and Neck Cancers, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Lung Cancer, Prostate Cancer, Stomach Cancer
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	NI
Comorbidities	Carnitine deficiency; carnitine deficiency was defined as free carnitine less than 35 µmol/L for males or less than 25 µmol/L for females (normal range 35-67 and 25-55, respectively), or an acyl-carnitine ratio of more than 0.4 (acylcarnitine ratio 0.4 total acyl-carnitine - free acyl-carnitine/free acyl-carnitine)
Current cancer therapies	Chemotherapy, NI, Radiation therapy
Specifications on cancer therapies	The protocol was amended during the course of the study, and patients receiving chemotherapy or radiation therapy were allowed under the modified protocol.
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	55% female
Age groups	Adults (18+)
Age groups specification	Mean (SD): 66–70 (13) years

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	17
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Phase 1 n=7 Phase 2 n=1
Drop-out reasons	Phase 1: n=2 death, n=3 deteriorations, n=1 diarrhea, n=1 missed follow-up Phase 2: no reasons given
Intervention	L-Carnitine
Dosage and regime	0.5 g/day for 2 days, then 1 g/day for 2 days, and then 2 g (2x1g) daily for 10 days in 10 ml syrup = 14 days + 14 days after unblinding
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.	28
Side effects / Interactions	1 case of constipation and 1 case of diarrhea were reported by the authors to be associated with carnitine

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	12
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Phase 1 n=5 Phase 2 n=1
Drop-out reasons	Phase 1: n=1 death, n=2 deteriorations, n=2 with low fatigue Phase 2: no reasons given
Intervention	Placebo
Dosage and regime	14 days, then L-Carnitine 2g (2x 1g) daily for 14 days
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.	28
Side effects / Interactions	NI

Outcomes

Fatigue

Outcome type As specificed by the authors	Primary
Outcome specification	NA
Type of measurement	FACT (Functional Assessment of Cancer 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 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
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".	Exploratory analysis: After 4 weeks (end of phase II; PMA, pattern mixture analysis): greater change for the intervention arm compared to the placebo arm (b=2.6; p=0.03; adjusted), Intervention arm: Baseline: Mean (SD) = 16.0 (8.5) – 4 weeks: Mean (SD) = 22.4 (10.7), Placebo arm: Baseline: Mean (SD) = 11.8 (6.1) – 4 weeks: Mean (SD) = 15.1 (4.8)

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	?

Quality of life

Outcome type As specificed by the authors	Primary
Outcome specification	Quality of Life and Well-being
Type of measurement	FACT (Functional Assessment of Cancer Therapy), LASA (Linear Analogue Self-Assessment)
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 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
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".	Exploratory analysis: After 4 weeks (end of phase II, PMA Analysis): significant difference for the functional subscale (b=1.9; p=0.03; unadjusted; b=2.0; p=0.002; adjusted); Intervention arm: Baseline: Mean (SD) = 11.4 (5.1) – 4 weeks: Mean (SD) = 11.0 (3.2), Placebo arm: Baseline: Mean (SD) = 10.8 (6.0) – 4 weeks: Mean (SD) = 9.2 (3.8); this difference is due to the decrease in values in the placebo arm; no direct comparison was conducted

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	?

Mental status/ function

Outcome type As specificed by the authors	Primary
Outcome specification	NA
Type of measurement	MMSE (Mini-Mental State Exam)
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 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
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".	Exploratory analysis: No differences between arms and/or time points for PMA-Analysis

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	?

Physical functioning

Outcome type As specificed by the authors	Primary
Outcome specification	NA
Type of measurement	KPS (Karnofsky Performance Status)
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 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
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".	Exploratory analysis: After 4 weeks (end of phase II, PMA Analysis): significant difference between the arms (b=2.58; p=0.003, unadjusted; b=2.7; p=0.002, adjusted), Intervention arm: Baseline: Mean (SD) = 58.2 (8.8) – 4 weeks: Mean (SD) = 64.2 (9.0), Placebo arm: Baseline: Mean (SD) = 57.0 (4.8) – 4 weeks: Mean (SD) = 50.0 (15.5); with higher values for the intervention arm and lower values for the placebo arm

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	Primary
Outcome specification	NA
Type of measurement	Interview
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".	Adverse events were observed in 21 out of 29 patients (hospice patients); 7 were hospitalized (intervention arm: 4 times, placebo arm: 3 times). Fifteen hospice patients and eight non-hospice patients reported adverse events, including: Nausea/vomiting (intervention arm: 2 times); Stomach problems (intervention arm: 2 times); Increased pain (placebo arm: 2 times); Diarrhea (intervention arm: 2 times); Confusion (placebo arm: 1 time); Tinnitus (placebo arm: 1 time) According to the authors, only one case of constipation and one case of diarrhea were associated with carnitine.
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	“The study was funded by grant # R21AT01025 from the National Institutes of Health.”
Conflicts of Interest	NI

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:

• Ethical approval obtained.
• Intention-to-treat analysis.
• Block randomization according to RTX or CTX, gender, and hemoglobin level.
• Power analysis conducted.
• Explanation provided for unequal group sizes (block randomization).
• Critical discussion of results.

CONTRA:

• Inclusion of baseline values only in an additional secondary analysis (PPA).
• Effects in PPA only for control of baseline values and age.
• Small sample size.
• Differing reports of required free carnitine for men in the abstract and main text.