Kraft et al. (2012): L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN) - a randomized multicentre trial

Reference ↗
Title	L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN) - a randomized multicentre trial
Topic	Carnitine
Author	Kraft, M, Kraft, K, Gärtner, S, Mayerle, J, Simon, P, Weber, E, Schütte, K, Stieler, J, Koula-Jenik, H, Holzhauer, P, Gröber, U, Engel, G, Müller, C, Feng, YS, Aghdassi, A, Nitsche, C, Malfertheiner, P, Patrzyk, M, Kohlmann, T, Lerch, MM
Year	2012
Journal	Deutsche Zeitschrift für Onkologie
DOI	http://www.nutritionj.com/content/11/1/52

Brief summary

This study included 72 patients with advanced pancreatic cancer who were randomly and fairly evenly divided into two groups. One group received the carnitine and the other group the placebo. The authors investigated the influence of carnitine on the weight caused by the disease, as well as the influence on general quality of life, symptoms of fatigue, general survival times and length of hospital stay. After 12 weeks, the results showed a statistically relevant increase in weight and BMI in the carnitine group compared to the placebo group. For general life satisfaction, there were improvements for the carnitine group in some subcategories of the questionnaire after the intervention, but no differences for the total score. There were no group differences for the other endpoints examined. By the end of the study, only 26 of the initial 72 patients remained, meaning that more than half of the patients did not complete the study. This makes the sample very small and the results not very reliable or trustworthy. Differences were also found on the other endpoints surveyed, which were presumably not statistically relevant due to the small sample. However, a high number of missing patients by the end of the study also speaks against the real feasibility of the intervention.

Diese Studie schloss 72 Patienten mit fortgeschrittenem Pankreaskrebs ein, welche zufällig und recht gleichmäßig in zwei Gruppen eingeteilt wurden. Die eine Gruppe erhielt das Carnitin und eine andere Gruppe das Placebo. Die Autoren untersuchten den Einfluss von Carnitin auf das Gewicht verursacht durch die Erkrankung, sowie den Einfluss auf die allgemeine Lebensqualität, Erschöpfungssymptome, allgemeine Überlebenszeiten und Länge des Krankenhausaufenthalts. Nach 12 Wochen zeigen die Ergebnisse eine statistisch relevante Steigerung des Gewichts bzw. Erhöhung des BMI in der Carnitingruppe im Vergleich zur Placebogruppe. Für die allgemeine Lebenszufriedenheit zeigten sich nach der Intervention Verbesserungen für die Carnitingruppe auf einigen Unterkategorien des Fragebogens, aber keine Unterschiede für die Gesamtpunktzahl. Es zeigten sich keine Gruppenunterschiede für die anderen untersuchten Endpunkte. Bis zum Ende der Studie waren von den anfänglichen 72 Patienten nur noch 26 übrig, damit hat über die Hälfte der Patienten die Studie nicht zu Ende geführt. Dadurch wird die Stichprobe sehr klein und die Ergebnisse wenig zuverlässig bzw. vertrauenswürdig. Es wurden auch auf den anderen erhobenen Endpunkten Unterschiede gefunden, welche vermutlich aufgrund der kleinen Stichprobe nicht statistisch relevant wurden. Jedoch spricht eine hohe Anzahl an fehlenden Patienten bis zum Ende der Studie auch gegen die reale Durchführbarkeit der Intervention.

Study Design

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	No
Number of arms	2

Study characteristics

Inclusion criteria	Histologically proven, advanced and irresectable adenocarcinoma of the pancreas (UICC Stage IV), had a Karnofsky performance status of >60
Exclusion criteria	Liver failure, a second malignancy, treatment with omega-3-fatty acids and the presence of a mental disorder precluding informed consent
N randomized	72
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 Analysis planned, but no results of it reported. Sample size calculation was based on previous studies investigating the effect of L-Carnitine on inflammatory markers, with TNFα level differences as the primary endpoint, and resulted in a recruitment goal of 90 patients (45 per treatment arm) for a statistical power of 90% with an error probability of <5%. After a prescheduled interim analysis for sample size recalculation of 72 blinded datasets showed a wide variation of the standard errors for inflammatory markers, a recruitment of 554 patients (277 per group) would have been necessary. Since this goal was unattainable, the study was closed after enrolment of 72 patients and the data were unblinded for statistical analysis.
Countries of data collection	Germany
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline before intervention T1: 6 weeks after intervention T2: 12 weeks after intervention

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	Gastrointestinal Cancers - Pancreatic 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	Not operable Pancreas carcinoma, stage IV
Comorbidities	NA
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	At entry 88% of patients in the placebo and 92% of patients in the L-Carnitine group received chemotherapy.
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	40.3% female
Age groups	Adults (18+)
Age groups specification	Mean (SD): 64.4 (1.7) 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	38
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	After 6 weeks n=17 After 12 weeks n=6
Drop-out reasons	Reasons not seperated by arm: 11x deceased, 9x other illness, 8x nausea, 5x excessive demands, 2x diarrhea, 7x other reasons, 2x Omega-3-FA intake, 1x uncooperative behavior when taking carnitine on the part of the patient Drop-out rates and reasons: No difference between arms.
Intervention	L-Carnitin
Dosage and regime	4g daily Duration: 12 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.	84
Side effects / Interactions	Not seperated by arm: Predominantly nausea, vomiting, diarrhea without differences between the arms (p=kA); according to the authors a consequence of chemotherapy

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	34
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	After 6 weeks n=14 After 12 weeks n=6
Drop-out reasons	Reasons not seperated by arm: 11x deceased, 9x other illness, 8x nausea, 5x excessive demands, 2x diarrhea, 7x other reasons, 2x Omega-3-FA intake, 1x uncooperative behavior when taking carnitine on the part of the patient Drop-out rates and reasons: No difference between arms.
Intervention	Placebo
Dosage and regime	Daily Duration: 12 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.	84
Side effects / Interactions	Not seperated by arm: Predominantly nausea, vomiting, diarrhea without differences between the arms (p=kA); according to the authors a consequence of chemotherapy

Outcomes

Body composition

Outcome type As specificed by the authors	Primary
Outcome specification	BMI and body composition (BIA) : baseline + 6, 12 weeks
Type of measurement	BIA (Bioelectrical impedance analysis)
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 6 weeks: no significant difference between arms After 12 weeks: significantly higher weight (MD=3.4%; SD=1.35) due to higher body fat percentage (p<0.014) and BCM (p<0.013) in intervention compared to placebo arm
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	?

Quality of life

Outcome type As specificed by the authors	Primary
Outcome specification	With EORTC-QLQ-C3
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
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 6 weeks: Higher values in cognitive function (p<0.034) in the intervention arm compared to the placebo arm After 12 weeks: Better values for overall health status (p<0.041) and reduced gastrointestinal symptoms (p<0.033) in the intervention arm compared to the placebo arm
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	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".	No difference between arms and/or points in time
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	?

OS (Overall Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	From diagnosis to death
Type of measurement	Observation
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 and/or points in time
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

This study was supported by the Alfried-Krupp-von-Bohlen-und-Hahlbach Foundation (Graduate Schools Tumour Biology and Free Radical Biology), the Deutsche Krebshilfe/Dr. Mildred-Scheel-Stiftung (109102), the Deutsche Forschungsgemeinschaft (DFGgRK840-E3/E4, MA 4115/1-2/3, NI 1297/1-1), the Federal Ministry of Education and Research (BMBFgANI-MED 03152061A and BMBF 0314107), and the European Union (EU-FP-7: EPC-TM and EU-FP7-REGPOT-2010-1). KK and SG both received a Gerhard-Domagk-Stipendium of Greifswald University Medicine made possible through unrestricted educational grants from Medinal GmbH, Greven, Germany, Fresenius Kabi Germany GmbH, Bad Homburg, Germany, and Nutricia GmbH, Erlangen, Germany. L-Carnitine bulk compound was kindly provided by Lonza Ltd., Basel, Switzerland.

Conflicts of Interest

See Funding, no further conflict of interest declared.

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 for CARPAN protocol obtained.
• Registered as a clinical trial.
• Consideration of baseline values for carnitine.
• Critical evaluation of own results and reasons for findings.
• Power analysis conducted.

CONTRA:

• No clear categorization of dropout reasons into individual groups, and overall very high dropout rate, resulting in a small sample size (even though dropout was unavoidable due to disease stage), especially since power analysis required approximately 300 participants per group.
• No listing of questionnaire results.
• Baseline values not included as covariates.
• Although an intention-to-treat analysis was initially reported, no data was provided; imprecise description of applied analyses (where was what actually applied?) in the results section, with confusing reporting and statistically questionable procedures.