Sun et al. (2016): A prospective study to evaluate the efficacy and safety of oral acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy

Reference ↗
Title	A prospective study to evaluate the efficacy and safety of oral acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy
Topic	Carnitine
Author	Sun, Y, Shu, Y, Liu, B, Liu, P, Wu, C, Zheng, R, Zhang, X, Zhuang, Z, Deng, Y, Zheng, L, Xu, Q, Jiang, B, Ouyang, X, Gao, J, Xu, N, Li, X, Jiang, S, Liang, C, Yao, Y
Year	2016
Journal	Experimental and therapeutic medicine
DOI	https://doi.org/10.3892/etm.2016.3871

Brief summary

This study shows the influence of acetyl-L-carnitine (ALC) on peripheral neuropathy as a result of chemotherapy. A total of 239 subjects participated in the study, of which 118 patients received ALC every day for 8 weeks (intervention arm) and 121 patients received a placebo during the same period (placebo control arm). The results show a significant improvement in negative symptoms associated with peripheral neuropathy and relief of fatigue/fatigue in the intervention arm compared to the placebo control arm after 8 weeks. The results are promising, however the improvement in fatigue/exhaustion and improvement in peripheral neuropathy disappear again between the arms after 12 weeks and the difference for fatigue/exhaustion at 8 weeks only emerges for a non-representative analysis. The sample is large, but subject drop-outs are difficult to track and overall patient demographics are lacking. The statistical analysis has a few gaps, particularly in the presentation of the results and their interpretability.

Diese Studie zeigt den Einfluss von Acetyl-L-Carnitin (ALC) auf periphere Neuropathie als Folge einer Chemotherapie. Insgesamt nahmen 239 Probanden an der Studie teil, davon erhielten 118 Patienten das ALC jeden Tag für 8 Wochen (Interventionsgruppe) und 121 Patienten erhielten in dem Zeitraum ein Placebo (Placebo-Kontrollgruppe). Die Ergebnisse zeigen eine deutliche Verbesserung der negativen Symptome verbunden mit peripherer Neuropathie und eine Linderung der Erschöpfung/Müdigkeit in der Interventionsgruppe im Vergleich zur Placebo-Kontrollgruppe nach 8 Wochen. Die Ergebnisse sind vielversprechend, allerdings verschwinden die Verbesserung der Müdigkeit/Erschöpfung und die Besserung der peripheren Neuropathie nach 12 Wochen zwischen den Gruppen wieder und der Unterschied für die Müdigkeit/Erschöpfung nach 8 Wochen taucht nur für eine nicht-repräsentative Analyse auf. Die Stichprobe ist groß, doch die Drop-Outs der Probanden sind schwer nachzuvollziehen und auch insgesamt fehlen demografische Eckdaten über die Patienten. Die statistische Analyse hat ein paar Lücken, insbesondere in der Darstellung der Ergebnisse und deren Interpretationsfähigkeit.

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	?
Exclusion criteria	?
N randomized	239
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	?
Countries of data collection	?
LoE Level of evidence	?
Outcome timeline Data collection times	?

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.	?
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	?
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	?
Specifications on cancer stages	?
Comorbidities	?
Current cancer therapies	?
Specifications on cancer therapies	?
Previous cancer therapies	?
Gender	?
Gender specifications	?
Age groups
Age groups specification	?

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	109
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Unclear/NI
Drop-out reasons	The safety analysis set contained 236 patients, 118 in the intervention and 118 in the placebo arm. The full analysis set (FAS) contained 225 patients, 109 in the intervention and 116 in the placebo arm. The per-protocol set (PPS) contained 203 patients, 95 in the intervention and 108 in the placebo arm.
Intervention	Acetyl-L-Carnitine
Dosage and regime	Oral, 3 x 1000 mg daily (in two 500 mg tablets) 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	Most common: Gastrointestinal reactions (vomiting, diarrhea, bloating), p>0.05; Second most common: Reduced white blood cell count (only in intervention arm), liver dysfunction, and sleep disturbances For severe adverse events: no connection with administered medications; p>0.05 No difference between arms for adverse reactions and events (p=0.5816; p=0.3903)

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	116
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Unclear/NI
Drop-out reasons	The safety analysis set contained 236 patients, 118 in the intervention and 118 in the placebo arm. The full analysis set (FAS) contained 225 patients, 109 in the intervention and 116 in the placebo arm. The per-protocol set (PPS) contained 203 patients, 95 in the intervention and 108 in the placebo arm.
Intervention	Placebo
Dosage and regime	Lactose, 3 x 1000 mg 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	Most common: Gastrointestinal reactions (vomiting, diarrhea, bloating), p>0.05; Second most common: Reduced white blood cell count (only in intervention arm), liver dysfunction, and sleep disturbances For severe adverse events: no connection with administered medications; p>0.05 No difference between arms for adverse reactions and events (p=0.5816; p=0.3903)

Outcomes

Neurotoxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Improvement by ≥1 grade according to NCI-CTC criteria
Type of measurement	NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria)
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".	Full analysis set: Significant differences between arms at all time points with more improvement in intervention arm: 4 weeks: Intervention: 26.6%, Placebo: 13.8%; χ² = 5.766; p = 0.016 8 weeks: Intervention: 50.5%, Placebo: 24.1% (CI: 14.1, 38.5%); χ² = 16.772; p < 0.001 At 8 weeks: Improvement of intervention arm by ≥1 grade compared to placebo arm (χ² = 6.242; p = 0.0441), but the difference disappears by 12 weeks. As well as an overall significantly steeper improvement in intervention arm (p < 0.05) 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".	Full analysis set: Significant differences between arms at all time points with more improvement in intervention arm: 12 weeks (4 weeks after intervention): Intervention: 57.8%, Placebo: 39.7%; χ² = 7.406; p = 0.007 But no difference of ≥1 grade between arms. As well as an overall significantly steeper improvement in intervention arm (p < 0.05) compared to 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	?

Nerve conduction velocity

Outcome type As specificed by the authors	Secondary
Outcome specification	Electrophysiological examination and evaluation of electrophysiology
Type of measurement	Electrophysiological evaluation
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".	Electrophysiological examination: Improvement from baseline to 8 weeks is statistically significant between the groups only for NCV of the sural nerve (p < 0.05), direction not available (data not shown) Evaluation of electrophysiology: in Full analysis set: improved in intervention arm (60.7%), compared with placebo arm (56.9%; p<0.05); Similar results could be observed in the PP analyis, with a 76.8% improvement in the intervention arm and a 59.3% in the placebo arm (p<0.05)
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	Physical examination
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".	At 8 weeks: Full analysis set: no difference between arms PP analysis: less fatigue/improvement of symptoms in intervention compared to placebo arm (intervention: 33.7%, placebo: 18.5%; χ² = 6.100; p = 0.014)
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".	At 12 weeks: Full analysis set: no difference between arms PP analysis: less fatigue/improvement of symptoms in intervention compared to placebo arm (intervention: 41.1%, placebo: 25%; χ² = 5.936; p = 0.015); Overall p = 0.0135

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	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".	At 8 weeks: Full analysis set: Significantly more frequent improvement in values in intervention (29.3%) compared to placebo arm (13%; p < 0.022), also significant in PP-analysis.
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".	At 12 weeks: In full analysis set and PP-analysis significant change from baseline (p < 0.01, no further data shown).

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	?
Conflicts 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

?