Hershman et al. (2013): Randomized Double-Blind Placebo-Controlled Trial of Acetyl-L-Carnitine for the Prevention of Taxane-Induced Neuropathy in Women Undergoing Adjuvant Breast Cancer Therapy

Reference ↗
Title	Randomized Double-Blind Placebo-Controlled Trial of Acetyl-L-Carnitine for the Prevention of Taxane-Induced Neuropathy in Women Undergoing Adjuvant Breast Cancer Therapy
Topic	Carnitine
Author	Hershman, DL, Unger, JM, Crew, KD, Minasian, LM, Awad, D, Moinpour, CM, Hansen, L, Lew, DL, Greenlee, H, Fehrenbacher, L, Wade, JL, Wong, SF, Hortobagyi, GN, Meyskens, FL, Albain, KS
Year	2013
Journal	Journal of clinical oncology: official journal of the American Society of Clinical Oncology
DOI	https://doi.org/10.1200/JCO.2012.44.8738

Study Note

A Follow-up study from 2018 is available: Hershman et al. (2018): Two-Year Trends of Taxane-Induced Neuropathy in Women Enrolled in a Randomized Trial of Acetyl-L Carnitine

Brief summary

This large-scale study, initially involving 409 breast cancer patients, focused primarily on the effect of carnitine on peripheral neuropathy (an increased toxicity in the brain that negatively affects all functions of the body) caused by taxane-based chemotherapy. The study lasted a total of 24 weeks, i.e. 6 months. The patients were randomly divided into 2 groups, one arm received 3g of carnitine daily while the comparison group received a placebo. After 12 weeks, there were still no significant differences between the arms, although both groups showed a deterioration in physical function. After 6 months, the arm receiving carnitine showed a significant deterioration in general functionality and increased toxicity, resulting in an increased worsening of peripheral neuropathy compared to the placebo group. Measurements of the influence on tiredness/exhaustion were statistically inconclusive. Overall, the authors advise against taking carnitine, as it significantly worsened the patients' symptoms.

Diese groß angelegte Studie mit anfänglich 409 Brustkrebspatienteninnen, beschäftigte sich vorranging mit dem Einfluss von Carnitin auf durch Taxane-basierte-Chemotherapie verursachte periphere Neuropathie (eine erhöhte Toxizität im Gehirn, welche alle Funktionen des Körpers negativ beeinflusst). Die Studie dauerte insgesamt 24 Wochen, also 6 Monate. Die Patientinnen wurden zufällig in 2 Gruppen eingeteilt, eine Gruppe erhielt 3g Carnitin täglich während die Vergleichsgruppe ein Placebo erhielt. Nach 12 Wochen zeigten sich noch keine bedeutsamen Unterschiede zwischen den Gruppen, auch wenn beide Gruppen eine Verschlechterung der körperlichen Funktionen zeigen. Nach 6 Monaten zeigt die Gruppe, welche Carnitin erhielt eine deutliche Verschlechterung in der allgemeinen Funktionalität und eine erhöhte Toxizität, damit eine erhöhte Verschlechterung der peripheren Neuropathie im Vergleich zur Placebogruppe. Messungen zur Beeinflussung der Müdigkeit/ Erschöpfung blieben statistisch ergebnislos. Die Autoren raten insgesamt von einer Einnahme von Carnitin ab, da dies die Symptome der Patientinnen deutlich verschlechtert hat.

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	Women with a history of stage I to III breast cancer, scheduled to undergo adjuvant taxane-based chemotherapy with one of the following standard regimens were included: paclitaxel 80 mg/m2 once per week for 12 cycles, paclitaxel 175 mg/m2 once every 2 weeks for four cycles, paclitaxel 175 mg/m2 once every 2 weeks for six cycles, docetaxel 75 mg/m2 once every 3 weeks for four cycles, or docetaxel 75 mg/m2 once every 3 weeks for six cycles; Zubrod performance status of 0 to 2
Exclusion criteria	History of diabetes, history of peripheral neuropathy resulting from other causes, or seizure disorder; receiving any of the following medications used to treat CIPN were excluded: vitamin E, glutamine, gabapentin, nortriptyline, amitriptyline or duloxetine hydrochloride (HCL), and other nutritional supplements used to treat CIPN
N randomized	409
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	NA
Countries of data collection	NI
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: baseline T1: after 12 weeks T2: after 24 weeks T3: after 36 weeks T4: after 52 weeks T5: after 104 weeks

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.	Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast 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	Early Stage, Advanced Stage
Specifications on cancer stages	>50% stage III
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Taxan-based chemotherapy; paclitaxel 80 mg/m2 once per week for 12 cycles, paclitaxel 175 mg/m2 once every 2 weeks for four cycles, paclitaxel 175 mg/m2 once every 2 weeks for six cycles, docetaxel 75 mg/m2 once every 3 weeks for four cycles, or docetaxel 75 mg/m2 once every 3 weeks for six cycles
Previous cancer therapies	NI
Gender	Female
Gender specifications	NA
Age groups	Adults (18+)
Age groups specification	Mean (range): intervention arm 52 (27-80) years; placebo arm 50 (26-77) 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	208
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not evaluable for toxicity n=7 After 12 weeks n=191 (92%) evaluable After 24 weeks n=174 (84%) evaluable
Drop-out reasons	No difference between arms for drop-out.
Intervention	Acetyl-L-carnitine (ALC)
Dosage and regime	3g (6 capsules each (hydrochloride, cellulose, 500mg ALC)) daily for 24 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.	168
Side effects / Interactions	Caused by taxane therapy, Grade 3 Toxicities (CTCAE): Vomiting: 1 instance Neuropathy (caused by taxanes): 8 instances

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	201
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not evaluable for toxicity n=7 After 12 weeks n=181 (90%) evaluable After 24 weeks n=173 (86%) evaluable
Drop-out reasons	No difference between arms for drop-out.
Intervention	Placebo
Dosage and regime	6x capsules (cellulose) daily for 24 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.	168
Side effects / Interactions	Caused by taxane therapy, Grade 3 Toxicities (CTCAE): Sleep disturbance: 1 instance Neuropathy (caused by taxanes): 1 instance

Outcomes

Peripheral neuropathy

Outcome type As specificed by the authors	Primary
Outcome specification	Chemotherapy induced peripheral neuropathy with NXT from FACT
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 12 weeks: Lower values for the intervention arm (higher CIPN) compared to the placebo arm (Baseline to 12 weeks: Intervention: -5.2 points vs. Placebo: -4.5 points), but the difference is not significant (linear regression, adjusted for baseline values: 0.9 points between arms, 95% CI: -2.2, 0.4; p = 0.17). There is a higher likelihood for the intervention arm to decrease by more than 5 points on the FACT-NTX, but this is not significant (OR: 1.48; 38% vs. 30%; p = 0.08) After 24 weeks: Baseline to 24 weeks: Intervention arm -5.3 points vs. placebo arm -3.6 points; linear regression: the intervention arm had 1.8 points less than the placebo arm, indicating a significant difference between arms (95% CI: -3.2, -0.4; p = 0.01), meaning more self-reported neuropathy symptoms in the intervention arm. There is a greater likelihood for the intervention arm to decrease by more than 5 points on the FACT-NTX (OR: 1.57; 38% vs. 28%; 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	?

Functionality

Outcome type As specificed by the authors	Secondary
Outcome specification	With FACT–Trial Outcome Index (TOI)
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 12 weeks: No difference in the intervention arm (Baseline: M = 99.3 – 12 weeks: M = 91.9; MD = 7.4) compared to the placebo arm (Baseline - 12 weeks MD = 7.4); p = 0.92. After 24 weeks: Mean difference between the intervention arm and the placebo arm = 3.5 points; 95% CI: -6.5, -0.4; p = 0.03, representing a significant reduction 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	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".	No difference between arms (12 weeks: p=0.20; 24 weeks: p=0.51), higher values in both arms over 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	?

Neurotoxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	Grade of neurotoxicity with FACT-NTX score
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".	No difference between arms
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	Financial support by Dawn L. Hershman.
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:

• Ethical approval obtained.
• Exclusion of other medications: no other medications for the treatment of CIPN were allowed.
• Clinical relevance: a 5-point deterioration in the FACT-NTX score is stated to be clinically relevant.
• Power analysis conducted.
• Large sample size appropriate to the prior power analysis.
• Compliance measured: no difference between groups.

CONTRA:

• Patient awareness: patients were informed about the study's goal; symptom assessment is subjective and could be influenced by knowledge of the study's objectives.
• Lack of effect sizes: not reported.
• No laboratory values collected: lack of objective measures.
• No intention-to-treat analysis was performed.