Mondal et al. (2014): Comparative study among glutamine, acetyl-L-carnitine, vitamin-E and methylcobalamine for treatment of paclitaxel-induced peripheral neuropathy

Reference ↗
Title	Comparative study among glutamine, acetyl-L-carnitine, vitamin-E and methylcobalamine for treatment of paclitaxel-induced peripheral neuropathy
Topic	Vitamin E, Carnitine, Vitamin B12
Author	Mondal, S, Choudhury, KB, Sharma, S, Gupta, A, Dutta, S
Year	2014
Journal	Clinical Cancer Investigation Journal
DOI	https://doi.org/10.4103/2278-0513.132113

Brief summary

In this study, four different arms of cancer patients were examined, all of whom received chemotherapy. During chemotherapy, one arm received additional vitamin E, one arm vitamin B12, one arm glutamine and the last arm carnitine. Components of peripheral neuropathy (sensory function, motor function and pain), a typical side effect of chemotherapy, were examined. There were no significant differences between the vitamin E and vitamin B12 arms in terms of the onset of the three components or their progression. However, patients in the vitamin E arm reported a later onset of symptoms and a better course in all components than patients in the glutamine and carnitine arms. Points of criticism of this study are the small sample sizes in the individual arms and the lack of a control arm. It was not shown whether significantly better effects were achieved in the vitamin E arm than in the placebo/nothing at all arm.

In dieser Studie werden vier verschiedene Gruppen von Krebspatienten untersucht, die alle Chemotherapie erhielten. Während der Chemotherapie bekam eine Gruppe zusätzlich Vitamin E, eine Gruppe Vitamin B12, eine Gruppe Glutamin und die letzte Gruppe Carnitin. Betrachtet wurden Komponenten der peripheren Neuropathie (Sensorik, Motorik und Schmerz), einer typischen Nebenwirkung der Chemotherapie. Dabei fanden sich sowohl hinsichtlich des Beginns der drei Komponenten als auch bezüglich des Verlaufs keine bedeutsamen Unterschiede zwischen der Vitamin E und der Vitamin B12 Gruppe. Patienten der Vitamin E Gruppe berichteten jedoch jeweils in allen Komponenten über einen späteren Beginn der Symptome und einen besseren Verlauf als Patienten der Glutamin- und der Carnitin-Gruppe. Kritikpunkte dieser Studie sind die kleinen Stichprobengrößen in den einzelnen Gruppen und die fehlende Kontrollgruppe. Es wurde nicht gezeigt, ob in der Vitamin E Gruppe bedeutsam bessere Effekte erzielt werden, als in einer Gruppe, die ein Placebo/ überhaupt nichts bekommt.

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	Monocentric
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	No
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	4

Study characteristics

Inclusion criteria	Histology proven evidence of carcinomas of lung, breast and ovary and would be treated with 1st line or 2nd line chemotherapeutic drugs, patients receiving paclitaxel either as first line or second line chemotherapeutic drug, either as a single agent or in combinations and with baseline clinical evaluation negative for any existing peripheral neuropathy; when paclitaxel is administered as second like drug, the exact details of previous chemotherapeutic agents would be necessary; those who have already received platinum, vincristine would be included provided no peripheral neuropathy is detected at the time of enrollment
Exclusion criteria	Patients with co‑morbidities like diabetes, autoimmune diseases which include lupus, rheumatoid arthritis, kidney disease, liver disease and thyroid (hypothyroidism, tested pre‑enrollment by thyroid‑stimulating hormone, T4, T3) and with infections like hepatitis C and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV)/AIDS (all patients would undergo laboratory confirmation for shingles, hepatitis B, C and HIV/AIDS (at any Voluntary Confidential Counselling and Testing Centre, India) prior to inclusion in study), spinal cord injuries, peripheral vascular disorders known to be associated with peripheral neuropathy; uncontrolled diabetes or compromised cardiac function or any other major organ dysfunctions, other than cancer, which would require curtailment of full doses of paclitaxel at 175 mg/m2, 3 weekly regimens
N randomized	160
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	Patients receiving < 4 cycles of paclitaxel or any dose curtailments were excluded from the analysis
Countries of data collection	India
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T1: after 3 chemotherapy cycles T2: after 6 chemotherapy cycles T3: 6 months post-chemotherapy

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	Breast Cancer, Gynecologic Cancers - Ovarian Cancer, Lung 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	II – IV
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	With paclitaxel as first or second line treatment
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	44.4% female
Age groups	Adults (18+)
Age groups specification	Mean (SD) = 54.2 (1.1) 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	21
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Unclear per group, overall n=70
Drop-out reasons	NI
Intervention	Vitamin E
Dosage and regime	Day 0 of chemotherapy: 400 mg 1x daily Duration: until 1 month after the end of chemotherapy
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.	-999
Side effects / Interactions	NI

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	-999
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Unclear per group, overall n=70
Drop-out reasons	NI
Intervention	Vitamin B12, methylcobalamin
Dosage and regime	Oral, day 0 chemotherapy: 500 µg 3x daily Duration: until 1 month after the end of chemotherapy
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.	-999
Side effects / Interactions	NI

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	-999
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Unclear per group, overall n=70
Drop-out reasons	NI
Intervention	Acetyl-L-Carnitine (ALC)
Dosage and regime	Day 0 chemotherapy: 250 mg 1x daily Duration: 7 days in each chemotherapy cycle
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.	-999
Side effects / Interactions	NI

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	-999
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Unclear per group, overall n=70
Drop-out reasons	NI
Intervention	Glutamine
Dosage and regime	Day 2 chemotherapy: 10 mg 3x daily Duration: Day 2 to Day 5 in each chemotherapy cycle
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.	-999
Side effects / Interactions	NI

Outcomes

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Toxicity of chemotherapy Components of Peripheral Neuropathy (according to CTCAE 4.02): sensory, motor, and pain Data collection points: Start with the first chemotherapy cycle, before each cycle, and then monthly
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".	Onset of symptoms (Mean (95% CI), days): Sensory Vitamin E: 8.24 (6.87, 9.61), Vitamin B12: 5.61 (4.50, 6.72), Carnitine: 5.75 (4.70, 6.80), Glutamine: 4.95 (3.94, 5.97); p < 0.001 Motor Vitamin E: 8.38 (6.92, 9.84), Vitamin B12: 5.78 (4.61, 6.96), Carnitine: 5.75 (4.84, 6.66), Glutamine: 4.95 (3.94, 5.97) Pain Vitamin E: 8.71 (7.64, 9.79), Vitamin B12: 6.26 (5.10, 7.42), Carnitine: 6.13 (5.11, 7.14), Glutamine: 4.68 (3.53, 5.83) Progression of symptoms over time Mean (95% CI, after 3 chemotherapy cycles/ after 6 chemotherapy cycles) Sensory Vitamin E: 2.05 (1.66, 2.44)/2.00 (1.58, 2.42), Vitamin B12: 1.65 (1.34, 1.96)/1.90 (1.48, 2.33), Carnitine: 1.42 (1.09, 1.74)/1.19 (0.72, 1.66), Glutamine: 1.09 (0.76, 1.42)/ 1.00 (0.54, 1.46) F-Wert (ANOVA, including values from 6 month post-chemotherapy) = 1.824; p = 0.115, ns. Motor Vitamin E: 2.00 (1.70, 2.30)/ 1.84 (1.47, 2.21), Vitamin B12: 1.57 (1.20, 1.93)/ 1.73 (1.39, 2.07), Carnitine: 1.00 (0.69, 1.31)/ 0.62 (0.35, 0.89), Glutamine: 0.91 (0.61, 1.21)/ 0.67 (0.37, 0.97), F(ANOVA, including values from 6 month post-chemotherapy) = 2.267; p = 0.045, sign. Pain Vitamin E: 1.75 (1.38, 2.12)/ 1.79 (1.38, 2.20), Vitamin B12: 1.83 (1.54, 2.11)/ 2.05 (1.70, 2.39), Carnitine: 0.67 (0.43, 0.91)/ 0.48 (0.20, 0.75), Glutamine: 0.27 (0.07, 0.47)/ 0.62 (0.39, 0.85), F (ANOVA, including values from 6 month post-chemotherapy)= 3.358; p = 0.004, sign.
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".	Mean (95% CI, 6 months after chemotherapy) Sensory Vitamin E: 1.72 (1.35, 2.10), Vitamin B12: 1.60 (1.09, 2.11), Carnitine: 0.65 (0.30, 1.00), Glutamine: 0.58 (0.21, 0.95) F-Wert (ANOVA, including values from after 3 chemotherapy cycles and after 6 chemotherapy cycles) = 1.824; p = 0.115, ns. Post-Hoc Analysis: Vitamin E vs. Vitamin B12: p = 0.446 Vitamin E vs. Carnitine: p < 0.001, sign. Vitamin E vs. Glutamine: p = 0.002, sign. No difference between Vit. E and Vit. B12, but Vit. E better progression than glutamine and ALC Motor Vitamin E: 1.39 (1.09, 1.69), Vitamin B12: 1.40 (1.08, 1.72), Carnitine: 0.20 (0.01, 0.39), Glutamine: 0.32 (0.09, 0.55), F(ANOVA, including values from after 3 chemotherapy cycles and after 6 chemotherapy cycles) = 2.267; p = 0.045, sign. Post-Hoc Analysis: Vitamin E vs. Vitamin B12: p = 0.227, ns. Vitamin E vs. Carnitine: p < 0.001, sign. Vitamin E vs. Glutamine: p < 0.001, sign. No difference between Vit. E and Vit. B12, but Vit. E better progression than glutamine and ALC Pain Vitamin E: 1.33 (0.95, 1.71), Vitamin B12: 1.30 (0.99, 1.61), Carnitine: 0.10 (-0.04, 0.24), Glutamine: 0.26 (0.05, 0.48), F (ANOVA, including values from after 3 chemotherapy cycles and after 6 chemotherapy cycles)= 3.358; p = 0.004, sign. Post-Hoc-Analysis: Vitamin E vs. Vitamin B12: ns.; p = NI Vitamin E vs. Carnitine: p < 0.001, sign. Vitamin E vs. Glutamine: p < 0.001, sign. No difference between Vit. E and Vit. B12, but Vit. E better progression than glutamine and ALC

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	NI
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

CONTRA:

• Small sample size.
• No blinding.
• No control group receiving either no intervention or placebo, only active controls whose efficacy is also not proven.
• Possible baseline differences (e.g., in pain perception) were not recorded.
• High dropout rate (overall 44%), with no information on reasons and group distribution.
• No information on compliance.
• Poor reporting quality (e.g., unclear how often patients received the intervention).