Vitale et al. (2020): ZeOxaNMulti Trial: A Randomized, Double-Blinded, Placebo-Controlled Trial of Oral PMA-Zeolite to Prevent Chemotherapy-Induced Side Effects, in Particular, Peripheral Neuropathy

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Title	ZeOxaNMulti Trial: A Randomized, Double-Blinded, Placebo-Controlled Trial of Oral PMA-Zeolite to Prevent Chemotherapy-Induced Side Effects, in Particular, Peripheral Neuropathy
Topic	Zeolites
Author	Vitale, MG, Barbato, C, Crispo, A, Habetswallner, F, De Martino, BM, Riccardi, F, Maione, A, Eisenwagen, S, Vitale, G, Cartenì, G
Year	2020
Journal	molecules
DOI	https://doi.org/10.3390/molecules25102297

Brief summary

In this study, 120 patients were randomly assigned to two arms. One arm received a preparation containing zeolite, while the other arm received a placebo. The occurrence and severity of peripheral neuropathy due to oxaliplatin chemotherapy were measured. After 6 months, no differences in the occurrence or severity between the arms were found. Further analyses seemed to show a benefit for men, but this result must be critically viewed due to missing information and the lack of consideration of important influences. However, it was shown that the zeolite arm completed more cycles than the placebo arm, although there is little information provided on why patients dropped out. Regarding the impact on hematological toxicity, no difference between the arms was found. Overall, the study was well-planned and conducted, but many important pieces of information necessary for a correct interpretation of the results are missing. An initial imbalance in age and comorbidities, as well as a high dropout rate without adjusted analysis, are also critical factors. Additionally, it is reported that most patients also had diabetes, which can be a significant factor in the development of peripheral neuropathy. Although this was apparently considered in an analysis, it cannot be interpreted because no exact distribution figures are given. The study indicates good tolerability of the preparation, but zeolites in the gut can bind substances, which means interactions with oral medications and medications with enterohepatic circulation must be considered.

In dieser Studie wurden 120 Patienten zufällig in 2 Gruppen eingeteilt. Die eine Gruppe erhielt ein Präparat, welches Zeolith enthielt und die andere Gruppe erhielt ein Placebo. Gemessen wurde das Auftreten und die Stärke von peripherer Neuropathie aufgrund einer Oxaliplatin Chemotherapie. Nach 6 Monaten konnten keine Unterschiede im Auftreten oder der Stärke zwischen den Gruppen gefunden werden. Weitere Analysen scheinen hier nur einen Vorteil für Männer zu finden, jedoch muss dieses Ergebnis aufgrund fehlender Informationen und nicht Berücksichtigen wichtiger Einflüsse kritisch betrachtet werden. Es konnte jedoch gezeigt werden, dass die Gruppe mit Zeolith mehr Zyklen absolvieren konnte als die Placebogruppe, aber auch hier werden wenig Informationen geliefert warum die Patienten ausstiegen. Bezüglich des Einflusses auf hämatologische Toxizität konnte kein Unterschied zwischen den Gruppen gefunden werden. Insgesamt ist die Studie gut geplant und durchgeführt wurden, jedoch fehlen viele wichtige Informationen die zu einer korrekten Interpretation der Ergebnisse notwendig wären. Auch eine schon zu Beginn der Studie sichtbare Ungleichverteilung bezüglich Alter und Komorbiditäten, sowie eine hohe Ausstiegsrate aus der Studie ohne angepasste Analyse sind als kritischer Einfluss zu betrachten. Des Weiteren wird berichtet, dass der Großteil der Patienten unter zusätzlichem Diabetes litt. Was ein entscheidender Faktor für die Entwicklung von peripherer Neuropathie sein kann. Auch wenn dies in einer Analyse scheinbar berücksichtigt wird, kann dies nicht interpretiert werden, da keine genauen Zahlen zur Verteilung gegeben werden. Die Studie gibt eine gute Verträglichkeit des Präparates an, jedoch können Zeolithe im Darm Substanzen an sich binden, wodurch Wechselwirkungen mit oralen Medikamenten und Medikamenten mit enterohepatischem (Darm- Leber-) Kreislauf berücksichtigt werden müssen.

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	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 confirmed diagnosis of cancer, at least 18 years of age, oxaliplatin chemotherapy, and adequate hematologic parameters to allow chemotherapy
Exclusion criteria	Chemotherapy treatment with neurotoxic drugs (cisplatin, carboplatin, oxaliplatin, vincristine, vinblastine, paclitaxel, or docetaxel) in the 6 months prior to the start of oxaliplatin-chemotherapy, pregnancy, or breastfeeding
N randomized	120
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	- Two-sided t-test
Countries of data collection	Italy
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: Baseline T1: after 3 months of chemotherapy T2: after 6 months of 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.	Curative, Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Colorectal Cancer, Other Cancers
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	NI
Specifications on cancer stages	NI
Comorbidities	54.2% had diabetes and hypertension
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Oxaliplatin, 1. or 2. line
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	45 % female
Age groups	Adults (18+)
Age groups specification	40.8% < 60 years (Intervention: 50% and placebo: 31.7%)

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	60
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	After 3 months: n=3 After 6 months: n=18
Drop-out reasons	Disease progression, unacceptable toxicity, or the patient’s refusal to continue the treatment No number was given for the individual reasons of Drop-outs
Intervention	Panaceo-micro-activation PMA-zeolite (Multizeo Med©)
Dosage and regime	6g/day in two doses of 3g at the start 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	Only general indication of good tolerability Not separated between arms

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	60
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	After 3 months: n=4 After 6 months: n=26
Drop-out reasons	Disease progression, unacceptable toxicity, or the patient’s refusal to continue the treatment No number was given for the individual reasons of Drop-outs
Intervention	Placebo microcrystalline cellulos
Dosage and regime	6 g/day of placebo in two daily doses of 3g
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	Not separated between arms Only general indication of good tolerability

Outcomes

Peripheral neuropathy

Outcome type As specificed by the authors	Primary
Outcome specification	Oxiplatin-based chemotherapy induced
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".	NA
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".	After 6 months: Intervention n=42, Placebo n=34, >8 cycles): Placebo had 70.6% and Intervention had 64.3% chemotherapy-induced peripheral neuropathy (not significant, p = 0.56) Secondary analysis showed lower chemotherapy-induced peripheral neuropathy in men in Intervention-arm compared to Placebo-Arm based on 39 patients (p = 0.047, adjusted for age, comorbidity, cycles). Intervention-arm was able to complete more cycles of chemotherapy than Placebo-arm (>8 cycles: 71.7% vs. 56.7%, p = 0.03). No difference in the severity of hematologic toxicity (p = 0.09); due to low overall toxicity, no further analyses were 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	?

Funding and Conflicts of Interest

Funding	Indication of no external funding, preparation Multizeo Med© is from the manufacturer Panaceo International Gmbh, where one of the authors (Sandra Eisenberg) works
Conflicts of Interest	Other authors declared 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	?