Iovino et al. (2018): High-dose zinc oral supplementation after stem cell transplantation causes an increase of TRECs and CD4+ naive lymphocytes and prevents TTV reactivation

Reference ↗
Title	High-dose zinc oral supplementation after stem cell transplantation causes an increase of TRECs and CD4+ naive lymphocytes and prevents TTV reactivation
Topic	Zinc
Author	Iovino, L, Mazziotta, F, Carulli, G, Guerrini, F, Morganti, R, Mazzotti, V, Maggi, F, Macera, L, Orciuolo, E, Buda, G, Benedetti, E, Caracciolo, F, Galimberti, S, Pistello, M, Petrini, M
Year	2018
Journal	Leukemia Research
DOI	https://doi.org/10.1016/j.leukres.2018.04.016

Brief summary

The study by Iovino et al. focused on investigating various preclinical data related to immune system parameters following hematopoietic stem cell transplantation. Of 18 patients, 9 were given zinc sulfate after the transplantation, and the patients' blood was subsequently analyzed. Additionally, they recorded side effects reported by patients due to zinc administration. Instances of nausea, diarrhea, and fever were observed, but these were not more frequent in the zinc arm compared to the placebo arm. Thus, it can be concluded that zinc does not have negative effects, even when administered in higher doses. However, the results should be interpreted with caution, as the sample size of 18 individuals is very small, making generalizations quite limited.

Die Studie von Iovino und Kollegen beschäftigte sich in ihrem Schwerpunkt mit der Untersuchung verschiedener präklinischer Daten, die im Zusammenhang mit Parametern des Immunsystems nach einer hämatopoetischen Stammzelltransplantation standen. Von 18 Patienten gaben sie 9 Personen nach der Transplantation Zinksulfat und untersuchten nachfolgend das Blut der Patienten. Zusätzlich dazu erhoben sie Nebenwirkungen, die aufgrund der Zinkgabe von den Patienten beschrieben wurden. Es zeigten sich Fälle von Übelkeit und Durchfall, sowie auftretendes Fieber, wobei dies im Zink-Arm nicht häufiger beobachtet wurde, als im Placebo-Arm. Somit lässt sich schlussfolgern, dass Zink keine negativen Auswirkungen hat, obwohl es in höherer Dosis verabreicht wurde. Insgesamt kann man die Ergebnisse jedoch nur mit Vorsicht interpretieren, da es sich bei 18 Personen um eine sehr kleine Stichprobe handelt und Verallgemeinerungen dadurch nur sehr beschränkt möglich sind.

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	Single
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

Pilot study

Inclusion criteria	Patients affected by Multiple Myeloma (MM) eligible to auto-hematopoietic stem cell transplantation (HSCT)
Exclusion criteria	NI
N randomized	18
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.	NI
Specifications on analyses	The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study
Countries of data collection	Italy
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: first day of stem cell collection T1: the day before the starting of the conditioning treatment T2: day +30 after transplant T3: day +100 after transplant

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.	NI
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Hematologic Cancers - Multiple Myeloma
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	NI
Current cancer therapies	Surgery
Specifications on cancer therapies	After stem cell transplantation
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	n=6 female (intervention arm=22.3%; control arm=44.4%)
Age groups	Adults (18+)
Age groups specification	Intervention arm: 63 (49-72) Control arm: 58 (47-65)

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	9
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Zinc sulfate eptahydrate
Dosage and regime	600 mg zinc sulfate eptahydrate per day, equivalent to 150 mg of elementary zinc per day, from day +5 post-transplant in addition to the same prophylaxis of the control arm
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.	95
Side effects / Interactions	Incidence of nausea (44.4%) and diarrhea (11.1%) was the same in the two groups, 1 patient per group had fever > 100.4 °F at home

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	9
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Standard antimicrobial prophylaxis
Dosage and regime	From day +5 post-transplant
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.	95
Side effects / Interactions	Incidence of nausea (44.4%) and diarrhea (11.1%) was the same in the two groups, 1 patient per group had fever > 100.4 °F at home

Outcomes

Zinc level

Outcome type As specificed by the authors	NI
Outcome specification	NI
Type of measurement	Blood Test
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 statistical differences in baseline zinc serum levels; at the end of the supplementation period, although zinc serum levels were higher in the zinc group, the difference between the groups was not significant
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".	NI

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 of School of Medicine of the University of Pisa and AIL Pisa
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	?