Comparison of Combined Vitamin B12 and Folic Acid Supplementation with Placebo for the Prevention of Thrombocytopenia in Patients Receiving Concomitant Treatment with Meropenem and Linezolid: A Randomized Double-Blind Clinical Trial

To compare vitamin B12 and folic acid with placebo for preventing platelet count reduction and thrombocytopenia in adults receiving concomitant meropenem and linezolid.

A phase 3 randomized, double blind, placebo controlled, parallel group clinical trial involving 36 participants allocated in a one to one ratio using permuted blocks of four.

The study will be conducted at Shahid Sadoughi Hospital in Yazd. Blood counts will be measured at baseline and on days 3 and 7. An independent pharmacist will code identical packages and retain the allocation key.

Hospitalized adults aged at least 18 years, with a baseline platelet count above 150,000 per microliter and an indication for at least seven days of concomitant linezolid and meropenem, will be included. Exclusions include hematologic disease, severe hepatic or renal impairment, underlying causes of thrombocytopenia, severe sepsis or septic shock with low platelets before treatment, active bleeding, platelet affecting medicines, piperacillin, and recent vitamin B12 or folic acid use.

The intervention group will receive oral vitamin B12, 1,000 micrograms daily, and oral folic acid, 1 milligram daily, for seven days plus standard treatment. The control group will receive matching oral placebo for seven days plus standard treatment.

Change in platelet count from baseline to days 3 and 7; incidence and severity of thrombocytopenia by day 7.

The individual participant will be the unit of randomization. After confirmation of eligibility and obtaining written informed consent, 36 participants will be allocated in a 1:1 ratio to either the intervention group with 18 participants or the placebo control group with 18 participants. Before the beginning of recruitment, the allocation sequence will be generated by the independent research pharmacist using permuted block randomization with a fixed block size of four and the Sealed Envelope web-based randomization tool available at https://www.sealedenvelope.com/simple-randomiser/v1/lists. No stratification will be used. Each allocation will be linked to a unique sequential code, and the independent pharmacist will prepare identically appearing, sequentially numbered intervention and placebo packages according to the randomization sequence. Each eligible participant will receive the next consecutively numbered package in the order of enrollment. The allocation list and the code key will be securely retained by the independent pharmacist and will not be accessible to recruiters, participants, clinical care providers, investigators, outcome assessors, or the data analyst until completion of the final analysis. This procedure will ensure allocation concealment

The random allocation sequence will be provided to an independent research pharmacist. The pharmacist will prepare, package, and code the intervention products, including vitamin B12 and folic acid, and the matching placebo so that they are identical in appearance, color, size, shape, and packaging. Participants, clinical care providers, principal investigators, outcome assessors and data collectors, and the data analyst will remain unaware of group allocation and the meaning of the codes. The allocation code will be kept exclusively by the independent research pharmacist and will be disclosed to the research team after completion of the final data analysis. No independent data safety and monitoring committee will be established for this study

Deidentified individual participant data underlying the published results will be shared, including demographic variables, baseline characteristics, intervention allocation, platelet counts, occurrence and severity of thrombocytopenia, antibiotic discontinuation, length of hospital stay, and adverse events. The study protocol, statistical analysis plan, blank informed consent form, clinical study report, data dictionary, and statistical analysis syntax will also be available. Direct identifiers, signed consent forms, and information that could reasonably identify participants will not be shared.

Access will begin six months after publication of the main study results and will remain available for five years.

Qualified researchers affiliated with recognized academic, healthcare, or scientific research institutions may request access to the data and documents.

The data and documents may be used for replication of the study findings, secondary analyses, systematic reviews, or meta analyses after approval of a scientifically and ethically sound proposal. Applicants must provide their institutional affiliation, research proposal, analysis plan, and ethics approval when applicable. They must sign a data use agreement prohibiting participant reidentification, unauthorized use, and onward sharing. Proper acknowledgment and citation of the original study will be required.

Requests should preferably be submitted by email to Mohamadreza Heidarzadeh, Infectious Diseases Resident, Department of Infectious Diseases, Shahid Sadoughi Hospital, Yazd, Iran, at mohamadrezaheidarzadeh0776@gmail.com. Postal correspondence may be sent to the Department of Infectious Diseases, Shahid Sadoughi Hospital, Ebne Sina Boulevard, Shahid Ghandi Boulevard, Safaieh, Yazd, Iran. Telephone: +98 35 38224000. The principal investigator may also be contacted at jamshidayatollahi@yahoo.com.

The applicant must submit a written request including their name, institutional affiliation, research question, proposed analyses, requested variables, ethics approval when applicable, funding source, and conflicts of interest. Receipt of the request will be confirmed within seven working days. The research team will review the request within 30 working days and may request additional information. If approved, a data use agreement will be signed and the requested files will be transferred securely within 15 working days after completion of the agreement. The reason for rejection will be communicated to the applicant.

All shared participant data will be coded and deidentified. Access will be limited to the approved applicants, purposes, variables, and access period. The participant identification key and signed consent forms will remain confidential and will not be shared. Data sharing will be subject to the approved informed consent form and applicable ethics committee requirements.