The goal of this clinical trial is to learn about the effect of zinc supplementation once daily for 12 months in older acute medical patients. The main question it aims to answer is:

• Can daily zinc supplementation for 12 months increase Days Alive and Out of Hospital (DAOH)? Researchers will compare zinc supplementation to a control group, a group who do not receive zinc supplementation, to see if zinc supplementation can increase Days Alive and Out of Hospital, reduce antibiotic use, readmissions and mortality.

Participants will take 22 mg zinc supplementation once daily for 12 months or not.

The researchers will draw data on readmissions, antibiotic use and mortality during the 12 months follow-up period.

1. Study purpose Older adults are at increased risk of micronutrient deficiencies, including zinc, due to sparse food intake. Zinc deficiency is known to increase the susceptibility to infections, further exacerbating the vulnerability of older adults to health complications. Infections are common among older adults and are a leading causes of acute hospital admissions and readmissions.

   The hypothesis is that zinc supplementation for older acutely admitted medical patients can increase Days Alive and Out of Hospital regardless of baseline plasma zinc level

   Objectives:

   Primary objective: To test in older acute medical patients if zinc supplementation once daily for 12 months can increase Days Alive and Out of Hospital.

   Secondary objectives: To evaluate if zinc supplementation once daily can reduce antibiotic use, readmissions and mortality during the 12 months follow-up period.

2. Short background A large proportion of older adults are malnourished, which can lead to increased morbidity, mortality, prolonged hospitalization and reduced quality of life (QoL). With malnutrition the patient lacks vitamins and minerals, including zinc, which is essential for older adults. Early detection and treatment of malnutrition has been shown to be beneficial for patients, including reducing length of stay in the hospital. The older adults are at increased risk of zinc deficiency, with less than half of the free-living older adults having a sufficient zinc intake. Zinc is essential for immune function and acute deficiency weakens both innate and adaptive immunity, increasing susceptibility to infections. The effects of zinc supplementation on infections are conflicting, some studies do not find an effect of zinc supplementation in patients with infections, while other studies of healthy or institutionalized older adults, found that zinc supplementation significantly reduce the incidence of infections, antibiotic use and prevention of symptomatic COVID-19. Despite previous findings, the effect of zinc supplementation has not been studied in older acutely admitted medical patients on a large scale.

3. Method This study is a cluster randomized controlled trail. A total of 8000 patients will be included and divided into three groups. Patients ≥ 65 years, who come to the Medical Emergency Department at Herlev Hospital, and who meet the inclusion criteria, will be offered participations in the study. An automatic pop-up in the patient medical record will appear in blocks of time and will randomly assign patients to intervention with zinc supplementation (intervention n = 1000), recommendation of zinc supplementation (recommendation n = 3000) or control (n = 4000), regardless of plasma zinc levels at admission. The treating doctor will assess if the patient is eligible and include the patient to the study.

   Measurements and collection of clinical data Date on readmissions and mortality will be collected from the electronic medical chart EPIC (Sundhedsplatformen). Data on prescribed antibiotics will be drawn from the Danish National Prescription Register. Antibiotic prescriptions within 15 days, will be considered as a single treatment, as described in a previous study.

   Research plan Project "ZOOM" will be included in a PhD programme. Inclusion is expected to start in February 2026. The inclusion period is anticipated to span 12 months, followed by a 12-month intervention period. Consequently, the intervention period ends in January 2028.

   Assessment of compliance To minimize waste of zinc supplements, patients in the intervention group will be contacted every 3 months, to assess further need of zinc supply, which will reflect the adherence of intervention.

4. Statistical consideration

   1. Power calculation No available data exists to estimate the primary endpoint of Days Alive and Out of Hospital 12 months after acute hospitalization of older medical patients. However, a previous study that investigated this for patients with non-STEMI found a mean (SD) of 273 (123) days. Assuming that zinc supplementation can increase days alive and out of the hospital with 3% (8 days), we estimated a sample size of approximately 7422 patients (3712 in each arm), with an estimated power of 80%, 2-sided α-level of 0.05. Due to an estimated rate of loss to follow-up of approximately 10 %, we aim to enroll 8000 patients in the study. We plan to randomize participants into three groups: intervention, recommendation and control. However, the intervention and recommendation group will be considered as a single group for analysis. We plan to include patients during a 1-year study period. About 16.900 older patients (≥ 65 years) are hospitalized to the Medical Emergency Department, Herlev Hospital every year.
   2. Plan for statistical analysis of data Categorical variables will be compared using Chi-square test where appropriate; otherwise, Fisher's exact test will be used. Descriptive analyses of continuous variables will be per-formed using the Wilcoxon rank sum test. Binary outcomes will be analyzed by logistic re-gression and presented as odds ratios (ORs) and 95% confidence intervals (Cis). Overall sur-vival (OS) will be analyzed by the Kaplan Meier estimator; hazard ratios (HRs) and 95% CIs will be estimated by Cox proportional hazards regression. The primary endpoint (Days Alive and Out of Hospital) will be compared as a continuous variable between the two groups us-ing the analysis of variance test.

5. Risks, adverse events and disadvantages

   a. Safety measures that minimize pain, discomfort, fear, and other risks All patients will receive standard treatment during and after hospitalization. The intervention group receives one capsule of 22 mg zinc sulfate once daily for 12 months. This dose is based on an assessment of achieving efficacy in reducing infections, improve immune function, while also being safe, with no serious adverse effects. The dose is far from the toxic zinc level of 1-2 grams per day, with no risk of serious adverse effects and below the U.S. Food and Drug Administration (40 mg/day). Adverse events of the zinc in doses around 22 mg daily are mild and most often consist of gastrointestinal symptoms (nausea, upset stomach, dizziness) and dry mouth. In a recent Cochrane review, it was not possible to distinguish between adverse events cause by zinc supplementation and events caused by the cold itself (e.g. headache).

   Chronic zinc toxicity leads to copper deficiency with bone marrow (granulocytopenia, sideroblastic anemia, myelodysplastic syndrome) and neurologic effects (ascending, sen-sorimotor polyneuropathy syndrome). Copper deficiency is the most serious adverse event of long-term zinc overdose. The daily zinc dose at 45 mg has previously been shown to be safe in a healthy cohort of older adults; by not reducing plasma-copper and at the same time the zinc supplementation significantly reduced the number of infections. Zinc is not considered being carcinogenic in general. A 30-year follow-up study showed that low zinc intake < 9mg/day may increase the risk of prostate cancer, whereas extremely high doses of > 75 mg/day and long-term supplementation could increase the risk of aggressive prostate cancer.

6. Information from patient records We will not use medical records without consent.

   Specific information will be collected for implementation of the trial:

   • Age, to evaluate if certain age-groups could benefit more from zinc supplementation than others.
   • Results of routine blood parameters (CRP, neutrophils, leucocytes, platelets, hemoglobin, electrolytes, creatinine, eGFR, liver enzymes, lipids, HbA1c)
   • Weight, height
   • Demographic data
   • Results of routinely assess Clinical Frailty Scale
   • Disease history and the number of ICD-10 discharge diagnoses 5 years prior to admission, to assess comorbidity.
   • Number of medications and type of medication at admission, to evaluate polypharmacy
   • Length of hospitalization
   • Readmission, cause and number of days admitted within 6 and 12 months
   • Antibiotic use within 6 and 12 months
   • Date of death and cause or day of follow-up if alive at 12 months after inclusion

7. Processing of personal data in the project Data will be handled in accordance with The Data Protection Regulation and the Data Protection Act. The study is approved by the Danish National Medical Research Ethics Committee (VMK) and the Danish Data Protection Agency, before inclusion of patients. Data will be stored up to 5 years after end of study.

   Patient discontinuation Discontinuation may occur if the participant withdraws consent to participate in the study and/or withdraws consent for the use of their data. If a participant withdraws their consent, they will not be included in the study and their data will not be stored or analyzed. Information related to withdrawal will be obtained through "Sundhedsplatformen". The participant will be informed that they can withdrawal their consent at any time. Participants will receive a digital letter, two weeks after discharge, describing their participations in the study and informing them of their right to withdraw consent.

8. Finances The study has received funding from the "Independent Research Fund Denmark", "Herlev and Gentofte Hospital Internal PhD Fellowship Funds", "Clinical Academic Groups", and "Novo Nordic Foundation". The investigators have no financial ties to the sponsor, or any other interests related to the trial.

9. Recruitment of participants and informed consent

   a. Recruitment of participants This is a cluster randomized trial, in which each cluster consists of time. The treating doctor will assess if the patient is eligible (none of the exclusion criteria are present) and then include the patient.

10. Publication and sharing data Results from the study, both negative, inconclusive, and positive, will be published in rele-vant peer-reviewed international scientific journals The investigators will be co-authors on all publications according to Vancouver guidelines. The project will be reported according to CONSORT guidelines and registered at www.clinicaltrials.gov before initiation.

11. Patient insurance All participants are secured via the Danish Patient Compensation.

Inclusion Criteria:

• All medical patients aged ≥ 65 years assessed at the Medical Emergency Department, Herlev Hospital

Exclusion Criteria:

• Self-supplementing with zinc at time of assessment (> 10 mg zinc/day)
• Terminal illness (life expectancy < 6 months, estimated by Clinical Frailty Scale ≥8)
• Patients receiving parenteral nutrition (partial or complete)
• Patients treated with hemodialysis or peritoneal dialysis
• Patients know with known severe dementia
• Patients who do not understand Danish and patients with temporary civil person registration numbers (CPR)

IPD will be avilable from January 2029 to 2034 and

Will be available from the corresponding author upon reasonable request and only after approval has been granted by an ethics committee.