A Phase 2 interventional study of ceftazidime and ciprofloxacin in Large B-Cell Lymphoma (LBCL), Multiple Myeloma (MM) and Gut Microbiota, sponsored by Zealand University Hospital. Not yet recruiting at 1 site in Denmark. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-25.
Sponsored by Zealand University Hospital · Phase 2, Interventional, and Supportive care
The purpose of the CARMic study is to investigate whether a restrictive, microbiome-sparing antibiotic strategy can better preserve the gut microbiota in patients undergoing chimeric antigen receptor T-cell (CAR-T) therapy without compromising infectious safety.
This is a randomized, open-label Phase II trial enrolling 150 adults with large B-cell lymphoma or multiple myeloma who are scheduled to receive standard-of-care CAR-T therapy. Participants will be randomly assigned in a 1:1 ratio to either a restrictive antibiotic strategy based on ceftazidime and/or ciprofloxacin or an unrestricted standard-of-care antibiotic strategy. The assigned strategy will apply from randomization until 28 days after CAR-T-cell infusion. Antibiotic treatment may be modified or broadened at any time when clinically indicated.
The primary question is whether the restrictive antibiotic strategy results in greater gut microbial diversity 28 days after CAR-T-cell infusion compared with standard-of-care antibiotic treatment. Gut microbial diversity will be assessed in stool samples using the Shannon diversity index.
The study will also compare infections, antibiotic exposure, adherence to the assigned strategy, CAR-T-related toxicities, treatment response, relapse, progression-free survival, and overall survival between the two groups. Changes in gut microbiota composition and in blood and stool metabolomic and proteomic profiles will be evaluated over time. Blood and stool samples will be collected at randomization, around the time of CAR-T-cell infusion, 28 days after infusion, and at the end-of-treatment evaluation approximately 3-6 months after infusion.
CAR-T-cell therapy is associated with substantial exposure to antibacterial agents because patients frequently develop fever, neutropenia, and suspected or confirmed infections during the peri-infusion period. Broad-spectrum antibacterial agents, particularly those with extended anaerobic activity, may cause marked disruption of the intestinal microbiota. Retrospective studies have associated peri-CAR-T antibiotic exposure and reduced gut microbial diversity with inferior treatment response, increased toxicity, and shorter survival. However, these associations may be affected by confounding related to infection severity, disease status, and other clinical factors. Prospective randomized evidence is therefore needed to determine whether a microbiome-sparing antibacterial strategy can preserve gut microbial diversity while remaining clinically feasible and safe.
In the restrictive-strategy group, intravenous ceftazidime will be used as initial empirical antibacterial treatment when antibacterial therapy is clinically indicated. Oral ciprofloxacin may be used as protocol-defined step-down treatment after adequate infection control and clinical stabilization. Ciprofloxacin may also be used as antibacterial prophylaxis when prophylaxis is clinically indicated and there is no suspected ongoing infection. Ciprofloxacin will not be used as initial empirical monotherapy for suspected infection.
A switch from intravenous ceftazidime to oral ciprofloxacin may be considered when the participant is clinically stable; fever and other clinical signs of infection have resolved or clearly improved; no microbiologically documented infection or suspected infectious focus requires alternative or additional coverage; any identified pathogen is susceptible to ciprofloxacin; oral absorption is considered reliable; and there is no known colonization or previous infection with a fluoroquinolone-resistant pathogen that would make ciprofloxacin inappropriate.
Participant safety takes priority over adherence to the restrictive strategy. The treating physician may modify or broaden antibacterial treatment at any time in response to clinical deterioration, persistent or recurrent fever, microbiological findings, suspected resistance, organ-specific infection, or a need for additional Gram-positive, anaerobic, or other antimicrobial coverage. All decisions to modify or escalate treatment and the reasons for doing so will be recorded. In the standard-of-care group, antibacterial prophylaxis and treatment will be selected according to local clinical practice without protocol-defined restrictions.
The biological effects of the two strategies will be characterized through longitudinal collection of stool and blood samples. Samples will be obtained at randomization, around the time of CAR-T-cell infusion, at day 28 after infusion, and at the end-of-treatment evaluation approximately 3-6 months after infusion. Stool samples will be used to assess microbial diversity, community composition, and the relative abundance of selected bacterial taxa. Blood and stool samples will also be used for exploratory metabolomic analyses, including microbiota-associated metabolites such as short-chain fatty acids, tryptophan-derived metabolites, secondary bile acids, and other immunomodulatory metabolites, depending on assay coverage. Blood proteomic profiles will be explored in relation to microbiota changes, antibacterial exposure, toxicity, and clinical outcomes.
Longitudinal microbiota analyses will include measures of within-sample diversity and between-sample community composition. Repeated measurements will be evaluated using appropriate mixed-effects models incorporating treatment strategy, sampling time, treatment-by-time interaction, and disease cohort. Community-level differences may be assessed using ordination methods and permutational multivariate analysis of variance. Differential abundance analyses will use appropriate multivariable microbiome methods with adjustment for multiple testing.
Analyses will primarily compare participants according to their randomized treatment strategy. Complementary analyses will characterize actual antibacterial exposure, including total antibacterial days of therapy, timing of exposure in relation to CAR-T-cell infusion, and duration of exposure to broad-spectrum agents with extended anaerobic activity. Exploratory exposure groups may include participants receiving no antibacterial treatment, participants receiving ceftazidime and/or ciprofloxacin only, and participants receiving other standard-of-care antibacterial regimens. Where appropriate, actual antibacterial exposure may also be analyzed as a time-dependent variable.
Potentially relevant concomitant treatments, including proton pump inhibitors, statins, corticosteroids, and tocilizumab, will be considered in adjusted or sensitivity analyses. Exploratory analyses will assess whether microbiota and metabolomic patterns differ between participants with large B-cell lymphoma and multiple myeloma. Data may also be compared with external microbiota datasets from healthy individuals and patients with newly diagnosed, treatment-naive large B-cell lymphoma.
Infectious events and antibacterial exposure will be evaluated during predefined periods before and after CAR-T-cell infusion. CAR-T-related toxicities will be assessed using established grading systems for cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hematotoxicity. Participants will be followed for clinical outcomes for 24 months, after which the final study analysis is planned.
Age 18 years or older. Relapsed or refractory large B-cell lymphoma according to the current World Health Organization classification, or relapsed or refractory multiple myeloma according to the current International Myeloma Working Group classification.
Eligible for treatment with a CAR-T-cell product authorized in the European Union and recommended for reimbursement by the Danish Medicines Council.
A clinical decision to proceed with CAR-T-cell therapy has been made jointly by the participant and the treating physician.
Written informed consent to participate in the trial.
Exclusion Criteria:
Pregnancy or breastfeeding. Psychiatric illness or other condition that may interfere with the ability to understand or comply with the trial requirements.
Clinical signs of an uncontrolled serious infection. Severe colitis. Previous allergic reaction to cephalosporins or ciprofloxacin. Participants with a known allergy to other beta-lactam antibiotics, including penicillins, may be enrolled provided that they do not have a known allergy to cephalosporins.
Participants will follow a protocol-defined restrictive antibacterial strategy from randomization until day 28 after CAR-T-cell infusion. Intravenous ceftazidime will be used as initial empirical antibacterial treatment when clinically indicated. Oral ciprofloxacin may be used as step-down therapy following adequate infection control and clinical stabilization or as antibacterial prophylaxis when clinically indicated in the absence of suspected ongoing infection. Antibacterial treatment may be modified or broadened at any time when clinically required.
Drug: ceftazidime · Drug: ciprofloxacin
Participants will receive antibacterial prophylaxis and treatment according to unrestricted local standard-of-care practice from randomization until day 28 after CAR-T-cell infusion. Selection, modification, escalation, and duration of antibacterial treatment will be determined by the treating physician according to clinical findings, microbiological results, and local guidelines.
Other: Standard-of-Care Antibiotic Strategy
Intravenous ceftazidime will be used as initial empirical antibacterial treatment when clinically indicated during the period from randomization through day 28 after CAR-T-cell infusion. Dosing and renal dose adjustment will follow the applicable product information and local clinical practice. Treatment may be modified or broadened at any time when clinically required.
Oral ciprofloxacin may be used as protocol-defined step-down therapy after adequate infection control and clinical stabilization or as antibacterial prophylaxis when clinically indicated in the absence of suspected ongoing infection. Ciprofloxacin will not be used as initial empirical monotherapy for suspected infection. Dosing and renal dose adjustment will follow the applicable product information and local clinical practice.
Participants will receive antibacterial prophylaxis and treatment according to unrestricted local standard-of-care practice. Selection, dosing, modification, escalation, and duration of antibacterial treatment will be determined by the treating physician according to clinical findings, microbiological results, and local guidelines.
Gut Microbiota Alpha Diversity at Day 28
Gut microbiota alpha diversity measured by the Shannon diversity index in a stool sample collected at day 28 after CAR-T-cell infusion. The Shannon index quantifies within-sample microbial diversity by incorporating both microbial richness and evenness. The treatment effect will be expressed as the adjusted mean difference in the Shannon diversity index between the restrictive antibiotic strategy and the standard-of-care antibiotic strategy, calculated as restrictive strategy minus standard of care. A positive difference favors the restrictive strategy.
Time frame: Day 28 after CAR-T-cell infusion (±3 working days)
Longitudinal Gut Microbiota Alpha Diversity
Gut microbiota alpha diversity measured by the Shannon diversity index in stool samples collected at randomization, around CAR-T-cell infusion, at day 28, and at the end-of-treatment evaluation. Longitudinal differences between treatment groups will be assessed across the protocol-defined sampling time points.
Time frame: From randomization through the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion
Gut Microbiota Beta Diversity
Differences in gut microbial community composition between treatment groups, assessed using beta-diversity metrics in stool samples collected at the protocol-defined sampling time points.
Time frame: From randomization through the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion
Relative Abundance of Predefined Beneficial Bacterial Taxa
Between-group differences and longitudinal changes in the relative abundance of predefined beneficial bacterial taxa in stool samples.
Time frame: From randomization through the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion
Infectious Complications
Number, type, and severity of infectious complications, including clinically documented infection, fever of unknown origin, bloodstream infection, sepsis, Clostridioides difficile infection, infection-related intensive care unit admission, and infection-related mortality. Events will be summarized separately for each predefined period.
Time frame: Randomization to CAR-T-cell infusion; day 0-28; and day 29-90 after infusion
Total Systemic Antibacterial Exposure
Total systemic antibacterial exposure measured as days of therapy. Exposure will be summarized by treatment group and antibacterial agent or class.
Time frame: From randomization through day 28 after CAR-T-cell infusion
Exposure to Broad-Spectrum Antibiotics With Extended Anaerobic Coverage
Number of participants exposed to broad-spectrum antibacterial agents with extended anaerobic coverage and the total duration of this exposure, measured in days of therapy.
Time frame: From randomization through day 28 after CAR-T-cell infusion
Cytokine Release Syndrome
Incidence and maximum grade of cytokine release syndrome assessed according to the American Society for Transplantation and Cellular Therapy consensus grading criteria.
Time frame: From CAR-T-cell infusion through day 28
Immune Effector Cell-Associated Neurotoxicity Syndrome
Incidence and maximum grade of immune effector cell-associated neurotoxicity syndrome assessed according to the American Society for Transplantation and Cellular Therapy consensus grading criteria.
Time frame: From CAR-T-cell infusion through day 28
Immune Effector Cell-Associated Hematotoxicity
Incidence and severity of immune effector cell-associated hematotoxicity assessed according to applicable consensus criteria.
Time frame: From CAR-T-cell infusion through day 90
Clinical Response in Large B-Cell Lymphoma
Complete response rate and overall response rate among participants with large B-cell lymphoma, assessed according to the Lugano 2014 response criteria.
Time frame: At the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion
Clinical Response in Multiple Myeloma
Proportion of participants with multiple myeloma achieving very good partial response or better, assessed according to International Myeloma Working Group response criteria.
Time frame: At the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion
Relapse at 1 Year
Proportion of participants experiencing disease relapse or progression within one year after CAR-T-cell infusion, assessed according to disease-specific response criteria.
Time frame: One year after CAR-T-cell infusion
Progression-Free Survival
Time from CAR-T-cell infusion to disease progression, relapse, or death from any cause, whichever occurs first. Participants without an event will be censored at the date of last disease assessment.
Time frame: From CAR-T-cell infusion through 24 months
Overall Survival
Time from CAR-T-cell infusion to death from any cause. Participants alive at the end of follow-up will be censored at the date last known alive.
Time frame: From CAR-T-cell infusion through 24 months
Adherence to the Assigned Antibiotic Strategy
Proportion of participants managed in accordance with the assigned antibiotic strategy. Protocol-defined modifications and clinically justified escalation will be distinguished from deviations from the assigned strategy.
Time frame: From randomization through day 28 after CAR-T-cell infusion
Modification or Escalation of Antibacterial Treatment
Number and proportion of participants requiring modification or escalation of antibacterial treatment, including the timing and documented reason for each modification
Time frame: From randomization through day 28 after CAR-T-cell infusion
Blood and Stool Metabolomic Profiles
Between-group differences and longitudinal changes in global blood and stool metabolomic profiles and predefined microbiota-associated metabolites and pathways.
Time frame: From randomization through the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion
Blood Proteomic Profiles
Between-group differences and longitudinal changes in global blood proteomic profiles, including predefined proteins and pathways related to microbiota, immune activation, and CAR-T-cell toxicity
Time frame: From randomization through the end-of-treatment evaluation, approximately 3-6 months after CAR-T-cell infusion
Plan to share: No — Individual participant data will not be made publicly available. The study includes sensitive clinical, microbiome, metabolomic, and proteomic data from patients with relatively uncommon hematological malignancies, which may create a risk of re-identification even after removal of direct identifiers. Data may only be processed and transferred in accordance with participant consent, the General Data Protection Regulation, applicable Danish legislation, institutional requirements, and relevant data-transfer agreements. Aggregate and anonymized study results will be reported through the applicable trial registries and scientific publications.
No publications or documents are linked to this record.
This study is not yet recruiting, as verified in Sep 2026. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Zealand University Hospital