920. A Phase 2 Multi-Center, Prospective, Randomized, Double-Blind Study to Assess the Clinical and Antiviral Efficacy and Safety of Nitazoxanide for the Treatment of Norovirus in Hematopoietic Stem Cell and Solid Organ Transplant Recipients
Authors: Boutin Catherine-Audrey , Callegari Michelle A , Florescu Diana F , Nguyen Minh-Hong , Kaul Daniel , Avery Robin K , Chong Pearlie P , Fisher Cynthia E , Limaye Ajit , Clough Lisa A , Pergam Steven A , Green Michael D , Michaels Marian G , Danziger-Isakov Lara A , Angarone Michael P , Keefer Laurie , Daud Amna , Ison Michael 
Published: November 2023

Abstract

Background
Norovirus (NoV) results in potentially severe, relapsing, remitting diarrhea in immunocompromised hosts (ICH). A number of interventions, including nitazoxanide (NTZ), have been tried with unclear success in managing cases of NoV in ICH.

Methods
We conducted a NIH-sponsored multi-center, prospective, randomized, double-blind study of NTZ for the treatment of Norovirus in adult HSCT and SOT recipients between 2018 and 2021. Subjects with a positive Norovirus test within 14 days of enrollment and active GI symptoms were randomly assigned (1:1) to NTZ 500 mg twice daily or placebo (P) for 56 consecutives doses and were followed for 6 months, including patient reported outcomes (PRO) diary assessments. Primary endpoint was to determine the clinical efficacy, assessed as the time from randomization until symptoms resolution for at least 48 hours. Secondary endpoints included virologic efficacy assessed as the time from randomization to first negative viral load and safety through frequency of adverse events.

Results
31 subjects (16 NTZ, 15 P) were enrolled and had balanced demographics (See Table 1). Early withdrawal was documented in 5 subjects from each group. Thirty (30) had received solid organ transplants. Most had chronic ( &gt; 14 days) symptoms (77%). In the mITT population, the median time to initial clinical resolution was 19.0 days (95% CI: 1.0, 31.0) for the Nitazoxanide group and 11.0 days (95% CI: 2.0, 14.0) for the placebo group (p-value=0.459). The difference between time to first negative viral load for the Norovirus GII genotype was not significant (p-value=0.873). Patients appear to have clinical improvement based on PRO results while on active therapy. No serious adverse event related to the study treatment was documented. One severe unsolicited adverse event, abdominal pain, was reported on the day of first dose NTZ. Hospitalization and non-serious or laboratory adverse events were not significantly different between the two arms. Analysis of PK and viral genetics is ongoing and will be reported at the meeting.

Conclusion
NTZ did not shorten time to clinical resolution or viral shedding duration but may have resulted in transient symptom improvement. Although NTZ appears safe, its role is likely limited in the setting of chronic NoV among ICHs.

Disclosures
Daniel Kaul, MD, Medscape: Honoraria|Nobelpharma: Grant/Research Support|Takeda: Grant/Research Support Robin K. Avery, MD, Aicuris: Grant/Research Support|Astellas: Grant/Research Support|Astra-Zeneca: Grant/Research Support|Chimerix: Grant/Research Support|Merck: Grant/Research Support|Oxford Immunotec: Grant/Research Support|Qiagen: Grant/Research Support|Regeneron: Grant/Research Support|Takeda: Grant/Research Support Ajit Limaye, Professor/MD, MedPace: DSMB member|merck: Advisor/Consultant|merck: Grant/Research Support|moderna: Advisor/Consultant|moderna: site investigator|syneos: DSMB member Steven A. Pergam, MD, MPH, Cidara: Investigator in clinical trials|F2G: Investigator in clinical trials|Global Life Technologies: Grant/Research Support|Symbio: Investigator in clinical trials Michael D. Green, MD, MPH, ADMA: Advisor/Consultant|Allovir: Advisor/Consultant|Bristol Myers Squibb: Advisor/Consultant|ITB-MED: Advisor/Consultant Marian G. Michaels, MD, MPH, Merck: Grant/Research Support|Viracor: Grant/Research Support Lara A. Danziger-Isakov, MD, MPH, Aicuris: Contracted Clinical Research|Ansun Biopharma: Contracted Clinical Research|Astellas: Contracted Clinical Research|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Contracted Clinical Research|Pfizer: Contracted Clinical Research|Roche Diagnostics: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Contracted Clinical Research Michael P. Angarone, DO, Abbvie Pharmeciuticals: Advisor/Consultant|DKBMed Inc: Advisor/Consultant|DKBMed Inc: Honoraria