The overall objective of the RESTORATiVE303 study is to evaluate the safety and the Clostridioides difficile infection (CDI) recurrence rate at Week 8 in participants who receive a 14-day course of VE303 or matching placebo. The objectives and endpoints are identical for Stage 1 (recurrent CDI) and Stage 2 (high-risk primary CDI).

Key Inclusion Criteria (For enrollment in Stage 1: recurrent CDI population):

• Age ≥ 12 years where permitted, and ≥ 18 years in other locations, with a laboratory-confirmed qualifying episode of CDI and at least 1 prior occurrence within the last 6 months

Key Inclusion Criteria (For enrollment in Stage 2: primary CDI with high-risk for recurrence population):

• Age ≥ 75 years with a laboratory-confirmed qualifying episode of CDI

• OR age ≥ 12 years where permitted, and ≥ 18 years in other locations, with least two of the following risk factors:

  1. Age ≥ 65 years
  2. Kidney dysfunction, defined as estimated creatinine clearance < 60 mL/min/1.73 m^2 at the time of the qualifying CDI episode
  3. History of regular use of a proton pump inhibitor (PPI) within the past 2 months and expectation of continued use of PPIs throughout the study
  4. History of a prior CDI episode between 6 and 12 months prior to enrollment
  5. Immunosuppression due to an underlying disease or its treatment
  6. Has undergone solid organ or hematopoietic stem cell transplantation

Key Inclusion Criteria (For enrollment in Stage 1 or 2):

• The qualifying episode of CDI must meet all the following criteria:

  1. New onset of ≥ 3 unformed bowel movements (ie, Types 5 to 7 on the Bristol stool scale) within 24 hours for 2 consecutive days
  2. CDI symptoms started within 4 weeks prior to initiation of standard of care (SoC) antibiotic therapy for CDI
  3. Stool sample collected before (or no later than 72 hours after) initiation of SoC antibiotic therapy that was positive in a CDI laboratory test, defined as enzyme immunoassay (EIA) for toxin A/B and glutamate dehydrogenase (GDH) with polymerase chain reaction (PCR) reflex testing for discordant EIA/GDH results, performed at either a local laboratory or the central laboratory
  4. Diarrhea considered unlikely to have another etiology

• Prior to receiving any study medication, the participant should:

  1. Receive and complete a course of SoC antibiotic therapy for at least 10 days, up to a maximum of 28 days (Note: choice of agent is at the physician's discretion and antibiotic tapering is not allowed). It is permissible for decentralized participants to be randomized during SoC antibiotic administration.
  2. Meet the criterion of a successful clinical response, defined attaining symptomatic control of the qualifying CDI episode, ie, < 3 loose/unformed bowel movements per 24 hours for at least 2 consecutive days

• Able to receive the first dose of study drug on the last planned day of SoC antibiotic administration for a qualifying CDI episode, or no later than 2 days after completion of antibiotic dosing

• Recovered from any complications of severe or fulminant CDI and be clinically stable by the time of randomization

Key Exclusion Criteria (For both Stage 1 and Stage 2):

• History of chronic diarrhea (defined as ≥ 3 loose stools per day lasting for at least 4 weeks) within 3 months prior to randomization that is not related to CDI
• Known or suspected toxic megacolon or small bowel ileus at the time of randomization
• History of confirmed celiac disease, inflammatory bowel disease, microscopic colitis, short gut, GI tract fistulas, or a recent episode (within 6 months of screening) of intestinal ischemia or ischemic colitis
• Receipt of bezlotoxumab during the course of SoC antibiotic treatment for the qualifying CDI episode
• Use of antidiarrheal drugs (eg, loperamide, diphenoxylate) within 3 days prior to the planned first dose of study drug
• Anticipated administration of oral or parenteral antibacterial therapy for a non-CDI indication after randomization through Week 24 (end of study)
• Probiotics, whether characterized as a dietary/food supplement, or a drug, are prohibited within 2 days before starting study drug and through the dosing period. (Note: consumption of food-based products such as yogurt, kombucha, and kefir are permitted.)
• Absolute neutrophil count (ANC) of < 0.5 ×10^9 cells/L on 2 consecutive occasions within 7 days prior to randomization, or sustained ANC < 1.0 × 10^9 cells/L