PRISM

To evaluate the efficacy of AZD5148 administered as a single dose (IM or IV push), during standard of care (SoC) antibacterial drug therapy for CDI b, to reduce rCDI a compared to placebo through Day 91 

Key secondary:

• To evaluate the efficacy of AZD5148 administered as a single dose (IM or IV push), during SoC antibacterial drug therapy for CDI b in achieving sustained clinical cure compared to placebo through Day 91 

Secondary:

• To evaluate the efficacy of AZD5148 administered as a single dose (IM or IV push) during SoC antibacterial drug therapy for CDI in reducing the duration of rCDI a compared to placebo through Day 91 
• To evaluate the efficacy of AZD5148 administered as a single dose (IM or IV push), during SoC antibacterial drug therapy for CDI, to reduce severe a or fulminant a rCDI a compared to placebo through Day 91
• To evaluate the efficacy of AZD5148 administered as a single dose (IM or IV push), during SoC antibacterial drug therapy for CDI, to reduce participant reported CDI diarrhea symptoms compared to placebo through Day 91 
• To evaluate the efficacy of AZD5148 administered as a single dose (IM or IV push), during SoC antibacterial drug therapy for CDI, to prevent rCDI-related hospitalization compared to placebo through Day 91 
• To evaluate the efficacy of AZD5148 administered as a single dose (IM or IV push), during SoC antibacterial drug therapy for CDI, to prevent mortality related to rCDI compared to placebo through Day 91 
• To describe the safety of AZD5148 administered as a single dose (IM or IV push) compared to placebo
• To characterize the pharmacokinetics (PK) of AZD5148 in serum
• To evaluate the immunogenicity of AZD5148 in serum

Age 
1. Participant must be ≥ 18 years of age at the time of signing the informed consent.

Informed Consent  
2. Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 

Type of Participant and Disease Characteristics 
3. Participants with a qualifying CDI episode at the time of providing informed consent defined by:

• History of 3 or more unformed stools (Bristol stool scale 6 or 7) in ≤ 24 hours for 2 consecutive calendar days, and
  • Positive local C difficile toxin test (eg, immune assay or CCNA) on an unformed stool sample collected during this episode, and
  • Receipt of SoC antibacterial drug therapy for CDI (fidaxomicin, vancomycin, or metronidazole) for this episode, with planned duration of at least 10 and at most 25 days at time of IMP administration.
  • Note: Diarrhea is not required to be present on the day of IMP administration. 

4. Participants who are able to understand and comply with study requirements/procedures including attending all scheduled study visits (if applicable, with assistance by caregiver, surrogate, or legally authorized representative or equivalent representative as locally defined) based on the assessment of the Investigator.  

Weight 
5. Body weight ≥ 40 kg

Sex and Contraceptive/Barrier Requirements 
6. WOCBP (defined in Appendix C) must have a negative urine pregnancy test result at screening and at Visit 1 before the administration of the study intervention. For women unable to produce urine due to underlying disease a serum pregnancy test may be performed.  
7. WOCBP must not be lactating and if heterosexually active, must agree to use an approved method of highly effective contraception, as detailed in Appendix C, to avoid pregnancy from 4 weeks prior to administration of the IMP until 180 days after the dose of the IMP. 
8. Women of non-childbearing potential must be confirmed at the Screening Visit by 
fulfilling one of the criteria defined in Appendix C.

Medical Conditions 
1. History of inflammatory bowel disease (eg, ulcerative colitis, Crohn’s disease, 
microscopic colitis).  
2. Participant with a non-CDI condition such that the participant routinely passes loose stool (eg, patients with an ostomy). 
3. For IM administration only: History of clinically significant bleeding disorder (eg, factor VIII deficiency, coagulopathy, platelet disorder, prior history of significant bleeding, or bruising following IM injections or venipuncture). 
4. Planned surgery for CDI within 24 hours of enrollment.
5. Current toxic megacolon and/or small bowel ileus. 
6. Any history of total colectomy or bariatric surgery (bariatric surgery which does not disrupt the GI lumen, ie, restrictive procedures such as banding, are permitted). 
7. Major GI surgery as assessed by the Investigator (eg, significant bowel resection or diversion) within 90 days before enrollment (this does not include appendectomy or cholecystectomy).  
8. Current admission to (or expected to be admitted to) an ICU for mechanical ventilatory support, new dialysis, or vasopressor/inotropic support. 
9. Not expected to survive for the next 3 months.  
10. Absence of suitable venous access for serum sampling. 
11. Blood drawn in excess of a total of 450 mL (1 unit) for any reason within 30 days prior to IMP administration. 
12. Any other condition that, in the opinion of the Investigator, might interfere with 
evaluation of the study intervention or interpretation of participant safety or study results.

Prior/Concomitant Therapy 
13. Due to receive more than 25 days of SoC antibacterial drug therapy for the qualifying CDI episode. 
14. Prior receipt of AZD5148. 
15. Treatment with a fecal donor transplant or fecal microbiota product in the 180 days before IMP administration, are receiving or planned administration for the qualifying episode of CDI, or planned administration during the 180 days after IMP administration. 
16. Treatment with bezlotoxumab in the 180 days before IMP administration, are receiving or planned administration for the qualifying episode of CDI, or planned administration during the 180 days after IMP administration. 
17. Oral cholestyramine, oral nitazoxanide, oral rifaximin; IV tigecycline, or oral or IV fusidic acid treatment in the 2 days before IMP administration, or due to receive more than a 24-hour regimen of any of these medications in the 180 days after IMP administration (ie, cannot stop or avoid them). 
18. Administration of any licensed vaccine within 14 days before, or planned administration within 14 days after, IMP administration. 
19. Receipt of human immunoglobulin to a total dose of > 0.7 g/kg (via any route) within the 4-week period before IMP administration, or planned administration of a total dose > 0.7 mg/kg over any 4-week period from IMP administration during the 180 days after IMP administration.
20. Medications given to decrease GI peristalsis, such as loperamide (Imodium™) or diphenoxylate hydrochloride/atropine sulfate (Lomotil™) planned at any time during the 14 days after IMP administration.  
21. Participants receiving opioid medications at the onset of diarrhea. (They may be included if they are expected to be on stable doses of these medications or there is anticipation of a dose decrease or cessation of their use.) 
22. Receipt of donated blood or plasma from the time of informed consent, or planned during the 180 days after IMP administration.

Prior/Concurrent Clinical Study Experience 
23. Participation in any other clinical trial of an IMP or investigational intervention in the 90 days before enrollment, or scheduled to participate within 360 days after 
administration of AZD5148 in this study. 
24. Known hypersensitivity to any component of AZD5148. 
25. History of severe adverse reaction and/or serious or severe hypersensitivity reaction (eg, anaphylaxis) after administration of a mAb.

Other Exclusions 
26. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 
27. Judgment by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements. 
28. Female participants who plan to donate ova before the Day 361 Study Visit. 

The purpose of this study is to evaluate the safety and efficacy of a single 400 mg dose of AZD5148 administered IV or IM, compared with placebo, in preventing rCDI among participants undergoing SoC antibacterial drug therapy for CDI at enrollment.