An Exploratory, Open-Label, Oligo-Center Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Intravenous DNV3837 in Subjects With Clostridium Difficile Infection
An Exploratory, Open-Label, Oligo-Center Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Intravenous DNV3837 in Subjects With Clostridium Difficile Infection
This is an open-label study to evaluate the safety, efficacy, and PK of DNV3837 at a dose of
 1.5 mg/kg actual body weight(BW)/day administered via IV infusion in subjects with CDI. The
 study will be conducted in 2 subsequent parts. In Part 1 of the study, 10 subjects of either
 sex with non-severe CDI will be enrolled to receive DNV3837. In Part 2 of the study, up to 30
 subjects with severe CDI will be enrolled and randomized in a 2:1 ratio to receive DNV3837 or
 SOC.

 In both parts of the study, treatment infusions will be administered at a constant rate
 resulting in a total IV infusion duration of 6 hours per day, for a total daily dose of 120
 mg DNV3837. Infusions will be administered once daily for 10 consecutive days. The objectives
 of the study are:

 -  To evaluate the safety of intravenous (IV) DNV3837;

 -  To evaluate the efficacy of IV DNV3837 versus standard of care (SOC);

 -  To assess the pharmacokinetics (PK) of DNV3837 and DNV3681 in plasma and of DNV3681 in
 urine and feces;

 -  To assess C. difficile using microbiological assessments;

 -  To assess the proportion of subjects colonized with vancomycin-resistant enterococci
 (VRE), extended-spectrum beta-lactamase (ESBL) organisms, or carbapenem-resistant
 Enterobacteriaceae (CRE) in feces; and

 -  To assess changes in the fecal microbiome using 16S ribosomal ribonucleic acid (RNA)
 analysis
POPULATION:

 Inclusion Criteria:

 Subjects must meet all of the following inclusion criteria to be enrolled in the study:

 1. The subject or a legally authorized representative must sign informed consent;

 2. The subject must be 18 years of age;

 3. Subjects must have a diagnosis of CDI defined as follows:

 1. Diarrhea, defined as a change in bowel habits, with > 3 liquid stools or unformed
 bowel movements (UBMs) [Bristol Stool Scale 6 or 7] or > 200 mL unformed stool
 for subjects having rectal collection devices in the 24 hours prior to start of
 study drug; AND

 2. The subject has the following positive tests on a stool sample produced within 72
 hours prior to the start of study drug as determined by:

 -  A positive C. difficile glutamate dehydrogenase (GDH) test by a Food and
 Drug Administration (FDA)-cleared enzyme immunoassay (EIA); AND

 -  A positive toxin test (presence of either C. difficile Toxin A [TcdA] and/or
 C. difficile Toxin B [TcdB]) by an FDA-cleared EIA; OR

 -  A positive toxin gene test (presence of either C. difficile Toxin A gene
 [tcdA] and/or C. difficile Toxin B gene [tcdB]) by an FDA-cleared nucleic
 acid amplification test; OR

 -  A positive cell cytotoxicity neutralization assay; OR

 -  positive toxigenic culture;

 4. Subjects with a diagnosis of non-severe CDI must have a white blood cell (WBC) count
 ≤15,000 cells/µL (15 × 10^9 cells/L) and serum creatinine <1.5 mg/dL;

 5. Subjects with a diagnosis of severe CDI must have any of the following criteria:

 a. Criterion 1

 i. WBC count >15,000 cells/µL (15 x 10^9 cells/L); OR

 ii. Serum creatinine 1.5 mg/dL;

 b. Criterion 2

 i. Evidence of pseudomembranous colitis on endoscopy; OR

 ii. Colitis on computed tomography or magnetic resonance imaging scan or ultrasound;

 c. Criterion 3

 i. Severe abdominal pain, vomiting, ileus, temperature >38.9°C, WBC count >15,000
 cells/µL (15 x 10^9 cells/L), or albumin level <2.5 g/dL in which CDI is strongly
 suspected and other non-CDI causes of infection have been ruled out;

 6. The subject has received no more than 24 hours of prior antimicrobial treatment for
 the current episode of CDI with oral/rectal vancomycin, IV/oral metronidazole, or oral
 fidaxomicin prior to Screening;

 7. Female subjects of non-childbearing potential must be either surgically sterile
 (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy
 at least 26 weeks before Screening) or post-menopausal, defined as spontaneous
 amenorrhea for at least 2 years, with follicle-stimulating hormone in the
 post-menopausal range at Screening, based on the central laboratory's ranges;

 8. Women of childbearing potential (ie, not post-menopausal or surgically sterilized)
 must have a negative urine and serum pregnancy test result before randomization.
 Participating women of childbearing potential must agree to use 1 highly effective
 method of contraception AND an acceptable barrier method (condom plus spermicide) OR 2
 highly effective methods of contraception throughout the duration of the study and for
 30 days following the last study drug administration. Highly effective methods of
 contraception that result in a low failure rate (ie, <1% per year) when used
 consistently and correctly include the following:

 1. Combined (estrogen and progestogen containing) hormonal contraception associated
 with inhibition of ovulation (oral, intravaginal, or transdermal),
 progestogen-only hormonal contraception associated with inhibition of ovulation
 (oral, injectable, or implantable), intrauterine device, or intrauterine
 hormone-releasing system for at least 12 weeks before Screening;

 2. Bilateral tubal occlusion or vasectomized partner at least 26 weeks before
 Screening;

 3. Sexual abstinence; NOTE: True abstinence, when in line with the preferred and
 usual lifestyle of the subject, is considered a highly effective method only if
 defined as refraining from heterosexual intercourse during the entire period of
 risk associated with the study drug treatment. Periodic abstinence (eg, calendar,
 ovulation, symptothermal, post ovulation methods) and withdrawal are not
 acceptable methods of contraception;

 9. Male subjects must agree to abstain from sperm donation and use condoms with
 spermicide during sexual intercourse between Screening and at least 90 days after
 administration of the last dose of study drug. Male subjects must ensure non pregnant
 female partners of childbearing potential comply with the contraception requirements
 in Inclusion Criterion 8.

 Exclusion Criteria:

 Subjects will not be enrolled in the study if they meet any of the following exclusion
 criteria:

 1. The subject is likely to require surgical intervention (eg, subjects with fulminant
 CDI who fail to respond and progress to systemic toxicity, peritonitis, or toxic
 colonic dilatation and bowel perforation) and/or be switched to an already approved
 treatment regimen in the coming 48 hours due to a rapidly degrading condition;

 2. The subject displays evidence of acute renal impairment with a creatinine clearance of
 <50 mL/min as measured by the Cockcroft Gault formula;

 3. The subject is receiving hemodialysis or continuous venous hemofiltration;

 4. The subject has ALT or AST serum levels >3 × ULN, and total bilirubin serum
 concentration >2 × ULN per the testing laboratory;

 5. The subject displays evidence of chronic hepatic impairment (Child-Pugh class B or C);

 6. The subject is pregnant or breastfeeding;

 7. The subject requires the ongoing use of anti-motility agents (eg, anti-diarrheals,
 anti peristaltics) or laxatives, unless approved by the Medical Monitor. Chronic and
 continued use of such products may be permitted during the study if bowel motility has
 stabilized;

 8. The subject requires the ongoing use of concomitant antibiotics to treat CDI (other
 than study drug) (eg, oral/rectal vancomycin, IV/oral metronidazole, oral fidaxomicin)
 or IV immunoglobulin;

 9. The subject has a known hypersensitivity or intolerance to DNV3837 or sorbitol;

 10. The subject has a history of active hepatitis B virus or hepatitis C virus that
 requires ongoing therapy, or human immunodeficiency virus with the most current
 cluster of differentiation 4 (CD4+) <200 copies/mL;

 11. The subject has participated in other clinical research studies using an
 investigational antibacterial or non antibacterial agent within 1 month prior to
 Screening;

 12. The subject is unable or unwilling, in the judgment of the Investigator, to comply
 with the protocol; or

 13. The subject is an employee of the Investigator, study site, Sponsor, or contract
 research organization with direct involvement in the proposed study or other studies
 under the direction of the Investigator, study site, or Sponsor, or a family member of
 the site employee or the Investigator.