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An Exploratory, Open-Label, Oligo-Center Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Intravenous DNV3837 in Subjects With Clostridium Difficile Infection

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ClinicalTrials.gov Identifier: NCT03988855
Recruitment Status : Recruiting
First Posted : June 18, 2019
Last Update Posted : March 26, 2021
Sponsor:
Information provided by (Responsible Party):
Deinove

Tracking Information
First Submitted Date  ICMJE June 12, 2019
First Posted Date  ICMJE June 18, 2019
Last Update Posted Date March 26, 2021
Actual Study Start Date  ICMJE August 2, 2019
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 13, 2019)
  • Treatment Success at Test of Cure [ Time Frame: Day 12 ]
    [Bristol Stool Scale 6 or 7]) that results in the subject receiving antimicrobial treatment active against C. difficile. Confirmed relapse is further defined as a new episode of diarrhea (>3 liquid stools or UBMs [Bristol Stool Scale 6 or 7]) with a positive C. difficile free toxin test and the requirement of antimicrobial treatment active against C. difficile;
    • Alive;
    • No additional antimicrobial or anti-diarrheal therapies for CDI
  • All Cause Mortality [ Time Frame: Day 30 ]
  • Clostridium Difficile Infection attributable mortality [ Time Frame: Day 30 ]
  • Incidence of relapse at Test of Cure [ Time Frame: 12 Days ]
  • Time to resolution of diarrhea [ Time Frame: 12 days ]
  • Treatment failure at test of cure [ Time Frame: 12 days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Exploratory, Open-Label, Oligo-Center Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Intravenous DNV3837 in Subjects With Clostridium Difficile Infection
Official Title  ICMJE An Exploratory, Open-Label, Oligo-Center Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Intravenous DNV3837 in Subjects With Clostridium Difficile Infection
Brief Summary

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
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Clostridium Difficile (C. Difficile)
Intervention  ICMJE
  • Drug: DNV3837
    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.
  • Drug: Standard of Care
    Standard of care will be administered at the discretion of the Investigator. All regimens according to current guidelines (Infectious Diseases Society of America/Society for Healthcare Epidemiology of America and European Society of Clinical Microbiology and Infectious Diseases guidance on CDI) and bezlotoxumab are acceptable.
Study Arms  ICMJE
  • Experimental: Part 1
    10 subjects of either sex with severe or non-severe CDI will be enrolled to receive DNV3837. 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 1.5 mg/kg actual body weight(BW)/day DNV3837. Infusions will be administered once daily for 10 consecutive days.
    Intervention: Drug: DNV3837
  • Experimental: Part 2
    30 subjects with severe CDI will be enrolled and randomized in a 2:1 ratio to receive DNV3837 or standard of care. 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 1.5 mg/kg actual body weight(BW)/day DNV3837. Infusions will be administered once daily for 10 consecutive days
    Interventions:
    • Drug: DNV3837
    • Drug: Standard of Care
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 13, 2019)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2021
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Georges Gaudriault +33 4 48 19 01 24 georges.gaudriault@deinove.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03988855
Other Study ID Numbers  ICMJE 001C16
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Deinove
Study Sponsor  ICMJE Deinove
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Deinove
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP