A Safety, Tolerability and Pharmacokinetic Study of Two Formulations of Metronidazole Versus Immediate Release Metronidazole in Patient With C. Difficile Colitis

Study Overview
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Brief Summary
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Clostridium difficile bacteria can be a cause of significant diarrheal disease, particularly in people who have taken potent antibiotics. When C. difficile multiplies within the colon, it produces two toxins that cause inflammation and resultant abdominal pain, fever and diarrhea. Current treatment of mild to moderate disease is with immediate release metronidazole, an antibiotic that kills C. difficile. Dr. Reddy's Laboratories has developed a delayed release form of metronidazole to release just before the colon to increase the concentration of antibiotic in the colon to improve the effectiveness of metronidazole treatment and potentially to allow less whole body exposure to the antibiotic. This study will measure the amount of metronidazole in the blood and stool of patients with C. difficile associated diarrhea (CDAD) to confirm that the new formulations are releasing the antibiotic as designed, immediately before the colon.

Official Title
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A Randomized, Open Label, Active Control, Safety, Tolerability and Pharmacokinetics Study of Two Dr. Reddy's Formulations of Metronidazole Versus Immediate Release Metronidazole (Flagyl) in Patients With Mild to Moderate C. Difficile Associated Diarrhea (CDAD)

Conditions
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Clostridium Difficile Associated Diarrhea

Intervention / Treatment
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* Drug: Metronidazole
* Drug: Metronidazole-DRF1
* Drug: Metronidazole-DRF2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients 18 years of age or older Mild to moderate C.difficile associated diarrhea (CDAD) with a positive stool C.difficile toxin (by ELISA). Either a first episode of CDAD or a first recurrence (patients with more than 1 recurrence are not eligible) Greater than 3 watery or unformed bowel movements in the prior 24 hours Females of child bearing potential having a negative pregnancy test and taking adequate birth control measures. Patients should not consume alcohol at least 12 hours prior to dosing (i.e. in-house monitoring) and until 48 hours after the last dose of drug administration (until Day 14). Able to comprehend and give informed consent for the study and able to adhere to study schedules and protocol requirements. Exclusion Criteria: Known prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives Life expectancy ≤ 60 days Sepsis, severe sepsis, or septic shock Signs or symptoms of peritonitis, megacolon or ileus History of ulcerative colitis or Crohn's disease Oral or parenteral antibiotic therapy with metronidazole or vancomycin or other drugs effective in treating DCAD (e.g., bacitracin, fusidic acid) within the 1 week prior to enrollment Recent history of significant drug or alcohol abuse within 1 year Any findings on physical examination, medical history, 12-lead ECG or clinical laboratory tests which, in the judgment of the Principal Investigator, would exclude patients from participating in the study Patients with history of blood dyscrasias, porphyria and active non-infectious disease of the central nervous system Patients with history of rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption Pregnant or lactating female patients Participation within 30 days before the start of this study in any experimental drug or device study, or currently participating in a study in which the administration of investigational drug or device within 60 days is anticipated Unable to participate in the study for any reason in the opinion of the Principal Investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metronidazole<br>Immediate release metronidazole | Drug: Metronidazole<br>* Immediate release metronidazole 500 mg orally three times a day for 14 days<br>* Other names: Flagyl®;|
| Experimental: Metronidazole-DRF1<br>Modified release metronidazole (DRF1) | Drug: Metronidazole-DRF1<br>* Modified release metronidazole (DRF1) 500 mg orally three times a day for 14 days.<br>* Other names: Metronidazole;|
| Experimental: Metronidazole-DRF2<br>Modified release metronidazole (DRF2) | Drug: Metronidazole-DRF2<br>* Modified release metronidazole (DRF2) 500 mg orally three times a day for 14 days.<br>* Other names: Metronidazole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability | Tolerability as assessed by physical examination, ECG, clinical laboratory tests and adverse events | 44 Days | 
| Pharmacokinetics | Systemic pharmacokinetics of metronidazole on Days 1 and 14. Intraluminal colonic concentration of metronidazole as reflected in excreted stool on Days 1 and 14. | 14 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Cure | Response rate to treatment 2 days after completion of 14 days of metronidazole treatment with no recurrence 30 days after 14 days of metronidazole treatment (Day 44). | 44 Days | 
| Recurrence Rate | Recurrence defined as re-establishment of diarrhea after clinical cure. | 44 Days | 
| 30-Day Cure Rate | Clinical cure with no recurrence and no retreatment for 30 days after 14 days of metronidazole treatment (Day 44). | 44 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clostridium difficile associated diarrhea, Metronidazole, CDAD