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

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)

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.

Study Overview

• Status: Completed
• Conditions: Clostridium Difficile Associated Diarrhea
• Intervention / Treatment: Drug: Metronidazole; Drug: Metronidazole-DRF1; Drug: Metronidazole-DRF2

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• India
  • Karnataka
    • Bangalore, Karnataka, India
      • St. John's Medical college and Hospital
    • Bangalore, Karnataka, India
      • Dr. B.R. Ambedkar Medical College
  • Kerala
    • Trivandrum, Kerala, India
      • PRS Hospitals
  • Maharashtra
    • Mumbai, Maharashtra, India
      • B.Y.L. Nair Hospital
    • Nashik, Maharashtra, India
      • Chopda Research and Medical Center Pvt
    • Pune, Maharashtra, India
      • Ruby Hall Clinic
  • Maharastra
    • Pune, Maharastra, India
      • Deenanath Mangeshkar Hospital
  • Rajasthan
    • Bikaner, Rajasthan, India
      • S.P. Medical College and Hospital
    • Jaipur, Rajasthan, India
      • Apex Medicical College
  • Tamil Nadu
    • Madurai, Tamil Nadu, India
      • Meenakshi Mission Hospital and Research Center
    • Salem, Tamil Nadu, India
      • SKS Hospital India Pvt. Ltd.
  • Varanasi
    • Lanka, Varanasi, India
      • Heritage Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male and female patients 18 years of age or older
2. Mild to moderate C.difficile associated diarrhea (CDAD) with a positive stool C.difficile toxin (by ELISA).
3. Either a first episode of CDAD or a first recurrence (patients with more than 1 recurrence are not eligible)
4. Greater than 3 watery or unformed bowel movements in the prior 24 hours
5. Females of child bearing potential having a negative pregnancy test and taking adequate birth control measures.
6. 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).
7. Able to comprehend and give informed consent for the study and able to adhere to study schedules and protocol requirements.

Exclusion Criteria:

1. Known prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives
2. Life expectancy ≤ 60 days
3. Sepsis, severe sepsis, or septic shock
4. Signs or symptoms of peritonitis, megacolon or ileus
5. History of ulcerative colitis or Crohn's disease
6. 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
7. Recent history of significant drug or alcohol abuse within 1 year
8. 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
9. Patients with history of blood dyscrasias, porphyria and active non-infectious disease of the central nervous system
10. Patients with history of rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
11. Pregnant or lactating female patients
12. 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
13. Unable to participate in the study for any reason in the opinion of the Principal Investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Metronidazole; Immediate release metronidazole	Drug: Metronidazole; Immediate release metronidazole 500 mg orally three times a day for 14 days; Other Names: Flagyl®
EXPERIMENTAL: Metronidazole-DRF1; Modified release metronidazole (DRF1)	Drug: Metronidazole-DRF1; Modified release metronidazole (DRF1) 500 mg orally three times a day for 14 days.; Other Names: Metronidazole
EXPERIMENTAL: Metronidazole-DRF2; Modified release metronidazole (DRF2)	Drug: Metronidazole-DRF2; Modified release metronidazole (DRF2) 500 mg orally three times a day for 14 days.; Other Names: Metronidazole

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Dr. Reddy's Laboratories Limited
• Collaborators: Reliance Clinical Research Services (Navi Mumbai, India)
• Investigators: Study Director: Dilip Pawar, MD, Dr. Reddy's Laboratories Limited

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (ACTUAL): February 1, 2013
• Study Completion (ACTUAL): March 1, 2013

Study Registration Dates

• First Submitted: March 19, 2012
• First Submitted That Met QC Criteria: March 20, 2012
• First Posted (ESTIMATE): March 21, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): June 7, 2013
• Last Update Submitted That Met QC Criteria: June 6, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: Metronidazole; CDAD; Clostridium difficile associated diarrhea
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Metronidazole
• Other Study ID Numbers: DFA-03-CD-002