Healthy
Conditions
Brief summary
Drug interaction study evaluating the pharmacokinetic profiles of Metronidazole administered alone & in combination with MMX® Mesalazine/mesalamine
Interventions
DRUGMetronidazole + MMX Mesalazine/mesalamine placebo
Metronidazole 750 mg twice daily + MMX Mesalazine/mesalamine placebo once daily for 3 days orally, then Metronidazole 750 mg single dose + MMX Mesalazine/mesalamine placebo single dose on Day 4 orally
DRUGMetronidazole + MMX Mesalazine/mesalamine
Metronidazole 750 mg twice daily + MMX Mesalazine/mesalamine 4.8 g once daily for 3 days orally, then Metronidazole 750 mg single dose + MMX Mesalazine/mesalamine 4.8 g single dose on Day 4 orally
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 18-55 years inclusive at the time of consent. The date of signing informed consent is defined as the beginning of the Screening Period. 2. Subject is willing to comply with any applicable contraceptive requirements of the protocol and is: * Male, or * Non-pregnant, non-lactating female * Females must be at least 90 days post-partum or nulliparous.
Exclusion criteria
1. A history of current or recurrent disease that could affect the colon. This includes gastrointestinal disease, peptic ulceration, gastrointestinal bleeding, celiac disease, lactose intolerance, ulcerative colitis, Crohn's disease, or Irritable Bowel Syndrome. Subjects who have a history of chronic constipation, which is physician diagnosed and treated, will also be excluded from the study (frequency of bowel movements \>48 hours between samples). 2. A history of current or relevant serious, severe, or unstable (acute or progressive) physical or psychiatric illness. 3. A history of gastrointestinal surgery performed within the past 12 months prior to the first dose of investigational product, with the exception of an appendectomy. 4. A history of or current clinically relevant moderate or severe renal or hepatic impairment. 5. A history of asthma or bronchospasm associated with the use of 5-ASA or other non-steroidal anti-inflammatory drugs. 6. Known or suspected intolerance or hypersensitivity to the investigational product or metronidazole, closely related compounds, or any of the stated ingredients 7. A history of, or current, pancreatitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Curve (AUC) at Steady State for Metronidazole | Assessed over a 24-hour period starting post-dose on day 4 | AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body. |
| Maximum Plasma Concentration (Cmax) at Steady State for Metronidazole | Assessed over a 24-hour period starting post-dose on day 4 | Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administrated. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metronidazole + MMX Placebo First Metronidazole 750 mg twice daily + MMX placebo once daily for 3 days orally, then Metronidazole 750 mg single dose + MMX placebo single dose on Day 4 orally,first; then Metronidazole 750 mg twice daily + MMX Mesalazine/mesalamine 4.8 g once daily for 3 days orally, then Metronidazole 750 mg single dose + MMX Mesalazine/mesalamine 4.8 g single dose on Day 4 orally, second | 15 |
| Metronidazole + MMX Mesalazine/Mesalamine First Metronidazole 750 mg twice daily + MMX Mesalazine/mesalamine 4.8 g once daily for 3 days orally, then Metronidazole 750 mg single dose + MMX Mesalazine/mesalamine 4.8 g single dose on Day 4 orally, first; then Metronidazole 750 mg twice daily + MMX placebo once daily for 3 days orally, then Metronidazole 750 mg single dose + MMX placebo single dose on Day 4 orally, second | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Non-compliance | 1 | 0 |
| First Intervention | Withdrawal by Subject | 0 | 1 |
| Second Intervention | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Metronidazole + MMX Placebo First | Metronidazole + MMX Mesalazine/Mesalamine First | Total |
|---|---|---|---|
| Age, Continuous | 35.9 years STANDARD_DEVIATION 8.84 | 31.2 years STANDARD_DEVIATION 11 | 33.6 years STANDARD_DEVIATION 10.1 |
| Age, Customized Between 18 and 55 years | 15 Participants | 15 Participants | 30 Participants |
| Region of Enrollment United States | 15 Participants | 15 Participants | 30 Participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 29 | 6 / 29 |
| serious Total, serious adverse events | 0 / 29 | 0 / 29 |
Outcome results
Primary
Area Under the Plasma Concentration Curve (AUC) at Steady State for Metronidazole
AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body.
Time frame: Assessed over a 24-hour period starting post-dose on day 4
Population: Pharmacokinetic Analysis Set defined as all subjects in the Safety Analysis Set for whom the primary pharmacokinetic data were considered sufficient and interpretable. The Safety Analysis Set consists of subjects who took at least 1 dose of investigational product and had at least 1 postdose safety assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metronidazole + MMX Placebo | Area Under the Plasma Concentration Curve (AUC) at Steady State for Metronidazole | 217686 ng*h/ml | Standard Deviation 49693 |
| Metronidazole + MMX Mesalazine/Mesalamine | Area Under the Plasma Concentration Curve (AUC) at Steady State for Metronidazole | 215809 ng*h/ml | Standard Deviation 48681 |
90% CI: [0.961, 0.998]ANOVA
Primary
Maximum Plasma Concentration (Cmax) at Steady State for Metronidazole
Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administrated.
Time frame: Assessed over a 24-hour period starting post-dose on day 4
Population: Pharmacokinetic Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metronidazole + MMX Placebo | Maximum Plasma Concentration (Cmax) at Steady State for Metronidazole | 28193 ng/ml | Standard Deviation 6249 |
| Metronidazole + MMX Mesalazine/Mesalamine | Maximum Plasma Concentration (Cmax) at Steady State for Metronidazole | 28057 ng/ml | Standard Deviation 5522 |
90% CI: [0.951, 1.04]ANOVA