Pilot Mouthwash Study of Pioglitazone and Simvastatin in Healthy Volunteers

Study Overview
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Brief Summary
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Inflammation clearly contributes to the progression of the cystic fibrosis (CF) lung disease, and administration of the anti-inflammatory agent high-dose ibuprofen retards the rate of decline of pulmonary function. However, utilization of this valuable drug has been suboptimal because of its rare, but dramatic, adverse effects. Therefore, alternative anti-inflammatory agents are urgently needed. One strategy for identifying new anti-inflammatory agents is to determine the mechanism by which the only proven anti-inflammatory agent for the CF lung disease, high-dose ibuprofen, exerts its effect. If this were known, then other drugs that act by a similar mechanism become candidates for treating the CF inflammatory disease. The investigators have shown, in our preliminary studies, that high dose ibuprofen limits the delivery of neutrophils to an inflamed mucosal surface, the gingival crevices. The investigators plan to test pioglitazone and simvastatin, (ibuprofen (positive control)) to determine their anti inflammatory affects on neutrophil migration to the oral mucosa. The hypothesis to be tested is that pioglitazone, and/or simvastatin will reduce neutrophils in the oral mucosa after 10 days of therapy in mouthwashes of healthy volunteers. Ibuprofen will be used as a positive control. This study will provide pilot data from healthy volunteers to support an FDA Grant to be submitted at a future date.

Detailed Description
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The entire study period for each subject will be 15 days, and consist of 3 periods defined as: Baseline (Day 1,2,3), Treatment (Day 3-10), and Recovery (Day 13-15). Healthy volunteers will be screened on Day 1 (and assessed for eligibility); Eligible subjects will be divided into 3 drug treatment groups pioglitazone, simvastatin and ibuprofen the positive control. The two treatment groups will consist of 4 healthy volunteers who meet the inclusion criteria. There will be 2 healthy volunteers in the positive control group. Group 1 will receive pioglitazone 30 mg once daily, Group 2 will receive simvastatin 40 mg daily and Group 3 the positive control will receive ibuprofen (15-23 mg/kg twice daily, maximum 3200 mg/day) during the Treatment period and serve as the positive control group. This dose is 25% of that prescribed to CF patients. As healthy volunteers are recruited, the first will be assigned to Group 1, the second to Group 2, and so on. After the third subject has been assigned to Group 3, this pattern of assignment will be repeated with subjects 4, 5 and 6, The following 4 healthy volunteers will be assigned to group 1 and 2 (7, 8, 9, 10).

Official Title
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A Pilot Study Evaluating the Effect of Pioglitazone, Simvastatin, and Ibuprofen on Neutrophil Migration in Vivo in Healthy Subjects

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Pioglitazone
* Drug: Simvastatin
* Drug: Ibuprofen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 < 50 years of age Healthy volunteers must be in general good health as determined by a medical history. Ability to understand and sign the informed consent form Ability to adhere to the protocol. Willing to use an acceptable form of birth control Exclusion Criteria: History of diabetes requiring insulin The use of NSAIDS (ibuprofen) or corticosteroids including inhaled steroids. Nasal steroids are acceptable. The use of statin lowering medications Active gingival disease (Active tooth or gum disease) Any chronic inflammatory condition that immuno compromises the volunteer as determined by medical history. Pregnant or planning to become pregnant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1-pioglitazone<br>Pioglitazone | Drug: Pioglitazone<br>* 30 mg once a day<br>* Other names: ACTOS;|
| Experimental: 2-simvasatin<br>Simvastatin | Drug: Simvastatin<br>* 40 mg once a day<br>* Other names: Zocor;|
| Active Comparator: 3-Ibuprofen 1000-1600 mg/day<br>Ibuprofen 1000-16-- mg/day, maximum 3200 mg/day | Drug: Ibuprofen<br>* Ibuprofen 15-23 mg/kg twice daily, maximum 3200 mg/day<br>* Other names: Motrin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil Delivery to the Oral Mucosa Using a Non-invasive Mouthwash Technique | Oral mucosal polymorphonuclear leukocytes (PMN) are obtained and assessed using a modification of the mouthwash method of (Wright et.al. Blood 1986;67:1023-30). For each subject, PMN counts are assessed on days 1, 2, 3 [Baseline (B)]; days 8, 9, 10 [Treatment (T)]; and days 11, 13, 15 [Recovery (R)]. The PMN counts for each subject are averaged for each study time period (B, T or R) within each study arm (Pioglitazone, Simvastatin and Ibuprofen). The mean baseline (B) PMN counts are compared to the mean treatment (T) PMN counts for each study arm, with the results expressed as the percent change in PMN counts . Paired T-tests between baseline and treatment PMN counts are used to analyze for significance. The recovery period is used to verify that the PMN counts return to baseline following the treatment period. Data from the recovery period is not shown. | 3X Before treatment (Days 1,2,3) 3X During treatment (Days 8,9,10) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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healthy volunteers, neutrophil migration, anti inflammatory non-steroidal agent, simvastatin, pioglitazone