Cystic Fibrosis
Conditions
Keywords
healthy volunteers, neutrophil migration, anti inflammatory non-steroidal agent, simvastatin, pioglitazone
Brief summary
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
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).
Interventions
DRUGPioglitazone
30 mg once a day
DRUGSimvastatin
40 mg once a day
DRUGIbuprofen
Ibuprofen 15-23 mg/kg twice daily, maximum 3200 mg/day
Sponsors
University Hospitals Cleveland Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Masking description
No person associated with the study was masked
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neutrophil Delivery to the Oral Mucosa Using a Non-invasive Mouthwash Technique | 3X Before treatment (Days 1,2,3) 3X During treatment (Days 8,9,10) | 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. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from lab personnel and CF Center employees and UH employees and by word of mouth. Due to the vulnerability of this population every effort was made to avoid coercion. No one was enrolled that was directly supervised by the PI. The recruitment log was kept in a secure location in the CF Team Office.
Pre-assignment details
Inclusion and exclusion criteria were reviewed at screening. Concomitant medications were reviewed prior to randomization. Subjects were excluded if they were on NSAIDS, corticosteroids (including inhaled steroids and statin lowering medications.
Participants by arm
| Arm | Count |
|---|---|
| 1-Pioglitazone Pioglitazone
Pioglitazone: 30 mg once a day | 10 |
| 2-Simvastin Simvastatin
Simvastatin: 40 mg once a day | 10 |
| 3-Ibuprofen 1000-1600 mg Twice Daily Ibuprofen 1000-1600 mg twice daily (max 3200 mg/day) | 5 |
| Total | 25 |
Baseline characteristics
| Characteristic | 1-Pioglitazone | 2-Simvastin | 3-Ibuprofen 1000-1600 mg Twice Daily | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 5 Participants | 25 Participants |
| Age, Continuous | 29.4 years STANDARD_DEVIATION 8.8 | 28.8 years STANDARD_DEVIATION 9.1 | 24.5 years STANDARD_DEVIATION 4 | 27.6 years STANDARD_DEVIATION 2.8 |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 3 Participants | 14 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 2 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 2 / 10 | 0 / 5 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 5 |
Outcome results
Primary
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.
Time frame: 3X Before treatment (Days 1,2,3) 3X During treatment (Days 8,9,10)
Population: Healthy volunteers free of gingival disease were randomized 2:2:1 to oral Pioglitazone, Simvastatin or Ibuprofen respectively for 10 days.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1-Pioglitazone | Neutrophil Delivery to the Oral Mucosa Using a Non-invasive Mouthwash Technique | 6.4 % change in mean PMN counts: B vs T |
| 2-Simvastatin | Neutrophil Delivery to the Oral Mucosa Using a Non-invasive Mouthwash Technique | -19.6 % change in mean PMN counts: B vs T |
| 3-Ibuprofen 1000-1600 mg Twice Daily (Max 3200 mg/Day) | Neutrophil Delivery to the Oral Mucosa Using a Non-invasive Mouthwash Technique | -28.4 % change in mean PMN counts: B vs T |