Fungal Infection
Conditions
Brief summary
This single site study will examine plasma and alveolar compartment (AC) levels of posaconazole in cystic fibrosis (CF) and non-cystic fibrosis (non-CF) lung transplant recipients receiving routine post-operative anti-fungal prophylaxis. Invasive fungal infection rates will be assessed following transplantation.
Interventions
DRUGPosaconazole
DRUGCalogen®
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Scheduled to undergo lung transplantation * Able to take oral/nasogastric medication * Females of childbearing potential, males, and the sexual partners of males must use an effective method of birth control during this study and for 6 weeks after completing the study.
Exclusion criteria
* Severe liver disease * Current use of cytochrome P-450 (CYP)-3A4 inhibitors including terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine within 7 days before transplant * Treatment with posaconazole within 14 days before transplant * Breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach 90% of the Steady State Serum Concentration of Posaconazole | Four hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43 | Blood samples for measurement of serum posaconazole were collected approximately 4 hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43. The time to reach 90% of the steady state serum posaconazole concentration was to be estimated from fitting a linear model to the concentration data over time. The data did not permit estimation of the endpoint from the modeling proposed in the protocol. |
| Concentration of Posaconazole in Bronchoalveolar Lavage (BAL) and Serum | Up to Day 42 | Concurrent BAL and serum samples for measurement of posaconazole concentration were to be collected during any clinically-indicated bronchoscopy. A participant could have more than 1 bronchoscopy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Develop Invasive Fungal Infection | Up to Day 84 | Invasive fungal infection was assessed using the Mycoses Study Group/European Organisation for Research and Treatment of Cancer (MSG/EORTC) criteria. Infections counted in the analysis were those classified as 'proven', 'probable', or 'possible' according to the criteria. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cystic Fibrosis Participants Cystic fibrosis participants received posaconazole 400 mg oral solution twice daily administered with Calogen® to optimize absorption for a total of 6 weeks starting within 12 hours of leaving surgery, thereafter administered in the hospital or as an outpatient; the dose could be changed to posaconazole 200 mg 4 times per day if the participant is unable to meet the conditions for optimal absorption of posaconazole. | 8 |
| Non-Cystic Fibrosis Participants Non-cystic fibrosis participants received posaconazole 400 mg oral solution twice daily administered with Calogen® to optimize absorption for a total of 6 weeks starting within 12 hours of leaving surgery, thereafter administered in the hospital or as an outpatient; the dose could be changed to posaconazole 200 mg 4 times per day if the participant is unable to meet the conditions for optimal absorption of posaconazole. | 18 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Tolerability issues | 0 | 2 |
Baseline characteristics
| Characteristic | Cystic Fibrosis Participants | Non-Cystic Fibrosis Participants | Total |
|---|---|---|---|
| Age, Continuous | 30.0 Years STANDARD_DEVIATION 7.82 | 52.4 Years STANDARD_DEVIATION 10.39 | 45.5 Years STANDARD_DEVIATION 14.22 |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 3 Participants | 11 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 8 | 2 / 18 |
| serious Total, serious adverse events | 6 / 8 | 10 / 18 |
Outcome results
Primary
Concentration of Posaconazole in Bronchoalveolar Lavage (BAL) and Serum
Concurrent BAL and serum samples for measurement of posaconazole concentration were to be collected during any clinically-indicated bronchoscopy. A participant could have more than 1 bronchoscopy.
Time frame: Up to Day 42
Population: The population analyzed included all enrolled participants who had BAL and serum samples collected at the time of bronchoscopy and analyzed for posaconazole concentration. A participant could have more than 1 pair of samples (BAL and serum) included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cystic Fibrosis Participants | Concentration of Posaconazole in Bronchoalveolar Lavage (BAL) and Serum | BAL | 1.116 mg/L | Standard Deviation 1.1699 |
| Cystic Fibrosis Participants | Concentration of Posaconazole in Bronchoalveolar Lavage (BAL) and Serum | Serum | 0.829 mg/L | Standard Deviation 0.3742 |
| Non-Cystic Fibrosis Participants | Concentration of Posaconazole in Bronchoalveolar Lavage (BAL) and Serum | BAL | 0.764 mg/L | Standard Deviation 0.8 |
| Non-Cystic Fibrosis Participants | Concentration of Posaconazole in Bronchoalveolar Lavage (BAL) and Serum | Serum | 0.7488 mg/L | Standard Deviation 0.3131 |
Comparison: Spearman rank correlation between concurrent BAL and serum posaconazole concentrationsp-value: 0.139Spearman rank correlation
Comparison: Spearman rank correlation between concurrent BAL and serum posaconazole concentrationsp-value: 0.057Spearman rank correlation
Primary
Time to Reach 90% of the Steady State Serum Concentration of Posaconazole
Blood samples for measurement of serum posaconazole were collected approximately 4 hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43. The time to reach 90% of the steady state serum posaconazole concentration was to be estimated from fitting a linear model to the concentration data over time. The data did not permit estimation of the endpoint from the modeling proposed in the protocol.
Time frame: Four hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43
Population: The population to be analyzed included participants who complied with the protocol sufficiently to ensure that the results would exhibit the effects of treatment
Secondary
Percentage of Participants Who Develop Invasive Fungal Infection
Invasive fungal infection was assessed using the Mycoses Study Group/European Organisation for Research and Treatment of Cancer (MSG/EORTC) criteria. Infections counted in the analysis were those classified as 'proven', 'probable', or 'possible' according to the criteria.
Time frame: Up to Day 84
Population: Participants were analyzed according to the group in which they were enrolled
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cystic Fibrosis Participants | Percentage of Participants Who Develop Invasive Fungal Infection | 12.5 Percentage of participants |
| Non-Cystic Fibrosis Participants | Percentage of Participants Who Develop Invasive Fungal Infection | 16.7 Percentage of participants |
Post Hoc
Maximum Serum Concentration of Posaconazole (Cmax)
Blood samples for measurement of serum posaconazole were collected approximately 4 hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43. The maximum serum concentration of posaconazole was recorded.
Time frame: Four hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43
Population: The population analyzed included all enrolled participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cystic Fibrosis Participants | Maximum Serum Concentration of Posaconazole (Cmax) | 1.481 mg/L | Standard Deviation 0.6014 |
| Non-Cystic Fibrosis Participants | Maximum Serum Concentration of Posaconazole (Cmax) | 1.539 mg/L | Standard Deviation 0.8471 |
Post Hoc
Time to Maximum Serum Concentration of Posaconazole (Tmax)
Blood samples for measurement of serum posaconazole were collected approximately 4 hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43. The time required to achieve the maximum serum concentration of posaconazole was recorded.
Time frame: Four hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43
Population: The population analyzed included all enrolled participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cystic Fibrosis Participants | Time to Maximum Serum Concentration of Posaconazole (Tmax) | 19.5 Days | Standard Deviation 12.39 |
| Non-Cystic Fibrosis Participants | Time to Maximum Serum Concentration of Posaconazole (Tmax) | 23.1 Days | Standard Deviation 13.73 |
Post Hoc
Time to Reach a Serum Concentration of Posaconazole of >=0.5 mg/L
Blood samples for measurement of serum posaconazole were collected approximately 4 hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43. A posaconazole concentration \>=0.5 mg/L is the therapeutic level, the concentration thought to lead to antifungal efficacy. The time at which the serum posaconazole concentration reached \>=0.5 mg/mL and remained at that level for all subsequent assessments was recorded.
Time frame: Four hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43
Population: The population analyzed included all enrolled participants who reached and maintained posaconazole concentration of \>=0.5 mg/L
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cystic Fibrosis Participants | Time to Reach a Serum Concentration of Posaconazole of >=0.5 mg/L | 12.2 Days | Standard Deviation 8.82 |
| Non-Cystic Fibrosis Participants | Time to Reach a Serum Concentration of Posaconazole of >=0.5 mg/L | 11.9 Days | Standard Deviation 9.86 |