Clinical Trial Results:
A Pharmacokinetic Analysis of Posaconazole in the Plasma and Alveolar Compartment of Lung Transplant Recipients (PAPAL)
Summary
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EudraCT number |
2012-003140-68 |
Trial protocol |
GB |
Global end of trial date |
16 Jan 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Feb 2016
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First version publication date |
13 Jun 2015
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MK-5592-105
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01667107 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Merck Sharp & Dohme Corp.
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Sponsor organisation address |
2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
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Public contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Scientific contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
16 Jan 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
16 Jan 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Jan 2014
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
This single site study will examine plasma and alveolar compartment levels of posaconazole in cystic fibrosis and non-cystic fibrosis lung transplant recipients receiving routine post-operative anti-fungal prophylaxis. Invasive fungal infection rates will be assessed following transplantation.
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Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Jan 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 26
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Worldwide total number of subjects |
26
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EEA total number of subjects |
26
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
24
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
All participants were scheduled to undergo lung transplantation. Participants with severe liver disease or receiving cytochrome P-450 (CYP)-3A4 inhibitors were excluded. Other inclusion and exclusion criteria applied. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
There were no screening failures for cystic fibrosis participants and one for non-cystic fibrosis participants. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Posaconazole Treatment (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cystic Fibrosis Participants | ||||||||||||||||||||||||
Arm description |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Posaconazole
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Investigational medicinal product code |
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Other name |
MK-5592, Noxafil®
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole.
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Investigational medicinal product name |
Calogen®
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral emulsion
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Routes of administration |
Oral use
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Dosage and administration details |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole.
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Arm title
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Non-cystic Fibrosis Participants | ||||||||||||||||||||||||
Arm description |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Posaconazole
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Investigational medicinal product code |
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Other name |
MK-5592, Noxafil®
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole.
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Investigational medicinal product name |
Calogen®
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral emulsion
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Routes of administration |
Oral use
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Dosage and administration details |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole.
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Baseline characteristics reporting groups
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Reporting group title |
Cystic Fibrosis Participants
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Reporting group description |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Non-cystic Fibrosis Participants
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Reporting group description |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cystic Fibrosis Participants
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Reporting group description |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole. | ||
Reporting group title |
Non-cystic Fibrosis Participants
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Reporting group description |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole. |
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End point title |
Time to Reach 90% of the Steady State Serum Concentration of Posaconazole [1] | ||||||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
Four hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The data did not permit estimation of the endpoint from the modeling proposed in the protocol |
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Notes [2] - The data did not permit estimation of the endpoint from the modeling proposed in the protocol [3] - The data did not permit estimation of the endpoint from the modeling proposed in the protocol |
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No statistical analyses for this end point |
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End point title |
Concentration of Posaconazole in Bronchoalveolar Lavage (BAL) and Serum [4] | ||||||||||||||||||
End point description |
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. Spearman rank correlation coefficients between BAL and serum posaconazole concentrations were 0.53 (P-value 0.139) for cystic fibrosis participants and 0.057 (P-value 0.59) for non-cystic fibrosis participants.
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End point type |
Primary
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End point timeframe |
Up to Day 42
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Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No between-group statistical analyses were planned for this endpoint |
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Notes [5] - The 5 participants had a total of 9 paired BAL and serum samples for analysis [6] - The 7 participants had a total of 11 paired BAL and serum samples for analysis |
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No statistical analyses for this end point |
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End point title |
Percentage of Participants Who Develop Invasive Fungal Infection | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Up to Day 84
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No statistical analyses for this end point |
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End point title |
Time to Reach a Serum Concentration of Posaconazole of >=0.5 mg/L | ||||||||||||
End point description |
Blood samples for measurement of serum concentration of 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.
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End point type |
Secondary
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End point timeframe |
Four hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43
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Notes [7] - Participants who reached and maintained a posaconazole concentration >=0.5 mg/L [8] - Participants who reached and maintained a posaconazole concentration >=0.5 mg/L |
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No statistical analyses for this end point |
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End point title |
Maximum Serum Concentration of Posaconazole (Cmax) | ||||||||||||
End point description |
Blood samples for measurement of serum concentration of 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.
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End point type |
Secondary
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End point timeframe |
Four hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43
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No statistical analyses for this end point |
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End point title |
Time to Maximum Serum Concentration of Posaconazole (Tmax) | ||||||||||||
End point description |
Blood samples for measurement of serum concentration of 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.
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End point type |
Secondary
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End point timeframe |
Four hours after the first daily dose on Days 1-12 and every Monday and Thursday on Days 13-43
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Up to Day 88
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
Cystic Fibrosis Participants
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Reporting group description |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Non-cystic Fibrosis Participants
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Reporting group description |
Posaconazole 400 mg oral solution twice daily administered with Calogen® 30 mL oral emulsion (administered before the posaconazole 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 and Calogen® 15 mL if the participant was unable to meet the conditions for optimal absorption of posaconazole. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||||||
Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
None reported |