Clinical trial NCT01075984: Pharmacokinetics, Safety, and Tolerability of Intravenous Posaconazole Solution Followed by Oral Posaconazole Suspension in Subjects at High Risk for Invasive Fungal Infections (P05520)
Official title: Pharmacokinetics, Safety, and Tolerability of Intravenous Posaconazole Solution Followed by Oral Posaconazole Suspension (SCH 56592) in Subjects at High Risk for Invasive Fungal Infections (Phase 1b; Protocol No. P05520)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Fungal Infection
Keywords: Antifungal Agents pharmacokinetics
Mycoses prevention and control
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2010-02-25
Enrollment: 279
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to collect pharmacokinetic (PK) information related to how well intravenous Posaconazole (POS IV), is distributed in the body and to determine the safety and tolerability of this new formulation. In addition, the PK, safety, and tolerability of switching from taking POS IV to taking Posaconazole Oral Suspension (POS Oral) will be evaluated. The data collected in this study will be compared to data collected in previous studies.

Individuals who have been diagnosed by their physicians with a blood disease or cancer that can affect their infection-fighting white blood cells will be asked to participate in the trial. Since these blood diseases and their treatments can weaken the immune system, they may put these individuals at a high risk for getting a serious fungal infection of their internal organs or blood (invasive fungal infection). As these fungal infections can be hard to detect early and can be life-threatening, many physicians believe that individuals diagnosed with these diseases should receive antifungal therapy to try to lower their risk of getting this type of infection.

Enrollment into this study will take place in several stages (cohorts). The determination of which cohort an individual will be asked to participate in is based on which cohort is open at the site at the time the individual is approached to consider study participation.


Eligibility criteria: Inclusion Criteria:

* Adult subjects greater than or equal to 18 years of age (weighing greater than 34 kg \[75 lb\]), of either sex and of any race/ethnicity.
* Disease definition for each subject: Anticipated (likely to develop within 3 days to 5 days) or documented prolonged neutropenia (absolute neutrophil count \[ANC\] \<500/mm\^3 \[0.5 x 10\^9/L\]) at Baseline and likely to last for at least 7 days due to:

  * a. Standard intensive chemotherapy, anthracycline-based or other accepted regimen (excluding any investigational agent), for a new diagnosis of acute myelogenous leukemia (AML);
  * b. Chemotherapy for AML in first relapse; or
  * c. Therapy for myelodysplastic syndromes in transformation to AML or other diagnoses of secondary AML (therapy related, antecedent hematological disorders) or chronic myelogenous leukemia in blast crisis
* Disease definition for each Cohort 3 subject: In addition to subjects defined above, allogeneic hematopoietic stem cell transplant (HSCT) subjects may be randomized in either the pre-engraftment period (i.e., after they have received their conditioning regimen for the transplant, but while they are still neutropenic) or in the post-engraftment period if they are receiving immunosuppressive therapy for prevention or treatment of graft-versus-host disease (e.g., steroids, tacrolimus, cyclosporin, mycophenolate mofetil, and antithymocyte globulin).

Exclusion Criteria:

* A female subject must not be pregnant, must not intend to become pregnant during the study, or must not be nursing.
* Excluded prior treatments. A subject must not have received systemic antifungal therapy (oral, intravenous, or inhaled) for the treatment of proven or probable IFI within 30 days of Enrollment.
* A subject must not have moderate or severe liver dysfunction at Baseline, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal (ULN), AND a total bilirubin level greater than two times the ULN. For Cohorts 1 and 2, a subject must not have a known or suspected history of Gilbert's disease.
* A subject must not have an electrocardiogram (ECG) with a prolonged QTc interval by manual reading: QTc greater than 500 msec.
* A subject must not have prior enrollment in this study, or other POS studies within 90 days of study entry.
* A subject must not have a known or suspected invasive or systemic fungal infection at Baseline. Those subjects receiving empiric anti-fungal therapy within 7 days prior to Baseline must have had a diagnostic work-up that ruled out a possible invasive fungal infection.
* A subject must not have creatinine clearance levels (measured or calculated) below 50 mL/min.
* A subject must not have a history of Type I hypersensitivity or idiosyncratic reactions to azole agents.

Primary outcomes:
measure: Single Dose Trough Concentration of IV Posaconazole (Cmin)
timeFrame: 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2)
measure: Steady State Trough Concentration of IV Posaconazole (Cmin)
timeFrame: 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
measure: Single Dose Maximum Concentration of IV Posaconazole (Cmax)
timeFrame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2)
measure: Steady State Maximum Concentration of IV Posaconazole (Cmax)
timeFrame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
measure: Single Dose Time of Observed Maximum Concentration of IV Posaconazole (Tmax)
timeFrame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0 and 1)
measure: Steady State Time of Observed Maximum Concentration of IV Posaconazole (Tmax)
timeFrame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
measure: Single Dose Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC)
timeFrame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 1 (Cohorts 0, 1 and 2)
measure: Steady State Area Under the Concentration Versus Time Curve of IV Posaconazole (AUC)
timeFrame: Predose and 1, 1.5, 1.75, 4, 8, 12, and 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
measure: Steady State Average Concentration of IV Posaconazole (Cavg)
timeFrame: Predose and 1, 1.5, 1.75, 4, 8, 12, and 24 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
measure: Steady State Total Body Clearance of IV Posaconazole (CL)
timeFrame: Predose and 1, 1.5, 1.75, 4, 8, and 12 hours after start of infusion on Day 14 (Cohorts 1 and 2), or Day 10 (Cohort 3)
measure: Steady State Trough Concentration of Oral Posaconazole (Cmin)
timeFrame: 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
measure: Steady State Maximum Concentration of Oral Posaconazole (Cmax)
timeFrame: Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
measure: Steady State Time of Observed Maximum Concentration of Oral Posaconazole (Tmax)
timeFrame: Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
measure: Steady State Area Under the Concentration Versus Time Curve of Oral Posaconazole (AUC)
timeFrame: Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
measure: Steady State Average Concentration of Oral Posaconazole (Cavg)
timeFrame: Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
measure: Steady State Apparent Total Body Clearance of Oral Posaconazole (CL/F)
timeFrame: Predose and 3, 5, 8 and 12 hours after dosing on Day 7 (Cohort 0), or Day 28 (Cohorts 1 and 2)
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
References:
citation: Maertens J, Cornely OA, Ullmann AJ, Heinz WJ, Krishna G, Patino H, Caceres M, Kartsonis N, Waskin H, Robertson MN. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease. Antimicrob Agents Chemother. 2014 Jul;58(7):3610-7. doi: 10.1128/AAC.02686-13. Epub 2014 Apr 14.
citation: Cornely OA, Robertson MN, Haider S, Grigg A, Geddes M, Aoun M, Heinz WJ, Raad I, Schanz U, Meyer RG, Hammond SP, Mullane KM, Ostermann H, Ullmann AJ, Zimmerli S, Van Iersel MLPS, Hepler DA, Waskin H, Kartsonis NA, Maertens J. Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease. J Antimicrob Chemother. 2017 Dec 1;72(12):3406-3413. doi: 10.1093/jac/dkx263.