A Pharmacokinetic Study of JK1211(Itraconazole [Itrizole]) Oral Solution in Participants With Deep Mycosis and Those With Febrile Neutropenia Suspected of Fungal Infection

A Pharmacokinetic Study of JK1211 in Patients With Systemic Fungal Infection (SFI) and Patients With Febrile Neutropenia (FN) Suspected of Fungal Infection.

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00784368

Enrollment

Registered

2008-11-03

Start date

2008-01-31

Completion date

2009-05-31

Last updated

2013-07-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Aspergillosis, Blastomycosis, Candidiasis, Cryptococcosis, Histoplasmosis, Mycoses, Neutropenia

Keywords

Mycoses, Candidiasis, Aspergillosis, Cryptococcosis, Blastomycosis, Histoplasmosis, Neutropenia, Itraconazole, JK1211

Brief summary

The purpose of this study is to assess the pharmacokinetics (how the drug is absorbed in the body, distributed within the body, and how it is removed from the body over time) of itraconazole (ITCZ) oral solution in participants with Systemic Fungal Infection (SFI) and those with febrile (with fever) neutropenia (FN, decrease in white blood cells) suspected of fungal infection.

Detailed description

This is an open-label (all people know the identity of the intervention), multicenter (conducted in more than 1 center) and uncontrolled (no competitive drugs involved) study. Participants with SFI will receive treatment with ITCZ oral solution or switch treatment from intravenous (into a vein) infusion of itraconazole (ITCZ-intravenous) to ITCZ oral solution as per Investigator's discretion. All the participants with FN suspected of fungal infection will receive the switch treatment from ITCZ- intravenous to ITCZ oral solution. The study will include 3 periods: Pre-observation period (7 days), Treatment period (85 days for ITCZ oral solution monotherapy and 99 days for switch treatment) and Follow-up observation period (30 days). The participants who receive ITCZ oral solution monotherapy will receive ITCZ oral solution without ITCZ-intravenous in the dose range of 20 milliliter (ml) per day to 40 ml per day for 12 weeks (85 days) and those on the switch treatment will receive 400 milligram (mg) per day ITCZ-intravenous twice for first 2 days followed by 200 mg per day ITCZ-intravenous up to 14 days and then they will be administered treatment as per ITCZ oral solution monotherapy. Efficacy will primarily be evaluated by assessing the pharmacokinetics. Participants' safety will be monitored throughout the study.

Interventions

DRUGITCZ Oral Solution

ITCZ syrup product containing ITCZ 10 mg per ml in dose range of 20 ml to 40 ml daily for 7 days up to 12 weeks

DRUGITCZ-IV

200 mg IV twice daily for 2 days and once daily for the next 1 to 12 days

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 79 Years

Healthy volunteers

Inclusion criteria

* In case of participants with deep-seated mycosis (systemic fungal infection \[SFI\]) they should be either clinically suspected case or proven case * All participants administered need to be hospitalized during the itraconazole intravenous treatment * For participants with febrile (with fever) neutropenia (a decrease in white blood cells) suspected of fungal infection who have persistent fever (greater than equal to 37.5 degree celsius; greater than equal to 3 days) and have neutrophil count less than 500 per cubic millimeter (or less than 1000 per cubic millimeter and expected to decrease toward less than 500 per cubic millimeter

Exclusion criteria

* No past history of hypersensitivity to azole antifungal agents * No current medication with antifungal agents such as amphotericin B (intravenous injection \[injection of a substance into a vein\], tablets, syrup), nystatin (tablets), fluconazole (capsules, intravenous injection), flucytosine (oral agent), miconazole (intravenous injection, gel), micafungin (intravenous infusion), fosfluconazole (intravenous injection,) voriconazole (intravenous injection, tablets), liposomal amphotericin B (intravenous injection), posaconazole * No medication with itraconazole in any formulation within the last 28 days * Participants with history of severe hepatic disease (except hepatic dysfunction because of fungal infection) and congestive heart failure * Female participants who are either pregnant, nursing, suspected to be pregnant or will become pregnant during the trial duration

Design outcomes

Primary

Measure	Time frame	Description
Maximum Plasma Itraconazole Concentration (Cmax)	Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment	The Cmax is defined as the maximum observed analyte concentration. Cmax was measured in microgram per milliliter (mcg/ml).
Area Under the Curve From Time Zero to 24 Hours Post-dose Observed Plasma Itraconazole Concentration (AUC[0-24])	Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment	The AUC(0-24) is area under the plasma concentration time curve from time zero (pre-dose) to 24 hours post-dose. It is usually calculated by linear trapezoidal method. AUC was measured in mcg\*hour(hr) per ml.
Minimum Inhibitory Concentration (MIC)	Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment	The MIC is the lowest concentration of an antimicrobial that inhibits the visible growth of a microorganism after incubation.
Maximum Plasma Drug Concentration by Minimum Inhibitory Concentration (Cmax/MIC)	Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment	The Cmax is maximum observed analyte concentration and MIC is the lowest concentration of an antimicrobial that inhibits the visible growth of a microorganism after incubation. The Cmax/MIC was calculated only in participants for whom the MIC was obtained.
Area Under the Curve During 24 Hours by Minimum Inhibitory Concentration (AUC 0-24/MIC)	Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment	The AUC (0-24) is defined as area under the plasma concentration-time curve over the dosing interval (24 hr). It is usually calculated by linear trapezoidal method. MIC is the lowest concentration of an antimicrobial that inhibits the visible growth of a microorganism after incubation. The AUC 0-24/MIC was calculated only in participants for whom the MIC was obtained.
Time Above Minimum Inhibitory Concentration (T>MIC)	Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment	The T\>MIC was calculated only in participants for whom the MIC was obtained.

Secondary

Measure	Time frame	Description
Number of Participants With Serological Effect Against Fungi by Centralized Assessment	Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI and FN Switched treatment)	Serological effect against fungi was assessed as changed to negative (if the test values became negative), improved (if the test values decreased), no change (if there was no change in the test values), no change (if there was no change in the test values) , worsened (if the test values increased) and could not be assessed (if it was difficult to make the above-noted assessments due to a reason such as a lack of detection in the tests before and after dosing).
Number of Participants With Serologic Effect Against Fungi by Diagnosis Name (Centralized Assessment)	Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI Switched treatment)	Serological effect against fungi was assessed as changed to negative (if the test values became negative), improved (if the test values decreased), no change (if there was no change in the test values), worsened (if the test values increased) and could not be assessed (if it was difficult to make above-noted assessments due to a reason such as a lack of detection in the tests before and after dosing). The cases evaluated were candidemia, esophageal candidiasis, invasive aspergillosis, C.N.P.A, P.A. and P.C.
Number of Participants With Change in Clinical Symptoms by Centralized Assessment	Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI and FN Switched treatment)	Level of improvement in the clinical symptoms was assessed as: disappeared (if clinical symptoms disappeared), improved (significant improvement in clinical symptoms ), no change (almost no improvement in the clinical symptoms), worsened (if the clinical symptoms worsened) and could not be assessed (if it was difficult to make the above-noted assessments).
Number of Participants With Change in the Endoscopy or Image Diagnosis by Diagnosis Name (Centralized Assessment)	Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI Switched treatment)	Level of Improvement in Endoscopy was assessed as disappeared, decreased, improved, no change, worsened and could not be assessed. The cases evaluated were candidemia, esophageal candidiasis, invasive aspergillosis, C.N.P.A, P.A. and P.C.
Number of Participants With Change In the Endoscopy or Image Diagnosis By Centralized Assessment	Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI and FN Switched treatment)	Level of Improvement in the Endoscopy or Image diagnosis was assessed as disappeared (if the abnormal findings were normalized), decreased (if level of pathogenic fungus was decreased in culture), improved (if significant improvement was observed in the abnormal findings), no change (if no significant improvement was observed in the abnormal findings), worsened (if the abnormal findings were worsened) and could not be assessed (if it was difficult to make the above-noted assessments due to a reason such as a lack of detection in the tests before and after dosing).
Number of Participants With Change in Clinical Symptoms by Diagnosis Name (Centralized Assessment)	Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI Switched treatment)	Level of improvement in the clinical symptoms was assessed as: disappeared (if clinical symptoms disappeared), improved (significant improvement in clinical symptoms ), no change (almost no improvement in the clinical symptoms), worsened (if the clinical symptoms worsened) and could not be assessed (if it was difficult to make the above-noted assessments). The cases evaluated were candidemia, esophageal candidiasis, invasive aspergillosis, chronic necrotic pulmonary aspergillosis (C.N.P.A), pulmonary aspergilloma (P.A.) and pulmonary cryptococcosis (P.C).
Percentage of Participants With Overall Response by Centralized Assessment	Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI and FN Switched treatment)	Efficacy rate (E.R.) was calculated as number of cases for whom treatment was judged to be effective divided by sum of number of cases for whom treatment was judged to be effective and cases for whom treatment was judged to be ineffective multiplied by 100. Treatment success rate (T.S.R.) was calculated as number of cases for whom treatment was judged to be effective divided by sum of number of cases for whom treatment was judged to be effective, cases for whom treatment was judged to be ineffective and cases for whom the efficacy could not be assessed multiplied by 100.
Percentage of Participants With Overall Response by Diagnosis Name (Centralized Assessment)	Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI Switched treatment)	E.R. was calculated as number of cases for whom treatment was judged to be effective divided by sum of number of cases for whom treatment was judged to be effective and number of cases for whom treatment was judged to be ineffective multiplied by 100. T.S.R. was calculated as number of cases for whom treatment was judged to be effective divided by sum of number of cases for whom treatment was judged to be effective, number of cases for whom treatment was judged to be ineffective and number of cases for whom the efficacy could not be assessed multiplied by 100.
Number of Participants With Mycological Efficacy by Centralized Assessment	Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI and FN Switched treatment)	Mycological efficacy was assessed as disappeared (if results for pathogenic fungus became negative, or if it was not possible to obtain the appropriate specimens), decreased (if level of pathogenic fungus was decreased in culture), no change (if there was no quantitative change in pathogenic fungus), increased (if there was a quantitative increase in pathogenic fungus, if results for pathogenic fungus became positive after start of dosing or if new pathogenic fungus was identified) , could not be assessed (if it was difficult to make the above assessment due to lack of detection in tests).
Number of Participants With Mycological Efficacy by Diagnosis Name (Centralized Assessment)	Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI Switched treatment)	Mycological efficacy was assessed as disappeared, decreased, no change, increased, could not be assessed. The cases evaluated were candidemia, esophageal candidiasis, invasive aspergillosis, C.N.P.A, P.A. and P.C.

Countries

Japan

Participant flow

Participants by arm

Arm	Count
SFI (ITCZ Oral Solution Monotherapy) Participants with deep-seated mycosis (Systemic Fungal Infection \[SFI\]) received itraconazole (ITCZ) oral solution in the dose range of 20 milliliter (ml) per day to 40 ml per day for 12 weeks as per Investigator's discretion.	15
SFI (Switched Treatment) Participants with SFI received 200 milligram (mg) twice daily itraconazole intravenous infusion (ITCZ-IV) for first 2 days followed by 200 mg per day ITCZ-IV up to 14 days. Participants then received ITCZ oral solution in the dose range of 20 ml per day to 40 ml per day for 12 weeks as per Investigator's discretion.	16
FN (Switched Treatment) Participants with febrile neutropenia (FN) with suspected fungal infection received 200 mg twice daily ITCZ-IV for first 2 days followed by 200 mg per day ITCZ-IV up to 14 days. Participants then received ITCZ oral solution in the dose range of 20 ml per day to 40 ml per day for 12 weeks as per Investigator's discretion.	22
Total	53

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	6	9	2
Overall Study	Diagnosis of fever	0	0	1
Overall Study	Lack of Efficacy	2	0	1
Overall Study	Physician Decision	0	0	6
Overall Study	Withdrawal of informed consent	0	1	0
Overall Study	Worsening of complications	0	0	1
Overall Study	Worsening of symptoms	0	1	0

Baseline characteristics

Characteristic	SFI (ITCZ Oral Solution Monotherapy)	SFI (Switched Treatment)	FN (Switched Treatment)	Total
Age Continuous	61.7 years STANDARD_DEVIATION 13.6	64.2 years STANDARD_DEVIATION 12	58.3 years STANDARD_DEVIATION 12.7	61.1 years STANDARD_DEVIATION 12.8
Sex: Female, Male Female	1 Participants	6 Participants	7 Participants	14 Participants
Sex: Female, Male Male	14 Participants	10 Participants	15 Participants	39 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	15 / 16	16 / 16	22 / 23
serious Total, serious adverse events	4 / 16	8 / 16	3 / 23

Outcome results

Primary

Area Under the Curve During 24 Hours by Minimum Inhibitory Concentration (AUC 0-24/MIC)

The AUC (0-24) is defined as area under the plasma concentration-time curve over the dosing interval (24 hr). It is usually calculated by linear trapezoidal method. MIC is the lowest concentration of an antimicrobial that inhibits the visible growth of a microorganism after incubation. The AUC 0-24/MIC was calculated only in participants for whom the MIC was obtained.