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

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Drug: ITCZ Oral Solution
* Drug: ITCZ-IV


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SFI (ITCZ Oral Solution Monotherapy)<br>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. | Drug: ITCZ Oral Solution<br>* 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<br>* Other names: Itrizole Oral Solution 1%, JK1211;|
| Experimental: SFI (Switched Treatment)<br>Participants with SFI received 200 milligram (mg) twice daily itraconazole intravenous (into the vein) 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. | Drug: ITCZ Oral Solution<br>* 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<br>* Other names: Itrizole Oral Solution 1%, JK1211;Drug: ITCZ-IV<br>* 200 mg IV twice daily for 2 days and once daily for the next 1 to 12 days<br>|
| Experimental: FN (Switched treatment)<br>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. | Drug: ITCZ Oral Solution<br>* 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<br>* Other names: Itrizole Oral Solution 1%, JK1211;Drug: ITCZ-IV<br>* 200 mg IV twice daily for 2 days and once daily for the next 1 to 12 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Itraconazole Concentration (Cmax) | The Cmax is defined as the maximum observed analyte concentration. Cmax was measured in microgram per milliliter (mcg/ml). | Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment | 
| Area Under the Curve From Time Zero to 24 Hours Post-dose Observed Plasma Itraconazole Concentration (AUC[0-24]) | 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. | Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment | 
| Minimum Inhibitory Concentration (MIC) | The MIC is the lowest concentration of an antimicrobial that inhibits the visible growth of a microorganism after incubation. | Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment | 
| Maximum Plasma Drug Concentration by Minimum Inhibitory Concentration (Cmax/MIC) | 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. | Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment | 
| 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. | Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment | 
| Time Above Minimum Inhibitory Concentration (T>MIC) | The T>MIC was calculated only in participants for whom the MIC was obtained. | Day 85 for SFI (ITCZ Oral Solution Monotherapy); and Day 99 for SFI and FN Switched treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Change in Clinical Symptoms by Centralized Assessment | 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). | Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI and FN Switched treatment) | 
| Number of Participants With Change in Clinical Symptoms by Diagnosis Name (Centralized Assessment) | 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). | Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI Switched treatment) | 
| Percentage of Participants With Overall Response by Centralized Assessment | 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. | Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI and FN Switched treatment) | 
| Percentage of Participants With Overall Response by Diagnosis Name (Centralized Assessment) | 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. | Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI Switched treatment) | 
| Number of Participants With Mycological Efficacy by Centralized Assessment | 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). | Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI and FN Switched treatment) | 
| Number of Participants With Mycological Efficacy by Diagnosis Name (Centralized Assessment) | 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. | Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI Switched treatment) | 
| Number of Participants With Serological Effect Against Fungi by Centralized Assessment | 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). | Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI and FN Switched treatment) | 
| Number of Participants With Serologic Effect Against Fungi by Diagnosis Name (Centralized Assessment) | 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. | Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI Switched treatment) | 
| Number of Participants With Change In the Endoscopy or Image Diagnosis By Centralized Assessment | 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). | Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI and FN Switched treatment) | 
| Number of Participants With Change in the Endoscopy or Image Diagnosis by Diagnosis Name (Centralized Assessment) | 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. | Baseline up to end of treatment (Day 85 for SFI [ITCZ Oral Solution Monotherapy] and Day 99 for SFI Switched treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mycoses, Candidiasis, Aspergillosis, Cryptococcosis, Blastomycosis, Histoplasmosis, Neutropenia, Itraconazole, JK1211