SUBA-Itraconazole Therapy for Coccidioidomycosis Refractory or Intolerant to Fluconazole (SITRIS)

The purpose of this study is to determine how safe, effective, and well tolerated a new investigational antifungal drug, SUBA-itraconazole, is for patients who have been previously treated with fluconazole and have had either an insufficient response to treatment with fluconazole or a negative reaction to fluconazole preventing their further treatment with it.

Study Overview

• Status: Withdrawn
• Conditions: Coccidioidomycosis; Valley Fever
• Intervention / Treatment: Drug: SUBA-itraconazole

Detailed Description

This is a prospective, multi-center, open-label study involving subjects with proven or probable coccidioidomycosis refractory to fluconazole therapy following >40 days of treatment or subjects with proven or probable coccidioidomycosis who are intolerant to fluconazole.

The availability "Super Bioavailability" (SUBA) itraconazole 65 mg capsules with twice-daily dosing options with improved pharmacokinetics and lack of food or acidity requirements offers a substantial opportunity to improve the treatment of subjects with coccidioidomycosis.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • University of California, Davis Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. All subjects ≥ 18 years who have given written informed consent to participate

2. Subjects with a proven or probable coccidioidomycosis according to current European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria, including subjects who:

   • Are immunosuppressed, including as a result of HIV/AIDS
   • Have had a heart, lung or bone marrow transplant
   • Have had chemotherapy for cancer
   • Are otherwise not immunocompromised

   Note: central nervous system (CNS) infection is an exclusionary criteria

3. Refractory for ≥ 40 days, or intolerant to fluconazole treatment for coccidioidomycosis in the opinion of the investigator

   • Refractory disease defined as failure to obtain an adequate therapeutic response after ≥40 days of therapy:
   • Lack of improvement in signs, symptoms or imaging findings OR
   • Continued isolate of Coccidioides or histopathologic findings of • Coccidioides despite antifungal therapy
   • Rising Complement Fixation Titers
   • Progression of disease (requires worsening of attributable signs, symptoms or imaging, or a new site of infection
   • Intolerance defined as adverse events attributable to fluconazole therapy defined as organ toxicity of grade 3 or higher, nephrotoxicity (Creatinine twice the upper limit of normal), or idiosyncratic reactions therapy that in the opinion of the investigator may be relieved by a therapeutic change OR refusal of the patient to take further fluconazole

4. Subjects of childbearing potential should be non-pregnant and not breastfeeding (and not planning to become pregnant)

   • Postmenopausal for ≥1 year
   • Post-hysterectomy or bilateral oophorectomy
   • If of child-bearing potential have a negative pregnancy test at screening and using an acceptable effective method of birth control throughout course of study or remain abstinent for duration of study. Subjects with a partner of childbearing potential should agree to use appropriate contraception.

Exclusion Criteria:

1. Significant liver dysfunction as evidenced by total bilirubin > 1.5 × the upper limit of normal (ULN) range unless considered due to Gilbert syndrome, in which case > 3 × the ULN, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels > 1.5 x the ULN.
2. Evidence of CNS infection.
3. Unable to take PO medications.
4. Documented intolerance, allergy or hypersensitivity to itraconazole.
5. Inability to comply with study treatment, study visits, and study procedures.
6. Known history or presence of congestive cardiac failure, fungal endocarditis, or other causes of ventricular dysfunction that may outweigh the benefit of itraconazole.
7. Subjects with active tuberculosis.

8. Concurrent use of drugs that effect SUBA™-itraconazole concentrations

   • Subjects who washout from prohibited medications can be included

9. Any known or suspected condition of the subject that may jeopardize adherence to the protocol requirements or impede the accurate measurement of efficacy.
10. Treatment with any investigational agent in the 30 days prior to study entry.
11. Subjects unlikely to survive 30 days based on the opinion of the investigator.
12. Subjects with body weight < 40 kg.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SUBA-itraconazole; Drug: SUBA-itraconazole Dosage Form: 65 mg capsules Dosage: 260 mg/day Frequency: 130 mg twice daily (BID) Duration: Up to 180 days	Drug: SUBA-itraconazole; Participant will receive treatment with SUBA-itraconazole; Other Names: Tolsura

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1. The Proportion of Participants Who Achieve Clinical Improvement, in All Participants Who Took at Least One Dose of Study Drug	Clinical Improvement is defined as at a) at least a 50% reduction in coccidioidomycosis Mycoses Study Group (MSG Score) from baseline value, or b) the unequivocal documentation of clinical improvement as recorded on the progress note of the medical provider, or c) a 25%-49% decrease in the MSG score from baseline value and a physician's impression of improvement as recorded on the progress note. The MSG score is a composite scoring system that has been used in numerous past studies of coccidioidomycosis. This system comprises the sum of points assigned based on the findings of: (1) clinical assessments, (2) radiographic imaging, and (3) serologic assays, with a lower score indicating better health.	180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Treatment-Emergent Adverse Events	Treatment-emergent adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state. Severity grading will be based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. This is a descriptive scoring system which can be used for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term as follows: Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death related to AE.	180 days
Number of Participants with Abnormal Laboratory Evaluations of Safety	Abnormal is defined as at least a 1 grade shift from baseline. Severity grading will be based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. This is a descriptive scoring system which can be used for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term as follows: Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death related to AE.	180 days
Number of Participant Discontinuations of Therapy Due to Treatment-Emergent Adverse Events and/or Laboratory Evaluations of Safety	Number of Participant Discontinuations of Therapy Due to Treatment-Emergent Adverse Events and/or Laboratory Evaluations of Safety	180 days
Number of Participants with Any Interruptions of Therapy due to Treatment-Emergent Adverse Events and/or Abnormal Laboratory Evaluations of Safety	Number of Participants with Any Interruptions of Therapy due to Treatment-Emergent Adverse Events and/or Abnormal Laboratory Evaluations of Safety	180 days
Number of Participants with Interruptions of Therapy 7 Days or More in Duration due to Treatment-Emergent Adverse Events and/or Abnormal Laboratory Evaluations of Safety	Number of Participants with Interruptions of Therapy 7 Days or More in Duration due to Treatment-Emergent Adverse Events and/or Abnormal Laboratory Evaluations of Safety	180 days
Mean, Median, and Quartile Score Values for Mental Component Summary and Physical Component Summary Scores of the SF-12v2 Survey	The Short Form 12 Question Health Survey, version 2 (SF-12v2) is a 12-question multipurpose survey instrument derived from the larger, Short Form 36 Question Survey. The SF-12v2 is to help determine the participant's overall state of wellbeing and health-related quality of life by means of assessing both physical and mental status at the time of the survey. The 8 domains of the survey are: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role- emotional (RE), and mental health (MH). Mental and physical composite scores (MCS & PCS) are computed using the scores of twelve questions. MCS and PCS values can range from 0 to 100, where a higher score indicates better health.	42 days
Mean, Median, and Quartile Score Values for Mental Component Summary and Physical Component Summary Scores of the SF-12v2 Survey	The Short Form 12 Question Health Survey, version 2 (SF-12v2) is a 12-question multipurpose survey instrument derived from the larger, Short Form 36 Question Survey. The SF-12v2 is to help determine the participant's overall state of wellbeing and health-related quality of life by means of assessing both physical and mental status at the time of the survey. The 8 domains of the survey are: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role- emotional (RE), and mental health (MH). Mental and physical composite scores (MCS & PCS) are computed using the scores of twelve questions. MCS and PCS values can range from 0 to 100, where a higher score indicates better health.	180 days

Collaborators and Investigators

• Sponsor: George R Thompson
• Collaborators: Mayne Pharma International Pty Ltd
• Investigators: Principal Investigator: George R Thompson, MD, University of California, Davis

Study record dates

Study Major Dates

• Study Start (Anticipated): May 15, 2021
• Primary Completion (Anticipated): September 1, 2022
• Study Completion (Anticipated): September 1, 2022

Study Registration Dates

• First Submitted: March 1, 2021
• First Submitted That Met QC Criteria: March 18, 2021
• First Posted (Actual): March 22, 2021

Study Record Updates

• Last Update Posted (Actual): July 19, 2021
• Last Update Submitted That Met QC Criteria: July 13, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Parasitic Diseases; Protozoan Infections; Mycoses; Coccidioidomycosis; Coccidiosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole
• Other Study ID Numbers: 1666482

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No