| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of Candidemia and other invasive Candida infections |
|
| E.1.1.1 | Medical condition in easily understood language |
| Infection caused by fungus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060573 |
| E.1.2 | Term | Candidemia |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective:
- To compare safety and efficacy of treatment with isavuconazole (ISA) versus a caspofungin (CAS) → voriconazole (VRC) regimen in patients with candidemia or other invasive Candida infections.
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
- To compare the effects of treatment on:
- Time to first negative blood culture
- All-cause Mortality at day 14, End of Treatment (EOT) and all Follow Up visits. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
At selected sites with appropriate facilities and equipment, the PK of isavuconazole (BAL4815) and cleavage product (BAL8728) will be evaluated in patients randomized to ISA.
Seven plasma samples including approximately 25 patients aged < 42 years and 25 patients aged > 65 years will be collected on Day 7 or preferably Day 14 for PK profiling. Day 7 or 14 is chosen to obtain PK profiling during either IV or oral treatments based upon the attainment of steady state. |
|
| E.3 | Principal inclusion criteria |
1. Patients and/or legally authorized representative(s), if applicable,
who have been fully informed and have given voluntary written informed consent OR patients unable to write and/or read but who fully understand the oral information given by the Investigator (or nominated representative)who have given oral informed consent witnessed in writing by an independent person. HIPAA authorization for US sites or equivalent privacy language as per national regulations must be obtained.
2. Ability and willingness to comply with the protocol
3. Male and female patients aged ≥ 18 years at the time of signing
informed consent.
4. Female patients must be non-lactating and at no risk of pregnancy for one of the following reasons
- Postmenopausal (amenorrhea for at least 1 year)
- Post-hysterectomy and/or post-bilateral ovariectomy
- If of childbearing potential, having a negative serum or urine human chroonic gonadotrophin (hCG) pregnancy test at screening and is using a highly effective method of birth control throughout the study. Reliable sexual abstinence throughout the course of the study is acceptable as a highly effective method of birth control for the purposes of this study.
5. Patients with candidemia or with an invasive candida infection who have a positive blood or tissue culture obtained within 96 hours prior to randomization, accompanied by related clinical signs and symptoms or histological or cytological changes. Final culture results may still be pending at randomization if histology/cytology reveals yeast.
6. Presence of fever (on one occasion > 38°C oral, or equivalent) or hypothermia (on one occasion <36°C oral, or equivalent) or hypotension (SBP < 100 mmHg or a decrease in SBP of at least 30 mmHg) or appropriate local signs within 96 hours prior to randomization. |
|
| E.4 | Principal exclusion criteria |
1. Women who are pregnant or breastfeeding
2. Known history of allergy, hypersensitivity, or any serious reaction to any of the azole or echinocandin class of antifungal or to any component of the study medication.
3. Patients for whom CAS or VRC is contra-indicated.
4. Patients at high risk for QT/QTc prolongation e.g.
a. Baseline prolongation of QTcF >/= 500 msec
b. Risk factors for Torsade de Pointes (e.g. uncompensated heart failure, abnormal potassium or magnesium levels that cannot be corrected, any unstable cardiac condition during the last 30 days, or a family history of long QT syndrome);
c. The use of concomitant medications that prolong the QT/QTc interval
5. Patients with evidence of persistent moderate to severe hepatic or renal dysfunction with any of the following abnormalities at the time of randomization (may be rechecked using local laboratory):
- Total bilirubin ≥ 3 x upper limit of normal (ULN) OR
- Alanine transaminase or aspartate transaminase ≥ 5 x ULN OR
Patients with known cirrhosis or chronic liver failure OR
- Calculated creatinine clearance < 10 mL/minute OR
- Currently on dialysis or likely to require dialysis during adminstration of study medication.
6. Concomitant use of sirolimus, efavirenz, ritonavir, astemizole,
cisapride, rifampicin/rifampin, rifabutin, ergot alkaloids, long acting barbiturates, carbamazepine, pimozide, quinidine, neostigmine, ketoconazole, valproic acid, St. John's Wort, or terfenadine in the 5 days prior to first administration of study medication.
7. Patients with a sole diagnosis of mucocutaneous candidiasis, i.e.
oropharyngeal, esophageal or genital candidiasis; or candidal lower
urinary tract infection or Candida isolated solely from respiratory tract specimens.
8. Patients with candidemia who failed a previous antifungal therapy for the same infection.
9. Patients with any invasive fungal infection other than candida spp., e.g., cryptococcosis, mould infection or endemic fungal infection.
10. Microbiological (e.g. bacterial infections) findings or other potential conditions that
are temporally related and suggest an alternative etiology of the clinical features in the absence of culture/histology/cytology evidence of systemic Candida infection.
11. Patients who have received systemic antifungal therapy for more than 48 hours within 96 hours prior to the first administration of study medication.
12. Severe prolonged immunosuppression (e.g. chronic granulomatous disease, severe combined immunodeficiency, advanced human immunodeficiency virus infection with CD4 count < 200 or acquired immunodeficiency syndrome-defining condition, severe graft versus host disease [grade III-IV associated with e.g., failure of initial treatment, increased liver enzymes or hypoalbuminaemia]), or any other concomitant medical condition that may impede the accurate assessment of efficacy of study drug treatment.
13. Any known or suspected condition of the patient that may jeopardize adherence to the protocol requirements such as patients with fungal endocarditis, fungal osteomyelitis, fungal meningitis, or with life expectancy of < 30 days.
14. Patients with a concomitant medical condition that, in the opinion of the investigator, may be an unacceptable additional risk to the patient should he/she participates in the study.
15. Patients previously enrolled in a phase III study with isavuconazole.
16. Treatment with any investigational drug in any clinical trial within 30 days prior to the first administration of study medication except for open label trials.
17. Patients with a body weight < 40kg. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response at follow-up 1 (FU1) visit (2 weeks after EOT). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Outcome Measures:
•Overall response [ Time Frame: 2 weeks after last study dose ]
Resolution of signs and symptoms of infection plus mycological
(presumed) eradication |
|
| E.5.2 | Secondary end point(s) |
•Overall response assessment
•Mycological response
•Clinical response
•Time to first confirmed negative culture
•All-cause mortality |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Overall response assessment [ Time Frame: Day 7, end of treatment (up to Day 56), 6 weeks after last study drug ]
•Mycological response [ Time Frame: Day 7, end of treatment (up to Day 56), 2 weeks after last study drug, 6 weeks after last study drug ]
•Clinical response [ Time Frame: Day 7, end of treatment (up to Day 56),
2 weeks after last study drug, 6 weeks after last study drug ]
•Time to first confirmed negative culture [ Time Frame: Up to 2 weeks after last study drug ] [ Designated as safety issue: No ]
•All-cause mortality [ Time Frame: Day 14, end of treatment (up to Day 56), 2 weeks after last study drug, 6 weeks after last study drug ] |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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