Chronic Pulmonary Aspergillosis MedDRA version: 20.0 Level: LLT Classification code 10003488 Term: Aspergillosis System Organ Class: 100000154164 MedDRA version: 20.0 Level: LLT Classification code 10003493 Term: Aspergillus fumigatus bronchopulmonary infection System Organ Class: 100000015649 MedDRA version: 20.0 Level: LLT Classification code 10003494 Term: Aspergillus fumigatus infection System Organ Class: 100000154164 MedDRA version: 20.0 Level: PT Classification code 10006473 Term:
Conditions
Interventions
Trade Name: Cresemba 100 mg hard capsules
Product Name: Cresemba 100 mg hard capsules
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Isavuconazole
CAS Number: 946075-13-4
Other descriptive na
Sponsors
University Hospital of South Manchester NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Participants must be willing to give written informed consent and be able to adhere to dosing, study visit schedules, and study procedures 2.Male or female aged 18 years or older 3.Participants must have been diagnosed with CPA for whom treatment with azoles is indicated. Diagnosis of CPA must fulfil the following criteria: i.Radiological evidence on chest CT scan; all or some evidence of cavities, fibrosis, nodules or aspergillomas (see exclusions below) AND ii.Clinical symptoms consistent with CPA, must include respiratory AND/OR systemic symptoms present for at least 3 months, e.g presence of at least one of the symptoms of significant cough, haemoptysis, weight loss, malaise, sweating and anorexia. Symptoms must be sufficiently severe to have a SGRQ score of at least 50 on screening AND Absence of alternative diagnosis accounting for the findings AND iii.Microbiological and/or serological evidence of Aspergillus infection a.Positive Aspergillus precipitins or Aspergillus IgG (>40mg/L) AND/OR b.Two positive respiratory cultures for Aspergillus (sputum or BAL) 4.Participants must have not received antifungals for treatment of CPA in the last 6 months, and not for longer than 3 months. 5.Sexually active female participants of childbearing age must agree to maintain highly effective contraception during the study and for 3 months thereafter. Female participants of childbearing age must have a negative pregnancy test at screening and each visit. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 15 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 5
Exclusion criteria
Exclusion criteria: 1.Concomitant active tuberculosis or non-tuberculosis mycobacterium infection (NTM). For patients with previously treated NTM, a negative mycobacterial culture at least 12 months before recruitment is required. 2.Immune compromise HIV such as infection with a CD4 count 10mg of prednisolone for more than 4 weeks. 3.Patients with ‘destroyed lung’ (complete replacement of one lung by fibrosis on chest CT scan) 4.Patients with isolated ‘Aspergillus nodules’ without presence of cavities, pleural thickening or fibrosis 5.Patients with simple aspergilloma (radiologically stable, single aspergilloma in thin walled cavity) 6.Severe hepatic impairment (Child-Pugh class C) 7.Familial short QT syndrome (QTc interval <360ms) 8.Female participants who are or intend to become pregnant or are nursing, or who have a positive pregnancy test at screening 9.Evidence of isavuconazole resistance in any clinically significant isolate of Aspergillus cultured from sputum. 10.If evidence of Aspergillus niger is the only clinically significant isolate from sputum or BAL 11.Participants who may require treatment with other medications that cannot be stopped and for which there is a known contraindication to co-administration of Isavuconazole (see section 2 and Appendix II of protocol). 12.Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-lives of enrolment, whichever is longer 13.Participants who are members of the research team and their family members. 14.Known hypersensitivity to any of the components of the study drug or any of the triazoles. 15.Use of potent CYP3A4/5 inducers such as rifampicin, rifabutin, carbamazepine, long-acting barbiturates (e.g., phenobarbital), phenytoin and St. John's wort, or with moderate CYP3A4/5 inducers such as efavirenz, nafcillin and etravirine, are contraindicated, since these medicinal products can significantly decrease plasma concentrations of isavuconazole.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): A. Clinical and radiological evidence of response to treatment after 12 months of therapy, as assessed by response on chest CT scan and clinical response (assessed using the Saint George's Respiratory Questionnaire (SGRQ) and classified as improvement, stability and deterioration as follows: 1.Radiological response: a. improvement: >30% decrease in volume of fungus ball AND/OR 20% decrease in cavity wall thickening AND/OR 20% improvement in pleural thickening b.Radiological deterioration :>30% increase in volume of fungus ball AND/OR 20% increase in cavity wall thickening AND/OR 20% increase in pleural thickening. For patients with measurements fulfilling both a and b, will be classified as deteriorated. c.Radiological stability: all other outcomes. 2.Clinical response: a.Improvement: Decrease in SGRQ by =8 points b.Stability: Change in SGRQ between: increase by <4 to decrease by <8 c.Deterioration: Increase in SGRQ by =4 points B.Monitoring of clinical and biochemical evidence of toxicity throughout treatment period as assessed by: a.Biochemical indicators for liver and renal function tests by hepatic dysfunction (bilirubin =3 × upper limit of normal [ULN], alanine transaminase or aspartate transaminase =5 × ULN, cirrhosis or chronic hepatic failure), or moderate to severe renal dysfunction (calculated creatinine clearance <50 mL/min). b.Safety and tolerability of Isavuconazole assessed by evaluation of the frequency of adverse events, serious adverse reactions greater than grade 3 according to CTCAE version 4.03 criteria, the number of SUSARS and deaths among the participants on treatment at monthly intervals. An Interim primary endpoint analysis will be carried when 20 participants have completed 6 months of therapy to assess efficacy and safety of the study drug at 6 months. ;Timepoint(s) of evaluation of this end point: Patients will be evaluated for treatment at 6 month and 12 months. Those patients, who are coming off the | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): a.Response after 12 months of treatment b.Serological response (improvement in Aspergillus IgG by 20% or to 8 points at 6 and 12 months f.Proportion of patients showing deterioration SGRQ by >4 points at 6 and 12 months g.Weight gain or loss of >3Kg at 6 and 12 months h.Recurrence 6 months after therapy discontinuation, assessed by deterioration in SGRQ by =8 points. i.Positive respiratory culture for Aspergillus fumigatus with emergence of isavuconazole resistance ;Timepoint(s) of evaluation of this end point: The time points for evaluation of the secondary endpoints are as for primary enpoints at 6 and 12 months . | — |
Countries
United Kingdom
Contacts
Public ContactAzad Aziz
University Hosptial of South Manchester NHS Foundation Trust
Outcome results
None listed