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    Summary
    EudraCT Number:2016-003921-40
    Sponsor's Protocol Code Number:2016IF002
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-07-10
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-003921-40
    A.3Full title of the trial
    Open label study of the efficacy and safety of isavuconazole for the treatment of Chronic Pulmonary Aspergillosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Open label study of the efficacy and safety of isavuconazole for the treatment of Chronic Pulmonary Aspergillosis
    A.3.2Name or abbreviated title of the trial where available
    Isavuconazole for CPA
    A.4.1Sponsor's protocol code number2016IF002
    A.5.4Other Identifiers
    Name:EUdraCTNumber:2016-003921-40
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity Hospital of South Manchester NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hosptial of South Manchester NHS Foundation Trust
    B.5.2Functional name of contact pointAzad Aziz
    B.5.3 Address:
    B.5.3.1Street AddressR&D Directorate, NIHR Building, Southmoor Road
    B.5.3.2Town/ cityManchester
    B.5.3.3Post codeM23 9QZ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01612915774
    B.5.6E-mailazad.aziz@uhsm.nhs.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Cresemba 100 mg hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderBasilea Medical Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1284
    D.3 Description of the IMP
    D.3.1Product nameCresemba 100 mg hard capsules
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIsavuconazole
    D.3.9.1CAS number 946075-13-4
    D.3.9.3Other descriptive nameIsavuconazonium Sulfate
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Pulmonary Aspergillosis
    E.1.1.1Medical condition in easily understood language
    Chronic chest infection caused by fungus species Aspergillus.
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10003488
    E.1.2Term Aspergillosis
    E.1.2System Organ Class 100000154164
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10003493
    E.1.2Term Aspergillus fumigatus bronchopulmonary infection
    E.1.2System Organ Class 100000015649
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10003494
    E.1.2Term Aspergillus fumigatus infection
    E.1.2System Organ Class 100000154164
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10006473
    E.1.2Term Bronchopulmonary aspergillosis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10059259
    E.1.2Term Pulmonary aspergillosis
    E.1.2System Organ Class 100000015649
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Isavuconazole is an antifungal agent that was recently approved for the treatment of invasive aspergillosis on the basis of non-inferior outcomes compared to the standard of care, voriconazole. Isavuconazole is associated with a lower incidence of side effects than current standard treatment with antifungal drugs. There are no data on the use of isavuconazole in chronic pulmonary aspergillosis (CPA). The trial hypothesis is that isavuconazole will be at least as effective and safe as current available therapy for CPA.

    The primary objective of the study is to assess the efficacy and safety of isavuconazole in the treatment of CPA.
    E.2.2Secondary objectives of the trial
    The secondary research questions are as follows:
    1.what is the rate of development of resistance to isavuconazole compared to the current therapies?
    2.Assesment of pharmacokinetics of Isavucoanzole over months of treatment in CPA
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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 <500 x10^6/L, current cancer or condition requiring immunosuppressive or immunomodulatory medications (e.g. methotrexate, anti-TNF inhibitors) at an equivalent of >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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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 therapy after 12 weeks and before 26 weeks, will have their last assessment carried forward to the 26 week assessment schedule regime If therapy had stopped between 26th week and 52nd week then their last assessment will be carried forward to the 52nd week scheduled assessment regime. All evaluable patients (patients receiving therapy for 12 weeks or longer) would be followed up for 6 months.
    E.5.2Secondary end point(s)
    a.Response after 12 months of treatment
    b.Serological response (improvement in Aspergillus IgG by 20% or to <40mg/L after 6 and 12 months of treatment)
    c.Discontinuation of study drug before 12 months
    d.Symptomatic improvement (any 2 key symptoms other than weight gain)
    e.Proportion of patients showing improvement in SGRQ by >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
    E.5.2.1Timepoint(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 .
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    The study is deemed to have been ended 30 days after the last patient's last visit. There will be a 6 month period for analysis and report writing. For all other purposes, the study end date is deemed to be the date of last data capture.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 20
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients are provided with treatment for one year and follow up for 6 months...
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-06-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-21
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-05-02
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