| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Invasive pulmonary aspergillosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Invasive pulmonary aspergillosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10022881 |
| E.1.2 | Term | Invasive bronchopulmonary aspergillosis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 |
| The primary objective of this study is to compare the safety and tolerability of 80 mg of Voriconazole Inhalation Powder BID in subjects with acute IPA to the safety and tolerability of BID oral voriconazole tablets administered per standard of care (SOC) after a 13 week treatment period. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are as follows:
•To evaluate voriconazole plasma exposure of multi-dose inhalation of Voriconazole Inhalation Powder versus oral voriconazole tablets.
•To compare 80 mg BID of Voriconazole Inhalation Powder to SOC oral voriconazole tablets in treating acute IPA for up to 13 weeks.
•To evaluate the clinical cure of IPA in subjects treated with 80 mg of Voriconazole Inhalation Powder compared to SOC oral voriconazole
tablets.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects meeting the following inclusion criteria may be enrolled into the study:
1.Male or non-pregnant, non-lactating female aged 18 years or older at screening.
2.Diagnosed with acute proven or probable IPA prior to randomization
3.Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at Screening (Visit 1) and must agree to use highly effective contraceptive methods or abstinence from the time of screening for the duration of time on the study and continue to use acceptable contraceptive methods for 3 months after administration of the last dose of study treatment. Male subjects with female partners of childbearing potential must be congenitally sterile or surgically sterile (vasectomy with confirmation of aspermia) or agree to use 2 effective methods of contraception including 1 barrier method (e.g., condom with spermicide and contraception by female partner) for the duration of time on the study and for 3 months after administration of the last dose of study treatment.
4.Subject is considered clinically stable to participate in a 4-month study.
5.Capable of administering inhaled or oral drug product.
6.Subjects taking medications for treatment of other conditions that require or have recommended dose adjustment may be enrolled in the trial but must be willing to be carefully monitored and have medications managed in accordance with the VFEND summary of product characteristics
7.Continuous non-smoker or previous smoker who has not used nicotinecontaining products (including vaping) for at least 3 months prior to the first dosing and throughout the study, based on subject's self-reporting at Screening.
8.Body mass index (BMI) ≥ 16.0 and ≤ 32.0 kg/m2 at screening, and a minimum weight of at least 45.0 kg and a maximum weight of 120 kg at screening.
9.Succeeds in training on the use of the dry powder inhaler and is willing and able to perform adequate inhalation technique in the PI's (or designee's) opinion.
10.Able to generate an inspiratory flow rate of 60 L/minute using the In Check inspiratory peak flow meter or spirometry. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following exclusion criteria must not be enrolled into the study:
1.Is legally incapacitated at the time of the screening visit or expected to be so during the conduct of the study in the opinion of the PI or designee.
2.History or presence of uncontrolled clinically significant medical condition or disease that, in the opinion of the PI or designee, would put the safety of the subject at risk, or that could affect the efficacy or safety analysis.
3.Evidence of disseminated systemic aspergillosis or any other systemic fungal diseases.
4.Presence of alcoholism or drug abuse or its history within the past 2 years prior to the first dosing.
5.History or presence of hypersensitivity or idiosyncratic reaction to voriconazole or any triazole antifungal.
6.Has had surgery or any medical condition within 6 months prior to first dosing which may affect the absorption, distribution, metabolism, or excretion (ADME) of the study drug, in the opinion of the PI or designee.
7.Evidence of a mycetoma within the 12 months prior to screening.
8.Evidence of active systemic candidiasis upon screening or randomization.
9.Has active solid tumor cancer requiring chemotherapy and/or radiation therapy during the study. Hematological malignancies that have completed induction chemotherapy and are currently receiving consolidation therapy are allowed.
10.Current suspected or confirmed sepsis.
11.Positive results at screening for tuberculosis, human immunodeficiency virus, hepatitis B surface antigen or hepatitis C virus.
12.Subjects having an ECG with a prolonged QTcF (QT interval corrected according to Fridericia) greater than 450 msec for men and greater than
470 msec for women or has ECG findings deemed abnormal with clinical significance by the PI or designee at screening.
13.Subjects are to be excluded if they are taking medications that are contraindicated in the VFEND summary of product characteristics.
14.Subjects with moderate or severe liver disease as defined by aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper limit of normal (ULN) or a total bilirubin level > 3 times the ULN.
15.Subjects who have participated in another clinical study of an investigational drug or device medicine within 1 month before dosing, or
participation within 5 half-lives of receiving the last dose of an experimental drug (whichever is longer). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is safety and tolerability as assessed by the following:
•Incidence and severity of TEAEs.
•Incidence of TEAEs leading to study discontinuation.
•Incidence of TEAEs leading to death (all-cause mortality)
•Incidence and severity of study drug-related TEAEs. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The Timepoint of evaluation of these secondary endpoints will be within 13 weeks of treatment period |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are as follows:
•Voriconazole plasma concentration at specified timepoints.
•When possible, for evaluable subjects when a series of samples has been collected, voriconazole plasma pharmacokinetic (PK) parameters; time to reach maximum observed concentration (Tmax), maximum observed concentration (Cmax), area under the concentration-time curve, from time 0 to the last observed non-zero concentration (AUClast), area under the concentration-time curve, from time 0 to the 12-hour time point (AUC0-12h), area under the concentration-time curve, from time 0 extrapolated to infinity (AUCinf), half-life, mean residence time (MRTlast), apparent volume of distribution during terminal phase (Vz/F), apparent total plasma clearance after oral administration (Cl/F) and other parameters considered appropriate, such as a comparison of systemic exposure between oral and inhaled routes.
•Radiologic response as evidenced by improvement in lesion size and/or lesion number.
•Clinical response as evidenced by improvement in the sign and symptom severity score using a 5-point severity scale adapted from the Common Terminology Criteria for Adverse Events.
•Mycologic response as evidence by clearance of Aspergillus infection.
•Change in plasma, serum, or bronchoalveolar lavage (BAL) galactomannan (GM) antigen at 8 and 13 weeks. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The Timepoint of evaluation of these secondary endpoints will be within 13 weeks of treatment period |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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