| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Invasive aspergillosis (IA) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Invasive aspergillosis (IA) is a fungal infection that occurs in severely immunocompromised patients |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003488 |
| E.1.2 | Term | Aspergillosis |
| 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 |
| 1. To evaluate the safety of posaconazole (POS) intravenous (IV) and oral formulations overall |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of POS IV and oral formulations overall in participants with possible, probable or proven invasive aspergillosis (IA)
2. To evaluate relapse in participants with possible, probable or proven IA
3. To characterize the pharmacokinetics (PK) of POS overall and by formulation
4. To summarize the palatability of POS powder-for-suspension (PFS) formulation
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A participant will be eligible for inclusion in the study if the participant:
1. Has a diagnosis of possible, probable, or proven IA per 2020
EORTC/MSG disease definitions.
2. If enrolled with a possible or probable IA diagnosis, has one or more of the following risks as per 2020 EORTC/MSG disease definitions:
- Recent history of neutropenia (<0.5 × 109 neutrophils/L [<500
neutrophils/mm3]) (within 30 days before to screening).
- Receipt of an allogeneic HSCT.
- Receipt of a solid organ transplant.
- Hematologic malignancy currently under treatment or has been treated in the recent past.
- Treatment with other recognized T-cell immunosuppressants, such as calcineurin inhibitors, TNF-α blockers, specific monoclonal antibodies(such as alemtuzumab), or nucleoside analogues during the past 90 days.
- Prolonged use corticosteroids for ≥3 weeks in the past 60 days (average minimum dose of ≥0.3 mg/kg/day of prednisone equivalent).
- Congenital or inherited severe immunodeficiency (including but not limited to chronic granulomatous disease, STAT 3 deficiency, CARD9 deficiency, STAT-1 gain of function, or severe combined
immunodeficiency).
- Treatment with recognized B-cell immunosuppressants, such as
Bruton's tyrosine kinase inhibitors, eg, ibrutinib.
- Acute graft-versus-host disease grade III or IV involving the gut,
lungs, or liver that is refractory to first-line treatment with steroids.
3. If enrolled with a possible or probable IA diagnosis, meets mycologic and clinical criteria as per 2020 EORTC/MSG disease definitions:
- Possible IA includes participants with clinical criteria, with the
anticipation that further diagnostic workup is in progress as clinically feasible and may result in updated classification of the invasive fungal infection as per the 2020 EORTC/MSG disease definitions.
- Probable IA includes participants with clinical criteria, along with mycological criteria including serum, plasma, CSF, or BAL fluid Aspergillus galactomannan antigen, or Aspergillus PCR test positive in plasma, serum, whole blood, or BAL fluid, or evidence of Aspergillus by histology or microscopy, or positive culture of a specimen taken by nonsterile sampling of an infected site as per 2020 EORTC/MSG disease definitions.
4. If enrolled with a proven IA diagnosis, has demonstrated fungal elements (by cytology, microscopy, or histopathology, including Aspergillus nucleic acid probe where available) or positive culture for Aspergillus of a tissue specimen obtained from an otherwise sterile site as per 2020 EORTC/MSG disease definitions.
5. Has a central line (eg, central venous catheter, peripherally-inserted central catheter) in place or planned to be in place before beginning IV study treatment.
6. Has clinical symptoms consistent with an acute episode of IA, defined as duration of clinical syndrome of <30 days.
7. Is male or female, and ≥2 years of age and <18 years of age at the time of first dose of study treatment and weighs at least 10 kg. Participants may be of any race/ethnicity.
8. Male participants are eligible to participate if they agree to the
following during the intervention period and for at least 30 days] after the last dose of study treatment:
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
- Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause Appendix 5) as detailed below:
- Agree to use a male condom plus partner use of an additional
contraceptive method when having penile-vaginal intercourse with a female of childbearing potential who is not currently pregnant. Contraceptive use by females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a female of childbearing potential
OR
- Is a female of childbearing potential and using a contraceptive method
that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 30 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
- A female of childbearing potential must have a negative highly
sensitive pregnancy test (urine or serum as required by local
regulations) within 24 hours before the first dose of study intervention.
Due to character limitation, inclusion criteria #9 was adjusted and 10 was removed. Please refer to the Protocol.
|
|
| E.4 | Principal exclusion criteria |
The participant must be excluded from the study if the participant:
1. Has chronic (≥30 days’ duration) IA, relapsed/recurrent IA, or refractory IA that has not responded to prior antifungal treatment.
2. Has cystic fibrosis, pulmonary sarcoidosis, aspergilloma, or allergic bronchopulmonary aspergillosis.
3. Has known hypersensitivity or other serious adverse reaction to any azole antifungal therapy, or to any other ingredient of the study treatment used.
4. Has any known history of torsade de pointes, unstable cardiac arrhythmia or proarrhythmic conditions, a history of recent myocardial infarction, congenital or acquired QT prolongation, or cardiomyopathy in the context of cardiac failure within 90 days of time of first dose of study treatment.
5. Has known hereditary fructose intolerance.
6.Has known galactose intolerance, Lapp lactase deficiency, or glucosegalactose malabsorption.
7. Is on artificial ventilation at the time of first dose of study treatment.
8. Has any condition that, in the opinion of the investigator, may
interfere with optimal participation in the study.
9. Has received any treatment specifically listed in Table 2 within the specified timeframes before the start of study treatment
10. Has enrolled previously in the current study and been discontinued.
11. Has QTc prolongation (based on either Fridericia or Bazett's
correction) at screening >500 msec.
12. Has significant liver dysfunction (defined as total bilirubin >1.5 × ULN AND AST or ALT >3 × ULN with normal alkaline phosphatase) at screening.
13. Has calculated creatinine clearance <20 mL/min (Cockroft-Gault formula) or<20 mL/min/1.73 m2 (modified Schwartz formula) at screening.
14. Is not expected, in the opinion of the investigator, to survive for at least 1 month after the initiation of study treatment.
15. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Percentage of participants who experience one or more treatment-related adverse events (AEs) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to 14 days after treatment (up to Day 100) |
|
| E.5.2 | Secondary end point(s) |
1. Percentage of participants who have a favorable global clinical response
2. Percentage of participants who have a relapse of IA at any point after achieving favorable global clinical response
3. Average plasma concentration (Cavg) of POS
4. Minimum plasma concentration (Cmin) of POS
5. Maximum plasma concentration (Cmax) of POS
6. Area under the concentration-time curve (AUC) of POS
7. Time to reach Cmax (Tmax) of POS
8. Percentage of participants with different categories of palatability after treatment with the POS PFS formulation
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to End of Trial (EOT) visit (up to Day 87)
2. Up to 28 days post-treatment (up to Day 114)
3. Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
4. Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
5. Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
6. Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
7. Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
8. Day 8 and Day 84
|
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 20 |
| 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 |
| Israel |
| Korea, Republic of |
| Mexico |
| Peru |
| United States |
| Greece |
| Italy |
| Belgium |
| Hungary |
| Russian Federation |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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