Posaconazole (MK-5592) IV and oral in children with invasive aspergillosis

Phase 1

Conditions: Invasive aspergillosis (IA)
MedDRA version: 20.0Level: LLTClassification code 10003488Term: AspergillosisSystem Organ Class: 100000004862
Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Registration Number: EUCTR2019-002267-10-GR

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 30

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-a 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 det

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.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 1. To evaluate the safety of posaconazole (POS) intravenous (IV) and oral formulations overall;Secondary Objective: 1. To evaluate the efficacy of POS IV and oral formulations overall in participants with possible, probable or proven invasive aspergillosis (IA)<br>2. To evaluate relapse in participants with possible, probable or proven IA<br>3. To characterize the pharmacokinetics (PK) of POS overall and by formulation<br>4. To summarize the palatability of POS powder-for-suspension (PFS) formulation<br>;Primary end point(s): 1. Percentage of participants who experience one or more treatment-related adverse events (AEs);Timepoint(s) of evaluation of this end point: 1. Up to 14 days after treatment (up to Day 100)

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Percentage of participants who have a favorable global clinical response <br>2. Percentage of participants who have a relapse of IA at any point after achieving favorable global clinical response<br>3. Average plasma concentration (Cavg) of POS<br>4. Minimum plasma concentration (Cmin) of POS<br>5. Maximum plasma concentration (Cmax) of POS<br>6. Area under the concentration-time curve (AUC) of POS<br>7. Time to reach Cmax (Tmax) of POS<br>8. Percentage of participants with different categories of palatability after treatment with the POS PFS formulation<br>;Timepoint(s) of evaluation of this end point: 1. Up to End of Trial (EOT) visit (up to Day 87)<br>2. Up to 28 days post-treatment (up to Day 114)<br>3. Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12<br>4. Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12<br>5. Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12<br>6. Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12<br>7. Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12<br>8. Day 8 and Day 84<br>

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