Open-label, Dose-escalation Study to Evaluate the Pharmacokinetics of Inhaled Teicoplanin in Cystic Fibrosis Patients

NCT04176328 | Completed Phase 1 DMC

• 1 other identifier: NEU-PR-01.2019
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Cystic Fibrosis (CF) is the most common autosomal recessive lethal disorders affecting 1:2.500 newborns among Caucasians. CF patients are peculiarly susceptible to infection and colonization of the respiratory tract with pathogens. In particular, Methicillin-resistant Staphylococcus aureus (MRSA) has become the third most prevalent bacterium in CF in the U.S. and has been increasing in other countries. Apart from the difficulty of treating the infection because of its antimicrobial resistances, MRSA is transmissible between individuals with and without CF. Chronic MRSA infection is associated with worse outcomes, and treatment/eradication is challenging. Antibiotic dosing and choices should be optimized to minimize further resistance and to maximize chances of successful therapy. Yet, MRSA has several mechanisms to escape clearance by the immune system and antibiotic killing. For these reasons, a better understanding of preventive measures and early therapy is of key importance. In consideration of all these assessments there is an emerging consensus that MRSA is an important pathogen in CF rather than simply a marker of severe disease. However, to date there are no guidelines or recommendations on the choice of antibiotics for MRSA in CF. Glycopeptides are an important class of antibiotics active against Gram-positive pathogens. These include teicoplanin and vancomycin, which are currently in widespread use and are active against MRSA. Teicoplanin is often preferred to vancomycin for intravenous treatment because of its better safety profile but its use in MRSA lung infection is limited by its limited lung penetration. Teicoplanin is mainly used for injection/infusion. Inhalation of anti-microbial drugs is a cornerstone in the treatment of patients with CF, since inhaled antibiotics decrease the rate of decline of lung function, improve the quality of life, and reduce the frequency of exacerbations and hospital admissions. It is expected that, using inhalation route, efficacy would be improved and risk of resistance reduced. At present, no antibiotic active against MRSA is available as an inhaled formulation. The objective of this phase I, first-in-man clinical study is to identify the dose providing, after single inhalation administration, a sputum Teicoplanin concentrations exceeding the drug concentration required to inhibit bacterial growth for at least 8 hours, while minimizing the development of resistance.

Conditions

Cystic Fibrosis

Keywords

Cystic Fibrosis; Methicillin-resistant Staphylococcus aureus; Teicoplanin

Outcome Measures

Primary Outcomes (1)

• Concentration of Teicoplanin in the sputum of CF patients treated with inhaled Teicoplanin.

  Measurement of the concentration (expressed as mg/L) of Teicoplanin in the sputum of patients suffering of Cystic Fibrosis after a single inhalation of 150 mg at scheduled time points after first inhalation: 0 hours, 0.5 hours, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 30 hours, 48 hours. In case a value of sputum AUC0-12 h above 300 μg/mL\*h will not be achieved with the first dosage inhalation of Teicoplanin, up to two additional inhalations with different dosages will be foreseen and the same time points will be measured for subsequent inhalations. In addition, the inhalation of Teicoplanin with the maximum (300 mg) dosage foreseen by study protocol is expected for all patients aiming to confirm the optimal intermediate dosage tested during the dose-escalation process.

  Change occurring from pre-inhalation (0 hours) to the following time points: after 0.5 hours, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 30 hours, 48 hours from each inhalation.

Secondary Outcomes (6)

• Concentration of Teicoplanin in the blood of CF patients treated with inhaled Teicoplanin.

  Change occurring from pre-inhalation (0 hours) to the following time points: after 0.5 hours, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours from each inhalation.

• Concentration of Teicoplanin in the urine of CF patients treated with inhaled Teicoplanin.

  Change occurring from pre-inhalation (0 hours) to the following time points: during the intervals 0-4 hours, 4-12 hours, 12-24 hours from each inhalation + after 48 hours from inhalation.

• Comparison between concentrations of Teicoplanin in the sputum, blood and urine of CF patients treated with inhaled Teicoplanin.

  During each inhalation visit throughout study period, an average of 3 months per patient.

• Percentage of change of FEV1 value (by means of Spirometry test) in comparison to baseline (pre-inhalation) in CF patients treated with inhaled Teicoplanin (as part of Tolerability outcome).

  30 minutes pre-inhalation + after 30 minutes, 60 minutes and 120 minutes (if needed) from each inhalation.

• Percentage of change of blood oxigen saturation value (by means of Pulse Oximetry test) in comparison to baseline (pre-inhalation) in CF patients treated with inhaled Teicoplanin (as part of Tolerability outcome).

  30 minutes pre-inhalation + after 30 minutes and 4 hours from each inhalation.

Study Arms (1)

Cystic Fibrosis patients treated with Teicoplanin

EXPERIMENTAL

Hospitalized male and female patients aged ≥ 18 years, suffering of Cystic Fibrosis.

Drug: Teicoplanin Sandoz 200 mg powder and solvent for solution for injection or infusion or oral solution.

Interventions

Teicoplanin Sandoz 200 mg powder and solvent for solution for injection or infusion or oral solution. DRUG

Teicoplanin Sandoz administered by inhalation (aerosol).

Also known as: Teicoplanin

Cystic Fibrosis patients treated with Teicoplanin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients, aged ≥18 years with a confirmed diagnosis of cystic fibrosis.
• Patients with body weight ≥50 kg and ≤100 kg
• Patients with body mass index (BMI) between 18.0 and 30 kg/m2.
• Patients with FEV1 \> 50% of predicted.
• Patients with regular mucus production due to cystic fibrosis.
• Patients who are able to understand the nature of the study and willing to comply with the protocol requirements.
• Patients who have signed written informed consent to participate to the study after risks have been fully explained.

You may not qualify if:

• Patients treated with nebulized antibiotics within 14 days or mucolytic agents, hypertonic saline solution within 48 hours before administration of the Investigational Product or during the study.
• Patients with medical history of hemoptysis (\> 300 cc in 30 days).
• Patients with decreased liver function (AST or ALT \> 3 times higher in comparison to reference values).
• Patients with eGFR \< 60 mL/min/1.73 m2
• Patients on the waiting list for lung transplantation.
• Patients with known or suspected allergy or hypersensitivity to glycopeptides.
• Patients treated with Teicoplanin for inhalation and systemic within 4 weeks before each dosing occasion.
• Patients with known episodes of bronchoconstriction after drug inhalation.
• Patients who are participating or have participated in other clinical studies within the 30 days before the study enrolment.
• Female patients who are pregnant or breast-feeding or who wish to become pregnant during the period of the clinical study and for one months later.
• Female patients of childbearing age (less than 24 months after the last menstrual cycle) who do not use adequate contraception. \* \* Methods at low risk of contraceptive failure (less than 1% per year) when used consistently, including: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), some intra-uterine devices, abstinence or vasectomized partner. Contraception should be maintained until 1 month after the last visit.

Sponsors & Collaborators

• Neupharma Srl: lead
• Sintesi Research Srl: collaborator
• Aptuit: collaborator
• Pari Pharma GmbH: collaborator

Study Sites (1)

Centro Ricerche Cliniche di Verona - Azienda Ospedaliera Universitaria Integrata di Verona

Verona, 37134, Italy

Location

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  BACKGROUND

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  BACKGROUND

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MeSH Terms

Conditions

Cystic Fibrosis

Interventions

Powders; Solvents; Solutions; Injections; Teicoplanin

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations; Specialty Uses of Chemicals; Chemical Actions and Uses; Drug Administration Routes; Drug Therapy; Therapeutics; Lipoglycopeptides; Glycopeptides; Glycoconjugates; Carbohydrates; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Giulia Paiola, MD

  U.O.C. Fibrosi Cistica - Azienda Ospedaliera Universitaria Integrata di Verona

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Prospective, single-arm, exploratory, open-label, dose-escalation study evaluating the pharmacokinetics of inhaled Teicoplanin in Cystic Fibrosis patients.

Study Record Dates

• First Submitted: November 8, 2019
• First Posted: November 25, 2019
• Study Start: October 25, 2019
• Primary Completion: September 16, 2020
• Study Completion: September 30, 2020
• Last Updated: December 9, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)