Clinical trial NCT02598999: Dose Escalation Study of ALX-009 in Healthy Men and Cystic Fibrosis (CF) and Non-CF Bronchiectasis Patients
Official title: Randomized, Double Blind, Placebo-controlled Study of the Safety, Tolerability and Pharmacokinetics After Single Ascending Doses or Multiple Ascending Doses of OSCN-, bLF or ALX-009 in Healthy Male and CF and Non-CF Bronchiectasis Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Cystic Fibrosis
Bronchiectasis
Lead sponsor: Alaxia SAS
Sponsor class: INDUSTRY
First posted: 2015-11-06
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability and pharmacokinetics of a single ascending doses (SAD) and multiple ascending doses (MAD) of Hypothiocyanite (OSCN-), bovine lactoferrin (bLF) and their combination (ALX-009) in healthy male volunteers and patients suffering from cystic fibrosis (CF) and non-CF bronchiectasis (NCFBE).

Detailed description: Part I: SAD of OSCN- and bLF in healthy male volunteers (cohorts 1 to 3) - Part II: SAD and MAD of ALX-009 in healthy male volunteers (cohorts 4 and 5) - Part III: MAD of OSCN- and bLF in patients suffering from cystic fibrosis (cohort III-1) and in healthy volunteers (cohorts III-2 and III-3) - Part IV: MAD of ALX-009 in healthy volunteers (Part IVa - Cohorts IV-1a to IV-3a) and in patients (Part IVb - Cohorts IV-1b to IV-3b)

Eligibility criteria: Inclusion Criteria:

* Healthy male subject or
* Patient suffering from cystic fibrosis defined as a positive sweat chloride test or CF-causing mutations, documented in the patient's medical record or patient suffering from non-CF and non COPD bronchiectasis with a diagnosis confirmed by a chest CT scan demonstrating bronchiectasis in 1 or more lobes documented in the patient's medical record
* Aged between 18 and 50 years inclusive
* Subject's Body Mass Index between 18 and 30 kg/m²
* Subject with normal blood pressure, heart rate, ECG recording and laboratory parameters at the screening visit
* Subject having given a written informed consent prior to selection
* Subject covered by Health Insurance System and/ or in compliance with the recommendations of National Law in force relating to biomedical research

Specific Inclusion Criteria for patients:

* FEV1 more than or equal to 60% of predicted normal value
* Subject in a stable state (no exacerbation for 1 month or prescription of antibiotic by intravenous route)
* Females of childbearing potential: commitment to consistently and correctly use an acceptable method of birth control for the duration of the trial and for 4 months after the last study drug administration / Female of non-childbearing potential: either surgically sterilized or at least 1 year postmenopausal

Exclusion Criteria:

* Presence of cardiovascular, pulmonary, gastro-intestinal, hepatic, renal, metabolic, haematological, neurologic, psychiatric, systemic or infectious disease
* Frequent headaches and/or migraines, recurrent nausea and/or vomiting
* Symptomatic hypotension
* Blood donation (including in the frame of a clinical trial) within 2 months before administration
* General anaesthesia within 3 months before administration
* Presence or history of drug hypersensitivity, or any allergic disease
* Medical history of reactions to cow's milk proteins
* Subject who can not be contacted in case of emergency
* History or presence of drug or alcohol abuse
* Positive Hepatitis B surface (HBs) antigen or anti Hepatitis C virus (HCV) antibody, or positive results for Human Immunodeficiency Virus (HIV) 1 or 2 tests
* Subject who, in the judgement of the Investigator, is likely to be non-compliant or uncooperative during the study, or unable to cooperate because of a language problem, poor mental development.

Specific exclusion criteria for study Parts III and IV:

* Known bronchial hyper-reactivity to drug inhalation
* Known contra-indication to inhaled salbutamol
* Subject with bronchial hyper-reactivity, defined by a positive response to bronchodilator with FEV1 increase ≥ 200 mL

Specific exclusion crtieria for patients:

* Active allergic bronchopulmonary aspergillosis currently treated
* Medical history of allergic bronchopulmonary aspergillosis in the past 2 years.

Primary outcomes:
measure: Safety and tolerability: number of subjects who experience serious adverse events, adverse events, potential clinically significant changes in ECG, 24-holter, vital signs, physical examinations, laboratory tests, spirometry, O2 saturation (Part III only)
timeFrame: Day (D) 8 post dosing for part I and D14 post dosing for parts II, III and IV
Secondary outcomes:
measure: Maximal concentration (Cmax) of bLF and SCN- in plasma, sputum and urine (for SCN- only)
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: Area under the curve (AUC) of bLF and SCN- in plasma, sputum and urine (for SCN- only)
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: First time to reach Cmax (Tmax) of bLF and SCN- in plasma, sputum and urine (for SCN- only)
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: Concentration half life of bLF and SCN- in plasma, sputum and urine (for SCN- only)
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: Concentration of anti-bLF antibodies in blood and sputum
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: Concentration of IL-1β in blood and sputum
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: Concentration of IL-6 in blood and sputum
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: Concentration of IL-8 in blood and sputum
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: Concentration of IL-10 in blood and sputum
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: Concentration of TNF-α in blood and sputum
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: Concentration of SC5b-9 in blood
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: Concentration of total IgE in blood
timeFrame: D8 post dosing for part I and D14 post dosing for parts II, III and IV
measure: For patients only, quantitative assessment of different species in sputum
timeFrame: D7 post dosing
measure: For patients only, volume of sputum over 24hours period
timeFrame: D8 post dosing
Other outcomes:
measure: For patients only, characterization of sputum microbiota using genomic technologies
timeFrame: D14 post dosing
Locations:
city: Grenoble
country: France
facility: Eurofins Optimed
Study officials:
affiliation: Hospices Civils de Lyon
name: Isabelle Durieu, Prof., MD
role: PRINCIPAL_INVESTIGATOR
References: