Dose Escalation Study of ALX-009 in Healthy Men and Cystic Fibrosis (CF) and Non-CF Bronchiectasis Patients

Study Overview
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Brief Summary
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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
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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)

Official Title
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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

Conditions
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Cystic Fibrosis, Bronchiectasis

Intervention / Treatment
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* Drug: ALX-009
* Drug: OSCN-
* Drug: bLF
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I, SAD<br>Single administration of OSCN- or bLF or Placebo in healthy male volunteers | Drug: OSCN-<br>* Solution for inhalation administered through nebulization<br>* Other names: Hypothiocyanite;Drug: bLF<br>* Solution for inhalation administered through nebulization<br>* Other names: bovine Lactoferrin;Drug: Placebo<br>* Solution for inhalation administered through nebulization, Sodium Chloride 0.9%<br>|
| Experimental: Part II, SAD and MAD<br>Single and multiple administrations of ALX-009 or Placebo in healthy male volunteers | Drug: ALX-009<br>* Solution for inhalation administered through nebulization<br>* Other names: Association of OSCN- and bLF;Drug: Placebo<br>* Solution for inhalation administered through nebulization, Sodium Chloride 0.9%<br>|
| Experimental: Part III, MAD<br>Multiple administrations of OSCN- or bLF or Placebo in CF patients in healthy volunteers | Drug: OSCN-<br>* Solution for inhalation administered through nebulization<br>* Other names: Hypothiocyanite;Drug: bLF<br>* Solution for inhalation administered through nebulization<br>* Other names: bovine Lactoferrin;Drug: Placebo<br>* Solution for inhalation administered through nebulization, Sodium Chloride 0.9%<br>|
| Experimental: Part IV, MAD<br>Multiple administrations of ALX-009 or Placebo in healthy volunteers and in patients (CF and NCFBE) | Drug: ALX-009<br>* Solution for inhalation administered through nebulization<br>* Other names: Association of OSCN- and bLF;Drug: Placebo<br>* Solution for inhalation administered through nebulization, Sodium Chloride 0.9%<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) |  | Day (D) 8 post dosing for part I and D14 post dosing for parts II, III and IV | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal concentration (Cmax) of bLF and SCN- in plasma, sputum and urine (for SCN- only) |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| Area under the curve (AUC) of bLF and SCN- in plasma, sputum and urine (for SCN- only) |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| First time to reach Cmax (Tmax) of bLF and SCN- in plasma, sputum and urine (for SCN- only) |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| Concentration half life of bLF and SCN- in plasma, sputum and urine (for SCN- only) |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| Concentration of anti-bLF antibodies in blood and sputum |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| Concentration of IL-1β in blood and sputum |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| Concentration of IL-6 in blood and sputum |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| Concentration of IL-8 in blood and sputum |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| Concentration of IL-10 in blood and sputum |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| Concentration of TNF-α in blood and sputum |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| Concentration of SC5b-9 in blood |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| Concentration of total IgE in blood |  | D8 post dosing for part I and D14 post dosing for parts II, III and IV | 
| For patients only, quantitative assessment of different species in sputum | Staphylococcus aureus, Staphylococcus aureus MRSA, Pseudomonas aeruginosa, Pseudomonas aeruginosa MDR, Haemophilus influenzae, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Burkholderia cepacia complex, Aspergillus fumigatus and Aspergillus terreus | D7 post dosing | 
| For patients only, volume of sputum over 24hours period |  | D8 post dosing |