Ascending Dose Tolerability Trial and PK Assessment in Healthy Volunteers After Single & Multiple Oral Intake of DF2755A

Study Overview
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Brief Summary
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Primary objective: •To evaluate the tolerability and safety of ascending single doses of DF2755A in healthy adultmale and female volunteers. Secondary Objectives: To determine the pharmacokinetics parameters of DF2755A To establish a dose concentration-response relationship over a wide range of doses in order toselect a narrower range of dose and dosing regimen to be subsequently studied in patients aftersingle administration To evaluate the effect of ascending single doses on the pharmacodynamics parameters To compare metabolites pathway in Human with the one observed in animals

Detailed Description
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The study is a phase I, single center, double-blind, placebo controlled, randomized, ascending single doses study in healthy male and female volunteers. The design consists of a double blind comparison of the test compound versus placebo in which the dose is increased in successive treatment periods. Dose was escalated in order to achieve enough safety information on an interval of doses possibly encompassing both the effective dose and the maximum tolerated dose (defined as the highest dose devoid of any clinical signs/symptoms). The study has been terminated after Part A (single ascending doses) so the methodology was revised accordingly.

Official Title
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An Ascending Dose Tolerability Study and Pharmacokinetic Assessment in Healthy Male and Female Volunteers After Single & Multiple Oral Administration of DF2755A

Conditions
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no Condition

Intervention / Treatment
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* Drug: DF2755A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For eligibility into the trial, subjects had to meet all the following inclusion criteria: Healthy male subject, aged between 18 and 55 years inclusive; Healthy female subject infertile or in post menopause for at least two years, aged between 18 and 60 years inclusive; Body Mass Index (BMI) between 18.5 and 29.9 kg/m2 inclusive and weight ≤ 90kg; Considered as healthy after a comprehensive clinical assessment (detailed medical history and complete physical examination); Normal Blood Pressure (BP) and Heart Rate (HR) at the screening visit after 10 minutes in supine position: 90 mmHg ≤ Systolic Blood Pressure (SBP) ≤ 140 mmHg or 150mmHg for subject > 45 years, 50 mmHg ≤ Diastolic Blood Pressure (DBP) ≤ 90 mmHg, 40 bpm ≤ HR ≤ 100 bpm, Or considered NCs by investigators; Smoker < 5cigarettes per day who stop totally during the study; Normal ECG recording on a 12-lead ECG at the screening visit: 120 < PR < 210 ms, QRS < 120 ms, QTcf ≤ 430 ms for male and < 450 ms for female, No sign of any trouble of sinusal automatism, Or considered NCs by investigators; Normal oral temperature; 36.3°C < oral body temperature < 37.5°C; Laboratory parameters within the normal range of the laboratory (haematological, blood chemistry tests, urinalysis). Individual values out of the normal range can be accepted if judged clinically non relevant by the Investigator; Normal dietary habits; Able to communicate well with the Investigator, understand and comply with the requirements of the study, and understand and sign a written informed consent prior to selection; Covered by Health Insurance System and / or in compliance with the recommendations of National Law in force relating to biomedical research. Exclusion Criteria: Subject has had a clinically significant illness in the six weeks before screening in the opinion of the Investigator. Subject has had a serious adverse reaction or significant hypersensitivity to any drug, has a known clinically significant allergy to anti-inflammatory drugs or chemically related compounds or has a clinically significant allergy to drugs, foods or other materials (in the opinion of the Investigator). However, subjects with mild hayfever may be included in the study. Subject has used prescription medication in the 14 days prior to dosing or over-the-counter preparations for 7 days prior to dosing (including vitamin supplements and herbal remedies), with the exception of paracetamol which was allowed during the study (maximum 500 mg per administration, total daily dose maximum 2 grams). Subject has a significant history of drug/solvent abuse or a positive drugs of abuse (DOA) test at any time during the study. Subject has a history of alcohol abuse in the last 5 years or currently drinks in excess of 21 and 14 units per week for males and female, respectively, or has a positive alcohol breath test (ABT) at any time during the study. Subject is not willing to refrain from caffeine/xanthine containing products in the 48 hours prior to admission to the clinical unit on Day -1 and for the duration of the residential period. Subject who has a positive human immunodeficiency virus (HIV) screen, Hepatitis B screen or Hepatitis C screen. Subject has donated blood or blood products (e.g., plasma or platelets) within the three months prior to screening. Subject who is not suitable to participate in the study in the opinion of the Investigator; Subject who has participated in any clinical study with an investigational drug/device within three months prior to the first day of dosing. Subject who is in the exclusion period from another study. Administrative or legal supervision. Subject who would receive more than 4500 euros as indemnities for his participation in biomedical research within the 12 last months, including the indemnities for the present study. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo was administered once a day (oad) as matching oral capsules. The administration took place at around 8:00 a.m with 200 mL of tap water, in sitting position, in fasting conditions. | Drug: DF2755A<br>* DF2755A was planned to be administered in two different parts: Part A: Single oral dose administration on D1 according to the randomization (50, 150, 300 and 300 mg oad). Part B: was planned (100 mg bid, 200 mg bid or 300 mg bid) not performed (repeated oral administration from Day 1 to Day 14). Hence, only part A of the study was accomplished.<br>* Other names: allosteric inhibitor of CXCR1/2;|
| Experimental: 50 mg DF2755A<br>The experimental drug was administered once a day (oad) as one oral capsule of 50 mg. The administration took place at around 8:00 a.m with 200 mL of tap water, in sitting position, in fasting conditions. | Drug: DF2755A<br>* DF2755A was planned to be administered in two different parts: Part A: Single oral dose administration on D1 according to the randomization (50, 150, 300 and 300 mg oad). Part B: was planned (100 mg bid, 200 mg bid or 300 mg bid) not performed (repeated oral administration from Day 1 to Day 14). Hence, only part A of the study was accomplished.<br>* Other names: allosteric inhibitor of CXCR1/2;|
| Experimental: 150 mg DF2755A<br>The experimental drug was administered once a day (oad) as oral capsules. The administration took place at around 8:00 a.m with 200 mL of tap water, in sitting position, in fasting conditions. | Drug: DF2755A<br>* DF2755A was planned to be administered in two different parts: Part A: Single oral dose administration on D1 according to the randomization (50, 150, 300 and 300 mg oad). Part B: was planned (100 mg bid, 200 mg bid or 300 mg bid) not performed (repeated oral administration from Day 1 to Day 14). Hence, only part A of the study was accomplished.<br>* Other names: allosteric inhibitor of CXCR1/2;|
| Experimental: 300 mg DF2755A<br>The experimental drug was administered once a day (oad) as oral capsules. The administration took place at around 8:00 a.m with 200 mL of tap water, in sitting position, in fasting conditions. | Drug: DF2755A<br>* DF2755A was planned to be administered in two different parts: Part A: Single oral dose administration on D1 according to the randomization (50, 150, 300 and 300 mg oad). Part B: was planned (100 mg bid, 200 mg bid or 300 mg bid) not performed (repeated oral administration from Day 1 to Day 14). Hence, only part A of the study was accomplished.<br>* Other names: allosteric inhibitor of CXCR1/2;|
| Experimental: 600 mg DF2755A<br>The experimental drug was administered once a day (oad) as oral capsules. The administration took place at around 8:00 a.m with 200 mL of tap water, in sitting position, in fasting conditions. | Drug: DF2755A<br>* DF2755A was planned to be administered in two different parts: Part A: Single oral dose administration on D1 according to the randomization (50, 150, 300 and 300 mg oad). Part B: was planned (100 mg bid, 200 mg bid or 300 mg bid) not performed (repeated oral administration from Day 1 to Day 14). Hence, only part A of the study was accomplished.<br>* Other names: allosteric inhibitor of CXCR1/2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events by severity | Adverse Event (AE), is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment/product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Serious Adverse Event or Reaction, a Serious Adverse Event (SAE) or Reaction (SAR) is any untoward medical occurrence, including intercurrent pathology, or effect that at any dose: Results in death; Is life-threatening. | Throughout the study, up to Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | It is the observed maximum plasma concentration of DF2755A | Days 1, 2, 3 and 4 | 
| tmax | It is the first time to reach Cmax | Days 1, 2, 3 and 4 | 
| t1/2 | It is the plasma concentration half life | Days 1, 2, 3 and 4 | 
| AUC0-t | The area under the concentration vs. time curve from time zero (pre-dose) to the time of last quantifiable concentration was calculated using a linear trapezoidal method. | Days 1, 2, 3 and 4 | 
| AUCinf | It is the area under the plasma concentration-time curve from administration up to infinity with extrapolation of the terminal phase. | Days 1, 2, 3 and 4 | 
| Vz/F | It is the apparent volume of distribution during terminal phase after non-intravenous administration | Days 1, 2, 3 and 4 | 
| CL/F | It is the apparent oral clearance of the drug, where CL = clearance and F = bioavailability | Days 1, 2, 3 and 4 | 
| Ae,f(0-72) total amount in faeces | After oral administration, the excretion of the drug in faeces is measured by the tracing of the radiolabelled compound [14C]DF2755A. The individual amount of DF2755A excreted in feces as DF2755Y over time in the whole sampling window (0-72 h) is reported. | Days 1, 2, 3 and 4 | 
| Fe,f(0-72) (fraction in faeces) | The individual corresponding fraction of DF2755A dose excreted in feces as DF2755Y over time in the whole sampling window (0-72 h) is reported. | Days 1, 2, 3 and 4 | 
| Ae,ur(0-72) (total amount in urine) | The individual amount of DF2755A excreted in urine as DF2755Y over time in the whole sampling window (0-72 h) is reported. | Days 1, 2, 3 and 4 | 
| Fe,ur(0-72) (fraction in urine) | The individual corresponding fraction of DF2755A dose excreted in urine as DF2755Y over time in the whole sampling window (0-72 h) is reported. | Days 1, 2, 3 and 4 | 
| CLR | It is the renal clearance of DF2755Y | Days 1, 2, 3 and 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers