Clinical trial NCT04803396: Ascending Dose Tolerability Trial and PK Assessment in Healthy Volunteers After Single & Multiple Oral Intake of DF2755A
Official title: An Ascending Dose Tolerability Study and Pharmacokinetic Assessment in Healthy Male and Female Volunteers After Single & Multiple Oral Administration of DF2755A
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: no Condition
Keywords: Healthy volunteers
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2021-03-17
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary objective:

•To evaluate the tolerability and safety of ascending single doses of DF2755A in healthy adult male 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 to select a narrower range of dose and dosing regimen to be subsequently studied in patients after single 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

Please note that the study has been closed after Part A (single ascending doses), so all the objectives were revised accordingly.

Detailed description: The study was a phase I, single center, double-blind, placebo controlled, randomized, ascending single doses study in healthy male and female volunteers.

The design consisted of a double blind comparison of the test compound versus placebo in which the dose is increased in successive treatment periods.

The escalating dose had the aim of achieving 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). Practically, of the two Parts planned - part A and Part B - only the Part A took place.

The Part A consisted of single doses of 50 mg oad, 150 mg oad, 450 mg oad or 700 mg oad of DF2755A tested in healthy male and female volunteers who were hospitalized approximately for 4 days (D-1 morning to D4 morning).

The planned Part B should have consisted of repeated doses of 100 mg bid, 200 mg bid or 300 mg bid of DF2755A) but it was not performed. Hence, the study was terminated at the end of Part A and, consequently, both the methodology and the endpoints were revised accordingly.

Eligibility criteria: Inclusion Criteria:

* For eligibility into the trial, subjects had to meet all the following inclusion criteria:

  1. Healthy male subject, aged between 18 and 55 years inclusive;
  2. Healthy female subject infertile or in post menopause for at least two years, aged between 18 and 60 years inclusive;
  3. Body Mass Index (BMI) between 18.5 and 29.9 kg/m2 inclusive and weight ≤ 90kg;
  4. Considered as healthy after a comprehensive clinical assessment (detailed medical history and complete physical examination);
  5. 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;
  6. Smoker \< 5cigarettes per day who stop totally during the study;
  7. 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;
  8. Normal oral temperature;
  9. 36.3°C \< oral body temperature \< 37.5°C;
  10. 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;
  11. Normal dietary habits;
  12. 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;
  13. Covered by Health Insurance System and / or in compliance with the recommendations of National Law in force relating to biomedical research.

Exclusion Criteria:

1. Subject has had a clinically significant illness in the six weeks before screening in the opinion of the Investigator.
2. 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.
3. 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).
4. Subject has a significant history of drug/solvent abuse or a positive drugs of abuse (DOA) test at any time during the study.
5. 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.
6. 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.
7. Subject who has a positive human immunodeficiency virus (HIV) screen, Hepatitis B screen or Hepatitis C screen.
8. Subject has donated blood or blood products (e.g., plasma or platelets) within the three months prior to screening.
9. Subject who is not suitable to participate in the study in the opinion of the Investigator;
10. Subject who has participated in any clinical study with an investigational drug/device within three months prior to the first day of dosing.
11. Subject who is in the exclusion period from another study.
12. Administrative or legal supervision.
13. 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. -

Primary outcomes:
measure: Number of Adverse Events by Severity
timeFrame: Throughout the study, up to Day 4
Secondary outcomes:
measure: Cmax of DF2755A
timeFrame: Day 1 (0,5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 h post-dose); Day 2 (24, 36, 40h post-dose); Day 3 (48, 60 h post-dose); Day 4 (72 h post dose)
measure: Tmax
timeFrame: Day 1 (0,5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 h post-dose); Day 2 (24, 36, 40h post-dose); Day 3 (48, 60 h post-dose); Day 4 (72 h post dose)
measure: t1/2
timeFrame: Day 1 (0,5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 h post-dose); Day 2 (24, 36, 40h post-dose); Day 3 (48, 60 h post-dose); Day 4 (72 h post dose)
measure: AUC0-t
timeFrame: Day 1 (0,5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 h post-dose); Day 2 (24, 36, 40h post-dose); Day 3 (48, 60 h post-dose); Day 4 (72 h post dose)
measure: AUC 0-inf
timeFrame: Day 1 (0,5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 h post-dose); Day 2 (24, 36, 40h post-dose); Day 3 (48, 60 h post-dose); Day 4 (72 h post dose)
measure: Vz/F
timeFrame: Day 1 (0,5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 h post-dose); Day 2 (24, 36, 40h post-dose); Day 3 (48, 60 h post-dose); Day 4 (72 h post dose)
measure: CL/F
timeFrame: Day 1 (0,5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 h post-dose); Day 2 (24, 36, 40h post-dose); Day 3 (48, 60 h post-dose); Day 4 (72 h post dose)
measure: Ae,f(0-72) Total Amount in Faeces
timeFrame: 0-24 h post-dose; 24-48 h post-dose, 48-72 h post dose
measure: Fe,f(0-72)
timeFrame: 0-24 h post-dose; 24-48 h post-dose, 48-72 h post dose
measure: Ae,ur(0-72)
timeFrame: 0-6 h post-dose; 6-10 h post-dose; 10-16h post-dose; 16-24h post-dose; 24-48h post-dose; 48-72h post-dose
measure: Fe,ur(0-72)
timeFrame: 0-6 h post-dose; 6-10 h post-dose; 10-16h post-dose; 16-24h post-dose; 24-48h post-dose; 48-72h post-dose
measure: CLR
timeFrame: 0-6 h post-dose; 6-10 h post-dose; 10-16h post-dose; 16-24h post-dose; 24-48h post-dose; 48-72h post-dose
measure: 12-lead ECG (HR)
timeFrame: day -1 (pre treatment), day 3 (last visit after treatment)
measure: 12-lead ECG PR, QRS, QT, and QTcF
timeFrame: day -1 (pre treatment), day 3 (last visit after treatment)
measure: Systolic and Diastolic Blood Pressure (SBP, DBP)
timeFrame: day -1 (pre treatment), day 2 (post-treatment)
measure: Heart Rate (HR)
timeFrame: day -1 (pre treatment), day 3 (last visit after treatment)
measure: Oral Body Temperature
timeFrame: day -1 (pre treatment), day 2 (post-treatment)
Other outcomes:
Locations:
city: Gières
country: France
facility: Eurofins Optimed
Study officials:
affiliation: Eurofins Optimed
name: Yves Donazzolo, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: