A Combined SAD and MAD Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile of IFB-088

Healthy Volunteers Clinical Trial

Official title:

A Double-blind, Randomized, Placebo-controlled, Combined Single and Multiple Ascending Dose Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile of IFB-088, in Healthy Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03610334
• Other study ID #: P188
• Secondary ID: 2018-000443-29
• Status: Completed
• Phase: Phase 1
• Start date: June 21, 2018
• Est. completion date: December 16, 2019

Study information

• Verified date: November 2021
• Source: InFlectis BioScience
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is the first study of single and multiple doses of IFB-088 in human subjects. The current study is designed to assess in the first part, the safety, tolerability, plasma and urine pharmacokinetics (PK) of single oral doses of IFB-088 in healthy subjects (Single Ascending Doses - SAD) and in a second part safety, tolerability, plasma and urine pharmacokinetics (PK) of multiple oral doses of IFB-088 in healthy subjects (Multiple Ascending Doses - MAD)

Description:

Randomized, double blind, placebo controlled study of single ascending doses (SAD) and multiple ascending doses (MAD).

The SAD part consists of 6 cohorts of 8 healthy young male subjects, each receiving a single oral dose of IFB-088 or placebo (6 verum and 2 placebo). In each cohort, 2 subjects (1 verum and 1 placebo) will be dosed first. If the safety and tolerability results are acceptable, the 6 remaining subjects will be dosed by 2 successive groups of 3 subjects, with an adequate period between the 2 groups to detect the occurrence of any reaction or adverse events, namely at least 48H for the first cohort and at least 36H for the following cohorts. Indeed, in the first cohort (2.5 mg IFB-088 base), dosing will be in the morning only. From the second cohort, the planned daily dose will be divided into 2 doses separated by an interval of 12 hours (1 dose in the morning fasting and 1 dose in the evening 2 hours before dinner).

The MAD part consists of 3 cohorts of 8 healthy young male subjects, each receiving an oral dose divided into two doses of IFB-088 or placebo (6 verum and 2 placebo) for 14 days. In each cohort, the 2 first subjects will be dosed on Day 1 (one on active treatment and one on placebo). The 6 remaining subjects will be dosed by 2 successive groups of maximum 3 subjects with an adequate period between the groups to observe for any reaction and adverse events. This period will be of at least 36H, corresponding to at least 5-fold the half-life of the drug (based on results obtained during the SAD part) when steady state will be achieved. In each MAD cohort, the total daily dose will be divided into 2 doses separated by an interval of 12 hours.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72
• Est. completion date: December 16, 2019
• Est. primary completion date: June 21, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

1. Healthy male 18 to 40 years of age inclusive, Caucasian.

2. Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests, vital signs and ECG.

3. AST, ALT, alkaline phosphatase and bilirubin < or = 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

4. ECG (12 leads) normal (120<PR<200ms; QRS<120ms; QTcF<450ms) and/or without clinically relevant impairments as judged by investigator.

5. Non-smoker, or user of not more than tobacco- or nicotine-containing products = 5 cigarettes a day.

6. Negative screen for alcohol and drugs of abuse at screening and admission.

7. No history of psychiatric disorders assessed by a clinical psychological evaluation and the Mini International Neuropsychiatric Interview (MINI).

8. Body mass index (BMI) between 19 and 27 kg/m² inclusive.

9. Subject with female partners of child bearing potential must agree to use one of the contraception methods listed in Section 6.6.1 (Contraception requirements). This criterion must be followed from the time of the first dose of study medication until the follow up visit (for female partners) and with an additional period of 90 days (for subjects themselves).

10. Willing and able to understand and sign an approved Informed Consent Form.

11. Able to understand the protocol and to come to the visits.

12. Who is, in the judgement of the investigator likely to be compliant during the study.

13. Subject registered in the VRB file (volontaires se prêtant à des recherches impliquant la personne humaine).

14. Covered by Health Insurance System and / or in compliance with the recommendations of National Law in force relating to biomedical research.

Exclusion Criteria:

1. 1. History of asthma, anaphylaxis or anaphylactoid reactions, severe allergic responses.

2. History of relevant atopy or drug hypersensitivity.

3. Known allergy to any component of IFB-088 oral capsule or its placebo (HPMC or cellulose microcrystalline).

4. History of major medical, psychiatric illness or surgery which, in the judgment of the investigator, puts them 'at risk' or is likely to modify their handling of the study drug.

5. Acute or chronic systemic disease or disorder (respiratory, gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, endocrine).

6. Impaired renal function defined by a creatinine clearance < 90 mL/min calculated using the Cockcroft-Gault equation (according the FDA Guidance for Industry: Pharmacokinetics in patients with Impaired Renal Function, March 2010).

7. History of nephritic colic and/or renal calculi.

8. History of drug abuse and/or regular use of tobacco- or nicotine-containing products > 5/day within three months of the study.

9. History of alcohol consumption exceeding, (on average 21 drinks/week for men) within 6 months of the first dose of study medication.

10. Drinking excessive amounts of tea, coffee, chocolate and/or beverage containing caffeine (> 4 cups / day).

11. Vital signs with a clinically significant abnormality at screening.

12. ECG with a clinically significant abnormality at screening.

13. Laboratory test values outside the clinically acceptable 'normal range' for healthy volunteers at screening.

14. Positive HIV, Hepatitis B or Hepatitis C at screening.

15. Positive urine drug test or positive breath alcohol test at screening or at admission to the clinical unit.

16. Any medication (including St John's Wort) within 14 days before administration, or within 5 times the elimination half-life of that drug, whichever is the longest (except paracetamol).

17. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to screening.

18. Unable to refrain from consumption of grapefruit or grapefruit juice within 7 days prior to the first dose of study medication.

19. Unwillingness to abstain from sexual intercourse with pregnant or lactating women or to use a condom and spermicide and another form of contraception (e.g., IUD, birth control pills taken by female partner, diaphragm with spermicide) if engaging in sexual intercourse with a woman who could become pregnant until discharge from the study and during 90 additional days.

20. Subjects unlikely to co-operate in the study, and/or poor compliance anticipated by the investigator.

21. Subject being in the exclusion period of a previous trial.

22. Subject having exceeded the earnings for the last 12 months, including the indemnities for the present study.

23. Subject who could not be contacted in case of emergency.

24. Subject refusing to give written informed consent.

25. Subject who has received blood or plasma derivatives in the year preceding the study.

26. Subject who has given blood within the past 3 months or has planned to give blood or sperm within the 90 days following the study.

27. Subject who has forfeited their freedom by administrative or legal award, or who is under guardianship or under limited judicial protection.

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• IFB-088 (2.5-60.0mg) oral capsule
SAD phase: IFB-088 will be administered during 1 day, in one (2.5mg) or 2 (5.0-60.0mg) intakes separated by an interval of 12 hours
• Placebo (2.5-60.mg) oral capsule
SAD phase: placebo (microcrystalline cellulosis) will be administered during 1 day, in one (2.5mg) or 2 (5.0-60.0mg) intakes separated by an interval of 12 hours
• IFB-088 (15.0-50.0mg) oral capsule
MAD phase: multiple doses of IFB-088 (15.0-50.0mg) will be administered daily during 14 days, in two intakes, separated by an interval of 12 hours.
• Placebo oral (15.0-50.0mg) capsule
MAD phase: multiple doses of placebo (microcrystalline cellulosis, 15.0-50.0mg) will be administered daily during 14 days, in two intakes, separated by an interval of 12 hours.

Locations

Country	Name	City	State
France	Eurofins|Optimed	Gières
France	Centre d'Investigation Clinique - Centre de Pharmacologie Clinique et d'Evaluations Thérapeutiques (CIC-CPCET)	Marseille

Sponsors (5)

Lead Sponsor	Collaborator
InFlectis BioScience	Assistance Publique Hopitaux De Marseille, Eurofins Optimed, Qualissima, Stragen France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	SAD Exploratory Biomarkers Analysis	Blood samples will be collected and stored in a biobank to explore potential biomarkers that remain to be identified	SAD phase: Day 1 at predose, 1.5 hours and 24 hours
Other	MAD Exploratory Biomarkers Analysis	Blood samples will be collected and stored in a biobank to explore potential biomarkers that remain to be identified	MAD phase: Day 1 and Day 14 at predose, 1.5 hours and 24 hours
Primary	Number of Participants With Treatment Emergent Adverse Events Per Group	This safety outcome lists the number of subjects experiencing adverse events (AEs), whether not related, possibly or unlikely related to the study treatment.; As all the parameters are developped in the pharmacovigilance section, please do refer to that section for further details.	SAD & MAD phases: Screening visit to End of study visit (7 to 14 days after last dosing) + 30 days
Secondary	Number of Participants With Change in Concomitant Medications	modification in Concomitant medication(s) occuring during the study (if applicable)	SAD & MAD phases: Continuous (Screening visit to End of study visit (7 to 14 days after last dosing) + 30 days)
Secondary	Pharmacokinetic: Maximum Observed Plasma Concentration (Cmax)	Plasma samples are collected: SAD phase - cohort 1 (one intake for daily administration): Day 1 at predose, 0.16, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 24, 32 hours; SAD phase - cohort 2 to 6 (two intakes for daily administration): Day 1 at predose, 0.33, 0.66, 1, 2, 3, 4, 5, 12, 12.25, 12.5, 13, 14, 16, 18, 24, 32 hours; MAD phase (two intakes for daily administration): Day 1 and Day 14 at predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 17, 19 and 21h ; Day 2 (24 hours); Day 7 (predose, 1h and 2 h post dose); Day 15 (24, 30, 36 and 42 hours after Day 14); Day 16 (48, 60 hours after Day 14).	Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17)
Secondary	Pharmacokinetic: Time to Reach the Maximum Concentration in Plasma (Tmax)	Plasma samples are collected: SAD phase - cohort 1 (one intake for daily administration): Day 1 at predose, 0.16, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 24, 32 hours; SAD phase - cohort 2 to 6 (two intakes for daily administration): Day 1 at predose, 0.33, 0.66, 1, 2, 3, 4, 5, 12, 12.25, 12.5, 13, 14, 16, 18, 24, 32 hours; MAD phase (two intakes for daily administration): Day 1 and Day 14 at predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 17, 19 and 21h ; Day 2 (24 hours); Day 7 (predose, 1h and 2 h post dose); Day 15 (24, 30, 36 and 42 hours after Day 14); Day 16 (48, 60 hours after Day 14).	Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17)
Secondary	Pharmacokinetic: Terminal Half-life (t1/2)	Plasma samples are collected: SAD phase - cohort 1 (one intake for daily administration): Day 1 at predose, 0.16, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 24, 32 hours; SAD phase - cohort 2 to 6 (two intakes for daily administration): Day 1 at predose, 0.33, 0.66, 1, 2, 3, 4, 5, 12, 12.25, 12.5, 13, 14, 16, 18, 24, 32 hours; MAD phase (two intakes for daily administration): Day 1 and Day 14 at predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 17, 19 and 21h ; Day 2 (24 hours); Day 7 (predose, 1h and 2 h post dose); Day 15 (24, 30, 36 and 42 hours after Day 14); Day 16 (48, 60 hours after Day 14).	Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17)
Secondary	Pharmacokinetic: Area Under Plasma Concentration-time Curve From Hour 0 to Last Sample With Measurable Plasma Concentrations (AUClast)	Plasma samples are collected: SAD phase - cohort 1 (one intake for daily administration): Day 1 at predose, 0.16, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 24, 32 hours; SAD phase - cohort 2 to 6 (two intakes for daily administration): Day 1 at predose, 0.33, 0.66, 1, 2, 3, 4, 5, 12, 12.25, 12.5, 13, 14, 16, 18, 24, 32 hours; MAD phase (two intakes for daily administration): Day 1 and Day 14 at predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 17, 19 and 21h ; Day 2 (24 hours); Day 7 (predose, 1h and 2 h post dose); Day 15 (24, 30, 36 and 42 hours after Day 14); Day 16 (48, 60 hours after Day 14).	Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17)
Secondary	Pharmacokinetic: Apparent Volume of Distribution (Vd/F)	Plasma samples are collected: SAD phase - cohort 1 (one intake for daily administration): Day 1 at predose, 0.16, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 24, 32 hours; SAD phase - cohort 2 to 6 (two intakes for daily administration): Day 1 at predose, 0.33, 0.66, 1, 2, 3, 4, 5, 12, 12.25, 12.5, 13, 14, 16, 18, 24, 32 hours; MAD phase (two intakes for daily administration): Day 1 and Day 14 at predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 17, 19 and 21h ; Day 2 (24 hours); Day 7 (predose, 1h and 2 h post dose); Day 15 (24, 30, 36 and 42 hours after Day 14); Day 16 (48, 60 hours after Day 14).	Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17)
Secondary	Pharmacokinetic: Apparent Total Body Clearance (CL/F)	Plasma samples are collected: SAD phase - cohort 1 (one intake for daily administration): Day 1 at predose, 0.16, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 24, 32h; SAD phase - cohort 2 to 6 (two intakes for daily administration): Day 1 at predose, 0.33, 0.66, 1, 2, 3, 4, 5, 12, 12.25, 12.5, 13, 14, 16, 18, 24, 32h; MAD phase (two intakes for daily administration): Day 1 and Day 14 at predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 13, 14, 17, 19 and 21h ; Day 2 (24 hours); Day 7 (predose, 1h and 2 h post dose); Day 15 (24, 30, 36 and 42 hours after Day 14); Day 16 (48, 60 hours after Day 14).	Starting 1 hour prior to dosing on Day 1 and until 72 hours after last dosing (Day 17)
Secondary	Pharmacokinetic: Renal Clearance (CLr)	Urine samples are collected: SAD phase - cohort 1 (one intake for daily administration): Day 1 at predose, 0-4 hours, 4-8 hours, 8-16 hours,16-32 hours SAD phase - cohort 2 to 6 (two intakes for daily administration): Day 1 at predose, 0-4, 4-8, 8-12, 12-24, 24-32 hours MAD phase (two intakes for daily administration): Day 1 and Day 14: predose, 0-4, 4-12, 12-24 hours; Day 6: predose, 0-4 and 4-12 hours; Day 15: 24-36, 36-48 hours after Day 14	Starting 1 hour prior to dosing on Day 1 and until 48 hours after last dosing (Day 16)
Secondary	Pharmacokinetic: Percent of Drug Recovered in Urine (Ae %Dose)	Urine samples are collected: SAD phase - cohort 1 (one intake for daily administration): Day 1 at predose, 0-4 hours, 4-8 hours, 8-16 hours,16-32 hours; SAD phase - cohort 2 to 6 (two intakes for daily administration): Day 1 at predose, 0-4, 4-8, 8-12, 12-24, 24-32 hours; MAD phase (two intakes for daily administration): Day 1 and Day 14: predose, 0-4, 4-12, 12-24 hours; Day 6: predose, 0-4 and 4-12 hours; Day 15: 24-36, 36-48 hours after Day 14	Starting 1 hour prior to dosing on Day 1 and until 48 hours after last dosing (Day 16)
Secondary	Number of Participants With Clinically Significant Change in Physical Evaluation During the Study	the following parameters are assessed during the physical evaluation visit: Cardiovascular system (see specific outcome measure), Digestive system (included spleen organ), alcohol consumption (Ethylotest), General condition, Liver and biliary tracts, Lymphatic system, Muco-cutaneous system, Neck/Thyroide, Nervous system, ENTsystem, Respiratory system, Visual system	SAD & MAD phases: Screening; Day 2 (SAD) or Day 17 (MAD); and at End of study visit (7 to 14 days after last dosing)
Secondary	Number of Participants With Clinically Significant Change in Physiological Parameters During the Study	Weight measured in kg and height measured in cm, were taken and Body Mass Index was calculated using those 2 values	SAD & MAD phases: Screening; Day 2 (SAD) or Day 17 (MAD); and at End of study visit (7 to 14 days after last dosing)
Secondary	Number of Participants With With Clinically Significant Change in Cardiovascular Functions During the Study	This safety outcome aims at monitoring cardiovascular functions and identify potential adverse events/reactions (clinical assessment combined with ECGs and vital signs assessments).	From screening visit until end of study visit (7 to 14 days after last dosing)
Secondary	Number of Participants With With Clinically Significant Change in Tympanic Body Temperature During the Study	Tympanic body temperature will be measured at the time frame described underneath.at the following Timepoints : change in body temperature (fever) will be reported per patient per group.	SAD phase (cohorts 1 to 6):Screening, Day -1;Day 1 ;end (7 to 14 days after last dosing) MAD phase: Screening;Day -1; Day 1 ;predose at Day 2, Day 4, Day 6, Day 8, Day 10, Day 12; Day 14 ; Day 17; end (7 to 14 days after last dosing)
Secondary	Number of Participants With With Clinically Significant Change in Hematology Parameters During the Study	This safety outcome aims at monitoring hematology parameters: Red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelets, reticulocyte count will be monitored from screening to end of study visit (7 to 14 days after last dosing), at several time points.; When a participant experienced clinically significant change in the parameter, at least once during the study, he/she is recorded in the table.	SAD phase: Screening; Day -1; Day 2 (24 hours); end of study visit (7 to 14 days after last dosing) MAD phase: Screening; Day -1; predose, at Day 3, Day 6, Day 10, Day 13; Day 17; end of study visit (7 to 14 days after last dosing)
Secondary	Number of Participants With With Clinically Significant Change in Coagulation Parameters During the Study	This safety outcome aims at monitoring coagulation parameters such as Activated partial thromboplastin time (APTT), international normalized ratio (INR)	SAD phase: Screening; Day -1; Day 2 (24 hours); end of study visit (7 to 14 days after last dosing) MAD phase: Screening; Day -1; predose at Day 3, Day 6, Day 10, Day ; Day 17; end of study visit (7 to 14 days after last dosing)
Secondary	Number of Participants With With Clinically Significant Change in Blood Biochemistry Parameters During the Study	This safety outcome aims at monitoring the following blood biochemistry parameters: Sodium, potassium, chloride, calcium, total bilirubin, alanine aminotransferase (ASAT), aspartate aminotransferase (ALAT), gamma-glutamyl transferase (GGT), alkaline phosphatases, total protein, albumin, urea, uric acid, bicarbonate, creatine phosphokinase (CPK), creatinine, glycaemia, lactate dehydrogenase (LDH), total cholesterol, HDL and LDL cholesterol, triglycerides	SAD phase: Screening; Day -1; Day 2 (24 hours); end of study visit (7 to 14 days after last dosing) MAD phase: Screening; Day -1; predose at Day 3, Day 6, Day 10, Day 13; Day 17; end of study visit (7 to 14 days after last dosing)
Secondary	Number of Participants With Clinically Significant Change in Urinary Functions/Parameters During the Study	This safety outcome aims at monitoring urinary functions/parameters: Specific gravity, pH, glucose, protein, blood, nitrites, leucocytes and ketones by dipstick.; Results are given as "absent" or "present, not clinically significant" or "present clinically significant".; A cytobacteriological exam will be done if abnormal results on dipstick). Beta 2 microglobulin (B2M), proteinuria and creatinuria will be also monitored.	SAD phase: Screening; Day -1; Day 1 (predose, 12, 24, 32 hours); end of study visit (7 to 14 days after last dosing) MAD phase: Screening; Day -1; predose at Day 1, Day 3, Day 6, Day 10, Day 13; Day 17; end of study visit (7 to 14 days after last dosing)
Secondary	Number of Participants With Clinically Significant Change in Vigilance and Mood During the Study	Assessment and monitoring of the vigilance/mood of healthy volunteers through the use of a Bond-Lader Visual Analogue Scale listing 16 mood items, with 2 words at the beginning and the end of the scale bar. Depending on the item, the scale would go from better to worse (ie strong to weak) or the opposite (Hostile to friendly). Alertness, Self-contentment, Calmness are computed by averaging their respective items and are mentionned in the volunteer file.	SAD Phase: Screening; Day 1 (predose, 1.5, 12, 32 hours) MAD Phase: Screening; Day 1 (predose, 1.5, 12 hours); Day 14 (predose, 1.5, 12 hours)

External Links

•   Website of InFlectis BioScience