Clinical trial NCT05117593: Investigate the Safety, Tolerability and Pharmacokinetics of FBL-MTX
Official title: Phase 1 Study to Investigate the Safety, Tolerability and Pharmacokinetics of Single-Ascending Doses of FBL-MTX in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Rheumatoid Arthritis
Keywords: rheumatoid arthritis
healthy
Lead sponsor: SOLFARCOS - Pharmaceutical and Cosmetic Solutions Ltd
Sponsor class: OTHER
First posted: 2021-11-11
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: A maximum of 4 dose levels (0.1 mg, 0.33 mg, 1 mg and 2.5 mg) is preplanned to be investigated in separate sequential cohorts. Each cohort will consist of 8 healthy male and female subjects (3 subjects of either sex on FBL-MTX, 1 of either sex on placebo).
Primary purpose: OTHER

Brief summary: This is a prospective, single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 study to evaluate the safety, tolerability and pharmacokinetics of FBL-MTX in healthy male and female subjects.

Detailed description: The product FBL-MTX consists of Methotrexate (MTX) encapsulating liposomes functionalized with a folate peptide (SP-DS3), which targets activated macrophages of rheumatoid arthritis (RA).

This is a prospective, single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 study in healthy subjects.

This study is planned to investigate up to 4 dose levels of FBL-MTX. Each dose level will consist of 8 healthy male and female subjects (ratio 1:1, male:female) to have 6 subjects being administered FBL-MTX and 2 subjects being administered placebo (ratio 3:1, active:placebo).

The study is designed to meet the following objectives:

* Primary: To evaluate the safety and tolerability of FBL-MTX following single-ascending intravenous doses to healthy male and female subjects.
* Secondary: To investigate the PK of FBL-MTX following single-ascending intravenous doses to healthy male and female subjects.

Eligibility criteria: Inclusion Criteria:

1. Signed informed consent prior to any study-mandated procedure.
2. Healthy male or female subjects aged between 18 and 55 years (inclusive) at Screening.
3. Body mass index (BMI) of 18.0 to 30.0 kg/m2 (inclusive) at Screening.
4. Ability to communicate well with the investigator, in a language understandable to the subject, and to understand and comply with the study requirements.
5. Systolic blood pressure (SBP) 100-140 mmHg, diastolic blood pressure (DBP) 50-90 mmHg, and pulse rate 50-90 bpm (inclusive), measured on the same arm after ≥5 min in the supine position, at Screening and on Day -1.
6. Estimated glomerular filtration rate calculated using the Cockcroft-Gault equation ≥ 90 mL/min at Screening.
7. A female subject of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day -1 and must agree to consistently and correctly use (from Screening, during the entire study, and for at least 6 months after investigational product administration) a highly effective method of contraception with a failure rate of ≤1% per year, be sexually inactive, or have a vasectomized partner. If a hormonal contraceptive is used, it must be initiated at least 1 month before the treatment administration.
8. A female subject of non-childbearing potential, must be post-menopausal (defined as 12 consecutive months with no menses without an alternative medical cause, confirmed by a follicle stimulating hormone \[FSH\] test), or must have a medical history of previous bilateral salpingectomy, bilateral salpingo-oophorectomy, hysterectomy, premature ovarian failure (confirmed by a specialist), XY genotype, Turner syndrome, or uterine agenesis.
9. A male subject must use adequate contraception (e.g., condom) from investigational product administration up to at least 6 months after, unless he is vasectomized or sexually inactive. In addition, the subject must ensure that his female partner of childbearing potential agrees to consistently and correctly use for the same period a highly effective method of contraception with a failure rate of ≤1% per year.
10. A male subject must agree to refrain from donation of semen from investigational product administration up to at least 6 months after.

Exclusion Criteria:

1. Previous exposure to FBL-MTX.
2. Known hypersensitivity to MTX or any other FBL-MTX components.
3. Clinically relevant findings on physical examination at Screening or on Day -1.
4. Clinically relevant abnormalities on 12-lead ECG, measured after 5 min in a supine position, at Screening or on Day -1.
5. Clinically relevant abnormalities on chest X-ray at Screening.
6. Clinically relevant findings in clinical laboratory tests (hematology, clinical chemistry, and urinalysis) at Screening or on Day -1.
7. Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia.
8. QTc \> 450ms in male and \> 470ms in female.
9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) above the normal range.
10. Any medical condition, acute, ongoing, recurrent or chronic, that presents a potential risk to the participant and/or that may compromise the objectives of the study.
11. History of major medical or surgical disorders which, in the opinion of the investigator, are likely to interfere with the distribution, metabolism, or excretion of the investigational product.
12. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator.
13. History of tuberculosis.
14. Presence of chronic or acute bacterial or viral infection.
15. History or presence of an autoimmune disorder.
16. History of known or suspected immunodeficiency syndrome
17. Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcer disease.
18. Any significant acute or chronic medical illness, including past or present liver disease.
19. Previous clinically relevant history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
20. Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access, or puncture, veins with a tendency to rupture during or after puncture).
21. Participation in a clinical study involving investigational product administration within 3 months prior to Screening or in more than 2 clinical studies within 1 year prior to Screening.
22. History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to Screening.
23. Excessive methylxanthines consumption, defined as ≥ 500 mg per day, at Screening.
24. Nicotine intake (e.g., smoking, nicotine patch, nicotine chewing gum, or electronic cigarettes) within 3 months prior to Screening and inability to refrain from nicotine intake from Screening up to End-of-Study (EOS).
25. Previous treatment with any prescribed medications or over-the-counter (OTC) medications (including herbal medicines such as St John's Wort, homeopathic preparations, vitamins, and minerals) within 3 weeks prior to investigational product administration.
26. Previous treatment with vaccines within 4 weeks prior to investigational product administration.
27. Loss of 250 mL or more of blood within 3 months prior to Screening.
28. Positive results from urine drug and alcohol screen at Screening or on Day -1.
29. Positive Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb) and/or HCV antibodies at Screening.
30. Positive HIV serology results at Screening.
31. Pregnant or lactating woman.
32. Any other circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

Primary outcomes:
measure: Change from baseline at each time point of measurement in systolic blood pressure
timeFrame: From study treatment administration up to end of study, an average of 1month
measure: Change from baseline at each time point of measurement in diastolic blood pressure
timeFrame: From study treatment administration up to end of study, an average of 1month
measure: Change from baseline at each time point of measurement in pulse rate
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in hemoglobin
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in red cell count
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in hematocrit
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in mean corpuscular volume
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in mean corpuscular hemoglobin
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in mean corpuscular hemoglobin concentration
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in red cell distribution width
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in white cell count with differential
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in platelet count
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in mean platelet volume
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in AST
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in clinical ALT
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in gamma-glutamyltransferase (GGT)
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in alkaline phosphatase (ALP)
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in total bilirubin
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in indirect bilirubin
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in direct bilirubin
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in lactate dehydrogenase (LDH)
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in creatinine
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in urea
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in urate
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in glucose
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in cholesterol
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in triglycerides
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in sodium
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in potassium
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in chloride
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in calcium
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in protein
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in albumin
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in creatine kinase (CK)
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in creatinine clearance
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in glucose in urine
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in bilirubin in urine
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in ketone in urine
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in specific gravity
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in hemoglobin in urine
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in pH in urine
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in protein in urine
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in urobilinogen
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in nitrite in urine
timeFrame: From study treatment administration up to end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in heart rate
timeFrame: From study treatment administration up to the end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in QT interval corrected with Bazett's formula
timeFrame: From study treatment administration up to the end of study, an average of 1 month
measure: Change from baseline at each time point of measurement in QT interval corrected with Fridericia's formula (QTcF)
timeFrame: From study treatment administration up to the end of study, an average of 1 month
measure: Treatment-emergent AEs
timeFrame: From study treatment administration up to the end of study, an average of 1 month
measure: Treatment-emergent SAEs
timeFrame: From study treatment administration up to the end of study, an average of 1 month
measure: Treatment-emergent AEs leading to premature study discontinuation.
timeFrame: From study treatment administration up to the end of study, an average of 1 month
Secondary outcomes:
measure: Maximum plasma concentration (Cmax)
timeFrame: Multiple pharmacokinetic sampling at predefined timepoints from Day 1 (pre-dose) up to Day 7.
measure: Time to reach Cmax (tmax).
timeFrame: Multiple pharmacokinetic sampling at predefined timepoints from Day 1 (pre-dose) up to Day 7.
measure: Area under the concentration-time curve (AUC) from time zero to last measurable plasma concentration (AUC0-t)
timeFrame: Multiple pharmacokinetic sampling at predefined timepoints from Day 1 (pre-dose) up to Day 7.
measure: AUC from time zero to infinity (AUC0-∞)
timeFrame: Multiple pharmacokinetic sampling at predefined timepoints from Day 1 (pre-dose) up to Day 7.
measure: Terminal elimination rate constant (λz).
timeFrame: Multiple pharmacokinetic sampling at predefined timepoints from Day 1 (pre-dose) up to Day 7.
measure: Terminal elimination half-life (t1/2).
timeFrame: Multiple pharmacokinetic sampling at predefined timepoints from Day 1 (pre-dose) up to Day 7.
measure: Apparent plasma clearance (CL/F).
timeFrame: Multiple pharmacokinetic sampling at predefined timepoints from Day 1 (pre-dose) up to Day 7.
measure: Apparent volume of distribution (Vz/F) during the terminal elimination phase
timeFrame: Multiple pharmacokinetic sampling at predefined timepoints from Day 1 (pre-dose) up to Day 7.
Other outcomes:
Locations:
city: Porto
country: Portugal
facility: BlueClinical Phase I
Study officials:
References: