Pharmacokinetics
Conditions
Keywords
Safety, Pharmacokinetics, Dose escalation study
Brief summary
This trial will be a Phase I open-label, placebo-controlled dose escalation study to evaluate safety and pharmacokinetics of Natrunix via subcutaneous injection in healthy subjects. The target enrollment is 8 healthy subjects per cohort (including six for Natrunix and two for placebo). Three cohorts for a total of 24 healthy volunteers.
Detailed description
Study Title: A Phase I open-label, placebo-controlled dose escalation study to evaluate safety and pharmacokinetics of Natrunix via subcutaneous injection in healthy subjects. Sponsor: XBiotech USA, Inc. Study Chair: Neha Reshamwala, MD Number of Planned Subjects: Eight healthy subjects per cohort (including six for Natrunix and two for placebo). Three cohorts for a total of 24 healthy volunteers. Approximate Duration: Approximately 38 days for each subject which includes a screening period of up to 10 days followed by one subcutaneous dose of Natrunix, and then evaluation over 28 days. Blood will be sampled at various time points for blood chemistry, hematological analysis, and Natrunix serum/plasma concentrations.
Interventions
BIOLOGICALNatrunix
The active ingredient in the drug product Natrunix is XB2001, a recombinant human Immunoglobulin G4 monoclonal antibody specific for human interleukin-1-alpha (IL-1-alpha). The entire XB2001 heavy and light chain sequences are identical to those found in naturally-occurring humans, with the light and heavy chain variable regions being identical to those originally expressed by a peripheral blood B lymphocyte that was obtained from a healthy individual.
BIOLOGICALPlacebo
Placebo control for Natrunix subcutaneous injection.
Sponsors
XBiotech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Each subject receives a single subcutaneous injection of Natrunix at one of the three doses (100 mg, 200 mg or 400 mg) and/or placebo for duration of 28 days. For each dose cohort, six subjects administer Natrunix and two subjects administer placebo. The study proceeds to the next dose level if the tested dose level have acceptable tolerability and safety. Subjects undergo blood sampling for toxicity and Pk analysis. Subjects are evaluated for the development of anti-drug antibodies (ADA).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Age: ≥ 18 2. Adequate bone marrow function defined as: * absolute neutrophil count (neutrophil and bands) of ≥ 1,500/mm3 (≥ 1.5 x 109/L) * platelet count \> 150,000/mm3 * hemoglobin of ≥ 10 g/dL 3. Adequate renal function, defined by serum creatinine ≤ 1.5 x lab ULN. 4. Adequate hepatic function defined as: 5. serum albumin ≥ 3.0 g/dL 6. total bilirubin ≤ 1.5 times lab ULN. 7. alanine aminotransferase (ALT) ≤ 2.0 times lab ULN. 8. aspartate aminotransferase (AST) ≤ 2.0 times lab ULN 9. For WOCBP, a negative pregnancy test at screening. For subjects with reproductive potential, willingness to use one method of contraception of high efficacy during the entire study period. These methods can include but not limited to hormonal contraceptives, intrauterine devices, condoms, diaphragms etc. Women of non-childbearing potential include those considered to have a medical history that indicates that pregnancy is not a reasonable risk, including post-menopausal women and those with a history of hysterectomy or surgically sterilized. 10. If the participant is a male participating in this clinical research study, the subject should not get a sexual partner pregnant during participation in this research study as the effect of the study drug on sperm is not known. The male contraception methods can include but not limited to mechanical methods (abstinence, withdrawal, non-vaginal intercourse) or contemporary methods comprising condoms and vasectomy. 11. Signed and dated Institutional Review Board (IRB) approved informed consent before any protocol-specific screening procedures are performed.
Exclusion criteria
1. Treatment with any biologicals (including intravenous immunoglobulin) or investigational agents within the last 4 weeks (or 5 half-lives, whichever is longer). 2. Uncontrolled or significant cardiovascular disease, including: * A myocardial infarction within the past 6 months. * Uncontrolled angina within the past 3 months. * Congestive heart failure within the past 3 months, defined as New York Heart Association (NYHA) Class II or higher. * Uncontrolled hypertension (blood pressure \>160 mm Hg systolic or \>100 mm Hg diastolic). 3. Dementia or altered mental status that would prohibit the understanding or rendering of informed consent. 4. Treatment with immunosuppressant agents, including corticosteroids or cyclosporine within the last 4 weeks. 5. Serious uncontrolled medical disorders, such as uncontrolled diabetes, active peptic ulcer disease, cerebrovascular accident within three months, ongoing congestive heart failure, and any other condition, which in the opinion of the investigator, would put the subject at risk by participating in the trial. 6. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. 7. Abnormal ECG with any clinically significant findings or with QTc \> 470 ms. 8. Infection requiring treatment with antibiotics within 3 weeks prior to screening. 9. Infectious disease: • Positive HIV, RPR, Hepatitis B or C, TB (QuantiFERON-TB Gold (QFT)/ IGRA) 10. History of immunodeficiency. 11. Female subjects who are pregnant, planning to become pregnant during the course of the study, or breast-feeding. 12. Major surgery within 28 days prior to Day 0. 13. History of progressive multifocal leukoencephalopathy (PML) or other demyelinating disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events | From Day 0 up to Day 28 | Participants were monitored for treatment-emergent adverse events (TEAEs) immediately after the initial subcutaneous administration on Day 0 (Visit 1) through the final follow-up on Day 28 (Visit 7). All identified adverse events were documented and graded for severity according to the "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials." |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | Plasma samples were collected at the following intervals: Day 0: Pre-injection and at 3, 6, and 10 hours post-injection. Post-Injection Follow-up: Days 2, 3, 4, 14, and 28. | This outcome measure represents the peak exposure following a single subcutaneous administration of Natrunix. Cmax is assessed using a proprietary immunoassay. Placebo participants were not assessed for PK Outcome Measures |
| Terminal Plasma Concentration | Day 28 | This outcome measure evaluates the circulating drug levels at the end of the study observation period. Plasma samples were analyzed using a validated proprietary immunoassay to detect and quantify concentration levels of Natrunix. Placebo participants were not assessed for PK Outcome Measures |
| Half-life | Plasma samples were collected at the following intervals: Day 0: Pre-injection and at 3, 6, and 10 hours post-injection. Post-Injection Follow-up: Days 2, 3, 4, 14, and 28. | Half-life is calculated by Thermo-Scientific Kinetica Version 5.1 SP1, using average observed Natrunix plasma concentration of all time points of all patients for each treatment cohort. Placebo participants were not assessed for PK Outcome Measures |
| Area Under the Curve | Plasma samples were collected at the following intervals: Day 0: Pre-injection and at 3, 6, and 10 hours post-injection. Post-Injection Follow-up: Days 2, 3, 4, 14, and 28. | This outcome measure calculates the area Under the Concentration-Time Curve (AUC) from the time of administration (Day 0) through the final observation point at Day 28. Placebo participants were not assessed for PK Outcome Measures |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on physician referral at a single research center.
Pre-assignment details
Out of the 28 subjects that were screened, 24 were enrolled based on the eligibility criteria. Two subjects were screen failures while 2 withdrew consent prior to receiving the study drug.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Age, Continuous | 29 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 |
| other Total, other adverse events | 2 / 6 | 0 / 2 | 1 / 6 | 0 / 2 | 0 / 6 | 0 / 2 |
| serious Total, serious adverse events | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 |
Outcome results
None listed