Study to Investigate the Effect of BL-8040 (Motixafortide) on the QTc Interval in Healthy Subjects

Study Overview
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Brief Summary
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The study will assess the corrected QT (QTc) effects (electrocardiogram [ECG]) of BL-8040 1.25 mg/kg (therapeutic dose) and 2 mg/kg (supratherapeutic dose) following a single subcutaneous (SC) injection relative to placebo in approximately 40 healthy subjects.

Detailed Description
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This is a randomized, double-blind (in respect to BL-8040 and BL-8040-matching placebo dosing), placebo- and positive-controlled, 4-period, 4-way crossover study in healthy subjects. A continuous 12-lead cardiodynamic ECG recording will be collected for approximately 24 hours on Day -1 of Period 1 for use in the optimized individual corrected QTc (QTcI) baseline calculations. On Day 1 of Period 1, subjects will be randomized to 1 of 12 treatment sequences. Each treatment sequence comprises 4 treatment periods. On Day 1 of each period, subjects will receive single-dose SC injection of BL-8040 (therapeutic or supratherapeutic dose), single-dose SC injection of BL-8040-matching placebo, or a single oral dose of moxifloxacin. Cardiodynamic readings, plasma PK samples, and blood PD samples will be collected at different time points prior to dosing and up to 24 hours postdose in each period, as appropriate. There will be a washout period of 5-7 days between dosing in each period. All subjects who received at least one dose of any study drug (including subjects who terminate the study early) will return to the clinical research unit (CRU) 7 ± 2 days after the last dose for follow-up procedures, and to determine if any adverse event (AE) has occurred since the last study visit.

Official Title
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A Single-Dose, Randomized, Double-Blind, Placebo-Controlled, Positive-Controlled, Four-Way Crossover Study to Investigate the Effect of BL-8040 (Motixafortide) on the QTc Interval in Healthy Subjects

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: 1.25 mg/kg BL-8040 + BL-8040-matching placebo
* Drug: 2 mg/kg BL-8040
* Drug: BL-8040-matching placebo
* Drug: 400 mg Moxifloxacin (1x400 mg tablet)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, adult, males and females between the ages of 18 and 55 years, inclusive, at Screening. Body weight between 50-109 kg (inclusive) and body mass index (BMI) within 18.0-29.99 kg/m2 (inclusive) at Screening. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or ECGs, as deemed by the PI or designee. Current non-smokers who have not used any nicotine-containing products (chewed or smoked) or replacement products including electronic cigarettes for at least 3 months prior to first dosing. Women must meet one of the following criteria: a) postmenopausal; b) surgically sterile; c) of childbearing potential and practicing contraception, as described below: Postmenopausal (postmenopausal women must have no menstrual bleeding for at least 1 year prior to first dosing and menopause is confirmed by FSH levels consistent with postmenopausal status), or Surgically sterile (e.g., hysterectomy, bilateral oophorectomy, hysteroscopic sterilization) for at least 6 months prior to first dosing, or Women of childbearing potential must be non-lactating and agree to either using a highly effective acceptable form of birth control (e.g., non-hormonal intrauterine device plus condom and spermicide). A non-vasectomized, male subject must agree to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days after the last dosing. (No restrictions are required for a vasectomized male provided his vasectomy has been performed 4 months or more prior to the first dosing. A male who has been vasectomized less than 4 months prior to study first dosing must follow the same restrictions as a non-vasectomized male.) If male, must agree not to donate sperm from the first dosing until 90 days after the last dosing. Understands the study procedures in the informed consent form (ICF), and is willing and able to comply with the protocol. Exclusion Criteria: Past or present diseases, which, as judged by the PI or designee, may affect the outcome of this study or pose an additional risk to the subject by their participation in the study, including, but not limited to, significant medical abnormality including: psychiatric, neurologic, pulmonary, cardiac, gastrointestinal, genitourinary, renal, metabolic, endocrinologic, or autoimmune disorder. Is mentally or legally incapacitated or has significant emotional problems at the time of the Screening visit or expected during the conduct of the study. Positive result for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody at Screening. Family history of QTc prolongation or of unexplainable sudden death at <50 years of age. History or presence of any of the following: sick sinus syndrome, second or third degree atrioventricular block, myocardial infarction, pulmonary congestion, symptomatic or significant cardiac arrhythmia, prolonged QTcF interval, or conduction abnormalities; ischemic heart disease, symptomatic arrhythmias, or poorly controlled hypertension. Knowledge of any kind of cardiovascular disorder/condition known to increase the possibility of QT prolongation or history of additional risk factors for torsade de pointes (e.g., heart failure, clinically significant hypokalemia, family history of Long QT Syndrome or Brugada Syndrome) or cardiac conduction disorders. Any condition that may interfere with the absorption, metabolism, or elimination of the study drug. History of, or active, alcohol or illicit drug abuse as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, manual, within 2 years prior to the first dosing. Alcohol abuse is defined as an average intake of two or more drinks (12 oz beer, 1.5 oz of hard liquor, or equivalent) per day. Laboratory safety test results that are outside of the normal reference ranges (unless clinically acceptable to the PI or designee) at Screening. Resting supine HR <50 bpm or >100 bpm at Screening or check-in (Day -2). Minor deviations will be acceptable if considered to be of no clinical significance by the PI or designee. Resting supine systolic blood pressure <90 mmHg or >140 mmHg; resting supine diastolic blood pressure <50 mmHg or >90 mmHg at Screening or check-in. Significant history or presence of ECG findings at Screening or check-in (Day -2), including: QTcF >450 msec QRS >110 msec, if >110 msec, result will be confirmed by a manual over read PR >200 msec Second or third-degree atrioventricular (AV) block. Significant history or presence of ECG findings as judged by the PI or designee at Screening or check-in (Day -2), including: ECG abnormalities which interfere with accurate QT measurement T wave flattening or other abnormalities which in the opinion of the PI (or designee) may interfere with the analysis of QT intervals Any rhythm other than sinus rhythm, which is interpreted by the PI (or designee) to be clinically significant. Significant safety laboratory abnormalities that would place the subject at undue risk in the PI or designee's opinion, including but not limited to serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) >1.2 x upper limit of normal at Screening or check-in. Positive urine cotinine at Screening. Unable to refrain from or anticipates the use of: * Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements beginning 14 days or 5 half-lives (whichever is longer) prior to the first dosing or likelihood that such treatment will be needed at any time during the study (unless approved in advance by the Sponsor). Medications listed in Section 11.4.2 will be allowed. Participation in another clinical study within 30 days prior to the first dosing. The 30-day window will be derived from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of Period 1 of the current study. Donation of blood or blood loss >500 mL within the 56 days prior to the first dosing. Plasma donation within 7 days prior to the first dosing. Any condition or situation that, in the opinion of the PI or designee, would prevent proper evaluation of the safety, PK, and/or PD of the study drug according to the study protocol (e.g., poorly compliant subject, poor venous access, allergies to medical plastics/latex/adhesive dressing/medical tape). History of hypersensitivity or allergy to moxifloxacin or any study medication. History of tendonitis or tendon rupture with moxifloxacin or any other quinolone type drug. History of unexplained loss of consciousness, unexplained syncope, near drowning with hospital admission. Use of any marijuana product within 6 months prior to the first dosing. Use of illicit drugs or tetrahydrocannabinol-containing medicines within 6 months prior to the first dosing. Female subjects with a positive pregnancy test at Screening or check-in or lactating. Positive urine drug or alcohol results at Screening or check-in. Has tattoo(s) or scarring at or near the site of injection or any other condition which may interfere with injection site examination, in the opinion of the PI or designee. Subjects intending to lose weight during the 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a randomized, double-blind (in respect to BL-8040 and BL-8040-matching placebo dosing), placebo- and positive-controlled, 4-period, 4-way crossover study. On Day 1 of Period 1, subjects will be randomized to 1 of 12 treatment sequences. Each treatment sequence comprises 4 treatment periods. Each subject will be assigned a unique identification number upon screening. Subjects who complete the study screening assessments and meet all the eligibility criteria will be assigned a unique randomization identification number at the time of the first dosing, different from the screening number, and will receive the corresponding study drug, according to a randomization scheme. Subjects will receive each of the 4 Treatments in a pre-defined order according to the sequence scheme determined at randomization.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.25 mg/kg BL-8040 + BL-8040-matching placebo administered via SC injection (Therapeutic)<br>1.25 mg/kg BL-8040 + BL-8040-matching placebo administered via SC injection (Therapeutic) | Drug: 1.25 mg/kg BL-8040 + BL-8040-matching placebo<br>* Administered via subcutaneous (SC) injection<br>|
| Experimental: 2 mg/kg BL-8040 administered via SC injection (Supratherapeutic)<br>2 mg/kg BL-8040 administered via SC injection (Supratherapeutic) | Drug: 2 mg/kg BL-8040<br>* Administered via subcutaneous (SC) injection<br>|
| Placebo Comparator: BL-8040-matching placebo administered via SC injection<br>BL-8040-matching placebo administered via SC injection | Drug: BL-8040-matching placebo<br>* Administered subcutaneous (SC) injection<br>|
| Active Comparator: 400 mg moxifloxacin (1 x 400 mg tablet) administered orally<br>400 mg moxifloxacin (1 x 400 mg tablet) administered orally | Drug: 400 mg Moxifloxacin (1x400 mg tablet)<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the QTc effects of BL-8040 1.25 mg/kg and 2 mg/kg following a single SC injection relative to placebo in healthy subjects | Evaluation of the relationship between the plasma concentration of BL-8040 and ΔΔQTcI (placebo adjustment for ΔQTcI will be performed in the concentration-QTc model). | Continuous 24 hour cardiodynamic ECG recording on Day -1 (one day prior to dosing) of Period 1 (each period is 24 hours long) | 
| Assessment of the QTc effects of BL-8040 1.25 mg/kg and 2 mg/kg following a single SC injection relative to placebo in healthy subjects | Evaluation of the relationship between the plasma concentration of BL-8040 and ΔΔQTcI (placebo adjustment for ΔQTcI will be performed in the concentration-QTc model). | Cardiodynamic ECG recordings on Day 1 (day of dosing) at different time points prior to dosing and up to 24 hours postdose in each period (each period is 24 hours long, a total of 4 periods) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the safety (by assessing AEs, ECGs, vital signs, clinical lab tests, physical examination) and tolerability (by assessing AEs) of single therapeutic and supratherapeutic SC injections of BL-8040 in healthy subjects. | Evaluation of AEs, 12-lead safety ECGs, vital signs, clinical laboratory tests, and physical examinations. | Blood for BL-8040 PK is collected prior to dosing and at 13 different time points following dosing up to 24 hours | 
| Evaluation of PK of single therapeutic and supratherapeutic SC injections of BL-8040 in healthy subjects. | Evaluation of AUC0-t, AUC0-inf, AUC%extrap, Cmax, Tmax, for BL-8040, as appropriate. | Blood for BL-8040 PK is collected prior to dosing and at 13 different time points following dosing up to 24 hours | 
| Evaluation of assay sensitivity (i.e., to evaluate the effect of a positive control, a single oral 400 mg dose of moxifloxacin on the QTc interval in healthy subjects | Evaluation of the relationship between the plasma concentration of moxifloxacin and ΔQTcI in order to demonstrate assay sensitivity | Blood for Moxifloxacin PK is collected prior to dosing and at 11 different time points following dosing up to 24 hours | 
| Assessment of the effects of single therapeutic and supratherapeutic SC injections of BL-8040 on non-QT interval ECG parameters | Time-point change from baseline, placebo-adjusted in ΔΔQTcI. Time-point change from baseline, placebo-adjusted, for HR, RR, QTcF, PR, and QRS. Categorical outliers for HR, RR, PR,QRS, QTcI, and QTcF. Frequency of treatment-emergent changes in ECG morphology | Continuous 24 hour cardiodynamic ECG recording on Day -1 (one day prior to dosing) of Period 1 (each period is 24 hours long) | 
| Assessment of the effects of single therapeutic and supratherapeutic SC injections of BL-8040 on non-QT interval ECG parameters | Time-point change from baseline, placebo-adjusted in ΔΔQTcI. Time-point change from baseline, placebo-adjusted, for HR, RR, QTcF, PR, and QRS. Categorical outliers for HR, RR, PR,QRS, QTcI, and QTcF. Frequency of treatment-emergent changes in ECG morphology | ardiodynamic ECG recordings on Day 1 (day of dosing) at different time points prior to dosing and up to 24 hours postdose in each period (each period is 24 hours long, a total of 4 periods) |