A Phase 1 Study of HBI-3000

NCT03397641 | Completed Phase 1 DMC

• 2 other identifiers: HBI-3000-3012017-003642-24
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1 randomised, double-blind, placebo-controlled, serial cohort, dose-escalation study in healthy adult volunteers. It is planned to enroll 5 cohorts (Cohorts A to E) of 8 subjects. Up to 2 additional cohorts (Cohorts F and G) may be enrolled as needed to establish the safety profile of HBI-3000 over a clinically relevant range of doses. Subjects will be randomly assigned to receive a single dose of HBI-3000 or matching placebo in a sequential escalating manner (Regimens A to E and optional Regimens F and G), with a minimum of 7 days and a maximum based on logistics of interim review between dose groups. As a safety precaution, in each cohort a sentinel dosing group of n = 2 (1 active:1 placebo) will be dosed at least 24 h ahead of the main group. Safety and tolerability will be assessed by the principal investigator or medically-qualified designee before continuing with dosing the remaining subjects. The first 2 subjects will be allocated to active or placebo in a 1:1 ratio. The remaining 6 subjects will be allocated to active or placebo in a 5:1 ratio. Doses of HBI-3000 may range from 20 mg to a level at which it is expected that the drug exposure will not exceed an AUC(0-t) of 20 μg.h/mL and Cmax of 20 μg/mL (based on the no-observed-adverse-effect levels \[NOAEL\] in both 14 day repeat dose toxicology species the rat and minipig) and the expected therapeutic dose range. Following administration to each cohort, there will be an interim data review during which the PK and safety data will be reviewed to determine the dose to be administered in the next cohort. Dose escalation for serial cohorts will progress unless safety concerns preclude further dose escalation. If the selected dose does not provide the required data, a previously tested dose may be used in a subsequent cohort. However, if the dose level met the dose escalation stopping criteria, that dose level must not be repeated. A previously untested intermediate dose may also be used in a subsequent cohort.

Conditions

Atrial Fibrillation

Outcome Measures

Primary Outcomes (9)

• Physical Examination (Safety and Tolerability)

  Typical physical examination, including general appearance; head, neck, and thyroid; ears, nose, and throat; cardiovascular; respiratory; lymph nodes; abdomen; dermatological; musculoskeletal; neurological/CNS; ocular/ophthalmology; and other (as specified) evaluation

  Change from screening (3 to 28 d prior to dosing), admission (2 d prior to dosing), 48 h post-start of infusion, and 7 d +/- 1 d post-start of infusion (follow-up visit)

• Safety Labs (Safety and Tolerability)

  Hematology (hemoglobin\[g/L\], HCT\[%\], RBC\[x10\^12/L\], MCV\[fL\], MCH\[pg\], MCHC\[g/L\], platelet\[x10\^9/L\], WBC\[x10\^9/L\], neutrophils\[x10\^9/L\], lymphocytes\[x10\^9/L\], monocytes\[x10\^9/L\], eosinophils\[x10\^9/L\], basophils\[x10\^9/L\], hematocrit\[%\]), coagulation (prothrombin time\[s\], APTT\[s\]), clinical chemistry (Na\[mmol/L\], K\[mmol/L\], Cl\[mmol/L\], bicarbonate\[mmol/L\], urea\[mmol/L\], creatinine\[µmol/L\], bilirubin\[µmol/L\], direct conj bilirubin\[µmol/L\], alkaline phosphatase\[IU/L\], aspartate aminotransferase\[IU/L\], alanine aminotransferase\[IU/L\], creatinine kinase\[IU/L\], gamma glutamyl transferase\[IU/L\], total protein\[g/L\], albumin\[g/L\], Ca\[mmol/L\], Mg\[mmol/L\], P\[mmol/L\], uric acid\[µmol/L\], random blood glucose\[mmol/L\], fasting blood glucose\[mmol/L\], triglycerides\[mmol/L\], fasting triglycerides\[mmol/L\], creatinine clearance\[mL/min\]), virology (Hepatitis B surface\[+/-\], Antigen\[+/-\], Hepatitis C\[+/-\], Antibody\[+/-\], HIV Antibody\[+/-\]); and FSH(IU/L) and beta H.C.G. serum(+/-)

  Change from screening (3 to 28 d prior to dosing), 1 d prior to dosing, 24 h and 48 h post-start of infusion, and 7 d +/- 1 d post-start of infusion (follow-up visit)

• Urinalysis (Safety and Tolerability)

  Bilirubin (-/+; +, ++, +++), urobilinogen (-/+; 2, 4, 8, 12 mg/dL), ketones (-/+; trace, +, ++, +++), glucose (-/+; 50, 100, 250, 500, ≥1000 mg/dL), pH (5.0, 6.0, 6.5, 7.0, 8.0, 9.0), hCG (female subjects; -/+), specific gravity (1.000, 1.005, 1.010, 1.015, 1.020, 1.025, 1.030), protein (-/+; trace, 30, 100, 500 mg/dL), blood (-/+; +ca.5-10, ++ca.50, +++ca.300, ca.5-10, ca.50, ca.300 ery/µL), nitrites (-/+; light pink, dark pink), leukocytes (-/+; ca.25, ca.75, ca.500 leuko/µL) (performed using dipsticks; if positive, tick correct result), microbiology (WBS \[HPF\], RBCS \[HPF\], hyaline casts \[HPF\], granular casts \[HPF\], cellular casts \[HPF\]) and urine microscopy (both at the discretion of the investigator based on urinalysis results), and drugs of abuse (amphetamines \[+/-\], barbiturates \[+/-\], benzodiazepines \[+/-\], cocaine \[+/-\], marijuana/cannabis \[+/-\], methadone \[+/-\], methamphetamine/ecstasy \[+/-\], morphine/opiates \[+/-\], phencyclidine \[+/-\], tricyclic antidepressants \[+/-\])

  Change from screening (3 to 28 d prior to dosing), admission (2 d prior to dosing), 24 h and 48 h post-start of infusion, and 7 d +/- 1 d post-start of infusion (follow-up visit)

• Pulmonary Function Tests (Safety and Tolerability)

  The following lung function tests will be performed using a standard calibrated spirometer: FEV1 (L), FVC (L), peak expiratory flow rate (PEFR) (L/min), and FEV1/FVC (%)

  Change from screening (3 to 28 d prior to dosing), pre-dose (within 24 h prior to dosing), and 0.75 h and 4 h post-start of infusion

• 12-Lead ECG (Safety and Tolerability)

  Measured after subject has been in supine position for at least 5 min.

  Change from screening (3 to 28 d prior to dosing), admission (2 d prior to dosing), pre-dose (within 24 h prior to dosing), 0.25 h, immediately prior to end of infusion, 1, 4, 6, 12, 24, and 48 h, and 7 d +/- 1 d post-start of infusion

• Holter ECG (Safety and Tolerability)

  Continuous ECG monitoring; subjects to be in supine position for at least 0.25 h before each extraction

  Data extractions on Day -1 will be time matched to the planned time of dosing on Day 1 (i.e., 12 extractions); the extraction time points on Day 1 are: pre-dose, 0.25 h, 0.5 h, 0.75 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-start of infusion

• Telemetry ECG (Safety and Tolerability)

  No data are collected (safety monitoring); if cardiac monitoring shows a potentially significant abnormality, a clinical assessment of the subject will be performed, including a 12-lead ECG, and treatment given.

  To commence approximately 10 min before dosing up to 6 h post-start of infusion

• Vital Signs (Safety and Tolerability)

  Blood pressure (mmHg), heart rate (bpm), oral temperature (degrees C or degrees F)

  Change from screening (3 to 28 d prior to dosing), admission (2 d prior to dosing), pre-dose (within 24 h prior to dosing), 0.25 h, immediately prior to end of infusion, 1, 2, 4, 6, 8, 12, 16, 24, 30, 36, and 48 h, and 7 d +/- 1 d post-start of infusion

• Adverse Events (Safety and Tolerability)

  All AEs are documented, including the date and time of onset, a description of the AE, severity, duration, actions taken, outcome and investigator's current opinion on the relationship between HBI-3000 and the event.

  0.25 h post-start of infusion through 7 d +/- 1 d post-start of infusion (follow-up visit)

Secondary Outcomes (17)

• HBI-3000 Levels Over Time in Plasma (Cmax)

  Change in Cmax from pre-dose (within 24 h prior to dosing), and 0.25 h, immediately prior to end of infusion, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 30 h, 36 h, 48 h, 72 h post-start of infusion

• HBI-3000 Levels Over Time in Plasma (Tmax)

  Change in Tmax from pre-dose (within 24 h prior to dosing), and 0.25 h, immediately prior to end of infusion, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 30 h, 36 h, 48 h, 72 h post-start of infusion

• HBI-3000 Levels Over Time in Plasma (AUC(0-last))

  Change in AUC(0-last) from pre-dose (within 24 h prior to dosing), and 0.25 h, immediately prior to end of infusion, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 30 h, 36 h, 48 h, 72 h post-start of infusion

• HBI-3000 Levels Over Time in Plasma (AUC(0-inf))

  Change in AUC(0-inf) from pre-dose (within 24 h prior to dosing), and 0.25 h, immediately prior to end of infusion, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 30 h, 36 h, 48 h, 72 h post-start of infusion

• HBI-3000 Levels Over Time in Plasma (AUC(0-24h))

  Change in AUC(0-24h) from pre-dose (within 24 h prior to dosing), and 0.25 h, immediately prior to end of infusion, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 30 h, 36 h, 48 h, 72 h post-start of infusion

Study Arms (2)

Active

ACTIVE COMPARATOR

x mg HBI-3000 as x mL of a 50 mg/mL solution for intravenous infusion. Doses of HBI-3000 (Cohorts A to G) may range from 20 mg to a level at which it is expected that the drug exposure will not exceed an AUC(0-t) of 20 µg.h/mL and Cmax of 20 µg/mL (based on the NOAEL) in both 14-day repeat-dose toxicology species rat and minipig) and the expected therapeutic dose.

Drug: HBI-3000

Placebo

PLACEBO COMPARATOR

Matching placebo for x mg HBI-3000 as x mL of a 50 mg/mL solution for intravenous infusion.

Other: Placebo

Interventions

HBI-3000 DRUG

Small molecule, multi-ion channel blocker

Also known as: Sulcardine sulfate

Active

Placebo OTHER

Normal Saline

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy males or non-pregnant, non-lactating healthy females
• Age 18 to 50 years
• Body mass index of 18.0 to 30.0 kg/m2 or, if outside the range, considered not clinically significant by the investigator
• Minimum body weight of 60 kg
• Must be willing and able to communicate and participate in the whole study
• Normal hepatic function as evidenced by AST and alanine aminotransferase (ALT) \<1.5 × ULN and alkaline phosphatase (ALP) and total bilirubin within the normal range
• Haemodynamically stable with systolic BP 90 to 150 mm Hg, diastolic BP \<95 mmHg and resting HR ≥45 and ≤100 bpm
• Forced expiratory volume in 1 s (FEV1) \>80% predicted value and FEV1/ forced vital capacity (FVC) ratio \>0.7
• Must provide written informed consent
• Must agree to use an adequate method of contraception

You may not qualify if:

• Subjects who have received any IMP in a clinical research study within the previous 3 months
• Subjects who are study site employees, or immediate family members of a study site or sponsor employee
• Subjects who have previously been enrolled in this study.
• History of any drug or alcohol abuse in the past 2 years
• Regular alcohol consumption in males \>21 units per week and females \>14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)
• Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening
• Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months
• Females of childbearing potential who are pregnant or lactating (all female subjects must have a negative pregnancy test). A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum follicle-stimulating hormone \[FSH\] concentration ≥40 IU/L)
• Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening
• Clinically significant abnormal biochemistry, haematology, coagulation or urinalysis as judged by the investigator, including:
• Serum K \<3.5 mmol/L
• Serum magnesium concentration of \<0.7 mmol/L
• Serum phosphate \<2.5 or \>4.5 mg/dL
• Positive drugs of abuse test result
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results

Sponsors & Collaborators

• HUYABIO International, LLC.: lead
• Quotient Clinical: collaborator

Study Sites (1)

Quotient Clinical

Nottingham, NG11 6JS, United Kingdom

Location

MeSH Terms

Conditions

Atrial Fibrillation

Interventions

sulcardine sulfate

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Stuart Mair

  Quotient Clinical

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 28, 2017
• First Posted: January 12, 2018
• Study Start: October 17, 2017
• Primary Completion: July 10, 2018
• Study Completion: July 10, 2018
• Last Updated: August 29, 2018

Record last verified: 2018-08

Locations

GB (1)