A Single and Multiple Ascending Dose Study of Niclosamide in Healthy Volunteers

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: Niclosamide
Drug: Placebo

Registration Number: NCT04705415

Lead Sponsor: NeuroBo Pharmaceuticals Inc.

Brief Summary: A single and multiple ascending dose study of ANA001 in healthy adults to assess the safety and pharmacokinetics

Detailed Description: This is a Phase 1, single center, randomized, double blind, single ascending dose (SAD) and multiple ascending dose (MAD) study to assess the safety and pharmacokinetics of ANA001 in healthy adult subjects. In the single ascending dose portion of the study, subjects in 3 cohorts of 10 subjects each will be randomized to receive a single daily oral dose of ANA001 or matching placebo. In the multiple ascending dose portion of the study, subjects in 3 cohorts of 12 subjects each will be randomized to receive twice or thrice daily oral dose of ANA001 or matching placebo.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

Inclusion Criteria

Sign the study informed consent form
Man or woman, 18 to 65 years of age inclusive at the time of signing the informed consent form
Overtly healthy as determined by medical evaluation
Body mass index (BMI) within 18 to 30.0 kg/m2 (inclusive) and body weight not less than 50 kg
Blood pressure at Screening and Day -1 between 90 and 140 mmHg systolic, inclusive, and no higher than 90 mmHg diastolic.
A 12-lead electrocardiogram (ECG) at Screening consistent with normal cardiac conduction and function, including:
- Sinus rhythm
- Pulse rate between 50 and 100 beats per minute (bpm)
- QTc interval 450 milliseconds (QT interval corrected using Fridericia correction method [QTcF])
- QRS interval of <120 milliseconds
- PR interval <200 milliseconds
- Morphology consistent with healthy cardiac conduction and function
Non-smoker or ex-smoker for >12 months
If male, must agree to use contraception methods outlined for the study during the treatment period and for at least 30 days (a spermatogenesis cycle) after the last dose of study treatment and refrain from donating sperm during this period
If female, is not pregnant, not breastfeeding, and meets at least one of the following conditions:

Not a woman of childbearing potential (WOCBP)

A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 30 days (one menstrual cycle) after the last dose of study treatment.

Exclusion Criteria

Has a history of or current clinically significant medical illness including but not limited to, cardiac arrhythmias or other cardiac disease; hematologic disease; coagulation disorders (including any abnormal bleeding or blood dyscrasias); lipid abnormalities; significant pulmonary disease, including bronchospastic respiratory disease; diabetes mellitus; hepatic or renal insufficiency (creatinine clearance below 60 mL/min); thyroid disease; neurologic or psychiatric disease; infection; or any other illness that the Investigator considers should exclude the subject or that could interfere with the interpretation of the study results.
Has known allergy to niclosamide or salicylate-containing medications.
Clinically significant abnormal values for hematology, clinical chemistry, or urinalysis at screening.
Clinically significant abnormal physical examination, vital signs or 12 lead ECG at screening.
Has a history of human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV; has a history of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease, or tests positive for HBsAg or anti-HCV at Screening.
History of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders (4th edition) criteria within 5 years before screening or positive test result(s) for alcohol and/or drugs of abuse at screening and admission
Has received an investigational drug or used an invasive investigational medical device within 1 month or within a period less than 10 times the drug's half-life, whichever is longer, before Day 1.
Has preplanned surgery or procedures that would interfere with the conduct of the study
Is an employee of the Investigator or study site, with direct involvement in the proposed study or other studies under the direction of that Investigator or study site, as well as family members of the employees or the Investigator

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SAD Cohort 1: ANA001 1000 mg po	Niclosamide	Subjects will receive a 1000 mg single oral dose of ANA001 with a standardized light meal presented at 4 x 250 mg capsules. Each capsule is 250 mg.
SAD Cohort 2: ANA001 2000 mg po	Niclosamide	Subjects will a 2000 mg single oral dose of ANA001 with a standardized light meal presented at 8 x 250 mg capsules. Each capsule is 250 mg.
SAD Cohort 3: ANA001 3000 mg po	Niclosamide	Subjects will a 3000 mg single oral dose of ANA001 with a standardized light meal presented at 12 x 250 mg capsules. Each capsule is 250 mg.
SAD Cohorts 1, 2 & 3: Pooled Matching Placebo	Placebo	Subjects will receive matching placebo hydroxypropylmethylcellulose (HPMC) as a single oral dose (4, 8, or 12 capsules) with a standardized light meal.
MAD Cohort 1: ANA001 1000 mg po BID	Niclosamide	Subjects will receive an oral dose of 1000mg ANA001 twice daily (BID) with a standardized light meal for 7 consecutive days. Each dose will be presented as 4 250mg capsules.
MAD Cohort 2: ANA001 1000 mg po TID	Niclosamide	Subjects will receive an oral dose of 1000mg ANA001 three times daily (TID) with a standardized light meal for 7 consecutive days. Each dose will be presented as 4 250mg capsules.
MAD Cohorts 1 & 2: Pooled Matching Placebo	Placebo	Subjects will receive an oral dose of matching Placebo to ANA001 two (BID) three times daily (TID) with a standardized light meal for 7 consecutive days. Each dose will be presented as 4 250mg capsules of hydroxypropylmethylcellulose (HPMC)

Primary Outcome Measures

Name	Time	Method
SAD: Number of Subjects Reporting TEAEs and STEAEs	Baseline to Day 7.	Number of Subjects Reporting treatment-emergent AEs (TEAEs) and Serious treatment-emergent AEs (STEAEs) in the SAD
SAD: Safety and Tolerability of ANA001 as Measured by Clinically Significant Changes in ECG Parameters	Baseline to Day 7	Number of Subjects with Clinically Significant changes in ECG parameters from Baseline (PR, QRS, QT, and QTc intervals)
MAD: Safety and Tolerability of ANA001 as Measured by Clinically Significant Changes in ECG Parameters	Baseline to Day 14	Number of Subjects with Clinically Significant changes in ECG parameters from Baseline (PR, QRS, QT, and QTc intervals)
MAD: Number of Subjects Reporting TEAEs and STEAEs	Baseline to Day 14.	Number of Subjects Reporting treatment-emergent AEs (TEAEs) and Serious treatment-emergent AEs (STEAEs) in the MAD
SAD: Safety and Tolerability of ANA001 as Measured by Clinically Significant Changes in Haematology	Baseline to Day 7	Number of Subjects with Clinically Significant changes in Haematology (Basophils (%),Eosinophils (%, Ery. Mean Corpuscular Hemoglobin, Ery. Mean Corpuscular Volume, Erythrocytes (10\^12/L), Hematocrit (%), Hemoglobin (g/dL). Hemoglobin (g/dL), Lymphocytes (%), Monocytes (%), Neutrophils (%)' Platelets (10\^9/L), Reticulocytes (%))
MAD: Safety and Tolerability of ANA001 as Measured by Clinically Significant Changes in Haematology	Baseline to Day 14	Number of Subjects with Clinically Significant changes in Haematology (Basophils (%),Eosinophils (%, Ery. Mean Corpuscular Hemoglobin, Ery. Mean Corpuscular Volume, Erythrocytes (10\^12/L), Hematocrit (%), Hemoglobin (g/dL). Hemoglobin (g/dL), Lymphocytes (%), Monocytes (%), Neutrophils (%)' Platelets (10\^9/L), Reticulocytes (%))
SAD: Safety and Tolerability of ANA001 as Measured by Clinically Significant Changes in Serum Chemistry	Baseline to Day 7	Number of Subjects with Clinically Significant changes in Serum Chemistry (Alanine Aminotransferase (U/L), Alkaline Phosphatase (U/L), Aspartate Aminotransferase (U/L), Bilirubin (mg/dL), Calcium (mg/dL), Creatinine (mg/dL), Direct Bilirubin (mg/dL, Glucose (mg/dL), Potassium (mmol/L), Protein (g/dL), Sodium (mmol/L), Urea Nitrogen (mg/dL)
MAD: Safety and Tolerability of ANA001 as Measured by Clinically Significant Changes in Serum Chemistry	Baseline to Day 14	Number of Subjects with Clinically Significant changes in Serum Chemistry (Alanine Aminotransferase (U/L), Alkaline Phosphatase (U/L), Aspartate Aminotransferase (U/L), Bilirubin (mg/dL), Calcium (mg/dL), Creatinine (mg/dL), Direct Bilirubin (mg/dL, Glucose (mg/dL), Potassium (mmol/L), Protein (g/dL), Sodium (mmol/L), Urea Nitrogen (mg/dL)
SAD: Safety and Tolerability of ANA001 as Measured by Clinically Significant Changes in Urinalysis	Baseline to Day 7	Number of Subjects with Clinically Significant changes in Urinalysis (Specific Gravity, Urobilinogen (EU), pH)
MAD: Safety and Tolerability of ANA001 as Measured by Clinically Significant Changes in Urinalysis	Baseline to Day 14	Number of Subjects with Clinically Significant changes in Urinalysis (Specific Gravity, Urobilinogen (EU), pH)
SAD: Safety and Tolerability of ANA001 as Measured by Clinically Significant Changes in Vital Signs	Baseline to Day 7	Number of Subjects with Clinically Significant changes in Vital Signs from Baseline (Diastolic Blood Pressure, Systolic Blood Pressure (mmHg), Pulse Rate (beats/min), Respiratory Rate (breaths/min))
MAD: Safety and Tolerability of ANA001 as Measured by Clinically Significant Changes in Vital Signs	Baseline to Day 14	Number of Subjects with Clinically Significant changes in Vital Signs from Baseline (Diastolic Blood Pressure, Systolic Blood Pressure (mmHg), Pulse Rate (beats/min), Respiratory Rate (breaths/min))

Secondary Outcome Measures

Name	Time	Method
SAD: Tmax	PK samples were collected before dosing and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours. A Follow-up sample was taken Day 7 (±2) after dosing.	Time to reach the maximum plasma concentration (SAD)
SAD: Cmax	PK samples were collected before dosing and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours. A Follow-up sample was taken Day 7 (±2) after dosing.	Maximum plasma concentration during a dosing interval (SAD)
SAD: AUC0-t	PK samples were collected before dosing and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours. A Follow-up sample was taken Day 7 (±2) after dosing.	Area under the plasma concentration-time curve from time 0 to time the last quantifiable concentration (SAD)
SAD: AUC0-∞	PK samples were collected before dosing and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours. A Follow-up sample was taken Day 7 (±2) after dosing.	Area under the plasma concentration time curve from time 0 extrapolated to infinity, calculated as AUC0-last + Clast/λ, where Clast is the last quantifiable concentration at time t (SAD)
SAD: t1/2	PK samples were collected before dosing and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours. A Follow-up sample was taken Day 7 (±2) after dosing.	Elimination half-life associated with the terminal slope (λ) of the semilogarithmic drug concentration-time curve, calculated as 0.693/λ (SAD)
SAD: CL/F	PK samples were collected before dosing and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours. A Follow-up sample was taken Day 7 (±2) after dosing.	Systemic Clearance (SAD)
SAD: Vz/F	PK samples were collected before dosing and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours. A Follow-up sample was taken Day 7 (±2) after dosing.	Volume of distribution (SAD)
MAD: Tmax Day 1	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Time to reach the maximum plasma concentration Day 1
MAD: Tmax Day 7	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Time to reach the maximum plasma concentration (Day 7)
MAD: Cmax Day 1	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: For BID but omitting samples at 10, and 12 hours after dosing.	Maximum plasma concentration during a dosing interval (Day 1)
MAD: Cmax Day 7	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Maximum plasma concentration during a dosing interval (Day 7)
MAD: AUC0-t Day 1	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Area under the plasma concentration-time curve from time 0 to time the last quantifiable concentration (Day 1)
MAD: AUC0-t Day 7	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Area under the plasma concentration-time curve from time 0 to time the last quantifiable concentration (Day 7)
MAD: AUC0-tau Day 1	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Area under the plasma concentration-time curve over the dosing interval at steady-state, calculated from the dosing interval (Day 1)
MAD: AUC0-tau Day 7	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Area under the plasma concentration-time curve over the dosing interval at steady-state, calculated from the dosing interval (Day 7)
MAD: t1/2 Day 1	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Elimination half-life associated with the terminal slope (λ) of the semilogarithmic drug concentration-time curve, calculated as 0.693/λ (Day 1)
MAD: t1/2 Day 7	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Elimination half-life associated with the terminal slope (λ) of the semilogarithmic drug concentration-time curve, calculated as 0.693/λ (Day 7)
MAD: CLss Day 1	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Systemic Clearance at steady state (Day 1)
MAD: CLss Day 7	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Systemic Clearance at steady state (Day 7)
MAD: Vdss Day 1	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Volume of distribution at steady state (Day 1)
MAD: Vdss Day 7	BID: Samples on Days 1 and 7 before dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours after dosing; Days 2, 4, 6, and 8 before dosing and before the 12 h. dose on Days 2, 4, and 6.TID: As BID but omitting samples at 10, and 12 hours after dosing.	Volume of distribution at steady state (Day 7)