Safety and Pharmacokinetics of a Novel Niclosamide Solution in Combination With Camostat

Study Overview
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Brief Summary
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Niclosamide is a well-established substance that is a promising candidate for a repurposing approach to treat COVID-19. Niclosamide is currently marketed as a chewing tablet for the treatment of intestinal worm infections. The marketed formulation is optimized for minimal drug substance absorption. A niclosamide solution has been developed that is expected to release the drug substance more readily and more reproducibly. Camostat is approved for oral treatment of chronic pancreatitis and reflux oesophagitis in Japan. Camostat has been shown to effectively block viral replication in a SARS-CoV-2 animal model. Since the mechanisms of actions are different, it was hypothesized that a combination of both substances might have an additive or even synergistic effect in the treatment of COVID-19 patients. This 3-part study is designed to investigate (1) safety and pharmacokinetics of single ascending doses of the new niclosamide solution after fasted and fed conditions, (2) the relative bioavailability of the niclosamide solution compared to the chewing tablet, and (3) safety and pharmacokinetics of the combination of niclosamide solution and camostat after multiple doses in healthy volunteers.

Official Title
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A 3-part Study to Investigate the Safety and Pharmacokinetics of a Novel Niclosamide Solution as a Treatment Option for COVID-19 in Combination With Camostat

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Niclosamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female subjects in good health as determined by past medical history physical examination, vital signs and safety lab at screening between 18 to 45 years of age Exclusion Criteria: Significant illness pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Part A is a randomized, double-blinded, placebo-controlled, single ascending dose (SAD) study with 3 planned cohorts. Part B consists of two randomized, open-label, two-sequence, two-period crossover cohorts comparing the new niclosamide solution with the marketed chewing tablets. Part C is a randomized, double-blinded, placebo-controlled multiple dose study investigating the safety and pharmacokinetics of the combination of niclosamide solution and camostat over a treatment period of 7 days.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Part A: verum niclosamide<br>The SAD cohorts are planned as follows: Cohort A1: 200 mg (fasted conditions) Cohort A2: 600 mg (fasted conditions) Cohort A3: 1600 mg (fasted and fed conditions) | Drug: Niclosamide<br>* Niclosamide will be applied in various dosage steps, galenic preparations and in combination with camostat<br>|
| Placebo Comparator: Part A: placebo to niclosamide<br>The SAD cohorts are planned as follows: Cohort A1: placebo to niclosamide 200 mg (fasted conditions) Cohort A2: placebo to niclosamide 600 mg (fasted conditions) Cohort A3: placebo to niclosamide 1600 mg (fasted and fed conditions) | Drug: Placebo<br>* placebo to the interventional drug<br>|
| Active Comparator: Part B: verum as solution (niclosamide)<br>Two different crossover designs are chosen. Both are randomized, open-label, two-sequence, two periods crossover designs comparing the new niclosamide solution with the marketed chewing tablets. Planned doses are 1600 mg once daily (oral solution), 2000 mg once daily (chewing tablets) and 500 mg three times daily of both dosage forms. | Drug: Niclosamide<br>* Niclosamide will be applied in various dosage steps, galenic preparations and in combination with camostat<br>|
| Active Comparator: Part B: verum as chewing tablet (niclosamide)<br>Two different crossover designs are chosen. Both are randomized, open-label, two-sequence, two periods crossover designs comparing the new niclosamide solution with the marketed chewing tablets. Planned doses are 1600 mg once daily (oral solution), 2000 mg once daily (chewing tablets) and 500 mg three times daily of both dosage forms. | Drug: Niclosamide<br>* Niclosamide will be applied in various dosage steps, galenic preparations and in combination with camostat<br>|
| Active Comparator: Part C: verum (niclosamide and camostat)<br>Subjects will receive the combination of niclosamide solution (planned 500 mg three times daily) + camostat (600 mg three times daily) or placebo over a treatment period of 7 days. The dose of the niclosamide solution depends on the safety and pharmacokinetic results of Part A and B but will not exceed 500 mg three times daily. | Drug: Niclosamide<br>* Niclosamide will be applied in various dosage steps, galenic preparations and in combination with camostat<br>|
| Placebo Comparator: Part C: placebo to niclosamide and camostat<br>Subjects will receive the combination of niclosamide solution (planned 500 mg three times daily) + camostat (600 mg three times daily) or placebo over a treatment period of 7 days. The dose of the niclosamide solution depends on the safety and pharmacokinetic results of Part A and B but will not exceed 500 mg three times daily. | Drug: Placebo<br>* placebo to the interventional drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment emergent number of Adverse Events | Assessment of severity of an AE will be based on CTCAE Version 5.0 | up to 14 days | 
| Maximum plasma concentration of niclosamide (µg/ml) | Measurement will start at Day 1 | from predose until 24 hours after intervention | 
| Area Under the Plasma Concentration Time Curve from predose until last detectable concentration of niclosamide(AUC0-last) of niclosamide [µg/ml*h] | Measurement will start at Day 1 | from predose until 24 hours after intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Food effect on maximum plasma concentration of niclosamide (µg/ml) | Measurement will start at Day 1 after a standard high fat breakfast | from predose until 24 hours after intervention | 
| Food effect on Area Under the Plasma Concentration Time Curve from predose until last detectable concentration of niclosamide (AUC0-last) [µg/ml*h] | Measurement will start at Day 1 after a standard high fat breakfast | from predose until 24 hours after intervention | 
| Maximum plasma concentration of niclosamide (µg/ml) at steady state after multiple dosing |  | from predose until Day 9 | 
| Area Under the Plasma Concentration Time Curve between two dosing intervals (AUC tau ss) of niclosamide [µg/ml*h] at steady state after multiple dosing |  | from predose until Day 9 |