Covid19
Conditions
Brief summary
An early stage trial to check how safe and tolerable, as well as how the body handles continuous daily use of Active IMP over 28 days in healthy volunteers.
Detailed description
Detailed information restricted because this is a Phase 1 clinical trial.
Interventions
DRUGIvermectin
Ivermectin: Investigation of the safety, tolerability and the pharmacokinetic profile of the active IMP in an exploratory study
DRUGPlacebo
Matching Placebo to the Active IMP.
Sponsors
MedinCell S.A
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Masking description
The study is double-blinded. Patients will be randomised to receive 1 of 3 doses of the Active IMP or a matching placebo.
Intervention model description
The study is a placebo-controlled, double-blinded exploratory study to investigate safety, Pk and tolerability of a continuous daily dosing of the active drugs (at 3 different doses) in healthy participants.
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
Important Inclusion Criteria: * Subject is male of any ethnic origin. * Subject is aged between 18 to 45 years, inclusive. * Subject has a body mass index (BMI) of 18.5 to 32.0 kg/m2, inclusive. * Subject is ≥50 kg. * Negative reverse transcription polymerase chain reaction (RT-PCR) Test for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at Screening and negative lateral flow immunoassay test for SARS-CoV-2 at Day -1. * Healthy as determined by a responsible physician, based on medical evaluation including medical history, physical examinations, neurological examinations, concomitant medication, vital signs, 12-lead ECG and clinical laboratory evaluations. * Male subjects must use a condom during the study and for 3 months after their final dose of study medication, if their partner is a woman of childbearing potential. In addition, their female partner of childbearing potential must use an additional method of highly effective contraception from first dosing until 3 months following final dosing. Important
Exclusion criteria
* Clinically relevant history of abnormal physical or mental health (defined as any subject requiring medical, psychological or pharmacotherapeutic intervention for mental illness) interfering with the study as determined by medical history and physical examinations obtained during Screening and Day -1 as judged by the Investigator (including \[but not limited to\], neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder). * Any other concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study as outlined in this Protocol, or that would, in the opinion of the Investigator, pose an unacceptable risk to the subject in this study. * Evidence of previous SARS-CoV-2 infection from medical history. * Ophthalmologic disorder (moderate and sever retina or optic nerve pathology; cataracts excluded). * Subjects with a diagnosis of asthma or any other respiratory conditions. * A neurologic disorder that may compromise blood brain barrier permeability (stroke within 90 days, brain tumour, multiple sclerosis, or other neuroinflammatory condition, a neurodegenerative disorder, epilepsy) or history of seizures. * Positive test for hepatitis B surface antigen (HBsAg), anti-hepatitis C antibody (anti-HCV) or human immunodeficiency virus I and II (anti-HIV I/II) at Screening. * The subject has participated in a clinical study and has received a medication or a new chemical entity within 3 months or 5 half-lives (whichever is longer) prior to first dosing of current study medication. * Use of any drugs that are known substrates of CYP3A4, P-glycoprotein (P-gp) from within 4 weeks of Screening and unable to refrain from them until the end of the study (e.g., rifampicin, quinidine, amiodarone, diltiazem, spironolactone, verapamil, clarithromycin, erythromycin, itraconazole, ketoconazole, cyclosporine, tacrolimus, indinavir, ritonavir or cobicistat). Use of critical CYP3A4 substrate drugs such as warfarin or coumarin anticoagulants. * Recent or expected microfilaricidal drug use, including ivermectin, or travel history to areas that are endemic for Loa loa or onchocerciasis (Angola, Cameroon, Central African Republic, Chad, Democratic Republic of Congo, Ethiopia, Equatorial, Guinea, Gabon, Republic of Congo, Nigeria and Sudan). * Use of medications having potential activity against SARS-CoV-2 such as hydroxychloroquine, chloroquine, lopinavir, ritonavir, remdesivir, azithromycin, in the 30 days prior to Screening and unable to refrain from them until the end of the study. * Consumption of any food or drinks containing cranberry, pomegranate, starfruit, grapefruit, pomelos, exotic citrus fruits or Seville oranges (including marmalade and juices made from these fruits) within 14 days prior to first dosing until the end of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax]) | D1, D2 and D28 | Maximum plasma concentration (Cmax) |
| Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax]) | D1, D2 and D28 | Time to reach Cmax (Tmax) |
| Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr]) | D1, D2 and D28 | area under the plasma concentration-time curve from zero to 24 hours (AUC0-24hr) concentration-time curve from zero to 24 hours (AUC0-24hr) |
| Pharmacokinetic Concentrations - (Apparent Terminal Half-Life [T1/2]) | D28 | apparent terminal half-life (t1/2) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | From Screening (Day -28) to Follow up visit (Day +42) plus 7 additional days. | Clinical safety data from adverse event (AE) reporting |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 50mcg/kg (Oral) Ivermectin loading dose of 200 mcg/kg followed by daily doses of 50mcg/kg from D2 to D28 | 6 |
| 75mcg/kg (Oral) Ivermectin loading dose of 200 mcg/kg followed by daily doses of 75mcg/kg from D2 to D28 | 6 |
| 100mcg/kg (Oral) Ivermectin loading dose of 200 mcg/kg followed by daily doses of 100mcg/kg from D2 to D28 | 6 |
| Matching Placebo (Oral) Placebo tablets matching the Active IMP | 6 |
| Total | 24 |
Baseline characteristics
| Characteristic | 50mcg/kg (Oral) | 75mcg/kg (Oral) | 100mcg/kg (Oral) | Matching Placebo (Oral) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 35.2 years | 29.3 years | 30.3 years | 28.2 years | 30.8 years |
| Body Mass Index | 24.95 kg/m^2 | 25.79 kg/m^2 | 25.84 kg/m^2 | 25.57 kg/m^2 | 25.54 kg/m^2 |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Region of Enrollment United Kingdom | 6 participants | 6 participants | 6 participants | 6 participants | 24 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 24 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 / 6 | 0 / 6 | 0 / 6 | 0 / 18 | 0 / 24 |
| other Total, other adverse events | 6 / 6 | 3 / 6 | 2 / 6 | 6 / 6 | 11 / 18 | 17 / 24 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 18 | 0 / 24 |
Outcome results
Primary
Pharmacokinetic Concentrations - (Apparent Terminal Half-Life [T1/2])
apparent terminal half-life (t1/2)
Time frame: D28
Population: 17 participants on active IMP were analysed for this endpoint. On day 21 one subject in the 100 μg/kg/day ivermectin treatment group was discontinued.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 50mcg/kg (Oral) | Pharmacokinetic Concentrations - (Apparent Terminal Half-Life [T1/2]) | 102 hr | Geometric Coefficient of Variation 60.1 |
| 75mcg/kg (Oral) | Pharmacokinetic Concentrations - (Apparent Terminal Half-Life [T1/2]) | 99.2 hr | Geometric Coefficient of Variation 47.3 |
| 100mcg/kg (Oral) | Pharmacokinetic Concentrations - (Apparent Terminal Half-Life [T1/2]) | 127 hr | Geometric Coefficient of Variation 47.2 |
Primary
Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr])
area under the plasma concentration-time curve from zero to 24 hours (AUC0-24hr) concentration-time curve from zero to 24 hours (AUC0-24hr)
Time frame: D1, D2 and D28
Population: All 18 participants on active IMP were eligible and analyzed for this endpoint. Number Analyzed per Row represents those with data available at each time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50mcg/kg (Oral) | Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr]) | Day 2 (first day on respective dose of active treatment) | 906 ng*h/mL | Geometric Coefficient of Variation 31.4 |
| 50mcg/kg (Oral) | Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr]) | Day 1 after loading dose of 200mcg/kg (oral) for all active treatment groups | 568 ng*h/mL | Geometric Coefficient of Variation 33.6 |
| 50mcg/kg (Oral) | Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr]) | Day 28 (last day of active treatment) | 1.06 ng*h/mL | Geometric Coefficient of Variation 36.6 |
| 75mcg/kg (Oral) | Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr]) | Day 2 (first day on respective dose of active treatment) | 779 ng*h/mL | Geometric Coefficient of Variation 53.1 |
| 75mcg/kg (Oral) | Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr]) | Day 1 after loading dose of 200mcg/kg (oral) for all active treatment groups | 449 ng*h/mL | Geometric Coefficient of Variation 62 |
| 75mcg/kg (Oral) | Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr]) | Day 28 (last day of active treatment) | 1.5 ng*h/mL | Geometric Coefficient of Variation 47.5 |
| 100mcg/kg (Oral) | Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr]) | Day 1 after loading dose of 200mcg/kg (oral) for all active treatment groups | 523 ng*h/mL | Geometric Coefficient of Variation 60.5 |
| 100mcg/kg (Oral) | Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr]) | Day 28 (last day of active treatment) | 1.75 ng*h/mL | Geometric Coefficient of Variation 20.6 |
| 100mcg/kg (Oral) | Pharmacokinetic Concentrations - (Area Under the Plasma Concentration-time Curve From Zero to 24 Hours [AUC0-24hr]) | Day 2 (first day on respective dose of active treatment) | 941 ng*h/mL | Geometric Coefficient of Variation 59 |
Comparison: Assessment of dose proportionality on D2 and D28p-value: 0.689Mixed Models Analysis
Primary
Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax])
Maximum plasma concentration (Cmax)
Time frame: D1, D2 and D28
Population: All 18 participants on active IMP were eligible and analyzed for this endpoint. Number Analyzed per Row represents those with data available at each time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50mcg/kg (Oral) | Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax]) | Day 28 (last day of active treatment) | 23.3 ng/mL | Geometric Coefficient of Variation 52.8 |
| 50mcg/kg (Oral) | Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax]) | Day 2 (first day on respective dose of active treatment) | 22.3 ng/mL | Geometric Coefficient of Variation 32.5 |
| 50mcg/kg (Oral) | Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax]) | Day 1 after loading dose of 200mcg/kg (oral) for all active treatment groups | 57.2 ng/mL | Geometric Coefficient of Variation 28.9 |
| 75mcg/kg (Oral) | Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax]) | Day 28 (last day of active treatment) | 31.9 ng/mL | Geometric Coefficient of Variation 27.6 |
| 75mcg/kg (Oral) | Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax]) | Day 1 after loading dose of 200mcg/kg (oral) for all active treatment groups | 41.7 ng/mL | Geometric Coefficient of Variation 73.5 |
| 75mcg/kg (Oral) | Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax]) | Day 2 (first day on respective dose of active treatment) | 24.4 ng/mL | Geometric Coefficient of Variation 42.5 |
| 100mcg/kg (Oral) | Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax]) | Day 2 (first day on respective dose of active treatment) | 33.2 ng/mL | Geometric Coefficient of Variation 62.6 |
| 100mcg/kg (Oral) | Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax]) | Day 1 after loading dose of 200mcg/kg (oral) for all active treatment groups | 46.5 ng/mL | Geometric Coefficient of Variation 53.6 |
| 100mcg/kg (Oral) | Pharmacokinetic Concentrations - (Maximum Plasma Concentration [Cmax]) | Day 28 (last day of active treatment) | 44.4 ng/mL | Geometric Coefficient of Variation 68.8 |
Comparison: Assessment of dose proportionality on D2 and D28p-value: 0.803Mixed Models Analysis
Primary
Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax])
Time to reach Cmax (Tmax)
Time frame: D1, D2 and D28
Population: All 18 participants on active IMP were eligible and analyzed for this endpoint. Number Analyzed per Row represents those with data available at each time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50mcg/kg (Oral) | Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax]) | Day 2 (first day on respective dose of active treatment) | 3.82 hr | Geometric Coefficient of Variation 36.7 |
| 50mcg/kg (Oral) | Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax]) | Day 1 after loading dose of 200mcg/kg (oral) for all active treatment groups | 2.53 hr | Geometric Coefficient of Variation 36.8 |
| 50mcg/kg (Oral) | Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax]) | Day 28 (last day of active treatment) | 2.83 hr | Geometric Coefficient of Variation 39.2 |
| 75mcg/kg (Oral) | Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax]) | Day 2 (first day on respective dose of active treatment) | 2.85 hr | Geometric Coefficient of Variation 38.8 |
| 75mcg/kg (Oral) | Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax]) | Day 1 after loading dose of 200mcg/kg (oral) for all active treatment groups | 3.03 hr | Geometric Coefficient of Variation 50.6 |
| 75mcg/kg (Oral) | Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax]) | Day 28 (last day of active treatment) | 3.03 hr | Geometric Coefficient of Variation 50.7 |
| 100mcg/kg (Oral) | Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax]) | Day 1 after loading dose of 200mcg/kg (oral) for all active treatment groups | 4.8 hr | Geometric Coefficient of Variation 47.2 |
| 100mcg/kg (Oral) | Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax]) | Day 28 (last day of active treatment) | 3.03 hr | Geometric Coefficient of Variation 39.4 |
| 100mcg/kg (Oral) | Pharmacokinetic Concentrations - (Time to Reach Cmax [Tmax]) | Day 2 (first day on respective dose of active treatment) | 3.23 hr | Geometric Coefficient of Variation 34.5 |
Secondary
Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs)
Clinical safety data from adverse event (AE) reporting
Time frame: From Screening (Day -28) to Follow up visit (Day +42) plus 7 additional days.
Population: All 24 included participants were eligible and analysed for this endpoint
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 24 TEAE |
| 50mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 0 TEAE |
| 50mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation - due to Study Medication-related TEAE | 0 TEAE |
| 50mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation - other reason | 0 TEAE |
| 50mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | TEAE - mild severity | 24 TEAE |
| 50mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | TEAE - moderate severity | 0 TEAE |
| 50mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Causality (All TEAEs) - Not related | 21 TEAE |
| 50mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Causality (All TEAEs) - Related (possibly and probably) | 3 TEAE |
| 75mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | TEAE - moderate severity | 0 TEAE |
| 75mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | TEAE - mild severity | 5 TEAE |
| 75mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 0 TEAE |
| 75mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Causality (All TEAEs) - Related (possibly and probably) | 2 TEAE |
| 75mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Causality (All TEAEs) - Not related | 3 TEAE |
| 75mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation - other reason | 0 TEAE |
| 75mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation - due to Study Medication-related TEAE | 0 TEAE |
| 75mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 5 TEAE |
| 100mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Causality (All TEAEs) - Not related | 2 TEAE |
| 100mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation - due to Study Medication-related TEAE | 0 TEAE |
| 100mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation - other reason | 1 TEAE |
| 100mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | TEAE - mild severity | 2 TEAE |
| 100mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | TEAE - moderate severity | 0 TEAE |
| 100mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Causality (All TEAEs) - Related (possibly and probably) | 0 TEAE |
| 100mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 2 TEAE |
| 100mcg/kg (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 0 TEAE |
| Matching Placebo (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation - due to Study Medication-related TEAE | 0 TEAE |
| Matching Placebo (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation - other reason | 0 TEAE |
| Matching Placebo (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 0 TEAE |
| Matching Placebo (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 21 TEAE |
| Matching Placebo (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | TEAE - mild severity | 20 TEAE |
| Matching Placebo (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Causality (All TEAEs) - Related (possibly and probably) | 1 TEAE |
| Matching Placebo (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | Causality (All TEAEs) - Not related | 20 TEAE |
| Matching Placebo (Oral) | Safety and Tolerability - Treatment Emergent Adverse Events (TEAEs) | TEAE - moderate severity | 1 TEAE |