AX-8 Drug Safety, Tolerability and Plasma Levels in Healthy Subjects

NCT04107441 | Completed Phase 1

• 2 other identifiers: AX8-0022019-002294-57
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The main purpose of the study is to see how safe the study drug AX-8 is and how well it is tolerated when administered at different dose levels in healthy participants. The study will also investigate pharmacokinetics (PK), i.e how the study drug is taken up, metabolized (broken down) and eliminated.

Conditions

Healthy

Keywords

open-label; phase 1; safety; tolerability; pharmacokinetics; healthy volunteers; AX-8

Outcome Measures

Primary Outcomes (63)

• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)

  Monitoring and recording of AEs will be performed throughout the study.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in biochemistry parameters - Total protein (g/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in biochemistry parameters - Albumin (g/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in biochemistry parameters - Total bilirubin (μmol/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in biochemistry parameters - Alanine transaminase (ALT, IU/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in biochemistry parameters - Aspartate transaminase (AST, IU/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in biochemistry parameters - Alkaline phosphatase (IU/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in biochemistry parameters - Gamma glutamyl transferase (GGT, IU/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in biochemistry parameters - Glucose (mmol/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days

• Changes in biochemistry parameters - Sodium (mmol/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in biochemistry parameters - Potassium (mmol/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in biochemistry parameters - Creatinine (μmol/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days

• Changes in biochemistry parameters - Urea (mmol/L)

  Quantified in participants' plasma.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Hemoglobin (g/L)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Hematocrit (HTC, %)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days

• Changes in hematology parameters - Mean cell volume (MCV, fL)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Mean cell hemoglobin (pg)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Mean cell hemoglobin concentration (g/dL)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Platelets (10^9/L)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Red blood cell count (10^12/L)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - White blood cell count (10^9/L)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Absolute neutrophils (10^9/L)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Absolute lymphocytes (10^9/L)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Absolute monocytes (10^9/L)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Absolute eosinophils (10^9/L)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Absolute basophils (10^9/L)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Percentage neutrophils (%)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Percentage lymphocytes (%)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Percentage monocytes (%)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Percentage eosinophils (%)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in hematology parameters - Percentage basophils (%)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in coagulation parameters - Prothrombin time (PTT, sec)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in coagulation parameters - International normalized ratio (INR)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in coagulation parameters - Activated partial thromboplastin time (aPTT, sec)

  Quantified in participant's whole blood.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Protein (positive or negative)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Glucose (positive or negative)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Specific gravity

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Ketones (positive or negative)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Urobilinogen (normal or abnormal)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Bilirubin (positive or negative)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - pH

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Nitrite (positive or negative)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Leukocytes (positive or negative)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Blood (positive or negative)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - White blood cells (per high power field, HPF)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Red blood cells (HPF)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Bacteria (organisms, HPF)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Hyaline casts (HPF)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Granular casts (HPF)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Cellular casts (HPF)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Epithelial cells (HPF)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in urinalysis parameters - Crystals (HPF)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in vital sign parameters - Body mass index (BMI, kg/m^2)

  Weight (kg) and height (m) will be combined to report BMI in kg/m\^2.

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in vital sign parameters - Pulse rate (beats/min)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in vital sign parameters - Systolic blood pressure (mmHg)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in vital sign parameters - Diastolic blood pressure (mmHg)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in vital sign parameters - Tympanic temperature (°C)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in 12-lead electrocardiogram (ECG) parameters - Heart rate (beats/min)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in 12-lead electrocardiogram (ECG) parameters - RR interval (msec)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in 12-lead electrocardiogram (ECG) parameters - PR interval (msec)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in 12-lead electrocardiogram (ECG) parameters - QRS interval (msec)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in 12-lead electrocardiogram (ECG) parameters - QT interval (msec)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

• Changes in 12-lead electrocardiogram (ECG) parameters - QTcF interval (msec)

  From screening visit to follow-up/early withdrawal visit, approximately 65 days for Part 1 and 44 days for Part 2.

Secondary Outcomes (22)

• Area under the plasma concentration-time curve from the first time point [t=0] to the time point of the last measured concentration [tlast] (AUC0-tlast) of AX-8 and its metabolite (ng.h/mL)

  Part 1 and Part 2: Treatment periods (Days 1 and 2).

• Maximum plasma concentration (Cmax) of AX-8 and its metabolite (ng/mL) for Dose 1 (Cmax1) and Dose 2 (Cmax2)

  Part 1 and Part 2: Treatment periods (Days 1 and 2).

• Percentage area extrapolated to infinity (%AUCx) of AX-8 and its metabolite (ng.h/mL)

  Part 1 and Part 2: Treatment periods (Days 1 and 2).

• Residual area, extrapolated area expressed as fraction of AUC(0-∞) (AUC(t-∞)) of AX-8 and its metabolite (ng.h/mL)

  Part 1 and Part 2: Treatment periods (Days 1 and 2).

• Time of maximum plasma concentration (tmax) of AX-8 and its metabolite for Dose 1 (tmax1) and Dose 2 (tmax2) (h)

  Part 1 and Part 2: Treatment periods (Days 1 and 2).

Study Arms (2)

Part 1 arm

EXPERIMENTAL

Ten healthy participants will receive one orally disintegrating tablet (ODT) with 5 mg, 10 mg, 20 mg or 40 mg AX-8 twice daily (8 hours apart, i.e. at 0 hour and +8 hours), during the treatment day (Day 1) of treatment periods 1, 2, 3 or 4, respectively.

Drug: AX-8 Part 1

Part 2 arm

EXPERIMENTAL

Ten healthy participants will receive one orally disintegrating tablet (ODT) with 5 mg AX-8 and one ODT with 40 mg AX-8 8 hours later (i.e. at 0 hour and +8 hours), during the treatment day (Day 1) of the treatment period.

Drug: AX-8 Part 2

Interventions

AX-8 Part 1 DRUG

5, 10, 20, and 40 mg AX-8 orally disintegrating tablets (ODTs), up to 80 mg/day split over 2 time points, 8 hours apart (i.e. Dose 1: 0 hour and Dose 2: + 8 hours). AX-8 ODTs will be administered orally and will be dissolved on the back of the tongue while the subject is in a sitting position. The subjects will be instructed not to suck, chew or swallow the tablet, i.e. to allow it to dissolve on the back of the tongue without any further intervention.

Part 1 arm

AX-8 Part 2 DRUG

5 and 40 mg AX-8 orally disintegrating tablets (ODTs), 45 mg/day split over 2 time points, 8 hours apart (i.e. Dose 1: 0 hour and Dose 2: + 8 hours). AX-8 ODTs will be administered orally and will be dissolved in the mouth while the subject is in a sitting position. The subjects will be instructed to actively move the tablet around in their mouth (i.e. active oral manipulation of the tablet) until it is fully dissolved.

Part 2 arm

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male and female volunteers aged ≥ 18 and ≤ 55 years at the time of informed consent
• Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method
• Female subjects (regardless of childbearing potential) must agree not to donate ova/oocytes during the study from the first dosing day and until 30 days after the last dose
• Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success, or use highly effective contraception together with their female partner(s)
• Male subjects must agree not to donate sperm during the study from the first dosing day and until 90 days after last dose
• Body mass index (BMI) ≥ 18.5 and ≤ 32.0 kg/m2 at Screening
• Have provided written informed consent
• Are willing and able to comply with all aspects of the protocol
• Normal electrocardiogram (ECG) and vital signs (or abnormalities which the clinical Investigator considers the deviation to be irrelevant for the purpose of the study) during screening and prior to first dose
• Laboratory values within the normal range (or the clinical Investigator considers the deviation to be irrelevant for the purpose of the study) during screening
• Findings within the range of clinical acceptability in medical history and physical examination (or the clinical Investigator considers the deviation to be irrelevant for the purpose of the study)

You may not qualify if:

• Prior treatment with AX-8
• Hypersensitivity or intolerance to transient receptor potential melastatin subfamily, member 8 (TRPM8) agonists (e.g. menthol, menthol-derivatives, eucalyptol) or any of the excipients of the AX-8 tablets
• Current smoker or individuals who have given up smoking for less than 12 months or ex smoker with \> 10 pack-years
• History of upper or lower respiratory tract infection within 4 weeks prior to screening or prior to first dose.
• Requiring concomitant therapy with prohibited medications
• Treatment with biologic therapies within 8 weeks or 5 half-lives, whichever is longer, prior to screening
• Treatment with any investigational therapy within 4 weeks prior to screening
• Serum creatinine, total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> the upper limit of normal (ULN) during screening
• Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency virus 1 or 2 (HIV-1 and HIV-2 Abs) during screening
• Positive tests for drugs of abuse or alcohol breath test at screening or prior to first dose
• History of malignancy, with the exception of completely treated and non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin, within 5 years prior to screening
• History of a major psychiatric condition (including major depressive disorder, bipolar disorder, or schizophrenia), suicidal ideation, or suicide attempt
• Presence of any medical condition or disability that, in the Investigator's opinion, could interfere with the assessment of safety or efficacy in this study or compromise the safety of the subject
• History or presence of alcoholism or drug abuse within the past 2 years prior to screening
• Females who are currently pregnant, breastfeeding or lactating, or who have a positive pregnancy test at screening or prior to first dose

Sponsors & Collaborators

• Axalbion SA: lead

Study Sites (1)

Medicines Evaluation Unit (MEU) Ltd

Manchester, M23 9QZ, United Kingdom

Location

Study Officials

• Dave Singh, MD

  Medicines Evaluation Unit (MEU) Ltd

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: A first group of 10 participants will be enrolled in the Part 1 of the study (arm 1). Based on the results of Part 1, a second group of 10 participants will be enrolled in Part 2 of the study (arm 2).

Study Record Dates

• First Submitted: September 19, 2019
• First Posted: September 27, 2019
• Study Start: September 9, 2019
• Primary Completion: February 25, 2020
• Study Completion: March 4, 2020
• Last Updated: April 30, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)