Visceral Leishmaniasis, Chagas Disease
Conditions
Keywords
LXE408, first-in-human study, Phase l, First-in-human, healthy subject, single ascending dose, multiple ascending dose, visceral leishmaniasis
Brief summary
The purpose of this first-in-human study is to generate the necessary safety, tolerability, and pharmacokinetics (PK) information that will support further clinical development of LXE408 for the treatment of patients with visceral leishmaniasis and potentially Chagas disease.
Interventions
DRUGLXE408
LXE408 comes in film coated tablets and is taken orally.
DRUGPlacebo
LXE408 matching placebo comes in film coated tablets and is taken orally.
DRUGIohexol
Iohexol is a nonionic, water-soluble radiographic contrast medium with a molecular weight of 821.14 and is administered to the participant via intravenous (IV) injection.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
exploratory, first-in-human, randomized, subject blinded, placebo-controlled, single and multiple ascending oral dose study in healthy volunteers
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Written informed consent must be obtained before any assessment is performed. * Healthy male and female subjects 18 to 65 years of age included, and in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening and baseline. * At screening and baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position and again in the standing position. Sitting vital signs should be within the following ranges: * oral body temperature between 35.0-37.5 °C * systolic blood pressure between 90-139 mmHg * diastolic blood pressure between 50-89 mmHg * pulse rate between 40-90 bpm * Subjects must weigh at least 50 kg to participate in the study and must have a body mass index (BMI) within the range of 18 - 30 kg/m2. \[BMI = Body weight (kg) / \[Height (m)\]2\] * Able to communicate well with the investigator, to understand and comply with the requirements of the study.
Exclusion criteria
* Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations. * Known history or current clinically significant cardiac arrhythmias. * Significant illness which has not resolved within two (2) weeks prior to baseline. * Recent (within the last three years) and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.). * Recent (within the last three years) and/or recurrent history of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated). * Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface antigen (HBsAg) test, or if standard local practice, a positive HBV core antigen test, excludes a subject. Subjects with a positive HCV antibody test should have HCV RNA levels measured. Subjects with positive (detectable) HCV RNA should be excluded. * Known family history or known presence of long QT syndrome. * History of immunodeficiency diseases, or a positive HIV (screening and confirmatory) test result. * History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. * Donation or loss of 450 mL or more of blood within eight weeks prior to baseline, or longer if required by local regulation. * Plasma donation (450 mL) within 8 weeks prior to baseline. * Hemoglobin levels or platelet counts below the lower limit of normal for the laboratory. * History of drug abuse or unhealthy alcohol use within the 12 months prior to baseline, or evidence of such abuse as indicated by the laboratory assays conducted during screening #Unhealthy alcohol use is defined as a history of, or current alcohol misuse/abuse, defined as "Five or more drinks on the same occasion on each of 5 or more days in the past 30 days." * History of recreational cannabis use within four weeks prior to baseline. This exclusion criterion applies even if cannabis use is legalized where the site is located. * A history of clinically significant ECG abnormalities, or any of the following ECG abnormalities at screening or baseline: * PR \> 200 msec * QRS complex \> 120 msec * QTcF \> 450 msec (males) * QTcF \> 460 msec (females) * Pregnant or nursing (lactating) women. * Smokers based on urine cotinine levels. Urine cotinine levels will be measured during screening and at each baseline for all subjects. Smokers will be defined as any subject who reports tobacco use and/or who has a urine cotinine ≥ 500 ng/mL. Other protocol-defined inclusion/exclusion may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parts A & B: Number of participants with Adverse Events, physical exam findings, vital signs, ECG findings, safety laboratory assessments including chemistry, hematology, and urinalysis results | Part A: Single Ascending Dose (SAD): 35 days; Part A: SAD (Food Effect): 63 days; Part B: Multiple Ascending Dose (MAD): 45 days | To assess the safety and tolerability of of single and multiple ascending oral doses of LXE408. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK) of LXE408 and its metabolite MAN519: AUC (AUC0-24; AUCtau, AUClast, AUCinf as relevant) Parts A (SAD) & B (MAD) | up to 72 hours post-dose for plasma PK in Part A, 48 hours post-dose for urine PK in Part A and Intensive PK samples for 24 hours post dose on Day 1 and 10 and trough samples from Day 2 to Day 9, in Part B | AUC, Area under Curve, represents the total amount of a drug that is actively present in the body over a specific period. |
| Pharmacokinetics of MAN519: Metabolite to parent ratio (MPTR) for AUC: MTPR_AUC | up to 72 hours post-dose for plasma PK in Part A, 48 hours post-dose for urine PK in Part A and Intensive PK samples for 24 hours post dose on Day 1 and 10 and trough samples from Day 2 to Day 9, in Part B | Metabolite-to-parent AUC ratio is the ratio of the overall exposure to a metabolite compared with the overall exposure to the parent drug. |
| PK of LXE408 and its metabolite (MAN519) Parts A & B: Tmax | up to 72 hours post-dose for plasma PK in Part A, 48 hours post-dose for urine PK in Part A and Intensive PK samples for 24 hours post dose on Day 1 and 10 and trough samples from Day 2 to Day 9, in Part B | Tmax, Time to Maximum, refers to the time required for a drug to reach its maximum concentration in the body. |
| PK of LXE408 and its metabolite (MAN519) Parts A & B: Cmax | up to 72 hours post-dose for plasma PK in Part A, 48 hours post-dose for urine PK in Part A and Intensive PK samples for 24 hours post dose on Day 1 and 10 and trough samples from Day 2 to Day 9, in Part B | Cmax, the maximum plasma concentration, is the highest peak concentration of a drug observed in the body's systemic circulation. |
| PK of LXE408 Parts A & B: CL/F | up to 72 hours post-dose for plasma PK in Part A, 48 hours post-dose for urine PK in Part A and Intensive PK samples for 24 hours post dose on Day 1 and 10 and trough samples from Day 2 to Day 9, in Part B | CL/F (Apparent Clearance) represents the efficiency of drug removal from the body following extravascular administration. |
| PK of LXE408 Parts A & B: V/F | up to 72 hours post-dose for plasma PK in Part A, 48 hours post-dose for urine PK in Part A and Intensive PK samples for 24 hours post dose on Day 1 and 10 and trough samples from Day 2 to Day 9, in Part B | V/F represents the apparent volume of distribution for a drug administered through a non-intravenous route. |
| PK of LXE408 Part A (excluding Cohort 3b, Food effect cohort): Ae | up to 72 hours post-dose for plasma PK in Part A, 48 hours post-dose for urine PK in Part A | Ae stands for the cumulative amount of an unchanged drug excreted in the urine. It is a critical parameter used to measure how much of the active, unmetabolized medication is expelled from the body via the kidneys over a specific period of time. |
| PK of LXE408 Part A (excluding Cohort 3b, Food effect cohort): CLR | up to 72 hours post-dose for plasma PK in Part A, 48 hours post-dose for urine PK in Part A | CLR stands for renal clearance. It is the volume of plasma completely cleared of a drug by the kidneys per unit of time. It represents the rate at which the kidneys filter, secrete, and excrete a specific medication into the urine. |
| PK of LXE408 and its metabolite (MAN519) Parts A & B: T1/2 | up to 72 hours post-dose for plasma PK in Part A, 48 hours post-dose for urine PK in Part A and and Intensive PK samples for 24 hours post dose on Day 1 and 10 and trough samples from Day 2 to Day 9, in Part B | T1/2 (half-life) is the time required for the concentration of a drug in the body or bloodstream to reduce by exactly 50%. |
| Plasma clearance of iohexol (measured glomerular filtration rate (mGFR) cohort) (Part B only) | Day -1 (before LXE408 administration), Day 5 & Day 10 (Post LXE408 administration) at 0,0.5,1,2,3,4,6,8,10,12 hours (post- iohexol dose) | To measure renal function (glomerular filtration rate (GFR)) after administration of LXE408. |
Countries
United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Outcome results
None listed