Treatment of visceral and/or cutaneous leishmaniasis Infections and Infestations Leishmaniasis
Conditions
Interventions
Sixty-four (64) healthy male volunteers, aged 18 to 50 will be included in the study. Randomization is performed by block of 2 (1:1 for placebo:active) for the sentinel group, followed by block of 6 (
Sponsors
Drugs for Neglected Diseases Initiative
Eligibility
Sex/Gender
Male
Age
18 Years to 50 Years
Inclusion criteria
Inclusion criteria: 1. Healthy Caucasian male volunteer aged 18 to 50 years inclusive 2. Non-smoker or light smoker of not more than 5 cigarettes a day. No smoking (or use of smoking substitute e.g. nicotine patch) is permitted from screening throughout the study 3. Body Mass Index (BMI) between 18 and 30.1 kg/m2 inclusive at screening 4. Considered as healthy after a comprehensive clinical assessment (detailed medical history and complete physical and neurological examination) 5. Normal Blood Pressure (BP) and Heart Rate (HR) at the screening visit after 10 minutes in supine position: 5.1. 95 mmHg = Systolic Blood Pressure (SBP) = 140 mmHg 5.2. 50 mmHg = Diastolic Blood Pressure (DBP) = 90 mmHg 5.3. 45 bpm = HR = 90 bpm 5.4. Or considered NCS by investigators 6. Normal ECG recording on a 12-lead ECG at the screening visit: 6.1. 120 ms < PR < 210 ms 6.2. QRS < 120 ms 6.3. QTcf = 430 ms for male 6.4. No sign of any relevant trouble of sinusal automatism 6.5. Or considered as non-clinically significant by investigators 7. Laboratory parameters within the normal range of the laboratory (hematological, hormonology, blood chemistry tests, urinalysis). Individual values out of the normal range can be accepted if judged non-clinically significant by the Investigator; for example, isolated elevated bilirubin is acceptable if judged by the physician without clinical relevance (i.e. Gilbert's syndrome) 8. ALAT, ASAT and Creatinine values strictly within the normal range 9. A negative result for diagnostic test of SARS-CoV-2 at D-1 10. Normal dietary habits 11. Provision of written informed consent to participate as shown by a signature on the volunteer consent form, after reading the information and consent form, and after having the opportunity to discuss the trial with the investigator or his delegate 12. Able to communicate well with the Investigator and research staff and to comply with the requirements of the entire study 13. Covered by Health Insurance System and/or in compliance with the recommendations of National Law in force relating to biomedical research 14. Must agree to adhere to the contraception requirements defined in Section 4.3: use of condom by the male volunteer plus an effective method of contraception for the volunteer or their partner of childbearing potential from study drug administration until 90 days post-dosing OR use of a condom for 10 days post-dosing if the partner is known to be pregnant
Exclusion criteria
Exclusion criteria: 1. Having previously received DNDI-6148, or who participated in another clinical trial within 3 months prior and during the study, or 5-times the half-life of the drug tested in the previous clinical trial, whichever is longer (time calculated relative to the last dose in the previous clinical trial) 2. Any history (direct questioning) or presence (physical examination) of cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematological, neurologic, psychiatric, systemic or infectious acute or chronic disease; including known or suspected HIV, HBV or HCV infection 3. With any clinically significant abnormality following review of pre-study laboratory tests, vital signs, full physical examination and ECG 4. Symptomatic hypotension whatever the decrease of blood pressure or asymptomatic postural hypotension defined by a decrease in SBP or DBP equal to or greater than 20 mmHg within two minutes when changing from the supine to the standing position 5. Who have a history of allergy, intolerance or photosensitivity to any drug 6. Who have a history of serious allergy, asthma, allergic skin rash or sensitivity to any drug 7. Who have a history of additional risk factors for “Torsades de Pointe” (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) 8. Current suicide risk or history of suicide risk (CSSRS baseline: “yes” answer to items 4 and/or 5); participants with a “yes” answer for current suicide risk should be referred for psychiatric evaluation 9. Participants with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency 10. Who used a prescription medicine during the 28 days before the first dose of trial medication or use of an over-the-counter medicine (including antacid drug, with the exception of acetaminophen (paracetamol)), during the 7 days before the first dose of trial medication 11. History or presence of drug or alcohol abuse (more than 14 units of alcohol per week, one unit = 8 g or about 10 mL of pure alcohol) 12. Excessive consumption of beverages with xanthine bases (more than one liter/day) 13. Who drink more than 8 cups daily of beverage containing caffeine 14. Who has regular daily consumption of more than 5 cigarettes daily, or use more than 3 grams (1/8 ounce) of tobacco 15. Who use dietary supplements or herbal remedies (such as St John’s Wort) known to interfere with the CYP3A4 and/or P-gp metabolic pathways during the 28 days before the first dose of trial medication 16. Grapefruit should also be avoided during the 7 days before the first dose of trial medication 17. Positive Hepatitis B surface (HBs) antigen or anti Hepatitis C Virus (HCV) antibody, or positive results for Human Immunodeficiency Virus (HIV 1 or 2) tests 18. Positive results of screening for drugs of abuse (opiates, cocaine, amphetamine, cannabis, benzodiazepines) 19. Blood donation (including in the frame of a clinical trial) within 12 weeks before administration 20. General anaesthesia within 3 months before trial medication administration 21. Inability to abstain from intensive muscular effort 22. Who have any clinical condition or prior therapy which, in the opinion, of the Investigator, made the participant unsuitable for the study 23. Who had surgery (e.g. stomach bypass) or medical condition that might affect absorption of study drug taken orally 24. Who had febrile illness within 1 week before the start of the study 25. Participant who, in t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety and tolerability of DNDI-6148 measured by: 1. Frequency of adverse events (AEs), based on the clinical judgement of the investigator, occurring from dosing up to 72 h post-dose 2. Frequency of participants reporting AEs, based on the clinical judgement of the investigator, from dosing up to 72 h post-dose 3. Causality of AEs based on the clinical judgement of the investigator, occurring from dosing up to 72 h post-dose, The possible relationship between the AE and the study drug will be quoted as following: Not related: There is no reasonable possibility of causal relationship. Related: There is at least a reasonable possibility of a causal relationship between an adverse event and an investigational medicinal product. This means that there are facts (evidence) or arguments to suggest a causal relationship. 4. Severity of AEs assessed based on the clinical judgement of the investigator, occurring from dosing up to 4 days post-dose, The severity of the AEs will be determined in the following manner: Mild: The participant is aware of the event or symptom, but the event or symptom is easily tolerated (e.g. no reduction in daily activities is required). Moderate: The participant experiences sufficient discomfort to interfere with or reduces his or her usual level of activity. Severe: Significant impairment of functioning: the participant is unable to carry out usual activities and/or the participant's life is at risk from the event. Life-threatening: The participant is at significant risk of life; it does not refer to an event which hypothetically might have caused death if it were more severe (life-threatening consequences, urgent intervention required). Death: Death related to an event. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. AUC0-8 (area under the plasma concentration-time curve from administration up to infinity with extrapolation of the terminal phase) calculated following quantification of DNDI-6148 by LC/MS-MS in plasma from dosing up to 72 hours post dose 2. Cmax (observed maximum plasma concentration) calculated following quantification of DNDI-6148 by LC/MS-MS in plasma from dosing up to 72 hours post dose 3. Other PK descriptive parameters derived from quantification of DNDI-6148 in plasma and urine by LC/MS-MS from dosing up to 72 hours post dose 4. Cardiologic pharmacodynamics parameters of DNDI-6148 measured from electrocardiograms (ECG) recordings from baseline up to 72 hours post dose | — |
Countries
France
Outcome results
None listed