The safety, tolerability and fluid exposure of a drug aimed to treat visceral and cutaneous leishmaniasis in healthy volunteers Not Applicable
Conditions
Interventions
The study will be conducted in three parts (Part A, Part B and Part C).
Part A: Multiple Ascending Dose Cohorts (Cohorts 1-4)
Part A will consist of up to four cohorts
two subjects will be dosed on the first dosing day of each cohort (1 subject on active IMP and 1 subject on matching placebo). The remainder of the cohort (five subjects on active IMP and two subjects
Sponsors
Drugs for Neglected Diseases Initiative
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Healthy males or healthy women of non-childbearing potential (WONCBP) between 18 and 55 years of age inclusive at the time of signing informed consent 2. Female subject of non-childbearing potential. WONCBP is defined as women who are postmenopausal or permanently sterilised (permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) 3. Female post-menopausal state is defined as no menses for 12 months without an alternative medical cause and confirmed by a serum FSH result of =40 IU/L at Screening 4. Male subject (and subject’s partner of childbearing potential) must use condom and also willing to use a highly effective method of contraception or 2 effective methods of contraception (see Section 10.5.2), if applicable (unless anatomically sterile or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) from first dose until 3 months after last dose of IMP 5. Body mass index (BMI) of 18.0 to 30.1 kg/m2 as measured at Screening and body weight =60 kg (BMI = body weight (kg) / [height (m)]2) 6. No clinically significant abnormal test results for serum biochemistry, haematology and/or urine analyses within 28 days before the first dose administration of the IMP 7. Subject with a negative urinary drugs of abuse (DOA) screen (including alcohol and cotinine) test results, determined within 28 days before the first dose administration of the IMP (N.B.: A positive test result may be repeated at the Investigator’s discretion) 8. Subject with negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg)) and hepatitis C virus antibody (HCV Ab) test results at Screening 9. General good physical health determined by medical and surgical history, physical examination, 12-lead ECG, vital signs and clinical laboratory tests 10. Normal blood pressure: systolic blood pressure between =90 and =140 mmHg, Diastolic blood pressure =90 mmHg, measured after 10 min rest in supine position at Screening, admission and pre-dose 11. A resting heart rate (HR) between =50 and =100 bpm measured after 10 min rest in supine position at Screening, admission and pre-dose 12. ECG recording without clinically significant abnormality, including QTcF measure of =450 msec at Screening, admission and pre-dose 13. No febrile seizures or infectious illness for at least 7 days prior to first administration of the IMP (Day 1) 14. Must agree to adhere to the contraception requirements and the life-style restrictions 15. Subject must be available to complete the study (including all follow-up visits) 16. Subject must satisfy an Investigator about his/her fitness to participate in the study 17. Subject must provide written informed consent to participate in the study
Exclusion criteria
Exclusion criteria: 1. Subjects who have received any IMP in a clinical research study within 90 days prior to Day 1 2. Subjects who are study site employees, or immediate family members of a study site or sponsor employee 3. Subjects who have previously been enrolled in this study and/or have received DNDI 0690 previously 4. History of any drug or alcohol abuse in the past 2 years 5. Demonstrating excess in caffeine/xanthine consumption (more than 6 cups of coffee or equivalent a day) 6. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 ml shot of 40% spirit, 1.5 to 2 Units = 125 ml glass of wine, depending on type). As confirmed by a positive urine alcohol test at Screening or admission 7. Current smokers or those who have smoked within the last 12 months with a positive cotinine result at Screening and Admission 8. Current users of cigarette replacements (i.e. e-cigarettes, nicotine patches or gums) and those who have used these products within the last 12 months 9. Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the Investigator or delegate at Screening 10. Clinically significant abnormal biochemistry, haematology, coagulation or urinalysis as judged by the Investigator or AST/ALT/total bilirubin/gamma-glutamyl transpeptidase [GGT]/ALP/creatinine >1.2 ULN. Subjects with Gilbert’s syndrome are allowed 11. Positive PCR COVID-19 test at admission 12. Evidence of renal impairment at Screening or admission, as indicated by an estimated Glomerular Filtration Rate (GFR) <lower limit of normal (LLN) using the CKD-EPI equation 13. History of clinically significant cardiovascular, renal, hepatic, neurological (especially seizures), immunological, psychiatric, myopathies, bleeding tendency, respiratory and particularly gastrointestinal (GI) disease, especially peptic ulceration and chronic gastritis, GI bleeding, ulcerative colitis, Crohn’s Disease or Irritable Bowel Syndrome, as judged by the Investigator 14. History of additional risk factors for Torsades des Pointe (i.e. heart failure, hypokalaemia, family history of long QT syndrome) 15. Rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency 16. Any relevant GI complaints within 7 days of dosing 17. Serious adverse reaction or clinically relevant hypersensitivity to any drug or the formulation excipients (Hypromellose [HPMC], sodium lauryl sulphate [SLS], sucrose, croscarmellose sodium and magnesium stearate) 18. Presence or history of clinically significant allergy requiring treatment (including asthma, urticaria, clinically significant allergic rash or other severe allergic diathesis), as judged by the Investigator. Hay fever is allowed unless it is active 19. Donation or loss of greater than 500 ml of blood within the previous 3 months or more than 100 ml within 30 days prior to signature of informed consent 20. Subjects who are taking, or have taken, any prescribed or over-the-counter drug (including anti-acid drugs) or vitamins/herbal remedies (i.e. St. John’s Wort and others which are known to interfere with the CY
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A & B: Safety and tolerability of DNDI-0690 after multiple oral doses in fasted conditions measured by: 1. Frequency of adverse events (AEs), based on the clinical judgement of the investigator, occurring from first dosing up to post-study follow-up visit (14 to 18 days post last dose) 2. Frequency of participants reporting AEs, based on the clinical judgement of the investigator, from first dosing up to post-study follow-up visit (14 to 18 days post last dose) 3. Causality of AEs based on the clinical judgement of the investigator, occurring from first dosing up to post-study follow-up visit (14 to 18 days post last dose) The possible relationship between the AE and the study drug will be quoted as follows: Not related: There is no reasonable possibility of a 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 first dosing up to post-study follow-up visit (14 to 18 days post last dose). The severity of the AEs will be determined in the following manner: 4.1. Mild: An AE that is easily tolerated by the subject, causes minimal discomfort, and does not interfere with everyday activities 4.2. Moderate: An AE that is sufficiently discomforting to interfere with normal everyday activities; intervention may be needed 4.3. Severe: An AE that prevents normal everyday activities; treatment or other intervention usually needed 4.4. Life-Threatening: The subject is at significant risk of life; it does not refer to an event which hypothetically might have caused death if it were more severe | — |
Secondary
| Measure | Time frame |
|---|---|
| Part A&B: 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-0690 by LC/MS-MS in plasma from last dosing up to 48 hours post dose 1. AUC0-24 (area under the plasma concentration-time curve from administration up to 24h post-dose) calculated following quantification of DNDI-0690 by LC/MS-MS in plasma on D1 and last day of dosing 2. Cmax (observed maximum plasma concentration) calculated following quantification of DNDI-0690 by LC/MS-MS in plasma on D1 and last day of dosing 3. Other PK descriptive parameters derived from quantification of DNDI-0690 in plasma and urine by LC/MS-MS from D1 up to 48 hours post dose 4. Cardiologic pharmacodynamics parameters of DNDI-0690 measured from electrocardiograms (ECG) recordings extracted from Holter at baseline and on last day of dosing | — |
Countries
United Kingdom, Wales
Outcome results
None listed