Healthy volunteers to test a treatment for Visceral Leishmaniasis Infections and Infestations
Conditions
Interventions
This trial will be a double-blind placebo-controlled (Part B only), randomised trial to evaluate the safety, tolerability, and pharmacokinetics of single dose in fed state, and repeat doses of DNDI- 6
Sponsors
Drugs for Neglected Diseases Initiative
Eligibility
Sex/Gender
All
Age
18 Years to 55 Years
Inclusion criteria
Inclusion criteria: 1. Participants must be 18 to 55 years of age inclusive, at the time of signing the informed consent and can be included in only one cohort of this trial. 2. Participants must be healthy as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. 3. Body weight =50 kg and body mass index (BMI) within the range 18.5 -30 kg/m² (inclusive). 4. Male Participants: Male participants with partners of childbearing potential must use either one of the male or female condom, with the female partner using an additional highly effective contraceptive method with a failure rate of <1% per year, during the treatment period, and for at least 90 days after the last dose of trial treatment. Other acceptable methods of contraception include: • Any highly effective method of contraception listed below for female participants • Progesterone-only oral contraception, where inhibition of ovulation is not the primary mode of action • Cap, diaphragm, or sponge with spermicide For participants who practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant, contraceptive requirements do not apply. Male participants should refrain from donating sperm during the treatment period and for at least 90 days after the last dose of trial treatment. For participants who are exclusively in same-sex relationships, contraceptive requirements do not apply. 5. Female Participants: Female participants who are of non-childbearing potential (i.e., due to being post menopausal for at least 1 year (confirmed by FSH assessment) or permanently sterile following hysterectomy, bilateral salpingectomy, bilateral oophorectomy) will not be required to use contraception. Female participants of childbearing potential must be willing to use a highly effective method of birth control (i.e. contraceptive measure with a failure rate of <1% per year when used consistently and correctly, as per described in protocol) with low user dependency, in conjunction with a barrier contraception (i.e. either one of the male or female barrier contraceptions) from the time of screening until 30 days after the final Follow up Visit. Use of any of the protocol defined contraception should have been established for at least 90 days prior to enrolment (the investigator should evaluate the potential for contraceptive method failure (e.g. non-compliance, recently initiated) in relationship to the first dose of trial treatment. Highly effective methods of contraception include: • Placement of intrauterine device or intrauterine system. • Established use of oral, injected or implanted hormonal methods of contraception associated with inhibition of ovulation. • Male sterilisation (with the appropriate post-vasectomy confirmation of surgical success). For female participants on the trial, the vasectomised male partner should be the sole partner for that participant. • Bilateral tubal ligation For participants who practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant, contraceptive requirements do not apply. For participants who are exclusively in same-sex relationships, contraceptive requirements do not apply. 6. Willing to participate in the trial and capable of giving signed informed consent.
Exclusion criteria
Exclusion criteria: 1. History or presence of current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the trial treatment; or interfering with the interpretation of data in the opinion of the investigator. 2. Previous history of leishmaniasis 3. Alanine transaminase (ALT) or Aspartate aminotransferase (AST) >upper limit of normal (ULN) confirmed by repeat assessment. 4. Bilirubin >ULN confirmed by repeat assessment. Participants with known Gilbert’s syndrome with total bilirubin 450 msec for male and 470 msec for female 9. Loss of blood or blood products in excess of 500 mL within a 56-day period. 10. The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current trial: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). 11. Sensitivity to any of the trial treatments, or components or drug or other allergy that, in the opinion of the Investigator or DNDi Medical Monitor, contraindicates participation in the trial. 12. Regular use of known drugs of abuse. 13. Participants with an estimated GRF (calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation) of = 80ml/min/1.73m2 or with significant hematuria or proteinuria (+or higher)on urinary dipstick testing. 14. Presence of Hepatitis B surface antigen (HBsAg) or positive Hepatitis C antibody test result at screening. 15. Positive human immunodeficiency virus (HIV) antibody test. 16. Positive pre-trial drug/alcohol screen (confirmed by repeat exam). 17. Clinically significant proteinuria and or haematuria, defined as positive urine dipstick test (1+). Urine dipstick should be repeated at least 3 days apart in case of urine dipstick test trace reading on previous occasion. 18. Participants with Spot urine protein creatinine ratio >0.5 will be excluded. 19. History or regular use of tobacco or nicotine-containing products within 3 months prior to screening. 20. Systolic BP of less than or equal to 90. 21. Use of vitamins, herbal therapies, minerals, supplements during 14 days before the first dose of trial medication (except St John’s Wort). Prescription medicine during the 14 days before the first dose of trial medication or use of an over-the-counter medicine during the 14 days before the first dose of trial medication (with the exception of the oral contraceptive pill or up to 2g of paracetamol daily). 22. Participants must not have travelled to an area (as determined by the investigator) with a high prevalence of leishmanial/parasitic infections in the 6 months before screening or intend to do so in the 3 months after the final dose of trial treatment. 23. Food Effect part only: Participant must have no dietary restrictions (e.g., lactose intolerance) or inability to eat an adapted standard meal (includes 35-40% fat content). 24. Food Effect part o
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To evaluate the safety and tolerability the participant will be monitored after taking IMP and at various timepoints after. Vital signs will also be taken regularly. 1.Adverse events 2.Clinically important laboratory values 3.PCI vital signs 4.12 lead electrocardiogram (ECG) findings 5.24 hours (hr) telemetry and Holter findings 6.Physical examination findings | — |
Secondary
| Measure | Time frame |
|---|---|
| 1.Plasma concentrations of DNDI-6899 plus derived parameters, as data allow. For Food Effect part: Derived PK parameters for DNDI-6899 following single dose under fasted and fed conditions including area under the plasma drug concentration versus time curve (AUC(0-t), AUC(0-8), maximum observed plasma drug concentration (Cmax), time to maximum observed plasma drug concentration (Tmax), and apparent terminal half-life (T1/2) as data allow. For Multiple Ascending Dose part: derived PK parameters^ : AUC(0-t), AUC (0-8), AUC(0-tau), Cmax, Tmax, Ctau and T1/2. Strategy: For the fed/fasted part: Fed PK parameters will be included if the participant had the fed dose and PK parameter from the fed part, and similarly for the fasted PK parameters. Multiple ascending dose part: Day 1 parameters will be included if the participant had Day 1 dose and Day 1 PK parameter available. Day 10 parameters will be included only if participant had all 10 doses and had Day 10 PK parameter available. Summary measure: For each group, geometric means of AUC(0-t), AUC (0-8), AUC(0-tau), Ctau and Cmax, median of Tmax and arithmetic mean of T1/2. 2. Food effect assessment using derived PK parameters^: AUC(0-t), AUC(0-8), T1/2, Tmax and Cmax. Strategy: Participants must have both fed and fasted doses. In addition, participants who do not have a particular PK parameter from both the fed and fasted doses will be excluded for that PK parameter. Summary measure: Geometric mean ratios fed:fasted for AUC(0-t), AUC(0-8), T1/2, Tmax and Cmax. 3. Dose-proportionality assessment using derived PK parameters^: AUC(0-tau), Tmax, Cmax, Ctau. Strategy: Data will be reported based on complete dosing and PK parameters from Day 10. That is, data from participants who do not complete all 19 doses will be excluded from analyses, and participants who do not have a particular PK parameter on Day 10 will be excluded for that PK parameter. Summary measure: Slope from power model for AUC(0-tau), Ctau | — |
Countries
England, United Kingdom
Contacts
Public ContactJan Dixon
Outcome results
None listed