Single Oral Dose Escalation Study of DNDI-0690 in Healthy Male Subjects

Overview

This study will evaluate how the test medicine DNDI-0690 is taken up and broken down by the body and will also look at the safety and tolerability of the test medicine after a single dose. This is the first time the test medicine DNDI-0690 will be administered to humans.

Full Title of Study: “A Phase I, Double-blind, Randomised, Single Centre, Parallel Group, Single-dose, Dose-escalation, Placebo Controlled Study of the Safety, Tolerability and Pharmacokinetics of DNDI-0690 After Oral Dosing in Healthy Male Subjects”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: September 2019

Detailed Description

DNDI-0690 is intended to be used as oral treatment for Visceral Leishmaniasis with potential for the cutaneous form of the disease, Cutaneous Leishmaniasis. The present protocol describes the first-in-human (FIH) study with DNDI-0690.

Interventions

  • Drug: DNDI-0690
    • capsules of 10, 100 and 200 mg
  • Drug: Placebo of DNDI-0690
    • capsules of matching placebo

Arms, Groups and Cohorts

  • Experimental: Active DNDI-0690
    • Single dose starting from 10 mg for the first cohort. Dose for following cohorts to be decided by the Safety Review Committee
  • Placebo Comparator: Placebo
    • Single dose placebo

Clinical Trial Outcome Measures

Primary Measures

  • Safety and Tolerability of DNDI-0690 by Assessing the Occurrence of Treatment-emergent adverse events (TEAEs)
    • Time Frame: from baseline up to 7-10 days post-dose
    • number of subjects experiencing TEAEs classified by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class and Preferred Terms
  • Safety and Tolerability of DNDI-0690 by Assessing the Changes in vital signs (pulse rate)
    • Time Frame: from baseline up to 7-10 days post-dose
    • Pulse rate (beats per minute)
  • Safety and Tolerability of DNDI-0690 by Assessing the Changes in vital signs (blood pressure)
    • Time Frame: from baseline up to 7-10 days post-dose
    • Blood pressure (mmHg)
  • Safety and Tolerability of DNDI-0690 by Assessing the Changes in 12-lead electrocardiogram (ECG) parameters
    • Time Frame: from baseline up to 7-10 days post-dose
    • corrected QT interval by Frideriecia’s formula (QTcF) (msec)
  • Safety and Tolerability of DNDI-0690 by Assessing the Changes of Safety laboratory parameters related to liver function
    • Time Frame: from baseline up 7-10 days post-dose
    • aspartate aminotransferase (AST)
  • Safety and Tolerability of DNDI-0690 by Assessing the Changes of Safety laboratory parameters related to liver function
    • Time Frame: from baseline up 7-10 days post-dose
    • alanine aminotransferase (ALT)
  • Safety and Tolerability of DNDI-0690 by Assessing the Changes of Safety laboratory parameters related to renal function
    • Time Frame: from baseline up 7-10 days post-dose
    • creatinine (mg/dL)
  • Safety and Tolerability of DNDI-0690 by Assessing the Changes of Safety laboratory parameters related to renal function
    • Time Frame: from baseline up 7-10 days post-dose
    • creatinine clearance (CLcr)
  • Safety and Tolerability of DNDI-0690 by Assessing the Changes of Troponin I as a cardiac safety marker
    • Time Frame: 4h, 9h, 24h and 48h post-dose
    • Troponin I

Secondary Measures

  • Area Under the Plasma Concentration Versus Time Curve (AUC) From Zero Extrapolated to Infinity (AUC0-inf)
    • Time Frame: pre-dose up to 72 hours post-dose
    • To assess plasma pharmacokinetic parameters
  • Observed Maximum Concentration (Cmax)
    • Time Frame: pre-dose up to 72 hours post-dose
    • To assess plasma pharmacokinetic parameters
  • Time to Maximum Observed Plasma Concentration (Tmax)
    • Time Frame: pre-dose up to 72 hours post-dose
    • To assess plasma pharmacokinetic parameters
  • Apparent elimination half-life (T1/2)
    • Time Frame: pre-dose up to 72 hours post-dose
    • To assess plasma pharmacokinetic parameters

Participating in This Clinical Trial

Inclusion Criteria

  • Healthy males
  • 18 to 55 years of age at the time of signing informed consent
  • Body mass index (BMI) of 18.0 to 30.1 kg/m2 as measured at screening
  • General good physical health determined by medical and surgical history, physical examination, 12-lead ECG, vital signs and clinical laboratory tests
  • 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 and pre-dose
  • A resting Heart Rate (HR) between ≥40 and ≤90 bpm measured after 10 min rest in supine position at screening and pre-dose
  • ECG recording without clinically significant abnormality, including QTcF measure of ≤450 msec at screening and pre-dose
  • Having had no febrile seizures or infectious illness for at least 7 days prior to administration of the Investigational Medicinal Product (IMP)
  • Must be willing and able to communicate and participate in the whole study
  • Must provide written informed consent
  • Must agree to adhere to the contraception requirements and life-style restrictions defined in the protocol

Exclusion Criteria

  • Subjects who have received any IMP in a clinical research study within the 3 months or 90 days prior to Day 1
  • Subjects who are study site employees, or immediate family members of a study site or sponsor employee
  • Subjects who have previously been enrolled in this study and/or have received DNDI-0690 previously
  • History of any drug or alcohol abuse in the past 2 years
  • Demonstrating excess in caffeine/xanthine consumption (more than 6 cups of coffee or equivalent a day)
  • Regular alcohol consumption in males >21 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 alcohol breath test at screening or admission
  • Current smokers and those who have smoked within the last 12 months. As confirmed by a breath carbon monoxide reading of greater than 10 ppm at screening or admission
  • Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months
  • Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening
  • Clinically significant abnormal biochemistry, haematology, coagulation or urinalysis (especially aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), creatinine, and blood urea nitrogen (BUN)) as judged by the investigator (laboratory parameters are listed in Appendix 1). Subjects with Gilbert's syndrome are allowed
  • Confirmed positive drugs of abuse test result
  • Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results
  • Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <80 mL/min using the Cockcroft-Gault equation
  • 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
  • History of additional risk factors for Torsades des Pointe (eg heart failure, hypokalaemia, family history of long QT syndrome)
  • Rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency
  • Any relevant GI complaints within 7 days of dosing
  • 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)
  • 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
  • Donation or loss of greater than 500 mL of blood within the previous 3 months or more than 100 mL within 30 days before signing Informed Consent Form (ICF) to this trial
  • Subjects who are taking, or have taken, any prescribed or over-the-counter drug (including anti-acid drugs) or vitamins/herbal remedies (eg St. John's Wort and others which are known to interfere with the Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) metabolic pathways) in the 21 days before IMP administration. Administration of up to 4 g of paracetamol per day within 7 days of IMP administration is allowed
  • Surgery within 12 weeks prior to screening, with the exception of appendectomy
  • Any surgery (eg gastric bypass) or medical condition that may affect absorption of orally administered drugs
  • Failure to satisfy the investigator of fitness to participate for any other reason

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 55 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Drugs for Neglected Diseases
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Sharan Sidhu, MD, Principal Investigator, Quotient Sciences
  • Overall Contact(s)
    • Senior Clinical Manager, +41 22 906 92 57, sblesson@dndi.org

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