Study of first dosing of a new compound DNDi-6148 in healthy volunteers to assess safety and drug levels in blood and urine after escalating single dose
| ISRCTN | ISRCTN54981564 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN54981564 |
| EudraCT/CTIS number | 2018-004023-37 |
| Secondary identifying numbers | DNDi-6148-01 / OP105718.DND |
- Submission date
- 26/06/2020
- Registration date
- 03/07/2020
- Last edited
- 27/06/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
DNDI-6148 is a drug developed to treat visceral leishmaniasis (VL), a potentially lethal disease caused by the Leishmania parasite and transmitted by the female sandfly (small insects that are morphologically similar to mosquitoes). This disease is endemic in East Africa, the Indian Peninsula and South America, where it affects vulnerable populations. To a lesser degree, it also affects a few people in Southern Europe, mainly immunocompromised patients.
The main aim of this study is to assess the safety and tolerance of the DNDI-6148 product after giving increasingly large single doses to healthy male volunteers, compared to a placebo (a medication that is indistinguishable the product to be tested, but does not contain the active molecule). This study will also be used to study DNDI-6148's pharmacokinetic properties (the fate of the medication in the blood) and pharmacodynamic properties (the effect of the medication on the volunteer, more specifically on the electrocardiogram).
Who can participate?
Healthy men aged 18 to 50
What does the study involve?
A study check-up for the selection appointment (physical examination, electrocardiogram, blood tests, alcohol and drug screens), then 5 days of hospitalization in the clinical unit, including several check-ups and dosing of the drug once. Participants are randomly allocated to receive either the active drug or a placebo. A single dose of treatment will be given as an oral suspension (liquid) with increasing doses for each group of participants. The last follow up visit is 72 hours later. A maximum of 450 ml of blood will be drawn.
What are the possible benefits and risks of participating in the study?
No benefit for health can be expected for participants to the study and taking medication of any kind poses some risks linked to individual reactions, which are difficult to predict. Drawing blood can cause bruising, pain or bleeding and carry a low risk of infection. Since this is a study of the first use of the product in humans, the adverse effects (frequent or not) of this medication have not yet been identified.
Where is the study run from?
Eurofins Optimed (France)
When is the study starting and how long is it expected to run for?
January 2018 to March 2022
Who is funding the study?
Wellcome Trust (UK) (grant 212346/Z/18/Z - 21st Century Treatments for Sustainable Elimination of Leishmaniasis)
Who is the main contact?
Sophie Delhomme
sdelhomme@dndi.org
Contact information
Scientific
DNDi
15 Chemin Louis Dunant
Geneva
1202
Switzerland
| Phone | +41 (0)22906 92 79 |
|---|---|
| sdelhomme@dndi.org |
Study information
| Study design | Single-center interventional blinded randomized parallel-group single-dose dose-escalation placebo-controlled study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | A Phase I, blinded, randomized, single-centre, parallel-group, single-dose, dose-escalation, placebo-controlled study of the safety, tolerability, and pharmacokinetics of DNDI-6148 after oral dosing in healthy male subjects |
| Study hypothesis | DNDI-6148 is safe to be dosed in humans and provides sufficient exposure in healthy volunteers to be further investigated to treat visceral leishmaniasis. |
| Ethics approval(s) | Approved 07/12/2018, Committee of people protection South-East and Overseas II (Comité de Protection des Personnes, Agence regionale de santé Occitanie, Bureau 1048, 10 chemin du raisin, 31050 Toulouse Cedex9, France; +33 (0)5 34 30 27 55; cppsoom2@ars.sante.fr), ref: 2-18-90 / SI 1823 |
| Condition | Treatment of visceral and/or cutaneous leishmaniasis |
| Intervention | 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 (1:5) for the main group of each dose cohort. A coding list was issued at the start of the trial, only available to unblinded personnel. Each cohort will include 8 participants (randomized in 6 active/2 placebo). A single dose of treatment will be administered as an oral suspension with increasing doses for each cohort of 8, such as 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 260 mg, 380 mg and 500 mg. The treatment will be administered as a single dose on Day 1. Last follow up visit is 72 h post-dosing. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | DNDI-6148 |
| Primary outcome measure | 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 outcome measures | 1. AUC0-∞ (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 |
| Overall study start date | 01/01/2018 |
| Overall study end date | 08/03/2022 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Male |
| Target number of participants | 64 |
| Total final enrolment | 64 |
| Participant 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 |
| Participant 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 the judgment of the Investigator, is likely to be non-compliant or uncooperative during the study, or unable to cooperate because of a language problem, poor mental development 26. No possibility of contact in case of emergency 27. Exclusion period of a previous study 28. Administrative or legal supervision 29. Who are unwilling to give their informed consent 30. Participant who would receive more than 4500 euros as indemnities for his participation in biomedical research within the 12 last months, including the indemnities for the present study |
| Recruitment start date | 04/02/2020 |
| Recruitment end date | 08/03/2022 |
Locations
Countries of recruitment
- France
Study participating centre
Gières
38610
France
Sponsor information
Research organisation
c/o Jean-Yves Gillon PharmD, PhD
Head of Translational Sciences
15 Chemin Louis-Dunant
Geneva
1202
Switzerland
| Phone | +41 (0)22 906 92 32 |
|---|---|
| jygillon@dndi.org | |
| Website | https://www.dndi.org/ |
"ROR" |
https://ror.org/01tp0e450 |
Funders
Funder type
Research organisation
Private sector organisation / International organizations
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 15/06/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. The protocol will be available. |
| IPD sharing plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version v7.0 | 17/06/2020 | 26/11/2020 | No | No |
| Protocol file | version 8.0 | 19/11/2020 | 23/08/2022 | No | No |
| Protocol file | version 9.0 | 24/02/2021 | 23/08/2022 | No | No |
| Protocol file | version 10.0 | 21/09/2021 | 23/08/2022 | No | No |
| Protocol file | version 11.0 | 25/11/2021 | 23/08/2022 | No | No |
| Statistical Analysis Plan | version 2.0 | 04/04/2022 | 15/12/2022 | No | No |
| Other unpublished results | version 1.0 | 08/06/2023 | 27/06/2023 | No | No |
Additional files
- ISRCTN54981564_PROTCOL_v7.0_17June2020.pdf
- uploaded 26/11/2020
- 38473 DNDi-6148-01_OP1057 Protocol v8.0 19Nov2020.pdf
- 38473 DNDi-6148-01_OP1057 Protocol v9.0 24Feb2021.pdf
- 38473 DNDi-6148-01_OP1057 Protocole v10.0_21 September 21_signed SD_JYG.pdf
- 38473 DNDi-6148-01_OP1057 Protocol v11.0_25nov2021.pdf
- ISRCTN54981564_SAP_V2.0_04Apr22.pdf
- ISRCTN54981564 DNDi-6148-01 Clinical Study Report Synopsis v1.0 08Jun2023.pdf
Editorial Notes
27/06/2023: An unpublished results synopsis was uploaded as an additional file.
24/05/2023: The intention to publish date was changed from 01/05/2023 to 15/06/2023.
04/04/2023: The intention to publish date was changed from 01/03/2024 to 01/05/2023.
15/12/2022: Statistical analysis plan uploaded.
15/11/2022: The intention to publish date was changed from 01/11/2022 to 01/03/2024.
23/08/2022: The following changes were made to the trial record:
1. Uploaded protocols (not peer-reviewed) as additional files.
2. The intention to publish date was changed from 30/08/2022 to 01/11/2022.
26/04/2022: The total final enrolment number has been added.
21/02/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 28/02/2022 to 08/03/2022.
2. The overall end date was changed from 28/02/2022 to 08/03/2022.
3. The intention to publish date was changed from 30/04/2022 to 30/08/2022.
4. The plain English summary was updated to reflect these changes.
13/09/2021: The following changes have been made:
1. The recruitment end date has been changed from 30/09/2021 to 28/02/2022.
2. The overall trial end date has been changed from 30/09/2021 to 28/02/2022 and the plain English summary updated accordingly.
3. The intention to publish date has been changed from 28/02/2022 to 30/04/2022.
19/05/2021: Sponsor details updated.
18/05/2021: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/05/2021 to 30/09/2021.
2. The overall trial end date was changed from 01/05/2021 to 30/09/2021.
3. The intention to publish date was changed from 31/12/2021 to 28/02/2022.
02/12/2020: Contact details updated.
01/12/2020: The recruitment end date was changed from 30/11/2020 to 01/05/2021. The overall trial end date was changed from 31/12/2020 to 01/05/2021.
26/11/2020: Uploaded protocol (not peer reviewed) Version 7.0, 17 June 2020.
03/07/2020: Trial's existence confirmed by Committee of people protection South-East and Overseas II.
