| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Uncomplicated Plasmodium falciparum malaria |
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| E.1.1.1 | Medical condition in easily understood language |
| Plasmodium falciparum malaria |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Parasitic Diseases [C03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10086289 |
| E.1.2 | Term | Uncomplicated malaria |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Core phase: To confirm the efficacy of KLU156 in adults and children ≥ 10 kg body weight suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection) by demonstrating that KLU156 is non-inferior to Coartem (non‑inferiority (NI) margin = 5%) based on the PCR2-corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29.
Primary clinical question of interest for the Core phase: "What is the difference in the proportion of patients with uncomplicated P. falciparum malaria (P. falciparum with or without other Plasmodium spp. co-infection) achieving PCR-corrected ACPR at Day 29 between KLU156 and Coartem treatment arms?" This assessment is to be made in patients who would: ● take the complete course of study treatment (at least 80% of study medication) regardless of treatment assignment. ● take non-study treatment with antimalarial activity prior to Day 29 only in case of recrudescence of parasites (rescue treatment). |
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| E.2.2 | Secondary objectives of the trial |
| Core phase: ● To further confirm the efficacy of KLU156 by demonstrating non-inferiority of KLU156 to Coartem (NI margin 7.5%) based on the uncorrected ACPR at Day 29. Secondary clinical question of interest for the Core phase: "What is the difference in the proportion of patients with uncomplicated P. falciparum malaria (P. falciparum with or without other Plasmodium spp. co-infection) achieving uncorrected ACPR at Day 29, without the need of non-study treatment with any antimalarial activities, between KLU156 and Coartem treatment arms?" |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
DMFA - Exploratory objective(s): Core and Extension phases: To explore the transmission-blocking activity of KLU156 (direct membrane feeding assay (DMFA) at selected sites in Core and Extension phases and RT-qPCR in the Core phase).
• by determining oocyst density and infection prevalence in female Anopheles gambiae mosquito colonies.
• by determining presence and clearance of gametocytes using reverse transcription quantitative polymerase chain reaction (RT-qPCR) as a proxy for infectivity.
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| E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria in order to be eligible for inclusion in the Core phase of this study:
1. Male or female patients ≥ 10 kg of body weight
2. Microscopically confirmed diagnosis of uncomplicated P. falciparum malaria with an asexual P. falciparum parasitemia ≥ 1,000 and ≤ 200,000 parasites/ μL at the time of pre-screening with or without other Plasmodium spp. co-infection.
3. Axillary temperature ≥ 37.5 ºC or oral temperature ≥ 38.0 ºC or tympanic/rectal temperature ≥ 38.5 ºC; or history of fever during the previous 24 h (at least documented verbally)
4. Negative pregnancy test for patients of childbearing potential
5. Signed informed consent (pre-screening and screening for the Core phase) must be obtained before any assessment is performed; for minors, signed informed consent must be obtained from parent/legal guardian (LAR). If the parent/LAR is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients who are capable of providing assent, must provide it along with parental/LAR consent or as per local ethical standards
6. The patient and/or their parent/LAR is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned. |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria are not eligible for inclusion in the Core phase of this study.
No additional exclusions may be applied by the Investigator, in order to ensure that the study population will be representative of all eligible patients:
1. Signs and symptoms of severe malaria according to WHO 2015
2. Significant, non-plasmodial co-infections including tuberculosis
3. Concurrent febrile illnesses (e.g., typhoid fever, known or suspected dengue fever, known COVID19)
4. Severe malnutrition:
• For patients ≥ 12 years: body mass index (BMI) < 16.0
• For children < 12 years: less than 70% of median normalized WHO reference weight or very low mid-upper arm circumference (MUAC < 115 mm)
5. Known relevant liver disease e.g., chronic hepatitis, cirrhosis or hepatitis B or A vaccination within the past month, known gallbladder or bile duct disease, acute or chronic pancreatitis
6. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection or family history of congenital or hereditary immunodeficiency
7. Repeated vomiting (defined as >3 times in the 24 h prior to start of screening) or severe diarrhea (defined as >3 watery stools in the 24 h prior to start of screening)
8. Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia
9. Anemia (hemoglobin level < 7 g/dL)
10. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs (e.g., HIV patients on ART therapy or TB patients on treatment), or which may jeopardize the patient in case of participation in the study.
11. Any of the following:
• AST/ALT > 3 x the upper limit of normal (ULN), regardless of the level of total bilirubin
• Total bilirubin > 3 x ULN
• Resting QT interval corrected by Fridericia’s formula (QTcF) > 450 ms at screening
12. Any severe disease condition (including malignancy), known chronic underlying disease such as sickle cell disease, and severe cardiac, renal, or hepatic impairment) which might prohibit participation in this study
13. Inability to swallow oral medication (in tablet, powder and/or liquid form)
14. Prior antimalarial therapy or antibiotics with antimalarial activity within minimum of their five plasma half-lives (or within 4 weeks of screening if half-life is unknown)
15. Use of other investigational drugs within 30 days of dosing or until the expected pharmacodynamic effect has returned to baseline, whichever is longer, or longer if required by local regulations
16. Use of medications prohibited by the protocol
17. Previous participation in any malaria study or any malaria vaccine study or having received a malaria vaccine in any other circumstance within 1 month prior to start of study treatment
18. History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease
19. Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of the study
20. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes
21. Pregnant or nursing (lactating) patients
22. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| PCR-corrected ACPR at Day 29 (i.e., 28 days post-first dose administration) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Uncorrected ACPR at Day 29 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Burkina Faso |
| Congo, The Democratic Republic of the |
| Gabon |
| Ghana |
| Mali |
| Nigeria |
| Rwanda |
| Tanzania, United Republic of |
| Uganda |
| Zambia |
| Niger |
| Côte d’Ivoire |
| India |
| Kenya |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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