Wirksamkeit, Sicherheit und Verträglichkeit von KLU156 bei Erwachsenen und Kindern ≥ 5 kg Körpergewicht mit unkomplizierter Malaria P. Falciparum (KALUMA)
Eine randomisierte, offene, multizentrische Studie zum Vergleich der Wirksamkeit, Sicherheit und Verträglichkeit von KLU156 mit Coartem® bei der Behandlung von unkomplizierter Plasmodium-Falciparum-Malaria bei Erwachsenen und Kindern ≥ 5 kg Körpergewicht, gefolgt von einer Verlängerungsphase mit wiederholter Behandlung mit KLU156
This study aimed to confirm the efficacy, safety and tolerability of KLU156, a fixed dose combination of ganaplacide (KAF156) and a solid dispersion formulation of lumefantrine (lumefantrine-SDF), when administered once daily for three days in adults and children ≥ 10 kg of body weight suffering from uncomplicated P. falciparum malaria (with or without other Plasmodium spp. co-infection).
In the extension phase, the safety, tolerability and efficacy of repeated treatment with KLU156 was assessed for a maximum of approximately 18 months in patients who did not experience early treatment failure (ETF), who did not experience any study treatment-related SAE (Serious Adverse Event) previously and who gave informed consent to participate in the Extension phase.
Studienübersicht
Status
Bedingungen
Intervention / Behandlung
Detaillierte Beschreibung
The purpose of this study was to confirm the efficacy, safety and tolerability of KLU156 in patients with uncomplicated P. falciparum malaria (with or without other Plasmodium spp. co-infection) by demonstrating that KLU156 is non-inferior to Coartem.
- The total study duration was up to approximately 20 months.
- The treatment duration was 3 days for each malaria episode.
- The visit frequency was Days 1-3 (hospitalized) and 5 follow-up visits (Days 4, 8, 22, 29 and 43) in the Core phase and Days 1-3 (hospitalized) and 3 follow-up visits (Days 4, 8 and 29) in the Extension phase.
This study had two different primary outcomes depending on the submission (US New Drug Application (NDA) or non-US submissions).
Protocol amendment 01 increased the minimum body weight requirement for study participation from ≥ 5 kg to ≥ 10 kg and revised the statistical analysis plan to exclude patients < 10 kg from the main analyses.
Studientyp
Einschreibung (Tatsächlich)
Phase
- Phase 3
Kontakte und Standorte
Studienorte
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Banfora, Burkina Faso
- Novartis Investigative Site
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Bobo-Dioulasso, Burkina Faso
- Novartis Investigative Site
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Nanoro, Burkina Faso, BP 18
- Novartis Investigative Site
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Ouagadougou, Burkina Faso
- Novartis Investigative Site
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Sabou, Burkina Faso
- Novartis Investigative Site
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Abidjan, Côte d'Ivoire, 13 BP 972
- Novartis Investigative Site
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Agboville, Côte d'Ivoire
- Novartis Investigative Site
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Azaguié, Côte d'Ivoire
- Novartis Investigative Site
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Bas-Congo Province
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Kimpese, Bas-Congo Province, Demokratische Republik des Kongo
- Novartis Investigative Site
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Kisantu, Bas-Congo Province, Demokratische Republik des Kongo
- Novartis Investigative Site
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Du Haut Katanga
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Lubumbashi, Du Haut Katanga, Demokratische Republik des Kongo, 7010
- Novartis Investigative Site
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Kwango
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Kenge, Kwango, Demokratische Republik des Kongo
- Novartis Investigative Site
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Kwilu
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Masi-Manimba, Kwilu, Demokratische Republik des Kongo
- Novartis Investigative Site
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Lambaréné, Gabun, BP 242
- Novartis Investigative Site
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Libreville, Gabun, BP 1437
- Novartis Investigative Site
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Kintampo, Ghana, 92037
- Novartis Investigative Site
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Navrango, Ghana, VWJ6+8WF
- Novartis Investigative Site
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Kombewa, Kenia, 40102
- Novartis Investigative Site
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Nairobi, Kenia, 00200
- Novartis Investigative Site
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Siaya, Kenia, 2300
- Novartis Investigative Site
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Sotouba, Mali
- Novartis Investigative Site
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Niamey, Niger, 8003
- Novartis Investigative Site
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Kigali, Ruanda
- Novartis Investigative Site
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Rubavu, Ruanda
- Novartis Investigative Site
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Rusizi, Ruanda
- Novartis Investigative Site
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Northern Province
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Gicumbi, Northern Province, Ruanda
- Novartis Investigative Site
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Ndola, Sambia, 71769
- Novartis Investigative Site
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Luapula Province
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Nchelenge, Luapula Province, Sambia, 70100
- Novartis Investigative Site
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Bagamoyo, Tansania, 78373
- Novartis Investigative Site
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Korogwe Tanga, Tansania, 9653
- Novartis Investigative Site
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Tanga, Tansania, 5004
- Novartis Investigative Site
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Tororo, Uganda, 10102
- Novartis Investigative Site
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Teilnahmekriterien
Zulassungskriterien
Studienberechtigtes Alter
Akzeptiert gesunde Freiwillige
Studienberechtigte Geschlechter
Beschreibung
Key Inclusion criteria (Core phase)
- Male or female patients ≥ 10 kg of body weight.
- 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.
- 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 hours (at least documented verbally)
- Negative pregnancy test for patients of childbearing potential
- Signed informed consent was obtained before any assessment is performed; for minors, signed informed consent was obtained from parent/legal guardian. If the parent/legal guardian was unable to read and write, then a witnessed consent according to local ethical standards was permitted. Patients who were capable of providing assent, must have provided it along with parent/legal guardian consent or as per local ethical standards
- The patient and/or their parent/legal guardian was able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and was likely to complete the study as planned.
Key Exclusion criteria (Core phase)
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Signs and symptoms of severe malaria according to WHO 2015 (World Health Organization)
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Concurrent febrile illnesses (e.g., typhoid fever, known or suspected dengue fever, known COVID19)
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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)
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Repeated vomiting (defined as > 3 times in the 24 hours prior to start of screening) or severe diarrhea (defined as > 3 watery stools in the 24 hours prior to start of screening)
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Clinically relevant abnormalities of electrolyte balance which required correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia
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Anemia (hemoglobin level <7 g/dL)
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Any surgical or medical condition which might have significantly altered the absorption, distribution, metabolism, or excretion of drugs (e.g., Human immunodeficiency virus (HIV) patients on antiretroviral therapy (ART) or tuberculosis (TB) patients on treatment), or which may have jeopardized the patient in case of participation in the study.
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Any of the following:
- Aspartate Aminotransferase/ Alanine Aminotransferase (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
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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 was unknown)
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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
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Pregnant or nursing (lactating) patients.
Studienplan
Wie ist die Studie aufgebaut?
Designdetails
- Hauptzweck: Behandlung
- Zuteilung: Zufällig
- Interventionsmodell: Parallele Zuordnung
- Maskierung: Single
Waffen und Interventionen
Teilnehmergruppe / Arm |
Intervention / Behandlung |
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Experimental: KLU156
KLU156 once daily (QD) for 3 days under fed conditions (light meal). |
Oral use. KLU156 (400/480 mg) was the dose for patients with a bodyweight ≥ 35kg. Patients < 35kg took a fraction of the dose according to weight group as defined in the protocol. |
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Aktiver Komparator: Coartem
Coartem twice a day (BID) for 3 days under fed conditions. |
Oral use. Dosing was selected based on patient's body weight as per product's label. |
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Experimental: KLU156 (Participants with <10 kg Body Weight)
KLU156 once daily (QD) for 3 days under fed conditions (light meal). |
Oral use. KLU156 (400/480 mg) was the dose for patients with a bodyweight ≥ 35kg. Patients < 35kg took a fraction of the dose according to weight group as defined in the protocol. |
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Aktiver Komparator: Coartem (Participants with <10 kg Body Weight)
Coartem twice a day (BID) for 3 days under fed conditions. |
Oral use. Dosing was selected based on patient's body weight as per product's label. |
Was misst die Studie?
Primäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
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Core Phase: PCR-corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29
Zeitfenster: Day 29 (i.e., 28 days post-first dose administration)
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PCR-corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 is defined as the percentage of participants who are clinically well and have no recrudescence (reappearance of the original malaria infection) by 29 days after treatment, with PCR genotyping used to distinguish new infections from recrudescence. This primary outcome was applicable to the non-US submission. |
Day 29 (i.e., 28 days post-first dose administration)
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Core Phase: Uncorrected ACPR (US NDA Submission) at Day 29
Zeitfenster: Day 29
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Uncorrected ACPR at Day 29 is defined as the percentage of participants who are clinically well and have no malaria parasite reappearance detected by Day 29 after treatment, without using parasite genotyping to distinguish new infections from recrudescence of the original infection. This primary outcome was applicable to US New Drug Application (NDA) submission. |
Day 29
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Sekundäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
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Core Phase: PCR-corrected ACPR at Days 22 and 43
Zeitfenster: Days 22 and 43 (i.e., 21 and 42 days post-first dose administration)
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To confirm the efficacy of KLU156 by assessing PCR-corrected ACPR at additional time points. |
Days 22 and 43 (i.e., 21 and 42 days post-first dose administration)
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Core Phase: Uncorrected ACPR at Days 22 and 43
Zeitfenster: Days 22 and 43 (i.e., 21 and 42 days post-first dose administration)
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To confirm the efficacy of KLU156 by assessing uncorrected ACPR at additional time points. |
Days 22 and 43 (i.e., 21 and 42 days post-first dose administration)
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Core Phase: Percentage of Participants With Recrudescence
Zeitfenster: Days 22, 29 and 43
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Recrudescence is defined as appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at baseline. Recrudescence had to be confirmed by PCR analysis. |
Days 22, 29 and 43
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Core Phase: Percentage of Participants With New Infection
Zeitfenster: Days 22, 29 and 43
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New infection is defined as appearance of asexual parasites after clearance of initial infection with a genotype different from those parasites present at baseline. New infection had to be confirmed by PCR analysis. |
Days 22, 29 and 43
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Core Phase: Fever Clearance Time
Zeitfenster: Up to Day 3
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Fever clearance time is defined as time from the first dose until the first time the axillary body temperature decreased below and remained below 37.5°C axillary or 38.0°C oral/tympanic/rectal for at least a further 24 hours. |
Up to Day 3
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Core Phase: Parasite Clearance Time
Zeitfenster: Up to Day 3
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Parasite clearance time is defined as time from the first dose until the first total and continued disappearance of asexual parasite forms which remained at least a further 48 hours. |
Up to Day 3
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Core Phase: Gametocyte Clearance Time
Zeitfenster: Up to Day 3
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To confirm the efficacy of KLU156 by assessing gametocyte clearance between the two treatment arms |
Up to Day 3
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Core Phase: Percentage of Participants With Parasitemia
Zeitfenster: 12, 24, 48 and 72 hours after treatment
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For the parasitemia assessment, blood sampling can be done by means of a finger prick except when the timing for parasitology assessments coincides with time for clinical laboratory tests, in which case, blood sample can be taken from the venous blood collected for clinical laboratory analyses. |
12, 24, 48 and 72 hours after treatment
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Core Phase: Clearance of Gametocytes in Participants With Gametocytemia at Baseline
Zeitfenster: From baseline up to Day 43
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Assessed by microscopy. Baseline was pre-first dose administration. |
From baseline up to Day 43
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Core Phase: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and AEs of Grade 3 Severity or Higher
Zeitfenster: Day 43
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Incidence and severity of TEAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs), and laboratory results qualifying and reported as AEs. Severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE): Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Life-threatening), and Grade 5 (Death). |
Day 43
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Core Phase: Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs), Graded by Severity
Zeitfenster: Day 43
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Incidence and severity of treatment-emergent SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs), and laboratory results qualifying and reported as AEs. Severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE): Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Life-threatening), and Grade 5 (Death). |
Day 43
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Extension Phase: PCR-corrected ACPR
Zeitfenster: Up to Day 29 for each KLU156 treatment episode
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To evaluate PCR-corrected ACPR over repeated treatment with KLU156 in adults and children ≥ 10 kg of body weight suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection). Patients were instructed to return to the study site whenever symptoms suggestive of malaria occurred. At each suspected malaria episode, eligibility for KLU156 treatment was reassessed, including confirmation of malaria diagnosis. |
Up to Day 29 for each KLU156 treatment episode
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Extension Phase: Uncorrected ACPR
Zeitfenster: Up to Day 29 for each KLU156 treatment episode
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To evaluate uncorrected ACPR over repeated treatment with KLU156 in adults and children ≥ 10 kg of body weight suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection). |
Up to Day 29 for each KLU156 treatment episode
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Extension Phase: Percentage of Participants With KLU156-related AEs by Malaria Episode
Zeitfenster: Up to approximately 18 months
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To assess the safety and tolerability over repeated treatment with KLU156 in adults and children ≥ 10 kg of body weight suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection). |
Up to approximately 18 months
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Extension Phase: Percentage of Participants With SAEs by Severity and Malaria Episode
Zeitfenster: Up to approximately 18 months
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To assess the safety and tolerability over repeated treatment with KLU156 in adults and children ≥ 10 kg of body weight suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection). |
Up to approximately 18 months
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Extension Phase: Gametocyte Carriage Over Time
Zeitfenster: Up to Day 29 for each KLU156 treatment episode
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To assess gametocyte carriage over time by malaria episode in the extension phase |
Up to Day 29 for each KLU156 treatment episode
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Mitarbeiter und Ermittler
Sponsor
Studienaufzeichnungsdaten
Haupttermine studieren
Studienbeginn (Tatsächlich)
Primärer Abschluss (Tatsächlich)
Studienabschluss (Tatsächlich)
Studienanmeldedaten
Zuerst eingereicht
Zuerst eingereicht, das die QC-Kriterien erfüllt hat
Zuerst gepostet (Tatsächlich)
Studienaufzeichnungsaktualisierungen
Letztes Update gepostet (Tatsächlich)
Letztes eingereichtes Update, das die QC-Kriterien erfüllt
Zuletzt verifiziert
Mehr Informationen
Begriffe im Zusammenhang mit dieser Studie
Schlüsselwörter
Zusätzliche relevante MeSH-Bedingungen
- Vektor-übertragene Krankheiten
- Durch Mücken übertragene Krankheiten
- Infektionen
- Protozoen-Infektionen
- Parasitäre Krankheiten
- Malaria
- Malaria, Falciparum
- Organische Chemikalien
- Pharmazeutische Präparate
- Kohlenwasserstoffe
- Kohlenwasserstoffe, zyklisch
- Terpene
- Polycyclische aromatische Kohlenwasserstoffe
- Kohlenwasserstoffe, aromatisch
- Polycyclische Verbindungen
- Anorganische Chemikalien
- Drogenkombinationen
- Reaktive Sauerstoffspezies
- Freie Radikale
- Artemether
- Artemisinine
- Lumefantrin
- Fluorenes
- Sesquiterpene
- Artemether, Lumefantrin-Medikamentenkombination
Andere Studien-ID-Nummern
- CKLU156A12301
- 2022-002675-10 (EudraCT-Nummer)
Plan für individuelle Teilnehmerdaten (IPD)
Planen Sie, individuelle Teilnehmerdaten (IPD) zu teilen?
Beschreibung des IPD-Plans
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
Arzneimittel- und Geräteinformationen, Studienunterlagen
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