Acute Uncomplicated Plasmodium Falciparum Malaria Clinical Trial
Official title:
A Phase 2 Interventional, Multicenter, Randomized Open Label Study to Determine the Effective and Tolerable Dose of KAF156 and Lumefantrine Solid Dispersion Formulation in Combination, Given Once Daily for 1, 2 and 3-days to Adults and Children With Uncomplicated Plasmodium Falciparum Malaria
| Verified date | December 2021 |
| Source | Novartis |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
This study was designed to determine the most effective and tolerable dose at the shortest dosing regimen of the investigational drug KAF156 in combination with a solid dispersion formulation of lumefantrine (LUM-SDF) in adult/adolescent and pediatric patients with uncomplicated Plasmodium falciparum malaria. There is unmet medical need for anti-malarial treatment with new mechanism of action to reduce probability of developing resistance, and for duration shorter than 3 days of treatment and/or reduced pill burden.
| Status | Completed |
| Enrollment | 524 |
| Est. completion date | June 28, 2021 |
| Est. primary completion date | June 14, 2021 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 2 Years and older |
| Eligibility | Inclusion Criteria: - Part A: male and female patients = 12 years and with a body weight = 35.0 kg. Part B: after determining the effective/tolerated doses and regimens in adolescent and adult patients, male and female patients = 2 and < 12 years and with a body weight = 10.0 kg will be included. - Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films. - P. falciparum parasitaemia of more than 1000 and less than 150 000 parasites/µL at the time of pre-screening (i.e., Study Visit 1). - Axillary temperature = 37.5 ºC or oral/tympanic/rectal temperature = 38.3 ºC; or similar history of fever during the previous 24 hours (history of fever must be documented). - Written informed consent must be obtained before any assessment is performed. If the patient is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients < 18 years old, who are capable of providing assent, must provide assent with parental/legal guardian consent or as per local ethical guidelines. Exclusion Criteria: - Mixed Plasmodium infections. - Signs and symptoms of severe malaria according to WHO (World Health Organization) 2015 criteria unless characterized by high parasitaemia only. - Patients with concurrent febrile illnesses (e.g., typhoid fever). - Severe vomiting, defined as more than 3 times in the 24 hours prior to inclusion in the study or severe diarrhea defined as more than 3 watery stools per day. - Pregnant or nursing (lactating) women. - Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia. - Anemia (Hemoglobin level < 8 g/dL). - Patients with prior antimalarial therapy or antibiotics with antimalarial activity within minimum of their five (5) plasma half-lives (or within 4 weeks of screening if half-life is unknown). - History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc (heart rate-corrected QT) interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease. - Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the patient in case of participation in the study. The investigator should make this determination in consideration of the patient's medical history and/or clinical or laboratory evidence of any of the following: - AST/ALT > 2 x the upper limit of normal range (ULN), regardless of the level of total bilirubin - AST/ALT > 1.5 and = 2 x ULN and total bilirubin is > ULN - Total bilirubin > 2 x ULN, regardless of the level of AST/ALT |
| Country | Name | City | State |
|---|---|---|---|
| Burkina Faso | Novartis Investigative Site | Nanoro | |
| Gabon | Novartis Investigative Site | Lambarene | |
| India | Novartis Investigative Site | Ranchi | Jharkhand |
| Kenya | Novartis Investigative Site | Kombewa | |
| Kenya | Novartis Investigative Site | Siaya | |
| Mali | Novartis Investigative Site | Sotuba | |
| Mozambique | Novartis Investigative Site | Chokwe | |
| Thailand | Novartis Investigative Site | Tak | |
| Uganda | Novartis Investigative Site | Masaka | |
| Uganda | Novartis Investigative Site | Tororo | |
| Vietnam | Novartis Investigative Site | Binh Phuoc Province | VNM |
| Lead Sponsor | Collaborator |
|---|---|
| Novartis Pharmaceuticals | Medicines for Malaria Venture |
Burkina Faso, Gabon, India, Kenya, Mali, Mozambique, Thailand, Uganda, Vietnam,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | PCR-corrected ACPR defined as the absence of parasitaemia was evaluated at Day 29 (i.e., 28 days post first dose) based on the short half-life of the study drugs. Microscopic species identification was confirmed and determined by PCR genotyping methods to establish malaria recrudescence/reinfection.
A participant was considered as PCR-corrected ACPR at Day 29 if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and was absence of parasitaemia on Day 29 irrespective of axillary temperature unless the presence of parasitaemia after 7 days was due to reinfection based on PCR. A presence of parasitaemia after 7 days of treatment initiation was considered as a reinfection only if the parasitaemia was clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later matched with the parasite strain at baseline based on PCR. |
28 days post first dose | |
| Primary | PK Run-in: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Treatment Dose (AUC0-24h) of KAF156 | Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. AUC0-24h was determined using non-compartmental methods. | 0, 1, 3, 6, 12, 18 and 24 hours post-dose | |
| Secondary | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | PCR-uncorrected ACPR defined as the absence of parasitaemia was evaluated at days 15, 29 and 43 (i.e., 14, 28 and 42 days post first dose).
A participant was considered as PCR-uncorrected ACPR at Days 15, 29 or 43 if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and was absence of parasitaemia on Days 15, 29 or 43 irrespective of axillary temperature. |
14, 28 and 42 days post first dose | |
| Secondary | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | PCR-corrected ACPR defined as the absence of parasitaemia was evaluated at days 15 and 43 (i.e., 14 and 42 days post first dose). Microscopic species identification was confirmed and determined by PCR genotyping methods to establish malaria recrudescence/reinfection.
A participant was considered as PCR-corrected ACPR at Day 15 or Day 43 if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and was absence of parasitaemia on Day 15 or Day 43 irrespective of axillary temperature unless the presence of parasitaemia after 7 days was due to reinfection based on PCR. A presence of parasitaemia after 7 days of treatment initiation was considered as a reinfection only if the parasitaemia was clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later matched with the parasite strain at baseline based on PCR. |
14 and 42 days post first dose | |
| Secondary | Part A and Part B: Number of Participants With Recrudescence Events | 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 must be confirmed by PCR analysis. | 42 days post first dose | |
| Secondary | Part A and Part B: Number of Participants With Reinfection Events | Reinfection is defined as appearance of asexual parasites after clearance of initial infection with a genotype different from those parasites present at baseline. Reinfection must be confirmed by PCR analysis. | 42 days post first dose | |
| Secondary | Part A and Part B: Fever Clearance Time (FCT) | Fever Clearance Time (FCT) is defined as the 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. In case a participant received rescue medication before (fever) clearance, the time to event was censored at the first use of rescue medication. | 42 days post first dose | |
| Secondary | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | Parasite Clearance Time (PCT) is defined as the time from the first dose until the first total and continued disappearance of asexual parasite forms which remained at least a further 48 hours. In case a participant received rescue medication before (parasite) clearance, the time to event was censored at the first use of rescue medication. | 42 days post first dose | |
| Secondary | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | Parasitaemia is the quantitative content of parasites in the blood determined by microscopy examination validated methods. Only Plasmodium Falciparum asexual form is used for parasitaemia assessments. | 12, 24 and 48 hours post last dose | |
| Secondary | Part A and Part B: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Last Treatment Dose (AUC0-24h) of KAF156 | Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. AUC0-24h was determined using non-compartmental methods. | 3, 6, 18 and 24 hours post last dose | |
| Secondary | Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. Cmax was determined using non-compartmental methods. | 3, 6, 18, 24, 27, 30, 48, 51, 54, 68, 72 and 168 hours post last dose | |
| Secondary | PK Run-in and Part A: Elimination Half-life (T½) of KAF156 | Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. T½ was determined using non-compartmental methods. | 0, 1, 3, 6, 12, 18, 24, 27, 30, 36, 48, 72, 96 and 168 hours post last dose | |
| Secondary | PK Run-in and Part A (Cohorts 1 and 2): Time to Reach Maximum Blood Concentrations (Tmax) of KAF156 | Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. Tmax was determined using non-compartmental methods. | 0, 1, 3, 6, 12, 18, 24, 30, 48, 96 and 168 hours post last dose |