Platform Study to Evaluate the Efficacy and Safety of Anti-malarial Agents in Participants With Uncomplicated Plasmodium Falciparum Malaria (Cohort B2)

Novartis Pharmaceuticals60 enrolled

Overview

This was Cohort B2 of the Platform study (NCT05750628) to evaluate the efficacy and safety of Cipargamin + KLU156 in participants with uncomplicated Plasmodium falciparum malaria.

The Cohort B2 of this Platfom study (NCT05750628) was the open-label, randomized, two-arm combination therapy evaluating a single oral dose of up to three anti-malarial agents as a loose combination vs. standard of care (SoC), Coartem in adult and adolescent participants.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Uncomplicated Plasmodium Falciparum Malaria

Interventions

KAE609DRUG

oral capsules administered in combination with KLU156

SoC (Coartem)DRUG

Standard of Care

KLU156DRUG

oral sachet formulation (KAF156+LUM-SDF) administered in combination with cipargamin (KAE609)

Eligibility

Sex: ALLMin age: 12 YearsMax age: 100 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male and female patients ≥12 years of age at screening. 2. Patients must have acute uncomplicated P. falciparum malaria mono infection at screening confirmed by a parasite count between 1,000 to 150,000 asexual parasite count/μl of blood for P. falciparum. 3. Patients must weigh between 35 kg and 90 kg at screening. 4. Axillary temperature ≥ 37.5ºC or oral/tympanic/rectal temperature ≥ 38.0ºC; or history of fever during the previous 24 hours. Exclusion Criteria: 1. Patients with signs and symptoms of severe/complicated malaria at screening or mixed Plasmodium infection (i.e., infection with more than one malaria species) at screening 2. Moderate to severe anemia, chronic hemoglobinopathy (Hemoglobin level \< 8 g/dL), or known chronic underlying disease such as sickle cell disease at screening 3. Known clinically significant liver disease (e.g., chronic hepatitis, liver cirrhosis (compensated or decompensated), history of hepatitis B or C, hepatitis A or B vaccination in the last 3 months, known gallbladder or bile duct disease, acute or chronic pancreatitis. Clinical or laboratory evidence of any of the following at screening: * AST/ALT \> 3 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 4. Any known/suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection at screening. 5. Pregnant or nursing (lactating) women, women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using methods of effective contraception, and sexually active patients not willing to practice effective contraception. 6. History or current diagnosis of ECG abnormalities indicating significant risk of safety for patients participating in the study such as: * Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker * History of familial long QT syndrome or known family history of Torsades de Pointe. * Resting heart rate (physical exam or 12 lead ECG) \< 50 bpm Other protocol-defined inclusion/exclusion criteria may apply.

Locations (3)

Novartis Investigative Site

Abidjan, Côte d’Ivoire

Novartis Investigative Site

Libreville, Gabon

Novartis Investigative Site

Ahero, Kenya

Outcomes

Primary Outcomes

Polymerase Chain Reaction (PCR) Corrected Adequate Clinical and Parasitological Response (ACPR)

ACPR is defined as absence of parasitaemia (PS) on Study Day 29 regardless of axillary temperature, in patients who have not previously met any of the criteria of Early Treatment Failure (ETF), Late Clinical Failure (LCF), or Late Parasitological Failure (LPF). A patient was considered as PCR-corrected ACPR at Day 29 when the patient did not meet any of the criteria of ETF (up to Day 4), LCF (Day 5 to Day 29), or LPF (Day 8 to Day 29), and was absence of PS on Day 29, unless the presence of PS detected after 7 days (Day 8 or later) was due to reinfection. The presence of PS after 7 days of treatment initiation was considered as a reinfection only when the PS had cleared before Day 8, and none of the parasite strain(s) detected on or after Day 8 matched with the parasite strain at baseline.

Time frame: Day 29

Secondary Outcomes

Parasite Clearance Time (PCT)

PCT is defined as time after administration of study drug until the first total and continued disappearance of asexual parasite forms which remained at least a further 48 hours. PCT was calculated using the Kaplan-Meier method.

Time frame: up to Day 7

PCR Uncorrected Adequate Clinical and Parasitological Response (ACPR)

Time frame: Day 29

Maximum Observed Plasma Concentration (Cmax)

Cmax is the maximum (peak) observed plasma concentration of the drug after dose administration. Pharmacokinetic parameters were calculated using a non-compartmental method (WinNonLin Version 6.4 or higher). The drug concentration was determined by a validated Liquid chromatography-mass spectrometry (LC-MS/MS) method. Concentrations were expressed in mass per volume units and referred to the free base. Concentrations below the lower limit of quantification (LLOQ) were reported as "zero¨.

Data from ClinicalTrials.gov

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Time frame: Pre-dose, 1, 2, 4, 6, 8, 12, 24, and 48 hours post dose.

Time to Reach Maximum Observed Plasma Concentration (Tmax)

Tmax is the time to reach maximum (peak) of the drug plasma concentration after single-dose administration (time). Pharmacokinetic parameters were calculated using a non-compartmental method (WinNonLin Version 6.4 or higher). The drug concentration was determined by a validated LC-MS/MS method. Concentrations were expressed in mass per volume units and referred to the free base. Concentrations below the lower limit of quantification (LLOQ) were reported as "zero¨.

Time frame: Pre-dose, 1, 2, 4, 6, 8, 12, 24, and 48 hours post dose.

Area Under Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24h)

The AUC from time zero to the 24-hour postdose sampling time. Pharmacokinetic parameters were calculated using a non-compartmental method (WinNonLin Version 6.4 or higher). The drug concentration was determined by a validated LC-MS/MS method. Concentrations were expressed in mass per volume units and referred to the free base. Concentrations below the lower limit of quantification (LLOQ) were reported as "zero¨.

Time frame: Pre-dose, 1, 2, 4, 6, 8, 12, and 24 hours post dose.

Area Under Plasma Concentration-time Curve From Time 0 to 48 Hours (AUC0-48h)

The AUC from time zero to the 48-hour postdose sampling time. Pharmacokinetic parameters were calculated using a non-compartmental method (WinNonLin Version 6.4 or higher). The drug concentration was determined by a validated LC-MS/MS method. Concentrations were expressed in mass per volume units and referred to the free base. Concentrations below the lower limit of quantification (LLOQ) were reported as "zero¨.

Time frame: Pre-dose, 1, 2, 4, 6, 8, 12, 24, and 48 hours post dose.

Area Under Plasma Concentration-time Curve (AUClast)

AUClast is the area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (tlast) of the drug. Pharmacokinetic parameters were calculated using a non-compartmental method (WinNonLin Version 6.4 or higher). The drug concentration was determined by a validated LC-MS/MS method. Concentrations were expressed in mass per volume units and referred to the free base. Concentrations below the lower limit of quantification (LLOQ) were reported as "zero¨.

Time frame: Pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours post dose.

Area Under Plasma Concentration-time Curve (AUC[0-inf])

AUC\[0-inf\] is the area under the plasma concentration-time curve from time zero extrapolated to infinity. Pharmacokinetic parameters were calculated using a non-compartmental method (WinNonLin Version 6.4 or higher). The drug concentration was determined by a validated LC-MS/MS method. Concentrations were expressed in mass per volume units and referred to the free base. Concentrations below the lower limit of quantification (LLOQ) were reported as "zero¨. PK parameters derived from AUCinf (AUCinf, CL/F and Vz/F) cannot be reported for patients for whom the extrapolated area under the curve (AUCextrapolated) is more than 20%.

Time frame: Pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours post dose.

Terminal Elimination Half-life (T1/2)

T1/2 is the elimination half-life associated with the terminal slope. Pharmacokinetic parameters were calculated using a non-compartmental method (WinNonLin Version 6.4 or higher). The drug concentration was determined by a validated LC-MS/MS method. Concentrations were expressed in mass per volume units and referred to the free base. Concentrations below the lower limit of quantification (LLOQ) were reported as "zero¨.

Time frame: Pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72 and 168 hours post dose.

Apparent Clearance (CL/F)

CL/F is the apparent total body clearance of the drug from plasma following extravascular administration. Pharmacokinetic parameters were calculated using a non-compartmental method (WinNonLin Version 6.4 or higher). The drug concentration was determined by a validated LC-MS/MS method. Concentrations were expressed in mass per volume units and referred to the free base. Concentrations below the lower limit of quantification (LLOQ) were reported as "zero¨. PK parameters derived from AUCinf (AUCinf, CL/F and Vz/F) cannot be reported for patients for whom the extrapolated area under the curve (AUCextrapolated) is more than 20%.

Time frame: Pre-dose, 1, 2, 4, 6, 8, 12, 24, and 48 hours post dose.

Apparent Volume of Distribution During Terminal Elimination Phase (Vz/F)

Vz/F is the apparent volume of distribution during terminal elimination phase following extravascular administration of the drug. Pharmacokinetic parameters were calculated using a non-compartmental method (WinNonLin Version 6.4 or higher). The drug concentration was determined by a validated LC-MS/MS method. Concentrations were expressed in mass per volume units and referred to the free base. Concentrations below the lower limit of quantification (LLOQ) were reported as "zero¨. PK parameters derived from AUCinf (AUCinf, CL/F and Vz/F) cannot be reported for patients for whom the extrapolated area under the curve (AUCextrapolated) is more than 20%.

Time frame: Pre-dose, 1, 2, 4, 6, 8, 12, 24, and 48 hours post dose.