Uncomplicated Plasmodium Falciparum Malaria
Conditions
Keywords
malaria, uncomplicated malaria, Plasmodium falciparum, platform study, PLATINUM
Brief summary
Platform study to evaluate the efficacy and safety of anti-malarial agents in patients with uncomplicated Plasmodium falciparum malaria
Detailed description
The purpose of this platform study is to evaluate the parasiticidal effect and potential for cure with different anti-malarial agents administered as monotherapy and/or in combination therapy with other anti-malarial agents in adults, adolescents, and children with uncomplicated Plasmodium falciparum malaria. Additionally, the safety, tolerability, and pharmacokinetics of these anti-malarial agents will be evaluated for dose selection for future studies.
Interventions
DRUGINE963
oral INE963
DRUGKAE609 (Cipargamin)
oral KAE609 (Cipargamin)
DRUGSoC (Coartem)
SoC (Coartem)
DRUGKLU156
oral sachet KLU156 (KAF156 + lumefantrine)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This study is open-label, but certain members of the CTT will be blinded to the treatment information
Eligibility
Sex/Gender
ALL
Age
2 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1. Male and female patients ≥18 years of age for Part A, ≥12 years of age for Part B and 2 to \<12 years of age for Part C at screening. 2. Patients must have acute uncomplicated P. falciparum malaria mono infection at screening confirmed by a parasite count between 5,000 to 150,000 asexual parasite count/μl of blood for P. falciparum for Part A and between 1,000 to 150,000 asexual parasite count/μl of blood for Parts B and C. 3. Patients in Part A must weigh between 40 kg and 90 kg. Patients in Part B must weigh between 35 kg and 90 kg at screening. Patients in Part C must weigh at least 10 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: parasite clearance time (PCT) | up to Day 7 | Part A: To assess the parasite clearance time (PCT) of oral doses of an anti-malarial agent administered as monotherapy in patients with uncomplicated P. falciparum malaria. PCT is defined as the time from the first positive blood slide at inclusion to the time of the first negative slide followed by two consecutive slides. |
| Part B and C: polymerase chain reaction (PCR) corrected adequate clinical and parasitological response (ACPR) | Day 29 | Part B and C: To assess the 28-day cure rate of an anti malarial agent administered orally as combination therapy versus the standard of care (SoC) in patients with uncomplicated P. falciparum malaria. ACPR is defined as the absence of parasitemia on Study Day 29 irrespective of axillary temperature, without previously meeting any of the criteria of Early Treatment Failure (ETF) or Late Clinical Failure (LCF) or Late Parasitological Failure (LPF). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts B and C: PCR-uncorrected ACPR | Day 29 | Part B and C: To assess the 28-day cure rate of an anti malarial agent administered orally as combination therapy versus the SoC in patients with uncomplicated P. falciparum malaria |
| Area under the concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of the anti-malarial agents (wherever possible) | Day 22 | To characterize the pharmacokinetics (PK) of each anti-malarial agent administered orally as monotherapy \[Part A\] and/or as combination therapy \[Parts B and C\] in patients with uncomplicated P. falciparum malaria. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sample time (tlast) |
| Area under the concentration-time curve from time zero to infinity (AUCinf) of the anti-malarial agents (wherever possible) | Day 22 | To characterize PK of each anti-malarial agent administered orally as monotherapy \[Part A\] and/or as combination therapy \[Parts B and C\] in patients with uncomplicated P. falciparum malaria. AUCinf is the AUC from time zero to infinity. |
| Maximum observed concentration (Cmax) of the anti-malarial agents | Day 22 | To characterize PK of each anti-malarial agent administered orally as monotherapy \[Part A\] and/or as combination therapy \[Parts B and C\] in patients with uncomplicated P. falciparum malaria. Cmax is the maximum (peak) observed plasma, blood, serum, or other blood fluid drug concentration after single dose administration. |
| Part A: PCR-corrected and uncorrected ACPR | Day 29 | Part A: To assess the 28-day cure rate of an anti malarial agent administered orally as monotherapy in patients with uncomplicated P. falciparum malaria |
| Elimination half-life (T1/2) of the anti-malarial agents (wherever possible) | Day 22 | To characterize PK of each anti-malarial agent administered orally as monotherapy \[Part A\] and/or as combination therapy \[Parts B and C\] in patients with uncomplicated P. falciparum malaria. T1/2 is the elimination half-life associated with the terminal slope of a semi-logarithmic concentration-time curve. |
| Total body clearance (CL/F) of the anti-malarial agents (wherever possible) | Day 22 | To characterize PK of each anti-malarial agent administered orally as monotherapy \[Part A\] and/or as combination therapy \[Parts B and C\] in patients with uncomplicated P. falciparum malaria. Cl/F is the total body clearance of drug from the plasma. |
| Apparent volume of distribution (V/F) of the anti-malarial agents (wherever possible) | Day 22 | To characterize PK of each anti-malarial agent administered orally as monotherapy \[Part A\] and/or as combination therapy \[Parts B and C\] in patients with uncomplicated P. falciparum malaria. V/F is the apparent volume of distribution during terminal phase. |
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 43 | Incidence and severity of AEs and SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs), and laboratory results qualifying and reported as AEs. |
| Time to reach maximum observed concentration (Tmax) | Day 22 | To characterize PK of each anti-malarial agent administered orally as monotherapy \[Part A\] and/or as combination therapy \[Parts B and C\] in patients with uncomplicated P. falciparum malaria. Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration. |
| Parts B and C: PCT | up to Day 7 | Part B and C: To assess the parasite clearance time (PCT) of oral combinations of anti malarial agents versus the standard of care (SoC) in patients with uncomplicated P. falciparum malaria |
Countries
Burkina Faso, Côte d’Ivoire, Gabon, Ghana, Kenya, Uganda
Contacts
Primary ContactNovartis Pharmaceuticals
Backup ContactNovartis Pharmaceuticals
Outcome results
None listed