Efficacy, Safety and Tolerability of KAF156 in Combination With Lumefantrine Solid Dispersion Formulation (LUM-SDF) in Pediatric Population With Uncomplicated Plasmodium Falciparum Malaria

Novartis Pharmaceuticals295 enrolled

Overview

This study aimed to determine the efficacy, safety and tolerability of the investigational drug KAF156 in combination with a solid dispersion formulation of lumefantrine (LUM-SDF) in pediatric patients (6 months to \< 18 years of age) with uncomplicated P. falciparum malaria. There is an unmet medical need for anti-malarial treatment with a new mechanism of action to reduce the probability of developing resistance.

This Phase 2 study aimed to evaluate the efficacy, safety and tolerability of the investigational drug KAF156 and a Solid Dispersion Formulation of lumefantrine (LUM-SDF) when administered in combination in pediatric patients 6 months to \< 18 years of age with uncomplicated Plasmodium falciparum malaria. In addition, pharmacokinetics (PK) of the drug combination was also evaluated. There were three age-descending cohorts in the study: Run-in Cohort (12 years to \< 18 years), Cohort 1 (2 years to \< 12 years) and Cohort 2 (6 months to \< 2 years). The rationale for separated cohorts 1 and 2 was to allow enrolment of the youngest patients (cohort 2) after safety and exposure review of older patients in cohort 1. Given the age-independent symptoms of acute malaria, and to increase statistical power, for all outcomes measures the cohorts 1 and 2 were pooled (cohort 1/2). This new study first explored the effect of food on lumefantrine and KAF156 pharmacokinetics (PK) in patients 12 to \< 18 years old with malaria caused by P. falciparum. Based on the data from the Run-in Cohort, recommendation on dose, dosing regimen, dosage administration (with food) and duration were provided before younger patients in Cohorts 1 and 2 were dosed with KAF156/LUM-SDF. Then, efficacy, safety, tolerability and PK of the combination of KAF156/LUM-SDF in comparison with Coartem®(Artemether/Lumefantrine) were evaluated in younger patients, in pooled Cohort 1/2.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. In run-in cohort: Male and female patients 12 to \< 18 years of age, with a body weight * 35.0 kg In Cohort 1: Male and female patients 2 to \< 12 years of age, with a body weight ≥ 10.0 kg In Cohort 2: Male and female patients 6 months to \< 2 years of age, with a body weight * 5.0 kg 2. Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films 3. P. falciparum parasitemia of ≥ 1,000 and ≤ 150,000 parasites/μL at the time of prescreening for the Run-in Cohort; and P. falciparum parasitemia of ≥ 1,500 and ≤ 150,000 parasites/μL at the time of pre-screening for Cohorts 1 and 2 4. Axillary temperature ≥ 37.5 ºC or oral/tympanic/rectal temperature ≥ 38.0 ºC; or history of fever during the previous 24 hours (at least documented verbally) 5. Written informed consent has been obtained from parent / legal guardian before any assessment is performed. If the parent/legal guardian 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 assent with parental/legal guardian consent or as per local ethical guidelines 6. The patient and his/her parent/legal guardian is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned Exclusion Criteria: 1. Mixed Plasmodium infections as per light microscopy results 2. Signs and symptoms of severe malaria according to WHO 2015 (see Section 16.4) 3. Significant, non-plasmodial co-infections including tuberculosis 4. Patients with concurrent febrile illnesses (e.g., typhoid fever, known or suspected COVID19) 5. Known relevant liver disease e.g. chronic hepatitis, cirrhosis, compensated or decompensated, history of hepatitis B or C, hepatitis B or A vaccination in last 3 months, known gallbladder or bile duct disease, acute or chronic pancreatitis 6. Major congenital defects 7. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection or family history of congenital or hereditary immunodeficiency 8. Immunosuppressive therapy (steroids, immune modulators or immune suppressors) within 3 months prior to recruitment. (For corticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaled and topical steroids are allowed) 9. Repeated 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 in the 24 hours prior to inclusion in the study) 10. Active duodenal ulcer, ulcerative colitis, Crohn's disease, chronic (i.e., \> 2 weeks) use of non-steroidal anti-inflammatory drugs (NSAIDs) 11. Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia 12. Anemia (hemoglobin level \<7 g/dL) 13. 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. 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 \> 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 14. Resting QT interval corrected by Fridericia's formula (QTcF) \> 450 ms at screening 15. Creatinine \> 2 x ULN in the absence of dehydration. In case of dehydration, creatinine should be \< 2 x ULN after oral/parenteral rehydration 16. Any severe disease condition which might prohibit participation in this study 17. Known chronic underlying disease such as sickle cell disease, and severe cardiac, renal, or hepatic impairment 18. Known active or uncontrolled thyroid disease 19. Inability to swallow oral medication (in tablet and/or liquid form) 20. 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) 21. Use of other investigational drugs within 30 days of dosing or until the expected pharmacodynamic effect has returned to baseline, whichever is longer 22. Patients taking medications prohibited by the protocol 23. Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance within 3 months of dosing 24. 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 25. Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study 26. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes For the Run-in Cohort only: 27. Pregnant or nursing (lactating) patients 28. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of investigational drug. Basic contraception methods include: * Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male sterilization (at least 6 m prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient * Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps). Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug. Women are considered not of child bearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. For Cohorts 1 and 2 only: 29. Patients of child bearing potential, defined as all girls post first menarche (except for Run-in Cohort)

Outcomes

Primary Outcomes

Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) - Cohorts 1 and 2 Pooled

PCR-corrected ACPR, defined as the absence of parasitemia(PS), was evaluated on Day29. 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 Day29 if the participant did not meet any of the criteria of early treatment failure (up to Day4), late clinical failure(Day5 to Day29) or late parasitological failure(Day8 to Day29), and had absence of PS on Day29 irrespective of axillary temperature unless the presence of PS after 7days(Day8 or later) was due to reinfection based on PCR genotyping.A presence of PS after 7days of treatment initiation was considered as a reinfection only if the PS was clear before Day8 and none of the parasite strain(s) detected on Day8 or later match with the parasite strain at baseline based on PCR genotyping.Given the age-independent symptoms of acute malaria, and to increase statistical power,the cohorts 1 and 2 were pooled.

Time frame: Day 29

Secondary Outcomes

PCR-corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR)

PCR-corrected ACPR, defined as the absence of parasitemia, was evaluated. Microscopic species identification was confirmed and determined by polymerase chain reaction (PCR) genotyping methods to establish malaria recrudescence/reinfection. A participant was considered as PCR-corrected ACPR if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and had absence of parasitemia on Days 15, 29 or 43 irrespective of axillary temperature unless the presence of parasitemia after 7 days was due to reinfection based on PCR. A presence of parasitemia after 7 days of treatment initiation was considered as a reinfection only if the parasitemia 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. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Time frame: Corrected ACPR: Day 15, Day 43; Uncorrected ACPR: Day 15, Day 29 and Day 43

PCR-corrected Adequate Clinical and Parasitological Response (ACPR) - Run-in Cohort

PCR-corrected ACPR, defined as the absence of parasitemia, was evaluated on Day 29. Microscopic species identification was confirmed and determined by polymerase chain reaction (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 (ETF) (up to Day 4), late clinical failure (LCF) (Day 5 to Day 29) or late parasitological failure (LPF) (Day 8 to Day 29), and had absence of parasitaemia on Day 29 irrespective of axillary temperature unless the presence of parasitaemia after 7 days (Day 8 or later) was due to reinfection based on PCR genotyping. 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 match with the parasite strain at baseline based on PCR genotyping.

Time frame: Day 29

Parasite Clearance Time (PCT)

PCT 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. PCT is based on uncorrected parasite counts. PCT was calculated using the Kaplan-Meier method. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Time frame: up to 43 days

Fever Clearance Times (FCT)

FCT 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. FCT was calculated using the Kaplan-Meier method. Participants who received any antimalarial medication (including rescue medication) before fever clearance are censored at the first use of antimalarial medication. Participants without fever clearance are censored at the time of last fever assessment. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Time frame: up to 43 days

Percentage Early Treatment Failure (ETF)

Participants were defined as early treatment failures (ETFs) if they developed danger signs or severe malaria on Day 2, Day 3, or Day 4 in the presence of parasitemia, parasitemia on Day 3 with a count higher than the Day 1 count irrespective of axillary temperature, parasitemia on Day 4 with axillary temperature ≥ 37.5°C, or parasitemia on Day 4 with a count equal to or more than 25% of the count on Day 1. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Time frame: From Day 1 to Day 4

Percentage Late Clinical Failure (LCF)

Participants were defined as late clinical failures (LCFs) if they developed danger signs or severe malaria on any day from Day 5 to Day 43 in the presence of parasitemia without previously meeting any of the criteria of ETF, or if they had parasitemia and an axillary temperature of ≥ 37.5°C on any day from Day 5 to Day 43 without previously meeting any of the criteria of ETF. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Time frame: Day 5 to Day 43

Percentage Late Parasitological Failure (LPF)

Participants were defined as late parasitological failures (LPFs) if they had parasitemia on any day from Day 8 to Day 43 and an axillary temperature \< 37.5°C without previously meeting any of the criteria of ETF or LCF. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Time frame: Day 8 to Day 43

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 had to be confirmed by PCR analysis. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Time frame: Day 15, Day 29 and Day 43

Number of Participants With New Infections Events

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. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Time frame: Day 15, Day 29 and Day 43

Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Number of participants with treatment emergent adverse events (any AE regardless of seriousness), and SAEs. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Time frame: Adverse events were reported from first dose of study treatment until end of study treatment up to a maximum duration of approximately 43 days.

KAF156 and Lumefantrine (LUM) Cmax

Cmax is the maximum observed plasma concentration following drug administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods. Analyte KAF156 is not applicable for Artemether80mg/LUM480mg arm.

Time frame: Run-in Cohort:Pre-dose,1,3,4,5,6,8,24,25,27,28,29,30,32,48,72,168 hours; Cohort 1 and 2 KAF400mg/LUM480mg-QDx3 6-12 years: 3,6,24,48,51,54,72,168 hours; 6 months -<6 years:24,48,51,54,72,168 hours;Cohort 1 and 2 Artemether80mg/LUM480mg:24,48,68,168 hours

KAF156 and Lumefantrine Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast)

AUC is the area under the plasma concentration-time curve. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. The Artemether80mg/LUM480mg arms (standard of care) involved limited pharmacokinetic sampling at 24, 48, 68, and 168 hours following the first dose administration. In contrast, the KAF156 arms had a more extensive sampling, varying by age group, which included time points at 3, 6, 24, 48, 51, 54, 72, and 168 hours following first dose. Due to the limited sampling in the Artemether80mg/LUM480mg arms, it was not planned (per protocol) to calculate AUC values.

KAF156 and Lumefantrine Time to Reach the Maximum Plasma Concentration After Drug Administration (Tmax)

Tmax is the time to reach maximum plasma concentration following drug administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods. The Artemether80mg/LUM480mg arms (standard of care) involved limited pharmacokinetic sampling at 24, 48, 68, and 168 hours following the first dose administration. In contrast, the KAF156 arm had a more extensive sampling, varying by age group, which included time points at 3, 6, 24, 48, 51, 54, 72, and 168 hours following first dose. PK samples for the Artemether80mg/LUM480mg arms were collected around the expected Tmax (at 68 hours, i.e., 8 hours after the last dose, based on the known Tmax of lumefantrine in Coartem) to determine Cmax values; in line with the protocol, separate Tmax values were not calculated.

KAF156 and Lumefantrine Plasma Drug Concentration 168 Hours Post First Dose Administration (C168h)

C168h is the plasma concentration at 168h post first dose administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods. Analyte KAF156 is not applicable for Artemether80mg/LUM480mg arm.

Time frame: at 168 hours

Efficacy, Safety and Tolerability of KAF156 in Combination With Lumefantrine Solid Dispersion Formulation (LUM-SDF) in Pediatric Population With Uncomplicated Plasmodium Falciparum Malaria

Overview

Conditions

Interventions

Eligibility

Locations (9)

Outcomes

Primary Outcomes

Secondary Outcomes