To Evaluate Efficacy, Safety, Tolerability and PK of Intravenous Cipargamin in Participants With Severe Plasmodium Falciparum Malaria

Novartis Pharmaceuticals254 enrolled

Overview

The purpose of this study was to identify the safe and effective dose of intravenous cipargamin in participants with moderately severe and severe malaria. The study also intended to evaluate clinical treatment success using a novel clinical endpoint for drug development in severe malaria. Severe malaria is a medical emergency and is affecting primarily young children in Africa. Injectable artesunate is the standard of care for the treatment of severe malaria and is highly efficacious. However, the spread of artemisinin-resistance in Plasmodium falciparum in Asian countries poses a threat for future treatment of patients with this life-threatening disease. To mitigate this risk, there is a need for another drug in malaria-endemic countries. Cipargamin treatment results in rapid clearance of parasites, including artemisinin-resistant parasites.

This study was an adaptive, multicenter, randomized, open label, sequential cohort study in participants aged ≥12 years old in Cohorts 1-2 and \<12 years old to ≥6 months in Cohorts 3-5 with a diagnosis of moderately severe (Cohort 1) and severe P. falciparum malaria (Cohorts 2-5). This study investigated the efficacy (parasite reduction and clinical outcome), safety, tolerability, and pharmacokinetics (PK) of different intravenous (IV) dose regimens of cipargamin in comparison to IV artesunate. Cohorts 1 and 2: Participants were randomized to one of three treatment arms in a 1:1:1 ratio: two cipargamin-based treatment arms with dose levels of 20 mg and 40 mg, and the control arm with IV artesunate, a standard of care. The analysis of results from Cohorts 1 and 2 was planned to be used to determine the safe and efficacious exposure range and the corresponding dose (in a weight-adjusted manner) for the participants in Cohorts 3 to 5. Cohorts 3 to 5: Participants were randomized to 40 mg of cipargamin administered in a dose-adjusted manner and standard dose of IV artesunate in 1:1 ratio. In all cohorts, participants in IV cipargamin arms were treated once daily for at least 24 hours (2 doses at 0 and 24 hour timepoints) and a maximum of 48 hours (3 doses at 0, 24, and 48 hour timepoints) and with IV artesunate as rescue medication. Participants in the IV artesunate arm received IV artesunate for at least 24 hours (3 doses at 0, 12, and 24 hours timepoints) and for a maximum of 8 doses (7 days), if necessary. Participants in all arms received Coartem twice daily (b.i.d.) for 3 days following IV therapy. The study was conducted in a hospital setting, and participants were followed up until Day 29.

Study Type

INTERVENTIONAL

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 100 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Cohort 1: Participants aged ≥ 12 years with moderately severe malaria as defined in (prostration and/or repeated vomiting) without presence of other signs of severe malaria (and with high P. falciparum parasitemia (60,000-250,000 parasites per µl) * Subsequent Cohorts 2 to 5: Participants diagnosed with severe malaria as defined in modified version of WHO criteria and P. falciparum parasite count of ≥ 5000 per µl * Cohort 2: Participants aged ≥ 12 years * Cohort 3: Participants aged 6 - \< 12 years * Cohort 4: Participants aged 2 - \< 6 years * Cohort 5: Participants aged ≥ 6 months - \< 2 years Exclusion Criteria: Exclusion criteria applying to all Cohorts 1 to 5: * Mixed Plasmodium infections * Treatment with quinine or artemisinin derivative or any other antimalarial drug or any antibiotic with known antimalarial activity within 12 hours of screening. * Signs/symptoms of severe malnutrition in general accordance with WHO guidelines: 1. Under 18 years: \<-3 Z-scores of WHO growth standard for weight-for-height/length (in children \< 5 years) or BMI for age (5-18 years), or very low mid-upper arm circumference (MUAC \< 115 mm in children \< 12 years, \< 160mm 12-18 years), or bilateral pitting edema 2. Over 18 years: BMI \< 16 kg/m2 or MUAC \< 160mm or bilateral pitting edema * Known underlying illness, surgical or medical condition, which is not related to ongoing event of severe malaria and which might jeopardize the participant's health in case of participation in the study or which might alter the distribution, metabolism or excretion of study treatment. For example: 1. neurological or neurodegenerative disorders, 2. cardiac, renal, or hepatic disease, diabetes, 3. epilepsy, cerebral palsy, 4. known or suspected to be HIV-1 positive and/or receiving antiretroviral treatment 5. malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases 6. known or suspected cases of active infections or concurrent febrile illness such as TB, Typhoid, COVID-19 etc. Additional exclusion criteria are as follows: Exclusion criteria for Cohort 1: * ALT \> 5 x the upper limit of normal range (ULN), regardless the level of total bilirubin * Total bilirubin is \> 3 mg/dL * Body weight of \< 35 kg or \>75 kg Exclusion criteria for Cohort 2: * Body weight of \< 35 kg or \>75 kg * Participants diagnosed as moderately severe malaria due to repeated vomiting without presence of any of the symptoms of severe malaria Exclusion criteria for Cohorts 3 to 5: * Body weight of \< 5 kg * Participants diagnosed as moderately severe malaria due to repeated vomiting without presence of any of the symptoms of severe malaria

Locations (9)

Novartis Investigative Site

Burkina Faso, Burkina Faso

Novartis Investigative Site

Ouagadougou, Burkina Faso

Novartis Investigative Site

Abidjan, Côte d’Ivoire

Novartis Investigative Site

Agboville, Côte d’Ivoire

Novartis Investigative Site

Kinsasha, Democratic Republic of Congo, Democratic Republic of the Congo

Novartis Investigative Site

Siaya, Kenya

Novartis Investigative Site

Manhiça, Maputo Province, Mozambique

Novartis Investigative Site

Kigali, Rwanda

Novartis Investigative Site

Tororo, Uganda

Outcomes

Primary Outcomes

Percentage of Participants Achieving at Least 90% Reduction in Plasmodium Falciparum (P. Falciparum) at 12 Hours

A blood draw was performed at each collection time point for parasitemia assessment.

Time frame: 12 Hours

Secondary Outcomes

Percentage of Participants Achieving Clinical Success at 48 Hours

Clinical success was a composite endpoint based on following criteria: 1. Was participant dead or alive 2. Presence of asexual parasites (yes/no) 3. Presence of any of the key signs of severe malaria (yes/no)

Time frame: 48 Hours

Percentage of Participants With Individual Signs of Severe Malaria Over Time

Individual signs of severe malaria over time were monitored for the presence of the following signs of severe malaria during the entire study duration: 1. Altered consciousness - Prostration or GCS \< 11 for participants \> 5 years / BCS \< 3 for participants =\< 5 years of age 2. Renal Impairment - Serum creatinine \> 3xULN or \> 3 mg/dL or need for renal replacement therapy 3. Acidosis - Serum lactate \> 4 mmol/L 4. Respiratory distress - present or absent 5. Severe anemia - Hb \< 5 g/dl or Hb \< 7g/dl in pediatric and adults respectively or need of blood transfusion 6. Jaundice - Serum bilirubin \> 3 g/dl 7. Hypoglycemia- plasma glucose \< 40 mg/dL

Time frame: Baseline to Day 29

Percentage of Participants Developing Hemolysis (Early and Delayed) After Treatment

Development (early and delayed) of hemolysis after treatments was defined as follows: Early Hemolytic anemia was defined as 10% or greater decrease in hemoglobin levels and an increase of lactate dehydrogenase (LDH) levels to \>390 U/L, or an increase of \>= 10% above baseline occurring up to Day 8 of the study. Delayed hemolytic anemia occurred \> 7 days after initiation of parenteral study drug (IV artesunate or IV cipargamin) during the study period. The event was characterized by a 10% or greater decrease in hemoglobin levels accompanied by increase of LDH levels to \>390 U/L, or an increase of \>= 10% compared to the values measured at Day 8 of the study.

Time frame: Day 8 and Day 29

Percentage of Participants With Neurological Sequelae at Day 29

Detailed neurological examination was conducted and relevant medical history collected to assess the extent of neurological signs and symptoms at baseline and to monitor the extent of neurological sequelae in follow-up visits.

Time frame: Day 29

Percentage of Participants Achieving at Least 90% Reduction in Plasmodium Falciparum (P. Falciparum)

A blood draw was performed at each collection time point for parasitemia assessment.

Time frame: 24 hours and 48 hours

Time to Parasite Clearance (PCT)

Parasite clearance time (PCT) was 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 24 hours.

Time frame: Up to 72 hours

Parasite Clearance Estimator (PCE) Slope Half-life

Slope half-life (hours) for parasite clearance was calculated for each patient using the WWARN (World Wide Antimalarial Resistance Network) Parasite Clearance Estimator.

Time frame: Up to 72 hours

Time to Fever Clearance (FCT)

Fever clearance time (FCT) was 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.

Time frame: Up to 72 hours

P. Falciparum Parasite Reduction Ratios (PRR) at 12, 24 and 48 Hours

PRR was defined as the ratio of asexual parasite at baseline divided by asexual parasite at post-baseline. If the asexual parasite count at post-baseline was 0, the half value of detection limit was used to calculate the ratio.

Time frame: 12 hours, 24 hours, and 48 hours

Percentage of Participants With Recrudescence and Reinfection

Recrudescence was defined as appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at baseline. Reinfection was defined as appearance of asexual parasites after clearance of initial infection with a genotype different from those parasites present at baseline. Reinfection and Recrudescence were confirmed by polymerase chain reaction (PCR) analysis.

Time frame: Day 29

Time to Switch to Oral Therapy

Time to switch participants from IV therapy to Coartem (standard of drug for oral therapy) was analyzed.

Time frame: Day 3 to Day 29

Time to Discharge From Hospital

Time frame: Day 3 to Day 29

Time to Recover From Prostration

To assess recovery of participants as measured by time to recovery from prostration compared to baseline.

Time frame: Day 1 to Day 29

Number of Participants With Adverse Events or Serious Adverse Events, or Who Died

Adverse events (AEs) and serious adverse events (SAEs) were collected from first dosing. Death routine laboratory assessments were assessed up to last follow-up visit or until the event had resolved to baseline grade or better, or the event was assessed stable by the investigator, or the participant was lost to follow-up or withdrew consent.

Time frame: Day 1 to Day 29

Observed Maximum Plasma Concentration (Cmax) of IV Cipargamin

Blood samples were collected for pharmacokinetics characterization. Cmax is the maximum (peak) observed plasma concentration of cipargamin after dose administration. Cmax was listed and summarized using descriptive statistics.

Time frame: Day 1 - Day 8

Time of Maximum Observed Drug Concentration Occurrence (Tmax) of IV Cipargamin

Blood samples were collected for pharmacokinetics characterization. Tmax was listed and summarized using descriptive statistics. Time to reach maximum observed plasma concentration of cipargamin after dose administration.

Time frame: Day 1 - Day 8

Area Under the Serum Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of IV Cipargamin

Blood samples were collected for pharmacokinetics characterization. AUClast was listed and summarized using descriptive statistics.

Time frame: Day 1 - Day 8

Area Under the Concentration Time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUCinf) of IV Cipargamin

Blood samples were collected for pharmacokinetics characterization. AUC(0-inf) post last dose was listed and summarized using descriptive statistics.

Time frame: Day 1 - Day 8

Area Under the Plasma Concentration-time Curve From the Time 0 to 24 Hours (AUC0-24hours) of IV Cipargamin

Blood samples were collected for pharmacokinetics characterization. AUC(0-24h) was listed and summarized using descriptive statistics.

Time frame: Day 1 - Day 8

Terminal Elimination Half Life (T1/2) of IV Cipargamin

Blood samples were collected for pharmacokinetics characterization. The half-life post last dose was summarized using descriptive statistics.

Time frame: Day 1 - Day 8

Total Systemic Clearance for Intravenous Administration (CL) of IV Cipargamin

Blood samples were collected for pharmacokinetics characterization. CL post last dose was summarized using descriptive statistics.

Time frame: Day 1 - Day 8

Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) of IV Cipargamin

Blood samples were collected for pharmacokinetics characterization. Vz post last dose was listed and summarized using descriptive statistics.

Time frame: Day 1 - Day 8

To Evaluate Efficacy, Safety, Tolerability and PK of Intravenous Cipargamin in Participants With Severe Plasmodium Falciparum Malaria

Overview

Conditions

Interventions

Eligibility

Locations (9)

Outcomes

Primary Outcomes

Secondary Outcomes