Severe Malaria
Conditions
Keywords
KAE609, cipargamin, artesunate, intravenous, i.v., pediatric, dose-finding, safety, tolerability, pharmacokinetics
Brief summary
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.
Detailed description
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.
Interventions
DRUGCipargamin
Cipargamin, 20 mg or 40 mg, by intravenous administration of solution for injection
DRUGIV Artesunate
Artesunate, 2.4 mg/kg or 3 mg/kg, by intravenous administration of reconstituted solution
DRUGCoartem
Oral standard of care (Coartem tablets, dosed per weight, as per label)
Sponsors
Novartis Pharmaceuticals
Wellcome Trust
European and Developing Countries Clinical Trials Partnership (EDCTP)
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Although the study was open label, in order to minimize the potential impact of treatment knowledge, treatment allocation, dose information, PK/AAG assessment schedule and concentration data, as well as other data that could result in systematic unblinding, were not available to the Clinical Trial Team (CTT) (particularly clinicians, trial statisticians, trial programmers) until the database was locked after IA of Cohorts 1-2. After interim database lock, the CTT would be unblinded with the results, however, the blinding would then be continued for Cohorts 3-5 until the final database was locked.
Intervention model description
This 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 and severe P. falciparum malaria. In Cohorts 1-2, participants were randomized to one of the three treatment arms (2 dose of intravenous cipargamin or intravenous artesunate - comparator). After Cohort 2, interim analysis was performed to take one best dose of intravenous cipargamin forward for Cohorts 3-5. Participants in Cohorts 3-5 were randomized to one of two treatments arms (intravenous cipargamin or intravenous artesunate - comparator).
Eligibility
Sex/Gender
ALL
Age
6 Months to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving at Least 90% Reduction in Plasmodium Falciparum (P. Falciparum) at 12 Hours | 12 Hours | A blood draw was performed at each collection time point for parasitemia assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Clinical Success at 48 Hours | 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) |
| Percentage of Participants With Individual Signs of Severe Malaria Over Time | Baseline to Day 29 | 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 |
| Percentage of Participants Developing Hemolysis (Early and Delayed) After Treatment | Day 8 and Day 29 | 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. |
| Percentage of Participants With Neurological Sequelae at Day 29 | 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. |
| Percentage of Participants Achieving at Least 90% Reduction in Plasmodium Falciparum (P. Falciparum) | 24 hours and 48 hours | A blood draw was performed at each collection time point for parasitemia assessment. |
| Time to Parasite Clearance (PCT) | Up to 72 hours | 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. |
| Parasite Clearance Estimator (PCE) Slope Half-life | Up to 72 hours | Slope half-life (hours) for parasite clearance was calculated for each patient using the WWARN (World Wide Antimalarial Resistance Network) Parasite Clearance Estimator. |
| Time to Fever Clearance (FCT) | Up to 72 hours | 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. |
| P. Falciparum Parasite Reduction Ratios (PRR) at 12, 24 and 48 Hours | 12 hours, 24 hours, 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. |
| Percentage of Participants With Recrudescence and Reinfection | Day 29 | 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 to Switch to Oral Therapy | Day 3 to Day 29 | Time to switch participants from IV therapy to Coartem (standard of drug for oral therapy) was analyzed. |
| Time to Discharge From Hospital | Day 3 to Day 29 | — |
| Time to Recover From Prostration | Day 1 to Day 29 | To assess recovery of participants as measured by time to recovery from prostration compared to baseline. |
| Number of Participants With Adverse Events or Serious Adverse Events, or Who Died | Day 1 to Day 29 | 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. |
| Observed Maximum Plasma Concentration (Cmax) of IV Cipargamin | Day 1 - Day 8 | 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 of Maximum Observed Drug Concentration Occurrence (Tmax) of IV Cipargamin | Day 1 - Day 8 | 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. |
| Area Under the Serum Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of IV Cipargamin | Day 1 - Day 8 | Blood samples were collected for pharmacokinetics characterization. AUClast was listed and summarized using descriptive statistics. |
| Area Under the Concentration Time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUCinf) of IV Cipargamin | Day 1 - Day 8 | Blood samples were collected for pharmacokinetics characterization. AUC(0-inf) post last dose was listed and summarized using descriptive statistics. |
| Area Under the Plasma Concentration-time Curve From the Time 0 to 24 Hours (AUC0-24hours) of IV Cipargamin | Day 1 - Day 8 | Blood samples were collected for pharmacokinetics characterization. AUC(0-24h) was listed and summarized using descriptive statistics. |
| Terminal Elimination Half Life (T1/2) of IV Cipargamin | Day 1 - Day 8 | Blood samples were collected for pharmacokinetics characterization. The half-life post last dose was summarized using descriptive statistics. |
| Total Systemic Clearance for Intravenous Administration (CL) of IV Cipargamin | Day 1 - Day 8 | Blood samples were collected for pharmacokinetics characterization. CL post last dose was summarized using descriptive statistics. |
| Volume of Distribution During the Terminal Phase Following Intravenous Elimination (Vz) of IV Cipargamin | Day 1 - Day 8 | Blood samples were collected for pharmacokinetics characterization. Vz post last dose was listed and summarized using descriptive statistics. |
Countries
Burkina Faso, Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Mozambique, Rwanda, Uganda
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Pre-assignment details
316 participants were screened for the study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 9.3 years STANDARD_DEVIATION 9.47 |
| Age, Customized 12 to <18 years | 23 Participants |
| Age, Customized 18 to <65 years | 11 Participants |
| Age, Customized 2 to <6 years | 76 Participants |
| Age, Customized 6 months to < 2 years | 0 Participants |
| Age, Customized 6 to <12 years | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 20 Participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 114 | 0 / 117 | 0 / 251 |
| other Total, other adverse events | 7 / 20 | 57 / 114 | 50 / 117 | 114 / 251 |
| serious Total, serious adverse events | 0 / 20 | 5 / 114 | 4 / 117 | 9 / 251 |
Outcome results
None listed