Severe Malaria
Conditions
Keywords
KAE609, cipargamin, artesunate, intravenous, i.v., pediatric, dose-finding, safety, tolerability, pharmacokinetics
Brief summary
The purpose of this study is to identify the safe and effective dose of intravenous cipargamin in participants with moderately severe and severe malaria. The study also intends 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 of another drug in malaria endemic countries. Cipargamin treatment results in rapid clearance of parasites including artemisinin resistant parasites.
Interventions
DRUGKAE609
Two doses of Intravenous Cipargamin will be evaluated in the initial phase of the study (Cohorts 1-2). These doses will cover a wider exposure range and facilitate the selection of an appropriate dose for later Cohorts 3-5.
DRUGIV Artesunate
Parenteral artesunate is the WHO recommended first line treatment for severe malaria. Hence IV artesunate is used as comparator. Also, this will be used as rescue medication for participants where IV KAE609 is not working.
DRUGCoartem
Oral Standard of Care
Sponsors
Wellcome Trust
European and Developing Countries Clinical Trials Partnership (EDCTP)
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Although the study is open label however 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 may result in systematic unblinding will not be available to the Clinical Trial Team (CTT) (particularly clinicians, trial statisticians, trial programmers) until the database is locked after IA of Cohorts 1-2. After interim database lock, the CTT would be unblinded with the results, however, the blinding will then be continued for Cohorts 3-5 until the final database is locked.
Intervention model description
This will be 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 will get randomized to one of the three treatment arms (2 dose of intravenous cipargamin or intravenous artesunate - comparator ). After Cohort 2, interim analysis will be performed to take one best dose of intravenous cipargamin forward for Cohorts 3-5. Participants in Cohorts 3-5 with be 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 | Day 1 (12 Hours) | A blood draw will be performed at each collection time point for parasitemia assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the plasma concentration-time Curve from the time 0 to the last observed quantifiable concentration (AUC(0-t)) of IV Cipargamin | Day 1 - Day 8 | Blood samples will be collected for activity-based pharmacokinetics characterization. AUC(0-t) will be listed and summarized using descriptive statistics. |
| Percentage of participants with individual signs of severe malaria over time | Day 1 to Day 29 | Individual signs of severe malaria over time will be 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 treatment are defined as follows: Early Hemolytic anemia is defined as 10% or greater decrease in hemoglobin levels and an increase of LDH levels to \>390 U/L, or an increase of \>= 10% above baseline occurring up to Day 8 of the study. Delayed hemolytic anemia might occur \> 7 days after initiation of parenteral study drug (IV artesunate or IV cipargamin) during the study period. The event is 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 will be conducted and relevant medical history collected under the following categories to assess the extent of neurological signs and symptoms at baseline and to monitor the extent of neurological sequelae in follow-up visits: 1. Consciousness 2. Cranial Nerve Palsy 3. Motor system 4. Convulsions 5. Sense organs (Examination more useful at time of hospital discharge and in follow-up visits) |
| Percentage of participants achieving at least 90% reduction in Plasmodium falciparum (P. falciparum) | Day 2 (24 hours), Day 3 (48 hours) | A blood draw will be performed at each collection time point for parasitemia assessment |
| Time to parasite clearance (PCT) | Day 1 (12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) | Parasite Clearance Time (PCT) is 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 to fever clearance (FCT) | Day 1 (12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) | Fever Clearance Time (FCT) is 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. |
| Percentage of participants achieving P. falciparum parasite reduction ratios (PRR) at 12, 24 and 48 hours | Day 1 (12 hours), Day 2 (24 hours) and Day 3 (48 hours) | PRR is defined as the ratio of asexual parasite at baseline divided by asexual parasite at post-baseline. If the asexual parasite count at post-baseline is 0, the half value of detection limit will be used to calculate the ratio. |
| Percentage of participants with recrudescence and reinfection | Day 29 | Time to event (recrudescence or reinfection) will be calculated from the time of first study medication to the date of first event if a patient experiences the event and be censored at the time of last parasite assessment if a patient does not experience the event due to whatever reason. Reinfection is defined as appearance of asexual parasites after clearance of initial infection with a genotype different from those parasites present at baseline. Recrudescence is defined as appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at baseline. Reinfection and Recrudescence must be confirmed by PCR analysis. |
| Time to recover from prostration | Day 1 to Day 29 | To assess recovery of participants as measured by time (days and hours) to discharge from hospital or recovery from prostration compared to baseline. |
| Percentage of participants achieving clinical success over time | Day 3 (48 Hours), Day 4 to Day 29 | Clinical success is a composite endpoint based on following criterias: 1. Is 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 to discharge from hospital | Day 3 to Day 29 | All participants will be hospitalized. Time (Days and Hours) to discharge from hospital will be analyzed. |
| Number of Participants impacted on safety and tolerability assessments | Day 1 to Day 29 | Adverse events (AE), Serious Adverse events (SAEs) will be collected from first dosing, Death including whether in-hospital death and routine laboratory assessments will be done up to last follow-up visit or until the event has 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 will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics. |
| Time of maximum observed drug concentration occurrence (Tmax) of IV Cipargamin | Day 1 - Day 8 | Blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics. |
| 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 will be collected for activity-based pharmacokinetics characterization. AUClast will be 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 will be collected for activity-based pharmacokinetics characterization. AUC(0-inf) will be listed and summarized using descriptive statistics. |
| AUC(0-t) divided by the dose administered (AUC(0- t)/D) of IV Cipargamin | Day 1 - Day 8 | Blood samples will be collected for activity-based pharmacokinetics characterization. AUC(0-t)/D will be listed and summarized using descriptive statistics. |
| Terminal elimination half life (T^1/2) of IV Cipargamin | Day 1 - Day 8 | Blood samples will be collected for activity-based pharmacokinetics characterization. The half-live will be listed and summarized using descriptive statistics. |
| Total systemic clearance for intravenous administration (CL) of IV Cipargamin | Day 1 - Day 8 | Blood samples will be collected for activity-based pharmacokinetics characterization. CL will be listed and summarized using descriptive statistics. |
| volume of distribution during the terminal phase following intravenous elimination (Vz) of IV Cipargamin | Day 1 - Day 8 | Blood samples will be collected for activity-based pharmacokinetics characterization. Vz will be listed and summarized using descriptive statistics. |
| 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) will be analyzed. |
Countries
Burkina Faso, Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Mozambique, Rwanda, Uganda
Outcome results
None listed