Malaria
Conditions
Keywords
Malaria, KAE609
Brief summary
This study aims to determine the Minimum Inhibitory Concentration of KAE609 in adult male patients with acute, uncomplicated malaria due to P.falciparum monoinfection after single dosing with KAE609
Detailed description
There will be a total of approximately 45 patients recruited into this study and six doses of KAE609 and will be investigated.The dose groups will run in sequence. Patient will be given a single dose of KAE609 and be followed up for 42 days.
Interventions
DRUGKAE609
Patients will receive KAE609 single dose at a different dose level in each cohort.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Monoinfection with P. falciparum confirmed by microscopy * Asexual P. falciparum parasitemia count of 5,000 to 50,000/µL * Axillary temperature ≥37.5 ºC or oral/tympanic/rectal temperature ≥38 ºC; or similar documented temperature during the previous 24 hours * Body weight between 40 to 90 kg Key
Exclusion criteria
* Signs and symptoms of severe malaria according to World Health Organization (WHO) 2010 criteria * Mixed Plasmodium infection, i.e. infection with more than one species of malaria parasites * Use of other investigational drugs within 30 days or within 5 half-lives of enrollment, whichever is longer * History of antimalarial use within 2 months of screening * Use of any antibiotics with antimalarial activity or other prohibited medication within 14 days of screening * Long QT syndrome or QTc using Fridericia's formula \>430 msec * History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases * Hemoglobin level \<10 g/dL * Liver disease or injury as indicated by elevated liver tests such as SGPT (ALT) or SGOT (AST) \>2 times the upper limit of normal * Renal dysfunction as indicated by serum creatinine \>2 times the upper limit of normal in the absence of dehydration; in case of dehydration, serum creatinine should be \<2 times the upper limit of normal after oral or parental rehydration * Known to be immunocompromised (including HIV infection) or are receiving immunosuppressive therapy at the time or enrollment; HIV testing is not required * Known history of hepatitis B or C; testing is not required * Febrile condition due to diseases other than malaria (e.g. acute lower respiratory tract infection), known underlying chronic or severe disease (e.g. cardiac, hepatic, renal, gastrointestinal, neurologic, or psychiatric disease), or any condition precluding enrollment into this study according to the investigator * Severe vomiting defined as \>3 times during the previous 24 hours or inability to tolerate oral medication; severe diarrhea defined as ≥3 watery stools during the previous 24 hours * Severe malnutrition defined by a body mass index (BMI) \<18.5 kg/m2 or unintentional loss of weight ≥10% with evidence of suboptimal intake resulting in loss of subcutaneous fat and/or severe muscle wasting * Active tuberculosis or history of taking anti-tuberculosis medications within 24 months prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Minimum Inhibitory Concentration (MIC) of KAE609 | Up to Day 8 after a single dose of KAE609 | To observe the exposure-response (PK/PD) relationship for a single dose of KAE609. The key parameter is MIC, defined as the concentration at which the relative rate of change in parasitemia is equal to zero. Approximation of MIC will assist in identifying the optimal dose of KAE609, which will be one component of a future combination antimalarial. MIC could not be determined due to small sample size no data was collected from any participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Parasite Clearance | pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, 66, 72 hours post dose of KAE609 | Parasite clearance time will be estimated using thick/thin blood films. |
| Median Time to Fever Clearance | Day 1 to Day 5 | Fever is monitored on participants every 4 hours for the first 24 hours, then every 6 hours until negative reading obtained. |
| Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 28, Day 35 & Day 42 | PCR-corrected cure rate after a single dose of KAE609 by Day 28, Day 35 & Day 42. PCR-corrected cure rate accounts for failures due to reappearance of parasites that were present in the blood before treatment (i.e. recrudescent infection) but not for failures due to a post-treatment inoculation (i.e. new infection). |
Countries
Vietnam
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose 1: 30 mg Single dose of KAE609 30 mg | 7 |
| Dose 2: 20 mg Single dose of KAE609 20 mg | 4 |
| Dose 3: 10 mg Single dose of KAE609 10 mg | 7 |
| Dose 4: 15 mg Single dose of KAE609 15 mg | 7 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Unsatisfactory therapeutic effect | 3 | 2 | 5 | 6 |
Baseline characteristics
| Characteristic | Dose 1: 30 mg | Dose 2: 20 mg | Dose 3: 10 mg | Dose 4: 15 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 32.7 years STANDARD_DEVIATION 11.84 | 32.8 years STANDARD_DEVIATION 7.93 | 30.6 years STANDARD_DEVIATION 8.24 | 34.7 years STANDARD_DEVIATION 8.79 | 32.7 years STANDARD_DEVIATION 9.04 |
| Sex/Gender, Customized MALE | 7 participants | 4 participants | 7 participants | 7 participants | 25 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 7 | 3 / 4 | 7 / 7 | 5 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 4 | 0 / 7 | 0 / 7 |
Outcome results
Primary
Minimum Inhibitory Concentration (MIC) of KAE609
To observe the exposure-response (PK/PD) relationship for a single dose of KAE609. The key parameter is MIC, defined as the concentration at which the relative rate of change in parasitemia is equal to zero. Approximation of MIC will assist in identifying the optimal dose of KAE609, which will be one component of a future combination antimalarial. MIC could not be determined due to small sample size no data was collected from any participants.
Time frame: Up to Day 8 after a single dose of KAE609
Population: The primary Outcome Measure (OM) could not be determined due to small sample size no data was collected from any participants.
Secondary
Median Time to Fever Clearance
Fever is monitored on participants every 4 hours for the first 24 hours, then every 6 hours until negative reading obtained.
Time frame: Day 1 to Day 5
Population: Pharmacodynamic Analysis Set includes all enrolled patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose 1: 30 mg | Median Time to Fever Clearance | 9.83 hours |
| Dose 2: 20 mg | Median Time to Fever Clearance | 12.38 hours |
| Dose 3: 10 mg | Median Time to Fever Clearance | 15.75 hours |
| Dose 4: 15 mg | Median Time to Fever Clearance | 11.83 hours |
Secondary
Median Time to Parasite Clearance
Parasite clearance time will be estimated using thick/thin blood films.
Time frame: pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, 66, 72 hours post dose of KAE609
Population: Pharmacodynamic Analysis Set includes all enrolled patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose 1: 30 mg | Median Time to Parasite Clearance | 24.00 hours |
| Dose 2: 20 mg | Median Time to Parasite Clearance | 63.00 hours |
| Dose 3: 10 mg | Median Time to Parasite Clearance | 54.00 hours |
| Dose 4: 15 mg | Median Time to Parasite Clearance | 60.00 hours |
Secondary
Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42
PCR-corrected cure rate after a single dose of KAE609 by Day 28, Day 35 & Day 42. PCR-corrected cure rate accounts for failures due to reappearance of parasites that were present in the blood before treatment (i.e. recrudescent infection) but not for failures due to a post-treatment inoculation (i.e. new infection).
Time frame: Day 28, Day 35 & Day 42
Population: Pharmacodynamic Analysis Set includes all enrolled patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose 1: 30 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 28 | 57.1 Percentage of Patients |
| Dose 1: 30 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 42 | 57.1 Percentage of Patients |
| Dose 1: 30 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 35 | 57.1 Percentage of Patients |
| Dose 2: 20 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 28 | 50.0 Percentage of Patients |
| Dose 2: 20 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 42 | 50.0 Percentage of Patients |
| Dose 2: 20 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 35 | 50.0 Percentage of Patients |
| Dose 3: 10 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 35 | 28.6 Percentage of Patients |
| Dose 3: 10 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 28 | 28.6 Percentage of Patients |
| Dose 3: 10 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 42 | 28.6 Percentage of Patients |
| Dose 4: 15 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 28 | 14.3 Percentage of Patients |
| Dose 4: 15 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 42 | 14.3 Percentage of Patients |
| Dose 4: 15 mg | Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 | Day 35 | 14.3 Percentage of Patients |