Malaria
Conditions
Keywords
Plasmodium falciparum, pharmacokinetics, antimalarials (antimalarial drugs), chloroquine (chloroquine-resistant), QT (QTc) interval
Brief summary
This is an initial efficacy study of a candidate antimalarial in human subjects with uncomplicated malaria caused by the most common and most important parasite in Africa (Plasmodium falciparum). This study will enroll 66 adult Malian males with uncomplicated P. falciparum malaria and randomize them to treatment with 1750 mg of the investigational drug (AQ-13) by mouth over 3 days or the current standard treatment, which is 2 doses of Coartem twice daily for 3 days. The hypothesis underlying this study is that AQ-13 will be similarly effective to Coartem for the treatment of uncomplicated P. falciparum malaria due to both chloroquine-susceptible and chloroquine-resistant parasites. Funding Source - FDA Office of Orphan Product Development (OOPD).
Detailed description
This is an initial efficacy study (Phase 2 Proof of Concept Study) of a candidate antimalarial in human subjects with uncomplicated malaria caused by the most common and most important parasite in Africa (Plasmodium falciparum). This study will enroll 66 adult Malian males with uncomplicated P. falciparum malaria and randomize them to treatment with 1750 mg of the investigational drug (AQ-13) by mouth over 3 days or the current standard treatment, which is 80 mg of artemether and 480 mg of lumefantrine twice daily for 3 days. The hypothesis underlying this study is that AQ-13 will be similarly effective to Coartem for the treatment of uncomplicated P. falciparum malaria due to both chloroquine-susceptible and chloroquine-resistant parasites.
Interventions
DRUGAQ-13 Treatment
Adult Malian males 18 years of age or older with uncomplicated P. falciparum malaria who agree to participate and provide their informed consent will be randomized to receive treatment with either AQ-13 or Coartem. Intervention 'AQ-13 Treatment' Participants randomized to the AQ-13 arm will be treated with two (350 mg) capsules on days 1 and 2 and one (350 mg) AQ-13 capsule on day 3 for a total oral dose of 1750 mg of AQ-13 (5 capsules containing 350 mg apiece) over 3 days.
DRUGCoartem Treatment
Adult Malian males 18 years of age or older with uncomplicated P. falciparum malaria who agree to participate and provide their informed consent will be randomized to receive treatment with either AQ-13 or Coartem. Intervention 'Coartem Treatment' Participants randomized to the Coartem arm will receive six doses of Coartem tablets over 3 days (each dose containing 80 mg artemether and 480 mg lumefantrine). Those six doses will be given at the time of diagnosis and 8 hours later on day 1, at 24 and 36 hours on day 2 and at 48 and 60 hours on day 3 for total doses of 480 mg artemether and 2880 mg lumefantrine over 3 days.
Sponsors
Tulane University
University of the Sciences, Techniques and Technologies of Bamako
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Adult Malian males ≥ 18 years of age, 2. Uncomplicated malaria with ≥ 2,000 asexual P. falciparum parasites per ul, and 3. Informed consent obtained and signed.
Exclusion criteria
1. Severe or complicated malaria (including temperature ≥ 40o C), 2. ≥ 100,000 asexual parasites per ul of blood, 3. Anemia or other laboratory results (other than malaria) that require treatment (e.g., Hb ≤ 7 gm/dL, K+ ≤ 3.5 millimolar (mM), BP ≥ 140/90), 4. Seizures or impaired consciousness, 5. Recent antimalarial treatment by history (within ≤ 2 weeks), 6. Chronic medications (including inducers of Cytochrome P450 3A4 \[CYP3A4\] activity such as rifampin and nevirapine), 7. Ventricular or atrial arrhythmias, or second or third degree heart block on the screening ECG or Holter recording, 8. Infection with other plasmodial species on the blood smear (P. ovale, P. ovale, P. vivax).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cure Rates of AQ-13 and Coartem for Uncomplicated Plasmodium Falciparum Malaria in Adult Malian Males. | Subjects are followed for 42 days after beginning treatment with either AQ-13 or Coartem.. | Cure rate is defined as a lack of recrudescence within 42 days PCR-corrected (correcting for new infections due to treatment failures). The investigators were looking for no evidence of recurrent infection with the same parasite genotype after reduction of the asexual parasitemia to less than 25% of the admission value by day 3 and clearance of asexual parasites and fever by day 7 to measure the cure rate. Failure is defined as lack of cure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parasite Clearance Time | From the time of beginning treatment with either AQ-13 or Coartem to the first of 2 successive negative blood smears, assessed during the 1 week inpatient stay. | Blood smears are performed at the time of diagnosis and then (for persons who have been enrolled after providing their informed consent to participate) twice daily until two successive negative smears have been obtained. |
| Number of Participants With Recrudescence of Infection | Within 42 days after beginning treatment with either AQ-13 or Coartem | Recrudescence of infection with malaria is the reactivation of the disease after treatment due to incomplete eradication of the parasite, Plasmodium. The parasites causing these recurrences had the same molecular markers as the original infections in these participants, they were considered recrudescences (late treatment failures) rather than new infections. The investigators counted the number of participants who had recrudescence of infection. |
| QTc Interval Response Following Antimalarial Treatment | Between dosing and 4 hours after dosing | Corrected QT (QTc) interval was measured at antimalarial dosing and at 4 hours after dosing using HolterCare (version 10.6.0) monitors. |
| Mean Fever Clearance Time in Days | Days 1-7 after beginning treatment with either AQ-13 or Coartem | Body temperature was measured twice daily with an electronic (digital) thermometer during the 5-7 day inpatient stay. Fever clearance time was defined as the first persistently normal temperature (\<37·5°C) during week 1 of inpatient stay. |
| Peak Cmax | 42 Days | One of the pharmacokinetic parameters for AQ-13 that was measured was Peak Cmax (Cmax=maximal concentration) which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment). |
| Number of Participants With Adverse Events | Within 4 weeks of beginning treatment with either AQ-13 or Coartem | Adverse events (AEs) are defined as events possibly related to the study drug(s) as judged by blinded physician observers that occur within 4 weeks of beginning treatment with AQ-13 or Coartem. The investigators asked participants to report the less serious adverse events (≤ grade 1) and the grade 2-4 adverse events and counted the number of participants who had those adverse events happen. |
| 1-week AUC | 42 days | One of the pharmacokinetic parameters for AQ-13 that was measured was 1-week area under the curve (AUC) for the first 7 days, which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment). |
| Mean Residence Time | 42 Days | One of the pharmacokinetic parameters for AQ-13 that was measured was Mean Residence Time (MRT), which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment). |
| Clearance | 42 Days | One of the pharmacokinetic parameters for AQ-13 that was measured was clearance (Cl/f), which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment). |
| Elimination t½ | 42 Days | One of the pharmacokinetic parameters for AQ-13 that was measured was elimination t½ (t½=elimination half-life) which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment). |
| Time to Peak Tmax | 42 days | One of the pharmacokinetic parameters for AQ-13 that was measured was time to peak tmax (tmax is time from beginning treatment to the maximal concentration), which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment). |
Countries
Mali
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AQ-13 Adult Malian males 18 years of age or older with uncomplicated P. falciparum malaria who agree to participate and provide their informed consent will be randomized to receive treatment with either AQ-13 or Coartem. Intervention 'AQ-13 Treatment' Participants randomized to the AQ-13 arm will be treated with two (350 mg) capsules on days 1 and 2 and one (350 mg) AQ-13 capsule on day 3 for a total oral dose of 1750 mg of AQ-13 (5 capsules containing 350 mg apiece) over 3 days.
AQ-13 Treatment: Adult Malian males 18 years of age or older with uncomplicated P. falciparum malaria who agree to participate and provide their informed consent will be randomized to receive treatment with either AQ-13 or Coartem. Intervention 'AQ-13 Treatment' Participants randomized to the AQ-13 arm will be treated with two (350 mg) capsules on days 1 and 2 and one (350 mg) AQ-13 capsule on day 3 for a total oral dose of 1750 mg of AQ-13 (5 capsules containing 350 mg apiece) over 3 days. | 33 |
| Coartem Treatment Adult Malian males 18 years of age or older with uncomplicated P. falciparum malaria who agree to participate and provide their informed consent will be randomized to receive treatment with either AQ-13 or Coartem. Intervention: Active Comparator: Coartem. Participants randomized to the Coartem arm will be treated with 80 mg artemether and 480 mg lumefantrine at the time of diagnosis and 8 hours later on day 1, the same doses (80 mg artemether and 480 mg lumefantrine) twice on day 2 (24 and 36 hours after diagnosis) and twice more on day 3 (48 and 60 hours after diagnosis) for total oral doses of 480 mg artemether and 2880 mg lumefantrine over 3 days.
Coartem Treatment: Adult Malian males 18 years of age or older with uncomplicated P. falciparum malaria who agree to participate and provide their informed consent will be randomized to receive treatment with either AQ-13 or Coartem. Intervention 'Coartem Treatment' Participants randomized to the Coartem arm will receive six doses of Coartem tablets over 3 days (each dose containing 80 mg artemether and 480 mg lumefantrine). Those six doses will be given at the time of diagnosis and 8 hours later on day 1, at 24 and 36 hours on day 2 and at 48 and 60 hours on day 3 for total doses of 480 mg artemether and 2880 mg lumefantrine over 3 days. | 33 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | AQ-13 | Coartem Treatment | Total |
|---|---|---|---|
| Age, Continuous | 30.3 Years STANDARD_DEVIATION 12.2 | 31.9 Years STANDARD_DEVIATION 14.8 | 31.1 Years STANDARD_DEVIATION 13.56 |
| CVIET and CVMNK genotype parasites | 5 Participants | 6 Participants | 11 Participants |
| CVIET genotype parasites | 16 Participants | 13 Participants | 29 Participants |
| CVMNK genotype parasites | 12 Participants | 14 Participants | 26 Participants |
| Haemoglobin concentration | 12.1 g/dL STANDARD_DEVIATION 1.8 | 12.5 g/dL STANDARD_DEVIATION 2.1 | 12.3 g/dL STANDARD_DEVIATION 1.96 |
| Height | 174.3 cm STANDARD_DEVIATION 7.2 | 175.5 cm STANDARD_DEVIATION 7.1 | 174.9 cm STANDARD_DEVIATION 7.15 |
| Median number of asexual parasites per μL | 11850 Asexual parasites per microliter STANDARD_DEVIATION 28900 | 12000 Asexual parasites per microliter STANDARD_DEVIATION 21575 | 11925 Asexual parasites per microliter STANDARD_DEVIATION 25501.87 |
| Region of Enrollment Mali | 33 participants | 33 participants | 66 participants |
| Sex/Gender, Customized Males | 33 Participants | 33 Participants | 66 Participants |
| Weight | 64.2 kg STANDARD_DEVIATION 7.8 | 67.5 kg STANDARD_DEVIATION 11.7 | 65.85 kg STANDARD_DEVIATION 9.94 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 33 |
| other Total, other adverse events | 32 / 33 | 33 / 33 |
| serious Total, serious adverse events | 0 / 33 | 0 / 33 |
Outcome results
Primary
Cure Rates of AQ-13 and Coartem for Uncomplicated Plasmodium Falciparum Malaria in Adult Malian Males.
Cure rate is defined as a lack of recrudescence within 42 days PCR-corrected (correcting for new infections due to treatment failures). The investigators were looking for no evidence of recurrent infection with the same parasite genotype after reduction of the asexual parasitemia to less than 25% of the admission value by day 3 and clearance of asexual parasites and fever by day 7 to measure the cure rate. Failure is defined as lack of cure.
Time frame: Subjects are followed for 42 days after beginning treatment with either AQ-13 or Coartem..
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AQ-13 | Cure Rates of AQ-13 and Coartem for Uncomplicated Plasmodium Falciparum Malaria in Adult Malian Males. | 28 Participants |
| Coartem Treatment | Cure Rates of AQ-13 and Coartem for Uncomplicated Plasmodium Falciparum Malaria in Adult Malian Males. | 31 Participants |
Secondary
1-week AUC
One of the pharmacokinetic parameters for AQ-13 that was measured was 1-week area under the curve (AUC) for the first 7 days, which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment).
Time frame: 42 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AQ-13 | 1-week AUC | 205.4 μM/h |
Secondary
Clearance
One of the pharmacokinetic parameters for AQ-13 that was measured was clearance (Cl/f), which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment).
Time frame: 42 Days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AQ-13 | Clearance | 5.86 L/h |
Secondary
Elimination t½
One of the pharmacokinetic parameters for AQ-13 that was measured was elimination t½ (t½=elimination half-life) which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment).
Time frame: 42 Days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AQ-13 | Elimination t½ | 3.85 Days |
Secondary
Mean Fever Clearance Time in Days
Body temperature was measured twice daily with an electronic (digital) thermometer during the 5-7 day inpatient stay. Fever clearance time was defined as the first persistently normal temperature (\<37·5°C) during week 1 of inpatient stay.
Time frame: Days 1-7 after beginning treatment with either AQ-13 or Coartem
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AQ-13 | Mean Fever Clearance Time in Days | 1.0 Days |
| Coartem Treatment | Mean Fever Clearance Time in Days | 1.23 Days |
Secondary
Mean Residence Time
One of the pharmacokinetic parameters for AQ-13 that was measured was Mean Residence Time (MRT), which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment).
Time frame: 42 Days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AQ-13 | Mean Residence Time | 7.19 Days |
Secondary
Number of Participants With Adverse Events
Adverse events (AEs) are defined as events possibly related to the study drug(s) as judged by blinded physician observers that occur within 4 weeks of beginning treatment with AQ-13 or Coartem. The investigators asked participants to report the less serious adverse events (≤ grade 1) and the grade 2-4 adverse events and counted the number of participants who had those adverse events happen.
Time frame: Within 4 weeks of beginning treatment with either AQ-13 or Coartem
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AQ-13 | Number of Participants With Adverse Events | Less serious adverse events (≤ grade 1) | 32 Participants |
| AQ-13 | Number of Participants With Adverse Events | Grade 2-4 adverse events | 0 Participants |
| Coartem Treatment | Number of Participants With Adverse Events | Less serious adverse events (≤ grade 1) | 33 Participants |
| Coartem Treatment | Number of Participants With Adverse Events | Grade 2-4 adverse events | 0 Participants |
Secondary
Number of Participants With Recrudescence of Infection
Recrudescence of infection with malaria is the reactivation of the disease after treatment due to incomplete eradication of the parasite, Plasmodium. The parasites causing these recurrences had the same molecular markers as the original infections in these participants, they were considered recrudescences (late treatment failures) rather than new infections. The investigators counted the number of participants who had recrudescence of infection.
Time frame: Within 42 days after beginning treatment with either AQ-13 or Coartem
Population: Two participants who withdrew on day 4 and three who were lost to follow-up were not included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AQ-13 | Number of Participants With Recrudescence of Infection | 0 Participants |
| Coartem Treatment | Number of Participants With Recrudescence of Infection | 2 Participants |
Secondary
Parasite Clearance Time
Blood smears are performed at the time of diagnosis and then (for persons who have been enrolled after providing their informed consent to participate) twice daily until two successive negative smears have been obtained.
Time frame: From the time of beginning treatment with either AQ-13 or Coartem to the first of 2 successive negative blood smears, assessed during the 1 week inpatient stay.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AQ-13 | Parasite Clearance Time | 47.3 Hour |
| Coartem Treatment | Parasite Clearance Time | 32.5 Hour |
Secondary
Peak Cmax
One of the pharmacokinetic parameters for AQ-13 that was measured was Peak Cmax (Cmax=maximal concentration) which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment).
Time frame: 42 Days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AQ-13 | Peak Cmax | 2.526 μM |
Secondary
QTc Interval Response Following Antimalarial Treatment
Corrected QT (QTc) interval was measured at antimalarial dosing and at 4 hours after dosing using HolterCare (version 10.6.0) monitors.
Time frame: Between dosing and 4 hours after dosing
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AQ-13 | QTc Interval Response Following Antimalarial Treatment | -1.2 ms |
| Coartem Treatment | QTc Interval Response Following Antimalarial Treatment | 0.4 ms |
Secondary
Time to Peak Tmax
One of the pharmacokinetic parameters for AQ-13 that was measured was time to peak tmax (tmax is time from beginning treatment to the maximal concentration), which was calculated based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment).
Time frame: 42 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AQ-13 | Time to Peak Tmax | 28.1 Hours |