Malaria, Plasmodium Vivax
Conditions
Keywords
malaria, Plasmodium vivax, adults, treatment, tafenoquine
Brief summary
This Phase II study is designed to determine whether a single 600 mg dose or 400mg/day for 3 days of tafenoquine is efficacious, and well tolerated for clearing P. vivax malaria infection (blood schizontocidal and gametocytocidal activity) and preventing P. vivax relapse (hypnozoite eradication). It will also further establish the safety and tolerability of these doses of tafenoquine.
Detailed description
This was a randomized, active-control, double-blind, double-dummy study to be conducted in 2 sequential cohorts. Cohort 1 was randomized 2:1 to receive tafenoquine, 400mg/day for 3 days, or the standard blood schizontocidal dosing regimen of chloroquine (1000mg for 2 days followed by 500mg for 1 day) followed by a standard hypnozoite eradication dosing regimen for primaquine (15mg base per day for 14 days). Cohort 2 was to be randomized 2:1 to receive a single 600mg dose of tafenoquine or the standard blood schizontocidal dosing regimen of chloroquine (1000mg for 2 days followed by 500mg for 1 day) followed by a standard hypnozoite eradication dosing regimen for primaquine (15mg base per day for 14 days). A planned interim analysis was performed after all subjects in Cohort 1 had completed the day 28 assessment and an Independent Data Monitoring Committee (IDMC) convened to evaluate the efficacy and safety of the tafenoquine dosing regimen (400mg once per day for 3 days) used in Cohort 1. Only if the results from Cohort 1 met pre-defined efficacy and safety criteria was enrollment to begin for Cohort 2. The efficacy criterion for achieving the primary endpoint was that the lower limit of the one-sided 95% confidence interval was no less than 85%, and for safety that a review of trends in all AEs, tolerability, medical observations, methemoglobin and other lab data for all subjects indicated the dose was well tolerated. During the IDMC review it was determined that Cohort 1 failed to meet the pre-specified endpoint for the day 28 cure rate and therefore Cohort 2 should not be initiated and follow-up in Cohort 1 should be completed according to protocol. Following last subject last visit for Cohort 1 the study was terminated.
Interventions
DRUGTafenoquine
Tafenoquine: 2 capsules (200mg base/capsule for a total of 400mg base) and 4 chloroquine placebo capsules for 2 days, followed by 2 tafenoquine capsules and 2 chloroquine placebo capsules for 1 day, followed by 1 primaquine placebo capsule/day for 14 days.
Chloroquine (1000 mg chloroquine phosphate) and tafenoquine placebo x 2 day, followed by chloroquine (500 mg chloroquine phosphate) and tafenoquine placebo x 1day, followed by primaquine, 15 mg/day for 14 days.
DRUGtafenoquine
Tafenoquine (600 mg base) and chloroquine placebo x 1d, chloroquine placebo x 2 days, followed by primaquine placebo for 14 days.
Sponsors
GlaxoSmithKline
U.S. Army Medical Research and Development Command
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Only if Cohort 1 met specified endpoint criteria would Cohort 2 begin enrollment
Eligibility
Sex/Gender
ALL
Age
20 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Positive smear for P. vivax. 2. Parasite density \> 500 and \< 200,000/μl 3. Age: 20-60 years old 4. Willing to sign consent form 5. Willing to be hospitalized for 29 days and remain in a malaria free region for 60 days thereafter for follow-up. 6. A female is eligible to enter and participate in this study if she is of: a non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post-menopausal or, b child-bearing potential, has a negative pregnancy (urine or serum) test at screen, and agrees to comply with recognized contraceptive methods during the treatment stage of the study and for a period of 12 weeks after stopping study drug. Recognized contraceptive methods include, abstinence, implants of levonorgestrel, injectable progestogen, or appropriate double barrier methods using licensed contraceptives such as diaphragm and condom (by the partner) or intrauterine device and condom. The use of oral/patch contraceptives during the study is not considered sufficient contraceptive protection.
Exclusion criteria
1. Mixed malaria infections by Field's stain. 2. Female subjects who are pregnant, lactating or unwilling/unable to comply with recognized contraceptive methods during the treatment stage of the study and for a period of 12 weeks after stopping study drug. 3. Symptoms of severe vomiting (no food or inability to take food during the previous 8 hours). 4. Demonstrated glucose-6-phosphate dehydrogenase deficiency. 5. Subject has taken other anti-malarials (mefloquine, primaquine, chloroquine) within the past 30 days by history 6. Clinically significant illness (intercurrent illness e.g. pneumonia, pre-existing condition e.g. renal disease, malignancy or conditions that may affect absorption of study medication e.g. severe diarrhea or any signs of malnutrition as defined clinically). 7. Clinically significant abnormal laboratory values as determined by history, physical examination or routine blood chemistries and hematology values (laboratory guideline values for exclusion are hemoglobin \<7 gm/dL, platelets \< 50,000/μl, White Blood Cell count (WBC) \< 2000/μl, serum creatinine \>2.0mg/dL, or ALT or AST more than 3 times the upper limit of normal for age. 8. History of allergy to chloroquine, mefloquine, tafenoquine, primaquine or any other 8-aminoquinolines. 9. Subject has taken another investigational drug within 30 days or 5 half lives (whichever is longer), of study start. 10. History of previous eye surgery or have evidence of corneal or retinal abnormalities identified in baseline ophthalmological examination. 11. Subjects taking concomitant medications likely to affect renal or ophthalmic function or that are known to be metabolized primarily by the cytochrome P450 isoforms 3A4/5 and 2C9 and whose therapeutic effect occurs within a narrow plasma concentration range (e.g. warfarin, ketoconazole). 12. Subjects whom, after examination by the study ophthalmologist, are judged to be at risk for acute angle closure glaucoma. 13. Females who are pre-menarchal.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adequate Clinical Response (ACR) of Tafenoquine: 28 Day Cure Rate | 28 Days | A subject will be considered a success (cure) if they have an Adequate Clinical Response (ACR). Tafenoquine was efficacious if the lower bound of the two-sided 90% confidence interval for the day 28 cure rate was not less than 85% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Without Relapse of P. Vivax | Day 28, Months 2, 3 and 4 | Number of subjects without relapse of P. vivax at 2, 3 and 4 months \- Blood smears were obtained at Days 28, 60, 90 and 120 to confirm the continued absence of P. vivax parasitemia |
| Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | 90 Days | To evaluate the safety and tolerability of the tafenoquine dosing regimens as defined by the most common AE's overall, occurring in \>10% of subjects in either treatment group |
| Parasite and Gametocyte Clearance Time (PCT and GCT) | up to day 7 after baseline smear | Serial blood smears to detect the presence of P. vivax parasites and gametocytes, conducted every 12 hours up to and including day 7, until blood smear became negative were utilized to determine the time to clearance. PCT and GCT were considered cleared if 2 consecutive blood smears were negative. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Fever Clearance Time (FCT) | through day 7 | Measure of body temperature every 12 hours through day 7 was used to determine the time (to nearest 12 hours) from initiation of treatment until subjects temperature decreased to 37.2C and remained at or below that level for a minimum of 24 hours. |
Countries
Thailand
Participant flow
Recruitment details
70 subjects were randomized and hospitalized at the Bangkok Hospital for Tropical Diseases for the first 29 days of the study and asked to remain in a malaria non-endemic area until 90 days after study start. Subs had f/u's at D60 and D90, and were contacted at D120 for follow-up blood smear. Subjects remained in the study for 121 days.
Pre-assignment details
During the IDMC review it was determined that Cohort 1 failed to meet the pre-specified endpoint for the day 28 cure rate and therefore Cohort 2 should not be initiated and follow-up in Cohort 1 should be completed according to protocol. Following last subject last visit for Cohort 1 the study was terminated.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Tafenoquine Tafenoquine: 2 capsules (200mg base/capsule for a total of 400mg base) and 4 chloroquine placebo capsules for 2 days, followed by 2 tafenoquine capsules and 2 chloroquine placebo capsules for 1 day, followed by 1 primaquine placebo capsule/day for 14 days.
Tafenoquine: Tafenoquine: 2 capsules (200mg base/capsule for a total of 400mg base) and 4 chloroquine placebo capsules for 2 days, followed by 2 tafenoquine capsules and 2 chloroquine placebo capsules for 1 day, followed by 1 primaquine placebo capsule/day for 14 days. | 46 |
| Cohort 1-Chloroquine Chloroquine (1000 mg chloroquine phosphate) and tafenoquine placebo x 2 day, followed by chloroquine (500 mg chloroquine phosphate) and tafenoquine placebo x 1day, followed by primaquine, 15 mg/day for 14 days.
Chloroquine + Primaquine: Chloroquine (1000 mg chloroquine phosphate) and tafenoquine placebo x 2 day, followed by chloroquine (500 mg chloroquine phosphate) and tafenoquine placebo x 1day, followed by primaquine, 15 mg/day for 14 days. | 24 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 | 0 |
| Overall Study | Lack of Efficacy | 2 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 7 | 2 | 0 | 0 |
| Overall Study | Other | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1-Chloroquine | Total | Cohort 1 Tafenoquine |
|---|---|---|---|
| Age, Continuous | 29.7 years STANDARD_DEVIATION 8.57 | 29.7 years STANDARD_DEVIATION 8.57 | 25.5 years STANDARD_DEVIATION 6.37 |
| Race/Ethnicity, Customized Oriental | 24 Participants | 70 Participants | 46 Participants |
| Region of Enrollment Thailand | 24 participants | 70 participants | 46 participants |
| Sex: Female, Male Female | 4 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Male | 20 Participants | 57 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 24 |
| other Total, other adverse events | 46 / 46 | 22 / 24 |
| serious Total, serious adverse events | 5 / 46 | 0 / 24 |
Outcome results
Primary
Adequate Clinical Response (ACR) of Tafenoquine: 28 Day Cure Rate
A subject will be considered a success (cure) if they have an Adequate Clinical Response (ACR). Tafenoquine was efficacious if the lower bound of the two-sided 90% confidence interval for the day 28 cure rate was not less than 85%
Time frame: 28 Days
Population: Intent to treat population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 Tafenoquine | Adequate Clinical Response (ACR) of Tafenoquine: 28 Day Cure Rate | Adequate Clinical Response (ACR) | 40 Participants |
| Cohort 1 Tafenoquine | Adequate Clinical Response (ACR) of Tafenoquine: 28 Day Cure Rate | Early Treatment Failure | 5 Participants |
| Cohort 1 Tafenoquine | Adequate Clinical Response (ACR) of Tafenoquine: 28 Day Cure Rate | Late Treatment Failure | 1 Participants |
| Cohort 1-Chloroquine | Adequate Clinical Response (ACR) of Tafenoquine: 28 Day Cure Rate | Adequate Clinical Response (ACR) | 22 Participants |
| Cohort 1-Chloroquine | Adequate Clinical Response (ACR) of Tafenoquine: 28 Day Cure Rate | Early Treatment Failure | 0 Participants |
| Cohort 1-Chloroquine | Adequate Clinical Response (ACR) of Tafenoquine: 28 Day Cure Rate | Late Treatment Failure | 2 Participants |
Secondary
Number of Subjects Without Relapse of P. Vivax
Number of subjects without relapse of P. vivax at 2, 3 and 4 months \- Blood smears were obtained at Days 28, 60, 90 and 120 to confirm the continued absence of P. vivax parasitemia
Time frame: Day 28, Months 2, 3 and 4
Population: Intent to treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 Tafenoquine | Number of Subjects Without Relapse of P. Vivax | Cleared at Day 28 | 40 participants |
| Cohort 1 Tafenoquine | Number of Subjects Without Relapse of P. Vivax | Relapsed by Day 60 | 0 participants |
| Cohort 1 Tafenoquine | Number of Subjects Without Relapse of P. Vivax | Relapsed by Day 90 | 0 participants |
| Cohort 1 Tafenoquine | Number of Subjects Without Relapse of P. Vivax | Relapsed by Day 120 | 0 participants |
| Cohort 1 Tafenoquine | Number of Subjects Without Relapse of P. Vivax | Without Relapse by Day 120 | 35 participants |
| Cohort 1 Tafenoquine | Number of Subjects Without Relapse of P. Vivax | Unevaluable by Day 120 | 5 participants |
| Cohort 1-Chloroquine | Number of Subjects Without Relapse of P. Vivax | Without Relapse by Day 120 | 19 participants |
| Cohort 1-Chloroquine | Number of Subjects Without Relapse of P. Vivax | Cleared at Day 28 | 22 participants |
| Cohort 1-Chloroquine | Number of Subjects Without Relapse of P. Vivax | Relapsed by Day 120 | 1 participants |
| Cohort 1-Chloroquine | Number of Subjects Without Relapse of P. Vivax | Relapsed by Day 60 | 0 participants |
| Cohort 1-Chloroquine | Number of Subjects Without Relapse of P. Vivax | Unevaluable by Day 120 | 2 participants |
| Cohort 1-Chloroquine | Number of Subjects Without Relapse of P. Vivax | Relapsed by Day 90 | 1 participants |
Secondary
Parasite and Gametocyte Clearance Time (PCT and GCT)
Serial blood smears to detect the presence of P. vivax parasites and gametocytes, conducted every 12 hours up to and including day 7, until blood smear became negative were utilized to determine the time to clearance. PCT and GCT were considered cleared if 2 consecutive blood smears were negative.
Time frame: up to day 7 after baseline smear
Population: Intent to treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Tafenoquine | Parasite and Gametocyte Clearance Time (PCT and GCT) | Parasite Clearance Time | 83.4 Hours | Standard Deviation 31.85 |
| Cohort 1 Tafenoquine | Parasite and Gametocyte Clearance Time (PCT and GCT) | Gametocyte Clearance Time | 48.3 Hours | Standard Deviation 33.27 |
| Cohort 1-Chloroquine | Parasite and Gametocyte Clearance Time (PCT and GCT) | Parasite Clearance Time | 40.0 Hours | Standard Deviation 15.69 |
| Cohort 1-Chloroquine | Parasite and Gametocyte Clearance Time (PCT and GCT) | Gametocyte Clearance Time | 22.7 Hours | Standard Deviation 16.44 |
Secondary
Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs)
To evaluate the safety and tolerability of the tafenoquine dosing regimens as defined by the most common AE's overall, occurring in \>10% of subjects in either treatment group
Time frame: 90 Days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Blood methemoglobin present | 46 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Headache | 14 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Keratopathy | 14 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Upper respiratory tract infection | 13 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Dizziness | 12 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Retinopathy | 9 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Eosinophilia | 8 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Abdominal pain | 6 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Nausea | 6 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Thrombocytopenia | 6 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Eosinophil count increased | 5 AEs |
| Cohort 1 Tafenoquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Pyrexia | 5 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Eosinophil count increased | 3 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Blood methemoglobin present | 22 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Eosinophilia | 7 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Headache | 4 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Thrombocytopenia | 0 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Keratopathy | 0 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Abdominal pain | 5 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Upper respiratory tract infection | 5 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Pyrexia | 3 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Dizziness | 3 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Nausea | 3 AEs |
| Cohort 1-Chloroquine | Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | Retinopathy | 1 AEs |
Other Pre-specified
Fever Clearance Time (FCT)
Measure of body temperature every 12 hours through day 7 was used to determine the time (to nearest 12 hours) from initiation of treatment until subjects temperature decreased to 37.2C and remained at or below that level for a minimum of 24 hours.
Time frame: through day 7
Population: Intent to treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 Tafenoquine | Fever Clearance Time (FCT) | 41.5 Hours | Standard Deviation 30.61 |
| Cohort 1-Chloroquine | Fever Clearance Time (FCT) | 24.7 Hours | Standard Deviation 17.69 |