Falciparum Parasitaemia
Conditions
Keywords
Falciparum Parasitaemia, Malaria
Brief summary
This was a placebo controlled, randomised, double-blind, double-dummy study of the efficacy of weekly tafenoquine compared with weekly mefloquine or placebo in the chemosuppression of P. falciparum in Nyanza Province, western Kenya.
Detailed description
Subjects were treated for 3 days with halofantrine to clear any existing parasitaemia. At the end of the clearance period, subjects free from malaria parasitaemia were randomized and received a loading dose of the study treatment (tafenoquine 200 mg, Mefloquine 250 mg or placebo) for tree days, followed by study treatment (tafenoquine 200 mg, mefloquine 250 mg or placebo, respectively) once a week for 24 weeks. After the treatment period subjects attended weekly follow-up safety visits until week 28.
Interventions
DRUGTafenoquine
Tafenoquine 200 mg for three days followed by Tafenoquine 200 mg once a week for 24 weeks.
DRUGMefloquine
Mefloquine 250 mg for three days followed by Mefloquine 250 mg once a week for 24 weeks.
DRUGPlacebo
Placebo for three days followed by placebo once a week for 24 weeks
Sponsors
SmithKline Beecham
U.S. Army Medical Research and Development Command
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female volunteers who provided informed consent (a healthy volunteer was defined as one who was free of ailments that might cause difficulty in evaluating drug efficacy or adverse experiences). * Subjects aged 18-55 years. * Subjects planning to reside in the study area for the entire study duration of approximately 70 weeks
Exclusion criteria
* Subjects with positive parasitaemia following halofantrine treatment for radical cure. * Subjects with any medical condition which, in the opinion of the investigator, made the subject unsuitable to enter the study. * Subjects with personal or family history of seizures. * Female subjects with a positive serum beta-HCG5 (tested during screening and within 48 hours of first drug administration and approximately monthly thereafter). * Women who were pregnant or lactating or who in the opinion of the investigator were at risk of becoming pregnant. * Subjects with clinically significant abnormalities (to include but not limited to abnormal hepatic or renal function) as determined by history, physical and routine blood chemistries and haematology values. Subjects who had demonstrated hypersensitivity to any of the study drugs especially to any other 8-aminoquinolines. * Subjects unwilling to report for drug administration or blood drawing during the 70 week duration of the study. * Subjects with G6PD deficiency. * Subjects with laboratory guideline values for exclusion: haemoglobin \<10 gm/dL, platelets \<80,000/mm3, WBC \<3000ul3, creatinine or ALT more than twice the upper limit of normal for age. * Subjects with an abnormal ECG, particularly an extended QTc interval \> 0.42 seconds. * Subjects taking any other anti-malarial product, or who had taken an antimalarial drug other than halofantrine within the previous two weeks. * Subjects who had received an investigational drug (a new chemical entity not registered for use) within 30 days or 5 half-lives whichever was the longer. * Subjects with a history of psychiatric disorder.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prophylactic Outcome Defined by the Subject Having no Positive Smears | 24 Weeks | Prophylactic outcome (success/failure) at the end of the prophylactic treatment phase; outcome was based on absence/presence of asexual stage parasites of any Plasmodium species on a single blood smear. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Protective Efficacy Based on Two Consecutive Positive Smears | 24 Weeks | Kaplan-Meier survival curves were produced for time to parasitaemia for both first positive smear and two consecutive positive smears. Analysis was based on a calculation of protective efficacy (PE) of tefaenoquine, defined as (1-relative risk of developing parasitaemia tafenoquine: placebo) x100% and 95.5% confidence intervals were constructed for the relative risk using Koopman's method. |
| Time to a Single Positive Smear | 24 Weeks | Kaplan-Meier survival curves were produced for time to parasitaemia for both first positive smear and two consecutive positive smears. 95.5% confidence intervals were constructed for the relative risk. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety (SAEs and AEs) | 28 weeks | The most commonly reported experiences in subject occurring in at least 20% of subjects in any treatment group. |
Participant flow
Recruitment details
This study was conducted at Kombewa Clinic, Kenya. 517 subjects were screened for entry in to the study. 211 of those subjects were not randomized to treatment due either to abnormal lab results, G6PD deficiency, extended QTc interval, failure to clear parasitaemia or other reason.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo
Placebo: Placebo for three days followed by placebo once a week for 24 weeks | 99 |
| Tafenoquine Tafenoquine 200 mg for three days followed by Tafenoquine 200 once a week for 24 weeks.
Tafenoquine: Tafenoquine 200 mg for three days followed by Tafenoquine 200 mg once a week for 24 weeks. | 102 |
| Mefloquine Mefloquine 250 mg for three days followed by Mefloquine 250 once a week for 24 weeks.
Mefloquine: Mefloquine 250 mg for three days followed by Mefloquine 250 mg once a week for 24 weeks. | 99 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Protocol Violation | 2 | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo | Tafenoquine | Mefloquine | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 98 Participants | 100 Participants | 97 Participants | 295 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 99 Participants | 102 Participants | 99 Participants | 300 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Kenya | 99 participants | 102 participants | 99 participants | 300 participants |
| Sex: Female, Male Female | 36 Participants | 36 Participants | 33 Participants | 105 Participants |
| Sex: Female, Male Male | 63 Participants | 66 Participants | 66 Participants | 195 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 92 / 101 | 98 / 104 | 97 / 101 |
| serious Total, serious adverse events | 4 / 101 | 10 / 104 | 2 / 101 |
Outcome results
Primary
Prophylactic Outcome Defined by the Subject Having no Positive Smears
Prophylactic outcome (success/failure) at the end of the prophylactic treatment phase; outcome was based on absence/presence of asexual stage parasites of any Plasmodium species on a single blood smear.
Time frame: 24 Weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Success (total) | 6 participants |
| Placebo | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Success (assumed) | 6 participants |
| Placebo | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Success (known) | 0 participants |
| Placebo | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Failure | 93 participants |
| Tafenoquine | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Success (total) | 12 participants |
| Tafenoquine | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Failure | 90 participants |
| Tafenoquine | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Success (assumed) | 6 participants |
| Tafenoquine | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Success (known) | 6 participants |
| Mefloquine | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Failure | 92 participants |
| Mefloquine | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Success (assumed) | 7 participants |
| Mefloquine | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Success (known) | 0 participants |
| Mefloquine | Prophylactic Outcome Defined by the Subject Having no Positive Smears | Prophylactic Success (total) | 7 participants |
Secondary
Protective Efficacy Based on Two Consecutive Positive Smears
Kaplan-Meier survival curves were produced for time to parasitaemia for both first positive smear and two consecutive positive smears. Analysis was based on a calculation of protective efficacy (PE) of tefaenoquine, defined as (1-relative risk of developing parasitaemia tafenoquine: placebo) x100% and 95.5% confidence intervals were constructed for the relative risk using Koopman's method.
Time frame: 24 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Protective Efficacy Based on Two Consecutive Positive Smears | 0 Percentage of Protective Efficacy |
| Tafenoquine | Protective Efficacy Based on Two Consecutive Positive Smears | 77.9 Percentage of Protective Efficacy |
| Mefloquine | Protective Efficacy Based on Two Consecutive Positive Smears | 56.8 Percentage of Protective Efficacy |
Secondary
Time to a Single Positive Smear
Kaplan-Meier survival curves were produced for time to parasitaemia for both first positive smear and two consecutive positive smears. 95.5% confidence intervals were constructed for the relative risk.
Time frame: 24 Weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to a Single Positive Smear | First positive smear | 43 Days |
| Placebo | Time to a Single Positive Smear | Two consecutive positve smears | 63 Days |
| Tafenoquine | Time to a Single Positive Smear | First positive smear | 57 Days |
| Tafenoquine | Time to a Single Positive Smear | Two consecutive positve smears | 0 Days |
| Mefloquine | Time to a Single Positive Smear | First positive smear | 50 Days |
| Mefloquine | Time to a Single Positive Smear | Two consecutive positve smears | 165 Days |
Other Pre-specified
Safety (SAEs and AEs)
The most commonly reported experiences in subject occurring in at least 20% of subjects in any treatment group.
Time frame: 28 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Safety (SAEs and AEs) | Rhinitis | 21 participants |
| Placebo | Safety (SAEs and AEs) | At least one AE | 92 participants |
| Placebo | Safety (SAEs and AEs) | Back Pain | 12 participants |
| Placebo | Safety (SAEs and AEs) | Myalgia | 25 participants |
| Placebo | Safety (SAEs and AEs) | Headache | 37 participants |
| Placebo | Safety (SAEs and AEs) | Coughing | 13 participants |
| Placebo | Safety (SAEs and AEs) | Abdominal Pain | 24 participants |
| Placebo | Safety (SAEs and AEs) | Upper Respiratory Tract Infection | 17 participants |
| Tafenoquine | Safety (SAEs and AEs) | Coughing | 24 participants |
| Tafenoquine | Safety (SAEs and AEs) | Abdominal Pain | 25 participants |
| Tafenoquine | Safety (SAEs and AEs) | Back Pain | 28 participants |
| Tafenoquine | Safety (SAEs and AEs) | Myalgia | 27 participants |
| Tafenoquine | Safety (SAEs and AEs) | Rhinitis | 12 participants |
| Tafenoquine | Safety (SAEs and AEs) | Upper Respiratory Tract Infection | 30 participants |
| Tafenoquine | Safety (SAEs and AEs) | At least one AE | 98 participants |
| Tafenoquine | Safety (SAEs and AEs) | Headache | 45 participants |
| Mefloquine | Safety (SAEs and AEs) | Rhinitis | 20 participants |
| Mefloquine | Safety (SAEs and AEs) | Myalgia | 29 participants |
| Mefloquine | Safety (SAEs and AEs) | Abdominal Pain | 19 participants |
| Mefloquine | Safety (SAEs and AEs) | At least one AE | 97 participants |
| Mefloquine | Safety (SAEs and AEs) | Headache | 49 participants |
| Mefloquine | Safety (SAEs and AEs) | Upper Respiratory Tract Infection | 26 participants |
| Mefloquine | Safety (SAEs and AEs) | Coughing | 29 participants |
| Mefloquine | Safety (SAEs and AEs) | Back Pain | 10 participants |