A Phase 2 interventional study of Chloroquine 600mg and Chloroquine 300mg in Malaria, Vivax, sponsored by GlaxoSmithKline. Completed at 14 sites in 8 countries. Open to participants aged 16 Years and older. Per ClinicalTrials.gov, last updated 2018-04-23.
Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Treatment
The purpose of this two part study is to test the safety and efficacy of Tafenoquine (with Cholorquine) as a radical cure for Plasmodium vivax (P.vivax) malaria relative to the control Chloroquine.Part 1 aims to select an efficacious and well tolerated dose that can be co-administered with Chloroquine. Part 2 will investigate the safety and efficacy of the selected dose (300 mg tafenoquine) in the treatment and radical cure of Plasmodium Vivax Malaria.
Plasmodium vivax represents 50-80% of all malarial cases in Latin America and South East Asia. It is able to establish a dormant liver stage called the hypnozoite. Hypnozoite activation after initial infection can cause a relapse. Currently the only widely available drug is primaquine which requires administration over 14 days, resulting in poor compliance and treatment failure. Tafenoquine (an 8-aminoquinoline anti-malarial drug) has been shown to possess activity against all stages of the plasmodium life cycle, including the dormant stage in the liver. This is a multi-centre, double dummy, double blind, parallel group, randomized, active control study which is conducted in two parts. For both parts, subjects are treated with Chloroquine on days 1 to 3 (600mg, 600mg, and 300mg) to treat the blood stage vivax malaria. Part 1 will include at least 324 subjects and part 2 at least 600 subjects. Part 1 has 6 treatment arms, arms 1 to 4 contain different doses of Tafenoquine (50mg, 100mg, 300mg, and 600mg) dosed on day 1 or 2, arm 5 contains primaquine (15mg) dosing over 14 days (days 2-15 (15mg)) and arm 6 contains chloroquine only. The aim of this is to find a dose of Tafenoquine which meets the defined dose criteria. Based on Part 1 efficacy and safety, a single Tafenoquine dose (300 mg) will be studied in the pivotal Part 2. Part 2 contains 3 treatment arms one with the selected Tafenoquine dose (300 mg), the second arm will be 15mg Primaquine which will again be dosed over 14 days and the final arm contains chloroquine only dosed days 1-3 (600mg, 600mg, 300mg). Therefore as with Part 1, in Part 2 all subjects will receive Chloroquine. The aim of Part 2 is to investigate the safety and efficacy of the selected Tafenoquine/Chloroquine dose in the treatment and radical cure of Plasmodium vivax malaria. In addition to the Primary and Secondary endpoints stated below we will also be collecting; other efficacy endpoints (gametocyte clearance time, Recrudescence defined as any Plasmodium vivax parasitemia occurring on or before Day 29 (blood stage treatment failure), Incidence of Plasmodium falciparum malaria and Incidence of recrudescence and new Plasmodium vivax infection, determined by Polymerase Chain Reaction (PCR), safety endpoints (clinically relevant haemolysis leading to drops in haemoglobin / haematocrit or complications thereof (required transfusions, acute renal failure), changes in methaemoglobin, gastrointestinal (GI) tolerability - incidence of abdominal pain, heartburn, diarrhoea, constipation, nausea and vomiting and ophthalmic safety - incidence of corneal deposits, retinal and visual field abnormalities. Data collected at up to four centres . Additionally, the incidence and severity of adverse events and abnormal laboratory observations will be presented).Pharmacokinetic endpoints (Population pharmacokinetic parameters for tafenoquine including but not limited to oral clearance (CL/F) and volume of distribution (V/F)and Pharmacokinetic/Pharmacodynamic endpoints (e.g. tafenoquine plasma concentrations) and selected Pharmacodynamic endpoints (e.g. relapse efficacy, change in methaemoglobin) if appropriate, will be explored.
1,299 studies on the registry are indexed under Malaria; 86 are open to participants now.
This study's enrollment of 851 is above the median of 220 across 1,027 interventional studies indexed under Malaria.
Browse Malaria studies →GlaxoSmithKline is the lead sponsor of 3,562 studies on the registry; 117 are open to participants now.
Of its 258 completed or terminated interventional studies of FDA-regulated products, 232 (90%) have results posted.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria: - Positive Giemsa smear for P. vivax
NB Assent is obtained from subjects \<18 years, where applicable and written or oral witnessed consent has been obtained from parent or guardian.
Part 1 - Males: Any subject with an enzyme level \<70% of the site median value for Glucose 6-phosphate dehydrogenase normals will be excluded. Females: Those females with a screening Hb ≥ 10 g/dL will only be excluded if their enzyme level is \<70% of the site median value for Glucose 6-Phosphate dehydrogenase normals. hose females with Hb ≥7 but \< 10 g/dL will be excluded if an enzyme level is not > 90% of the site median value for Glucose 6-Phosphate dehydrogenase normals.
Part 2 - Any subject with enzyme level \<70% of the site median value for Glucose 6-phosphate dehydrogenase normals will be excluded
On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 50mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.
Drug: Chloroquine 600mg · Drug: Chloroquine 300mg · Drug: Tafenoquine 50mg
On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 100mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.
Drug: Chloroquine 600mg · Drug: Chloroquine 300mg · Drug: Tafenoquine 100mg
On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 300mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.
Drug: Chloroquine 600mg · Drug: Chloroquine 300mg · Drug: Tafenoquine 300mg
On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 600mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.
Drug: Chloroquine 600mg · Drug: Chloroquine 300mg · Drug: Tafenoquine 600mg
On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 15mg Primaquine once daily Days 2-15.
Drug: Chloroquine 600mg · Drug: Chloroquine 300mg · Drug: Primaquine 15mg
On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered.
Drug: Chloroquine 600mg · Drug: Chloroquine 300mg
On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 300mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.
Drug: Chloroquine 600mg (Part 2 ) · Drug: Chloroquine 300mg (Part 2 ) · Drug: Tafenoquine 300mg (Part 2)
On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 15mg Primaquine once daily Days 2-15
Drug: Chloroquine 600mg (Part 2 ) · Drug: Chloroquine 300mg (Part 2 ) · Drug: Primaquine 15mg (Part2 )
On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered
Drug: Chloroquine 600mg (Part 2 ) · Drug: Chloroquine 300mg (Part 2 )
600mg Chloroquine given to each subject on Day 1 and Day2 of the trial
300mg Chloroquine given to each subject on Day 3 of the trial
single dose 50mg Tafenoquine given to subject on treatment arm 1 on Days 1 or 2
single dose 100mg Tafenoquine given to subject on treatment arm 2 on Days 1 or 2
single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2
single dose 600mg Tafenoquine given to subject on treatment arm 4 on Days 1 or 2
15mg Primaquine given once daily to subject on treatment arm 5 on Days 2 to 15.
600mg Chloroquine given to each subject on Day 1 and Day2 of the trial.
300mg Chloroquine given to each subject on Day 3 of the trial.
single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2.
15mg Primaquine given once daily to subject on treatment arm 3 on Days 2 to 15.
Number of Participants With Recurrence-free Efficacy at 6 Months Post Dose
A participant was considered to have demonstrated recurrence-free efficacy at 6 months if: a) Participant had non-zero P vivax asexual parasite count at Baseline. b) Participant showed initial clearance of P vivax parasitemia defined as two negative asexual P vivax parasite counts, with at least 6 hours between the counts, and no positive counts in the interval. c) Participant had no positive asexual P vivax parasite count at any assessment prior to or on Study Day 201 following initial parasite clearance. d) Participant did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment. e) Participant is parasite-free at 6 months. Participants were censored if they did not have P.vivax at Baseline, or took a drug with anti-malarial action despite not having malaria parasites, or did not have a 6 month assessment. The number of participants with recurrence-free efficacy at 6 months has been summarized.
Time frame: 6 months post dose
Number of Participants With Recurrence-free Efficacy at 4 Months Post Dose
A participant (par) was considered to have demonstrated recurrence-free efficacy at 4 months if: a) Par had non-zero P vivax asexual parasite count at Baseline. b) Par showed initial clearance of P vivax parasitemia. c) Par had no positive asexual P vivax parasite count at any assessment prior to or on Study Day 130 following initial parasite clearance. d) Par did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment after Study Day 109 (up to and including Study Day 130). e) Par is parasite-free at 4 months defined as a negative asexual P vivax parasite count at the first parasite assessment performed after Study Day 109 (up to and including Study Day 130). Par were censored if they did not have P.vivax at Baseline, or took a drug with anti-malarial action despite not having malaria parasites or did not have a 4 month assessment. The number of par with recurrence-free efficacy at 4 months has been summarized.
Time frame: 4 months post dose
Time to Recurrence of P Vivax Malaria
Recurrence was defined as the first confirmed presence of P vivax asexual stage parasites after clearance of initial parasitemia following CQ treatment. Time to recurrence was defined as the time (in days) from initial parasite clearance to recurrence. The time to recurrence was analyzed by the Kaplan-Meier method. NA indicates data was not available due to insufficient number of participants with events during the follow up period in the study. The median number of days to recurrence along with 95% confidence interval has been presented for each treatment group.
Time frame: Up to Day 180
Time to Parasite Clearance
Parasite clearance time was defined as time needed to clear asexual parasite from the blood that is, parasite numbers falling below the limit of detection in the thick blood smear and remaining undetectable after 6 to 12 hours. The time taken to achieve parasite clearance was analyzed using Kaplan Meier Methodology. The median parasite clearance time along with 95% confidence interval has been presented for each treatment group.
Time frame: Up to Day 180
Time to Fever Clearance
Fever clearance time was defined as time from first dose of treatment to the time when body temperature falls to normal within Study Days 1-4 and remains normal for at least 48 hours up to the Day 8 visit. Fever clearance was considered to have been achieved once an initial temperature of more than 37.40 degree Celsius is reduced to a value less than or equal to 37.40 degree Celsius and in the absence of value more than 37.40 degree Celsius in the following 48 hours up to the Day 8 visit. The time taken to achieve fever clearance was analyzed using Kaplan Meier Methodology. The median fever clearance time along with 95% confidence interval has been presented for each treatment group.
Time frame: Up to Day 180
Number of Participants With Hemoglobin Decline From Baseline Over First 29 Days
Glucose-6-phosphate dehydrogenase deficiency (G6PD) deficiency is known to be a risk factor for hemolysis in participants treated with 8-aminoquinolines. Blood samples were collected for the evaluation of hemoglobin levels. Hemoglobin decreases of \>=30% or \>3 grams/deciliter (g/dL) from Baseline; or, an overall drop in hemoglobin below 6.0 g/dL in the first 15 days of the study were considered as protocol defined serious adverse events (SAEs). Number of participants with maximum hemoglobin decline from Baseline over first 29 days of study has been summarized. Safety Population consisted of all randomized participants who received at least one dose of study medication.
Time frame: Baseline and up to Day 29
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Potentially Related to Hemoglobin Decrease
TEAEs are defined as adverse events (AEs) with an onset date and time on or after that of the start of first dose of study medication (including CQ). The number of participants with TEAEs potentially related to hemoglobin decrease has been presented.
Time frame: Up to Day 180
Number of Participants Who Received Blood Transfusion
The number of participants who received blood transfusion as a result of hemoglobin decline has been summarized.
Time frame: Up to Day 180
Number of Participants With Acute Renal Failure
There were no participants with acute renal failure in the study.
Time frame: Up to Day 180
Change From Baseline in Percent Methemoglobin
Methemoglobin assessment was made with the aid of a non-invasive signal extraction pulse CO-Oximeter handheld machine (Masimo). The change from Baseline in percent methemoglobin by treatment, time and sex has been summarized. The last assessment performed prior to the first dose of study medication (CQ or randomized treatment) was considered as Baseline. Change from Baseline was calculated as the post baseline assessment minus the Baseline assessment for percent methemoglobin. Only those participants with data available at the specified data points were analyzed.
Time frame: Baseline and up to Day 120
Number of Participants With Gastrointestinal Disorders
Gastrointestinal tolerability was analyzed by the number of par experiencing gastrointestinal disorders such as abdominal pain, heartburn, diarrhea, constipation, nausea, and vomiting. The number of participants with gastrointestinal disorders for each treatment group has been summarized.
Time frame: Up to Day 180
Number of Participants With Keratopathy
Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. The number of participants displaying keratopathy in each eye was summarized for each visit. The number of participants with new keratopathy at any time post Baseline was also reported. Ophthalmic Safety Population comprised of all participants in the Safety Population who have results from any eye assessments. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to Day 180
Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores
Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. Best corrected visual acuity was assessed individually for each eye. Scores were recorded as a ratio. The values were used to derive a logMAR score for statistical analysis where logMAR=-1x log10 (ratio score). The mean and standard deviation of logMAR score for each treatment group has been summarized. High scores were associated with worse vision, and low scores with better vision. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to Day 180
Number of Participants With Retinal Changes From Baseline
Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment. The number of participants with definite retinal change and questionable (ques) retinal change from Baseline was presented. Only those participants with data available at the specified data points were analyzed.
Time frame: Baseline and up to Day 180
Number of Participants With TEAEs and Serious TEAEs
An AE is defined as any untoward medical occurrence in a participant under clinical investigation, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/ birth defect, other situations and is associated with possible drug induced liver injury with hyperbilirubinemia. TEAEs is defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with TEAEs and serious TEAEs have been presented.
Time frame: Up to Day 180
Number of Participants With TEAEs by Maximum Intensity
An AE is defined as any untoward medical occurrence in a participant under clinical investigation, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE is defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with AEs based on severity has been presented.
Time frame: Up to Day 180
Number of Participants With Hematology Laboratory Data Outside the Reference Range
Blood samples were collected for the evaluation of hematology parameters including eosinophils, leukocytes, lymphocytes, neutrophils, platelets, reticulocytes and methemoglobin. The number of participants with hematology laboratory data outside the extended normal range (F3) was presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to Day 120
Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range
Blood samples were collected for the evaluation of clinical chemistry parameters including Alanine Aminotransferase (ALT), Alkaline Phosphatase (Alk. Phos), Aspartate Aminotransferase (AST), bilirubin, creatine kinase, creatinine, glomerular filtration rate (GFR), indirect bilirubin and urea. The number of participants with clinical chemistry laboratory data outside the extended normal range (F3) was presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to Day 120
Cost Associated With Recurrence Episode of P Vivax Malaria
Health outcomes were evaluated based on the total costs spent on treatment, transport, medication and tests. The cost was summarized according to the place at which the participant went to for care (drug shop, trial clinic, other clinic, hospital (inpatient/outpatient), traditional healer, other). The reported costs by type and by site has been summarized. Where costs have not been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to Day 180
Cost Incurred With Purchase of Medications Associated With Recurrence Episode of Malaria
Health outcomes were evaluated based on the cost of medications purchased. The reported total medication cost for paracetamol associated with recurrence episode of P vivax malaria has been reported by site. Where costs have not been reported at a visit, the number of participants analyzed is given as 0. Medications recorded as "Other" and medications without costs are excluded from the analysis. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to Day 180
Time Lost by Participants or Care Givers From Normal Occupation
Health outcomes were evaluated based on total time lost by participants or care givers due to an episode of malaria. The reported time lost due to recurrence episode of P vivax malaria has been summarized by category and by site. Where categories by site have not been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to Day 180
Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria
Health outcomes were evaluated based on the actions taken by the participants to treat recurrence episode of P vivax malaria. The reported action taken by site is summarized. Where no action by site have been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.
Time frame: Up to Day 180
Oral Clearance (CL/F) of TQ
Apparent population oral clearance of TQ
Time frame: Day 2, Day 8, Day 15, Day 29 and Day 60
Volume of Distribution (Vc/F) of TQ
Apparent population central volume of distribution of TQ
Time frame: Day 2, Day 8, Day 15, Day 29 and Day 60
This was a multi-centre, double-blind, randomized, parallel-group, active-controlled study to evaluate the efficacy, safety and tolerability of tafenoquine (TQ) in participants with Plasmodium vivax (P vivax) malaria. TAF112582 consisted of two parts-Part 1 (Phase 2 dose ranging) and Part 2 (Phase 3 pivotal). Results have been presented for Part 2.
| Milestone | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Started | 133 | 260 | 129 |
| Completed | 129 | 250 | 123 |
| Not completed | 4 | 10 | 6 |
| Withdrew: Lost to follow-up | 2 | 4 | 2 |
| Withdrew: Physician decision | 1 | 1 | 0 |
| Withdrew: Withdrawal by subject | 1 | 5 | 4 |
A participant was considered to have demonstrated recurrence-free efficacy at 6 months if: a) Participant had non-zero P vivax asexual parasite count at Baseline. b) Participant showed initial clearance of P vivax parasitemia defined as two negative asexual P vivax parasite counts, with at least 6 hours between the counts, and no positive counts in the interval. c) Participant had no positive asexual P vivax parasite count at any assessment prior to or on Study Day 201 following initial parasite clearance. d) Participant did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment. e) Participant is parasite-free at 6 months. Participants were censored if they did not have P.vivax at Baseline, or took a drug with anti-malarial action despite not having malaria parasites, or did not have a 6 month assessment. The number of participants with recurrence-free efficacy at 6 months has been summarized.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Number of Participants With Recurrence-free Efficacy at 6 Months Post Dose | 35 | 155 | 83 |
A participant (par) was considered to have demonstrated recurrence-free efficacy at 4 months if: a) Par had non-zero P vivax asexual parasite count at Baseline. b) Par showed initial clearance of P vivax parasitemia. c) Par had no positive asexual P vivax parasite count at any assessment prior to or on Study Day 130 following initial parasite clearance. d) Par did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment after Study Day 109 (up to and including Study Day 130). e) Par is parasite-free at 4 months defined as a negative asexual P vivax parasite count at the first parasite assessment performed after Study Day 109 (up to and including Study Day 130). Par were censored if they did not have P.vivax at Baseline, or took a drug with anti-malarial action despite not having malaria parasites or did not have a 4 month assessment. The number of par with recurrence-free efficacy at 4 months has been summarized.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Number of Participants With Recurrence-free Efficacy at 4 Months Post Dose | 47 | 177 | 90 |
Recurrence was defined as the first confirmed presence of P vivax asexual stage parasites after clearance of initial parasitemia following CQ treatment. Time to recurrence was defined as the time (in days) from initial parasite clearance to recurrence. The time to recurrence was analyzed by the Kaplan-Meier method. NA indicates data was not available due to insufficient number of participants with events during the follow up period in the study. The median number of days to recurrence along with 95% confidence interval has been presented for each treatment group.
| Days | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Time to Recurrence of P Vivax Malaria | 86 (63 to 109) | NA (NA to NA) | NA (NA to NA) |
Parasite clearance time was defined as time needed to clear asexual parasite from the blood that is, parasite numbers falling below the limit of detection in the thick blood smear and remaining undetectable after 6 to 12 hours. The time taken to achieve parasite clearance was analyzed using Kaplan Meier Methodology. The median parasite clearance time along with 95% confidence interval has been presented for each treatment group.
| Hours | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Time to Parasite Clearance | 43 (41 to 48) | 45 (42 to 47) | 42 (39 to 45) |
Fever clearance time was defined as time from first dose of treatment to the time when body temperature falls to normal within Study Days 1-4 and remains normal for at least 48 hours up to the Day 8 visit. Fever clearance was considered to have been achieved once an initial temperature of more than 37.40 degree Celsius is reduced to a value less than or equal to 37.40 degree Celsius and in the absence of value more than 37.40 degree Celsius in the following 48 hours up to the Day 8 visit. The time taken to achieve fever clearance was analyzed using Kaplan Meier Methodology. The median fever clearance time along with 95% confidence interval has been presented for each treatment group.
| Hours | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Time to Fever Clearance | 7 (5 to 14) | 7 (5 to 12) | 8 (6 to 18) |
Glucose-6-phosphate dehydrogenase deficiency (G6PD) deficiency is known to be a risk factor for hemolysis in participants treated with 8-aminoquinolines. Blood samples were collected for the evaluation of hemoglobin levels. Hemoglobin decreases of \>=30% or \>3 grams/deciliter (g/dL) from Baseline; or, an overall drop in hemoglobin below 6.0 g/dL in the first 15 days of the study were considered as protocol defined serious adverse events (SAEs). Number of participants with maximum hemoglobin decline from Baseline over first 29 days of study has been summarized. Safety Population consisted of all randomized participants who received at least one dose of study medication.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| <=20 grams/liter (g/L) | 120 | 214 | 114 |
| >20g/L to <=30 g/L | 11 | 31 | 12 |
| >30 g/L or >=30% | 2 | 14 | 3 |
TEAEs are defined as adverse events (AEs) with an onset date and time on or after that of the start of first dose of study medication (including CQ). The number of participants with TEAEs potentially related to hemoglobin decrease has been presented.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Haemoglobin decreased | 2 | 14 | 2 |
| Fatigue | 2 | 1 | 0 |
| Hyperbilirubinaemia | 1 | 0 | 0 |
| Pallor | 0 | 1 | 0 |
The number of participants who received blood transfusion as a result of hemoglobin decline has been summarized.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Number of Participants Who Received Blood Transfusion | 0 | 0 | 0 |
There were no participants with acute renal failure in the study.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Number of Participants With Acute Renal Failure | 0 | 0 | 0 |
Methemoglobin assessment was made with the aid of a non-invasive signal extraction pulse CO-Oximeter handheld machine (Masimo). The change from Baseline in percent methemoglobin by treatment, time and sex has been summarized. The last assessment performed prior to the first dose of study medication (CQ or randomized treatment) was considered as Baseline. Change from Baseline was calculated as the post baseline assessment minus the Baseline assessment for percent methemoglobin. Only those participants with data available at the specified data points were analyzed.
| Percent Methemoglobin | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Day 2, Male | -0.18 ± 1.525 | -0.03 ± 1.246 | -0.10 ± 1.372 |
| Day 2, Female | -0.22 ± 0.895 | 0.10 ± 0.830 | -0.01 ± 0.438 |
| Day 3, Male | -0.15 ± 1.256 | -0.01 ± 1.254 | -0.02 ± 1.454 |
| Day 3, Female | -0.20 ± 0.902 | 0.26 ± 0.781 | 0.11 ± 0.443 |
| Day 5, Male | -0.28 ± 1.329 | 0.42 ± 1.633 | 1.28 ± 2.619 |
| Day 5, Female | -0.20 ± 0.789 | 1.37 ± 1.263 | 0.90 ± 0.885 |
| Day 8, Male | -0.12 ± 1.135 | 0.98 ± 1.870 | 3.01 ± 3.214 |
| Day 8, Female | -0.16 ± 0.857 | 2.04 ± 1.716 | 2.58 ± 2.565 |
| Day 11, Male | -0.07 ± 1.348 | 1.17 ± 2.074 | 3.61 ± 3.498 |
| Day 11, Female | -0.13 ± 0.676 | 2.13 ± 1.667 | 3.41 ± 2.659 |
| Day 15, Male | 0.12 ± 1.404 | 0.94 ± 1.963 | 3.51 ± 3.369 |
| Day 15, Female | -0.08 ± 0.684 | 1.67 ± 1.349 | 3.63 ± 2.678 |
| Day 22, Male | 0.07 ± 1.211 | 0.54 ± 1.431 | 1.96 ± 2.401 |
| Day 22, Female | -0.05 ± 0.467 | 0.93 ± 1.042 | 1.86 ± 1.494 |
| Day 29, Male | -0.10 ± 1.428 | 0.23 ± 1.350 | 0.58 ± 1.835 |
| Day 29, Female | -0.18 ± 0.927 | 0.24 ± 0.717 | 0.49 ± 0.502 |
| Day 60, Male | 0.44 ± 1.925 | -0.10 ± 1.362 | 0.20 ± 1.940 |
| Day 60, Female | 0.19 ± 1.080 | 0.03 ± 0.700 | 0.16 ± 0.620 |
| Day 120, Male | 0.20 ± 1.783 | 0.07 ± 1.503 | 0.37 ± 2.153 |
| Day 120, Female | 0.10 ± 1.332 | -0.03 ± 0.906 | 0.37 ± 1.552 |
Gastrointestinal tolerability was analyzed by the number of par experiencing gastrointestinal disorders such as abdominal pain, heartburn, diarrhea, constipation, nausea, and vomiting. The number of participants with gastrointestinal disorders for each treatment group has been summarized.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Nausea | 12 | 21 | 9 |
| Vomiting | 9 | 22 | 11 |
| Abdominal pain upper | 13 | 11 | 7 |
| Diarrhoea | 6 | 15 | 5 |
| Abdominal pain | 5 | 8 | 6 |
| Dyspepsia | 5 | 6 | 2 |
Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. The number of participants displaying keratopathy in each eye was summarized for each visit. The number of participants with new keratopathy at any time post Baseline was also reported. Ophthalmic Safety Population comprised of all participants in the Safety Population who have results from any eye assessments. Only those participants with data available at the specified data points were analyzed.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Baseline; right eye | 0 | 0 | 0 |
| Baseline; left eye | 0 | 0 | 0 |
| Day 1; right eye | 0 | 0 | 0 |
| Day 1; left eye | 0 | 0 | 0 |
| Day 29; right eye | 0 | 0 | 0 |
| Day 29; left eye | 0 | 0 | 0 |
| Day 90; right eye | 0 | 1 | 0 |
| Day 90; left eye | 0 | 0 | 0 |
| Day 180; right eye | — | 0 | 0 |
| Day 180; left eye | — | 0 | 0 |
| Any time post Baseline; right eye | 0 | 1 | 0 |
| Any time post Baseline; left eye | 0 | 0 | 0 |
Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. Best corrected visual acuity was assessed individually for each eye. Scores were recorded as a ratio. The values were used to derive a logMAR score for statistical analysis where logMAR=-1x log10 (ratio score). The mean and standard deviation of logMAR score for each treatment group has been summarized. High scores were associated with worse vision, and low scores with better vision. Only those participants with data available at the specified data points were analyzed.
| logMAR scores | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Baseline; right eye | 0.041 ± 0.0825 | 0.046 ± 0.1045 | 0.029 ± 0.0461 |
| Baseline; left eye | 0.048 ± 0.0859 | 0.039 ± 0.0652 | 0.048 ± 0.1306 |
| Day 29; right eye | 0.039 ± 0.0906 | 0.049 ± 0.1159 | 0.021 ± 0.0412 |
| Day 29; left eye | 0.032 ± 0.0580 | 0.032 ± 0.0565 | 0.045 ± 0.1325 |
| Day 90; right eye | 0.044 ± 0.0928 | 0.038 ± 0.1083 | 0.016 ± 0.0374 |
| Day 90; left eye | 0.041 ± 0.0599 | 0.028 ± 0.0971 | 0.041 ± 0.1303 |
| Day 180; right eye | — | 0.033 ± 0.0577 | 0.000 ± NA |
| Day 180; left eye | — | 0.033 ± 0.0577 | 0.000 ± NA |
Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment. The number of participants with definite retinal change and questionable (ques) retinal change from Baseline was presented. Only those participants with data available at the specified data points were analyzed.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Day 29, Definite change, right eye | 1 | 0 | 0 |
| Day 29, Ques change, right eye | 0 | 0 | 0 |
| Day 29, Definite change, left eye | 1 | 0 | 0 |
| Day 29, Ques change, left eye | 0 | 0 | 0 |
| Day 90, Definite change, right eye | 1 | 1 | 1 |
| Day 90, Ques change, right eye | 0 | 0 | 1 |
| Day 90, Definite change, left eye | 1 | 1 | 0 |
| Day 90, Ques change, left eye | 0 | 1 | 2 |
| Day 180, Definite change, right eye | 0 | 0 | — |
| Day 180, Ques change, right eye | 0 | 0 | — |
| Day 180, Definite change, left eye | 0 | 0 | — |
| Day 180, Ques change, left eye | 0 | 0 | — |
An AE is defined as any untoward medical occurrence in a participant under clinical investigation, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/ birth defect, other situations and is associated with possible drug induced liver injury with hyperbilirubinemia. TEAEs is defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with TEAEs and serious TEAEs have been presented.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| TEAEs | 86 | 164 | 76 |
| Serious TEAEs | 6 | 21 | 4 |
An AE is defined as any untoward medical occurrence in a participant under clinical investigation, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE is defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with AEs based on severity has been presented.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Mild or Grade 1 | 30 | 70 | 38 |
| Moderate or Grade 2 | 52 | 89 | 37 |
| Severe or Grade 3 | 3 | 2 | 1 |
| Grade 4 | 1 | 0 | 0 |
| Grade 5 | 0 | 1 | 0 |
Blood samples were collected for the evaluation of hematology parameters including eosinophils, leukocytes, lymphocytes, neutrophils, platelets, reticulocytes and methemoglobin. The number of participants with hematology laboratory data outside the extended normal range (F3) was presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Only those participants with data available at the specified data points were analyzed.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Blood eosinophils, High | 18 | 38 | 28 |
| Blood leukocytes, Low | 0 | 3 | 2 |
| Blood lymphocytes, Low | 7 | 4 | 0 |
| Blood lymphocytes, High | 23 | 32 | 13 |
| Blood neutrophils, Low | 2 | 5 | 7 |
| Blood platelets, Low | 14 | 35 | 15 |
| Blood reticulocytes, High | 72 | 141 | 85 |
| Methemoglobin, High | 4 | 5 | 11 |
Blood samples were collected for the evaluation of clinical chemistry parameters including Alanine Aminotransferase (ALT), Alkaline Phosphatase (Alk. Phos), Aspartate Aminotransferase (AST), bilirubin, creatine kinase, creatinine, glomerular filtration rate (GFR), indirect bilirubin and urea. The number of participants with clinical chemistry laboratory data outside the extended normal range (F3) was presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Only those participants with data available at the specified data points were analyzed.
| Participants | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| ALT, High | 11 | 10 | 5 |
| Alk Phos, High | 3 | 1 | 1 |
| AST, High | 5 | 7 | 2 |
| Bilirubin, High | 18 | 23 | 12 |
| Creatine kinase, High | 8 | 5 | 8 |
| Creatinine, High | 0 | 1 | 0 |
| GFR, Low | 0 | 1 | 0 |
| Indirect bilirubin | 11 | 22 | 8 |
| Urea, High | 42 | 85 | 46 |
Health outcomes were evaluated based on the total costs spent on treatment, transport, medication and tests. The cost was summarized according to the place at which the participant went to for care (drug shop, trial clinic, other clinic, hospital (inpatient/outpatient), traditional healer, other). The reported costs by type and by site has been summarized. Where costs have not been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.
| US Dollars (USD) | First Malaria Recurrence | First Malaria Recurrence Follow-up |
|---|---|---|
| Brazil (Drug shop for care) | 4.76 ± 3.24 | — |
| Brazil (Enrollment clinic for care) | 6.17 ± 2.39 | 6.15 ± 2.14 |
| Brazil (other location for care) | 4.23 ± 0 | — |
| Peru (Drug shop for care) | 1.47 ± 1.30 | — |
| Peru (Enrollment clinic for care) | 8.78 ± 7.94 | 8.54 ± 8.52 |
| Peru (Attended another clinic) | 2.71 ± 4.69 | 3.94 ± 1.42 |
| Peru (Other location for care) | 0.72 ± 0.41 | 1.30 ± 0 |
| Thailand (Drug shop for care) | 4.60 ± 0 | — |
| Thailand (Enrollment clinic for care) | 19.15 ± 10.60 | — |
| Thailand (In-hospital care) | 6.13 ± 0 | — |
Health outcomes were evaluated based on the cost of medications purchased. The reported total medication cost for paracetamol associated with recurrence episode of P vivax malaria has been reported by site. Where costs have not been reported at a visit, the number of participants analyzed is given as 0. Medications recorded as "Other" and medications without costs are excluded from the analysis. Only those participants with data available at the specified data points were analyzed.
| USD | First Malaria Recurrence | First Malaria Recurrence Follow-up |
|---|---|---|
| Peru, n=23, 3 | 0.49 ± 0.1941 | 0.32 ± 1 |
| Brazil, n=6, 0 | 1.70 ± 0.144 | — |
Health outcomes were evaluated based on total time lost by participants or care givers due to an episode of malaria. The reported time lost due to recurrence episode of P vivax malaria has been summarized by category and by site. Where categories by site have not been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.
| Days | First Malaria Recurrence | First Malaria Recurrence Follow-up |
|---|---|---|
| Brazil, Housework | 1 | 0 |
| Brazil, Farming | 8 | 0 |
| Brazil, paid employment | 8 | 0 |
| Brazil, Other | 3 | 5 |
| Cambodia, Farming | 17 | 24 |
| Ethiopia, Housework | 4 | 3 |
| Ethiopia, Farming | 2.5 | 3 |
| Ethiopia, Student | 3 | 0 |
| Ethiopia, Paid employment | 2 | 4 |
| Ethiopia, Other | 1 | 7 |
| Peru, Housework | 24 | 29 |
| Peru, Farming | 19 | 28 |
| Peru, Student | 1 | 6 |
| Peru, Paid employment | 6 | 8.5 |
| Peru, Other | 26 | 32 |
| Philippines, Farming | 0 | — |
| Thailand, paid employment | 20 | 0 |
| Thailand, Other | 1 | 0 |
Health outcomes were evaluated based on the actions taken by the participants to treat recurrence episode of P vivax malaria. The reported action taken by site is summarized. Where no action by site have been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.
| Participants | First Malaria Recurrence | First Malaria Recurrence Follow-up |
|---|---|---|
| Brazil, Nothing | 21 | 5 |
| Brazil, Drug shop | 2 | 0 |
| Brazil, Trial clinic | 62 | 76 |
| Brazil, Other | 2 | 0 |
| Cambodia, Nothing | 13 | 14 |
| Ethiopia, Nothing | 12 | 13 |
| Ethiopia, Another clinic | 1 | 0 |
| Ethiopia, Other | 1 | 0 |
| Ethiopia, Trial clinic | 0 | 1 |
| Peru, Nothing | 1 | 0 |
| Peru, Drug shop | 8 | 0 |
| Peru, Trial clinic | 61 | 63 |
| Peru, Another clinic | 10 | 54 |
| Peru, Other | 15 | 1 |
| Philippines, Nothing | 1 | — |
| Thailand, Nothing | 1 | 16 |
| Thailand, Drug shop | 1 | 0 |
| Thailand, Trial clinic | 13 | 0 |
| Thailand, In hospital | 1 | 0 |
Apparent population oral clearance of TQ
| Liters per hour | Participants in TQ Only Arms |
|---|---|
| Oral Clearance (CL/F) of TQ | 2.96 (2.87 to 3.05) |
Apparent population central volume of distribution of TQ
| Liters | Participants in TQ Only Arms |
|---|---|
| Volume of Distribution (Vc/F) of TQ | 915 (879 to 956) |
Collected over On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the follow up contact (Up to Day 180). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| CQ Only | 0/133 (0%) | 6/133 (4.5%) | 72/133 (54.1%) |
| TQ + CQ | 0/260 (0%) | 21/260 (8.1%) | 119/260 (45.8%) |
| PQ + CQ | 0/129 (0%) | 4/129 (3.1%) | 56/129 (43.4%) |
| Event | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| Haemoglobin decreasedInvestigations | 2/133 | 14/260 | 2/129 |
| Electrocardiogram QT prolongedInvestigations | 3/133 | 0/260 | 0/129 |
| DiarrhoeaGastrointestinal disorders | 0/133 | 1/260 | 1/129 |
| NauseaGastrointestinal disorders | 0/133 | 0/260 | 1/129 |
| VomitingGastrointestinal disorders | 0/133 | 0/260 | 1/129 |
| DehydrationMetabolism and nutrition disorders | 0/133 | 0/260 | 1/129 |
| GastroenteritisInfections and infestations | 1/133 | 0/260 | 0/129 |
| Abscess limbInfections and infestations | 0/133 | 1/260 | 0/129 |
| Hepatitis EInfections and infestations | 0/133 | 1/260 | 0/129 |
| Urinary tract infectionInfections and infestations | 0/133 | 1/260 | 0/129 |
| Event | CQ Only | TQ + CQ | PQ + CQ |
|---|---|---|---|
| PruritusSkin and subcutaneous tissue disorders | 20/133 | 34/260 | 14/129 |
| HeadacheNervous system disorders | 19/133 | 27/260 | 10/129 |
| MyalgiaMusculoskeletal and connective tissue disorders | 19/133 | 15/260 | 10/129 |
| Abdominal pain upperGastrointestinal disorders | 13/133 | 11/260 | 7/129 |
| DizzinessNervous system disorders | 11/133 | 25/260 | 9/129 |
| NauseaGastrointestinal disorders | 12/133 | 21/260 | 8/129 |
| VomitingGastrointestinal disorders | 9/133 | 22/260 | 10/129 |
| NasopharyngitisInfections and infestations | 7/133 | 19/260 | 9/129 |
| PharyngitisInfections and infestations | 4/133 | 13/260 | 8/129 |
| Blood creatine phosphokinase increasedInvestigations | 8/133 | 10/260 | 7/129 |
| Age, Continuous(Years) | CQ Only | TQ + CQ | PQ + CQ | Total |
|---|---|---|---|---|
| Mean | 35.3 ± 14.23 | 35.0 ± 14.39 | 34.7 ± 14.26 | 35.0 ± 14.29 |
| Sex: Female, Male(Participants) | CQ Only | TQ + CQ | PQ + CQ | Total |
|---|---|---|---|---|
| Female | 36 | 64 | 30 | 130 |
| Male | 97 | 196 | 99 | 392 |
| Race/Ethnicity, Customized(Participants) | CQ Only | TQ + CQ | PQ + CQ | Total |
|---|---|---|---|---|
| American(Amer) Indian(Ind) or Alaska(Al) Native(N) | 43 | 81 | 41 | 165 |
| Asian-South East Asian (A) Heritage (Her) | 26 | 50 | 26 | 102 |
| Black or African (Afr) Amer | 14 | 28 | 13 | 55 |
| White-White/Caucasian(Cau)/European(Eur) Her | 3 | 4 | 2 | 9 |
| Multiple-Afr Amer/Afr Her/Amer Ind or Al N | 47 | 95 | 47 | 189 |
| Multiple-Afr Amer/Afr Her/White-White/Cau/Eur Her | 0 | 1 | 0 | 1 |
| Multiple-Amer Ind or Al N/A-Central/South A Her | 0 | 1 | 0 | 1 |
Plan to share: Yes — Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
This study is completed, as verified in Feb 2018. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
GlaxoSmithKline