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NEJM: Tafenoquine
1. 1
Journal Club - Article Presentation
Prepared by:
Dr. Bhargav Darji
1st Year Resident
Dept. of Pharmacology,
GMC, Surat.
Author: Marcus V. G. Lacerda, M.D. et al.
Single-Dose Tafenoquine to Prevent
Relapse of Plasmodium vivax Malaria
19 January 2019
2. BACKGROUND
■ Plasmodium vivax is a major cause of malaria in the Americas, the Horn of Africa,
and Asia.
■ The treatment and control of Plasmodium vivax are complicated by a latent,
undetectable form in the liver, known as the Hypnozoite.
219 January 2019
3. The WHO recommends:
Chloroquine or Artemisinin-based combination
therapy to clear asexual parasites
plus
Primaquine for 14 days to kill hypnozoites and
prevent relapse, a treatment termed “radical
cure”.
Nonadherence to the Primaquine regimen
jeopardizes the effectiveness of the treatment.
319 January 2019
4. TAFENOQUINE
■ Tafenoquine is a Single-Dose 8-Aminoquinoline
that has recently been approved by USFDA on July
20, 2018 for the radical cure of P. vivax.
■ Both Primaquine and Tafenoquine cause
hemolysis in persons with G6PD deficiency.
■ Hence, G6PD testing is recommended before
treatment with these agents.
419 January 2019
6. Inclusion Criteria:
■ Participants having 16 years of Age or Older.
(≥18 years of Age if in Ethiopia).
■ Microscopically confirmed P. vivax Infection.
(>100 to <100,000 Asexual Parasites per microliter).
■ Corrected QT Interval (QTcF) of <450 msec.
(According to Fridericia’s formula)
■ Female Participants having
1. Negative Pregnancy Tests
2. Not Lactating
3. Using Approved Contraception
619 January 2019
7. Exclusion Criteria:
■ Patients with G6PD deficiency or G6PD activity of <70% of the median
■ Mixed Plasmodium Species, Severe Malaria or Severe Vomiting
■ Hemoglobin level of <7 gm/dl
■ SGPT level >2 times the upper limit of the normal range
■ Clinically significant concurrent illness
■ Use of an antimalarial drug within the previous 30 days
■ Use of an investigational drug within the previous 30 days or within five half-lives
(whichever was longer)
■ Use of concomitant drugs that could affect trial results
■ Previous participation in or treatment within the trial
■ History of Allergies or Contraindications to Tafenoquine, Primaquine, or Chloroquine.
■ History of Ocular disease or Corneal or Retinal abnormalities
719 January 2019
8. Randomization:
■ All 522 patients on Day 1, were randomly assigned in a 2:1:1 ratio.
819 January 2019
10. Outcomes:
■ Primary Efficacy Outcome:
Percentage of patients who were free from recurrence at 6 months.
■ Secondary Efficacy Outcomes:
Freedom from recurrence at 4 months,
Time to recurrence,
Time to parasite clearance (aparasitemia maintained for 6 to 12 hours),
Time to fever clearance (apyrexia maintained for 48 hours).
■ Safety Outcomes:
Nature and Frequency of Adverse Events,
Hematologic and Clinical Chemistry Values Outside the Normal Range,
Abnormal ECG.
1019 January 2019
11. RESULTS
Out of 522 enrolled, 502 (96.2%) patients completed the trial & 406 (77.8%) patients were
included in the per protocol population.
In the Intention-to-treat population having recurrence of P. vivax parasitemia at 6 months:
32.7% in the Tafenoquine group (85 of 260 patients)
66.2% in the Placebo group (88 of 133 patients)
27.9% in the Primaquine group (36 of 129 patients)
In the Intention-to-treat population, the Kaplan-Meier estimates of the percentage of patients
who were free from recurrence at 6 months:
62.4% in the Tafenoquine group (95% CI, 54.9 to 69.0)
27.7% in the Placebo group (95% CI, 19.6 to 36.6)
69.6% in the Primaquine group (95% CI, 60.2 to 77.1)
The Hazard Ratio for the risk of recurrence was:
0.30 (95% CI, 0.22 to 0.40) with Tafenoquine as compared with placebo (P<0.001)
0.26 (95% CI, 0.18 to 0.39) with Primaquine as compared with placebo (P<0.001)
1119 January 2019
13. Safety:
■ There was no evidence that Tafenoquine exacerbated
the known Adverse Effects of Chloroquine.
■ Dizziness and decreased Hemoglobin level were more
common.
■ Hemoglobin declines of more than 3 gm/dl or at least
30% of the baseline level were noted
■ Tafenoquine was associated with asymptomatic
declines in hemoglobin levels, which resolved without
intervention.
1319 January 2019
14. DISCUSSION
■ In Phase 3, percentage of patients in Tafenoquine group who were free from
recurrence at 6 months (62.4%) was lower than in Phase 2b (89.2%).
■ The larger difference between percentage of patients who were free from recurrence
at 4 months & at 6 months in Phase 3 compared to Phase 2b.
■ No effect on the Efficacy of Tafenoquine in preventing recurrence was seen in patients
with intermediate CYP2D6 metabolic activity.
■ The reductions in Hemoglobin level in the Tafenoquine group (though mild) were
greater than those in the Placebo group.
1419 January 2019
15. ■ The 2 Female patients who were heterozygous for the G6PD Viangchan variant
were treated with 8-Aminoquinolines and neither one had adverse hematologic
events.
■ The Qualitative Test evaluated here Failed to identify 16 patients most at risk for
Hemolysis.
■ A Major Limitation of the trial was that P. vivax genotyping cannot differentiate
among recrudescence, relapse, and reinfection; all may appear homologous or
heterologous to the initial infection.
1519 January 2019
16. CONCLUSION
■ Single-Dose Tafenoquine resulted in a significantly lower risk of P. vivax recurrence than
placebo in patients with phenotypically normal G6PD activity.
1619 January 2019
1. Approximately 2.5 billion people worldwide are at risk for Plasmodium vivax malaria.
2. Hypnozoites can cause multiple clinical relapses, which can increase the disease burden and the potential for onward transmission and impede efforts to eliminate malaria.
3. Reported nonadherence rates (13.6 to 33.3%) probably underestimate the real-world situation.
1. The first 8-aminoquinoline, pamaquine (also known as plasmoquine or plasmochin), was synthesized in 1924.
Pamaquine had useful asexual stage activity against P. vivax and, when given in sufficient doses, prevented relapse, but these doses had substantial side effects.
The high rates of P. vivax relapse among soldiers fighting in the Asian theaters of the Second World War prompted intense research that yielded two slightly better 8-aminoquinolines — pentaquine and isopentaquine.
Then came primaquine in 1946, which had fewer side effects and was more effective.
Primaquine was rushed into service during the Korean war, and the adult-dose regimen that was recommended then (15 mg base per day for 14 days) has since remained unchanged for nearly 70 years.
2. G6PD deficiency is an X-linked enzymopathy, with an estimated mean prevalence of 8% across areas in which malaria is endemic.
3. NADPH Fluorescent "Spot Test": Results are not reliable in case of Female Heterozygotes because of High False Negative results.
X. Another Phase 3 trial (the Global Assessment of Tafenoquine Hemolytic Risk [GATHER]) compared the efficacy of tafenoquine with that of primaquine in preventing recurrence of P. vivax.
Study Design: A Phase 3 Multicentric, double-blind, double-dummy, parallel group, randomized, placebo controlled trial.
It was conducted in 6 countries: Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines.
Fridericia’s Formula: Fridericia had proposed an alternative correction formula using the cube-root of RR. Others: Bazzetts, Sagies.
1. Each trial site established a median value for normal G6PD activity among 36 healthy male volunteers who otherwise were not involved in the trial.
Patients with G6PD activity that was less than 70% of this median, as determined on the basis of a quantitative spectrophotometric phenotype assay were considered to have G6PD deficiency and were excluded.
Unbalanced Randomization: Should be considered in trial design especially where there are large differences between treatment costs, also for ethical reasons.
All patients received a 3-day course of Chloroquine (Total Dose of 1500 mg).
Tafenoquine Group: Received single 300mg dose of Tafenoquine on day 1 or 2 (260 patients)
Placebo Group: Received Placebo (133 patients)
Primaquine Group: Received a 15mg dose of Primaquine once daily for 14 days (129 patients).
1. Termed “recurrence-free efficacy”.
Freedom from recurrence was defined as microscopically confirmed clearance of the initial P. vivax infection without recurrent P. vivax parasitemia and without the receipt of other antimalarial treatment during follow-up plus a negative blood smear at the 6-month assessment.
Intention-to-treat (ITT) analysis of the results of an experiment is based on the initial treatment assignment and not on the treatment eventually received.
Per protocol population is usually defined as all patients completing the study without major protocol deviations - i.e., those who followed the rules of the study.
Kaplan–Meier estimator, also known as the product limit estimator, is a non-parametric statistic used to estimate the survival function from lifetime data.
Hazard ratio (HR) is the ratio of the hazard rates corresponding to the conditions described by two levels of an explanatory variable.
Non-inferiority trial aims to demonstrate that the test product is not worse than the comparator by more than a small pre-specified amount. (i.e. non-inferiority margin, or delta)
1. This could have resulted from variations in drug efficacy among trial populations, the use of different trial sites or geotemporal differences in transmission.
2. Suggests that reinfection rates were higher in phase 3 than in the previous phase.
3. A finding that is consistent with a previous analysis; however, more data on persons with poor CYP2D6 metabolic activity are required.
In contrast, the CYP2D6 enzyme is necessary to convert primaquine to active metabolites and evidence is emerging that CYP2D6 metabolism can modify primaquine efficacy.
4. Though decline in hemoglobin of more than 3 gm/dl or at least 30% of baseline levels were uncommon but occurred more in Tafenoquine group; none of them required clinical intervention.
1. Needs more data prior to reaching any conclusion.
2. If tafenoquine use is expanded, adoption of reliable quantitative point of care G6PD tests will be needed; such tests are not currently available but are in development.
3. As this trial was conducted in regions where tropical type P. vivax strains prevail (with relapses occurring 17 to 45 days after the initial infection), it is possible that not all relapses were observed.
