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Table of Contents
RESEARCH ARTICLE
Year : 2020  |  Volume : 57  |  Issue : 3  |  Page : 213-220

Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate in comparison with chloroquine phosphate in children with acute uncomplicated Plasmodium vivax malaria: A phase III, randomised, multicentric study


1 National Institute of Malaria Research, New Delhi, India
2 Department of Pediatrics, Panchsheel Hospital, Delhi, India
3 Nirmal Hospital, Jhansi, Uttar Pradesh, India
4 Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, Odisha, India
5 MV Hospital and Research Center, Lucknow, Uttar Pradesh, India
6 Department of Pediatrics, Popular Hospital, Varanasi, Uttar Pradesh, India
7 Department of Pediatrics, Chandulal Chandrakar Memorial Medical College (CCMMC), Durg, Chhattisgarh, India
8 Department of Pediatrics, Vintage Hospital & Medical Research Centre, Goa, India
9 Department of Pediatrics, Sudbhawana Hospital, Varanasi, Uttar Pradesh, India
10 Department of Pediatrics, Kasturba Medical College and Wenlock District Govt. Hospital (KMC & WDGH), Mangalore, Karnataka, India
11 National Institute of Malaria Research Field Station, Bangalore, India
12 Department of Pediatrics, A J Institute of Medical Science & Research Centre (AJIMSRC), Mangalore, Karnataka, India
13 Department of Pediatrics, Marudhar Hospital, Jaipur, Rajasthan, India
14 Department of Pediatrics, Subharti Medical College and Hospital, Meerut, Uttar Pradesh, India
15 Medical Affairs & Clinical Research, Sun Pharmaceutical Industries Limited, Gurgaon, Haryana, India

Date of Submission12-Dec-2018
Date of Acceptance24-Dec-2019
Date of Web Publication26-Aug-2021

Correspondence Address:
Dr Anupkumar R Anvikar
National Institute of Malaria Research, Sector 8 Dwarka, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9062.311781

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  Abstract 

Background & objectives: In India, the burden of Plasmodium vivax malaria has been projected to be highest in some areas. This study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate (AM) 37.5 mg and piperaquine phosphate 187.5 mg (PQP) dispersible tablets and (not with) chloroquine in the treatment of uncomplicated vivax malaria in pediatric patients.
Methods: This multicentric, open-label trial was carried out at 12 sites in India. A total of 164 patients aged 6 months to 12 years with P. vivax malaria were randomized in a ratio of 2:1 to AM-PQP (111 patients) or chloroquine (53 patients) arms. The duration of follow up was 42 days.
Results: At 72 hours, the proportion of a parasitaemic and afebrile patients was 100% in both treatment arms in per protocol (PP) population, and 98.2% and 100% [95% CI: -1.8 (-6.33 to 5.08)] in AM-PQP and chloroquine arms, respectively, in intent to treat (ITT) population. The efficacy and safety of AM-PQP was found to be comparable to chloroquine in the treatment of uncomplicated P. vivax malaria in pediatric patients. Overall, the cure rate at Day 28 and 42 was >95% for both AM-PQP or CQ. The commonly reported clinical adverse event was vomiting. No patient was discontinued for any QTc abnormality.
Interpretation & conclusion: The efficacy and safety of FDC of arterolane maleate and piperaquine phosphate was found to be comparable to chloroquine for treatment of uncomplicated P. vivax malaria in pediatric patients.

Keywords: ACT, Arterolane maleate, Plasmodium vivax, PCT, Pediatric


How to cite this article:
Valecha N, Goyal VK, Mishra DN, Das RR, Jauhri N, Bhardwaj AC, Khurana O, Choudhury R, Pandey M, Baliga BS, Ghosh SK, Srivastava B, Soans ST, Bahl RK, Punj A, Roy A, Sharma SK, Nasa A, Jalali RK, Anvikar AR. Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate in comparison with chloroquine phosphate in children with acute uncomplicated Plasmodium vivax malaria: A phase III, randomised, multicentric study. J Vector Borne Dis 2020;57:213-20

How to cite this URL:
Valecha N, Goyal VK, Mishra DN, Das RR, Jauhri N, Bhardwaj AC, Khurana O, Choudhury R, Pandey M, Baliga BS, Ghosh SK, Srivastava B, Soans ST, Bahl RK, Punj A, Roy A, Sharma SK, Nasa A, Jalali RK, Anvikar AR. Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate in comparison with chloroquine phosphate in children with acute uncomplicated Plasmodium vivax malaria: A phase III, randomised, multicentric study. J Vector Borne Dis [serial online] 2020 [cited 2021 Oct 18];57:213-20. Available from: https://www.jvbd.org/text.asp?2020/57/3/213/311781


  Introduction Top


Plasmodium vivax malaria is an important public health concern. Globally, 219 million cases of malaria were confirmed in 2017. In India, the burden of P. vivax malaria has been projected to be highest in some areas[1],[2],[3],[4]. The pediatric population aged 1–14 years with P. vivax malaria constitutes to be approximately 30% in India. P. vivax is a menace in urban areas where malaria control is challenging due to the growing slums, relocation and construction[1],[3]. Apart from curing the malaria episode, the treatment of P. vivax malaria also needs to prevent recurrence and interrupt transmission. So, to meet all these goals a combination of antimalarials is required for the treatment of P. vivax malaria[5].

The administration of artemisinin-based combination therapy (ACT) can be challenging in infants and young children[6],[7]. Further, the dosing could be incorrect in this age group due to splitting of adult tablets[6]. Therefore, a dispersible tablet of FDC of arterolane maleate (AM) 37.5 mg and piperaquine phosphate (PQP) 187.5 mg would be a new alternative antimalarial treatment to children. Arterolane maleate is a synthetic trioxolane, short and rapid acting antimalarial[8] whereas PQP is an antimalarial drug with long half-life. This combination offers an easy dosing of once daily administration.

From the results of phase II (n=141) and phase III (n=859) clinical trials, it was found that the dispersible tablets of FDC of AM and PQP are safe and efficacious in pediatric patients with uncomplicated P. falciparum malaria[9]. This phase III clinical trial was carried out to assess efficacy and safety of FDC of arterolane maleate 37.5 mg and PQP 187.5 mg in comparison to chloroquine in pediatric patients with acute uncomplicated P. vivax malaria.


  Material and Methods Top


Study Design

A phase III, randomised, open-label, parallel-group, multicentric clinical trial of 42 days’ duration was conducted at 12 centres in India between September 2015 and July 2016. The study sites were (i) Panchsheel Hospital, Delhi, India; (ii) Nirmal Hospital, Jhansi; (iii) Department of Pediatrics, AIIMS, Bhubaneswar, Odisha; (iv) MV Hospital and Research Center, Lucknow; (v) Popular Hospital, Varanasi; (vi) Chandulal Chandrakar Memorial Medical College, Durg; (vii) Vintage Hospital & Medical Research Centre, Goa; (viii) Sudbhawana Hospital, Varanasi; (xi) Kasturba Medical College & Hospital, Manipal University, Wenlock District Govt. Mangalore; (x) A J Institute of Medical Science & Research Centre, Mangalore; (xi) Marudhar Hospital, Jaipur; (xii) Subharti Medical College and Hospital, Meerut.

Patients

Patients aged 6 months to 12 years with confirmed P. vivax malaria were enrolled in the study. The following inclusion criteria were met: parasite density of >250/μl blood, weight of > 5 kg., axillary temperature ≥37.5°C or oral temperature ≥38°C or fever in previous 24 hours, and willingness to comply to the study protocol.

Following patients were excluded from the study having mixed Plasmodium infection; known allergy to investigational products, artesunate, artemisinin-derived products, piperaquine, chloroquine, primaquine or any other related drugs; haemoglobin <8 gm/dl; history of haemolytic anaemia or methaemoglobinaemia; severe malaria; evidence of gastro-intestinal dysfunction that could alter absorption or motility (e.g., diarrhoea defined as more than three episodes of watery stools in the previous 24 hours or patients who have had three episodes of vomiting within 24 hours prior to screening); any anti-malarial treatment taken during one month prior to screening; ongoing prophylaxis with drugs having anti-malarial activity such as malarone, doxycycline and cotrimoxazole; concomitant drug metabolized by the cytochrome enzyme CYP2D6; use of concomitant medications that could induce haemolysis or haemolytic anaemia or depressants of myeloid element of the bone marrow; participation in any other investigational drug study of at least three months prior to screening; any other significant disease, disorder that could put patient at risk, interfere with the study evaluations and cause concern regarding patient’s ability to participate in the study; electrocardiogram (ECG) abnormalities with clinical significance or relevance that required urgent management (these abnormalities included QTc interval >450 msec at screening and cardiac conduction disorders, with the exception of right bundle branch block); splenectomy conducted earlier as confirmed by history or clinical examination; G6PD-deficient patients; evidence of significant renal or hepatic impairment (serum creatinine >1.5 upper limit of normal, ULN, aspartate transaminase >2.5 × ULN, alanine transaminase >2.5 × ULN, serum bilirubin >3 mg/dL, serum potassium and serum sodium < lower limit of normal); retinal/ visual field defects or auditory defects and history of psoriasis and porphyria.

Randomization and blinding

According to the randomization schedule, patients were randomized in a ratio of 2:1 to receive either AM-PQP dispersible tablets or chloroquine phosphate oral suspension/tablets. Randomization list was generated site wise using Statistical Analysis System (SAS) software. Permuted block size of three was considered to ascertain equal distribution of patients across sites.

Treatment

In AM-PQP arm, tablets were administered to patients as per their age in a single dose irrespective of meals: 6 months to <2 years: 1 tablet, 2 years to <6 years: 2 tablets, and 6 years to ≤12 years: 3 tablets. In chloroquine arm, chloroquine oral suspension (50 mg/ 5ml) was administered as single dose in patients <9 years and chloroquine tablet (containing 250 mg of chloroquine phosphate) was administered as single dose in patients >9 years for 3 days as per the age category. In the event of vomiting within 30 min of administration of the study drug, a single repeat dose was permitted only once during 3 days of treatment period. Primaquine phosphate dispersible tablets 2.5 mg was given as anti-relapse therapy for 14 days after completing three day of treatment. Each dispersible tablet was dissolved in 10 ml of drinking water with continuous swirling.

Assessments

The assessments performed at screening, pre-dose (Day 0), and at 6 h intervals (after the first dose of study medication), thereafter at Day 3 and on all follow-up days included physical examination, vital signs, body temperature and parasite count measurement. Body temperature recording was continued till temperature normalized for 24 hours while blood smears were examined in a blinded manner till two consecutive smears were negative and average of two readings were reported.

The safety assessments included adverse events (AEs) recording, laboratory test analysis for hematology, biochemistry, and urine analyses, and 12-lead electrocardiograph (performed at screening and Day 2 between 2 and 4 hours after the 3rd dose of AM-PQP or chloroquine).

Statistical analysis

Approximately 150 patients (100 patients in AM-PQP arm and 50 patients in chloroquine arm) were planned to be enrolled in the study. Considering an expected failure rate of 5%, a confidence interval of 95% and a precision level of 5%, a minimum of 73 evaluable patients were required[11]. After accounting for additional 25% patients for lost to follow-up or withdrawn cases, 100 enrolled patients in test arm and 50 enrolled patients in comparator arm were considered sufficient to meet study objectives.

All available data were used in the analyses. Efficacy analyses (primary and secondary efficacy variables) were based on Per Protocol (PP) population. Analysis of PCT and FCT was done on all available subjects in ITT population. Intent-to-treat (ITT) analysis was used as supportive evidence. In addition, life-table analysis using Kaplan-Meier graph was done. Unless otherwise specified, all statistical tests were performed using a 2-sided, 5% level of significance. Descriptive statistics for continuous and ordinal variables included mean, standard deviation, 95% confidence interval of the mean, as well as median, minimum, maximum values and quartiles. Categorical variables were summarized using count and percentage. Time to event data (PCT, FCT) was summarized by number of events, median time and quartiles. Proportion of aparasitemic and afebrile patients at 72 hours, cure rate on Day 28 and Day 42 were estimated along with their 95% confidence interval for each treatment arm. Fisher’s exact test and 2-sided 95% Wilson’s confidence interval were used for comparison between arms. Centre effect was assessed using Cochran-Mentel-Haenzel (CMH) and logistic regression, if applicable. Wald test (without continuity corrected) 95% confidence interval (CI) based on normal approximation was also presented. Kaplan–Meier (KM) survival probabilities for parasite clearance at each visit was estimated along with 95%CI for both the treatments. Median time to failure along with 95% CI was determined. KM graphs were plotted and survival probabilities between two regimens were assessed either by Log rank test or Wilcoxon Gehan’s test. Log rank method was followed in case the two survival curves did not cross each other; otherwise Wilcoxon Gehan’s test was applied. The effect of treatment on PCT was investigated using Cox proportional hazards regression analysis, including factors for treatment and study centre. Hazard ratio between two treatments was calculated along with their confidence intervals. Analysis of FCT was done in a similar manner to PCT. The safety analysis was performed on the safety population. The analysis of adverse events (AEs), laboratory data, vital signs, physical findings and other safety evaluations was summarized and tabulated. All statistical tests were performed using SAS.

Ethical statement

Approvals from Institutional Ethics Committee of recruitment study sites are attached as a supporting information file of study were of the participating study sites and regulatory authority were sought prior to study initiation. This clinical trial was conducted in accordance with the Good Clinical Practice, Declaration of Helsinki and applicable regulatory requirements. All participants/their guardians provided written informed consent/assent. This study is registered at Clinical Trial Registry India with CTRI number CTRI/2015/08/006087.


  Results Top


One hundred and sixty-four patients were randomized with 111 patients receiving AM-PQP and 53 patients receiving chloroquine. A total of 160 patients completed the study and 4 patients discontinued. The patient population was dominated by males 109 (66.5%). Patient demography and baseline characteristics are summarized in [Table 1] and patient disposition in [Figure 1].
Figure 1: Patient Disposition.

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Table 1: Demographic and Baseline Characteristics of the Randomized Patients

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Efficacy

In PP population, the proportion of aparasitaemic and afebrile patients at 72 hours was 100% [95% CI: 0 (-3.4 to 6.76)] in both the treatment arms [Table 2]. In ITT population, the proportion of aparasitaemic and afebrile patients at 72 hours was 98.2% and 100% [95% CI: -1.8 (-6.33 to 5.08)] in AM-PQP and chloroquine arms, respectively [Table 3].
Table 2: Proportion of Patients Aparasitemic and Afebrile at 72 hours (PP Population)

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Table 3: Proportion of Patients Aparasitemic and Afebrile at 72 hours (ITT Population)

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Using Kaplan–Meier analysis of the ITT population, the proportion of patients with aparasitemia and febrile survival probability was assessed and found to be 100% in both the treatment arms [Figure 2]. In PP population, Day 28 cure rate was 100% [95% CI: 0 (-3.5 to 6.88)] in both treatment arms [Table 4].
Figure 2: Survival Analysis at Day 3 ITT Population (Drug A: FDC of Arterolane Maleate and PQP; Drug B: Chloroquine).

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Table 4: Cure rate at Day 28 (PP Population)

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In ITT population, cure rate at Day 28 was 97.3% (108/111) and 100% in AM-PQP and chloroquine arms, respectively [95% CI: -2.7 (-7.65, 4.29), [Table 5], [Figure 3]].
Figure 3: Survival Analysis at Day 28 ITT Population (Drug A: FDC of Arterolane Maleate and PQP; Drug B: Chloroquine).

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Table 5: Cure rate at Day 28 (ITT Population)

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In ITT population, cure rate at day 42 was 97.3% (108/111) and 98.1% (52/53) in AM-PQP and chloroquine arms, respectively. There was one treatment failure patient in chloroquine arm on Day 42 [95% CI: -0.82 (-6.00, 7.43)].

The median PCT was 21 hours in AM-PQP and 24 hours in chloroquine arm (p=0.8309, [Table 6], [Figure 4]). Similarly, median FCT was 12 hours in AM-PQP and 18 hours in chloroquine arm (p=0.6338, [Table 7], [Figure 5]).
Figure 4: Time To Parasite Clearance (PCT) Kaplan-Meier Method ITT Population (Drug A: FDC of Arterolane Maleate and PQP; Drug B: Chloroquine).

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Figure 5: Time to Fever Clearance (FCT) Kaplan-Meier Method ITT Population (Drug A: FDC of Arterolane Maleate and PQP; Drug B: Chloroquine).

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Table 6: Time to Parasite Clearance (PCT, hours) (ITT Population)

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Table 7: Fever Clearance Time (FCT, hours) (ITT Population)

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Safety

The overall incidence of treatment-emergent AEs was comparable in the two treatment arms (AM-PQP: 51.4% and chloroquine: 52.8%). The most commonly observed adverse event was vomiting (10.8% in AM-PQP vs. 7.5% in chloroquine arm; [Table 8]). Most of the AEs were “mild” in intensity and “resolved without sequelae” in both the treatment arms. The relationship of majority of the AEs was judged as “not related” to the study medication. Two patients (1.8%) were withdrawn from the study due to vomiting in AM-PQP arm. No death or other SAE was reported in this study. The mean (±SD) change from baseline in QTc interval (Fridericia’s correction) at Day 2 in AM-PQP and chloroquine arms was 2.3±21.65 msec and -0.9±14.29 msec, respectively. The prolongation of QTc>500 msec at Day 2 was not seen in any of the patients. More than 60 msec increases in QTc interval over baseline at Day 2 was reported in 1 patient (0.9%) in AM-PQP arm and none in chloroquine arm. However, no cardiac events were reported. Mean concentration/counts of laboratory parameters (haemoglobin, platelet count, neutrophil count, serum potassium and sodium) were similar after the treatment with arterolane maleate and PQP or chloroquine at the reported time points.
Table 8: Incidence of Adverse Events in Safety Population [No. (%) of Patients]

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  Discussion Top


In many areas, Plasmodium vivax is the dominant species of malaria. Effective treatment of this disease is the need of malaria control. It is recommended by WHO that in areas where ACTs (except artesunate plus sulfadoxine-pyrimethamine), has been adopted as the first-line treatment for falciparum malaria, it may also be used for vivax malaria. Also, in areas with chloroquine-resistant P. vivax, ACT is recommended for the treatment of vivax malaria[6]. However, the incorrect dosing to children is a major cause of concern which is due to splitting of adult tablets because of the scarcity of pediatric formulations. Therefore, FDC of AM 37.5 mg and PQP 187.5 mg dispersible tablet has been formulated for easy administration to children. The FDC of AM 150 mg and PQP 750 mg tablets is already marketed in India and some African countries for the treatment of P. falciparum and P. vivax malaria in adults.

Arterolane maleate contributes significantly in achieving early parasite clearance due to its short and rapid action[8],[9],[10] and its combination with a proven safe, effective PQP having long half-life offers a promising antimalarial for the treatment of P. vivax malaria[11],[12],[13]. Arterolane being synthetic in nature makes it an easily available drug. The results of this study at Day 3 showed that in PP population all patients treated with either of the treatment were aparasitaemic and afebrile. The efficacy result was similar to the phase III study of FDC of arterolane maleate and piperaquine phosphate tablets conducted in patients aged 13–65 years with P. vivax malaria[14]. At 72 hours, the efficacy rate of more than 95% was reported in both the treatment arms. In this study, no early treatment failure was reported. The PCT and FCT reported in this study are on anticipated lines since the efficacy of the artemisinins is characterized by an early onset of activity and rapid reduction of parasitaemia with complete clearance within 48 h[15]. Median PCT was 21 hours in AM-PQP arm and 24 hours in chloroquine arm. Median FCT was 12.0 hours in AM-PQP arm and 18.0 hours in chloroquine arm. In both the treatment arms, Day 28 cure rates were 100% in PP population whereas in ITT population Day 28 cure rates were 97.3% in AM-PQP and 100% in chloroquine arm. The results were found to be comparable.

Based on earlier studies, AM-PQP was found to be highly efficacious against P. falciparum[8],[9],[10],[14],[16],[17]. It has been reported that wrong diagnosis of P. falciparum as P. vivax led to the inappropriate treatment with chloroquine. Chloroquine cleared P. vivax slowly when compared to ACT. It is assumed that P. vivax malaria is activated due to P. falciparum malaria and treatment of P. falciparum with AM-PQP and primaquine would have the benefit in the treatment of P. vivax malaria. This could be the probable explanation for more number of vivax infections after P. falciparum treatment[18].

In this study, no death or other SAE was reported. The overall incidences of AEs were comparable in both the treatment arms. The incidence of vomiting was reported as 10.8% which is lesser as compared to 16.8% reported in the phase III study conducted in pediatric patients with P. falciparum malaria[10]. None of the patients reported QTc prolongation of >500 msec. Only one patient in AM-PQP group reported QTc prolongation of >60 msec from baseline in AM-PQP arm. It has been reported that assessment of changes in QT interval in malaria is difficult because of differences observed before giving antimalarial drugs versus early improvement. During first visit to physician, patients are usually worried, anxious, starving and febrile with increased autonomic tone and an elevated heart rate. After 3 days of treatment with antimalarials, the condition of patient improves when most of them feel relaxed, comfortable and afebrile. It has been debated that due to this improvement in condition there has been a constant increase in the QT interval, which might have been inadvertently related to the antimalarial class of drugs[19],[20].


  Conclusion Top


The results of this trial demonstrated the comparable efficacy and safety of FDC arterolane maleate 37.5 mg and PQP 187.5 mg dispersible tablets as compared to chloroquine for the treatment of uncomplicated P. vivax malaria in pediatric patients.

Conflict of interest

R.K.J., A.N., S.K.S., and A.R., are or were employed in Sun Pharmaceutical Industries Limited while developing the product. All other authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.


  Acknowledgements Top


Sun Pharmaceutical Industries Limited, India sponsored this trial as part of the clinical development program of arterolane maleate-PQP.

 
  References Top

1.
Anvikar AR, Shah N, Dhariwal AC, Sonal GS, Pradhan MM, Ghosh SK, et al. Epidemiology of Plasmodium vivax Malaria in India. Am J Trop Med Hyg 2016; 95(Suppl 6): 108–20.  Back to cited text no. 1
    
2.
WHO. world_malaria_report_2016.  Back to cited text no. 2
    
3.
Programme DoNVBDC. Strategic-Action-Plan-Malaria- 2012-17. NVBDCP; 2017.  Back to cited text no. 3
    
4.
WHO. World Malaria Report 2018.  Back to cited text no. 4
    
5.
Baird JK, Valecha N, Duparc S, White NJ, Price RN. Diagnosis and Treatment of Plasmodium vivax Malaria. Am J Trop Med Hyg 2016; 95(Suppl 6): 35–51.  Back to cited text no. 5
    
6.
WHO. Guidelines for the treatment of malaria; 2015.  Back to cited text no. 6
    
7.
Yeka A, Harris JC. Treating uncomplicated malaria in children: comparing artemisinin-based combination therapies. Curr Opin Pediatr 2010; 22(6): 798–803.  Back to cited text no. 7
    
8.
Valecha N, Looareesuwan S, Martensson A, Abdulla SM, Krud-sood S, Tangpukdee N, et al. Arterolane, a new synthetic trioxolane for treatment of uncomplicated Plasmodium falciparum malaria: a phase II, multicenter, randomized, dose-finding clinical trial. Clin Infect Dis 2010; 51(6): 684–91.  Back to cited text no. 8
    
9.
Toure OA, Rulisa S, Anvikar AR, Rao BS, Mishra P, Jalali RK, et al. Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated Plasmodium falciparum malaria : a phase II, multicentric, open –label study. Malaria J 2015: 1–12.  Back to cited text no. 9
    
10.
Sun P. A Phase III, Open Label, Randomized, Multicenter, Parallel Group Trial to Assess the Efficacy and Safety of the Fixed Dose Combination of Arterolane Maleate 37.5 mg and Pipera-quine Phosphate (PQP) 187.5 mg Dispersible Tablets in Co.  Back to cited text no. 10
    
11.
Paul M. O’Neill VEB, Stephen A. Ward, and James Chadwick. 4-Aminoquinolines Chloroquine, Amodiaquine and Next-Generation Analogues. Springer 2012: 19–44.  Back to cited text no. 11
    
12.
Timothy ME Davis, Ing-Kye Sim, Harin A. Karunajeewa,Ilett KF. Piperaquine a resurgent antimalarial drug. Drugs 2005; 65(1): 75–87.  Back to cited text no. 12
    
13.
WorldWide Antimalarial Resistance Network (WWARN) DP Study Group. The effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin-piperaquine: a pooled analysis of individual patient data. PLoS Med 2013; 10(12): e1001564.  Back to cited text no. 13
    
14.
Valecha N, Savargaonkar D, Srivastava B, Rao BHK, Tripathi SK, Gogtay N, et al. Comparison of the safety and efficacy of fixed - dose combination of arterolane maleate and piperaquine phosphate with chloroquine in acute, uncomplicated Plasmodium vivax malaria : a phase III, multicentric, open–label study. Malaria J 2016: 1–13.  Back to cited text no. 14
    
15.
P J de Vries, T K Dien. Clinical Pharmacology and Therapeutic Potential of Artemisinin and its Derivatives in the Treatment of Malaria. Drugs 1996; 52(6): 818–36.  Back to cited text no. 15
    
16.
Offianan Andre Toure, Neena Valecha, Antoinette K Tshefu, Ricardo Thompson, Srivicha Krudsood, Oumar Gaye, et al. A Phase 3, Double-Blind, Randomized Study of Arterolane Maleate – Piperaquine Phosphate vs Artemether – Lumefantrine for Falciparum Malaria in Adolescent and Adult Patients in Asia and Africa. Clin Infect Dis 2016; 62(8): 964–71.  Back to cited text no. 16
    
17.
Valecha N, Krudsood S, Tangpukdee N, Mohanty S, Sharma SK, Tyagi PK, et al. Arterolane Maleate Plus Piperaquine Phosphate for Treatment of Uncomplicated Plasmodium falciparum Malaria : A Comparative, Multicenter, Randomized Clinical Trial. Clin Infect Dis 2012; 55(5): 663–71.  Back to cited text no. 17
    
18.
Daniel Eibach, Nicolas Ceron, Karanchand Krishnalall, Keith Carter, Guillaume Bonnot, Anne-Lise Bienvenu, et al. Therapeutic efficacy of artemether-lumefantrine for Plasmodium vivax infections in a prospective study in Guyana. Malaria J 2012; 11: 347.  Back to cited text no. 18
    
19.
Oliver T. Mytton EAA, Leon Peto, Ric N. Price, Yar La, Rae Hae, Pratap Singhasivanon, et al. Electrocardiographic Safety Evaluation of Dihydroartemisinin–Piperaquine in the Treatment of Uncomplicated falciparum Malaria. Am J Trop Med Hyg 2007; 77(3): 447–50.  Back to cited text no. 19
    
20.
Sandeep K, Singh1 SS. A Brief History of Quinoline as Antimalarial Agents. Int J Pharm Sci Rev Res 2014; 25(1): 295–302.  Back to cited text no. 20
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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