174

Research Article

Assessment of clinical safety and efficacy of fixed dose combination of arterolane maleate and piperaquine phosphate versus artesunate, sulfadoxine and pyrimethamine in patients of uncomplicated falciparum malaria

Anil Kumar P.*, Shanmukananda P.

Dept. of Pharmacology, Dr B R Ambedkar medical college, Bangalore, India

*For correspondence

Dr Anil Kumar P.,

Dept of pharmacology, Dr B R Ambedkar medical college, Bangalore, India.

Email: anilkumarpothuru@ gmail.com

 

 

 

 

 

 

 

 

 

 

 

 

Received: 29 August 2016

Revised: 10 September 2016

Accepted: 13 September 2016

ABSTRACT

Objective: To compare the safety and efficacy of fixed dose combination (FDC) of Arterolane maleate, Piperaquine phosphate with AS+SP (Artesunate + sulfadoxine, pyrimethamine) in uncomplicated falciparum malaria.

Methods: Study was conducted in Dr B R Ambedkar Medical College & Hospital, by randomly allocating the subjects into 2 groups (n=30 each) and by comparison of their efficacy as well as safety of two FDC of drugs at regular follow ups at 0, 2, 7, 14 and 28 days.

Results: Thirty subjects in each group completed the 28 days follow-up. On day one, total 30 patients in both the groups were febrile and parasitaemic. Three patients of those divided groups, were afebrile and aparasitaemic which was assessed by fever clearance and parasite clearance time. There was no late clinical as well as parasitological failures were found in both the groups, total 60 patients demonstrated Adequate Clinical and Parasitological Response 96.5% (APCR) with the study drugs. No gametocytemia was seen in the two groups during follow up. Adverse drug effects were detected in four patients (two patients had anaemia, and one patient shown slight elevation in hepatic transaminases,one patient shown jaundice-unconjugated hyperbili-rubinemia? Haemolytic) in AM+PIP.PO4 group (GROUP1), and three patients (anaemia in two patients and slight elevation in hepatic transaminases in one patient) in AS+SP group (Group 2).

Conclusion: The study showed that Arterolane maleate and Piperaquine phosphate combination and Artesunate, Sulfadoxine and Pyrimethamine combination are equally potent in making the patient afebrile and aparasitemic on day 3, and achieving 96.5% APCR on day 28, and safety profile of the new drug (AM+PIP.PO4) is non inferior to AS+SP in the treatment of uncomplicated P. falciparum malaria.

Keywords: Artesunate, Sulfadoxine, Arterolane, ACT, Falciparum malaria

Introduction

Malaria, also sometimes known as "King of Diseases", is spread by protozoan parasites of the genus Plasmodium. It is one of the foremost causes of diseases and mortalities in the world. Out of ten deaths of these types nine occur in Africa and the rest occur in Asia and Latin America, being the world's most prevalent vector-borne disease. It is the fourth frontline cause of death of children under the age of five years and pregnant women in developing countries.1 Malaria is a protozoan disease communicated by infected Anopheles mosquitoes bite.

Medicines have a crucial role in management of malaria, beginning with the quinine discovery and later chloroquine in 1934. In the 1980s, the management of malaria was transformed with the usage of the natural product artemisinin, discovered by the Chinese first.2 Artemisinin derivative when combine with at least one other type of medicine in one tablet which is known as a fixed-dose artemisinin combination therapy (fACT). Presently fACTs are used as the first line treatment suggested for uncomplicated Malaria (WHO Treatment Guidelines 2010). A study has reported that AS plus SP (artesunate and sulfadoxine-pyrimethamine) is potent and safe drug in the management of uncomplicated type of P. falciparum malaria.3 In one study, arterolane maleate and piperaquine phosphate showed no treatment failure.4 Malaria since is a very common and dangerous disease in India, the two combinations of Arterolane maleate/Piperaquine phosphate and Artesunate and Sulfadoxine- Pyrimethamine are compared to evaluate which is having more safety and efficacy.

Several species of Plasmodium cause malaria in humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria and the simian Plasmodium knowlesi. The most deadly species is P. falciparum, found predominantly in Africa. If left untreated, P. falciparum can cause diseases like organ failures (severe malaria) and can accumulate in the capillaries of brain (cerebral malaria), can progress to coma and eventually death.5 Artemisinin based combination therapies (ACTs) are the presently used in management of uncomplicated malaria.

Objective: To compare the safety and efficacy of fixed dose combination (FDC) of Arterolane maleate + Piperaquine phosphate with AS+SP (Artesunate + sulfadoxine, pyrimethamine) in uncomplicated falciparum malaria.

Materials and Methods

This was a prospective, randomized, open-labelled interventional study carried out at Dr. B. R. Ambedkar Medical College and Hospital from November 2013 to October 2014 with the informed consent of all the subjects. Sixty subjects were selected based on eligibility criteria with uncomplicated malaria were allocated at a ratio of 1:1 to either arterolane maleate 150 mg + piperaquine phosphate 750 mg one tablet a day for three days or artesunate 100 mg one tablet a day for three days and sulfadoxine 1500 mg+ pyrimethamine 75 mg single dose by means of a computer-generated randomization chart. Thirty subjects were treated with arterolane maleate and piperaquine phosphate FDC. Another thirty subjects were treated with artesunate and sulfadoxine and pyrimethamine combination.

Inclusion criteria

  1. Age ≥18 years (18-65 years )
  2. Both genders
  3. Must be medically stable (not likely to require hospitalization for medical complication within 15 days).
  4. Mono infection with P. falciparum (smear positive) cases and subjects with typical clinical symptoms of malaria
  5. Suspected clinical case of acute uncomplicated malaria (Defintion: Fever (cold, hot and sweating stages) with chills and rigors, fever can be either continuous or intermittent, tertian, quartan, constitutional symptoms like headache, myalgia, anorexia, nausea and vomiting (centers for disease control and prevention)
  6. Fever (axillary temperature ≥ 37.5°C or oral ≥ 38°C).

Exclusion criteria

  1. Have contraindications for the use of either of the study medications
  2. Pregnant and lactating women
  3. Subjects having hypersensitivity to the study group of drugs
  4. Severe and complicated malaria or any significant co-morbidity
  5. Any antimalarials or other treatment within two weeks prior to screening, or previous participation in an investigational drug study during the past 30 days.

Primary end points:

  1. Fever clearance time (FCT) on day 0,7,14 and 28
  2. Parasite clearance time (PCT) on day 0,7,14 and 28
  3. APCR (adequate parasitological and clinical response), on day 0,7,14, and 28

Secondary end points:

  1. Changes in LFT at 0, 7, days.
  2. ECG at 0, 2 and 28 days
  3. CBP (Complete blood picture) at 0, 7 and 14 days

Investigations and follow-up:

  1. Liver Function test would be performed at Day 0, 7, if any changes in the seventh day are noted then it will be repeated on Day14.
  2. Peripheral smear for malaria parasite – on Day 0,7,14
  3. Complete blood picture and Serum electrolytes; on day 0,7,14
  4. ECG – day 0,2,28
  5. Urinary pregnancy test in females on admission.

Statistical methods

Results on continuous measurements were presented on mean ± SD and results on categorical measurements were presented in percentage. Significance was assessed at 5% level of significance. Student t test (two tailed, independent) was used to calculate the significance of study parameters on continuous scale between two groups (inter group analysis) on metric parameters. Chi-square and Fisher Exact test were used to find the significance of study parameters on categorical scale between two or more groups. P value less than 0.05 was considered as significant. SAS 9.2, SPSS 15.0, Stata 10.1, MedCalc 9.0.1, Systat 12.0 and R environment ver.2.11.1 were used for the analysis of the data.

Results and Discussion

Demographic and baseline characteristics:

Age, and weight are well matched in both the groups. Mean age group was 33-37 years with p value of 0.291(Table1). Mean weight was 58-62 years with p value of 0.640.Gender distribution in group 1(Arterolane+Piperaquine) are 16 (53.3%) male, 14 (46.7%) female patients and in group 2(Artesunate+SP), 17 (56.7%) patients are male, 13(43.3%) are females (Table 2). Samples are gender matched with p value of 0.795.Axillary temperature in both the groups are >37.5(°C).A total of sixty patients completed the study, thirty patients received Arterolane + Piperaquine (group 1), and thirty received Artesunate+SP (group 2).

Efficacy and safety evaluation:

Age and body weight are compared by students unpaired t- test and fisher exact test for sex distribution.

Primary end points like Fever clearance time (FCT), Parasite clearance time, and Adequate parasitological and clinical response on day 28 (APCR) were compared in both the groups, with p value of 1.000, <0.001 and <0.001 respectively (Table 3). FCT was 14-16 hrs in 90% of patients in both the groups. Parasite clearance time (PS for MP) of 30-33 hrs is seen in 90% of patients in group 1 and 65% of patients in group 2.

Table 1: Baseline characteristics (demographic variables) at enrollment of subjects included in intention to treat analysis, by study group.

Parameter

Group1

/AM+PIP.P04 (n=30)

Group 2/AS+SP

(n=30)

P value

Age (yrs) Range

15 – 65

15 – 65

0.291

Mean ± SD

33.37 ± 12.66

36.67 ± 11.31

 
Median (IQR)

33 (27-48)

35 (27-48)

 
Weight (kg) Range

42 - 85

42 – 80

0.640

Mean ± SD

58.9 ± 7.92

59.4 ± 8.11

 
Median (IQR)

58 (53-63)

59 (53-66)

 
Sex (%)

Male

 

16 (53.3%)

 

17 (56.7%)

 
Female

14 (46.7%)

13 (43.3%)

 
Axillary

Temperature (°C)

>37.5

28

29

 

P -Value in the last column is from intergroup comparison by student's unpaired t- test(for age and body weight).Fischer's exact test for sex distribution.SD- Standard Deviation, IQR- Interquartile range.

APCR of 97% observed in 90% patients in group 1 and APCR of 97% observed in 50% of patients in group 2. Even though parasite clearance time & APCR was statistically significant in between the groups it is not clinically significant in terms of patient response.

Secondary end points: 28 (93.3%) patients have no changes in LFT in group 1, one patient (3.3%) had increase in unconjugated sr.bilirubin & decrease in Hb%, and one patient (3.3%) had increase in hepatic transaminases (SGOT/SGPT). 29 (96.7%) patients had no changes in LFT in group 2, one patient (3.3%) had increase in hepatic transaminases, p=1.000, not significant (Table 4). LFTs are compared by fisher exact test. No changes is seen in ECG in both the groups. Hb, bilirubin and SGOT/SGPT are normalized in day 14 in both the groups (Table 5). Anemia is seen in 2 patients (6.7%) in both the groups p=1.000, not significant (Table 6). CBP (complete blood picture) are compared by fisher exact test. Hyponatremia is seen in 2 patients (6.7%) in group1, and in one patient (3.3%) in group 2, which were normalized in day 14 in both the groups. Serum electrolytes in both the groups are compared by fisher exact test with p=1.000, not significant (Table 7). ADRs like anemia (7%) in both the groups, increase in bilirubin (3.5%) in group1 and increase in SGOT/SGPT (3.5%) in both the groups are observed. These are compared by chi square test with p=1.000 (Table 8).

Table 2: Gender distribution of patients studied.

Gender

Group I

Group II

No

%

No

%

Female

14

46.7

13

43.3

Male

16

53.3

17

56.7

Total

30

100.0

30

100.0

Samples are gender matched with P=0.795

All the base line characteristics are well matched in the study. No clinically significant difference is seen in primary outcomes like fever clearance time (FCT), Parasite clearance time (PCT) and Adequate parasitological and clinical response (APCR) in both the groups. The patients in both the groups were responded well to the given treatment without any treatment failures. Most of the patients in both the groups became afebrile and aparasitemic. Gametocytemia was not seen in both the groups. Compliance was also good in both the groups.

Although the sample size was small, these data suggest that the combination of a 3-day course of artesunate given with a single dose of Sulfadoxine+pyrimethamine & Arterolane + Piperaquine once a day for 3 days is safe and well tolerated as a treatment for uncomplicated P. falciparum malaria.

Table 3: Primary end points in two groups of patients studied.

Primary end points

Group I (n=30)

Group II (n=30)

P value

No

%

No

%

Fever clearance time          
<14 hrs

4

13.3

5

16.7

1.000

14-16 hrs

25

83.3

25

83.3

>16 hrs

1

3.3

0

0.0

Parasite clearance time (PS for MP)
<30 hrs

3

10.0

0

0.0

<0.001**

30-33 hrs

25

83.3

17

56.7

>33 hrs

2

6.7

13

43.3

Adequate Parasitological and Clinical Response on day 28
96.50%

2

6.7

0

0.0

<0.001**

97.50%

1

3.3

12

40.0

97.90%

1

3.3

13

43.3

97%

26

86.7

0

0.0

98%

0

0.0

5

16.7

Artesunate is a derivative of artemisinin and is metabolized in vivo into the biologically active dihydroartemisinin (DHA). Artemisinin derivatives have now been used to treat more than 1 million patients without serious adverse events, both alone and in combination with other anti-malarial agents. Unlike both chloroquine and S/P, this class of drugs has a very short half-life and rapid anti-malarial activity. Although the number of patients/subjects enrolled in the present study was small, the new combination (group1) appeared to be equally effective to AS+SP (group 2) in terms of fever clearance rates on Day 2. The decline in the prevalence of dhfr/dhps (Dihdrofolate reductase/ Dihydropteroate synthase) genes combination mutations might indicate the recurrence of sensitive parasites in the population following SP (sulfadoxine- pyrimethamine) withdrawal. Therefore, further monitoring and assessment is important to determine the feasibility of re-introduction of SP (sulfadoxine-pyrimethamine) alone or in combination as a more affordable and safer drug in the future.

The concept of combined drug therapy for malaria has previously been encouraged and artemisinin derivatives have been broadly used in South-East Asia, usually in combination with mefloquine. The basic principle behind this approach is that the artemisinin derivative rapidly decreases the parasite biomass leaving only a relatively few parasites for the 2nd agent to eradicate. Such a strategy has the additional advantage of reducing the likelihood of drug-resistant parasites emerging as one drug protects the other-a concept that is widely established in the treatment of tuberculosis. The data presented here suggest that the combination of artesunate and S/P and Arterolane + Piperaquine are equally effective for the treatment of uncomplicated falciparum malaria. Safety profile of new ACT is non-inferior to the AS+SP.

Table 4: Liver Function Test in two groups of patients studied.

Liver Function Test

Group I

(n=30)

Group II

(n=30)

No

%

No

%

No changes

28

93.3

29

96.7

Changes

2

6.7

1

3.3

Liver Function Test-slight increase in Sr.Bilirubin (unconjugated)

1

3.3

0

0.0

Liver Function Test-increase in hepatic transaminases

1

3.3

1

0.0

P=1.000, Not significant, Fisher Exact test

Table 5: Secondary End Points in two groups of patients studied.

Secondary End Points Group I (n=30) Group II (n=30) P value
No % No %
Electrocardiogram & LFT(Day 7)          
No changes in ST 30 100.0 30 100.0 1.000
Elevation in SGOT/SGPT 1 3.3 1 3.3
Increase in sr. bilirubin (unconjugated) & decrease in Hb% 1 3.3 0 0.0
LFT (Day 14)          
Normalized SGOT/SGPT 1 3.3 1 3.3 1.000
Normalized Sr. Bilirubin & Hb 1 3.3 0 0.0

The patients in both the groups had axillary temperature of ≥ 37.5°C or oral ≥ 38°C with chills, rigors and headache. The subjects included in the study after obtaining informed consent. The study was approved by Institutional Ethical Committee. Thirty patients were assigned to group 1 (Arterolane maleate+Piperaquine) & thirty patient was assigned to group 2 (AS+SP). TPR charts are maintained for both the groups to record the temperature, pulse and respiratory rate. Regular follow-ups were done at DAY 0, 7, 14 and 28. Clinically significant differences were not seen in secondary outcomes-like, the following:

LFT (Liver function test): slight increase in unconjugated bilirubin (suggesting haemolytic, but not hepatocyte dysfunction) and decrease in Hb% on day 7 which was normalized on day 14 was seen in one patient in group 1. The possible explanation for this can be given by Haemolytic anaemia—jaundice. Slight increase in hepatic transaminases like SGOT/SGPT was seen in one patient in both the groups on day 7 which was normalized on day 14,with a p value of 1.000 (Fisher exact test) which is not significant. The study drugs can produce changes in ECG-like AV block, ST segment changes, prolongation of QT-interval, Torsades de pointes. In this study we used the risk assessment tool for QT prolongation by QT nomogram also listed other drugs which will prolong QT interval. No significant changes were seen in ECG in both the groups.

Table 6: Complete blood picture in two groups of patients studied.

Complete blood picture Group I Group II
No % No %
No changes 28 93.3 28 93.3
Anemia 2 6.7 2 6.7
Total 30 100.0 30 100.0

P=1.000, Not significant, Fisher Exact test

Table 7: Serum Electrolytes in two groups of patients studied.

Serum Electrolytes Group I Group II
No % No %
No changes 28 93.3 29 96.7
Normalized in day 14 2 6.7 1 3.3
Total 30 100.0 30 100.0

P=1.000, Not significant, Fisher Exact test

Table 8: Adverse Drug Reactions in two groups of patients studied.

Adverse Drug Reactions Group I (n=30) Group II (n=30) P value
No % No %
  1. Anemia
2 6.7 2 6.7 1.000
  1. Increase in SGOT/SGPT
1 3.3 1 3.3 1.000
  1. Increase in Sr.Bilirubin & Decrease in Hb (?Haemolytic Anaemia)
1 3.3 0 0.0 1.000

Chi-Square test/Fisher exact test

Serum electrolytes: slight changes in serum sodium concentration was seen in two patients in group1 and one patient in group 2 on day 7, with p value of 1.000 (Fisher exact test) which is not significant and was normalized in day 14. These patients were having vomiting and loose motions. So this hyponatremia could have been due to above reason.

CBP: Anaemia was seen in two patients in both the groups with p value of 1.000 (Fisher exact test) which is not significant. Some studies showed that co-infection of malaria in endemic areas with STH (soil transmitted helmenthic infections) and dengue fever.6,7 The haemo-globin values were used to assess the status of anemia. For haemoglobin, the cut-off criterion levels below which indicates anemia was the WHO cut-off of 12 g/dl for non-pregnant women above 15 years of age and 13 g/dl for men above 15 years of age.8 Most of the concurrent cases of dengue and malaria were found between September and November, with a peak in October; at which period the risk of contracting double infections would be more than in any other period.9

Conclusions

The study showed that Arterolane maleate + Piperaquine phosphate and Artesunate plus Sulfadoxine and Pyrimethamine are equally effective in making the patient as afebrile and aparasitemic on day 3, and achieving 96.5% APCR on day 28, and safety profile of the new drug (AM+PIP.PO4) is non inferior to AS+SP in the treatment of uncomplicated P. falciparum malaria.

References

  1. World malaria report 2011. [Online] Available at http://www.who.int/entity/ malaria/world_malaria_report_2011/9789241564403_eng.pdf. Accessed 15 July 2016.
  2. Wells TN, Poll EM. When is enough enough? The need for a robust pipeline of high-quality antimalarials. Discov Med. 2010;9(48):389-98.
  3. Elamin SB, Malik EM, Abdelgadir T. Artesunate plus sulfadoxine-pyrimethamine for treatment of uncomplicated Plasmodium falciparum malaria in Sudan. Malar J. 2005;4:41.
  4. Valecha N, Krudsood S, Tangpukdee N. 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.
  5. Biomonte MA, Wanner J, Le Roch KG. Recent advances in malaria drug discovery. Bioorg Med Chem Lett. 2013;23(10):2829-43.
  6. Alemu A, Shiferaw Y, Ambachew A, Hamid H. Malaria helminth co-infections and their contribution for aneamia in febrile patients attending Azzezo health center, Gondar, Northwest Ethiopia: a cross sectional study. Asian Pac J Trop Med. 2012;5(10):803-9.
  7. Hati AK, Bhattacharjee I, Mukherjee H, Bandyopadhayay B, Bandyopadhyay D, De R, et al. Concurrent dengue and malaria in an area in Kolkata. Asian Pac J Trop Med. 2012;5(4):315-7.
  8. WHO. Iron deficiency anemia: assessment, prevention and control, a guidelines for program managers. Geneva: WHO; 2007.
  9. Ward DIA. A case of fatal Plasmodium falciparum malaria complicated by acute dengue fever in East Timor. Am J Trop Med Hyg. 2006;75:182-5.

Refbacks

  • There are currently no refbacks.




Copyright (c) 2016 Pharmaceutical and Biological Evaluations

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.



Creative Commons License

 

© Copyright 2018 - Pharmaceutical and Biological Evaluations