As per WHO Guidelines, the current standard treatment for
Primaquine has a narrow therapeutic range and a short elimination half-life of about four to seven hours. Thus, primaquine requires daily administration for up to 2 weeks that may result in poor compliance [
The concept of developing primaquine SR 15 mg (manufactured by Ipca Labortories Ltd., India) and primaquine SR 30 mg (manufactured by Ipca Labortories Ltd., India) formulations was based on maintaining adequate therapeutic concentration over 24 hours and reducing the treatment duration from 14 days to seven days for better patient compliance. The hypnozoitocidal activity of primaquine is reported to depend more on the total dose administered than on the length of the treatment [
The objective of this study was to compare the efficacy, safety, and tolerability of primaquine SR 15 mg and primaquine SR 30 mg tablets with conventional primaquine 15 mg tablets in the prevention of relapse of
Patients of either sex, aged between 18 and 65 years, and body weight >40 kg were eligible for participation if they had microscopically confirmed
Patients with mixed malarial infections, severe or complicated malaria (as defined by WHO), G6PD deficiency, or any other significant concomitant illness were not included in the study. Patients with history of dark urine or significant hemoglobinuria related to previous primaquine treatment or those with history of methemoglobinemia were not included in the study. Patients with protracted vomiting and oliguria, or those with underlying condition compromising bone marrow function or having a tendency to granulocytopenia, were excluded from the study. Patients taking cardioactive drug or potentially hemolytic drugs or drugs that may interact with study drugs were not included in the study. Patients having history of hypersensitivity to any of the study related drugs and those on another investigational drug or history/presence of substance abuse were not included in the study. Pregnant or lactating women or women of child-bearing potential not using medically accepted means of birth control were also excluded from the study.
This double-blind, double-dummy, randomized, comparative, and multicentric study was conducted at eight centers according to GCP Guidelines and the Declaration of Helsinki. All suspected malaria cases were provided with a patient information sheet in a language understood by the patient and/or patient’s representative, as applicable. Only those patients who provided signed written informed consent were screened for the study. At screening, patients were evaluated for signs and symptoms of malaria. Blood and urine sample were collected to perform routine laboratory investigations. Patients satisfying study eligibility criteria were included in the study and were hospitalized for 3 days during which they received chloroquine therapy. Aparasitemic and asymptomatic patients after three days of chloroquine therapy were discharged from the hospital and were randomized in 1 : 1 : 1 ratio to receive conventional primaquine 15 mg (Group 1) or primaquine SR 15 mg (Group 2) or primaquine SR 30 mg (Group 3). Patients randomized to Group 1 received active conventional primaquine 15 mg for 14 days along with matching placebo of primaquine SR 15 mg and primaquine SR 30 mg. Patients randomized to Group 2 received active primaquine SR 15 mg for 14 days along with matching placebo of conventional primaquine 15 mg and primaquine SR 30 mg. Patients randomized to Group 3 received active primaquine SR 30 mg for 7 days and matching placebo of conventional primaquine 15 mg and primaquine SR 15 mg. For the remaining 7 days, patients from Group 3 received matching placebo of conventional primaquine 15 mg, primaquine SR 15 mg, and primaquine SR 30 mg. Randomization codes were generated using computer generated block randomization method. Patient specific sealed boxes of medicine were provided to each study site.
After discharge, patients were required to visit the hospital at Day 7, Day 14, Day 21, and Day 28 and then monthly for the next five months. Patients were instructed to visit the hospital immediately in case they became symptomatic at any other time during the study.
The primary efficacy parameter was the absence of microscopically proven asexual forms of
During chloroquine therapy, patients were hospitalized to allow evaluation of clinical signs and symptoms of malaria and to perform thick and thin blood smears examination every 12 hours. Axillary body temperature was measured at every six hrs. Each follow-up included a review of clinical signs and symptoms, peripheral blood smear examination, and body temperature recording.
Secondary efficacy parameter included compliance to study medication assessed based on patient diary and medication bottles returned by the patients. Patients who consumed the drug as prescribed were considered as compliant to the study medication.
Safety assessment was based on reported adverse events and changes in the laboratory parameters. Changes in the laboratory parameters were assessed by performing tests for routine hematology, biochemistry, and urinalysis at baseline and at the end of therapy. At screening visit, test to assess G6PD deficiency was performed for all patients and patients with G6PD deficiency were excluded from the study. Also, urine pregnancy test was performed for all female patients of child-bearing potential. Female patients with positive test result were excluded from the study. At each visit during the study, physical examination was performed and vital signs were recorded to perform safety assessments.
Sample size of 100 patients (without dropout) per treatment group was considered to give 80% power with 95% confidence interval (two-sided) (
Efficacy was assessed using modified intention-to-treat (ITT) analysis that included all randomized patients who completed 14 days of primaquine therapy without any protocol violation. Last observation carried forward approach was used to impute missing assessments.
The demographic and initial clinical and biological characteristics of the patients were compared using descriptive statistics. Data was provided in the form of mean ± SD (range) for continuous variables and percentage for categorical variables. At baseline, all patients were compared using analysis of variance (ANOVA) for parametric variables or Kruskal-Wallis test for nonparametric continuous variables and chi-square or Fisher’s exact test (if cell frequency is <5) for categorical variables for homogeneity.
The primary efficacy parameter was the absence of microscopically proven
Safety population included all patients who gave written informed consent for participation in the study. Changes in laboratory parameters were evaluated by paired
Of the 438 patients screened, 360 patients were included in the study to receive 3 days’ chloroquine therapy. Of these 360 patients, one patient was lost to follow-up on Day 1 of chloroquine therapy and one patient did not satisfy the eligibility criteria for receiving primaquine therapy. The remaining 358 aparasitemic and asymptomatic patients were randomized to receive either conventional primaquine 15 mg for 14 days (120 patients) or primaquine SR 15 mg (118 patients) for 14 days or primaquine SR 30 mg (120 patients) for 7 days. The complete disposition of study participants is given in Figure
Disposition of study participants. PT: primaquine therapy, CT: chloroquine therapy, and MP: malarial parasite.
Table
Demographic and baseline disease characteristics of patients.
Parameters | P 15 mg |
PSR 15 mg |
PSR 30 mg |
Total |
|
---|---|---|---|---|---|
Male |
99 (82.5) | 99 (83.9) | 98 (81.7) | 296 (82.7) | 0.923 |
|
|||||
Age (years) |
31 (23) | 28 (21) | 28 (18) | 29 (20) | 0.197 |
|
|||||
Weight (kg) |
56.77 ± 9.07 | 56.41 ± 9.36 | 57.13 ± 8.84 | 56.77 ± 9.07 | 0.760 |
40–86 | 32–92 | 40–86 | 32–92 | ||
|
|||||
Body temperature |
38.50 ± 0.84 | 38.5 ± 0.93 | 38.49 ± 0.76 | 38.5 ± 0.84 | 0.988 |
|
|||||
Respiration rate |
17.85 ± 3.74 | 17.98 ± 3.78 | 17.98 ± 3.79 | 17.95 ± 3.76 | 0.943 |
|
|||||
Parasite density |
6564.9 ± 12614.9 | 6168.7 ± 15128.1 | 6145.9 ± 13508.3 | 6293.9 ± 13744.5 | 0.969 |
1000–100000 | 1000–141300 | 800–121100 | 800–141300 | ||
|
|||||
Patients with parasites |
|||||
|
90 (75.0) | 92 (78.0) | 95 (79.2) | 277 (77.4) | 0.986 |
|
16 (13.3) | 15 (12.7) | 14 (11.7) | 45 (12.6) | |
|
10 (8.3) | 8 (6.8) | 7 (5.8) | 25 (6.9) | |
|
4 (3.3) | 3 (2.5) | 4 (3.3) | 11 (3.1) | |
|
|||||
Signs and symptoms |
|||||
Fever | 120 (100.0) | 118 (100.0) | 119 (99.17) | 357 (99.7) | 0.664 |
Chills | 118 (98.33) | 117 (99.15) | 118 (98.33) | 353 (98.5) | 0.999 |
Headache | 116 (96.67) | 113 (95.76) | 110 (91.67) | 338 (94.6) | 0.207 |
Nausea | 99 (82.5) | 88 (74.58) | 89 (74.17) | 276 (77.0) | 0.209 |
Malaise | 89 (74.17) | 81 (68.64) | 89 (74.17) | 258 (72.2) | 0.576 |
Vomiting | 59 (49.17) | 57 (48.31) | 58 (48.33) | 174 (48.4) | 0.981 |
Myalgia | 57 (47.5) | 59 (50.0) | 57 (47.5) | 173 (48.3) | 0.929 |
Anorexia | 59 (49.17) | 52 (44.07) | 57 (47.5) | 167 (46.7) | 0.729 |
Arthralgia | 11 (9.2) | 17 (14.4) | 14 (11.8) | 42 (11.7) | 0.461 |
Abdominal cramps | 9 (7.5) | 9 (7.6) | 8 (6.7) | 26 (7.3) | 0.999 |
Diarrhoea | 6 (5.0) | 6 (5.1) | 5 (4.2) | 17 (4.7) | 0.953 |
P 15 mg: conventional primaquine 15 mg, PSR 15 mg: primaquine sustained release 15 mg, and PSR 30 mg: primaquine sustained release 30 mg.
b indicates value shown as
c indicates value shown as median (IQR), Kruskal-Wallis test used for the comparison.
d indicates value shown as mean ± SD, one way ANOVA used for comparison.
There was a consistent reduction in mean parasite count throughout chloroquine therapy. At the end of chloroquine therapy, 99.4% of patients were aparasitemic and 97.8% of patients were afebrile (Table
Parasite clearance and fever clearance in number of patients during chloroquine therapy.
Time point | Parasite clearance |
Fever clearance |
---|---|---|
At 6 hrs | NA | 122 (33.9) |
At 12 hrs | 35 (9.7) | 150 (41.7) |
At 18 hrs | NA | 159 (44.2) |
At 24 hrs | 117 (32.5) | 173 (48.1) |
At 30 hrs | NA | 163 (45.3) |
At 36 hrs | 222 (61.7) | 241 (66.9) |
At 42 hrs | NA | 284 (78.9) |
At 48 hrs | 281 (78.1) | 314 (87.2) |
At 54 hrs | NA | 325 (90.3) |
At 60 hrs | 325 (90.3) | 345 (95.8) |
At 66 hrs | NA | 349 (96.9) |
At 72 hrs | 358 (99.4) | 352 (97.8) |
At 78 hrs | NA | 357 (99.2) |
At 84 hrs | NA | 358 (99.4) |
The data includes all patients who were included to receive chloroquine therapy, NA: not applicable values.
The mean PCT was
Of the 319 patients included in the m-ITT population for efficacy assessment, four patients (three patients from conventional primaquine 15 mg group (2.86%) and one from primaquine SR 30 mg group (0.93%)) returned to clinic with presence of parasitaemia and signs and symptoms of malaria. The PCR genotyping analysis confirmed the relapse of
Efficacy of PSR 15 mg and PSR 30 mg against relapse of
Characteristics | P 15 mg | PSR 15 mg | PSR 30 mg | PSR 15 mg + PSR 30 mg |
---|---|---|---|---|
Number of randomized patients | 120 | 118 | 120 | 238 |
|
||||
Duration of follow-up (days) | ||||
Mean | 142.3 | 149.6 | 149.0 | 149.3 |
Median | 168 | 168 | 168 | 168 |
Total | 17076 | 17652 | 17876 | 35528 |
|
||||
Number of relapse, |
3 (2.86) | 0 (0.0) | 1 (0.93) | 1 (0.42) |
|
||||
|
— | 0.076 | 0.293 | 0.069 |
|
||||
Relapses per persons-year |
0.064 | 0.00 | 0.02 | 0.01 |
|
||||
Reduction in incidence, % (95% CI) |
NA | 100 (−134 to 100) | 68.2 (−29.6 to 99.4) | 83.9 (−99.5 to 99.7) |
|
||||
|
0.059 | 0.176 | 0.057 |
P 15 mg: conventional primaquine 15 mg, PSR 15 mg: primaquine sustained release 15 mg, and PSR 30 mg: primaquine sustained release 30 mg.
NA: not applicable value.
All four cases of relapse were considered treatment failure and were excluded from the study and treated as per investigator’s discretion. The cumulative risk of relapse is summarized in Figure
Kaplan-Meier estimates of cumulative risk of relapse. P 15 mg: conventional primaquine 15 mg, PSR 15 mg: primaquine sustained release 15 mg, and PSR 30 mg: primaquine sustained release 30 mg. Numbers written over the line are patients still undergoing follow-up. Differences in cumulative risk of relapse are statistically insignificant;
Compliance to study medication was significantly better in primaquine SR 30 mg (95.57%) and primaquine SR 15 mg (95.5%) groups as compared to conventional primaquine 15 mg group (93.1%) (
All the study drugs were well tolerated and there was no report of SAE. Commonly reported AEs during primaquine therapy and subsequent follow-up were headache, malaise, nausea, fever, and myalgia (Table
Numbers of AEs reported during chloroquine therapy and primaquine therapy.
Adverse event |
Chloroquine therapy |
Primaquine therapy | |||
---|---|---|---|---|---|
P 15 mg |
PSR 15 mg |
PSR 30 mg |
Total | ||
Malaise | 2 | 3 | 4 | 1 | 8 |
Headache | 4 | 1 | 2 | 2 | 5 |
Nausea | 12 | 2 | 1 | 1 | 4 |
Decreased appetite | 8 | 0 | 3 | 0 | 3 |
Pyrexia | 1 | 1 | 1 | 1 | 3 |
Vomiting | 5 | 1 | 1 | 1 | 3 |
Dizziness | 0 | 0 | 1 | 1 | 2 |
Myalgia | 0 | 2 | 0 | 0 | 2 |
Asthenia | 0 | 0 | 1 | 1 | 2 |
Arthralgia | 0 | 0 | 1 | 0 | 1 |
Pruritus | 5 | 0 | 0 | 1 | 1 |
Haemoglobin decreased | 0 | 0 | 0 | 1 | 1 |
Muscle spasms | 0 | 0 | 1 | 0 | 1 |
Dyspnoea exertional | 0 | 0 | 1 | 0 | 1 |
Dyspepsia | 0 | 0 | 0 | 1 | 1 |
Diarrhoea | 0 | 0 | 1 | 0 | 1 |
Diarrhoea | 1 | 0 | 0 | 0 | 0 |
Cough | 1 | 0 | 0 | 0 | 0 |
Total events |
|
|
|
|
|
Total patients, |
|
|
|
|
|
P 15 mg: conventional primaquine 15 mg, PSR 15 mg: primaquine sustained release 15 mg, and PSR 30 mg: primaquine sustained release 30 mg.
In the present study, sustained release formulation of primaquine was studied for the first time for preventing relapse of
Experimental studies with different strains of
A clinical study conducted in Thailand [
The results of present study indicate that both primaquine SR 15 mg and primaquine SR 30 mg formulations are equally effective as that of primaquine 15 mg in terms of preventing relapse of
In conclusion, the results of the present study demonstrated comparable efficacy, safety, and tolerability of primaquine SR 15 mg and primaquine SR 30 mg with that of conventional regimen of primaquine 15 mg in the prevention of relapse of
The study was approved by ethics committee of each site prior to initiation of the study at respective site.
Anil Pareek and Nitin Chandurkar are the employees of Ipca Laboratories Limited who sponsored this trial. Nithya Gogtay, Arvind Jain, Arjun Kakrani, Mala Kaneria, Partha Karmakar, Alaka Deshpande, Arun Chogle, Dhanpat Kochar, and Arnab Ray were the study investigators and received funds from Ipca Laboratories Limited for conducting the study. These authors did not receive any personal financial benefits and declare that they have no conflict of interests of declarable nature.
Anil Pareek and Nitin Chandurkar were involved in the conceptualization, coordination, and execution of the study, at all centers. Nithya Gogtay, Alaka Deshpande, Arjun Kakrani, Mala Kaneria, Partha Karmakar, Arvind Jain, Dhanpat Kochar, Arun Chogle, and Arnab Ray were the study investigators at their respective sites. All authors read and approved the final paper. Anil Pareek and Nitin Chandurkar are the guarantors of this paper.
Authors would like to acknowledge the efforts of Ravikiran Payghan and Anita Parihar, employees of Ipca Laboratories Limited, for their support in coordinating for the study related activities at all the sites, Kumar Naidu, Suresh Padwal, and Uma Sargar, employees of Ipca Laboratories Limited, for statistical analysis and data management for this study, Tushar Jadhao for his help in labelling and packaging of clinical trial supplies, and Shruti Kulkarni, employee of Ipca Laboratories Limited, for her help in drafting this paper. The study was sponsored by Ipca Laboratories Limited.