Longitudinal Study Based on a Safety Registry for Malaria Patients Treated With Artenimol-Piperaquine in Six European Countries

doi:10.21203/rs.3.rs-138999/v1

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Longitudinal Study Based on a Safety Registry for Malaria Patients Treated With Artenimol-Piperaquine in Six European Countries

https://doi.org/10.21203/rs.3.rs-138999/v1

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Background

European travelers are exposed to imported malaria and may be affected by co-existing morbidities. In this context, the safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)-piperaquine (APQ) Eurartesim® during treatment of uncomplicated falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap.

Methods

Participants were recruited through Health Care Provider’s Safety Registry in 15 centers across 6 European countries in the period 2013-2016. Adverse Events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett’s (QTcB) or Fridericia’s (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females.

Results

Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m² (4.7).

Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection.. Women and Non-African participants had significantly (p<0.05) more AEs.

Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF>500 ms but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported.

The overall efficacy rate was 255/257 (99.2%).

Conclusions

APQ appears as an effective and well tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries.

(This study has been registered in EU Post-Authorization Studies Register as EUPAS6942)

Infectious Diseases

imported malaria

artenimol

piperaquine

Eurartesim

QTc prolongation

safety

adverse events

artemisinin

Plasmodium falciparum

Imported malaria into non-endemic regions, particularly Europe and North America is an ongoing threat and most of the cases are in travellers visiting family and relatives (1,2). Treatment regimens which are efficacious, well tolerated and with a simple administration schedule, to improve treatment out of hospital settings, are limited. The combination of artenimol 40 mg (previously dihydroartemisinin) and piperaquine tetraphosphate 320 mg (APQ), are marketed as Eurartesim® by Alfasigma (Italy) worldwide. Itis an effective artemisinin-based combination therapy which involves the simultaneous use of two blood schizontocidal compounds with independent modes of action, meeting all these needs (3,4).

The most common side-effects observed with APQ use in uncomplicated malaria patients (1-10 patients in 100) are anaemia, headache, corrected QT segment (QTc) prolongation and tachycardia (5).

Preclinical studies with artemisinin-related products in rats and dogs showed electrocardiographic (ECG) effects, in particular prolongation of QTc (6–8). Conversely, exposure to piperaquine was not associated with relevant ECG abnormalities (9). Malaria illness itself may also affect the heart and QT interval (10). Therefore the QTc prolongation risk was monitored during the clinical development of APQ, specifically in the pivotal clinical trials DM040010 and DM040011, where APQ was compared to loose combination of artesunate + mefloquine and fixed dose combination of artemether and lumefantrine regimen, respectively (11,12). In these studies, ECGs were performed on days 0 and 2 (last treatment day) and 7 after starting treatment. QTc interval was analysed using standard metrics according to ICH E14 guideline using the Bazett’s method correction (QTcB) (13). At baseline a certain number of QTc prolongation were observed and associated with the malaria infection. By day 2, a higher proportion of patients with prolonged QTc values were observed in the APQ group vs. comparators. However, only 7 subjects out of the 1,805 patients included in the two trials had a QTc >500 ms (0.38%). These changes were reversible, since by day 7, these differences disappeared. None of the prolongated QTc was associated with any clinically relevant arrhythmic event. Other studies showed less QTc prolongations after APQ treatment in fasting conditions (21.0 ms (15.7-26.4) vs 46.0 ms (39.6-52.3) with high-fat/high caloric breakfast) (5,14,15).

Following these studies the European marketing authorization for APQ was obtained for the treatment of uncomplicated Plasmodium falciparum malaria, including a warning not taking food 3 hours apart and that APQ should not be prescribed to patients with risk factors for QTc prolongation (i.e. family history of sudden death or of congenital prolongation of the QTc interval, known congenital prolongation of the QTc-interval, any clinical condition known to prolong the QTc interval, history of symptomatic cardiac arrhythmias, clinically relevant bradycardia, any predisposing cardiac conditions for arrhythmia, electrolyte disturbances, and recent or on-going treatment known to prolong the QTc interval) (5). However, no relevant observational data supporting this risk in patients based in Europe has been available.

In order to assess the actual safety profile and the potential for cardiotoxicity and QTc prolongation following APQ exposure in these patients, an European post-authorization safety registry was proposed with the goal to monitor all incoming patients with imported malaria. The present work is summarizing the results obtained in a study performed in patients from this registry.

Study design and participants

This study was an observational, registry-based, longitudinal, multicentric study assessing the safety profile of uncomplicated malaria patients receiving APQ treatment. Participants to the study were selected among patients included in an Health Care Provider (HCP) Safety Registry organized to monitor the outcome and safety of APQ treatment, consisting of 15 clinical centers across 6 European countries (Belgium, France, Germany, Italy, Spain and The United Kingdom) authorized for the use of APQ. Standard APQ treatment was given at the manufacturer recommended dosage of 320mg/40 mg coated-film tablets of either three tablets for participants weighting < 75 kg or four tablets in participants weighted ≥75 kg, administered three times at 24 hours interval.

Participants were selected based on the following inclusion criteria: clinical and parasitological diagnosis of uncomplicated Plasmodium falciparum malaria that met the SmPC indications, any genders and age, and signed informed consent and evidence of receiving the APQ treatment on the day of enrolment. Each HCPs were encouraged to include as many patients meeting the eligibility criteria. Pediatric patients (5 months to 18 years of age) could also be enrolled for inclusion in the registry with the child’s parent or legal guardian informed consent. To ensure sufficient power to conduct the analysis three hundred patients were considered an appropriate sample to define the drugs adverse events profile.

Safety data were collected during the normal course of patient care by HCPs preferably during a three-day hospitalisation or, when hospitalisation was refused or not possible, on an ambulatory basis. An ECG recording was recommended at baseline after patient enrolment (visit 1 defined as baseline day before or at the time of the first APQ administration) and after the last APQ dose (visit 2 = at the ‘final treatment day’, defined as the day of last APQ administration, applying a flexibility time-window of maximum 2 days in case of missing ECG assessment at the day of last APQ administration). For the purposes of the analysis, the subpopulation having an ECG on the ‘strict final treatment day’, defined as the day of last APQ administration, was also individualized and named ‘Strict QTc population’. A follow-up visit (visit 3) was planned between three to five weeks after hospital discharge or after the out-patient treatment. If the visit was not feasible, patients were contacted by an independent study monitor for follow-up between day 15 and day 45. Any AE and concomitant medication were recorded.

Safety outcome measurements

The primary objective was to study the safety profile associated to APQ treatments. The frequency and severity of all Adverse Events (AE) was recorded, with a particular attention to the main AE of Special Interest (AESI) for AQP treatment, i.e., cardiotoxicity, neurotoxicity, and phototoxicity. Investigators had to specify if AEs were suspected to be related to APQ. Differences between pre-treatment baseline values and post-treatment values were measured for blood chemistry markers, such as serum Alanine amino-transferase (ALAT), Aspartate amino-transferase (ASAT) and creatinine, and for ECG recording parameters, specifically the QTc intervals.

Measurements of blood chemistry markers such as serum ALAT, ASAT and creatinine were carried out in at each center using standard methodologies.

Measurements of ECG-based QTc interval (ms) were evaluated after correcting for the heart rate with Bazett’s (QTcB) and Fridericia’s formulae (QTcF) (13). QTc prolongation were defined by a value > 450 ms for males and children and > 470 ms for females (16). Borderline QTc was defined 430-450 ms for males and 430-470 for females. The QTc increase from baseline and the proportion of increase > 60 ms were also studied.

Other factors were also recorded using a questionnaire for multivariate analysis: age, gender, ethnicity, lifestyle (smoking status, alcohol consumption), co-morbidities and co-medications. Information about the time between intake of food and APQ dosing was also collected.

The cure rate was defined as negative parasitemia at Visit 3.

Statistical analyses

Three populations were analysed: (1) the general ‘safety population’ that include all subjects receiving at least one dose of APQ; (2) the ‘QTcF/QTcB population’ defined as all patients having at least two ECG, one at baseline-visit 1 and one at the ‘final treatment day’, and (3) the ‘Strict QTcF/QTcB population’ with the second ECG at the ‘strict final treatment day’.

Data were reported and tabled as mean + SD. Regarding the ECG measurements, differences in value of QTcF and QTcB were compared using ANOVA (p<0.05).

Change in the levels of ALAT, ASAT and creatinine were analysed with a non-parametric test of Wilcoxon’s.

Multivariate analysis were conducted with ANOVA including all covariates with a p<0.20 and using a Backward selection process with a p<0.05.

Ethics approval and consents to participate.

The study followed a centralized regulatory submission at the European Medicines Agency (approval 2013, prot. n° 3381). Ethical approval was received also by Hospital Ethics Committee in all the Countries participating in the study. Patients were enrolled after Informed consent signature.

From May 2013 to August 2016, a total of 297 patients were included by 15 active centers (among 29 contacted and 23 agreed to participate): two centers in Belgium (n=59 patients included), three in France (n=93), two in Germany (n=12), two in Italy (n=77), five in Spain (n=52) and one in the UK (n=4). Most of active centers were located at university hospitals (80.0%) in infectious and tropical diseases departments (66.6%). Additionally, 43 patients meeting the selection criteria were not included in the study because patient’s decision (34.3%), organizational reasons (20.0%) and medical reasons (17.1%).

Of these 297 patients, 294 patients received at least one dose of APQ and were considered in the analysis of the safety population registry (two patients were excluded because no information regarding APQ treatment was included in the CRF and one patient because he never received the drug). A total of 49 patients prematurely discontinued the study (38 lost to follow up, four moved away and seven for other reasons), most often after the final treatment day. They were considered in the analysis when information was available.

Characteristics of participants

Women accounted for 30.3 % of the participants (Table 1). The majority of patients were of African origin (84.6%) or Caucasian (13.7%). The mean age of patients was 39.8 years (SD: 13.2) with 3.4% 66-74 years old. The mean body weight of adult was 77.2 kg (range: 46-121) with 26 patients weighed at least 100 kg.

Median P. falciparum counts were 25.0 x10³/µL (IQR: 3.5-80.0) (n=273). Co-infection with other species were identified in 6 patients (P. vivax, n=1; P. ovale, n=2;P. malariae, n=3). The most frequent symptoms of malaria were fever and headache. Hemoglobin were below the lower normal range for 38.2% of participants at baseline [Additional file 2]. Liver and renal abnormalities were reported for 21.8% and 5.0% of participants, respectively.

Overall, 42.2% had a history of at least one comorbidity, of which 37.9% had hypertension, 10.5% diabetes, 14.5% HIV infection and 6.5% cardiac disorders (including 2 atrial fibrillations, 1 arrhythmia and 1 cardiac hypertrophy). Details of comorbidities can be viewed in [Additional file 1].

Among the 254/294 (86.4%) of patients who took concomitant medications at baseline, the most frequent were analgesics (77.2%), drugs for functional gastrointestinal disorders (21.3%), and antibiotics (21.3%). In total, between the month prior and the last day of APQ, 27.6% of participants had taken treatments known to prolong the QTc interval.

APQ was initiated on median the day of malaria diagnosis (IQR: 0-1) and 97.3% of patients received APQ for three days. APQ dosages were generally consistent with patient weight (minor inconsistencies, observed in 22 patients (7.9%), mainly 4 tablets per day for patient <75 kg). The 24 patients but one weighting 100 kg or more received adequate dosage (12 pills). The APQ administration more than three hours from food intake was respected in 182 of the 267 patients (68.2%) in whom information was available.

Parasitological outcome

The P. falciparum overall efficacy rate was 99.2% with 255/257 having negated his parasitemia during follow-up. Two patients were considered as developing a recurrence of malaria patients as they were found to have positive parasitemia at visit 3.

Safety parameters in Safety Population

No woman became pregnant after APQ administration. No substantial changes in hemoglobin and hematocrit were observed. Neutrophil granulocyte, platelet counts, liver parameters and C-reactive protein tended to improve during the course of the study. A total of 129 AEs were experienced by 75/294 patients (25.5%), of which 9 severe AE. In addition, 27 were serious AE were reported in the study (25 led to hospitalization / prolonged hospitalization, 11 to the prescription of corrective medications, 4 to APQ permanent discontinuation and 2 to another action) [Additional file 3]. Regarding the relationship with APQ, 46 were suspected to be related (Table 2), 11 of them were defined as serious AE (Table 3) and mostly labelled as due to haematological (anemia, hemolysis), gastrointestinal (vomiting, acute hepatitis), or infection (malaria, encephalitis brain stem) [Additional file 3].

Of the AE of special interest (AESIs), 28 occurred in 27 patients (9.2%). Among those reported, 21 cases (7.1%) were relation to cardiac abnormality (prolonged QTc, n=19, ventricular tachycardia, n=1, palpitation, n=1). The ventricular tachycardia occurring in a 36-year-old man with pre-existing ECG abnormalities five days after APQ administration, completely recovered, and was not suspected to be treatment-related but related to athlete cardiomyopathy. He received only one dose of APQ and switch for atovaquone/proguanil at Day 2 for 3 days due to vomiting. His QTcF/QTcB were normal at baseline and at day 2, and QTcF/QTcB changes after APQ were 5 and 9 ms respectively. Others cardiac AESIs were of mild intensity and of which 19 were considered related to APQ and 3 led to drug discontinuation. In addition, 6 cases (2.0%) of neurotoxicity (dizziness, n=4, hallucination, n=1, paraesthesia, n=1) were reported of which 4 cases were mild and 2 were of moderate intensity; 4 of them were considered APQ-related. Finally, 1 case (0.3%) of phototoxicity (rash of mild intensity) was raised, recovered after 3 weeks and was not considered drug related. Due to their rare occurrence, it was not possible to perform a factor analysis associated with AESIs.

According to multivariate analysis, Non-African patients and females were more likely to experience AEs (including AESIs) than African patients and males (p<0.05), respectively [Additional file 3]. Moreover, in univariate analysis, the percentage of patients who experienced at least one AE (including AESIs) suspected to be related to APQ was lower (p<0.05) in African patients and in patients without renal abnormalities [Additional file 4].

QTc prolongation

At baseline, among the 234 out of 237 patients with available ECG information, QTcF/QTcB values were normal for the majority of patients. Prolonged and borderline QTcF were observed in four (1.7%) and 10 (4.3%) patients, respectively. These figures were 13 (5.5%) and 27 (11.4%) for QTcB. Only one patient (male, 33 years) had a QTc value >500 ms at baseline (QTcB=557 ms and QTcF=478 ms), before APQ administration, but was lost to follow up without another ECG.

The ‘QTcF/QTcB population’ was of 143 out of 234 participants, whereas the ‘strict QTcF/QTcB population” was of 60 out of 143.

ECG changes are detailed in Table 4. In the ‘QTcF/QTcB population’, a QTc prolongation at final treatment day was observed for 5 patients/143 (3.4%) for QTcF and 9/143 (6.3%) for QTcB. In the ‘strict QTcF/QTcB population’, a QTc prolongation at the strict final treatment day was observed for 4 patients/60 (6.7%) for QTcF and 5/60 (8.3%) for QTcB. Increase >60 ms in value from baseline to visit 2 was reported for 9 and 2 patients for QTcF and QTcB (Table 4). Over the follow-up period, QTc values > 500 ms were reported in two patients: one on the second day (QTcB=510 ms and QTcF=501 ms) and one on the third day (QTcB=531 ms and QTcF=425 ms). The first patient was an African male (66 years) with a QTcB/QTcF already prolonged at baseline (557 /478ms) and a QTc assessment performed 4 hours after first APQ administration with food intake less than three hours from APQ and concomitant terbutaline intake. QTcF/QTcB returned to normal on the third day. The second patient was a 19-year-old African man with a QTcB at 413 ms at baseline before APQ and no other risk factors The QT anomalies resolved within 24 hours and had no clinical consequences.

The mean change in QTcF and QTcB from baseline to the strict final treatment day (n=60) was +17.5 and + 2.6 ms respectively. Multivariate assessment of the factors associated to changes in the eligible population is shown in Table 5. Patients who never smoked had a statistically significantly (p<0,05) lower increase in QTcB value from baseline to the final treatment day (visit 2) (but not significant for QTcF; p=0.18). Similarly, the four patients >65 years had a significantly greater increase in QTcB value than others ≤ 65 years but only in univariate analysis with QTcB and concerned a very small number of participants (n = 4). No other factors were found to have a statistically significant association with change in QTcB/F. In the strict QTcB/F population, some trends in mean QTcB/F change were observed for factors such as ‘APQ administered at least 3 hours from any meal’ and ‘alcohol consumption’, without being significant.

Blood Chemistry markers

Changes in ALAT, ASAT and creatinine from baseline to final treatment day were not significant. Factors associated with these changes are presented in [Additional file 5]. Univariate and multivariate analyses showed that the increase in ALAT value between baseline and visit 2 was significantly (p<0.05) smaller among people who never smoked.

Safety of APQ was studied in patients with diagnosis of uncomplicated acute P. Falciparum malaria using a post-registration longitudinal Registry in 15 HCP centres of 6 European countries. One in four participants reported a total of 129 AEs. Of the AEs, 46 (11 serious) were suspected to be related to APQ, the most common being gastrointestinal disorders. There were 28 AE of special interest (cardiotoxicity, neurotoxicity and phototoxicity), predominantly cardiological (n=21) (7.1%), therefore it was not possible to analyse the factors associated with the development of neurotoxicity and phototoxicity events.

Focusing on the cardiovascular safety outcome, on QTcF corrections, QT prolongation was observed in 5/143 participants serially assessed (11.9%), with no clinical symptoms. An increase of >60 ms occurred in 9 participants (6.3%). Almost all of the QTc prolongations were less than 500 ms and judged as non-serious AE. In the two patients with QT prolongation over 500 ms following the first dose of APQ, the maximum value was 531 ms (QTcB). An association was observed between older (age > 65 years) individuals, and increase in QTcB, but with only four patients >65 years it is difficult to draw conclusions without additional work. Furthermore, these differences were not observed with QTcF adjustments.

These findings are comparable to those observed during Eurartesim® development in the DM040011 study (n=1038 subjects; prolonged QTcB and QTcF intervals were observed in 8.6% and 4.7% of patients, respectively) and in the DM040010 study (n=756 subjects; prolonged QTcB intervals were observed in 9.1% of patients, and QTcB increase >60 ms in 2.7% patients). In these studies only 7 patients showed QTcF> 500 ms (0.4%) (2,3).

In a large prospective study (17) in four African countries evaluating the clinical safety of APQ among 10,925 uncomplicated malaria cases, 797 adverse events were reported (5%), mainly infections (3.24%) and gastrointestinal disorders (1.37%). Within this study, a nested cohort of 1,002 patients (161 adults and 841 children) who had completed three doses of APQ and who had complete cardiac monitoring with repeated ECGs, eighty-nine patients (8.9%) had an increase in the QTcF compared to their baseline measurements. On day 3 pre- and post-intake, 70 and 89 patients, respectively, had a QTcF increase of ≥60 ms compared to their baseline, but returned to nearly baseline values on day 7. No patient had QTcF > 500 ms prior to day 3. Three patients had QTcF > 500 ms (509 ms, 501 ms, 538 ms) three to four hours after intake of the last dose. All the QTcF values in the three patients had returned to <500 ms on day 7 (470 ms, 442 ms, 411ms).

Again, a clinical trial in Ghana evaluated safety of APQ, among 4563 patients (16.0% >18 years old) did not identify any serious safety concerns (18). Incidence of AEs was 7.6% (11.8% for participants >18 years old), mostly infections (4.6%) and gastrointestinal disorders (1.0%). Only 3/477 (0.6%) patients had QTcF above the 500 ms cutoff value and 38/477 (8.0%) an QTcF increase >60 ms, which were not clinically significant. Another post-licensure study conducted among 1147 patients (18.3% >=18 years) from four African countries found QTcF values>500 ms on day 3 in 37 (3.2%) of participants, none of which was clinically relevant (19). Further, in an open label trial conducted in Malawi and Mozambique on HIV-infected patients with uncomplicated malaria who were on efavirenz or nevirapine-based treatment, increase QT interval >60 ms from baseline occurred in 31.2% (48/154) and 13.3% (8/60) of the patients, respectively. These were not clinically significant and resolved spontaneously over time (20). In a randomized, multicenter, clinical trial conduct in three countries in Africa (7% >= 15 years old), QTcF increase of more than 60 ms occurred in 11% of participants treated with APQ and 6/797 (0.8%) had a post-dose QTcF value longer than 500 ms (21)(22).

Our results, in patients from non-endemic European countries, are therefore consistent with these studies from Africa or Asia, which describe infrequent episodes of reversible QTc prolongation with no clinical impact.

Among other observations, changes in ALAT and ASAT were of limited interest given the small change in values between groups. No factors were significantly associated with the changes in creatinine values.

Overall, few serious adverse event and no new safety signals were detected. At the multivariate analysis, AEs were significantly more often encountered among women and patients of non-African origin. To our knowledge, this is the first time this association was recognised, and the further research in these populations would be required to confirm and better understand these differences.

The study showed a cure rate of 99.2%, in line with the expected APQ efficacy (11,12).

The strength of the study is to be a registry-based, series of patients with imported malaria exposed to APQ in six European countries with a systematic collection of all AEs in a context where concerns arise about the tolerance of antimalarial treatments in Europe. It provides a better understanding of the use of APQ in people with co-morbidities. Our study has also several limitations: it is not a comparative study; the Registry contained a small number of patients; hereby its statistical power is limited; not all patients had an ECG performed on the day of the last APQ intake. The potassium value was not collected. Given these limitations, some differences are to be interpreted with caution.

This is the first study addressing the safety profile of APQ treatment in a consistent number of patients with uncomplicated malaria imported to European countries in a context of routine medical prescribing of APQ. The description of the range of AE’s and the analysis of the QTc interval and other safety data, led to the conclusion that there was no new safety signal or notable changes in their frequency as compared to previously identified signals in endemic populations. Although transient QTc prolongations up to a maximum of 531 ms was reported in one subject, no clinical consequence was observed. The efficacy rate at over 99%, was also as expected. APQ was found to be a well-tolerated ACT with efficacy and safety at least equivalent to the other artemisinin-based combination therapies available in the EU. It is also characterised by a simple administration modality, once a day for 3 days, which favors compliance to treatment and is a valuable option for use in the first-line treatment of uncomplicated P. falciparum imported malaria.

Consent for publication

All authors contributed, have reread and consented to the publication.

Availability of data and material

All relevant data for our analyses are fully described in the paper and can be made available on request.

Competing interests

GGM and EMP are full-time employee of Alfasigma S.p.A.. ST, MI, AB, were full employee for Alfasigma S.p.A at the time of the design, implementation and data analysis. OB, TJ, AB, ZB, EB, LV, CH, SD and RHB were on Euratesim® advisory board of Alfasigma and the legacy company Sigma-tau Industrie Farmaceutiche Riunite and received financial support for the study. NV declared that he has no competing interests.

Funding

This study was supported by the legacy company Sigma-tau Industrie Farmaceutiche Riunite S.p.A., Italy, currently Alfasigma S.p.A, Bologna. Italy

Authors' contributions

YB, ST, MI, AB, SC and RHB designed the research and organized the data collection. NV, OB, TJ, AB, ZB, EB, LV, CH, SD and RHB contributed to the inclusion of patients in the study. NV, OB, YB, ST, MI, AB, and SC prepared and analysed the data. All authors participated in the data interpretation. NV, OB, GGM, EMP and RHB performed the literature search and drafted the manuscript. All authors have critically proofread the article. NV, OB and RB had full access to all the data and final responsibility for the decision to submit for publication.

Acknowledgements

The authors would like to thank all the people who participated in the study, health care providers that included patients (Dr VAN LAETHEM, Travel Clinic – CHU St Pierre, Belgium, Dr Matthieu MECHAIN, Hôpital St André, France, Dr Frédéric BIDEGAIN, CHU Avicenne, France, Pr Christophe RAPP, Hôpital d’Instruction des Armées Begin, France, Dr NOTHDURFT, Klinikum der LMU Mûnchen, Germany, Dr RAMOS, Hospital General Universitario Alicante, Spain, Dr ROJO MARCOS, Hospital Universitario Principe de Asturias, Spain, Dr SALAS CORONAS, Hospital de Poniente, Spain, Dr ALCOCON, Hospital Universitario Fundacion Aldcorcon, Spain) , the MAPI group (Yann BOURHIS, Stéphanie CHRETIN), Alfasigma S.p.A. for the financing of the survey, the provision of data, and coordination of the survey and the APQ advisory board for its contribution to the interpretation and analysis of the results.

Mace KE. Malaria Surveillance — United States, 2015. MMWR Surveill Summ [Internet]. 2018 [cited 2020 Nov 13];67. Available from: https://www.cdc.gov/mmwr/volumes/67/ss/ss6707a1.htm
ECDC. Malaria - Annual Epidemiological Report for 2018 [Internet]. ECDC; 2020. Available from: https://www.ecdc.europa.eu/en/publications-data/malaria-annual-epidemiological-report-2018
Naing C, Mak JW, Aung K, Wong JYR. Efficacy and safety of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum malaria in endemic countries: meta-analysis of randomised controlled studies. Trans R Soc Trop Med Hyg. 2013 Feb;107(2):65–73.
Guidelines for the treatment of malaria - Third edition [Internet]. WHO Library Cataloguing-in-Publication Data. Geneva, Switzerland; 2015 [cited 2020 Nov 11]. 316 p. Available from: https://www.who.int/publications/i/item/9789241549127
Eurartesim Summay of product characteristics. [Internet]. European Medicines Agency; 2011 [cited 2020 Nov 24]. Available from: https://www.ema.europa.eu/en/documents/product-information/eurartesim-epar-product-information_en.pdf
Brewer TG, Grate SJ, Peggins JO, Weina PJ, Petras JM, Levine BS, et al. Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg. 1994 Sep;51(3):251–9.
Brewer TG, Peggins JO, Grate SJ, Petras JM, Levine BS, Weina PJ, et al. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg. 1994 Jun;88 Suppl 1:S33-36.
Classen W, Altmann B, Gretener P, Souppart C, Skelton-Stroud P, Krinke G. Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs. Exp Toxicol Pathol Off J Ges Toxikol Pathol. 1999 Nov;51(6):507–16.
Davis TME, Hung T-Y, Sim I-K, Karunajeewa HA, Ilett KF. Piperaquine: a resurgent antimalarial drug. Drugs. 2005;65(1):75–87.
Chan XHS, Win YN, Haeusler IL, Tan JY, Loganathan S, Saralamba S, et al. Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data. PLoS Med. 2020;17(3):e1003040.
Bassat Q, Mulenga M, Tinto H, Piola P, Borrmann S, Menéndez C, et al. Dihydroartemisinin-piperaquine and artemether-lumefantrine for treating uncomplicated malaria in African children: a randomised, non-inferiority trial. PloS One. 2009 Nov 17;4(11):e7871.
Valecha N, Phyo AP, Mayxay M, Newton PN, Krudsood S, Keomany S, et al. An open-label, randomised study of dihydroartemisinin-piperaquine versus artesunate-mefloquine for falciparum malaria in Asia. PloS One. 2010 Jul 30;5(7):e11880.
The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs : ICH [Internet]. [cited 2019 Aug 26]. Available from: https://www.ich.org/products/guidelines/efficacy/efficacy-single/article/questions-answers-the-clinical-evaluation-of-qtqtc-interval-prolongation-and-proarrhythmic-poten.html
Funck-Brentano C, Bacchieri A, Valentini G, Pace S, Tommasini S, Voiriot P, et al. Effects of Dihydroartemisinin-Piperaquine Phosphate and Artemether-Lumefantrine on QTc Interval Prolongation. Sci Rep. 2019 28;9(1):777.
Price RN, Dorsey G, Nosten F. Antimalarial therapies in children from Papua New Guinea. N Engl J Med. 2009 Mar 19;360(12):1254; author reply 1255.
Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol. 2008 Jun 17;51(24):2291–300.
Baiden R, Oduro A, Halidou T, Gyapong M, Sie A, Macete E, et al. Prospective observational study to evaluate the clinical safety of the fixed-dose artemisinin-based combination Eurartesim® (dihydroartemisinin/piperaquine), in public health facilities in Burkina Faso, Mozambique, Ghana, and Tanzania. Malar J. 2015 Apr 15;14:160.
Oduro AR, Owusu-Agyei S, Gyapong M, Osei I, Adjei A, Yawson A, et al. Post-licensure safety evaluation of dihydroartemisinin piperaquine in the three major ecological zones across Ghana. PloS One. 2017;12(3):e0174503.
Kabanywanyi AM, Baiden R, Ali AM, Mahende MK, Ogutu BR, Oduro A, et al. Multi-Country Evaluation of Safety of Dihydroartemisinin/Piperaquine Post-Licensure in African Public Hospitals with Electrocardiograms. PloS One. 2016;11(10):e0164851.
Sevene E, Banda CG, Mukaka M, Maculuve S, Macuacua S, Vala A, et al. Efficacy and safety of dihydroartemisinin-piperaquine for treatment of Plasmodium falciparum uncomplicated malaria in adult patients on antiretroviral therapy in Malawi and Mozambique: an open label non-randomized interventional trial. Malar J. 2019 Aug 20;18(1):277.
West African Network for Clinical Trials of Antimalarial Drugs (WANECAM). Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial. Lancet Lond Engl. 2018 07;391(10128):1378–90.
Funck-Brentano C, Ouologuem N, Duparc S, Felices M, Sirima SB, Sagara I, et al. Evaluation of the effects on the QT-interval of 4 artemisinin-based combination therapies with a correction-free and heart rate-free method. Sci Rep. 2019 29;9(1):883.

Table 1. Characteristics of participants - safety registry of malaria patients treated with artenimol-piperaquine.

	Safety population		QTcF population	Strict QTcF population
	N=294		N=143	N=60
Age (years)
Mean (SD)	39.8 (13.2)		37.5 (12.4)	37.7 (12.1)
Range	1.5 ; 74.0		12.0 ; 72.0	12.0 ; 72.0
Age category
<= 12 years old	5	(1.7%)	1 (0.7%)	1 (1.7%)
13-17 years old	5	(1.7%)	5 (3.5%)	2 (3.3%)
>= 18 years old	284	(96.6%)	137 (95.8%)	57 (95.0%)
Gender
Male	205	(69.7%)	98 (68.5%)	42 (70.0%)
Female	89	(30.3%)	45 (31.5%)	18 (30.0%)
Ethnicity
Missing	1
Oriental	1	(0.3%)
African	248	(84.6%)	118 (82.5%)	51 (85.0%)
Caucasian	40	(13.7%)	24 (16.8%)	8 (13.3%)
Hispanic	1	(0.3%)	1 (0.7%)	1 (1.7%)
Other	3	(1.0%)
Body Mass Index at Visit 1 (kg/m²)
Mean (SD)	25.9 (4.7)		25.6 (4.6)	26.1 (5.2)
Range	15.7 ; 42.2		17.1 ; 13.9	18.2 ; 37.8
Smoking Status
Missing	12		5	3
Never smoked	205	(72.7%)	101 (73.2%)	40 (70.2%)
Previous smoker	39	(13.8%)	16 (11.6%)	9 (15.8%)
Current smoker	38	(13.5%)	21 (15.2%)	8 (14.0%)
Alcohol consumption
Missing	14		5	3
Never/On special occasions (less than once a week)	237	(84.6%)	115 (83.3%)	45 (78.9%)
Ex-consumer	5	(1.8%)	3 (2.2%)	2 (3.5%)
Current consumer	38	(13.6%)	20 (14.5%)	10 (17.5%)
At least one illness history
Yes (cf Additional file for details)	124	(42.2%)	55 (38.5%)	26 (43.3%)
No	170	(57.8%)	88 (61.5%)	34 (56.7%)
Clinical symptoms at enrolment
Yes	278	(94.6%)	138	56 (93.3%)
No	16	(5.4%)	5	4 (6.7%)
Symptoms
Fever	261	(88.8%)	128 (89.5%)	50 (83.3%)
Headache	195	(66.3%)	99 (69.2%)	41 (68.3%)
Shivering	146	(49.7%)	78 (54.5%)	33 (55.0%)
Arthralgia	137	(46.6%)	72 (50.3%)	27 (45.0%)
Sweating	110	(37.4%)	55 (38.5%)	21 (35.0%)
Vomiting	107	(36.4%)	49 (34.3%)	15 (25.0%)
Anemia	26	(8.8%)	11 (7.7%)	7 (11.7%)
Jaundice	14	(4.8%)	6 (4.2%)	4 (6.7%)
Splenomegaly	14	(4.8%)	8 (5.6%)	1 (1.7%)
Hepatomegaly	3	(1.0%)	3 (2.1%)	3 (5.0%)
Retinal damage	0		0	0
Coma	1	(0.3%)	0	0
Other symptom	103	(35.0%)	51 (35.7%)	23 (38.3%)

QTcF population: patients with corrected QT interval calculated using Fridericia’s formulae, SD: Standard deviationStrict Strict QTcF/B population: patients with corrected a QT interval calculated at the strict final treatment day

Table 2: Overview of adverse events (AE) other than adverse event of special interest (AESI) suspected related to APQ by System Organ Class and Preferred Term

System Organ Class (MedDRA) Preferred Term (MedDRA)	Safety population
System Organ Class (MedDRA) Preferred Term (MedDRA)	Patients * N=294		Events N=46
Blood and lymphatic system disorders	4	(1.4%)	4
Haemolysis	2	(0.7%)	2
Anaemia	1	(0.3%)	1
Haemolytic anaemia	1	(0.3%)	1
Gastrointestinal disorders	16	(5.4%)	20
Vomiting	9	(3.1%)	9
Diarrhoea	4	(1.4%)	4
Abdominal pain	3	(1.0%)	3
Nausea	2	(0.7%)	2
Gastrointestinal pain	1	(0.3%)	2
General disorders and administration site conditions	2	(0.7%)	2
Asthenia	1	(0.3%)	1
Malaise	1	(0.3%)	1
Hepatobiliary disorders	2	(0.7%)	2
Hepatitis	1	(0.3%)	1
Hepatitis acute	1	(0.3%)	1
Infections and infestations	3	(1.0%)	3
Encephalitis brain stem	1	(0.3%)	1
Malaria	1	(0.3%)	1
Plasmodium falciparum infection	1	(0.3%)	1
Musculoskeletal and connective tissue disorders	4	(1.4%)	4
Back pain	2	(0.7%)	2
Myalgia	1	(0.3%)	1
Rhabdomyolysis	1	(0.3%)	1
Nervous system disorders	4	(1.4%)	7
Headache	3	(1.0%)	6
Insomnia	1	(0.3%)	1
Respiratory, thoracic and mediastinal disorders	2	(0.7%)	2
Dyspnoea	2	(0.7%)	2
Skin and subcutaneous tissue disorders	2	(0.7%)	2
Dry skin	1	(0.3%)	1
Pruritus	1	(0.3%)	1

*If one patient presented an event several times (same preferred term), s/he is counted once for that term. The same rule applies for results by System Organ Class.

An event is considered as suspected related to APQ if the relationship with APQ is 'related', 'suspected', 'unassessable' or 'missing' as reported by the investigator in the 'Adverse event' section of the CRF.

AE: Adverse event, SAE: Serious adverse event, AESI: Adverse event of special interest, APQ: artenimol-piperaquine, MedDRA: AEs are coded using MedDRA dictionary version 16.0.

Table 3: Overview of serious adverse events (AE) other than adverse event of special interest (AESI) suspected related to APQ by System Organ Class and Preferred Term

System Organ Class (MedDRA) Preferred Term (MedDRA)	Safety population
System Organ Class (MedDRA) Preferred Term (MedDRA)	Patients * N=294		Events N=11
Blood and lymphatic system disorders	3	(1.0%)	3
Haemolysis	2	(0.7%)	2
Anaemia	1	(0.3%)	1
Gastrointestinal disorders	2	(0.7%)	3
Vomiting	2	(0.7%)	2
Nausea	1	(0.3%)	1
General disorders and administration site conditions	1	(0.3%)	1
Malaise	1	(0.3%)	1
Hepatobiliary disorders	2	(0.7%)	2
Hepatitis	1	(0.3%)	1
Hepatitis acute	1	(0.3%)	1
Infections and infestations	2	(0.7%)	2
Encephalitis brain stem	1	(0.3%)	1
Plasmodium falciparum infection	1	(0.3%)	1

*If one patient presented an event several times (same preferred term), s/he is counted once for that term. The same rule applies for results by System Organ Class.

AE: Adverse event, SAE: Serious adverse event, AESI: Adverse event of special interest, APQ: artenimol-piperaquine, MedDRA: AEs are coded using MedDRA dictionary version 16.0.

Table 4. ECG after treatment administration: QTcB and QTcF (continuous parameter in ms) - Safety, QTcF/QTcB and strict QTcF/QTcB population

	Safety population		QTcF/QTcB population		Strict QTcF/QTcB population
	N=294		N=143		N=60
	QTcF	QTcB	QTcF	QTcB	QTcF	QTcB
Baseline
N	234	237	143	143	60	60
Missing	60	57	0	0	0	0
Mean (SD)	387.8 (29.6)	410.8 (32.3)	385.3 (28.6)	408.5 (29.8	386.8 (32.8)	407.7 (33.4)
Range	290 ; 478	290 ; 557	299 ; 470	309 ; 486	299 ; 470	309 ; 480
Final Treatment Day
N	186	186	143	143
Missing	108	108	0	0
Mean (SD)	405.9 (28.8)	413.9 (31.8)	404.2 (29.1)	411.8 (32.3)
Range	299 ; 494	289 ; 500	299 ; 494	289 ; 500
Strict Final Treatment Day
N	71	71	60	60	60	60
Missing	223	223	83	83	0	0
Mean (SD)	406.7 (36.2)	411.7 (38.8)	404.3 (35.3)	410.2 (38.4)	404.3 (35.3)	410.2 (38.4)
Range	299 ; 494	289 ; 500	299 ; 494	289 ; 500	299 ; 494	289 ; 500
Absolute change from Baseline to Final Treatment Day
N	143	146	143	143
Missing	151	148	0	0
Mean (SD)	18.9 (24.7)	4.0 (26.7)	18.9 (24.7)	3.3 (25.0)
Range	- 47 ; 81	- 68 ; 116	- 47 ; 81	- 68 ; 80
Absolute change from Baseline to Strict Final Treatment Day
N	60	62	60	60	60	60
Missing	234	232	83	83	0	0
Mean (SD)	17.5 (18.9)	4.7 (26.7)	17.5 (18.9)	2.6 (22.8)	17.5 (18.9)	2.6 (22.8)
Range	- 23 ; 69	- 46 ; 116	- 23 ; 69	- 46 ; 80	- 23 ; 69	- 46 ; 80
Change in QTcF/QTcB in classes from baseline to Final Treatment Day
Missing	151	148	0	0
Strict decrease or no change	28 (19.6%)	65 (44.5%)	28 (19.6%)	64 (44.8%)
Increase < 30 ms	70 (49.0%)	59 (40.4%)	70 (49.0%)	58 (40.6%)
Increase between 30 to 60 ms	36 (25.2%)	20 (13.7%)	36 (25.2%)	20 (14.0%)
Increase > 60 ms	9 (6.3%)	2 (1.4%)	9 (6.3%)	1 (0.7%)
Change in QTcF/QTcB in classes from baseline to Strict Final Treatment Day
Missing	234	232	83	83	0	0
Strict decrease or no change	10 (16.7%)	30 (48.4%)	10 (16.7%)	30 (50.0%)	10 (16.7%)	30 (50.0%)
Increase < 30 ms	36 (60.0%)	24 (38.7%)	36 (60.0%)	23 (38.3%)	36 (60.0%)	23 (38.3%)
Increase between 30 to 60 ms	12 (20.0%)	6 (9.7%)	12 (20.0%)	6 (10.0%)	12 (20.0%)	6 (10.0%)
Increase > 60 ms	2 (3.3%)	2 (3.2%)	2 (3.3%)	1 (1.7%)	2 (3.3%)	1 (1.7%)

QTcF/B population: patients with corrected QT interval calculated using Fridericia’s formulae/Bazett’s formulae; Strict QTcF/B population: patients with corrected a QT interval calculated at the strict final treatment day

Table 5: Factors associated with the change in QTcF and QTcB from baseline to the final treatment day or strict final treatment day

QTcF population (N=143)

Strict QTcF population (N=60)

QTcB population (N=143)

Strict QTcB population (N=60)

Change in QTcF value from baseline to the final treatment day (ms): mean [CI95%]

ANOVA: p-value and R-squared

Multivariate analysis (ANOVA, backward selection process)

Change in QTcF value from baseline to the strict final treatment day (ms): mean [CI95%]

Change in QTcF value from baseline to the final treatment day (ms): mean [CI95%]

ANOVA: p-value and R-squared

Multivariate analysis (ANOVA, backward selection process)

Change in QTcF value from baseline to the strict final treatment day (ms): mean [CI95%]

Total

143

18.9 [14.8;23.0]

17.5 [12.6;22.4]

143

3.3 [-0.8;7.4]

2.6 [-3.3;8.5]

Sex

Male

18.7 [14.1;23.4]

p=0.90

17.4 [10.9;23.8]

3.9 [-1.0;8.8]

p=0.67

2.9 [-4.4;10.3]

Female

19.3 [10.9;27.6]

R²=0.0%

17.7 [10.4;25.0]

2.0 [-6.0;10.0]

R²=0.1%

1.7 [-9.0;12.5]

Age category

< 18 years old

26.5 [1.0;52.0]

p=0.44

14.0 [_34.0;62.0]

- 0.5 [-19.6;18.6]

p=0.71

- 13.0 [-35.0;9.1]

>= 18 years old

137

18.6 [14.4;22.8]

R²=0.4%

17.6 [12.6;22.7]

137

3.5 [-0.8;7.7]

R²=0.1%

3.4 [-2.7;9.5]

<= 65 years old

139

18.4 [14.3;22.6]

p=0.19

Not retained

17.0 [12.0;22.0]

139

2.5 [-1.6;6.7]

p=0.03

Not retained

1.6 [-4.3;7.4]

> 65 years old

35.0 [20.9;49.1]

R²=1.2%

31.0 [-57.9;119.9]

30.5 [4.4;56.6]

R²=3.4%

32.0 [-120.5;184.5]

Ethnicity

African

118

18.3 [13.7;23.0]

p=0.54

17.2 [11.6;22.7]

118

2.3 [-2.5;7.0]

p=0.29

1.6 [-5.1;8.3]

Others

21.6 [13.1;30.2]

R²=0.3%

19.2 [7.9;30.5]

8.1 [0.2;16.0]

R²=0.8%

8.1 [-4.2;20.4]

Smoking status

Never smoked

101

17.1 [12.3;21.9]

p=0.18

Not retained

15.0 [10.3;19.7]

101

0.2 [-4.7;5.1]

p=0.02

p=0.0204

- 0.0 [-6.2;6.2]

Previous, current smoker or missing information

23.2 [15.3;31.1]

R²=1.3%

22.4 [10.6;34.2]

10.8 [3.4;18.2]

R²=3.8%

7.8 [-5.5;20.9]

Alcohol consumption

Never/On special occasions

115

19.3 [14.6;23.9]

p=0.74

19.3 [14.1;24.6]

115

3.2 [-1.4;7.8]

p=0.92

3.7 [-2.7;10.0]

Ex- or current consumer or missing information

17.5 [8.3;26.7]

R²=0.1%

11.9 [-0.7;24.5]

3.8 [-6.3;13.8]

R²=0.0%

- 0.8 [-16.1;14.5]

APQ administered at least 3 hours from any meal

Yes

19.1 [14.2;24.1]

p=0.87

20.8 [14.3;27.2]

1.9 [-3.3;7.1]

p=0.35

5.3 [-2.3;13.0]

No or missing information

18.4 [10.9;26.0]

R²=0.0%

10.4 [3.9;16.8]

6.0 [-0.9;13.0]

R²=0.6%

- 3.4 [-12.5;5.6]

Patient having taken other treatments known to prolong QTc

Yes

20.6 [12.0;29.3]

p=0.65

17.7 [8.0;27.3]

7.3 [-0.8;15.4]

p=0.30

8.7 [-4.4;21.8]

110

18.4 [13.7;23.1]

R²=0.1%

17.4 [11.6;23.2]

110

2.1 [-2.7;6.9]

R²=0.8%

0.9 [-5.9;7.6]

Liver abnormalities at baseline

Yes

15.9 [5.9;25.9]

p=0.51

11.8 [-3.0;26.6]

1.9 [-6.9;10.6]

p=0.76

2.3 [-13.1;17.8]

No or missing information

118

19.5 [15.0;24.1]

R²=0.3%

18.9 [13.7;24.0]

118

3.6 [-1.1;8.3]

R²=0.1%

2.6 [-4.0;9.2]

Renal abnormalities at baseline

Yes

27.7 [2.8;52.5]

32.5 [27.0;38.0]

23.7 [-27.3;74.6]

34.0 [-93.1;161.1]

No or missing information

140

18.7 [14.6;22.9]

16.9 [11.9;22.0]

140

2.9 [-1.3;7.0]

1.5 [-4.4;7.4]

QTcF/B: corrected QT interval with Fridericia’s or Bazett’s formulae, QTcF/B population: patients with corrected QT interval calculated using Fridericia’s formulae/Bazett’s formulae, ms: millisecond, CI95%: 95% confidence interval, R²: R-squared, APQ: artenimol-piperaquine; Strict QTcF/B population: patients with corrected a QT interval calculated at the strict final treatment day

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You are reading this latest preprint version

Longitudinal Study Based on a Safety Registry for Malaria Patients Treated With Artenimol-Piperaquine in Six European Countries

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Abstract

Introduction

Methods

Study design and participants

Safety outcome measurements

Statistical analyses

Ethics approval and consents to participate.

Results

Characteristics of participants

Parasitological outcome

Safety parameters in Safety Population

QTc prolongation

Blood Chemistry markers

Discussion

Conclusion

Declarations

Consent for publication

Availability of data and material

Competing interests

Funding

Authors' contributions

Acknowledgements

References

Tables

Supplementary Files

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