Clinical trial NCT01930331: Safety, Tolerability, Pharmacokinetics and Efficacy of ARCO
Official title: Safety, Tolerability, Pharmacokinetics and Efficacy, Phase Iv, Open Label Study of Fixed Arco® and Eurartesim® Therapies in Adults and Children With Uncomplicated P. Falciparum Malaria in Tanzania
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Plasmodium Falciparum
Malaria, Falciparum
Keywords: Uncomplicated Plasmodium falciparum Malaria
Lead sponsor: Ifakara Health Institute
Sponsor class: OTHER
First posted: 2013-08-28
Enrollment: 60
Sex: ALL
Minimum age (years): 6
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Phase IV, single center, 2 arms randomized controlled, open label study. Study will be conducted over a period of 42 days to determine the safety, tolerability, pharmacokinetics and efficacy of ARCO.

Detailed description: Evaluation of safety and tolerability of the administration of ARCO and Eurartesim in terms of blood biochemistry, full blood count, ECG assessments, vital signs and adverse events profile in patients with uncomplicated P. falciparum malaria. Dihydroartemisinin/piperaquine will be used as comparator.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent, in accordance with local practice, provided by patient, for children it will provided by either parents or legal representative and in addition children will provide assent.
2. Male or female patients between the age of 6 and 60 years (both inclusive)
3. Body weight between 20 kg and 90 kg (both inclusive)
4. Presence of mono-infection with P. falciparum (1,000 to 100,000 asexual count/µl of blood) microscopically confirmed.
5. Fever, as defined by axillary temperature ≥ 37.5°C to ≤ 39.5°C
6. Ability to swallow oral medication
7. Ability and willingness to adhere to all study procedures and access health facilities.
8. Agree to undergo study related procedures including being hospitalized for minimum of 3 days (0,1 and 2), and a follow up of up to 42 days.

Exclusion Criteria:

1. Patients with signs and symptoms of severe/complicated malaria as described in the WHO guideline(Third Edition 2012) for management of severe malaria(6)(Appendix 1)
2. Mixed Plasmodial infection.
3. Severe vomiting, defined as more than three times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment.
4. Severe diarrhoea defined as 3 or more watery stools per day.
5. Presence of other serious or chronic clinical condition requiring hospitalization.
6. Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, QTcF or QTcB interval greater than or equal to 450 msec), respiratory (including active tuberculosis), history of jaundice, hepatic, renal, gastrointestinal, immunological, neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions or other abnormality (including head trauma).
7. Family history of sudden death or of congenital prolongation of the QT interval or any other clinical condition known to prolong the QT interval.
8. Known congenital prolongation of the QT-interval or any clinical condition known to prolong the QT interval.
9. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.
10. Any predisposing cardiac conditions for arrhythmia such as severe hypertension, left ventricular hypertrophy (including hypertrophic cardiomyopathy) or congestive cardiac failure accompanied by reduced left ventricle ejection fraction.
11. Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia.
12. Any treatment which can induce a lengthening of QT interval, such as:

    i. Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol) ii. Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine) iii. Antidepressive agents, certain antimicrobial agents, including agents of the following classes macrolides (e.g. erythromycin, clarithromycin), fluoroquinolones (e.g. moxifloxacin, sparfloxacin), imidazole and triazole antifungal agents, and also pentamidine and saquinavir iv. Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine), cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide
13. Known history of hypersensitivity, allergic or adverse reactions to artemisinin containing compounds, piperaquine or naphthoquine or to any of the excipients contained in ARCO and Eurartesim.
14. Antimalarial treatment with different antimalarial drugs as follows i. Piperaquine-based compound, mefloquine, naphthoquine or sulphadoxine/pyrimethamine (SP) within the previous 3 months, ii. Amodiaquine or chloroquine within the previous 6 weeks, and with quinine, halofantrine, lumefantrine-based compounds and iii. Any other antimalarial treatment, antibiotics with antimalarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones, and azithromycin) or any herbal products, within the past 14 days
15. Have received an investigational drug within the past 6 weeks.
16. Liver function tests:

    i. If Total Bilirubin is normal, exclude the patient if liver function tests ASAT/ALAT ≥ 3xULN ii. If Total Bilirubin is \> 1 and ≤ 1.5xULN, exclude the patient if ASAT/ALAT ≥2xULN.

    iii. Total Bilirubin \>1.5xULN
17. Hb level below 9 g/dL.
18. Serum creatinine levels more than 2 times the upper limit of normal range in absence of dehydration. In case of important dehydration the creatinine should be lower than 2X ULN after oral/parenteral rehydration.
19. Female patients must be neither pregnant (as demonstrated by a negative serum pregnancy test) nor lactating, and must be willing to take measures not to become pregnant during the study period and safety follow-up period.
20. Previous participation in any malaria vaccine trial or received malaria vaccine in any other circumstance

Primary outcomes:
measure: Number of reported non serious and serious adverse events
timeFrame: Up to 6 Weeks
Secondary outcomes:
measure: 12-lead ECG recordings: Heart rate, PR interval, QRS duration, QT interval, QTc (Fridericia and Bazett corrections), any T wave or U-wave morphology.
timeFrame: Holter recording will run continuously during 12 hours after the last dose of treatment
Other outcomes:
measure: Frequency of abnormal safety laboratory parameters (hematology, clinical chemistry, urinalysis and coagulation) and clinical parameters (blood pressure, pulse rate, temperature)
timeFrame: weekly up to 6 weeks
Locations:
city: Bagamoyo
country: Tanzania
facility: Ifakara Health Institute
Study officials:
affiliation: Ifakara Health Institute
name: Salim Abdulla, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ali AM, Gausi K, Jongo SA, Kassim KR, Mkindi C, Simon B, Mtoro AT, Juma OA, Lweno ON, Gwandu CH, Bakari BM, Mbaga TA, Milando FA, Hamad A, Shekalaghe SA, Abdulla S, Denti P, Penny MA. Population Pharmacokinetics of Antimalarial Naphthoquine in Combination with Artemisinin in Tanzanian Children and Adults: Dose Optimization. Antimicrob Agents Chemother. 2022 May 17;66(5):e0169621. doi: 10.1128/aac.01696-21. Epub 2022 Apr 25.