Phase II Efficacy Study of Artefenomel & Piperaquine in Adults & Children With P. Falciparum Malaria.

• Status: Completed
• Trial end date: 2015-11-01
• Target enrollment: 0
• Participant gender: All

Summary

A randomised, double-blind single-dose study to determine the efficacy, safety, tolerability and pharmacokinetics of OZ439 (artefenomel) in combination with piperaquine (PQP) in patients > 0.5 years and <= 70 years of age with uncomplicated Plasmodium falciparum malaria in Africa and Asia (Vietnam).

Interim analyses for futility were planned. Adults and children will be included through progressive step-down in age following safety review by an independent safety monitoring board (ISMB).

If the study were to meets its efficacy objectives, this will inform dose setting for Phase III studies.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Medicines for Malaria Venture
• Treatments: Artefenomel; Piperaquine

Criteria

Inclusion Criteria:

1. Male or female patient age >6 months <70 years.

2. Body weight >5 kg <90 kg.

3. Presence of mono-infection of P. falciparum with:

1. Fever, as defined by axillary temperature ≥ 37.5°C or oral/rectal/tympanic temperature ≥ 38°C, or history of fever in the previous 24 hours (history of fever must be documented) and,

2. Microscopically confirmed parasite infection, in range 1,000 to 100,000 asexual parasites /µL of blood.

4. Written informed consent provided by the adult patient, or parent or legally acceptable representative (LAR) of the minor patient or by an impartial witness (if the patient or patient's LAR is illiterate), and by the medically qualified Investigator. Children will be asked to provide assent where appropriate. The age from which this will be sought will be defined by local legislation.

Exclusion Criteria:

1. Presence of severe malaria (according to World Health Organization (WHO) definition - WHO 2013)

2. Anti-malarial treatment:

1. With piperaquine -based compound, mefloquine, naphthoquine or sulphadoxine/pyrimethamine (SP) within the previous 6 weeks (after their inhibition of new infections has fallen below 50%).

2. With amodiaquine or chloroquine within the previous 4 weeks.

3. With quinine, halofantrine, lumefantrine-based compounds and any other anti-malarial treatment or antibiotics with anti-malarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones, and azithromycin) within the past 14 days.

4. With any herbal products or traditional medicines, within the past 7 days.

3. Known history or evidence of clinically significant disorders such as, respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological, neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions or other abnormality (including head trauma).

4. Family history of sudden death or of congenital or clinical conditions known to prolong QTcB or QTcF interval or e.g. patients with a history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.

5. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.

6. 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.

7. Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia.

8. Any treatment which can induce a lengthening of QT interval, such as:

1. Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol),

2. Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine),

3. Anti-depressive 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,

4. Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine), cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide.

5. Anti-emetics with known QT prolongation potential such as domperidone

9. Mixed Plasmodium infection

10. Severe vomiting, defined as more than three times in the 24 hours prior to enrolment in the study or inability to tolerate oral treatment, or severe diarrhoea defined as 3 or more watery stools per day

11. Severe malnutrition (defined for subjects aged ten years or less as the weight-for-height being below -3 standard deviation or less than 70% of median of the National Centre for Health Statistics (NCHS)/WHO normalised reference values, and for subjects aged greater than ten years, a body mass index (BMI) of less than 16 (WFP Manual, Chapter 1)).

12. Known history of hypersensitivity, allergic or adverse reactions to piperaquine or other aminoquinolones or to OZ439 or OZ277

13. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab).

14. If Total Bilirubin is normal, exclude the patient if liver function tests Aspartate transaminase (AST)/ Alanine transaminase (ALT) ≥ 2x Upper limit of normal (ULN).

15. If Total Bilirubin is > 1 and ≤ 1.5xULN, exclude the patient if AST/ALT >1.5xULN.

16. Total Bilirubin > 1.5XULN

17. Haemoglobin level below 8 g/dL.

18. Serum creatinine levels ≥2 x ULN

19. Female patients of child bearing potential must be neither pregnant (as demonstrated by a negative 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. Have received an investigational drug within the past 4 weeks.

21. Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance.