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

NCT ID: NCT02083380

Last Updated: 2017-03-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 448 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-31
• Study Completion Date: 2015-11-30

Brief 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.

Detailed Description

A randomised, double-blind single-dose (loose combination) study in the target patient population of children > 0.5 years and <= 5 years of age in Africa and patients of all ages in Asia (> 0.5 years and <= 70 years) with uncomplicated Plasmodium falciparum malaria. Patients > 5 years in Africa were also to be recruited in a safety age step down procedure. The underlying assumption was that children of 5 years or less in Africa and all ages in Asia will have a higher probability of having lower immunity and hence potentially require higher drug exposure to achieve efficacy and hence the study aimed to recruit 60-80% African children < = 5 years and 18-36% Asian patients (defined as the target population) and approximately 10% African patients >5 years,

Three OZ439/PQP treatment arms were to be included for patients >= 35 kg (800mg OZ439 in loose combination with PQP doses of either 640, 960, 1440 mg). Doses were scaled for patients < 35kg based on the weight to achieve similar exposures in patients >= 35kg.

The study was to test for futility and dose arms were to be dropped if the probability was >30% that PCR-adjusted ACPR at Day 28 (ACPR28) was less than 90% (the target efficacy for the study was >= 95% ACPR28). Only data from patients in Asia patients and Africa patients < 5 years were to be included in the Interim analysis, although all patients were to be included in the final analysis. Interim analyses were to occur after recruitment of approximately 50 evaluable patients per dose cohort and thereafter approximately after every 25 patients.

In a separate process, the safety of OZ439/PQP treatment arms was to be assessed at scheduled time points by an ISMB and adults and children were included through progressive step-down in age range following safety evaluation

Following Screening and informed consent, patients were to receive study drug and were to be followed for clinical signs of malaria (parasitaemia and temperature), safety assessments and pharmacokinetics up to Day 42 following dosing (Day 63 at selected sites).

Conditions

Uncomplicated Plasmodium Falciparum Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

A) Artefenomel 800mg: piperaquine 640mg

One single dose of Artefenomel 800mg: Piperaquine phosphate 640mg loose combination

Group Type: EXPERIMENTAL

Artefenomel 800mg: piperaquine 640mg

Intervention Type: DRUG

Active, loose combination

B) Artefenomel 800mg: piperaquine 960mg

One single dose of Artefenomel 800mg: Piperaquine phosphate 960mg loose combination

Group Type: EXPERIMENTAL

Artefenomel 800mg: piperaquine 960mg

Intervention Type: DRUG

Active, loose combination

C) Artefenomel 800mg: piperaquine 1440mg

One single dose of Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination

Group Type: EXPERIMENTAL

Artefenomel 800mg: piperaquine 1440mg

Intervention Type: DRUG

Active, loose combination

Interventions

Artefenomel 800mg: piperaquine 640mg

Active, loose combination

Intervention Type: DRUG

Artefenomel 800mg: piperaquine 960mg

Active, loose combination

Intervention Type: DRUG

Artefenomel 800mg: piperaquine 1440mg

Active, loose combination

Intervention Type: DRUG

Other Intervention Names

OZ439 ; PQP; OZ439 ; PQP; OZ439 ; PQP

Eligibility 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.

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medicines for Malaria Venture

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Fiona Macintyre, PhD

Role: STUDY_DIRECTOR

Medicines for Malaria Venture

Michael Ramharter, MD

Role: PRINCIPAL_INVESTIGATOR

CERMEL (Centre de Recherches Médicale de Lambaréné)

Locations

Centre D'Étude Et de Recherchesur Le Paludisme Associé À La Grossesse Et À L'Enfance (Cerpage) Cerpage

Cotonou, , Benin

Centre National de Recherche et de Formation sur le paludisme (CNRFP) Ouagadougou, Kadiogo

Ouagadougou, , Burkina Faso

Clinical research Unit of Nanoro (CRUN)/CMA Saint Camille de Nanoro, 11 BP 218 Ouagadougou CMS 11

Ouagadougou, , Burkina Faso

Kinshasa School of Public Health, School of Medicine University of Kinshasa

Kinshasa, , Democratic Republic of the Congo

Centre de Recherches Medicales de Lambarene, Albert Schweitzer Hospital

Lambaréné, , Gabon

arielle K. Bouyou-Akotet, Department of Parasitology-Mycology and Tropical Medicine, Faculty of Medicine, Université des Sciences de la Santé, BP 4009, Libreville, Gabon

Libreville, , Gabon

MANHIÇA HEALTH RESEARCH CENTER, Rua 12, Vila da Manhica, Maputa,

Chefe Maputa, , Mozambique

Tororo District Hospital

Tororo, , Uganda

National Institute of Malariology, Parasitology and Entomology, 245 Luong The Vinh Street, Trung van, Tu Liem, Hanoi, Vietnam

Hanoi, , Vietnam

Countries

Benin; Burkina Faso; Democratic Republic of the Congo; Gabon; Mozambique; Uganda; Vietnam

References

Leroy D, Macintyre F, Adoke Y, Ouoba S, Barry A, Mombo-Ngoma G, Ndong Ngomo JM, Varo R, Dossou Y, Tshefu AK, Duong TT, Phuc BQ, Laurijssens B, Klopper R, Khim N, Legrand E, Menard D. African isolates show a high proportion of multiple copies of the Plasmodium falciparum plasmepsin-2 gene, a piperaquine resistance marker. Malar J. 2019 Apr 10;18(1):126. doi: 10.1186/s12936-019-2756-4.

Reference Type: DERIVED

PMID: 30967148 (View on PubMed)

Macintyre F, Adoke Y, Tiono AB, Duong TT, Mombo-Ngoma G, Bouyou-Akotet M, Tinto H, Bassat Q, Issifou S, Adamy M, Demarest H, Duparc S, Leroy D, Laurijssens BE, Biguenet S, Kibuuka A, Tshefu AK, Smith M, Foster C, Leipoldt I, Kremsner PG, Phuc BQ, Ouedraogo A, Ramharter M; OZ-Piperaquine Study Group. A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria. BMC Med. 2017 Oct 9;15(1):181. doi: 10.1186/s12916-017-0940-3.

Reference Type: DERIVED

PMID: 28988541 (View on PubMed)

Other Identifiers

MMV_OZ439_13_003

Identifier Type: -

Identifier Source: org_study_id