Clinical trial NCT02083380: Phase II Efficacy Study of Artefenomel & Piperaquine in Adults & Children With P. Falciparum Malaria.
Official title: Randomised Phase IIb Study of Efficacy, Safety, Tolerability & Pharmacokinetics of a Single Dose Regimen of Artefenomel (OZ439) in Loose Combination With Piperaquine in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Uncomplicated Plasmodium Falciparum Malaria
Keywords: Plasmodium falciparum malaria
malaria
OZ439
piperaquine
PQP
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
First posted: 2014-03-11
Enrollment: 448
Sex: ALL
Minimum age (years): 6
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: PCR-adjusted ACPR at Day 28 in the PP Population (All Patients)
timeFrame: Day 28
measure: PCR-adjusted ACPR at Day 28 in the PP Population: Asia (All Ages)
timeFrame: Day 28
measure: PCR-adjusted ACPR at Day 28 in the PP Population: Africa (All Ages)
timeFrame: Day 28
measure: PCR-adjusted ACPR at Day 28 in the PP Population: Africa (> Than 5 Years)
timeFrame: Day 28
measure: PCR-adjusted ACPR at Day 28 in the PP Population: Africa (< = 5 Years)
timeFrame: Day 28
measure: PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>2 to <= 5 Years)
timeFrame: Day 28
measure: PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>= 0.5 to <= 2 Years)
timeFrame: Day 28
Secondary outcomes:
measure: PCR - Adjusted ACPR at Day 42 in the PP Population
timeFrame: Days 42
measure: PCR-adjusted ACPR at Day 63 in the PP Population
timeFrame: Day 63
measure: Crude ACPR at Day 28 in the PP Population
timeFrame: Day 28
measure: Crude ACPR at Day 42 in the PP Population
timeFrame: Day 42
measure: Crude ACPR at Day 63 in the PP Population
timeFrame: Day 63
measure: PCR-adjusted ACPR at Day 28 in the ITT Population
timeFrame: Day 28
measure: PCR-adjusted ACPR at Day 42 in the ITT Population
timeFrame: Day 42
measure: PCR-adjusted ACPR at Day 63 in the ITT Population
timeFrame: Day 63
measure: Crude ACPR at Day 28 in the ITT Population
timeFrame: Day 28
measure: Crude ACPR at Day 42 in the ITT Population
timeFrame: Day 42
measure: Crude ACPR at Day 63 in the ITT Population
timeFrame: Day 63
measure: Kaplan-Meier Estimate of Recurrence
timeFrame: Day 63
measure: Kaplan-Meier Estimate of Recrudescence
timeFrame: Day 63
measure: Kaplan-Meier Estimate of New Infection Rate
timeFrame: Day 63
measure: Parasite Clearance Time
timeFrame: 0, 6, 12, 18, 24, 30, 36, 48 and 72 hours post dose
measure: Fever Clearance Time
timeFrame: Day 42
measure: PRR48
timeFrame: 0, 6, 12, 18, 24, 30, 36 and 48 hours post dose
Other outcomes:
measure: Piperaquine: Cday7 Asia (All Ages)
timeFrame: Day 7
measure: Piperaquine: Cday7 Africa (> 5 Years)
timeFrame: Day 7
measure: Piperaquine: Cday7 Africa (>2 to <= 5 Years)
timeFrame: Day 7
measure: Piperaquine: Cday7 Africa (>=0.5 to <= 2 Years)
timeFrame: Day 7
measure: Artefenomel Cday7 Asian Patients (All Ages)
timeFrame: Day 7
measure: Artefenomel Cday7 African Patients (> 5 Years)
timeFrame: Day 7
measure: Artefenomel Cday7 African Patients (>2 to <= 5 Years)
timeFrame: Day 7
measure: Artefenomel Cday7 African Patients (>=0.5 to <= 2 Years)
timeFrame: Day 7
Locations:
city: Cotonou
country: Benin
facility: Centre D'Étude Et de Recherchesur Le Paludisme Associé À La Grossesse Et À L'Enfance (Cerpage) Cerpage
city: Ouagadougou
country: Burkina Faso
facility: Centre National de Recherche et de Formation sur le paludisme (CNRFP) Ouagadougou, Kadiogo
city: Ouagadougou
country: Burkina Faso
facility: Clinical research Unit of Nanoro (CRUN)/CMA Saint Camille de Nanoro, 11 BP 218 Ouagadougou CMS 11
city: Kinshasa
country: Congo, The Democratic Republic of the
facility: Kinshasa School of Public Health, School of Medicine University of Kinshasa
city: Lambarene
country: Gabon
facility: Centre de Recherches Medicales de Lambarene, Albert Schweitzer Hospital
city: Libreville
country: Gabon
facility: arielle K. Bouyou-Akotet, Department of Parasitology-Mycology and Tropical Medicine, Faculty of Medicine, Université des Sciences de la Santé, BP 4009, Libreville, Gabon
city: Chefe Maputa
country: Mozambique
facility: MANHIÇA HEALTH RESEARCH CENTER, Rua 12, Vila da Manhica, Maputa,
city: Tororo
country: Uganda
facility: Tororo District Hospital
city: Hanoi
country: Vietnam
facility: National Institute of Malariology, Parasitology and Entomology, 245 Luong The Vinh Street, Trung van, Tu Liem, Hanoi, Vietnam
Study officials:
affiliation: Medicines for Malaria Venture
name: Fiona Macintyre, PhD
role: STUDY_DIRECTOR
affiliation: CERMEL (Centre de Recherches Médicale de Lambaréné)
name: Michael Ramharter, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.