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

NCT02083380 | Completed Phase 2 Results DMC

• 1 other identifier: MMV_OZ439_13_003
• Study Type: interventional
• Target: 448
• Locations: 7 countries
• Sites: 9

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.

Conditions

Uncomplicated Plasmodium Falciparum Malaria

Keywords

Plasmodium falciparum malaria; malaria; OZ439; piperaquine; PQP

Outcome Measures

Primary Outcomes (7)

• PCR-adjusted ACPR at Day 28 in the PP Population (All Patients)

  Polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. Per protocol population (PP). 95% Clopper-Pearson 2-sided Confidence Interval (CI) constructed around the single binomial proportion per treatment arm and total.

  Day 28

• PCR-adjusted ACPR at Day 28 in the PP Population: Asia (All Ages)

  PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

  Day 28

• PCR-adjusted ACPR at Day 28 in the PP Population: Africa (All Ages)

  PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

  Day 28

• PCR-adjusted ACPR at Day 28 in the PP Population: Africa (> Than 5 Years)

  PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

  Day 28

• PCR-adjusted ACPR at Day 28 in the PP Population: Africa (< = 5 Years)

  PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

  Day 28

• PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>2 to <= 5 Years)

  PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

  Day 28

• PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>= 0.5 to <= 2 Years)

  PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28: defined as: absence of parasitaemia on Day 28, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure (ETF), late clinical failure (LCF) or late parasitological failure (LPF). Definition of ETF, LCF and LPF according to a modified standard WHO classification. 95% Clopper-Pearson 2-sided CI constructed around the single binomial proportion per treatment arm and total.

  Day 28

Secondary Outcomes (17)

• PCR - Adjusted ACPR at Day 42 in the PP Population

  Days 42

• PCR-adjusted ACPR at Day 63 in the PP Population

  Day 63

• Crude ACPR at Day 28 in the PP Population

  Day 28

• Crude ACPR at Day 42 in the PP Population

  Day 42

• Crude ACPR at Day 63 in the PP Population

  Day 63

Other Outcomes (8)

• Piperaquine: Cday7 Asia (All Ages)

  Day 7

• Piperaquine: Cday7 Africa (> 5 Years)

  Day 7

• Piperaquine: Cday7 Africa (>2 to <= 5 Years)

  Day 7

Study Arms (3)

A) Artefenomel 800mg: piperaquine 640mg

EXPERIMENTAL

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

Drug: Artefenomel 800mg: piperaquine 640mg

B) Artefenomel 800mg: piperaquine 960mg

EXPERIMENTAL

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

Drug: Artefenomel 800mg: piperaquine 960mg

C) Artefenomel 800mg: piperaquine 1440mg

EXPERIMENTAL

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

Drug: Artefenomel 800mg: piperaquine 1440mg

Interventions

Artefenomel 800mg: piperaquine 640mg DRUG

Active, loose combination

Also known as: OZ439 ; PQP

A) Artefenomel 800mg: piperaquine 640mg

Artefenomel 800mg: piperaquine 960mg DRUG

Active, loose combination

Also known as: OZ439 ; PQP

B) Artefenomel 800mg: piperaquine 960mg

Artefenomel 800mg: piperaquine 1440mg DRUG

Active, loose combination

Also known as: OZ439 ; PQP

C) Artefenomel 800mg: piperaquine 1440mg

Eligibility Criteria

• Age: 6 Months - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patient age \>6 months \<70 years.
• Body weight \>5 kg \<90 kg.
• Presence of mono-infection of P. falciparum with:
• 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,
• Microscopically confirmed parasite infection, in range 1,000 to 100,000 asexual parasites /µL of blood.
• 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.

You may not qualify if:

• Presence of severe malaria (according to World Health Organization (WHO) definition - WHO 2013)
• Anti-malarial treatment:
• 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%).
• With amodiaquine or chloroquine within the previous 4 weeks.
• 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.
• With any herbal products or traditional medicines, within the past 7 days.
• 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).
• 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.
• History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.
• 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.
• Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia.
• Any treatment which can induce a lengthening of QT interval, such as:
• Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol),
• Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine),
• 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,

Sponsors & Collaborators

• Medicines for Malaria Venture: lead

Study Sites (9)

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

Cotonou, FSS 01 BP 188, Benin

Location

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

Ouagadougou, Burkina Faso

Location

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

Ouagadougou, Burkina Faso

Location

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

Kinshasa, Democratic Republic of the Congo

Location

Centre de Recherches Medicales de Lambarene, Albert Schweitzer Hospital

Lambaréné, Gabon

Location

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

Location

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

Chefe Maputa, Mozambique

Location

Tororo District Hospital

Tororo, Uganda

Location

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

Hanoi, Vietnam

Location

Related Publications (2)

• 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.

  PMID: 30967148 DERIVED

• 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.

  PMID: 28988541 DERIVED

MeSH Terms

Conditions

Malaria, Falciparum; Malaria

Interventions

artefenomel; piperaquine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Results Point of Contact

• Title: Associate Professor Dr Michael Ramharter
• Organization: Medical University of Vienna, Division of Infectious Diseases and Tropical Medicine

michael.ramharter@meduniwien.ac.at

+43140400-44400

Study Officials

• Fiona Macintyre, PhD

  Medicines for Malaria Venture

  STUDY DIRECTOR

• Michael Ramharter, MD

  CERMEL (Centre de Recherches Médicale de Lambaréné)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 7, 2014
• First Posted: March 11, 2014
• Study Start: July 1, 2014
• Primary Completion: October 1, 2015
• Study Completion: November 1, 2015
• Last Updated: March 10, 2017
• Results First Posted: January 30, 2017

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will not share

Locations

MO (1); DE (1); BE (1); VN (1); UG (1); BU (2); GA (2)