Phase IIb Study to Investigate the Efficacy of OZ439 & Piperaquine Phosphate Co-administered to Adults & Children With Uncomplicated Plasmodium Falciparum.

Uncomplicated Plasmodium Falciparum Malaria Clinical Trial

Official title:

A Randomised, Double-blind, Phase IIb Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of a Single Dose Regimen of Artefenomel (OZ439) in Loose Combination With Piperaquine Phosphate in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02083380
• Other study ID #: MMV_OZ439_13_003
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: March 7, 2014
• Last updated: November 11, 2015
• Start date: July 2014
• Est. completion date: November 2015

Study information

• Verified date: November 2015
• Source: Medicines for Malaria Venture
• Contact: n/a
• Is FDA regulated: No
• Health authority: Gabon: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

A randomised, double-blind single-dose (loose combination) study in patients with uncomplicated Plasmodium falciparum malaria. The study will test for efficacy/futility through analyses, using Bayesian methodology. Adults and children will be included through progressive step-down in age following safety analyses.

This study investigates the efficacy exposure-response of OZ439/PQP combination in the target populations and if it meets its efficacy objectives, will inform dose setting for Phase III studies.

Description:

A randomised, double-blind single-dose (loose combination) study in patients spanning the age range greater than or equal to 6 months to less than 70 years, with uncomplicated Plasmodium falciparum malaria. Three OZ439/PQP treatment arms will be included (for patients > 35 kg), with doses scaled to target similar exposures in lighter patients.

The study aims to recruit predominantly patient populations with the highest probability of having 'lower immunity' to P. falciparum, while also including patients with a probability of having 'higher immunity'. Hence the study will recruit across a wide age range and across geographical regions (Africa, Asia and possibly Latin America). The underlying assumption is that children of 5 years or less in Africa and all ages in Asia/Latin America will have the lower immunity and hence potentially require the highest drug exposure to achieve effective treatment. For this reason, patients of 5 years or less in Africa will form the largest proportion of the population while patients of greater than 5 years in Africa will form the lowest proportion of the population.

The study will test for efficacy/futility at Day 28 (including data from patients discontinuing prior to Day 28) through interim analyses using Bayesian methodology. Only data from patients in Asia/Latin America and patients of 5 years or less in Africa (the 'lower immunity' population) will be included in the interim analyses. Interim assessment of efficacy and futility will occur after recruitment of approximately 50 evaluable patients per dose cohort and thereafter approximately every 25 patients.

Independently of the analyses for efficacy/futility, the safety of OZ439/PQP treatment arms will be assessed at scheduled time points by an Independent Safety Monitoring Board (ISMB).

Adults and children will be included through progressive step-down in age range following safety evaluation.

Following Screening and informed consent, patients will receive study drug and will 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 438
• Est. completion date: November 2015
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months to 70 Years

Eligibility

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 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 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 AST/ALT = 2xULN.

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum
• Uncomplicated Plasmodium Falciparum Malaria

Intervention

Drug:
• A) OZ439 800mg: PQP 1440mg

• B) OZ439 800mg: PQP 960mg

• C) OZ439 800mg: PQP 640mg

Locations

Country	Name	City	State
Benin	Centre D'Étude Et de Recherchesur Le Paludisme Associé À La Grossesse Et À L'Enfance (Cerpage) Cerpage	Cotonou
Burkina Faso	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
Congo, The Democratic Republic o	Kinshasa School of Public Health, School of Medicine University of Kinshasa	Kinshasa
Gabon	Centre de Recherches Medicales de Lambarene, Albert Schweitzer Hospital	Lambarene
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
Mozambique	MANHIÇA HEALTH RESEARCH CENTER, Rua 12, Vila da Manhica, Maputa,	Chefe Maputa
Uganda	Tororo District Hospital	Tororo
Vietnam	National Institute of Malariology, Parasitology and Entomology, 245 Luong The Vinh Street, Trung van, Tu Liem, Hanoi, Vietnam	Hanoi

Sponsors (1)

Lead Sponsor	Collaborator
Medicines for Malaria Venture

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28	PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28	Day 28	No
Secondary	PCR - adjusted ACPR at Day 42 and 63	PCR - adjusted ACPR at Day 42 and 63	Days 42, 63 (subset of patients)	No
Secondary	o Non-compartmental analysis (NCA) of concentrations of OZ439 and o Non-compartmental analysis (NCA) of concentrations of OZ439 and piperaquine	Non-compartmental analysis (NCA) of concentrations of OZ439 and piperaquine	Day 7,14,28,42,63	No
Secondary	Incidence of adverse events	Incidence of adverse events	Day0-Day63	Yes

External Links

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