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

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ClinicalTrials.gov Identifier: NCT02083380
Recruitment Status : Completed
First Posted : March 11, 2014
Results First Posted : January 30, 2017
Last Update Posted : March 10, 2017
Sponsor:
Information provided by (Responsible Party):
Medicines for Malaria Venture

Tracking Information
First Submitted Date  ICMJE March 7, 2014
First Posted Date  ICMJE March 11, 2014
Results First Submitted Date  ICMJE December 5, 2016
Results First Posted Date  ICMJE January 30, 2017
Last Update Posted Date March 10, 2017
Study Start Date  ICMJE July 2014
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 5, 2016)
  • PCR-adjusted ACPR at Day 28 in the PP Population (All Patients) [ Time Frame: Day 28 ]
    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.
  • PCR-adjusted ACPR at Day 28 in the PP Population: Asia (All Ages) [ Time Frame: Day 28 ]
    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.
  • PCR-adjusted ACPR at Day 28 in the PP Population: Africa (All Ages) [ Time Frame: Day 28 ]
    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.
  • PCR-adjusted ACPR at Day 28 in the PP Population: Africa (> Than 5 Years) [ Time Frame: Day 28 ]
    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.
  • PCR-adjusted ACPR at Day 28 in the PP Population: Africa (< = 5 Years) [ Time Frame: Day 28 ]
    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.
  • PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>2 to <= 5 Years) [ Time Frame: Day 28 ]
    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.
  • PCR-adjusted ACPR at Day 28 in the PP Population: Africa (>= 0.5 to <= 2 Years) [ Time Frame: Day 28 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 7, 2014)
PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28 [ Time Frame: Day 28 ]
PCR-adjusted adequate clinical and parasitological response (ACPR) at Day 28
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2017)
  • PCR - Adjusted ACPR at Day 42 in the PP Population [ Time Frame: Days 42 ]
    PCR - adjusted adequate clinical and parasitological response at Day 42
  • PCR-adjusted ACPR at Day 63 in the PP Population [ Time Frame: Day 63 ]
    PCR-adjusted adequate clinical and parasitological response at Day 63
  • Crude ACPR at Day 28 in the PP Population [ Time Frame: Day 28 ]
    Crude adequate clinical and parasitological response at Day 28
  • Crude ACPR at Day 42 in the PP Population [ Time Frame: Day 42 ]
    Crude adequate clinical and parasitological response at Day 42
  • Crude ACPR at Day 63 in the PP Population [ Time Frame: Day 63 ]
    Crude adequate clinical and parasitological response at Day 63
  • PCR-adjusted ACPR at Day 28 in the ITT Population [ Time Frame: Day 28 ]
    PCR-adjusted adequate clinical and parasitological response at Day 28. Intent to Treat ( ITT) population.
  • PCR-adjusted ACPR at Day 42 in the ITT Population [ Time Frame: Day 42 ]
    PCR-adjusted adequate clinical and parasitological response at Day 42 in the ITT population
  • PCR-adjusted ACPR at Day 63 in the ITT Population [ Time Frame: Day 63 ]
    PCR-adjusted adequate clinical and parasitological response at Day 63 in the ITT population
  • Crude ACPR at Day 28 in the ITT Population [ Time Frame: Day 28 ]
    Crude adequate clinical and parasitological response at Day 28 in the ITT population
  • Crude ACPR at Day 42 in the ITT Population [ Time Frame: Day 42 ]
    Crude adequate clinical and parasitological response at Day 42 in the ITT population
  • Crude ACPR at Day 63 in the ITT Population [ Time Frame: Day 63 ]
    Crude adequate clinical and parasitological response at Day 63 in the ITT population
  • Kaplan-Meier Estimate of Recurrence [ Time Frame: Day 63 ]
    Kaplan-Meier estimate of number of recurrent infections (either recrudescence or new infection)
  • Kaplan-Meier Estimate of Recrudescence [ Time Frame: Day 63 ]
    Kaplan-Meier estimate of number of patients with recrudescence
  • Kaplan-Meier Estimate of New Infection Rate [ Time Frame: Day 63 ]
    Kaplan-Meier estimate of number of patients with new infections
  • Parasite Clearance Time [ Time Frame: 0, 6, 12, 18, 24, 30, 36, 48 and 72 hours post dose ]
    Time post dose to parasite clearance
  • Fever Clearance Time [ Time Frame: Day 42 ]
    Time to fever clearance (hours)
  • PRR48 [ Time Frame: 0, 6, 12, 18, 24, 30, 36 and 48 hours post dose ]
    Parasite reduction ratio at 48 hours post dose
Original Secondary Outcome Measures  ICMJE
 (submitted: March 7, 2014)
  • PCR - adjusted ACPR at Day 42 and 63 [ Time Frame: Days 42, 63 (subset of patients) ]
    PCR - adjusted ACPR at Day 42 and 63
  • o Non-compartmental analysis (NCA) of concentrations of OZ439 and o Non-compartmental analysis (NCA) of concentrations of OZ439 and piperaquine [ Time Frame: Day 7,14,28,42,63 ]
    Non-compartmental analysis (NCA) of concentrations of OZ439 and piperaquine
  • Incidence of adverse events [ Time Frame: Day0-Day63 ]
    Incidence of adverse events
Current Other Pre-specified Outcome Measures
 (submitted: December 5, 2016)
  • Piperaquine: Cday7 Asia (All Ages) [ Time Frame: Day 7 ]
    Piperaquine concentration at Day7 in Asian patients all ages
  • Piperaquine: Cday7 Africa (> 5 Years) [ Time Frame: Day 7 ]
    Piperaquine concentration at Day7 in African patients > 5 years
  • Piperaquine: Cday7 Africa (>2 to <= 5 Years) [ Time Frame: Day 7 ]
    Piperaquine concentration at Day7 in African patients > 2 and <= 5years
  • Piperaquine: Cday7 Africa (>=0.5 to <= 2 Years) [ Time Frame: Day 7 ]
    Piperaquine concentration at Day7 in African patients >= 0.5 and <= 2 years
  • Artefenomel Cday7 Asian Patients (All Ages) [ Time Frame: Day 7 ]
    Artefenomel concentration on Day 7 in Asian Patients (all ages). All Treatment arms.
  • Artefenomel Cday7 African Patients (> 5 Years) [ Time Frame: Day 7 ]
    Artefenomel concentration on Day 7 in African Patients > 5 years. All Treatment arms.
  • Artefenomel Cday7 African Patients (>2 to <= 5 Years) [ Time Frame: Day 7 ]
    Artefenomel concentration on Day 7 in African Patients >2 to <= 5 years. All Treatment arms.
  • Artefenomel Cday7 African Patients (>=0.5 to <= 2 Years) [ Time Frame: Day 7 ]
    Artefenomel concentration on Day 7 in African Patients >= 0.5 to <=2 years. All Treatment arms.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase II Efficacy Study of Artefenomel & Piperaquine in Adults & Children With P. Falciparum Malaria.
Official Title  ICMJE 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.
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Uncomplicated Plasmodium Falciparum Malaria
Intervention  ICMJE
  • Drug: Artefenomel 800mg: piperaquine 640mg
    Active, loose combination
    Other Name: OZ439 ; PQP
  • Drug: Artefenomel 800mg: piperaquine 960mg
    Active, loose combination
    Other Name: OZ439 ; PQP
  • Drug: Artefenomel 800mg: piperaquine 1440mg
    Active, loose combination
    Other Name: OZ439 ; PQP
Study Arms  ICMJE
  • Experimental: A) Artefenomel 800mg: piperaquine 640mg
    One single dose of Artefenomel 800mg: Piperaquine phosphate 640mg loose combination
    Intervention: Drug: Artefenomel 800mg: piperaquine 640mg
  • Experimental: B) Artefenomel 800mg: piperaquine 960mg
    One single dose of Artefenomel 800mg: Piperaquine phosphate 960mg loose combination
    Intervention: Drug: Artefenomel 800mg: piperaquine 960mg
  • Experimental: C) Artefenomel 800mg: piperaquine 1440mg
    One single dose of Artefenomel 800mg: Piperaquine phosphate 1440mg loose combination
    Intervention: Drug: Artefenomel 800mg: piperaquine 1440mg
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 5, 2016)
448
Original Estimated Enrollment  ICMJE
 (submitted: March 7, 2014)
495
Actual Study Completion Date  ICMJE November 2015
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 70 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Benin,   Burkina Faso,   Congo, The Democratic Republic of the,   Gabon,   Mozambique,   Uganda,   Vietnam
Removed Location Countries Colombia
 
Administrative Information
NCT Number  ICMJE NCT02083380
Other Study ID Numbers  ICMJE MMV_OZ439_13_003
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Medicines for Malaria Venture
Study Sponsor  ICMJE Medicines for Malaria Venture
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Fiona Macintyre, PhD Medicines for Malaria Venture (MMV)
Principal Investigator: Michael Ramharter, MD CERMEL (Centre de Recherches Médicale de Lambaréné)
PRS Account Medicines for Malaria Venture
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP