| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A protozoal infection caused by Plasmodium falciparum |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Parasitic Diseases [C03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025487 |
| E.1.2 | Term | Malaria |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To confirm the hypothesis that azithromycin (AZ) when used in combination with chloroquine (CQ), is noninferior to artemether-lumefantrine (AL) for the treatment of symptomatic, uncomplicated malaria due to P. falciparum in children in Africa. |
|
| E.2.2 | Secondary objectives of the trial |
| Efficacy measurements and an assessment of the safety and tolerability of both treatment regimens. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed (or thumb printed) and dated informed consent document indicating that the legally acceptable representative of the subject has been informed of all pertinent aspects of the trial and that all questions by the representative have been sufficiently answered. Local IRBs will determine the age at which assent must be obtained from the subject.
2. Girls and boys of 5 to less than or equal to (<=) 12 years of age (Cohort 1); and 6 to <= 59 months of age (Cohort 2) with uncomplicated, symptomatic malaria as indicated by the presence of the following:
- Blood smears positive for monoinfection with Plasmodium. falciparum and asexual parasitemia between 1000 -100,000 parasites per microliters (mcL).
- Documented fever (38.0 degree Celsius (C) or 100.4 degree Fahrenheit (F) rectal or tympanic; 37.2 degree C or 99.0 degree F axillary or 37.5 degree C or 99.5 degree F) or history of fever (as reported by the legally acceptable representative) within the prior 24 hours.
3. Appropriate for outpatient treatment.
4. Blood glucose equal to greater than (>=) 60 milligram per deciliters (mg/dL).
5. Rapid diagnostic test (eg, Binax) positive for Plasmodium. falciparum.
6. Hemoglobin >=6 gram (g) per dL (via finger stick or peripheral blood collection) by HemoCue or hematocrit >=18 percent (%) without signs of anemia-induced Congestive Heart Failure.
7. Negative urine pregnancy test for females >=10 years of age (and of child bearing potential) where acceptable by local or national customs and regulations. Negative result must be obtained within 48 hours prior to start of study.
8. The subject’s legally acceptable representative must be willing to allow the subject to be treated in the inpatient setting for a minimum of three days and be willing or able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
|
|
| E.4 | Principal exclusion criteria |
1. Peripheral blood smear positive for mixed infection with multiple Plasmodium species.
2. Severe or complicated malaria including subjects with any of the following:
- Impaired consciousness
- Known hemoglobinuria
- Jaundice
- Persistent vomiting
- Gross hematuria, as reported by the subject’s legally acceptable representative
- Inability to drink or breastfeed
- Unable to sit or stand as appropriate for age
- Recent history of convulsions
- Respiratory distress >=50 breaths per minute in infants under 12 months of age;
- >= 40 breaths per minute in subjects aged 12–59 months; ≥36 breaths per minute in subjects aged 5-12 years; or deep breathing with retractions indicating acidotic breathing.
3. History of allergy to or hypersensitivity to azithromycin, any macrolide, chloroquine, artemether, any artemisinin derivative, lumefantrine.
4. History of treatment with any antimalarial drug (such as halofantrine, chloroquine, quinine, mefloquine, Malarone, SP, artemisinin compounds) or antibacterial with known antimalarial activity (macrolides, doxycycline, clindamycin) within 2 weeks prior to enrollment of a subject (and/or of the mother of a subject who is being breastfed) into the study.
5. Known or suspected cardiovascular, hepatic or renal abnormality that in the opinion of the investigator would place the subject at increased risk to participate in the study.
6. Any contraindication to any study drug including AZ, CQ and AL.
7. Known pregnancy or breast-feeding or positive urine pregnancy test (females >=10 years of age and of child bearing potential).
8. Subjects weighing less than 5 kilogram (kg).
9. Known severe Sickle Cell (SS) or Sickle-Hemoglobin C (SC) anemia.
10. Patients with other common febrile illnesses including acute otitis media, tonsillitis, measles, abscesses etc.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Percentage of Subjects With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitologic Response (ACPR) at Day 28 in the Modified Intent-to-treat (mITT) Population.
2. Percentage of Subjects With PCR-corrected ACPR at Day 28 in Per-Protocol (PP) Population |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Percentage of Subjects With PCR-corrected ACPR in the mITT Population
Days 7, 14, 21, 35, 42
Percentage of Subjects With PCR-corrected ACPR in PP Population
Days 7, 14, 21, 35, 42
Percentage of Subjects With PCR-uncorrected ACPR in the mITT Population
Days 7, 14, 21, 35, 42
Percentage of Subjects With PCR-uncorrected ACPR in the PP Population
Days 7, 14, 21, 35, 42
Percentage of Subjects With Early Treatment Failure (ETF) in the mITT Population (PCR-corrected)
Day 0 up to Day 3
Percentage of Subjects With Early Treatment Failure (ETF) in the PP Population (PCR-corrected)
Day 0 up to Day 3
Percentage of Subjects With Late Clinical Failure (LCF) in the mITT Population (PCR-corrected)
Days 7, 14, 21, 28, 35, 42
Percentage of Subjects With Late Clinical Failure (LCF) in the PP Population (PCR-corrected)
Days 7, 14, 21, 28, 35, 42
Percentage of Subjects With Late Parasitologic Failure (LPF) in the mITT Population (PCR-corrected)
Days 7, 14, 21, 28, 35, 42
Percentage of Subjects With LPF in the PP Population (PCR-corrected)
Days 7, 14, 21, 28, 35, 42
Percentage of Subjects With Asexual Parasitologic Response (PCR-corrected)
Days 7, 14, 21, 28, 35, 42
Percentage of Subjects With Gametocytologic Response
Days 7, 14, 21, 28, 35, 42
Fever Clearance Time
Baseline to Day 42
Asexual Plasmodium Falciparum Parasite Clearance Time
Baseline to Day 42
Time to Recurrence of Parasitemia
Baseline to Day 42
Number of Subjects With Recurrent Parasitemia Versus Baseline Plasmodium Falciparum Chloroquine Resistance Transporter (PfCRT) Status
Baseline to Day 42
Percentage of Subjects With PfCRT in True Failures
Baseline to Day 42
Nadir Hemoglobin Level
Day 0 through Day 3
Change From Nadir Hemoglobin Level at Days 14, 28, and 42
Day 14, 28, 42
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Days 7, 14, 21, 35, 42
Days 7, 14, 21, 35, 42
Days 7, 14, 21, 35, 42
Days 7, 14, 21, 35, 42
Day 0 up to Day 3
Day 0 up to Day 3
Days 7, 14, 21, 28, 35, 42
Days 7, 14, 21, 28, 35, 42
Days 7, 14, 21, 28, 35, 42
Days 7, 14, 21, 28, 35, 42
Days 7, 14, 21, 28, 35, 42
Days 7, 14, 21, 28, 35, 42
Baseline to Day 42
Baseline to Day 42
Baseline to Day 42
Baseline to Day 42
Baseline to Day 42
Day 0 through Day 3
Days 14, 28, and 42
Day 14, 28, 42 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Burkina Faso |
| Côte d’Ivoire |
| Ghana |
| Kenya |
| Mali |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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