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Chloroquine Alone or in Combination for Malaria in Children in Malawi

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00379821
First received: September 21, 2006
Last updated: March 28, 2013
Last verified: August 2012
History of Changes
Results First Received: June 30, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Plasmodium Falciparum Malaria
Interventions: Drug: Chloroquine
Drug: Atovaquone-proguanil
Drug: Artesunate
Drug: Azithromycin

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Children who were brought to the Ndirande Health Centre with symptoms suggestive of malaria were recruited from February 19, 2007 to August 13, 2008.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Chloroquine Plus Artesunate Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.
Chloroquine Plus Atovaquone-Proguanil Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.
CQ Plus Azithromycin Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.
CQ Monotherapy Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.

Participant Flow:   Overall Study
    Chloroquine Plus Artesunate     Chloroquine Plus Atovaquone-Proguanil     CQ Plus Azithromycin     CQ Monotherapy  
STARTED     160     160     160     160  
COMPLETED     87     71     93     81  
NOT COMPLETED     73     89     67     79  



  Baseline Characteristics
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Reporting Groups
  Description
Chloroquine Plus Artesunate Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.
Chloroquine Plus Atovaquone-Proguanil Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.
CQ Plus Azithromycin Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.
CQ Monotherapy Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.
Total Total of all reporting groups

Baseline Measures
    Chloroquine Plus Artesunate     Chloroquine Plus Atovaquone-Proguanil     CQ Plus Azithromycin     CQ Monotherapy     Total  
Number of Participants  
[units: participants]
 		  160     160     160     160     640  
Age  
[units: participants]
 		         
<=18 years     160     160     160     160     640  
Between 18 and 65 years     0     0     0     0     0  
>=65 years     0     0     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation 		  2.7  ± 1.2     2.7  ± 1.2     2.8  ± 1.1     2.7  ± 1.2     2.7  ± 1.2  
Gender  
[units: participants]
 		         
Female     70     82     73     77     302  
Male     90     78     87     83     338  
Region of Enrollment  
[units: participants]
 		         
Malawi     160     160     160     160     640  



  Outcome Measures
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1.  Primary:   Number of Clinical Malaria Episodes Per Year of Follow-up   [ Time Frame: 1 year ]
  Show Outcome Measure 1

2.  Secondary:   Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm   [ Time Frame: Day 28 of initial malaria episode (Episode 0) ]
  Show Outcome Measure 2

3.  Secondary:   Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm   [ Time Frame: Day 28 of first subsequent malaria episode (Episode 1) ]
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4.  Secondary:   Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm   [ Time Frame: Day 28 of second subsequent malaria episode (Episode 2) ]
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5.  Secondary:   Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm   [ Time Frame: Day 28 of third subsequent malaria episode (Episode 3) ]
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6.  Secondary:   Number of Participants With Day 28 Adequate Clinical and Parasitologic Response in Each Treatment Arm   [ Time Frame: Day 28 of fourth subsequent malaria episode (Episode 4) ]
  Show Outcome Measure 6

7.  Secondary:   Number of Cases of Severe Malaria in Each Treatment Arm   [ Time Frame: 1 Year ]
  Show Outcome Measure 7

8.  Secondary:   Mean Hemoglobin at the Last Study Visit in Each Treatment Arm for the Age Group of Participants 3 Years of Age or Younger.   [ Time Frame: 1 year ]
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9.  Secondary:   Mean Hemoglobin at the Last Study Visit in Each Treatment Arm for the Age Group of Participants Greater Than 3 Years to 5 Years of Age.   [ Time Frame: 1 year ]
  Show Outcome Measure 9

10.  Secondary:   Mean Creatinine in Each Treatment Arm (Renal Function)   [ Time Frame: Day 0 of initial malaria episode (Episode 0) ]
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11.  Secondary:   Mean Creatinine in Each Treatment Arm (Renal Function)   [ Time Frame: Day 14 of initial malaria episode (Episode 0) ]
  Show Outcome Measure 11

12.  Secondary:   Mean Creatinine in Each Treatment Arm (Renal Function)   [ Time Frame: Day 0 of first subsequent malaria episode (Episode 1) ]
  Show Outcome Measure 12

13.  Secondary:   Mean Creatinine in Each Treatment Arm (Renal Function)   [ Time Frame: Day 14 of first subsequent malaria episode (Episode 1) ]
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14.  Secondary:   Mean Creatinine in Each Treatment Arm (Renal Function)   [ Time Frame: Day 0 of second subsequent malaria episode (Episode 2) ]
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15.  Secondary:   Mean Creatinine in Each Treatment Arm (Renal Function)   [ Time Frame: Day 14 of second subsequent malaria episode (Episode 2) ]
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16.  Secondary:   Mean Creatinine in Each Treatment Arm (Renal Function)   [ Time Frame: Day 0 of third subsequent malaria episode (Episode 3) ]
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17.  Secondary:   Mean Creatinine in Each Treatment Arm (Renal Function)   [ Time Frame: Day 14 of third subsequent malaria episode (Episode 3) ]
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18.  Secondary:   Mean Creatinine in Each Treatment Arm (Renal Function)   [ Time Frame: Day 0 of fourth subsequent malaria episode (Episode 4) ]
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19.  Secondary:   Mean Creatinine in Each Treatment Arm (Renal Function)   [ Time Frame: Day 14 of fourth subsequent malaria episode (Episode 4) ]
  Show Outcome Measure 19

20.  Secondary:   Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)   [ Time Frame: Day 0 of initial malaria episode (Episode 0) ]
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21.  Secondary:   Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)   [ Time Frame: Day 14 of initial malaria episode (Episode 0) ]
  Show Outcome Measure 21

22.  Secondary:   Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)   [ Time Frame: Day 0 of first subsequent malaria episode (Episode 1) ]
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23.  Secondary:   Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)   [ Time Frame: Day 14 of first subsequent malaria episode (Episode 1) ]
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24.  Secondary:   Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)   [ Time Frame: Day 0 of second subsequent malaria episode (Episode 2) ]
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25.  Secondary:   Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)   [ Time Frame: Day 14 of second subsequent malaria episode (Episode 2) ]
  Show Outcome Measure 25

26.  Secondary:   Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)   [ Time Frame: Day 0 of third subsequent malaria episode (Episode 3) ]
  Show Outcome Measure 26

27.  Secondary:   Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)   [ Time Frame: Day 14 of third subsequent malaria episode (Episode 3) ]
  Show Outcome Measure 27

28.  Secondary:   Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)   [ Time Frame: Day 0 of fourth subsequent malaria episode (Episode 4) ]
  Show Outcome Measure 28

29.  Secondary:   Mean Alanine Transaminase (ALT) in Each Treatment Arm (Hepatic Function)   [ Time Frame: Day 14 of fourth subsequent malaria episode (Episode 4) ]
  Show Outcome Measure 29

30.  Secondary:   Number of Participants in Each Treatment Arm Who Change From “Normal” to “Abnormal” on Any Questions of the Neurological Examination   [ Time Frame: 1 Year ]
  Show Outcome Measure 30

31.  Secondary:   Prevalence of Chloroquine Resistant Parasites, by Treatment Arm: Prevalence of Parasites With the Mutation Pfcrt 76T on Day 0 of Each Episode of Malaria, and in Cases of Recurrent Parasitemia After Therapy.   [ Time Frame: 1 year ]
Results not yet posted.   Anticipated Posting Date:   02/2012   Safety Issue:   No

32.  Secondary:   Incidence of Infections and Recrudescent Infections After Initial Treatment Per Treatment Arm.   [ Time Frame: 28 days to 1 year ]
Results not yet posted.   Anticipated Posting Date:   02/2012   Safety Issue:   No

33.  Secondary:   Incidence of New and Recrudescent Infections After Subsequent New Episodes   [ Time Frame: 1 year ]
Results not yet posted.   Anticipated Posting Date:   02/2012   Safety Issue:   No

34.  Secondary:   Effect of Population Movements on the Risk of Malaria Infection - Risk of Malaria in Children Who Travelled Outside the City vs Those That Did Not.   [ Time Frame: 1 year ]
Results not yet posted.   Anticipated Posting Date:   02/2012   Safety Issue:   No

35.  Secondary:   Spatial Patterns and the Environmental Determinants of Malaria Infection: Distribution of Malaria Cases in Relation to Environmental Factors in Ndirande.   [ Time Frame: 1 year ]
Results not yet posted.   Anticipated Posting Date:   02/2012   Safety Issue:   No

36.  Secondary:   Chloroquine Blood Levels at Which Chloroquine Sensitive and Resistant Parasites Are Able to Cause Infection: Chloroquine Pharmacokinetic Curve for the Population, and Drug Concentration at the Time of Parasitemia.   [ Time Frame: 1 year ]
Results not yet posted.   Anticipated Posting Date:   02/2012   Safety Issue:   No


  Serious Adverse Events
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  Other Adverse Events
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Time Frame No text entered.
Additional Description No text entered.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Chloroquine Plus Artesunate Participants receive chloroquine (CQ) at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Artesunate at a dose of 4 mg/kg once a day for 3 days.
Chloroquine Plus Atovaquone-Proguanil Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Atovaquone-Proguanil (AP) once a day for 3 days dosed as follows: 5-8 kg, 2 pediatric tablet (PT, 62.5 mg/25mg); 9-10 kg, 3 PT; 11-20 kg, 1 full strength tablet (FST, 250mg/100 mg); 21-30 kg 2 FST; >30 kg, 3 FST.
CQ Plus Azithromycin Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2; plus Azithromycin 30 mg/kg once a day for 3 days.
CQ Monotherapy Participants receive CQ at 10 mg/kg on days 0 and 1, and 5 mg/kg/day on day 2.

Other Adverse Events
    Chloroquine Plus Artesunate     Chloroquine Plus Atovaquone-Proguanil     CQ Plus Azithromycin     CQ Monotherapy  
Total, other (not including serious) adverse events          
# participants affected / at risk     144/160     140/160     143/160     145/160  
Blood and lymphatic system disorders          
Haemorrhagic anaemia * 1        
# participants affected / at risk     26/160 (16.25%)     28/160 (17.50%)     32/160 (20.00%)     38/160 (23.75%)  
# events     32     32     36     41  
Neutropenia * 2        
# participants affected / at risk     1/160 (0.63%)     4/160 (2.50%)     8/160 (5.00%)     1/160 (0.63%)  
# events     1     4     8     1  
Thrombocytopenia * 3        
# participants affected / at risk     11/160 (6.88%)     6/160 (3.75%)     6/160 (3.75%)     5/160 (3.13%)  
# events     11     6     6     6  
Eye disorders          
Conjunctivitis * 3        
# participants affected / at risk     27/160 (16.88%)     19/160 (11.88%)     31/160 (19.38%)     31/160 (19.38%)  
# events     29     21     39     38  
Gastrointestinal disorders          
Abdominal pain * 3        
# participants affected / at risk     12/160 (7.50%)     8/160 (5.00%)     16/160 (10.00%)     10/160 (6.25%)  
# events     15     9     20     10  
Diarrhoea * 3        
# participants affected / at risk     42/160 (26.25%)     25/160 (15.63%)     26/160 (16.25%)     35/160 (21.88%)  
# events     53     33     33     49  
Stomatitis * 3        
# participants affected / at risk     6/160 (3.75%)     5/160 (3.13%)     5/160 (3.13%)     14/160 (8.75%)  
# events     6     5     5     14  
Vomiting * 1        
# participants affected / at risk     4/160 (2.50%)     7/160 (4.38%)     11/160 (6.88%)     7/160 (4.38%)  
# events     4     7     11     8  
General disorders          
Pyrexia * 2        
# participants affected / at risk     31/160 (19.38%)     22/160 (13.75%)     29/160 (18.13%)     28/160 (17.50%)  
# events     35     22     31     30  
Infections and infestations          
Body tinea * 3        
# participants affected / at risk     14/160 (8.75%)     10/160 (6.25%)     9/160 (5.63%)     6/160 (3.75%)  
# events     14     10     10     6  
Bronchitis * 4        
# participants affected / at risk     1/160 (0.63%)     3/160 (1.88%)     5/160 (3.13%)     11/160 (6.88%)  
# events     1     3     5     11  
Conjunctivitis bacterial * 2        
# participants affected / at risk     2/160 (1.25%)     2/160 (1.25%)     7/160 (4.38%)     9/160 (5.63%)  
# events     2     2     7     9  
Dysentery * 3        
# participants affected / at risk     17/160 (10.63%)     8/160 (5.00%)     12/160 (7.50%)     11/160 (6.88%)  
# events     24     8     14     14  
Gastroenteritis * 3        
# participants affected / at risk     46/160 (28.75%)     38/160 (23.75%)     34/160 (21.25%)     40/160 (25.00%)  
# events     53     41     39     44  
Helminthic infection * 3        
# participants affected / at risk     8/160 (5.00%)     11/160 (6.88%)     21/160 (13.13%)     10/160 (6.25%)  
# events     8     12     22     11  
Impetigo * 5        
# participants affected / at risk     46/160 (28.75%)     42/160 (26.25%)     31/160 (19.38%)     44/160 (27.50%)  
# events     61     62     37     56  
Nasopharyngitis * 3        
# participants affected / at risk     128/160 (80.00%)     114/160 (71.25%)     120/160 (75.00%)     119/160 (74.38%)  
# events     358     297     340     335  
Oral herpes * 3        
# participants affected / at risk     8/160 (5.00%)     5/160 (3.13%)     2/160 (1.25%)     4/160 (2.50%)  
# events     9     5     2     4  
Otitis media * 1        
# participants affected / at risk     12/160 (7.50%)     11/160 (6.88%)     11/160 (6.88%)     15/160 (9.38%)  
# events     12     18     13     20  
Parotitis * 1        
# participants affected / at risk     8/160 (5.00%)     1/160 (0.63%)     4/160 (2.50%)     7/160 (4.38%)  
# events     8     1     4     7  
Pneumonia * 2        
# participants affected / at risk     36/160 (22.50%)     18/160 (11.25%)     29/160 (18.13%)     40/160 (25.00%)  
# events     50     23     39     50  
Tinea capitis * 3        
# participants affected / at risk     23/160 (14.38%)     10/160 (6.25%)     14/160 (8.75%)     14/160 (8.75%)  
# events     27     11     17     15  
Varicella * 2        
# participants affected / at risk     17/160 (10.63%)     11/160 (6.88%)     5/160 (3.13%)     16/160 (10.00%)  
# events     17     11     5     16  
Injury, poisoning and procedural complications          
Excoriation * 3        
# participants affected / at risk     10/160 (6.25%)     6/160 (3.75%)     6/160 (3.75%)     6/160 (3.75%)  
# events     10     6     6     6  
Thermal burn * 3        
# participants affected / at risk     9/160 (5.63%)     7/160 (4.38%)     5/160 (3.13%)     6/160 (3.75%)  
# events     9     7     5     6  
Investigations          
Alanine aminotransferase increased * 2        
# participants affected / at risk     6/160 (3.75%)     4/160 (2.50%)     10/160 (6.25%)     7/160 (4.38%)  
# events     6     4     10     7  
Respiratory, thoracic and mediastinal disorders          
Cough * 3        
# participants affected / at risk     26/160 (16.25%)     28/160 (17.50%)     28/160 (17.50%)     30/160 (18.75%)  
# events     31     36     32     37  
Skin and subcutaneous tissue disorders          
Pruritus * 3        
# participants affected / at risk     5/160 (3.13%)     23/160 (14.38%)     32/160 (20.00%)     21/160 (13.13%)  
# events     5     25     34     23  
Rash papular * 1        
# participants affected / at risk     18/160 (11.25%)     24/160 (15.00%)     20/160 (12.50%)     19/160 (11.88%)  
# events     20     26     21     20  
Rash pruritic * 6        
# participants affected / at risk     9/160 (5.63%)     4/160 (2.50%)     4/160 (2.50%)     2/160 (1.25%)  
# events     10     4     5     2  
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA (12.0)
2 Term from vocabulary, MedDRA (10.1)
3 Term from vocabulary, MedDRA (11.0)
4 Term from vocabulary, MedDRA (9.0)
5 Term from vocabulary, MedDRA (10.0)
6 Term from vocabulary, MedDRA (11.1)



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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.  


Results Point of Contact:  
Name/Title: Christopher Plowe, MD, MPH
Organization: Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine
phone: 410-706-2491
e-mail: cplowe@medicine.umaryland.edu


Publications:


Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00379821     History of Changes
Other Study ID Numbers: 06-0022
Study First Received: September 21, 2006
Results First Received: June 30, 2011
Last Updated: March 28, 2013
Health Authority: Malawi: College of Medicine Research and Ethics Committee
United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board