5 august 2004 version

The study listed may include approved and non-approved uses, formulations, or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country.
Study No.: 115-127
Title: Comparative Clinical Trial of a Combination of Atovaquone and Proguanil Versus a Combination of Quinine and
Tetracycline in the Treatment of Acute P. falciparum Malaria in Adults in Brazil
Rationale: Malaria is one of the major health problems of Brazil, especially in the Amazon region. Most cases are due
to Plasmodium falciparum, but nearly as many are due to P. vivax. Standard treatment of falciparum malaria in this
region is quinine/tetracycline for seven days. Typically, subjects are given enough drug for the initial four days and told to return for an additional three days of medication. Many, however, do not return and recrudescences are thought to be common. Recrudescences of P. falciparum following treatment with quinine/tetracycline are usually treated with mefloquine or artesunate, both of which are available locally. Clinical studies with concurrent administration of atovaquone and other selected drugs were performed during 1990-1993 in Thailand. These studies showed the optimum drug regimen to be once daily 1,000 mg doses of atovaquone administered concurrently with once daily doses of 400 mg of proguanil for three days. This regimen cured all 24 evaluable subjects with acute falciparum malaria. The present study was designed to compare the efficacy, safety, and tolerance of atovaquone/proguanil with quinine/tetracycline in adult subjects with acute falciparum malaria in Brazil.
Phase: III
Study Period: April 1995 - February 1996
Study Design: This was an open-label, randomized, controlled, comparative trial of atovaquone plus proguanil
compared to quinine plus tetracycline.
Centers: The study was conducted in one study center in Brazil.
Indication: Treatment of acute P. falciparum malaria
Treatment: The test product was atovaquone/proguanil co-administered in separate tablets, each containing 250 mg
and 100 mg respectively. Four tablets of each drug were given every 24 hours for 3 days. The reference product was 325 mg quinine tablets/250 mg tetracycline capsules. Quinine was administered as two tablets every eight hours for seven days and tetracycline as one capsule every six hours for seven days. The test product and reference therapy were administered orally. The duration of treatment was 3 days for the test product and 7 days for the reference therapy.
Objectives: (1) To compare the efficacy of a combination of atovaquone and proguanil with quinine and tetracycline in
adult subjects with acute falciparum malaria in Brazil and (2) to compare the safety and tolerance of a combination of atovaquone and proguanil with quinine and tetracycline in adult subjects with acute falciparum malaria in Brazil
Primary Outcome/Efficacy Variable: The primary efficacy parameter was the 28-day cure rate. Cure rate was
defined as the percentage of subjects in whom parasitemia was eliminated within 7 days and did not recur during 28 days of follow-up.
Secondary Outcome/Efficacy Variable(s): This study did not have secondary efficacy parameters. The rates of
parasite clearance from the peripheral blood and resolution of fever were considered collaborative evidence of efficacy.
Statistical Methods: Cure rates, parasite clearance times (PCTs), and fever clearance times (FCTs) were calculated
and summarised descriptively for each treatment group.
Study Population: All male subjects who had acute, uncomplicated falciparum malaria with parasite counts between
1,000 and 100,000/µl, who were 18-65 years of age, whose weight exceeded 40 kg, who had no significant
concomitant disease, and who granted their informed consent were acceptable for admission into the study. Subjects with severe or cerebral malaria, mixed infections, or persistent vomiting were not acceptable for inclusion in the study.
Number of Subjects: Atovaquone
Quinine and
Proguanil
Tetracycline
Withdrawn Due to Lack of Efficacy, n (%) Demographics: Atovaquone
Quinine and
Proguanil
Tetracycline
Efficacy Results:
Cure Rate
Atovaquone and
Quinine and
Proguanil
Tetracycline
PCT (Hours)
Atovaquone and
Quinine and
Proguanil
Tetracycline
FCT (Hours)
Atovaquone and
Quinine and
Proguanil
Tetracycline
Safety Results: On-therapy adverse events (AEs) were defined as treatment-emergent signs or symptoms first
occurring or increasing in severity within 7 days of initiation of treatment. On-therapy serious adverse events (SAEs) include all serious AEs that occurred on treatment or within 7 days of initiation of treatment.
Most Frequent Adverse Events – On-Therapy
Atovaquone and
Quinine and
Proguanil
Tetracycline
Serious Adverse Events - On-Therapy
n (%) [n considered by the investigator to be related to study medication]
Atovaquone
Quinine and
Proguanil
Tetracycline
Subjects with Fatal SAEs, n (%) [related]
Conclusion:
See publication below
Publications:
de Alencar FEC, Cerutti C, Durlacher RF, Boulos M, Alves FP, Milhous W, Pang LW. Atovaquone and proguanil for the treatment of malaria in Brazil. JID 1997;175:1544–7.

Source: http://www.gsk-clinicalstudyregister.com/files2/789.pdf