For study , molecular detection of the K76T mutation associated with CQ resistance was detected by means of a standardised real-time PCR-based diagnostic assay [ 9 , 10 ].
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In addition, specimens collected on Day 0 from subjects who responded to treatment also were analysed for pfcrt gene mutations. All subjects were hospitalised and monitored until three consecutive blood smears were negative for asexual P. Peripheral blood smears for parasite counts were obtained at eight-hour intervals until clearance was demonstrated, then on Day 7 and weekly thereafter through Day 42 to monitor recrudescence. Vital signs, clinical signs and symptoms, adverse events AEs , and concomitant medications were assessed for all subjects on each day of treatment Days 0, 1, and 2 and at each post-therapy visit Days 7, 14, 21, 28, 35, and Haematology and serum chemistry laboratory tests were performed at Baseline and Day 3 and at subsequent visits if clinically indicated.
Haematology tests included red blood count, white blood count with differential, haemoglobin, haematocrit, and platelets. Serum chemistry tests included electrolytes, urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. The primary endpoint was the asexual P. Efficacy was assessed at Days 28 primary endpoint and 42 in the per protocol PP population. Treated subjects were excluded from the PP population if they did not meet the disease definition, did not receive all three days of study medication unless designated a treatment failure, defined as the development of signs of severe malaria in the presence of parasitaemia , or did not have a blood smear at the specified time point unless due to recurrent parasitaemia before that time point.
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Subjects were assigned a response of eradicated if parasitaemia cleared within seven days after initiation of treatment and did not recur through the time point of interest. Failure was defined as not achieving clearance of asexual P. Secondary efficacy analyses included time required for asexual parasite clearance, fever clearance time, and assessment of the percentage of subjects with early and late treatment failures as defined by the World Health Organization [ 12 ].
All subjects who received at least one dose of study medication were evaluated for safety. Subjects were monitored closely for clinical evidence of illness progression. All subjects with persistent or recurrent parasitaemia received therapy consistent with the local standard of care and were monitored until parasite clearance was documented.
Other safety evaluations included AE and vital sign monitoring throughout the study, haematology and serum chemistry laboratory evaluations, and physical examinations. The primary efficacy analysis compared the PCR-corrected asexual P. A two-sided confidence interval CI , using the appropriate confidence level, was constructed for the difference between treatment groups in asexual parasite clearance rates using normal approximation to the binomial, and also for within group rates.
A CI was computed for the clearance rate within a treatment group using exact methods when no failures were observed. The confidence level in the final analysis for study required a small adjustment upward from 95 to There was no adjustment for centres in the analyses. Clearance time comparisons up to Day 7 were generated using Kaplan-Meier estimates.
Chloroquine (CQ) and Azithromycin (AZ) Combination for Malaria Prophylaxis
Parasite clearance time was defined as the time in days from Baseline to the first of the three consecutive zero parasite counts. Fever clearance time was defined as the time in days from Baseline to the first of the two consecutive time points without evidence of elevated temperature. These studies were conducted in compliance with the Declaration of Helsinki, institutional review boards, informed consent regulation, and the International Conference on Harmonisation Good Clinical Practice guidelines. All local regulatory requirements were followed. The clinical protocol was conducted in accordance with FDA regulations.
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Pfizer Inc conducted the clinical monitoring of the study. Similar numbers of subjects on each regimen completed therapy. Subject disposition in study A and study B. All subjects with persistent or recurrent parasitaemia during the follow-up period were to receive rescue therapy with an anti-malarial regimen that was consistent with the local standard of care. Ten and five subjects treated with AZCQ and five and three patients treated with MQ in studies and , respectively, received rescue medication.
The most common rescue mediation used was quinine in both treatment groups. The median time to clearance of asexual P. Median time to resolution of fever was observed to be 1. No LPFs were observed in study in either treatment group. No such mutations were identified [ 13 ]. CQ—resistance-associated mutation rates varied among the countries participating in these studies, from Treatment-emergent AEs considered related to study medication were observed in Overall, three 1. No clinically significant changes were observed in any laboratory values over the duration of the study and abnormal laboratory values did not result in any study discontinuations see Additional files 1 and 2.
A severe AE of vomiting was seen in one 0. The mean time to resolution of parasitaemia was comparable in each regimen, as was the time to resolution of fever. Given the level of parasite clearance achieved at Day 28 in studies and , lower limits of the CIs comparing the two treatments would indicate a difference relative to MQ of no worse than 5. Based on this observation, it is clear that AZCQ displayed efficacy in areas with a high prevalence of CQ-resistant falciparum malaria. There was a trend to lower rates of CQ resistance in the clinical trial sites in Ghana and Zambia over this time period, which may be related to anti-malarial policies in these countries vs the other countries included in this study.
While no CQ monotherapy control arm was included in this trial, the historical rates of clinical response to CQ in areas with significant in vitro CQ resistance would be expected to be significantly lower than those observed on this combination therapy [ 17 ]. Whether the enhanced efficacy of the combination is a consequence of the direct effects of AZ on the parasite or the effect of AZ on the resistance mechanisms mediating CQ resistance, or both, cannot be established from these data.
Moreover, anti-malarial immunity in malaria-endemic areas also can assist in parasite clearance and may play a role in the enhanced efficacy of the combination therapy, although innate immunity is equally likely to be effective in those subjects who received either AZ or CQ alone [ 18 ]. Discontinuations due to AEs were infrequent and numbers were similar in each regimen. Pruritus was seen more frequently with the AZCQ combination, a well-described effect associated with the use of CQ in subjects with melanoderma [ 19 ].
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Central nervous system AEs were seen more frequently with MQ, and again this is consistent with historical experience [ 20 ]. Gastrointestinal AEs occurred with both regimens to a similar degree. For a regimen to be considered appropriate as a therapy for malaria, it first must demonstrate that it is safe and effective in the target subject population. Other considerations, however, should be addressed with regard to the AZCQ combination. CQ is no longer recommended for the treatment of malaria in Africa due to the generally high rates of background CQ resistance and subsequent poor clinical response to therapy throughout the continent.
The position of the World Health Organization is that all therapy for the treatment of malaria should be combination therapy, primarily combinations that include an artemisinin derivative [ 21 ]. The combination therapy should include a partner drug with sufficient efficacy to protect the artemisinin from the development of resistance.
Alternatively, new modelling suggests that the introduction of a variety of therapy may be more effective in managing the rate at which resistance appears [ 22 ]. A limitation of this study was the recruitment of adults with symptomatic uncomplicated malaria only and thus, other target populations, including pregnant women, should be studied, as it is known that pregnant women are more susceptible to malaria compared with non-pregnant women within the same age group [ 23 ].
Other areas of study also may include use in the paediatric population and, given the activity of AZ in a variety of bacterial infections [ 25 , 26 ], home-based management of fever.
As the primary endpoint was analysed using the intent-to-treat population, lack of tolerability of the combination treatment may have resulted in a higher dropout rate leading to the inclusion of missing data as a failure in the interim analysis. New therapy for the prevention and treatment of malaria in the context of a broader campaign of public health interventions is, therefore, needed to help limit the morbidity and mortality associated with this disease. Trape JF: The public health impact of chloroquine resistance in Africa.
Am J Trop Med Hyg. Malar J. Antimicrob Agents Chemother. Clin Infect Dis. J Infect Dis. J Clin Microbiol. N Engl J Med. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria.
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PLoS One. Trop Doct. Baird JK: Effectiveness of antimalarial drugs. Guidelines for the treatment of malaria [second ed]. Lancet Infect Dis. Pfizer Inc: Zithromax [prescribing information]. Download references. The authors also thank Jeanne Breen, MD previously of Pfizer Inc , for help in the preparation of the manuscript, and Bob Burnside Pfizer Inc for assistance in statistical data management. Correspondence to Jeffery Robbins.
These studies were funded by Pfizer Inc. Willing to comply with all protocol procedures and time commitments No plans to participate in another clinical research study for the duration of this study. Subjects with a history of retinopathy, sickle cell disease or trait, psoriasis, or porphyria. Subjects who take certain prescribed or over the counter OTC concomitant medication including: ampicillin, antacids including kaolin , cimetidine, digoxin, ergot alkaloids, statins HMG-CoA reductase inhibitors , cyclosporine, warfarin, fluconazole, nelfinavir, or rifabutin, within 2 weeks of dosing start, and during the duration of the study.
Are known or suspected of drinking too much alcohol for men, more than 28 standard alcohol drinks and for women more than 21 standard alcohol drinks per week standard drink is defined as a 12 oz beer, 5 oz glass of wine, or 1. Subjects who have donated more than mL males or mL females blood in the previous 12 months, including the maximum volume of blood mL to be taken in this study.
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Subjects who are currently enrolled in another study involving an investigational product, or if recently involved in another clinical trial which has ended, have not received any investigational products within the past 3 months or 5 half-lives whichever is longer from the time of screening.
Any history of malaria infection in the past 3 years. History of travel to malaria endemic areas in the 3 months prior to day of challenge, or plans to travel to malaria endemic areas during the duration of the study 56 days post challenge. Any other significant finding that in the opinion of the PI would increase the risk of having an adverse outcome from participating in this study.
Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials. More Information. Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya. Clin Infect Dis. Biswas S. In-vitro antimalarial activity of azithromycin against chloroquine sensitive and chloroquine resistant Plasmodium falciparum.