Intermittent Preventive Treatment With Azithromycin-containing Regimens in Pregnant Women in Papua New Guinea

Overview

The purpose of this study is to determine whether repeated courses of sulphadoxine-pyrimethamine (SP) in combination with azithromycin given at Antenatal Clinic, leads to lower rates of low birth weight deliveries (<2.5 kg) among Papua New Guinean women, than the current standard treatment of SP and chloroquine.

Full Title of Study: “Intermittent Preventive Treatment With Azithromycin-containing Regimens for the Prevention of Malarial Infections and Anaemia and the Control of Sexually Transmitted Infections in Pregnant Women in Papua New Guinea”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Single (Participant)
  • Study Primary Completion Date: December 2012

Interventions

  • Drug: chloroquine, sulphadoxine pyrimethamine, LLIN
    • > 50Kg: chloroquine base 150 mg 4 tablets daily for 3 days, plus sulphadoxine pyrimethamine 1500/75 mg single dose. < 50 Kg: chloroquine base 150 mg 3 tablets daily for 3 days, plus sulphadoxine pyrimethamine 1500/75 mg single dose. Given at enrolment, 14-26 weeks gestation, by mouth.
  • Drug: azithromycin, sulphadoxine pyrimethamine, LLIN
    • sulphadoxine pyrimethamine (1500 mg/75 mg as single dose) plus azithromycin (1 g twice daily for 2 days). Given three times by mouth at monthly intervals, commencing at between 14 and 26 weeks gestation.

Arms, Groups and Cohorts

  • Active Comparator: SP, chloroquine treatment; bed net
    • Treatment course of sulphadoxine pyrimethamine and chloroquine on enrolment. Long lasting insecticide treated bed net
  • Experimental: 3 x SP plus azithromycin; bed nets
    • Three x monthly courses of azithromycin and sulphadoxine pyrimethamine plus long lasting insecticide treated bed net.

Clinical Trial Outcome Measures

Primary Measures

  • Proportion of women delivering low birth weight babies, <2500 g
    • Time Frame: At delivery

Secondary Measures

  • Prevalence of P falciparum at delivery in peripheral, placental and cord blood films and on placental histology
    • Time Frame: at delivery
  • Mean maternal hemoglobin concentration at delivery, and proportion of women anaemic (Hb < 11 g/dl).
    • Time Frame: At delivery
  • Prevalence (at enrolment, second treatment, and delivery) and consequences (maternal haemoglobin, birth weight and placental pathology) of P. vivax infection in pregnancy
    • Time Frame: up to 26 weeks
    • From enrolment at 14-26 weeks gestation, until delivery
  • Incidence of symptomatic malaria during pregnancy
    • Time Frame: Up to 26 weeks
    • From enrolment at 14-26 weeks until delivery
  • Proportion of women carrying azithromycin-sensitive sexually transmitted infections at second treatment visit (28-34 weeks).
    • Time Frame: 28-34 week gestation study visit
  • Incidence of Adverse Events, including severe adverse events (SAEs), and AEs possibly or probably associated with study medications
    • Time Frame: 14-26 weeks
    • From enrolment at 14-26 weeks gestation until delivery
  • Prevalence of drug resistance markers in parasites infecting women in late pregnancy, particularly in the P falciparum and P vivax dihydrofolate reductase and dihydropteroate synthase enzymes, associated with SP resistance
    • Time Frame: at delivery
  • Prevalence and antibiotic sensitivity patterns of S. pneumoniae in nasopharyngeal swabs collected at delivery
    • Time Frame: at delivery
  • Maternal, perinatal and infant mortality rates
    • Time Frame: Mothers; up to 32 weeks, from enrolment at 14-26 weeks gestation, until delivery. Pernatal: 16 weeks, from 28 weeks gestation to 4 weeks of age. Infant: from live birth to 1 year of age
    • maternal mortality is during pregnancy and until 6 weeks post partum. Perinatal mortality is from 28 weeks gestation until 6 weeks postpartum. Infant mortality is from irth to 12 months of age
  • Impact of IPTp on development of immunity to malaria in pregnancy
    • Time Frame: at delivery
  • Characteristics of parasites infecting pregnant women
    • Time Frame: Up to 26 weeks, from 14-26 weeks gestation until delivery

Participating in This Clinical Trial

Inclusion Criteria

  • pregnant – 14-26 weeks'gestation – permanent resident of study area – exclusive use of study health facilities for primary health care – Age is between 16 and 49 years Exclusion Criteria:

  • Known chronic illness, e.g. TB, diabetes, renal failure – Severe anaemia requiring hospitalisation (Hb < 6 g/dl accompanied by symptoms requiring urgent treatment) – permanent disability, that prevents or impedes study participation and/or comprehension – Known multiple pregnancy

Gender Eligibility: Female

Minimum Age: 16 Years

Maximum Age: 49 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Melbourne
  • Collaborator
    • Papua New Guinea Institute of Medical Research
  • Provider of Information About this Clinical Study
    • Principal Investigator: Stephen Rogerson, Professor of Medicine – University of Melbourne
  • Overall Official(s)
    • Stephen J Rogerson, FRACP PhD, Principal Investigator, University of Melbourne

References

Steketee RW, Nahlen BL, Parise ME, Menendez C. The burden of malaria in pregnancy in malaria-endemic areas. Am J Trop Med Hyg. 2001 Jan-Feb;64(1-2 Suppl):28-35. doi: 10.4269/ajtmh.2001.64.28.

Guyatt HL, Snow RW. The epidemiology and burden of Plasmodium falciparum-related anemia among pregnant women in sub-Saharan Africa. Am J Trop Med Hyg. 2001 Jan-Feb;64(1-2 Suppl):36-44. doi: 10.4269/ajtmh.2001.64.36.

Brabin B, Piper C. Anaemia- and malaria-attributable low birthweight in two populations in Papua New Guinea. Ann Hum Biol. 1997 Nov-Dec;24(6):547-55. doi: 10.1080/03014469700005312.

Benet A, Khong TY, Ura A, Samen R, Lorry K, Mellombo M, Tavul L, Baea K, Rogerson SJ, Cortes A. Placental malaria in women with South-East Asian ovalocytosis. Am J Trop Med Hyg. 2006 Oct;75(4):597-604.

Allen SJ, Raiko A, O'Donnell A, Alexander ND, Clegg JB. Causes of preterm delivery and intrauterine growth retardation in a malaria endemic region of Papua New Guinea. Arch Dis Child Fetal Neonatal Ed. 1998 Sep;79(2):F135-40. doi: 10.1136/fn.79.2.f135.

Schultz LJ, Steketee RW, Macheso A, Kazembe P, Chitsulo L, Wirima JJ. The efficacy of antimalarial regimens containing sulfadoxine-pyrimethamine and/or chloroquine in preventing peripheral and placental Plasmodium falciparum infection among pregnant women in Malawi. Am J Trop Med Hyg. 1994 Nov;51(5):515-22. doi: 10.4269/ajtmh.1994.51.515.

Parise ME, Ayisi JG, Nahlen BL, Schultz LJ, Roberts JM, Misore A, Muga R, Oloo AJ, Steketee RW. Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. Am J Trop Med Hyg. 1998 Nov;59(5):813-22. doi: 10.4269/ajtmh.1998.59.813.

Verhoeff FH, Brabin BJ, Chimsuku L, Kazembe P, Russell WB, Broadhead RL. An evaluation of the effects of intermittent sulfadoxine-pyrimethamine treatment in pregnancy on parasite clearance and risk of low birthweight in rural Malawi. Ann Trop Med Parasitol. 1998 Mar;92(2):141-50. doi: 10.1080/00034989859979.

Shulman CE, Dorman EK, Cutts F, Kawuondo K, Bulmer JN, Peshu N, Marsh K. Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial. Lancet. 1999 Feb 20;353(9153):632-6. doi: 10.1016/s0140-6736(98)07318-8.

Casey GJ, Ginny M, Uranoli M, Mueller I, Reeder JC, Genton B, Cowman AF. Molecular analysis of Plasmodium falciparum from drug treatment failure patients in Papua New Guinea. Am J Trop Med Hyg. 2004 Mar;70(3):251-5.

ter Kuile FO, van Eijk AM, Filler SJ. Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: a systematic review. JAMA. 2007 Jun 20;297(23):2603-16. doi: 10.1001/jama.297.23.2603.

Kalilani L, Mofolo I, Chaponda M, Rogerson SJ, Alker AP, Kwiek JJ, Meshnick SR. A randomized controlled pilot trial of azithromycin or artesunate added to sulfadoxine-pyrimethamine as treatment for malaria in pregnant women. PLoS One. 2007 Nov 14;2(11):e1166. doi: 10.1371/journal.pone.0001166.

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