A Safety, Tolerability, Pharmacokinetic and Efficacy Study of Azithromycin Plus Piperaquine as Presumptive Treatment in Pregnant PNG Women

A Safety, Tolerability, Pharmacokinetic and Efficacy Study of Azithromycin Plus Piperaquine as Presumptive Treatment in Pregnant Papua New Guinean Women

Plasmodium falciparum parasitaemia in pregnancy is associated with maternal anaemia, low birth-weight and increased perinatal mortality. Whilst continuous prophylaxis is difficult to implement, intermittent presumptive treatment in pregnancy (IPTp) has proved to be practical and effective. In PNG, pregnant women currently receive IPTp using sulfadoxine-pyrimethamine, however, this therapy has the potential to be compromised by parasite resistance.

The aim of the present trial is to assess the safety, tolerability, pharmacokinetics and efficacy of azithromycin (AZI) plus piperaquine (PQ) given as IPTp to pregnant Papua New Guinea women. The study will comprise of two sub-studies:

(i) A safety, tolerability and pharmacokinetic study of AZI-PQ in pregnancy. (ii) A safety, tolerability and preliminary efficacy study of AZI-PQ in pregnancy.

Study Overview

• Status: Unknown
• Conditions: Pregnancy; Clinical Efficacy; Drug Kinetics; Infections, Plasmodia
• Intervention / Treatment: Drug: Sulfadoxine-pyrimethamine; Drug: Azithromycin plus piperaquine phosphate

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 4

Contacts and Locations

Study Locations

• Papua New Guinea
  • Madang Province
    • Madang, Madang Province, Papua New Guinea, 511
      • Recruiting
      • Papua New Guinea Institute of Medical Research
      • Contact: Brioni R Moore, BSc, PhD; Phone Number: (+61) 0466266334; Email: brioni.moore@uwa.edu.au
      • Contact: Leanne J Robinson, BSc, PhD, MPH; Phone Number: (+675) 422 2909; Email: robinson@wehi.edu.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• >14 weeks and <30 weeks gestation
• No signs of severe malaria by World Health Organisation criteria
• No significant concomitant disease (such as TB)
• No prior history of an adverse reaction to AZI or PQP
• No prior treatment with these drugs in the past 4 weeks
• Can attend all follow-up visits
• Provide informed consent

Exclusion Criteria:

• Have signs of severe malaria by WHO criteria
• Significant concomitant disease such as TB as assessed by the attending clinician
• A history/family history of sudden death or of congenital prolongation of the QTc interval
• Any clinical condition known to prolong the QTc interval
• A history of complicated pregnancies/deliveries
• A prior history of an adverse reaction to AZI or PQP
• Have taken these drugs in the past 4 weeks
• Cannot attend any of the follow-up visits
• Do not provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Efficacy Study: Azithromycin plus piperaquine; At baseline, participants receive three daily doses (0, 24 and 48 hours) of i) 1 g azithromycin as 2 x film-coated 500 mg tablets ii) 960 mg piperaquine tetraphosphate tablets as 3 x 320 mg tablets	Drug: Azithromycin plus piperaquine phosphate; Other Names: Sandoz Azithromycin; Sigma-Tau Piperaquine tetraphosphate
Active Comparator: Efficacy Study Control: National Standard Treatment; At baseline, participants receive a single dose of sulfadoxine-pyrimethamine comprising 1,500 mg of sulfadoxine and 75 mg pyrimethamine in tablet form	Drug: Sulfadoxine-pyrimethamine
Experimental: Pharmacokinetic Study: Azithromycin plus piperaquine; At baseline, participants receive three daily doses (0, 24 and 48 hours) of i) 1 g azithromycin as 2 x film-coated 500 mg tablets ii) 960 mg piperaquine tetraphosphate tablets as 3 x 320 mg tablets	Drug: Azithromycin plus piperaquine phosphate; Other Names: Sandoz Azithromycin; Sigma-Tau Piperaquine tetraphosphate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of azithromycin plus piperaquine for the prevention of malaria during pregnancy	The efficacy of azithromycin plus piperaquine for the prevention of malaria infection during pregnancy will be investigated in 120 women. Women will be randomized to receive either (i) 3 daily doses of AZI plus PQ, or, (ii) single dose sulfadoxine-pyrimethamine Participants will be actively followed for a period of 42 days (1, 2, 3, 4, 7, 14, 21, 28 and 42 days after treatment). At each follow-up time point the participant will have a clinical examination, fundal height measurement and assessment of foetal lie, perform a symptoms questionnaire, blood film for malaria and other scheduled safety tests (eg. Hb, glucose, ultrasound). A single blood sample for pharmacokinetic analysis will be collected at Day 4. At delivery all participants and their babies will be assessed, including blood sample for Hb, glucose, blood spot for PCR, cord blood and maternal blood. Breast milk samples will be collected for 2 weeks (Day 1, 2, 3, 4, 7, 14) after the establishment of lactation.	42 days intensive follow-up, final end-point at 2 weeks post delivery

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetics - distribution, terminal elimination and absorption half-life(t1/2) of azithromycin and piperaquine	42 days intensive follow-up, final end-point at 2 weeks post delivery
Pharmacokinetics - area under the plasma concentration versus time curve (AUC) of azithromycin and piperaquine	42 days intensive follow-up, final end-point at 2 weeks post delivery
Pharmacokinetics - peak plasma concentration (Cmax) of azithromycin and piperaquine	42 days intensive follow-up, final end-point at 2 weeks post delivery
Pharmacokinetics - clearance (CL) of azithromycin and piperaquine	42 days intensive follow-up, final end-point at 2 weeks post delivery
Pharmacokinetics - volume of distribution (Vd) of azithromycin and piperaquine	42 days intensive follow-up, final end-point at 2 weeks post delivery
PCR adjusted 28 day cure	28 days
PCR adjusted 42 day cure	42 days
Number of participants with adverse events as a measure of safety and tolerability	42 days intensive follow-up, final end-point at 2 weeks post delivery

Other Outcome Measures

Outcome Measure	Time Frame
Change in maternal hemoglobin over 28 days	28 days
Change in maternal weight over 28 days	28 days
Infant birth weight	Time of delivery
Maternal parasitaemia	Time of delivery
Placental parasitaemia	Time of delivery
Cord blood parasitaemia	Time of delivery
Maternal hemoglobin at delivery	Time of delivery

Collaborators and Investigators

• Sponsor: Papua New Guinea Institute of Medical Research
• Collaborators: University of Melbourne; The University of Western Australia; Malaria in Pregnancy Consortium

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Anticipated): July 1, 2016
• Study Completion (Anticipated): October 1, 2016

Study Registration Dates

• First Submitted: October 8, 2015
• First Submitted That Met QC Criteria: October 14, 2015
• First Posted (Estimate): October 15, 2015

Study Record Updates

• Last Update Posted (Estimate): October 15, 2015
• Last Update Submitted That Met QC Criteria: October 14, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Efficacy; Pharmacokinetics; Azithromycin; IPTp; Piperaquine
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Anti-Infective Agents, Urinary; Renal Agents; Pyrimethamine; Azithromycin; Piperaquine; Sulfadoxine; Fanasil, pyrimethamine drug combination
• Other Study ID Numbers: MRAC10.53