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

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
Pregnancy, Infections, Plasmodia, Drug Kinetics, Clinical Efficacy

Intervention / Treatment
-----------------
* Drug: Azithromycin plus piperaquine phosphate
* Drug: Sulfadoxine-pyrimethamine


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Efficacy Study: Azithromycin plus piperaquine<br>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<br> <br> * Other names: Sigma-Tau Piperaquine tetraphosphate;|
| Active Comparator: Efficacy Study Control: National Standard Treatment<br>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<br> <br> |
| Experimental: Pharmacokinetic Study: Azithromycin plus piperaquine<br>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<br> <br> * Other names: 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 | Measure Description | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
IPTp, Azithromycin, Piperaquine, Pharmacokinetics, Efficacy