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

Sponsor

Papua New Guinea Institute of Medical Research (Other)

Overall Status

Unknown status

CT.gov ID

NCT02575755

Collaborator

The University of Western Australia (Other), University of Melbourne (Other), Malaria in Pregnancy Consortium (Other)

150

Enrollment

Location

Arms

Duration (Months)

3.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pregnancy Infections, Plasmodia Drug Kinetics Clinical Efficacy	Drug: Azithromycin plus piperaquine phosphate Drug: Sulfadoxine-pyrimethamine	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Study Start Date :

Oct 1, 2012

Anticipated Primary Completion Date :

Jul 1, 2016

Anticipated Study Completion Date :

Oct 1, 2016

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Efficacy of azithromycin plus piperaquine for the prevention of malaria during pregnancy [42 days intensive follow-up, final end-point at 2 weeks post delivery]
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.

Secondary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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