Trial Outcomes & Findings for S. Japonicum and Pregnancy Outcomes (NCT NCT00486863)

Last Updated: 2016-01-26

Results Overview

Birth weight was collected for live infants at the time of delivery by a trained midwife, or within 24 hours of delivery for participants who chose to deliver at home with a helot, a birth attendant without formal training.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

370 participants

Primary outcome timeframe

Within 24 hours of delivery.

Results posted on

2016-01-26

Participant Flow

Participants were otherwise healthy schistosomiasis-infected women at 12-16 weeks gestation, recruited from approximately 50 schistosomiasis-endemic villages served by 6 municipal health centers in Leyte, The Phillipines. Participants were enrolled between 13Aug2007 and 5Nov2012.

Participant milestones

Participant milestones
Measure	Placebo Control at 12-16 Weeks Gestation Placebo was made with the same color-coded gelatin capsules as the test agent, but with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours. The agent was gel encapsulated to reduce appreciation of odor and taste and mimic appearance of the placebo.
Overall Study STARTED	184	186
Overall Study COMPLETED	183	183
Overall Study NOT COMPLETED	1	3

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

S. Japonicum and Pregnancy Outcomes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo Control at 12-16 Weeks Gestation n=184 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=186 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.	Total n=370 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	184 Participants n=5 Participants	186 Participants n=7 Participants	370 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	25.9 years STANDARD_DEVIATION 6.3 • n=5 Participants	26.2 years STANDARD_DEVIATION 6.6 • n=7 Participants	26.1 years STANDARD_DEVIATION 6.4 • n=5 Participants
Sex: Female, Male Female	184 Participants n=5 Participants	186 Participants n=7 Participants	370 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Philippines	184 participants n=5 Participants	186 participants n=7 Participants	370 participants n=5 Participants

PRIMARY outcome

Timeframe: Within 24 hours of delivery.

Population: All newborns for whom birth weights were reported were included in the analysis.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=181 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=180 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Mean Newborn Birth Weight	2.85 kilograms Standard Deviation 0.39	2.85 kilograms Standard Deviation 0.44

SECONDARY outcome

Timeframe: At delivery

Population: All participants for whom the status of the infant at delivery was reported are included in the analysis.

Each participant was followed until delivery to record if the outcome of the pregnancy was a live birth. Live births were defined as the complete expulsion or extraction from its mother of a product of conception, irrespective of the duration of the pregnancy, which, after such separation, breathes or shows any other evidence of life such as heartbeat, umbilical cord pulsation, or definite movement of voluntary muscles, whether the umbilical cord had been cut or the placenta was attached.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=183 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=183 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Number of Participants Whose Pregnancy Resulted in a Live Birth	181 participants	181 participants

SECONDARY outcome

Timeframe: 14 weeks and 32 weeks gestation

Population: All participants for whom hemoglobin concentrations were reported are included in the analysis.

Hemoglobin concentration in a venous blood sample collected at 14 and 32 weeks gestation was measured using a multi-analyte analyzer. Each participant's change in hemoglobin concentration between the two timepoints was determined, and the mean and standard deviation for each group calculated.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=183 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=181 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Mean Change in Maternal Hemoglobin From 14 to 32 Weeks Gestation	-0.42 grams/deciliter Standard Deviation 1.39	-0.44 grams/deciliter Standard Deviation 1.38

SECONDARY outcome

Timeframe: 14 weeks and 32 weeks gestation

Population: All participants for whom transferrin receptor:ferritin ratio was reported at both timepoints are included in the analysis.

To assess total body iron, one needs to assess the storage compartment, which will contain sequestered iron, and the functional compartment, which represents bioavailable iron. Body iron status is defined by the two laboratory measurements that reflect these compartments, ferritin and serum transferrin receptor. The serum transferrin receptor:ferritin ratio has been shown in quantitative phlebotomy studies to provide an accurate assessment of total body iron over the entire range of status. At 14 and 32 weeks gestation, a blood sample was collected for assessment of total body iron by determination of the transferrin receptor:ferritin ratio. Each participant's change in ratio was calculated, and the median and interquartile range were determined for each group.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=183 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=181 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Median Change in Maternal Transferrin Receptor:Ferritin Ratio From 14 to 32 Weeks Gestation	0.0 ratio Inter-Quartile Range 75.88 • Interval 0.0 to 15.47	0.0 ratio Inter-Quartile Range 162.4 • Interval 0.0 to 7.56

SECONDARY outcome

Timeframe: 32 weeks gestation

Population: All participants for whom hepcidin levels were reported are included in the analysis.

Anemia of inflammation was assessed via maternal urine hepcidin levels. In response to inflammation, elevated serum levels of hepcidin is synthesized. Hepcidin causes sequestration of iron from bio-available forms to storage forms such as ferritin and decreases intestinal absorption of iron. Hepcidin was measured in participants' urine at 32 weeks gestation.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=183 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=181 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Median Maternal Hepcidin at 32 Weeks Gestation	2.58 nanograms/milliliter Inter-Quartile Range 5.06 • Interval 0.94 to 6.0	3.38 nanograms/milliliter Inter-Quartile Range 4.32 • Interval 1.18 to 5.5

SECONDARY outcome

Timeframe: 14 and 32 weeks gestation

Population: All participants for whom weight was reported at both timepoints were included in this analysis.

Maternal weight gain was assessed by measuring participants' weight in kilograms. The weight increase from 14 to 32 weeks was determined for each participant, and the mean and standard deviation calculated.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=183 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=181 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Mean Change in Maternal Weight From 14 to 32 Weeks Gestation	0.33 kilograms Standard Deviation 0.13	0.32 kilograms Standard Deviation 0.13

SECONDARY outcome

Timeframe: 14 and 32 weeks gestation

Population: All participants for whom thigh skinfold thickness was reported at both timepoints were included in this analysis.

Maternal fat stores were measured by thigh skinfold thickness obtained using a Holtain skinfold caliper. The thickness increase from 14 to 32 weeks was determined for each participant, and the mean and standard deviation calculated.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=183 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=181 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Mean Change in Maternal Thigh Skinfold Thickness From 14 to 32 Weeks Gestation	0.08 millimeters Standard Deviation 0.09	0.08 millimeters Standard Deviation 0.09

SECONDARY outcome

Timeframe: 0-6 days after delivery.

Population: All infants for whom transferrin receptor and ferritin were reported are included in the analysis.

To assess total body iron, the serum transferrin receptor:ferritin ratio was assessed in the infant. At delivery, a heel stick blood sample and a cord blood sample were collected for assessment of total body iron by determination of the transferrin receptor:ferritin ratio.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=181 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=181 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Newborn Median Serum Transferrin Receptor:Ferritin Ratio Cord Blood	1.76 ratio Inter-Quartile Range 480.39 • Interval 0.0 to 5.29	1.33 ratio Inter-Quartile Range 1392.55 • Interval 0.0 to 4.36
Newborn Median Serum Transferrin Receptor:Ferritin Ratio Heel Stick	0.00 ratio Inter-Quartile Range 239.81 • Interval 0.0 to 0.1	0.00 ratio Inter-Quartile Range 162.24 • Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: Screening and 22 weeks gestation

Population: All participants for whom egg counts were reported are included in the analysis.

Parasitologic response to treatment was evaluated by counting S. japonicum eggs per gram of stool at screening and again at 22 weeks gestation. Success of treatment was pre-specified as greater than 90 percent reduction in egg count from screening to 22 weeks gestation.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=184 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=184 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Number of Subjects With Reduction in S. Japonicum Egg Counts From Screening to 22 Weeks Gestation of Greater Than 90 Percent	92 participants	157 participants

SECONDARY outcome

Timeframe: Within 24 hours of dosing

Population: All participants were included in this analysis.

Participants were observed in hospital for 24 hours after dosing for serious adverse events. Serious adverse events included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required in-patient hospitalization or prolongation thereof (for reasons other than the 24-hour observation period); resulted in a congenital anomaly/birth defect; or may have jeopardized the participant, or required intervention to prevent one of these outcomes.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=184 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=186 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Number of Participants Reporting Serious Adverse Events Within 24 Hours of Dosing	0 participants	0 participants

SECONDARY outcome

Timeframe: After dosing and before 20 weeks gestation

Population: All participants were included in this analysis.

Abortion was defined by the protocol as bleeding followed by fetal loss as supported by ultrasound before 20 weeks gestation. Abortion was an important safety outcome measure due to the fact that abortion would occur closer to the time of dosing than miscarriage or stillbirth. Participants were observed in hospital for 24 hours after dosing and asked to return for any bleeding at any time.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=184 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=186 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Number of Participants Experiencing Fetal Loss by Abortion	0 participants	0 participants

SECONDARY outcome

Timeframe: Just before and 24 hours after dosing

Population: All participants were included in this analysis.

Toxicity to maternal bone marrow, kidney, and liver was assessed by laboratory parameters collected just before and 24 hours after dosing. Specifically, blood was drawn just before the dose at 12-16 weeks gestation to determine baseline complete blood count, including white blood count (WBC), platelets, and hemoglobin. Blood was then drawn 24 hours after the second part of the split dose and before discharge from the hospital to assess any changes in these parameters. White blood count was abnormal at or above 10,800 or at or below 3500 cells/square millimeter (sq mm), platelets were abnormal at or below 140,000 cells/sq mm, and hemoglobin was abnormal at or below 10.9 grams/deciliter (g/dL).

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=184 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=186 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Number of Participants Reporting Abnormalities in Hematology Assessments Within 24 Hours of Dosing White Blood Cell Abnormal	69 participants	60 participants
Number of Participants Reporting Abnormalities in Hematology Assessments Within 24 Hours of Dosing Platelets Abnormal	3 participants	0 participants
Number of Participants Reporting Abnormalities in Hematology Assessments Within 24 Hours of Dosing Hemoglobin Abnormal	54 participants	56 participants

SECONDARY outcome

Timeframe: Just before and 24 hours after dosing

Population: All participants were included in this analysis.

Toxicity to maternal kidney and liver was assessed by laboratory parameters collected just before and 24 hours after dosing. Specifically, blood was drawn just before the dose at 12-16 weeks gestation to determine baseline blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin. Blood was then drawn 24 hours after the second part of the split dose and before discharge from the hospital to assess any changes in these parameters. Any values that were 1.1 times the upper limit of normal or greater for the parameter were considered abnormal.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=184 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=186 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Number of Participants Reporting Abnormalities in Clinical Chemistry Assessments Within 24 Hours of Dosing Blood Urea Nitrogen (BUN) Abnormal	127 participants	137 participants
Number of Participants Reporting Abnormalities in Clinical Chemistry Assessments Within 24 Hours of Dosing Creatinine Abnormal	23 participants	39 participants
Number of Participants Reporting Abnormalities in Clinical Chemistry Assessments Within 24 Hours of Dosing Aspartate Aminotransferase (AST) Abnormal	8 participants	9 participants
Number of Participants Reporting Abnormalities in Clinical Chemistry Assessments Within 24 Hours of Dosing Alanine Aminotransferase (ALT) Abnormal	13 participants	10 participants
Number of Participants Reporting Abnormalities in Clinical Chemistry Assessments Within 24 Hours of Dosing Bilirubin Abnormal	127 participants	137 participants

SECONDARY outcome

Timeframe: At delivery, within 2-6 days of delivery, and at 28 days

Population: All newborns are included in the analysis.

The newborn was examined by the midwife at delivery and within 2-6 days of delivery to assess the presence of congenital anomalies and well-being. The newborn was also examined by study pediatrician at 28 days of life.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=181 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=181 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Number of Participants Whose Infant Was Born With Congenital Anomalies	1 participants	1 participants

SECONDARY outcome

Timeframe: 22 weeks and 32 weeks

Population: All participants seen at both timepoints are included.

Participants were assessed for the presence of pre-eclampsia at both the 22 and 32 week visits. Pre-eclampsia was defined by the presence of proteinurea (2+ protein on urine dipstick) and a single diastolic blood pressure reading of 100 millimiters of mercury (mm Hg) or above OR more than one reading, four hours apart, of 90 mm Hg or above.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=183 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=181 Participants Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Number of Participants With Pre-eclampsia	0 participants	0 participants

SECONDARY outcome

Timeframe: At 32 weeks gestation

Extra-placental mechanisms mediating improved outcomes in the PZQ group were planned to be evaluated with maternal serum cytokine levels, particularly TNF-alpha, TNF-alpha receptors I and II, IL-1, and IL-6. These assays were intended to be performed only if the primary objective of the study was met; therefore, there will be no results reported for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At delivery

Cytokine assays were planned to be performed with culture supernatant harvested from placental explant cultures. The cytokines were to be measured with a multi-analyte analyzer. These assays were intended to be performed only if the primary objective of the study was met; therefore, there will be no results reported for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 32 weeks gestation

A study hypothesis was that peripheral serum obtained from S. japonicum infected, treated mothers would induce a lower level of apoptosis (programmed cell death) in cultured trophoblasts as measured by cytokeratin 18 neo-epitope staining compared to peripheral serum obtained from S. japonicum infected, PZQ untreated mothers. This assay was planned to be completed only if the primary objective was met; therefore, there will be no data for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 4.5 and 8 hours after the first praziquantel dose (subjects assigned to an even study number) or 6 and 10 hours after the first praziquantel dose (subjects assigned to an odd study number).

Population: The analysis population for pharmacokinetics descriptive analyses was defined as all subjects who had plasma samples collected and who were randomized to receive PZQ (N=99; 50 subjects at 4.5 and 8 hr after first PZQ dose and 49 at 6 and 10 hr after first PZQ dose).

Two plasma samples were collected during the overnight hospitalization from approximately 200 subjects that remained at the time of study modification to incorporate PK studies. Subjects had samples collected based on one of two sample collection strategies: 4.5 and 8 hr after the first praziquantel dose or 6 and 10 hr after the first praziquantel dose. Subjects randomized to an even study number were assigned to the 4.5 and 8 hour schedule. Subjects randomized to an odd study number were assigned to the 6 and 10 hour schedule. Samples only from subjects randomized to receive praziquantel were analyzed for praziquantel. Samples drawn from subjects randomized to the control group were not analyzed. Praziquantel concentrations (ng/ml) were assayed using high performance liquid chromatography-electrospray mass spectrometry in the University of California at San Diego Pediatric Clinical Pharmacology Laboratory.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=99 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Praziquantel Pharmacokinetic Concentrations 4.5 Hours, n=50	814.7 ng/mL Interval 289.8 to 1580.6	—
Praziquantel Pharmacokinetic Concentrations 6 Hours, n=49	945.2 ng/mL Interval 362.0 to 1365.0	—
Praziquantel Pharmacokinetic Concentrations 8 Hours, n=50	687.8 ng/mL Interval 107.7 to 1137.6	—
Praziquantel Pharmacokinetic Concentrations 10 Hours, n=49	422.2 ng/mL Interval 50.5 to 769.1	—

SECONDARY outcome

Since pregnancy is associated with increased cytochrome P450 activity and physiologic changes in the gastrointestinal tract that tend to reduce drug absorption, praziquantel pharmacokinetics may be affected by pregnancy. Thus, the metabolite-to-parent drug ratio may serve as a differential marker to help determine if variability in drug exposure following oral administration during pregnancy is due to altered metabolism or drug absorption. Samples that were collected from subjects who were randomized to receive praziquantel were analyzed for praziquantel and 4-hydroxy praziquantel concentrations. Assays were performed using high performance liquid chromatography-electrospray mass spectrometry in the University of California at San Diego Pediatric Clinical Pharmacology Laboratory. Descriptive statistics were obtained for concentrations at each of the four sparse sampling timepoints.

Outcome measures

Outcome measures
Measure	Placebo Control at 12-16 Weeks Gestation n=99 Participants Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
4-hydroxy Praziquantel Pharmacokinetic Concentrations 4.5 Hours, n=50	4020.1 ng/ml Interval 2022.1 to 5846.6	—
4-hydroxy Praziquantel Pharmacokinetic Concentrations 6 Hours, n=49	4590.8 ng/ml Interval 2982.5 to 7514.5	—
4-hydroxy Praziquantel Pharmacokinetic Concentrations 8 Hours, n=50	5373.7 ng/ml Interval 1476.6 to 7503.2	—
4-hydroxy Praziquantel Pharmacokinetic Concentrations 10 Hours, n=49	4304.1 ng/ml Interval 994.2 to 6344.3	—

Adverse Events

Placebo Control at 12-16 Weeks Gestation

Serious events: 34 serious events

Other events: 159 other events

Deaths: 0 deaths

Praziquantel at 12-16 Weeks Gestation

Serious events: 45 serious events

Other events: 176 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Jennifer Friedman, M.D., Ph.D

Warren Alpert Medical School of Brown University, Lifespan Center for International Health Research

Phone: (401) 444-7449

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Placebo Control at 12-16 Weeks Gestation n=184 participants at risk Placebo was made with the same color-coded gelatin capsules with the inert compound dextrose.	Praziquantel at 12-16 Weeks Gestation n=186 participants at risk Praziquantel was administered orally as 60 mg/kg given in a split dose (30/mg/kg each) separated by 3 hours.
Blood and lymphatic system disorders Anaemia	27.7% 51/184 • Number of events 52 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	25.3% 47/186 • Number of events 48 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Gastrointestinal disorders Abdominal pain lower	8.2% 15/184 • Number of events 16 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	6.5% 12/186 • Number of events 12 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
General disorders Pyrexia	25.5% 47/184 • Number of events 47 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	21.0% 39/186 • Number of events 39 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Infections and infestations Nasopharyngitis	3.8% 7/184 • Number of events 8 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	8.1% 15/186 • Number of events 16 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Infections and infestations Urinary tract infection	7.1% 13/184 • Number of events 13 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	5.4% 10/186 • Number of events 11 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Investigations Blood pressure increased	5.4% 10/184 • Number of events 10 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	1.6% 3/186 • Number of events 3 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Investigations Haemoglobin decreased	8.7% 16/184 • Number of events 17 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	4.8% 9/186 • Number of events 9 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Investigations Urine leukocyte esterase positive	5.4% 10/184 • Number of events 10 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	2.2% 4/186 • Number of events 4 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Pregnancy, puerperium and perinatal conditions Uterine contractions during pregnancy	8.2% 15/184 • Number of events 16 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	5.4% 10/186 • Number of events 10 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Renal and urinary disorders Dysuria	2.2% 4/184 • Number of events 4 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	8.1% 15/186 • Number of events 15 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Respiratory, thoracic and mediastinal disorders Cough	20.1% 37/184 • Number of events 41 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	19.9% 37/186 • Number of events 40 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Nervous system disorders Headache	44.6% 82/184 • Number of events 82 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	53.2% 99/186 • Number of events 99 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
General disorders Malaise	37.0% 68/184 • Number of events 68 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	43.5% 81/186 • Number of events 81 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Gastrointestinal disorders Abdominal Pain	34.2% 63/184 • Number of events 63 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	40.9% 76/186 • Number of events 76 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Gastrointestinal disorders Nausea	37.0% 68/184 • Number of events 68 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	50.5% 94/186 • Number of events 94 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Gastrointestinal disorders Vomiting	28.8% 53/184 • Number of events 53 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	41.4% 77/186 • Number of events 77 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.0% 11/184 • Number of events 11 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	7.5% 14/186 • Number of events 14 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Nervous system disorders Dizziness	27.2% 50/184 • Number of events 50 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	53.8% 100/186 • Number of events 100 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.
Skin and subcutaneous tissue disorders Rash	6.0% 11/184 • Number of events 11 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.	10.8% 20/186 • Number of events 20 • Solicited systemic symptoms were observed in clinic 24 hours after treatment and recorded for 14 days post treatment. Unsolicited adverse events and SAEs were evaluated at clinic visits and passively reported through 28 days post delivery. For solicited symptoms recorded on the Memory Aid in the 14 days after treatment, a participant was considered to have one event if it was reported as experienced at any time in the 14-day period.