Conditions: Hepatitis B Chronic Infection Pregnancy
Keywords: Hepatitis B Hepatitis B sAg Hepatitis B eAg pregnancy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 654
Healthy volunteers: no

Brief summary:
Chronic hepatitis B (CHB) infection is complicated by cirrhosis and liver cancer. In Thailand, 7% of adults are chronically infected by Hepatitis B virus (HBV). The risk of perinatal transmission of HBV is about 12% when a mother has a high HBV load in her plasma, even if her infant receive specific immunoglobulin and vaccine.

The hypothesis of this study is that a potent antiviral, tenofovir, can decrease HBV load in HBV infected pregnant women and therefore reduce the risk of perinatal transmission/ Pregnant women participating in this study will receive tenofovir or placebo during the last trimester of pregnancy and two months postpartum. The risk of perinatal transmission will be compared between the two groups.

The results of the study will help define policy to manage HBV infected pregnant women to prevent perinatal transmission.

Detailed description:
This is a phase III, placebo controlled, double blind, randomized clinical trial to assess the efficacy and safety of tenofovir disoproxil fumarate (TDF) given from 28 weeks' gestation until 2 months postpartum to pregnant women with Hepatitis B (HB) virus (HBV) chronic infection and positive for HB s and e antigen to prevent perinatal transmission of HBV to their infants. All infants will receive HBV passive (HB specific immunoglobulin) and active (vaccine) immunization.

Chronic hepatitis B (CHB) infection is complicated by cirrhosis and hepatocellular carcinoma (HCC), the 10th leading cause of death worldwide.

In 2011, about 7% of adults in Thailand were HBsAg carriers. Infant hepatitis B (HB) immunization and HB immune globulin (HBIg) administered at birth effectively prevent most mother-to-child transmission (MTCT) of HBV. However, about 12% of mothers with high load of HBV transmit the virus to their infants, despite active and passive immunization.

Studies have suggested that antiviral treatment at the end of pregnancy and during early postpartum can reduce the risk of transmission to the child. A potential limitation to this approach is the risk of hepatic disease exacerbation following discontinuation of antiviral treatment postpartum, and this risk has not been properly evaluated. No randomized clinical trials have adequately demonstrated the efficacy and safety of maternal antiviral treatment the prevention of mother to child transmission of HBV. This is the reason why this approach is not currently recommended by the Associations for the Study of Liver Diseases.

We hypothesize that a potent antiviral, tenofovir, can decrease HBV viral load in HBV infected pregnant women and therefore reduce the risk of perinatal transmission, before infants are definitely protected by passive-active immunization. We also hypothesize that only moderate exacerbations of liver disease will be observed after discontinuation of a short antiviral course (5 months). While the primary objective of the study is to assess the efficacy of tenofovir versus placebo for the prevention of perinatal transmission, an important secondary objective is the assessment of the risk of postpartum hepatic disease exacerbation.

Within 2 years, 328 women and their infants will be enrolled from public hospitals in Thailand and randomized to receive either tenofovir disoproxil fumarate or matching placebo from 28 weeks of pregnancy until 2 months postpartum. Mothers and infants will be followed until one year postpartum.

The primary endpoint will be the detection of HBsAg and HBV DNA in infants at six months of life. An interim analysis will be conducted when half of the outcomes are available.

Arms:
arm 1: tenofovir disoproxil fumarate, 300 mg tablets arm 2: matching placebo (of tenofovir disoproxil fumarate)

Interventions: intervention 1: tenofovir disoproxil fumarate intervention 2: placebo
Intervention descriptions: intervention 1: administration: tablet 300 mg, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum intervention 2: administration: one tablet, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum

Protocol document:
Prot_000.pdf: 
Official title: Study Protocol 
NCT number: NCT01745822 
Document date: April 20, 2015 
 


PHPT 
Protocol 
A phase III, placebo controlled, double blind, randomized clinical 
trial to assess the efficacy and safety of tenofovir disoproxil 
fumarate given from 28 weeks' gestation until 2 months 
postpartum to Hepatitis B (HB) virus chronically infected, HBsAg 
and HBeAg positive pregnant women to prevent perinatal 
transmission of HBV to their infants who receive passive-active 
HBV immunization 
Short title: 
Maternal antiviral prophylaxis to prevent perinatal 
transmission of HBV in Thailand (iTAP) 
Principal investigators: 
1. Dr. Gonzague Jourdain 
2. Dr. Nantasak Chotivanich 
Coordinating Center: 
Version 3.0 
April 20, 2015 
IRD PHPT -187/10 Changklan Rd., Changklan, Muang, Chiang Mai, 50100 Thailand 
Phone: 05381 9125-9 - Fax: 0 5325 2253, 0 5381 9130 
Email: Gonzague.Jourdain@phpt.org, Nicole.Ngo-Giang-Huong@phpt.org 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Table of Contents 
1. 
Title of the project ............................................................................................................. 3 
2. 
Principal Investigator and Co-Investigators' names and contact information ..................... 3 
3. 
Project Summary .............................................................................................................. 8 
4. 
Background information .................................................................................................... 9 
4.1. 
Epidemiology ............................................................................................................. 9 
4.2. 
Hepatitis B virus ......................................................................................................... 9 
4.3. 
Natural history ........................................................................................................... 9 
4.4. 
Antiviral treatment of HBV infection .......................................................................... 10 
4.5. 
HBV infection during pregnancy and postpartum ..................................................... 11 
4.6. 
Perinatal transmission of HBV in the era of HBV immunization ................................ 11 
4.7. 
Additional interventions to potentially prevent perinatal transmission ....................... 12 
4.7.1. Elective C-section ................................................................................................. 12 
4.7.2. HBlg during pregnancy .......................................................................................... 12 
4.7.3. Antivirals administered to the mother .................................................................... 12 
4.7.4. Conclusion ............................................................................................................ 16 
4.8. 
Sub-studies .............................................................................................................. 16 
5. 
Study objectives .............................................................................................................. 16 
6. 
Study sites and duration of the study .............................................................................. 18 
6.1 . 
Study sites ............................................................................................................... 18 
6.2. 
Duration of the study ................................................................................................ 20 
7. 
Workplan ......................................................................................................................... 20 
7.1. 
Selection of participants ........................................................................................... 20 
7.1.1. Eligibility criteria .................................................................................................... 20 
7.1.2. Inclusion and exclusion criteria .............................................................................. 21 
7.1.3. Discontinuation criteria .......................................................................................... 22 
7.2. 
Implementation, data collection and monitoring procedures ..................................... 23 
7.2.1. Maternal follow up ................................................................................................. 23 
7.2.2. Liver enzyme exacerbations .................................................................................. 25 
7.2.3. Assessment of Maternal Tenofovir Plasma Exposure ........................................... 26 
7.2.4. Bone Mineral Density Evaluations ......................................................................... 27 
7.2.5. Infant follow up and diagnosis of HBV infection ..................................................... 27 
7.3. 
Study drugs .............................................................................................................. 29 
7.4. 
Statistical considerations .......................................................................................... 29 
7.4.1. Endpoints .............................................................................................................. 29 
7.4.2. Randomization and Stratification ........................................................................... 29 
7.4.3. Sample size and Accrual ....................................................................................... 30 
7.4.4. Information of the co-investigators ........................................................................ 30 
7.4.5. Monitoring by the program scientists ..................................................................... 30 
Page 1 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
7.4.6. Data and Safety Monitoring Board (DSMB) ........................................................... 31 
7.4.7. Analyses for the primary objective/endpoint .......................................................... 31 
7.4.8. Analyses for secondary objectives/endpoints ........................................................ 32 
7.4.9. Pharmacokinetic data to estimate individual maternal tenofovir exposure ............. 32 
7.4.10. Bone mineral density measurements .................................................................. 32 
7.4 .11. Exploratory analyses ........................................................................................... 33 
8. 
Ethical considerations ..................................................................................................... 33 
8.1. 
Possible risks including preventive or alleviative measures ...................................... 33 
8.1.1. Potential Risks to Participants ............................................................................... 33 
8.2. 
Adequacy of protection against risks ........................................................................ 35 
8.2.1. Recruitment and informed consent (see Consent Form in Appendix 1) ................. 35 
8.3. 
Protection against risk .............................................................................................. 36 
8.3.1. Institutional Review Board ..................................................................................... 36 
8.3.2. Expedited Adverse Experience Reporting ............................................................. 36 
8.3.3. Confidentiality ....................................................................................................... 36 
8.3.4. Biohazard Containment. ........................................................................................ 36 
9. 
References ..................................................................................................................... 38 
Appendix 1: Informed Consent Form to Participate in iTAP Study (Thai Language) ............... 43 
Appendix 1 (continued): Informed Consent Form to Participate in iTAP Study (English 
Language) .............................................................................................................................. 52 
Appendix 2: Exempted Congenital Anomaly/Birth Defect (Listed by Body Site) ...................... 59 
Appendix 3: Screening program for symptoms possibly associated with mitochondrial 
dysfunction in the EPF cohort (68) ......................................................................................... 61 
Appendix 4: Cockcroft-Gault formula for women .................................................................... 62 
Appendix 5: How to Measure Head Circumference, Length and Weight ................................ 63 
Appendix 6: Additional Informed Consent Form to Participate in Tenofovir Plasma Level 
Measurements (Thai Language) ............................................................................................ 64 
Appendix 6 (continued): Additional Informed Consent Form to Participate in Tenofovir Plasma 
Level Measurements (English Language) .............................................................................. 68 
Appendix 7: Additional Informed Consent Form to Participate in DXA Scan Assessments (Thai 
Language) .............................................................................................................................. 71 
Appendix 7 (continued): Additional Informed Consent Form to Participate in DXA Scan 
Assessments (English Language) .......................................................................................... 75 
Page 2 of 77 


Maternal antiviral prophylaxis to prevent perinatal transrnission of HBV in Thailand, version 3.0 dated 20 April 2015 
1. Title of the project 
A phase III, placebo controlled, double blind, randomized clinical trial to assess the 
efficacy and safety of tenofovir disoproxil fumarate given from 28 weeks' gestation 
until 2 months postpartum to Hepatitis B (HB) virus chronically infected, HBsAg and 
HBeAg positive pregnant women to prevent perinatal transmission of HBV to their 
infants who receive passive-active HBV immunization. 
Short title: 
Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand 
2. Principal Investigator and Co-Investigators' names and contact information 
Principal Investigators: 
Gonzague Jourdain, MD, PhD 
Nantasak Chotivanich, MD 
PHPT -IRD 
Obstetrics &Gynecology Department 
187/10, Changklan Rd., Changklan, Muang 
Chonburi Hospital, Chonburi 
Chiang Mai 50100 
69 M. 2 Sukumvith Rd., T. Ban Suan, Muang, 
Tel: +665381 9125 
Chonburi 20000 
Fax: +665381 9130 
Tel: +663893 1390, +66 3893 1000 
Email: Gonzague.Jourdain@phpt.org 
Fax +66 3827 4911 
Email: nantasak.cho@gmail.com 
Co-investigators: 
Nicole Ngo-Giang-Huong, PharmD, PhD 
Tim Roy Cressey, PhD 
PHPT -IRD 
PHPT -IRD 
187/10, Changklan Rd., Changklan, Muang 
187/10, Changklan Rd., Changklan, Muang 
Chiang Mai 50100 
Chiang Mai 50100 
Tel: +66 5381 9125- Fax: +665381 9130 
Tel: +66 5381 9125 - Fax: +665381 9130 
Email: Nicole.Ngo-Giang-Huong@phpt.org 
Email: tim.cressey@phpt.org 
Satawat Thongsawat, MD 
Thanyawee Puthanakit, MD 
Division of Gastroenterology 
Department of Pediatrics, 
Department of Internal Medicine, 
Faculty of Medicine Chulalongkorn University 
Faculty of Medicine, Chiang Mai University 
1873 Rama 4 Road, Pathumwan, 
Muang, Chiang Mai 50200 
Bangkok10330 
Tel: +66 5394 5483-5 - Fax: +6653945481 
Tel: +66 2256 4951- Fax: +6622564911 
Email: satawat@yahoo.com 
Email: thanyawee.p@hivnat.org 
Chureeratana Bowonwatanuwong, MD 
Virat Klinbuayaem, MD 
Medical Department 
Medical Department 
Chonburi Hospital 
Sanpatong Hospital 
69 M. 2 Sukumvith Rd., T. Ban Suan, Muang 
149 M.9 T. yuwa Sanpatong, 
Chonburi 20000 
Sanpatong, Chiang Mai 50120 
Tel: +66 3827 4200 -7- Fax: +66 3893 1100 
Tel:+6653311404,53311711 
Email: c.bowon@gmail.com 
Fax: +665331 1712 
Email: kggvirat@hotmail.com 
Page 3 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Porn napa Suriyachai, MD 
Pannarai Srisuwan, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Phayao Hospital 
Phayao Hospital 
269 Phaholyothin Rd., T. Tom, Muang, Phayao 
269 Phaholyothin Rd., T. Tom, Muang, Phayao 
56000 
56000 
Tel: +66 5443 1209 - Fax: +6654409330 
Tel: +66 5443 1169 -Fax: +6654481708 
Email: whan76_1@hotmail.com 
Email: pcaipyhos@gmail.com 
Chaiwat Putiyanun, MD 
Sudanee Buranabanjasatean, MD 
Obstetrics & Gynecology Department 
Obstetrics & Gynecology Department 
Chiang Kham Hospital 
Mae Chan Hospital 
244 MA T. Yuan, Chiang Kham, Phayao 56110 
274 M.5 Phaholyothin Rd., Mae Chan, Chiang Rai 
Tel: +6654451300-1 - Fax: +6654416615 
57110 
Email: putiyanun@hotmail.com 
Tel: +66 5377 1056 - Fax: +6653660961 
Email: sudanee2011@windowslive.com 
Jullapong Achalapong, MD 
Chulapong Chanta, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Chiangrai Prachanukroh Hospital 
Chiangrai Prachanukroh Hospital 
1039 Sathanpayaban Rd., Muang, Chiang Rai 
1039 Sathanpayaban Rd., Muang, 
57000 
Chiang Rai 57000 
Tel: +66 5371 1300 ext 1217 - Fax: +665371 3044 
Tel: +66 5371 1300 ext 1274 - Fax: +66 5371 3044 
Email: drjullapong@gmail.com 
Email: ChuLchan@yahoo.com 
Aram Limtrakul, MD 
Arunrat Suwannarat, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Nakornping Hospital 
Nakornping Hospital 
159 M.10 Chotana Rd., T. Don Keaw, Mae Rim, 
159 M.10 Chotana Rd., T. Don Keaw, Mae Rim, 
Chiang Mai 50180 
Chiang Mai 50180 
Tel: +6653999200 - Fax: +6653222152 
Tel: +66 5399 9200 - Fax: +6653222152 
Email: arunrat11@yahoo.com 
Suraphan Sangsawang, MD 
Kanokwan JiUayanun, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Health Promotion Center Region 10 
Health Promotion Center Region 10 
51 Prachasumphan Rd., T. Changklan, Muang, 
51 Prachasumphan Rd., T. Changklan, Muang, 
Chiang Mai 50100 
Chiang Mai 50100 
Tel: +66 5327 2740 - Fax: +66 5327 4015 ext 119 
Tel: +66 5327 2740 - Fax: +6653274015 ext 119 
Email: suraphan@anamaLmoph.go.th 
Email: kkulsawad@yahoo.co.th 
Wanmanee Matanasarawut,MD 
Rosalin Somsamai, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Lamphun Hospital 
Lamphun Hospital 
177 Sai Rim Ping Rd., T. Tonthong, Muang, 
177 Sai Rim Ping Rd., T. Tonthong, Muang, 
Lamphun 51000 
Lamphun 51000 
Tel: +6653569100 ext 2150 - Fax: +6653569123 
Tel: +66 5356 9100 - Fax: +6653569123 
Email: obgyn.lph@gmail.com 
Email: sukannika_waan@hotmail.com 
Prateung Liampongsabuddhi, MD 
Kultida Pongdetudom, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Lampang Hospital 
Lampang Hospital 
280 Paholyothin Rd., Huawieng, Muang, Lamphang 
280 Paholyothin Rd., Huawieng, Muang, Lamphang 
52000 
52000 
Tel: +66 5422 3623-7 - Fax: +66 5422 6126 
Tel: +66 5422 3623-7 - Fax: +66 5422 6126 
Email: prateung@yahoo.com 
Email: pongdetudom@yahoo.com 
Page 4 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Thitiporn Siriwachirachai, MD 
Ussanee Srirompotong, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Khon Kaen Hospital 
Khon Kaen Hospital 
56 Srichan Rd, Naimuang, Muang, 
56 Srichan Rd, Naimuang, Muang, 
Khon Kaen 40000 
Khon Kaen 40000 
Tel: +6643336789 - Fax: +6643236974 
Tel: +6643336789 - Fax: +6643236974 
Email: siriwachirachai@hotmail.com 
Prapap Yuthavisuthi, MD 
Chaiwat Ngampiyasakul, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Prapokklao Hospital 
Prapokklao Hospital 
38 Leibnern Rd., Muang Chantaburi 22000 
38 Leibnern Rd., Muang Chantaburi 22000 
Tel: +6639324975 ext. 5253 - Fax: +66 39311511 
Tel: +66 39324975 ext. 5253 - Fax: +663931 1511 
Email: yuthavisuthi@gmail.com 
Email: chaiwat008@gmail.com 
Prateep Kanjanavikai, MD 
Siriluk Phanomcheong, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Banglamung Hospital 
Banglamung Hospital 
669 M.5 Phattaya-Naklua T. Naklua, Banglamung, 
669 M.5 Phattaya-Naklua T. Naklua, Banglamung, 
Chonburi 20150 
Chonburi 20150 
Tel: +663841 1551-2 - Fax: +66 38428464 
Tel: +66 3841 1551-2 - Fax: +6638428464 
Email: prateep48@hotmail.com 
Email: sirilukJukk@yahoo.com 
Sombat Thanprasertsuk, MD 
Suchat Hongsiriwon, MD 
Senior Consultant 
Pediatrics Department 
Department of Disease Control 
Chonburi Hospital, Chonburi 
Ministry of Public Health 
69 M. 2 Sukumvith Rd., T. Ban Suan, Muang, 
Tivanont Road, Muang 
Chonburi 20000 
Nonthaburi 11000 
Tel: +66 3827 4000-7 Fax: +6638274911 
Tel: +6625903201 - Fax: +6625918413 
Email: suchat.hong@gmail.com 
Supang Varadisai, MD 
Sawitree Krikajornkitti, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Samutsakhon Hospital 
Samutsakhon Hospital 
1500 Akekachai Rd., T. Mahachai, Muang, 
1500 Akekachai Rd., T. Mahachai, Muang, 
Samutsakorn 74000 
Samutsakorn 74000 
Tel: +6634427099-104 - Fax: +66 34411488 
Tel: +66 3442 7099-104 - Fax: +663441 1488 
Email: yuiwitree@gmail.com 
Veeradate Chalermpolprapa, MD 
Suthunya Bunjongpak, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Nakhonpathom Hospital 
Nakhonpathom Hospital 
196 Thesa Rd., T. Prapathomjadee, Muang, 
196 Thesa Rd., T. Prapathomjadee, Muang, 
Nakhonpathom 73000 
Nakhonpathom 73000 
Tel: +6634213606, +66 34213607-8 
Tel: +66 34213606, +66 34213607-8 
Fax: +6634251553 
Fax: +6634251553 
Email: veeradate@hotmail.com 
Email: suthunya12@thaimail.com 
Prapan Sabsanong, MD 
Achara Puangsombat, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Samutprakarn Hospital 
Samutprakarn Hospital 
71 Chakapak Rd., T. Pak Nam, Muang, 
71 Chakapak Rd., T. Pak Nam, Muang 
Samutprakarn 10280 
Samutprakarn 10280 
Tel: +66 27018132-9, +66 2387 0053 
Tel: +6627018132-9, +66 2387 0053 
Fax: +6621738551 
Fax: +6621738551 
Email: prapandr@hotmail.com 
Page 5 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Orada Patamasingh Na Ayudhaya, MD 
Anita Luvira, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Nopparat Rajathanee Hospital 
Nopparat Rajathanee Hospital 
679 Ram-Indra Rd., Kannayao, Bangkok 10230 
679 Ram-Indra Rd., Kannayao, Bangkok 10230 
Tel: +6625174270-9 - Fax: +66 2917 8800 
Tel: +66 25174270-9 - Fax: +66 2917 8800 
Email: oradaaom@hotmail,com 
Email: aluvira@yahoo.com 
Sinart Prommas, MD 
Prapaisri Layangool, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Bhumibol Adulyadej Hospital 
Bhumibol Adulyadej Hospital 
Phaholyothin Rd., Saimai, Bangkok 10220 
Phaholyothin Rd., Saimai, Bangkok 10220 
Tel: +6625347317 - Fax: +6625238873 
Tel: +66 2534 7306 - Fax: +6625347295 
Email: n_prommas@hotmail,com 
Email: p_layangool@yahoo.com 
Rapee Chalermwutanont,l MD 
Uraiwan Tuntrakul, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Ranong Provincial Hospital 
Ranong Provincial Hospital 
11 Kamlangsupt Rd., Khao Niwet Muang 
11 Kamlangsupt Rd., Khao Niwet Muang 
Ranong, Thailand 85000 
Ranong, Thailand 85000 
Tel: +667781 1574-5, +66 7781 2630-3 
Tel: +66 77811574-5, +66 77812630-3 
Fax: +667782326-7 
Fax: +66 7782 326-7 
Pichit Puernngoluerm, MD 
Anucha Saeresjittima, MD 
Obstetrics &Gynecology Department 
Pediatrics Department 
Maharaj Nakornratchasrima Hospital 
Maharaj Nakornratchasrima Hospital 
49 Changpuag Rd, Muang 
49 Changpuag Rd, Muang 
Nakornratchasrima 30000 
Nakornratchasrima 30000 
Tel: +6644235000 - Fax: +6644246389 
Tel: +66 4423 5000 - Fax: +6644246389 
Linda Harrison, MS 
Camlin Tierney, PhD 
Harvard School of Public Health 
Harvard School of Public Health 
Center for Biostatistics in AIDS Research 
Center for Biostatistics in AIDS Research 
FXB Building 514 
FXB Building 514 
651 Huntington Ave 
651 Huntington Ave 
Boston, MA 02115, USA 
Boston, MA 02115, USA 
Tel: +1 6174320062 
Tel: +16174320547 
Email: Iharriso@sdac.harvard.edu 
Email: tierney@sdac.harvard.edu 
Wasna Sirirungsi, PhD 
Stanislas Pol, MD, PhD 
Faculty of Associated Medical Sciences 
Department of Hepato-Gastroenterology, Cochin 
Chiang Mai University 
University Hospital, 
110 Intawaroros Rd. T. Sripoom 
27 rue du Faubourg Saint-Jacques, 75679 Paris 
Muang, Chiang Mai 50200 
Cedex 14, France 
Tel: +6653945063 - Fax: +6653946042 
Tel: +33 1 5841 1955 
Email: wasna.s@cmu.ac.th 
Email: stanislas.pol@cch.aphpJr 
Raymond T. Chung, MD 
George Siberry, MD, MPH 
Massachusetts General Hospital 
Pediatric, Adolescent, and Maternal AIDS (PAMA) 
Gastrointestinal Unit 
Branch 
WRN 1007C, GI Unit 
Eunice Kennedy Shriver National Institutes of Child 
55 Fruit St 
Health and Human Development 
Boston, MA 02114, USA 
National Institutes of Health 
Tel: +1 617/724-7562 - Fax: +1 617/643-0446 
6100 Executive Boulevard, Room 4B 11 H 
Email: rtchung@partners.org 
Bethesda, MD 20892-7510, USA 
Tel: 301-496-7350 - Fax: 301-496-8678 
Email: siberryg@mail,nih.gov 
lwhen formally approved by the sponsors (NICH, US CDC) 
Page 6 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Trudy Murphy, MD 
Heather Watts, MD 
Centers for Disease Control and Prevention 
Pediatric, Adolescent, and Maternal 
DHHS/CDCIINCHHSTP/DVHIVaccine Unit 
AIDS Branch 
Bldg Corporate SQ 12, Room 3111 
NIH, NICHD, CRMC 
Atlanta GA 30329-1902, USA 
6100 Executive Blvd, Room 4B11, MSC 7510 
Tel: +1 4046398845 - Fax: +14047188595 
Bethesda, MD 20892-7510, USA 
Email: trudy. murphy@cdc.hhs.gov;tkm4@cdc.gov 
Tel:+1 301 435-6874 - Fax: +1 301 496-8678 
Email: wattsh@exchange.nih.gov, hw591@nih.gov 
Woottichai Khamduang, PhD 
Noele P. Nelson, MD, PhD, MPH 
PHPT -IRD 
Centers for Disease Control and Prevention 
187/10, Changklan Rd., Changklan, Muang 
Division of Viral Hepatitis I NCHHSTP/CDC 
Chiang Mai 50100 
Vaccine Research and Policy Unit, 
Tel: +66 53819125 - Fax: +66 53819130 
National Center for HIV/AIDS, Viral Hepatitis, STD, 
Email: woottichaLkhamduang@phpt.org 
and TB Prevention 
1600 Clifton Road, MS-G37, Atlanta, GA 30333, 
USA 
Tel:+1 4047188576 - Fax: 404-718-8595 
Email: xdg9@cdc.gov, nnelson@cdc.gov 
Page 7 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
3. Project Summary 
This is a phase III, placebo controlled, double blind, randomized clinical trial to assess the 
efficacy and safety of tenofovir disoproxil fumarate given from 28 weeks' gestation until 2 
months postpartum to pregnant women with HBsAg/HBeAg-positive Hepatitis B virus (HBV) 
chronic infection in Thailand to prevent perinatal transmission of HBV to their infants who 
receive HBV passive-active immunization. 
Chronic hepatitis B (CHB) infection is complicated by cirrhosis and hepatocellular carcinoma 
(HCC), which is the 10th leading cause of death worldwide. In 2011, about 7% of Thai adults 
were HBsAg carriers. Universal immunization programs have dramatically reduced the 
prevalence of infection wherever they have been implemented. 
Infant hepatitis B (HB) immunization and HB immune globulin (HBlg) administered at birth 
effectively prevents most mother-to-child transmission (MTCT) of HBV. However, according to 
published studies often with limited sample sizes, using various methods for the diagnosis of 
infection in infants, it is thought that about 12% of HBV highly viremic mothers transmit the 
virus to their infants, despite active and passive immunization. It is likely that HBlg has no 
effect on infection already established in utero. 
The presence in blood of a hepatitis B virus antigen, HBe (HBeAg), is a marker of high viral 
replication. Studies have suggested that antiviral treatment at the end of pregnancy and 
during early postpartum can reduce the risk of transmission to the child. A potential limitation 
to this approach is the risk of hepatic disease exacerbation (flare) following discontinuation of 
antiviral treatment postpartum, and this risk has not been properly evaluated. No randomized 
clinical trials have adequately demonstrated the efficacy and safety of maternal antiviral 
treatment for HBV MTCT prevention, and this approach is not currently recommended by the 
Associations for the Study of Liver Diseases. 
We hypothesize that a potent antiviral, tenofovir, can decrease HBV viral load in HBV infected 
pregnant women and therefore reduce the risk of late in utero, intrapartum and postpartum 
transmission before infants are definitely protected by passive-active immunization. We also 
hypothesize that only moderate flares will be observed after discontinuation of a short antiviral 
course (5 months). While the primary objective of the study is to assess the efficacy of 
tenofovir versus placebo for the prevention of perinatal transmission, an important secondary 
objective is the assessment of the risk of postpartum hepatic disease exacerbation. 
HBsAg positive pregnant women will be enrolled if they have a positive HBeAg test and AL T 
::;30 U/L. They will be randomized to receive tenofovir or placebo from 28 weeks of pregnancy 
until 2 months postpartum. Within 2 years, 328 women and their infants will be enrolled from 
19 public hospitals in Thailand where the health care teams have considerable experience in 
conducting trials for the prevention of mother to child transmission of HIV over the past 15 
years. Mothers and infants will be followed until one year postpartum. 
The primary endpoint will be the detection of HBsAg and HBV DNA in infants at six months of 
life. An interim analysis will be conducted when half of the outcomes are available. 
The results of the study will help define policy to manage HBV infected pregnant women to 
prevent perinatal transmission. 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
4. Background information 
4.1. 
Epidemiology 
An estimated 250 to 350 million people are chronically infected with the HBV worldwide [1], of 
whom over 100 million are in Asia [2]. The risk of adverse outcome from chronic HBV infection 
may approach 25% for cirrhosis and hepatocellular carcinoma (HCC). Chronic hepatitis B 
(CHB) is the 10th leading cause of death worldwide with 600,000 to 1.2 million deaths per year 
due to cirrhosis and HCC [3]. The prevalence of HBsAg, a marker of chronic infection, varies 
widely worldwide. Forty-five percent of the world's population lives in highly endemic 
countries, with prevalence of HBsAg ;:::8%. In Thailand, an estimated 7%-8% of the adults born 
before 1992 (which includes most child-bearing women), when the national pediatric anti-HBV 
immunization program began, are chronic HBsAg carriers [4]. 
4.2. 
Hepatitis B virus 
HBV is present in blood, saliva, semen, vaginal secretions, and to a lesser extent, 
perspiration, breast milk, tears, and urine. HBV is easily transmitted through contact with 
infected body fluids, and unprotected sexual activities. HBV, a prototype member of the 
Hepadnaviridae family, is a small (3.2 kb), partially double-stranded DNA virus. The 
hepatocytes represent the main target of HBV infection although the receptor for HBV is still 
unknown [5]. During active replication, viral particles are found in serum: the 42 nm complete 
virion and the empty viral envelopes made of HBsAg in the form of either the 22 nm sphere or 
filamentous forms [6, 7]. During highly replicative phases, a soluble antigen, HBeAg, is also 
found in serum, and is used as a marker of high replication. 
Ten HBV genotypes (A to J) are known [8-12]: C and B predominate in Asia [13,14] (Thailand 
85% C and 15% B). Genotype C, compared to B, is associated with later and less sustained 
HBeAg seroconversion [15, 16], more hepatic necro-inflammation, more rapid progression to 
cirrhosis, and higher incidence of HCC [17-20]. 
4.3. 
Natural history 
The natural history of HBV infection differs according to the age of acquisition. 
-
In areas of low HBV endemicity, most infections are acquired in early adult life through 
sexual transmission or intravenous drug use [21]. The cytotoxic immune reaction is 
responsible for destruction of hepatocytes and increase in AL T, hyperbilirubinemia and 
jaundice and, in some cases, liver failure and death. In a minority of adults, HBV infection 
becomes chronic with HBsAg carriage [22, 23]. 
-
In areas of high or intermediate endemicity, most transmissions occur in utero or during 
delivery when the newborn is exposed to maternal blood and contaminated secretions, or 
during the first years of life through contact with infected parents, siblings or other 
children. Without immunization, about 10% of infants born to HBsAg carrier mothers are 
found infected by one year, and 90% of these become HBsAg chronic carriers. Twenty-
five to 30% of children infected between 1 and 5 years of age, develop chronic infection. 
The World Health Organization (WHO) recommends that HBsAg positive mothers 
breastfeed their infants based on studies finding similar rates of HBV infection in 
breastfed compared to bottle fed children [24]. 
There are 4 phases of chronic infection whose length depends on the age at HBV acquisition 
and HBV genotype: (1) "Immunotolerant" with minimal inflammation, (2) "Immune active" 
corresponding to chronic active disease and risk of progression to cirrhosis and liver cancer; 
(3) "Non-replicative" and (4) "HBeAg-negative chronic active" due to pre-core or core promoter 
mutants with progression to cirrhosis and liver cancer. 
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Maternal antiviral prophylaxis to prevent perinatal transrnisslon of HBV in Thailand, version 3.0 dated 20 April 2015 
While most carriers infected during adulthood eventually lose HBeAg and develop antibodies 
to HBeAg (anti-HBeAb), the vast majority of infected children enter in an immune tolerant 
phase with normal AL T levels and a rate of clearance of HBeAg much lower than in adults. 
The age at which HBeAg is lost varies with genotypes, and areas of the world: in Asia, about 
40% of adult HBsAg carriers are HBeAg positive and about 10% outside Asia. In Asia, some 
HBV infected subjects test negative for HBeAg regardless of the level of HBV replication, due 
to a mutation in the pre-core region of HBV, which prevents the production of HBeAg [25], or a 
mutation in the basic core promoter (at nucleotides 1762 and 1764) [26-28]. However, among 
52 HBsAg positive and HBeAg negative Thai pregnant women, we found only 2 with a HBV 
viral load > 6 log10 IU/mL [29]. 
4.4. 
Antiviral treatment of HBV infection 
Since, in most cases, chronic HBV infection is not cleared, the goal of therapy is primarily to 
decrease the risk of cirrhosis and HCC. Current therapy uses interferon-alpha and 
nucleos(t)ide analogues. Interferon inhibits viral replication and acts as an immunomodulator. 
It is used as a short-term treatment that, when successful, may lead to long-term immune 
control without the need for further antiviral therapy. In contrast, it is considered that 
nucleos(t)ide analogs, which inhibit HBV replication, cannot usually be discontinued. While 
resistance mutations have been described in patients receiving long term treatment with 
lamivudine, emtricitabine, telbivudine, entecavir, and adefovir, they have not been reported for 
tenofovir [30, 31]. 
Studies have shown that interferon therapy or lamivudine therapy (with maintained virological 
response) reduce the risk of cirrhosis or HCC. Long term studies with other antiviral drugs are 
not available. However, the optimal time for starting therapy also depends on the risk of drug 
toxicity, development of resistance mutations and hepatic flares-liver inflammation indicated 
by AL T elevation-after discontinuation of therapy. The American Association for the Study of 
Liver Diseases (AASLD) [32] and Asian Pacific Association for the Study of the Liver (APASL) 
[33] recommend treatment for patients with an AL T level >2 ULN, and liver biopsy to guide 
treatment decisions if AL T is 1-2 x ULN, particularly if the age is >40 years. The recent 
European Association for the Study of Liver Diseases (EASL) [34] recommends therapy in 
patients with significant fibrosis, and AL T above the upper limit of normal or HBV DNA> 2000 
IU/mL. Current guidelines recommend lifelong treatment except when HBeAg seroconversion 
and undetectable HBV-DNA have been documented. In HBeAg-negative patients, treatment 
discontinuation can be considered if undetectable HBV-DNA has been documented on three 
separate occasions 6 months apart [33]. 
The selection of tenofovir disoproxil fumarate (TDF) as the antiviral agent used in this study 
was based on safety, efficacy and cost considerations. Tenofovir is very potent anti HBV drug 
(median serum HBV DNA reduction after 1 year of treatment 6.2 log10 copies/mL in HBV-
infected HBeAg positive patients). It has been approved for HIV treatment and for HBV 
treatment for several years. Tenofovir has a high genetic barrier to resistance [31]. In previous 
studies, up to 192 weeks of tenofovir monotherapy, no mutations have been associated with 
resistance to tenofovir (genotypic and phenotypic analyses). [Viread Package insert, Gilead, 
Revised: January 2012]Previous studies have shown that the bioavailability and tolerance 
profile of tenofovir during pregnancy is favorable [35, 36]. No dose adjustment is currently 
recommended for TDF during pregnancy. 
It is part of WHO recommended drug combinations to be started in HIV infected pregnant 
women after 14 weeks' gestation and continued through the breastfeeding period to prevent 
mother to child HIV transmission [37]. The US FDA classifies tenofovir in B. The risks for the 
fetus associated with the use of tenofovir during pregnancy are discussed below. Tenofovir 
crosses the placenta barrier with the potential added possible benefit of pre-exposure 
prophylaxis in the fetus and infant. Tenofovir crosses the placenta barrier with the potential 
added possible benefit of pre-exposure prophylaxis in the fetus and infant. The tenofovir form 
is excreted in the breast milk but a very low portion of it is absorbed by the infant. Indeed, a 
recent study estimated that the infant receives 0.03% of the proposed dose for neQnates [38]. 
Q~dY~>~~: 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
4.5. 
HBV infection during pregnancy and postpartum 
HBV seems to have little effect on pregnancy but HBV viral load increases in pregnancy, 
probably in 
relation to immune-suppression and increased production 
of adrenal 
corticosteroids, estrogen and progesterone [39, 40]. Some women may experience increased 
in liver disease activity [41], with or without HBeAg seroconversion (HBeAg clearance 
occurred in 5 of 30 women in a study in Taiwan [42]), within the first months after delivery, 
presumably in relation with the rapid post-partum decrease in immunosuppression. See also 
"Antivirals administered to the mother" in Section 4.7.) 
WHO [24] and Thai guidelines recommend HBV infected mothers to breastfeed as there is no 
evidence of additional transmission during breastfeeding. 
4.6. 
Perinatal transmission of HBV in the era of HBV immunization 
WHO recommends universal perinatal HBV immunization, regardless of maternal HBV status. 
This strategy decreases perinatal transmission of HBV by 90-95% [43-46]. Since 1992, 
Thailand has integrated HBV vaccination in the national Expanded Program on Immunization 
(EPI). The recommended immunization schedule in Thailand is within 24 hours of birth 
(monovalent formulation), 2, 4 and 6 months (polyvalent formulations) [47], and an extra dose 
of monovalent HB vaccine is recommended at 1 month of age in infants born to HBsAg 
positive mothers (following the observation that infections occurred in infants whose 2-month 
dose was delayed [48]. As in Taiwan and Malaysia where this program has been 
implemented, a dramatic reduction in the prevalence of HBsAg carriers in children has been 
observed [49, 50]. However, a study in Thailand has shown that still 0.7% of children who 
have received immunization are HBV chronically infected [51]. 
HB Immune globulins (HBlg) at birth in infants born to HBsAg positive mothers. Administration 
of HBlg in addition to vaccine for infants born to HBsAg carriers, can halve the risk of 
transmission [52]. The injection of HBlg, in addition to vaccine, is thus recommended in 
newborns born to HBsAg+ mothers by the Royal College of Thai Pediatricians. Due to price 
($40 to $130 depending on manufacturer) and short shelf life (up to one year), HBlg is actually 
not always available in Thai public hospitals. Moreover, although donors are tested for several 
known pathogens, concerns remain about the risk of transmission of unknown blood borne 
pathogens. 
However, the combination of hepatitis B vaccine and HBlg does not protect all infants, in 
particular those born to mothers with high HBV replication (usually HBeAg positive). Such 
infants are at a significant risk of becoming HBV infected despite passive-active immunization, 
[53-55] mainly through in utero transmission, which may contribute to residual transmission of 
HBV. 
In previous clinical studies, the rates of transmission in infants/children born to HBsAg and 
HBeAg positive mothers despite the use of HBlg at birth and HBV immunization have been 
variable, probably in relation with the various definitions and methods of diagnosis, as well as 
the quality of follow-up. In two studies evaluating the efficacy of antiviral prophylaxis the rates 
of transmission were: 
- 7/88 (8%, 95% confidence interval [CI] 3% to 16%) HBsAg+ and HBV DNA + in infants at 7 
months of age in China [56], 
- 5/41 (12%, C14% to 26%) HBsAg+ in infants at 52 weeks of age in a randomized clinical 
trial in China and the Philippines [57] and 9/41 (22%, C111% to 38%) using HBV DNA. 
In addition, the report of a meta-analysis [58], based on non-randomized studies mainly 
published in Chinese journals and the Xu's study [57], provides rates of HBsAg+ between 9 
and 12 months in infants who received vaccine and HBlg at birth: 5/35 (14% CI 5% to 30%) 
(Han 2005), 7/44 (16%, CI 7% to 30%) (Li 2006), 16/42 (38%, CI 24% to 54°/~)ang 2007), 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
6/42 (14%, CI 5% to 29%) (Yang 2008), 2/19 (11%, CI 1% to 33%) (Yang 2008). However, 
this meta-analysis did not provide an overall single estimate of the transmission rate. Finally, 
in a recent cross sectional study conducted in Taiwan [59] in children of less than 2 years of 
age, 8 of 70 had HBsAg+ (11 %, CI 5% to 21 %). A reliable estimate of the transmission rate 
despite the use of HBlg at birth and HBV immunization cannot be drawn from these studies, 
owing the limited number of infants in each study and the methodological information 
provided. 
4.7. 
Additional interventions to potentially prevent perinatal transmission 
4.7.1. Elective C-section 
A systematic review of 4 studies conducted in China involving 789 women showed a favorable 
effect of elective C-section performed before labor and rupture of membranes, consistent with 
the hypothesis that a significant part of transmission occurs at the time of delivery [60]. There 
is no published report on the efficacy of C-section in a setting where passive-active immune 
prophylaxis has been provided to infants. 
Elective C-sections are not currently recommended for the prevention of HBV transmission. 
4.7.2. HBlg during pregnancy 
According to a meta-analysis of 37 studies, the administration of HBlg during pregnancy in 
HBsAg carrier women may decrease intrauterine transmission and the rate of infection at one 
year of age [61]. However, this intervention is not recommended by WHO or other 
organizations, owing to the cost and limited production of HBlg and limited efficacy data. 
4.7.3. Antivirals administered to the mother 
In HBsAg positive women, the reduction of HBV DNA load by nucleos(t)ide analogue therapy 
at the end of pregnancy may be effective and safe in reducing the risk of child vaccination 
breakthrough. Three studies, summarized below, have provided preliminary data. 
4.7.3.1. Efficacy 
a) Study by van Zonneveld et ai, 2003 [62]. In an open label study conducted in 
the Netherlands, 8 children born to 8 pregnant women (6 Caucasians and 2 
Blacks, no Asians) who received 150 mg of lamivudine daily from 34 weeks' 
gestation until delivery were compared to 25 historical controls born to 24 
mothers (4 Asians). All mothers had high HBV-DNA loads ~>150 pg/mL 
using a hybridization technique no longer used, i.e. around 10 copies/mL). 
All infants received passive-active immunization. HBV DNA, HBsAg, anti-
HBs and anti-HBc were measured in infants at birth and at 3, 6 and 12 
months. At 12 months, 1 of the 8 infants (12.5%) was still HBsAg and HBV-
DNA positive in the lamivudine group, versus 7 of the 25 controls (28%). 
b) Study by Xu et ai, 2009 [57]. This multicenter study conducted in China and 
the Philippines was originally designed as a randomized, double-blind, 3-
arm, placebo-controlled trial, with an expected sample size of 410 highly 
HBV viremic pregnant women. Subjects were to be randomized in a 2:2:1 
ratio to one of the three arms: (A) maternal lamivudine 100 mg once daily 
from 32 weeks of gestation until one month postpartum + infant passive-
active immunization; (B) maternal placebo + passive-active immunization; or 
(C) maternal lamivudine + vaccine but without HBlg. However, arm C was 
removed early during the study due to ethical concerns and the study faced 
a number of challenges. Firstly only 155 women were enrolled. Only 56 
infants in the lamivudine group and 59 in the placebo group received passive 
active immunization. A large and unbalanced number of infants were lost to 
follow up: 13% in the lamivudine arm and 31% in the placebo arm. More 
than 50% of the women had serum HBV DNA >1000 MEq/mL (using bDNA 
assay, about 108 IU/mL) at baseline. At week 52, 3 of the 49 infants 
evaluable (6%) in the lamivudine group versus 5 of 41 infants in the placebo 
QJ~ 
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Maternal antiviral prophylaxis to prevent perinatal transrnission of HBV in Thailand, version 3.0 dated 20 April 2015 
group (12%) had evidence of HBV transmission at one year of age 
(P=0.368). However, from the intent to treat analyses where missing 
outcomes were considered as failures, the authors concluded that there was 
a significant decrease in HBsAg infection in infants born in the lamivudine 
group (10/56 versus 23/59, P=0.014). There were no safety concerns 
although some women experienced flares. 
c) Study by Han G et ai, 2011 [56]. This was a prospective, non-randomized, 
open-label study of telbivudine during pregnancy for the prevention of 
perinatal HBV transmission. HBeAg+ women with HBV DNA load >107 
copies/mL were invited to choose either to receive 600 mg/day telbivudine 
from 20-32 weeks' gestation through week 4 after delivery or no treatment, 
and all infants received passive-active immunization. 187 women were 
enrolled: 94 chose to take telbivudine and 92 no treatment. The two groups 
had similar characteristics but 11 % in the telbivudine group had received 
previous antiviral treatment versus 0% in the control group. At baseline, the 
mean HBV DNA load was 8.07 10glO copies/mL versus 7.94 log10; at delivery, 
HBV DNA was below 1,000 copies/mL in 30% versus 0%, respectively. At 
week 28, in an intent-to-treat analysis where missing outcomes were 
considered as failures, 2% of infants were considered HBsAg positive in the 
telbivudine group, compared with 13% in the control group (p=0.004). The 
actual percentages were 0% and 9%, respectively. 
Recently, a retrospective study in the US reported that 11 infants born to 11 mothers who 
received tenofovir disoproxil fumarate starting at 29 weeks' gestation were all HBsAg negative 
at age 28-36 weeks of age [63]. In addition, a prospective open label study in Nanjing, China, 
reported that, of 88 HBeAg+ pregnant women receiving telbivudine, with levels of HBV DNA 6 
log10 copies/mL, and increased levels of AL T, none transmitted HBV to their infants [64]. 
In summary, it is not possible to draw solid efficacy conclusions from the first two lamivudine 
stUdies [57, 62] described above due to obvious methodological flaws. The third study by Han 
et al [56], although not randomized, suggests that an antiviral administered during pregnancy, 
in addition to passive-active immunization, may decrease HBV transmission. 
4.7.3.2. 
Safety 
a) Safety of a 5 month tenofovir course in pregnant /Iactating women 
The short- and long-term effects of TDF on pregnant and breastfeeding women, fetuses and 
children is a key research gap identified in the WHO Guidelines. These include bone effects 
on both the woman and HIV-exposed infant [65]. 
a.1) TDF renal toxicity in pregnant women 
The main safety concern related to TDF treatment is its long-term renal toxicity, which has 
been described in HIV-HBV co-infected patients on multidrug combination therapy. However, 
it is not expected that such toxicity will be observed in HBV mono-infected women receiving 
this drug for 5 months. In 152 HBV mono-infected Asian patients, no increase of serum 
creatinine >0.5 mg/dl or of eGFR<50 ml/min was found in up to 3 years of TDF treatment [66]. 
The effect of tenofovir on bone metabolism seems related to its renal toxicity, which may lead 
to a syndrome similar to the Fanconi syndrome that involves the proximal tubules of the 
kidneys, with hyperphosphaturia and hypophosphatemia affecting bone metabolism. During 
pregnancy, the mother provides phosphate and calcium to the fetus. As the toxicity may be 
dose dependent, there is a need to quantify maternal tenofovir exposure and renal 
disturbances during pregnancy in perinatal stUdies. 
Tenofovir exposure may cause maternal proximal renal tubular dysfunction and modification 
of calcium-phosphorus metabolism, resulting in lower maternal and/or infant BMD persisting 
until one year after delivery/birth. The relationship between maternal tenofovir exposure and 
infant/maternal low bone mineral density has never been studied in expos~~V-uninfected 
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Maternal antiviral prophylaxis to prevent perinatal transrnission of HBV in Thailand, version 3.0 dated 20 April 2015 
pregnant women and their infants. Within this study, there is a unique opportunity to clarify the 
relationship between tenofovir exposures and maternal and infant bone mineral density. 
a.2) TDF Bone toxicity 
Maternal bone metabolism during pregnancy and the lactating period is regulated through 
complex mechanisms that ensure the infant bone growth, involving the supply of large 
amounts of calcium by the mother, and minimize maternal consequences for the maternal 
bones. 
Few clinical trials have compared the effect of tenofovir versus placebo on bone mineral 
density as tenofovir is mostly prescribed to HIV-infected individuals. A study, conducted in the 
US, randomly assigned adolescents chronically infected with HBV to either TDF or placebo for 
72 weeks and showed that no patients met the safety endpoint of a 6% decrease in spine 
bone mineral density at week 72 [67]. A pre-exposure prophylaxis study in HIV uninfected 
men in San Francisco also compared TDF versus placebo. The study found a small but 
statistically significant decrease in mean BMD in the TDF vs. the pre-treatment/placebo group 
at some bone sites (femoral neck, hip, L2-L4 spine) [68]. Of note, a pooled analysis of two 
studies comparing TDF versus adefovir found no differences in loss of bone mineral density 
between Asian and non-Asian patients infected with HBV on TDF [69]. 
Maternal bone resorption seems necessary to provide significant amounts of calcium to the 
baby but this may result in a decrease in maternal bone mineral density in some bones. As 
TDF may cause hyperphosphaturia and hypophosphatemia, and secondary changes in bone 
resorption, the composition of the breast milk may be altered, which may in turn impact the 
bone mineral density of the infant. 
b) Safety of antiviral discontinuation given to HBV infected pregnant women 
During the course of HBV infection, acute exacerbations of liver inflammation or hepatic flares 
can occur spontaneously, be induced by IFN-a therapy or the discontinuation of treatment with 
nucleos(t)ide analogues. The AASLD defines "flares" as intermittent elevations of amino-
transferase activity to more than 10 times the upper limit of normal and more than twice the 
baseline value (for this study, flares will be defined as AL T elevations above 300 lUlL, 
regardless of baseline values). Flares are also observed during induced immune suppression, 
which favors viral replication. They are most often preceded by high levels of HBV replication 
and by progressive accumulation of HBV antigens. 
In 2000, Honkoop et al [70] reported that seven of 41 (17%) patients monitored for at least 6 
months after discontinuation of lamivudine therapy experienced hepatitis flares. AL T peak 
occurred at a median 16 weeks (range 7-44 weeks) after withdrawal of therapy. Two of these 
cases (5%) were associated with jaundice and liver failure. Among the 9 patients with cirrhosis 
at start of therapy, one developed a severe hepatic flare. High HBV-DNA levels were seen at 
the time of the AL T peak. Hepatitis after withdrawal of lamivudine resembled acute hepatitis B 
with a predominance of an icteric flares within a time frame of 6 months. 
Flares have been also observed within the first 4-8 weeks of tenofovir treatment, 
accompanied by decreases in HBV DNA levels but there have been no reports of hepatic 
decompensation in this setting. AL T flares typically resolved within 4 to 8 weeks without 
changes in therapy [Tenofovir Package Insert, Gilead, 2010]. 
In the first perinatal study described above, van Zonneveld et al [62] reported that SGPT/AL T 
levels increased in seven of eight women receiving lamivudine, but remained below 5 times 
the upper limit of normal (ULN) in all women and below 2 ULN in five of eight women after a 
follow-up of 1 to 7 months. 
In the second study by Xu et al [57], two subjects in the placebo group experienced an 
increase in AL T: in one case, AL T reached 21 ULN, with no bilirubin increase, at six weeks 
postpartum, then decreased to 2 ULN at 12 weeks postpartum; in the second case, ALT 
increased to 16-18 ULN with bilirubin >2.5 ULN at the end of study treatment (placebo) and 
persisted until 6 weeks after delivery, then AL T decreased to baseline I~~"with bilirubin 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
remaining elevated (1.8 ULN). During treatment and follow-up, Grade III/IV AL T elevations 
occurred in 22/89 (25%) of the mothers in the lamivudine group and 30/61 (49%) in the 
placebo group. After treatment discontinuation (week 4 postpartum) up to 12 weeks post-
partum (end of maternal follow-up), one or more Grade IIIIIV AL T elevations first occurred in 
16/83 (19%) mothers in the lamivudine group (3-5 ULN for 14 of the 16) and 15/46 (33%) 
mothers in the placebo group (3-5 ULN for 11 of the 15). One subject in each group had AL T 
levels increased to >10 ULN following treatment cessation. This is difficult to interpret because 
the rate of loss to follow up was higher in women on placebo, and the follow up after 
discontinuation of lamivudine was limited to 12 weeks post-partum, probably too short to 
adequately evaluate the risk of flare. 
As for the third study reported by Han et al [56], only 36 of 94 women discontinued telbivudine 
at 4 weeks postpartum as per protocol. AL T elevations, 2-5 ULN occurred in 13% of women 
who discontinued therapy in the treated arm and 18% in the control arm. No cases of severe 
hepatitis flares (AL T >10 x ULN) were reported. Also, the follow up after treatment 
discontinuation was too short to fully assess the risk of flare and the reasons for treatment 
continuation in the majority of women were not reported. We did not find any other study 
adequately designed for a rigorous assessment of flares after discontinuation of antiviral 
treatment used for the prevention of HBV perinatal transmission in young pregnant women 
with a positive HBeAg test. 
c) Safety in infants 
Tenofovir is classified B in the FDA Pregnancy Category.2Reproductive studies performed in 
rabbits and rats at doses up to 19 and 14 times the human dose, respectively, have shown no 
evidence of harm to the fetus. Of 1370 HIV infected women with first trimester use registered 
in the Pregnancy ARV registry [71], there have been no evidence of an association between 
major teratogenic effects and the use of tenofovir during pregnancy. 
Tenofovir crosses the placental barrier [36]. Since the end of the 1990's, studies have raised 
concerns about possible mitochondrial dysfunction associated with in utero exposure to 
nucleoside reverse transcriptase inhibitors to prevent HIV perinatal transmission [72-74]. 
However, these disorders have been described in infants exposed in utero to nucleoside 
analogues (such as zidovudine or lamivudine) and born to HIV infected mothers. To our 
knowledge, such disorders have never been reported with the use of the nucleotide reverse 
transcriptase inhibitor, tenofovir. 
Based on animal studies where high doses of TDF were administered, other safety concerns 
for TDF during pregnancy were raised about fetallinfant growth, bone mineralization and renal 
function. A study in Africa concluded that there was no evidence that in utero tenofovir 
affected growth after 2 years [75]. Another study in the US found that TDF use during 
pregnancy was not associated with increased risk for LBW or SGA but a slightly lower mean 
length-for-age z-scores and head circumference-for-age at one year age in TDF-exposed 
infants, of uncertain significance [76]. Recent data on bone mineralization and renal function 
in utero exposed infants found no impairment of growth and bone health [77]. A study 
conducted in the US in the context of the IMPMCT network recently reported the lack of 
effect of tenofovir in utero exposure and weight at birth and at 6 months of age (82). 
DXA scans in newborns have been found accurate [78]. The ionizing radiation exposure from 
a scan is extremely low, indeed within the range of "negligible" annual individual dose as 
recommended by the National Council of Radiation Protection and Measurements (NCRP). 
There are no DXA measure norms for infants but measurements obtained using Hologic 
scanners have been shown reliable enough to compare groups of infants [79, 80], which will 
be the case for the proposed investigations. 
2Category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate 
and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate 
and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in ~~ester. 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand. version 3.0 dated 20 April 2015 
TDF is currently recommended by WHO HIV treatment guidelines as part of one of the 
preferred drug combinations in pregnant women after 14 weeks' gestation and continued 
throughout breastfeeding. In the US Recommendations for Use of Antiretroviral Drugs in 
Pregnant HIV-1-lnfected Women [81]. TDF is recommended and is the preferred NRTI choice 
for women who are co-infected with hepatitis B virus. 
Finally, the recent 2012 Asia Pacific Association for the Study of the Liver (APASL) guidelines 
states that telbivudine or tenofovir can be used in mono HBV infected pregnant women [82]. 
4.7.4. Conclusion 
In summary, no interventions in addition to active-passive HBV immunization of the newborn 
are recommended to fully prevent perinatal transmission of HBV from mothers with high HBV 
viral loads. This remains an obstacle to HBV eradication. 
Elective C-section and use of HBlg during pregnancy may be efficacious but they are 
associated with logistic complications and risks. 
Previous studies of antivirals have failed to provide clear efficacy and safety data: two of the 
published studies were not randomized, and the other was randomized but not completed as 
planned; and none offers adequate information on the risk of hepatic flare in women after 
discontinuation of therapy. This placebo-controlled study is designed to formally test the 
concept in a rigorous manner and to provide data on the efficacy of a short maternal course of 
antiviral prophylaxis and the safety of antiviral discontinuation in mothers. Tenofovir disoproxil 
fumarate is approved by the Thai FDA in Thailand for HBV chronic infection treatment but not 
for the prevention of perinatal transmission. Due to the lack of such data, there are currently 
no or only weak recommendations for this approach by the Associations for the Study of Liver 
Diseases, the WHO or national health authorities in America, Europe and Asia. Moreover, the 
recent 2012 APASL Guidelines stated that previous studies "have shown that antiviral therapy 
administered in late pregnancy may further reduce the risk of perinatal HBV infection from 
highly viremic mothers, as compared with passive-active immunization alone. However, the 
extent of benefit, the threshold of serum HBV DNA level for initiating therapy, the optimal time 
to start therapy, the appropriate choice of antiviral agent, and the optimal duration of therapy 
have not been determined." [82] 
The study results could change clinical practice for pregnant women living with HBV in 
Thailand and throughout the world. 
4.8. 
Sub-studies 
The data and samples collected in this study may be a source for sub-studies regarding 
immune response during and after discontinuation of antiviral treatment (in particular 
analyzing immunologic and gene expression changes taking place before the occurrence of 
flares, using viable PBMC and total RNA from whole blood collected in the study), HBV 
resistance and other aspects, including HBV and host genetics. None of these sub-studies are 
included in this protocol. Specific protocols will be developed and submitted to ethics 
committees, and funding sought separately. 
5. Study objectives 
Primary objective 
1. 
To assess the efficacy of tenofovir disoproxil fumarate, versus placebo, in HBV 
infected HBsAg and HBeAg positive pregnant women, from 28 weeks' gestation until 2 
months postpartum (5- month course) to prevent perinatal transmission of HBV to their 
infants who receive HBV passive-active immunization. 
Page 16 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Hypothesis: an anti-HBV agent, tenofovir disoproxil fumarate (TDF) administered from 
the beginning of the last trimester of pregnancy to two months postpartum to HBV 
infected, HBeAg-positive, pregnant women with AL T :;;30 U/L will reduce the risk of in 
utero, intrapartum and early postpartum transmission to their infants from 12% to 3% 
or less. 
Secondary objectives 
1. 
To assess the safety of tenofovir disoproxil fumarate administered for 5 months 
perinatally in HBsAg and HBeAg positive women with AL T ::;30 U/L, and their in utero 
exposed infants. 
2. 
To compare the risk of acute exacerbation or flare (ALT >300 U/L) up to 12 months 
postpartum, following planned discontinuation of study treatment, in HBeAg positive 
women randomized to tenofovir disoproxil fumarate or placebo. 
The following secondary objectives have been added in Protocol Version 3.0. 
Hypothesis: Tenofovir exposure causes maternal proximal renal tubular dysfunction 
and modification of calcium-phosphorus metabolism, resulting in lower maternal 
and/or infant BMD persisting until one year after delivery/birth. 
3. 
To compare the bone mineral density (BMD) at 12 months postpartum in HBV 
chronically infected, breastfeeding mothers, randomized to receive TDF or matching 
placebo from 28 weeks gestational age to 2 months postpartum. 
4. 
To compare the bone mineral density (BMD) in infants at 12 months of age whose 
mothers were randomized to receive TDF or matching placebo within the iTAP 
clinical trial. 
Design 
The design of the study is a multicenter, controlled, double blind, randomized clinical trial to 
assess the efficacy to prevent hepatitis B virus (HBV) perinatal transmission, safety and 
tolerance of tenofovir disoproxil fumarate versus placebo, given from 28 weeks' gestation until 
2 months post-partum to hepatitis B sAg and eAg positive mothers. 
,---"------_.-
--------_ .. _ 
.. 
-~ 
Mothers 
Antepartum 
Postpartum 
OA 
3'" Trimester 
2 Months 
2S 'Z::._ .. _-_ ... ---.. ~ 
.. --.... - .. --. .-._ 
.... __ .. _ 
.. _-
. ...... 
'\.,,~-.. 
c: 
0 
Placebo 
~[ 
) 
'.<:0 
Reference Arm 
Placebo 
ro 
Follow-up 
N 'E 
until 
0 
~ [ 
) 
12 months 
"'0 
Tenofovir (TDF) 
TDF 
postpartum 
c: 
(300 mg, once daily) 
rn 
ex:: 
Birth to 12 Months 
------------~ ----~ 
All Infants 
.HBV vaccine: at birth, 
1, 2, 4 and 6 months 
Follow-up 
plus HBlg at birth 
Figure 1. Overview of the randomized trial design with 12 month follow-up 
~ 
Page 17 of77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
We opted for a design where antiviral drug will be discontinued because it is not currently 
recommended to start chronic antiviral treatment in case of AL T level < ULN, even with high 
replication. We considered that a two month postpartum treatment would ensure that the 
infant is protected from a maternal transmission until three vaccine injections have been 
administered. 
The study will involve a population of subjects easy to identify using tests widely available in 
Thailand (with HBsAg+, HBeAg+, ALT S 30 U/L), at high risk of transmission but in the 
immune tolerant phase and, therefore, at lower risk of liver enzyme elevation after 
discontinuation of treatment. 
6. Study sites and duration of the study 
6.1. 
Study sites 
PHPT affiliated Obstetrics, Internal Medicine and Pediatrics Departments in Thai public 
hospitals have been highly trained in conducting clinical research on prevention of perinatal 
transmission of HIV, and have been participating in NICHD and NIAID/DAIDS sponsored 
studies for the last 15 years. Each site is regularly monitored by a PHPT clinical research 
assistant to ensure that study procedures are implemented according to the protocol and 
regulations. 
Site 
FWA 
Phayao Provincial Hospital 
FWAOOO01646 
Chiangrai Prachanukroh Hospital 
FWAOOO01607 
Prapokklao Hospital 
FWAOOO01643 
Chonburi Hospital 
FWAOOO01604 
Bhumibol Adulyadej Hospital 
FWAOOO01651 
Health Promotion Center Region 10, Chiang Mai 
FWAOOOO 1608 
Lamphun Hospital 
FWAOOO02135 
Chiang Kham Hospital 
FWAOOO01609 
Mae Chan Hospital 
FWAOOO01619 
Banglamung Hospital 
FWAOOO01610 
Nakornping Hospital 
FWAOOO01605 
Nopparat Rajathanee Hospital 
FWAOOO02134 
Khon Kaen Hospital 
FWAOOO01612 
Samutsakhon Hospital 
FWAOOO01644 
Nakhonpathom Hospital 
FWAOOO01606 
Samutprakarn Hospital 
FWAOOO02128 
Lampang Hospital 
FWAOOOO7260 
Maharaj Nakornratchasrima Hospital 
FWAOOO07370 
Ranong Hospital* 
On process 
* Ranong Hospital after formal approval by the sponsor (NICHD and US CDC, USA). 
Ci:-~ 
Page 18 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Considering the data currently available regarding prevalence of HBV chronic infection in each 
site, the approximate number of patients to be enrolled per site is as follows: 
Site 
Estimate number of patients to be enrolled 
Phayao Provincial Hospital 
8 
Chiangrai Prachanukroh Hospital 
56 
Prapokklao Hospital 
25 
Chonburi Hospital 
8 
Bhumibol Adulyadej Hospital 
8 
Health Promotion Center Region 10, Chiang Mai 
30 
Lamphun Hospital 
8 
Chiang Kham Hospital 
8 
Mae Chan Hospital 
8 
Banglamung Hospital 
36 
Nakornping Hospital 
8 
Nopparat Rajathanee Hospital 
30 
Khon Kaen Hospital 
24 
Samutsakhon Hospital 
20 
Nakhonpathom Hospital 
5 
Samutprakarn Hospital 
16 
Lampang Hospital 
10 
Maharaj Nakornratchasrima Hospital 
10 
Ranong Hospital' 
10 
Total 
328 
* Ranong Hospital after formal approval by the sponsor (NICHD and US CDC, USA). 
Study co-investigators and study nurses will be trained before the beginning of and during the 
study to the specific aspects of Hepatitis B management and treatment. The pediatric nurses 
will receive refresher training at the outset to ensure that length, weight, head circumference 
are recorded in a standardized way. 
The PHPT Clinical Trial Unit (CTU) team is responsible for the overall organization and 
monitoring of the study, as well as data entry, data management and statistical analysis in 
compliance with Good Clinical Practices and reporting to the sponsors. The technical team in 
charge of the study at the CTU will be composed of 1 junior physician, 1 coordinator, 1 nurse 
in charge of the safety monitoring, at least 4 full-time-equivalent clinical research assistants, 1 
data manager, 3 data entry technicians, 1 laboratory technician, 1 logisticia~anslator and 
Page 19 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
1 secretary. In addition, the PHPT CTU pharmacist will oversee the management of study 
drugs. 
Site co-investigators are responsible for the medical management of the patients, the 
implementation of the study interventions according to the protocol and the completion of the 
Case Report Forms (CRFs). At each site, the study teams consist of obstetricians, 
pediatricians, nurses, laboratory technicians, pharmacists and counselors. 
The completed CRFs are reviewed and signed by the site co-investigator and forwarded to the 
CTU. Upon arrival at the CTU, they are immediately recorded in a tracking database and filed. 
The tracking database provides updated information on each patient every week, as well as 
the total number of patients at each stage of follow-up. 
Data will be keyed using a double data entry system, and programs check the datasets for 
range checks on each field within a form, consistency checks between fields on the same 
form, and between fields on different forms; The data managers generate queries as 
necessary until final validation of the CRFs. Validated CRFs serve as evidence that the history 
and clinical data has been recorded, and that all lab tests and procedures have been 
completed. All serious adverse events will be reported according to GCP. As required by 
GCP, any change made to the original CRFs/data set is fully documented. The databases are 
stored in My-SOL format in central computers with restricted access and regular backups are 
made and stored in another place to prevent accidental loss of data. All important operations 
are described in procedures within our IRD UMI 174 quality management system, accredited 
according to the standards of ISO 9001 :2008. 
As for previous studies conducted by our group, investigators and co-investigators will 
facilitate any audit of the data, procedures at study sites and at the laboratory by independent 
external monitors sent by sponsors. 
The PHPT laboratory has received ISO accreditation 15189: 2007. It is responsible for the 
centralized laboratory exams, virological testing, and samples repository. The blood samples 
will be stored at the central laboratory for retrospective assessments as needed. 
The PHPT laboratory staff will also monitor the quality control of the site laboratories. 
6.2. 
Duration of the study 
First enrollment: December 1, 2012 
Planned enrollment duration: 24 months 
Approximate duration of maternal follow up from enrollment to delivery: 3 months 
Postpartum and infant follow up: 12 months 
Planned date of last visit completed: March 31, 2016 
Final analysis and submission of a manuscript: last quarter 2016. 
7. Workplan 
7.1. 
Selection of participants 
7.1 .1. Eligibility criteria 
The population enrolled in the study will be composed of pregnant women meeting all 
eligibility and inclusion criteria, and none of the exclusion criteria, and their infants. 
Women who meet the eligibility criteria (see Table1, below) will be systematically approached, 
informed about HBV perinatal transmission and about the study, and proposed participation in 
the study. If they agree, they will be asked to sign the Study Informed Consent Form before 
any study procedures (see Appendix 1). 
Page 20 of?? 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
First ANC visit: 
HBsAg test 
~ 
....................... .l--__ 
"""";I, 
I 
HB~Agl 
HB~Ag 
L n~~~ti~~ .... I 
'~~~I~iV! __ ._ 
'9' ................................. ! 
'" 
Standard 
,----------'-----------, 
ANC Care 
Study Counseling, Information, 
Informed Consent 
.......................................................................... ,'---------, 
.~--
r 
ALT >30 
I 
r·· 
: , 
i 
f i 
.......... ..r,. _" . 
Referral to 
Internal Medicine 
dept. 
r .. ·· .. · .... ·· .. ··· .. ·· .. ··· .. ·· .. ··· .. L------, 
" _ 'if. .. 
HB~Ag negativ~ "I 
~ ; 
j 
: , 
i 
.. v_ ..... . 
Standard ANC 
care 
Figure 2: Selection of participants 
Table 1: Eligibility Criteria 
1 
Pregnancy 
2 
Age: at least 18 years 
3 
Negative Human Immunodeficiency Virus (HIV) serology test performed less than 3 
months prior to enrollment. 
4 
HBsAg test positive performed less than 6 months prior to enrollment. 
7.1.2. Inclusion and exclusion criteria 
Women who meet all inclusion criteria (see Table 2) and none of the exclusion criteria (see 
Table 3) will be offered enrollment in the study. 
Table 2: Inclusion Criteria 
1 
Gestational age of 28 weeks (+ or - 10 days) as determined by obstetrician. 
2 
Positive HBeAg test performed less than 6 months prior to enrollment. 
3 
AL T/SGPT ::;;30 U/L performed less than 3 months prior to enrollment and confirmed 
::;;60 U/L at the Pre-Entry visit. 
"W;0 ••• ~ 
Page 21 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
4 
Written informed consent for participation in this study. 
Agreeing to bring their infants at the planned study visits at one study site until one 
year after delivery and to inform the site investigators if they plan to move to another 
place and not be able to return to the clinic. 
Understanding the need for adequate infant immunization and agreeing to the blood 
draws from their infants and the need for close follow up to manage possible 
exacerbation of hepatitis. 
Table 3: Exclusion criteria 
1 
History of tenofovir at any time, or any other anti-HBV treatment during the current 
pregnancy. 
2 
Creatinine clearance <50 ml/min, calculated using the Cockcroft-Gault formula 
(Appendix 4). 
3 
Dipstick proteinuria>1 + (>30 mg/dL) or normoglycemic glucosuria confirmed on two 
separate occasions. 
4 
Positive serology for Hepatitis C infection less than 12 months prior to enrollment. 
5 
Evidence of pre-existing fetal anomalies incompatible with life. 
6 
Any concomitant condition or treatment that, in the view of the clinical site 
investigator, would contraindicate participation or satisfactory follow up in the study. 
7 
Concurrent participation in any other clinical trial without written agreement of the 
two study teams. 
As part of the consent process, participants will be asked for their authorization to record 
laboratory test results performed as part of their clinical care before their formal consent to 
participate in this study. 
Infant inclusion criteria 
• 
All live born infants, born to mothers participating in this study. 
Infant exclusion criteria 
• 
Stillbirth. 
7.1.3. Discontinuation criteria 
Maternal and infant discontinuation criteria 
Women enrolled in the study are free to withdraw their or their infants' participation in the 
study at any time without jeopardizing their access to standard medical care or possible 
participation in future research studies. 
Pregnant women and their infants will continue to be followed in the study, regardless of 
maternal adherence to study treatment. 
A study site co-investigator may decide to end a subject's participation in the study if, in 
his/her own judgment, such a participation would be detrimental to a subject's health or well-
being. However, all efforts should be made to inform the study team and discuss options prior 
such a decision. 
Page 22 of 77 


Maternal antiviral prophylaxis to prevent perinatal transrnission of HBV In Thailand, version 3.0 dated 20 April 2015 
Study treatment discontinuation: a site co-investigator in charge of the patient's care may 
consider, if possible after discussion with the study team, discontinuing double blind study 
treatment if he/she considers that a patient is experiencing toxicity that could be caused by 
tenofovir. In such a case, the patient should continue follow up in the study. 
The study could be discontinued if required by Thailand health authorities or the sponsors. 
7.2. 
Implementation, data collection and monitoring procedures 
7.2.1. Maternal follow up 
Eligibility and pre-enrolment tests should be performed within the previous 3 months prior to 
enrollment. After enrollment, maternal visits will be performed at 28, 32, 36 weeks' gestation, 
delivery, and at 1, 2, 3, 4, 6 and 12 months postpartum (see scheduled assessments in Table 
4). 
Study treatment will be provided every month from 28 weeks' gestation through 2 months 
postpartum. All effort should be made to strictly follow the maternal and infant visit schedule 
but occasional departures of no more than one week will be considered acceptable. 
For future sub-studies, in participants enrolled in sites with PBMC isolation capacity, PBMC 
will be isolated at the enrollment visit, prior to starting study treatment, and at 32, 36 weeks 
gestation, and at 1, 2, 3 and 4months postpartum and kept stored in liquid nitrogen until use 
for laboratory analyses. Total RNA from whole blood will be collected at the same visits. 
Urine sample collection 
Tenofovir has been associated with renal function impairment in HIV infected patients. In this 
study, participants are not HIV infected. In addition to the routine serum creatinine and 
phosphorus measurements already planned in the protocol, a maternal urine sample will be 
collected at study entry, at the 32 weeks' gestation visit, at time of study treatment 
discontinuation (visit scheduled at 2 months postpartum) and at the last maternal visit. Some 
urinary biomarkers, for example Kidney injury molecule-1, Neutrophil gelatinase associated 
lipocalin, have been found earlier indicators of proximal tubular injury, compared to traditional 
markers. After centrifugation, aliquots will be stored frozen. The samples could be used for 
individual investigation in case of serum creatinine elevation. If deemed necessary, a 
systematic analysis of the samples will be described in a separate protocol, which will be 
submitted for ethical approval and for funding. 
Page 23 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Table 4: Maternal assessments 
Maternal assessments 
Antepartum 
Delivery 
Postpartum (months) 
Scr 
Enroll 
Pre-
ment 
32 
36 
Before 
1 
z1 
3 
4 
6 
122 
een 
ing 
entry 
wks 
wks 
discharge 
28wks 
Study treatment 
Counseling and Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Obstetric exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study treatment dispensation, 
return of used study treatment 
X 
X 
X 
X 
X 
X 
bottles/adherence assessment 
Record results of HBsAg, HIV 
X 
serology and Ultra sound 
SGPT/ALT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBeAg test 
(if negative during postpartum 
X 
X 
X 
period, anti-HBeAb will be tested) 
Complete Blood Coune 
X 
X 
X 
Serum SGOT/AST, bilirubin 
(direct& conjugated), alkaline 
X 
X 
phosphatases, albumin 
Hepatitis C serology 
X 
Serum creatinine4 
X 
X 
X 
X 
X 
X 
X 
X
5 
Serum phosphorus 
X 
X 
X 
X 
X 
X 
X 
Dipstick glycosuria and proteinuria 
X 
X 
X 
X 
Urine sample collection8 
X 
X 
X 
X 
DXA assessment 
X10 
HBV DNA load (retrospective) 
X 
X6 
X6 
Tenofovir plasma level 
X9 
X9 
X 
Plasma/serum storage 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RNA storage 
X 
X 
X 
X 
X 
X 
X 
PBMC isolation7 
X 
X 
X 
X 
X 
X 
X 
Total blood volume (mL) 
5 
16 
3 
10 
10 
10 
4 
8 
13 
8 
8 
8 
10 
Total blood volume for PBMC(mL)7 
30 
30 
30 
30 
30 
30 
30 
Cord blood volume (mL) 
15 
Q~ 
Page 24 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
10r early study treatment discontinuation 
20r early study discontinuation (if subject consents) 
31ncluding platelet count; 
4Calculatecreatinine clearance using the Cockcroft-Gault formula (see Appendix 4) or online calculation at 
http://nephron.com/cgi-bin/CGSI.cgi). 
5 1n case of Grade 1 or higher creatinine at 2 months postpartum 
6Funding will be sought to retrospectively measure HBV DNA load in women who transmitted HBV and a control sample 
of women who did not, at time of delivery and 1 month postpartum. 
7For women enrolled in sites with PBMC isolation capacity (flares sub-studies) 
sif possible, a urine sample of 10 ml will be collected at study entry, at the 32 weeks' gestation visit, at time of stUdy treatment 
discontinuation (visit scheduled at 2 months postpartum) and at the last maternal visit to evaluate the potential renal toxicity of 
tenofovir. After centrifugation, 10 aliquots will be stored frozen. 
9 For women who consent for the pharmacokinetic sub-study 
10 For women who consent for the DXA assessment sub-study 
In case of liver enzyme exacerbation (see section 7.2.2 liver enzyme exacerbations below), additional immediate, 
prospective, and retrospective evaluations on stored samples will be performed: AST/SGOT, AL T/SGPT, gamma-
glutamyl-transferase, alkaline phosphatase, total bilirubin and albumin and HBV DNA load. 
Laboratory procedures for serum HBV quantitation, HBsAg test in infants for diagnosis purpose, Anti-HBs Ab, and 
determination of tenofovir plasma concentrations will be described in the Manual of operations. 
With patient's authorization, study teams will record contact information including mobile phone number 
and address (this information will not be entered in the study databases) to be used if she does not 
show up at a visit for contact and possible home visit by the hospital social workers. All patients starting 
study treatment will be introduced to a gastroenterologist or internist experienced in management of 
Hepatitis B, for future long term care. Women will be asked to report any concomitant treatments at all 
follow up visits. Women wishing to withdraw from the study will be referred to a specialist in Hepatitis B 
management in a public hospital as close as possible to her dwelling. In case of early discontinuation, 
the investigator will ask the mother the authorization to perform a last mother and infant blood draw for 
safety evaluations and for documentation of the infant's HBV status (see Tables 4 and 5). 
Grade 3 and 4 abnormalities as defined by the NIAID Division of AIDS in the Table for Grading the 
Severity of Adult and Pediatric Adverse Events (Version 1.0, December, 2004) will be reported 
immediately to the PHPT Clinical Trial Unit (CTU). Any serious adverse event, as defined by ICH Good 
Clinical Practice (GCP) [83], whether or not considered to be related to the study treatment, will be also 
reported within 3 business days to the Thai Ministry of Public Health and the drug manufacturer 
(following requirements). 
Management of toxicities will be discussed and reviewed with the site study teams during on-site 
trainings organized prior to starting the study, and described in detail in the Manual of onsite 
Operations. The PHPT CTU staff can be reached 24 hours a day through phone, and by fax and e-mail. 
At each visit, the study nurse in charge will record the history and the results of the physical exam, 
record and grade adverse experiences. Concomitant treatments and medical interventions, including 
details about mode of delivery, will be recorded in CRFs. 
7.2.2. Liver enzyme exacerbations 
After delivery, women will be closely followed up until one year postpartum and any confirmed 
elevations of SGPT/AL T will warrant consideration for prompt re-introduction of study treatment. There 
is no evidence that HBV exacerbation depends on the level of replication at the time of discontinuation; 
thus women in the post-treatment phase will be primarily monitored based on SGPJ:~~ levels. 
Page 25 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Women will be informed of possible adverse effects following discontinuation of antiviral treatment 
without medical supervision or imperfect adherence. In case of liver enzyme elevation, additional visits 
and tests will be performed for case management and documentation. 
In case of SGPT/AL T >60 U/L, with or without associated symptoms, a clinical assessment of the 
subject will be performed and SGPT/ALT will be repeated on another blood draw as soon as possible 
and within 3 days, along with the following laboratory examinations: bilirubin, prothrombin/lNR, and 
albumin. Plasma will be stored for further evaluations: HBV DNA load, HBeAg and antibodies and other 
viruses as appropriate. The site investigator will immediately inform a PHPT CTU physician by phone, 
at any time (24/24 hours, 7/7 days). 
-
If SGPT/ALT is confirmed between 60 and 150 U/L, a new SGPT/AL T test will be scheduled 2 
weeks later. The patient's contact information will be checked before the patient leaves the clinic and 
the patient informed that she should return to the clinic if she has any clinical symptoms. 
-
If SGPT/AL T >150 U/L is confirmed immediately, or if SGPT/AL T is confirmed between 60 and 150 
U/L two weeks after the first test, the site investigator will contact a PHPT CTU physician and re-
introduction of double blind study treatment will be considered by the reference site internist. 
SGPT/ALT >60 U/L: immediate clinical assessment 
Check patient's contact information, inform patient that 
she should return to the clinic if any clinical symptoms 
Inform PHPT CTU. 
and within 3 days: 
Repeat blood draw for SGPT/ALT, bilirubin, prothrombin/INR and 
albumin, store Plasma (for HBV DNA, HBeAg and antibodies) 
1 
SGPT/AlT S 60 
U/l 
60 S SGPT/ALT S 150 
U/L 
I, 
Schedule new SGPT/ALT test 
1 
SGPT/ALT 
>150 U/L 
within 2 weeks (+/- 3 days) 
i 
60 5 SGPT/At~~_15_0_U/L 
... ..1 
Contact 
reference site internist to 
consider re-introduction 
of study treatment 
Figure 3: Flow diagram of postpartum flare management 
Patients restarting antiviral treatment will be followed within the study until one year after delivery. After 
the end of the patient's participation in the study, her treatment will be replaced with the commercial 
form of the drug originally assigned (except if it was placebo), and followed off study by the reference 
internist according to current guidelines within the Thai Universal Health Coverage system. Patients will 
not discontinue antiviral treatment during their participation in the study but discontinuation may later be 
considered according to current APASL recommendations [33]. 
7.2.3. Assessment of Maternal Tenofovir Plasma Exposure 
Two extra blood samples will be drawn in a subset of women to measure study drug concentrations at 
the 32 week and 36 week maternal visits. Women will be asked to sign an addition~sent form to 
Page 26 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
join the sub-study (see Appendix 6. Additional consent form for plasma drug level measurements). 
These samples will be collected between 0.5 to 3 hours post-dose and between 3 to 6 hours post-dose 
(at least 1 hour after the previous sample). A population pharmacokinetic model will be used to 
estimate tenofovir exposure in all women. 
7.2.4. Bone Mineral Density Evaluations 
In sites with access to DXA scan equipment, the option for DXA scan evaluations in mothers and 
infants will be explained to women at their 6-month maternal visit, and/or at the 9 month infant visit. The 
examinations will be explained in detail, including their practical aspects (need for specific 
appointments, transfer to the DXA scan facility). Women who consent will be asked to sign an 
additional consent form. 
Consenting women will have DXA scans of their hip and lumbar spine at 12 months postpartum. 
For this study, a Hologic Discovery A DXA scan (Software Version: 4.0.2) is currently available at 3 
locations: 
Maharaja Nakorn Chiang Mai Hospital, Chiang Mai University; 
Bhumibol Adulyadej Hospital, Bangkok; 
Maharaja Nakhonratchasima Hospital, Nakhonratchasima. 
Each woman/infant pair will be accompanied by a study staff. 
We have estimated that a total of 98 women could have DXA scan measurements one year after 
delivery/birth, over a 1 year period. 
7.2.5. Infant follow up and diagnosis of HBV infection 
All infants will receive anti HBV passive immunization (HBlg) within 12 hours of birth (at a site different 
from the HBV vaccine), and intensive active immunization following Thai national guidelines for infants 
born to HBsAg positive mothers, i.e. within 12 hours of birth and at 1, 2, 4 and 6 months of age. Infant 
visits will be performed at birth, 1,2,4,6 and 12 months for clinical safety evaluation and determination 
of HBV status. 
A check list of signs and conditions suggesting possible mitochondrial dysfunction that may trigger 
other investigations will be completed at the 6 and 12 month visit (see list in Appendix 3) 
Page 27 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Table 5: Infant assessments 
Infant assessments 
Birth 
1 
2 
month 
months 
Physical examination including length, weight 
X 
X 
X 
and head circumference2 
Mitochondrial dysfunction check lisf 
Counseling and Questionnaire 
X 
X 
X 
Record date and time of HB Immune globulin 
(HBlg) injection4 
X 
Record date and time of HB immunization 
X 
X 
X 
Complete Blood Count 
X 
Serum creatinine 
X 
Serum phosphorus/calcium 
X 
HBsAg1.5 
X5 
X5 
X5 
HBV DNA1 
X 
SGPT/ALT 
X 
Anti-HBsAb 
X 
HBeAg and anti-HBeAb if positive HBsAg 
DXA assessment 
Plasma storage 
X5 
X5 
X5 
Total blood volume (mL) 
3 
3 
2 
Additional investigations if HBsAg+ (except at birth): retrospective HBV DNA loads, HBeAg 
10r early discontinuation, with mother's/guardian's/parents' consent. 
4 
6 
months 
months 
X 
X 
X 
X 
X 
X 
X 
X5 
X5 
X6 
X 
X 
X5 
X5 
2 
3 
9 
months 
X 
X 
X 
X 
X 
X5 
3 
21ncluding Ballard Score at birth. See also Appendix 5: How to Measure Head Circumference, Length and Weight. 
3 Assessment for possible mitochondrial dysfunction: see list of major and minor neurological and other organ signs in Appendix 3. 
41njectHBIg at a site different from HBV vaccine. 
5Draw blood before injection of HBlg and vaccine. 
S If HBsAg positive at this time point 
7 If anti-HBs < 10 lUlL (and HBsAg/HBV DNA negative), the pediatrician in charge will be encourage to consider revaccination. 
S For infants who consent for the DXA assessment sub-study 
Diagnosis of HBV infection in infants 
12 
months1 
X 
X 
X 
X 
X 
X6 
X6 
X7 
X 
X8 
X 
4 
The significance of a positive HBsAg or HBV DNA test within the first days of life is unclear as some 
infants may test negative a few weeks or months later [84, 85]. Blood will be systematically drawn 
before vaccine administration. 
In this study, for the interim and final analyses, HBV transmission will be defined by a positive HBsAg 
and positive HBV DNA at 6 months of age. All infants will be tested for HBV DNA at birth and at 9 
months of age, regardless of HBsAg test results. 
Appropriate laboratory analyses (HBV DNA and HBeAg) will be conducted retrospectively to determine 
the timing or clearance of infection in HBV DNA negative cases at 6 months with a positive HBsAg test 
at any time. Secondary analyses will include HBV transmission as defined by a positive HBsAg and 
positive HBV DNA through 12 months of age. 
Bone Mineral Density Evaluations in Infants 
In infants from sites where DXA scan evaluations are accessible, these evaluations will be explained to 
mothers at the occasion of the 6-month maternal visit, and/or at the 9 month infant visit, including their 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
practical aspects (See above BMD in Mothers). Infants will have a DXA scan of their lumbar spine at 12 
months of age. 
7.3. 
Study drugs 
Patients will receive study drugs (tenofovir disoproxil fumarate 300mg tablet or indistinguishable 
matching placebo) in the form of tablets manufactured by Gilead for clinical trials. 
For information, tenofovir disoproxil fumarate is commercialized in Thailand: 
Trade name: Viread® 
Generic name: tenofovir disoproxil fumarate tablets 
Manufacturer's: Gilead Sciences, Inc. 
Distributor's: IDS Marketing (Thailand) Limited 
Registration number of drug license: 1C 144/2549(NC) 
Study drugs (TDF and placebo) will be provided by Gilead Sciences, Inc, in the form of bottles of 30 
tablets. The PHPT CTU pharmacist will organize the labeling ("secondary packaging") of the study 
drugs in collaboration with the study statistician, in accordance to regulations. Each individual study 
treatment bottle will be uniquely identified and dispensation of study drugs will be documented. The 
details will be provided in the Manual of Operations. 
7.4. 
Statistical considerations 
7.4.1. Endpoints 
7.4.1.1 Primary Endpoint 
• Infant's HBV infection status, defined as HBsAg positive confirmed by HBV DNA, at 6 
months of age. 
Note: transmission to one or more offspring of a multiple pregnancy will be considered as only 
one transmission. 
7.4.1.2 Secondary Endpoints 
• Occurrence of maternal and infant adverse events (AE), including ICH SAEs and DAIDS 
grade 3/4 signs and symptoms, regardless of their relatedness to the study treatment. 
• Occurrence of acute exacerbation or flare of hepatitis B, following planned discontinuation of 
study treatment up to 12 months postpartum. The acute exacerbation or flare of hepatitis B is 
defined as AL T >300 lUlL regardless of baseline values. 
• 
Infant's HBV infection status, defined as HBsAg positive confirmed by HBV DNA, at or after 6 
months through 12 months of age. 
• 
Infant growth related outcomes, including weight, height and HC Z-scores at 6 months and 12 
months of age. 
7.4.2. Randomization and Stratification 
Participants will be randomized 1:1 to receive TDF or placebo stratified by site using permuted blocks 
of size determined by the study team. Subjects' baseline HBV viral load, which might affect 
transmission rate, is unavailable in real time and cannot be stratified. The imbalance of baseline HBV 
viral load will be evaluated. If an imbalance exists, an exact logistic regression accounting for baseline 
HBV viral load will be conducted as a sensitivity analysis. 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
7.4.3. Sample size and Accrual 
The sample size is calculated accounting for one interim efficacy monitoring between the TDF arm and 
the placebo arm. It is hypothesized that TDF will lower the transmission rate. To target 90% of power at 
a one-sided 
0.049 significance level in Fisher's exact test, 312 evaluable neonates, 156/arm, are needed to detect 
an infection rate of 3% in the TDF arm, assuming 12% infection rate in the placebo arm. This is 
equivalent to a relative reduction of 75% in infection rate in the TDF arm. The table below summarizes 
the power of the study 
if the infection rate in the placebo arm is lower than 12%, e.g., if the infection rate in the placebo arm is 
only 10%, the study has 83.2% of power to detect a 75% reduction in the infection rate, i.e., an infection 
rate at 2.5%, in the TDF arm. However, if the infection rate is only 8%, the power of detecting 75% 
reduction in the infection rate, i.e. 2% infection rate in the placebo arm, reduces to only 72.6%. 
Therefore the infection rate in the placebo arm needs to be considered carefully during the interim 
efficacy monitoring as outlined in the next section. 
Table: Power of the study assuming different infection rate in the placebo arm (based on one-sided 
Fisher's exact test at 0.049 significance level) 
Power (156/arm) 
Infection rate in the active treatment arms 
Infection rate in the 
1% 
2% 
2.5% 
3% 
placebo arm 
8% 
90.1% 
72.6% 
62.5% 
52.4% 
10% 
97.5% 
89.5% 
83.2% 
75.8% 
12% 
99.5% 
96.7% 
94.0% 
90.1% 
To further account for a maximum of 5% lost to follow-up, 328 pregnant women will be enrolled. 
7.4.4. Information of the co-investigators 
To inform the co-investigators about the study and its progress, a meeting will be held before the 
beginning of the study, then every year. In addition, a monthly progress report, prepared by the data 
management team at the PHPT CTU, will be provided to all co-investigators, including the Program 
Scientists during the trial. 
7.4.5. Monitoring by the program scientists 
Program scientists should be notified, within one week of protocol team awareness, of selected serious 
adverse events (maternal and fetal/infant), including: 
deaths; 
all Grade 4 adverse events (including hospitalizations; congenital anomalies (with the exception 
of those listed in Appendix 2); persistent or significant disability/incapacity. 
Sites will be asked to include a description of the event, an assessment of potential relatedness to 
study drug (TDF), description of how the subject was managed, and final outcome. To discuss the 
progress of the study, a quarterly teleconference will be held including program scientists and the study 
coordination team (including at least the study principal investigator, virologist, ph~ologist, study 
nurse coordinator). 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
7.4.6. Data and Safety Monitoring Board (DSMB) 
The Data and Safety Monitoring Board (DSMB) will be composed of at least 1 gastroenterologisU 
hepatologist, 1 pediatrician, 1 obstetrician, 1 infectious diseases specialist, and 1 statistician/ 
epidemiologist, at least 3 of them Thais. The program scientists will participate as observers on open 
sessions of DSMB calls/meetings. 
The study will be presented in detail to the DSMB during a protocol initiation review before study open. 
At this meeting, a detailed study monitoring plan, outlining open reports on study conduct and safety 
profiles pooled across study arms and closed reports on by-arm information and efficacy, will be 
presented. 
The study will be monitored by the DSMB at least annually. First DSMB data review will be held when 
100 pregnant women have been enrolled, or one year after the first enrollment. This meeting will allow 
for the review of the conduct of the study and Adverse Events (regardless of randomization). No 
efficacy analysis will be presented at this meeting. Additional DSMB reviews could be triggered if 
deemed necessary by the principal investigator, in particular in case of issues related to the occurrence 
of flares. DSMB could help program scientists with monitoring as a closed DSMB report would include 
by-arm information. 
The first interim efficacy monitoring will be performed when 50% of information on the primary endpoint 
is available, i.e. when 164 infants either have their 6 month HBV status available or are off study before 
the 6 month visit. A Haybittle-Peto use function will be employed for the group sequential design. At the 
interim efficacy monitoring, the comparison of the primary endpoint will be considered significant only if 
p < 0.001. In addition, sensitivity analysis considering any positive HBsAg, confirmed by HBV DNA, at 
or after month 6 up to 12 months of age as having a neonate HBV infection will be provided. Futilities 
will also be considered based on conditional powers, safety profiles of the treatment arm and possible 
low transmission rate in the placebo arm. Details will be provided in the study monitoring plan. 
Additional interim efficacy monitoring could be considered in conjunction with the DSMB, and the final 
analysis for the comparison between TDF and the placebo arm will employ an alpha level of 0.05 - N * 
0.001, where N represent the number of interim efficacy monitoring throughout the entire statistical 
consideration section. 
In case of premature discontinuation of the clinical trial for any reasons, further management of patients 
will be organized with the advice of the DSMB and health authorities. 
7.4.7. Analyses for the primary objective/endpoint 
Proportions of neonates, who have HBV infection at 6 months of age, along with their 95% confidence 
intervals, will be provided by arm based on exact Binomial distribution and compared between the TDF 
arm and the placebo arm based on Fisher's exact test. The tests will be adjusted for the interim efficacy 
monitoring by considering p < 0.05 - N * 0.001 as significant. The imbalance of mother's baseline HBV 
viral load between treatment arms will be evaluated based on Wilcoxon rank sum test. If imbalance 
exists, an exact logistic regression will be conducted as a sensitivity analysis. The primary analysis will 
be conducted as a complete case analysis including infants whose 6 month endpoint is available in 
their original randomized group, regardless of the duration of study treatment the mothers actually 
received if at least one dose was taken. A secondary analysis will be conducted in a modified intent to 
treat (miTT) population, where all randomized pregnant women who received at least one dose of study 
treatment, will be included and infants who are lost to follow-up before their 6 months HBV status is 
available will be considered as having an event. Further sensitivity analysis may be performed, 
including imputing infants' last available HBV infection status as their 6 months status for those who are 
lost to follow-up prior to 6 months or multiple imputations accounting for possible reasons of loss to 
follow-up, to explore the effect of loss to follow up. A secondary supporting 
considering any 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
positive HBsAg, confirmed by HBV DNA, at or after 6 months up to 12 months of age as having a 
neonate HBV infection, will be conducted in the complete case population. Logistic regressions, 
accounting for factors that are known to be associated with mother-to-child HBV transmission could 
also be conducted to provide an adjusted odds ratio between treatment arms. 
As indicated in literature, the significance of a positive HBsAg or HBV DNA test within the first days of 
life is unclear as some infants can test negative a few weeks or months later. Time to first HBsAg 
positive will not be considered in the primary analyses. 
7.4.8. Analyses for secondary objectives/endpoints 
7.4.8.1 Proportions of women with severe hepatic disease exacerbation or flare from study 
treatment discontinuation up to 12 months postpartum, along with their 95% confidence interval, 
will be provided by 
treatment arm and compared between treatment arms based on exact binomial distribution and 
Fisher's exact test. Flares will be defined as ALT elevations above 300 IU/L, regardless of 
baseline values. 
7.4.8.2 Proportions of women with any adverse event (AE) from randomization until study exit will 
be analyzed similarly as those specified in section 7.4.8.1. Poisson regressions, with an offset of 
follow-up time will be further conducted to model repeated occurrence of AE. 
- AEs in infants will be analyzed in a similar manner. 
7.4.8.3. Infants' mean weight, height and HC z-scores at 6 and 12 months, along with their 95% 
confidence intervals, will be provided by treatment arm and compared between arms based on 
normal approximation and two-sample t-test. 
7.4.9. Pharmacokinetic data to estimate individual maternal tenofovir exposure 
For each participant mother, a plasma sample will be available for PK analysis during pregnancy at 
Week 32 and 36 GA study visits (328 samples). It is expected that half of those women (164) will 
receive TDF. To ensure samples are available within the early part of the dosing interval an additional 
two timed samples will be collected in approximately 44 women at week 32 and 36 GA study visits (88 
samples). Overall, we expect a total of 208 samples from 164 women will be available to develop a 
population pharmacokinetic model. 
The tenofovir plasma concentration data available will be pooled to generate the population 
pharmacokinetic model. Non-linear mixed effects regression (NONMEM) will be used to estimate the 
population means and variances of tenofovir pharmacokinetic parameters. Individual patient 
characteristics will be evaluated for their inclusion in the model using a stepwise forward inclusion and 
backward elimination model building procedure. 
Post-hoc subject specific PK parameters will be 
estimated (Le. AUC, C12 and C24). The approach will be similar to that we used to develop a population 
pharmacokinetic model in HIV-infected adults receiving TDF containing antiretroviral therapy [86], 
7.4.10. Bone mineral density measurements 
Sample size estimate for BMD measurement: additional investigations will start after approval by ethical 
review committees and training of radiologists. All women who deliver after May 15, 2014 will have their 
12-month postpartum visit (window of 1.5 months) after July 1, 2015 and are therefore eligible to 
participate. Taking into account that enrollment and delivery are about 3 months apart, a maximum of 
231 women can be eligible for DXA evaluation. 
A recent study provides data on the expected lumbar spine bone mineral density (BMD) in infant of 1 
year of age (mean ± SD): 0.312 ± 0.070 g/cm2 [87]. An older paper provided a similar Jitstimation: 0.446 
t:L",f;~ 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
± 0.048 g/cm2 [88], but we will prefer the newer one which derived from measurements with more 
recent DXA technology. 
Assuming a lumbar spine BMD mean (standard deviation) of 0.312 g/cm2 (0.070 g/cm2) in the control 
group, a sample size of 45 infants per arm would ensure a power of 80% to detect a 13.5% mean 
difference, Le. 0.042 g/cm2 between the tenofovir and placebo groups (two-sided test with a=0.05). 
Assuming 5% un-evaluable cases, 47 infants and their mothers in each arm should undergo DXA scan 
assessments, Le. a total of 94 mothers. 
The relationship between maternal tenofovir exposure and one-year postpartum/age BMD measures 
will be studied using analysis of variance models, taking into account characteristics such as the 
duration of lactation. 
7.4.11. Exploratory analyses 
Proportions of infants with seroprotection, Le., proportions of infants with anti-HBs > 10 IU/L, along with 
their 95% confidence intervals will be provided by treatment arm and compared between arms based 
on either normal approximation or the non parametric method as appropriate for the data. 
Proportions of premature labors (birth before 37 weeks of gestational age assessed by Ballard Score), 
associated or not with flares, along with their 95% confidence intervals, will be provided by treatment 
arm and compared between arms based on either exact method or normal approximation as 
appropriate for the data. 
Additional analyses include, but not are limited to, analysis on time to treatment discontinuation and/or 
study discontinuation and analysis on adherence. 
Details on these analyses will be further provided in the statistical analysis plan before their initiation. 
f) Special considerations 
The number, quality and frequency of blood collection, as well the tests to be performed on these 
samples, are specified in Tables 4 and 5. 
8. Ethical considerations 
8.1. 
Possible risks including preventive or alleviative measures 
8.1.1. Potential Risks to Participants 
We hypothesize that there will be a significant reduction in the risk of HBV transmission to the 
fetus/infant born to women who receive tenofovir disoproxil fumarate during the last trimester of 
pregnancy and for two months following delivery, and this outweighs the risk of administering tenofovir 
to pregnant women and their fetuses in a carefully monitored trial. 
• 
Maternal risks associated with the use of tenofovir disoproxil fumarate (TDF) during pregnancy: 
TDF is a nucleotide analogue which inhibits both HIV and HBV viral replication through inhibition of the 
virus reverse transcriptase. TDF is indicated for HIV treatment and HBV treatment, and is part of a 
WHO recommended drug combination to be started in HIV infected pregnant women after 14 weeks' 
gestation and continued through the breastfeeding period to prevent mother to child HIV transmission. 
In subjects with chronic hepatitis B who participated in controlled clinical trials Gilead 0102 and 0103, 
more subjects treated with tenofovir during the 48-week double-blind period experienced nausea (9% 
versus 3% with adefovir) [89]. Other treatment-emergent adverse reactions reported in >5% of subjects 
treated 
with 
tenofovir 
included: 
abdominal 
pain, 
diarrhea, 
headache, 
dizziness, 
fatigue, 
nasopharyngitis, back pain and skin rash. No significant change in the tolerability profile (nature or 
~~ 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
severity of adverse reactions) was observed in subjects continuing treatment with tenofovir for up to 
144 weeks in these studies. 
Flares have been also observed within the first 4-8 weeks of treatment, accompanied by decreases in 
HBV DNA levels. No subject had evidence of decompensation. AL T flares typically resolved within 4 to 
8 weeks without changes in therapy [Viread Package insert, Gilead, October 2010]. 
• 
Maternal risks associated with discontinuation of antiviral treatment after delivery 
During the course of HBV infection, acute exacerbations of liver damage or hepatic flares can occur 
spontaneously, be induced by IFN-a therapy or the discontinuation of treatment with nucleos(t)ide 
analogues. Flares are also observed during induced immune suppression, favoring viral replication. 
They are most often preceded by high levels of HBV replication and by progressive accumulation of 
HBV antigens. 
The three perinatal studies presented above have provided more information on the risk of 
exacerbation after discontinuation of antiviral treatment for the prevention of HBV perinatal 
transmission: 
In the study by van Zonneveld et al [62], AL T levels increased in seven of eight women who received 
lamivudine from 36 weeks' gestation to delivery, but remained below 5 times the upper limit of normal 
(ULN) in all women and below 2 ULN in five of eight women after a follow-up of 1 to 7 months. 
In the second study by Xu et al [57], two subjects in the placebo group experienced an increase in AL T: 
in one case, AL T reached 21 ULN, with no bilirubin increase, at six weeks postpartum, then decreased 
to 2 ULN at 12 weeks postpartum; in the second case, AL T increased to 16-18 ULN with bilirubin >2.5 
ULN at the end of study treatment and persisted until 6 weeks after delivery, then AL T decreased to 
baseline levels with bilirubin remaining elevated (1.8 ULN). During treatment and follow-up, Grade III/IV 
AL T elevations occurred in 22/89 (25%) and 30/61 (49%) of the mothers in the lamivudine and placebo 
groups, respectively. After treatment was discontinuation (week 4 postpartum) up to 12 weeks post-
partum (end of maternal follow-up), one or more Grade III/IV AL T elevations first occurred in 16/83 
(19%) mothers in the lamivudine group (3-5 ULN for 14 of the 16) and 15/46 (33%) mothers in the 
placebo group (3-5 ULN for 11 of the 15). One subject in each group had AL T levels increased to >10 
ULN following treatment cessation. This is difficult to interpret because the rate of loss to follow up was 
higher in women on placebo, and the follow up after discontinuation of lamivudine was limited to 12 
weeks post-partum, probably too short to adequately evaluate the risk of flare. 
In the third study by Han et al [56], 36 of 94 women discontinued telbivudine at 4 weeks postpartum as 
per protocol. AL T flares 2-5 times the upper limit of normal occurred in 13% of women who 
discontinued therapy in the treated arm and 18% in the control arm. No cases of severe hepatitis flares 
(AL T > 10 x ULN) were reported. In this study, the duration of follow up was probably too short to fully 
evaluate the risk of flare after treatment discontinuation and the reasons for treatment continuation in 
the majority of women were not reported. 
In the proposed study, we will follow the protocol used for registrational clinical trials for TDF (for the 
management of flares following discontinuation of antiviral treatment. Women will be informed of 
possible adverse effects following discontinuation of antiviral treatment without medical supervision or 
imperfect adherence. In case of liver enzyme elevation, additional visits and tests will be performed for 
case management and documentation. After delivery, women will be closely followed up until one year 
postpartum and any confirmed significant elevations of AL T will warrant consideration for prompt re-
introduction of antiviral therapy (see Section 7.2.2. Liver enzyme exacerbations) 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
• 
Infant risks associated with in utero exposure to tenofovir 
Tenofovir is classified in category B of the US FDA. The data collected in the Antiretroviral in 
Pregnancy Registry show that there have been no increase in birth defects in 981 women exposed 
during the first trimester and 584 women during the second and third trimester (105). However, the 
Pediatric HIV/AIDS Cohort Study "Surveillance Monitoring of Antiretroviral Toxicity" (SMARTT), which 
enrolls HIV-exposed uninfected children in the US, recently reported a marginal increase in the risk of 
low length and weight z-scores at one year of age. However confounders may explain this finding. In 
the proposed study, the growth of the infants will be evaluated and compared between treatment arms. 
Prior to study commencement, a literature review will be performed to consider with the DSMB whether 
there is a need for additional evaluations. 
• 
Possible mitochondrial toxicity following exposure to nucleoside analogues in utero 
Tenofovir is phosphorylated intracellularly to compounds which compete not only with the natural 
substrates for HBV reverse transcriptase but also with those for DNA polymerase gamma, the enzyme 
necessary for the replication of mitochondrial DNA. 
Possible mitochondrial toxicity in children exposed to nucleoside analogues has been reported. 
Researchers observed an increase in febrile seizures in children in utero exposed to nucleoside [90]. 
The nucleoside safety review of perinatally-exposed children in US studies has revealed no excess 
deaths before the age of 5 that might represent toxic effects on the mitochondria among more than 
20,000 infants assessed [91]. European and U.S. investigators have found small transient reductions in 
hemoglobin, and more persistent but clinically insignificant reductions in granulocytes, and lymphocytes 
associated with perinatal exposure to nucleoside reverse transcriptase inhibitors (NRTI). In 2007, 
Brogly and colleagues [74] conducted a retrospective review of the 1,037 HIV-uninfected children born 
in 1991-2002 and enrolled in Pediatric AIDS Clinical Trials Group protocols 219/219C and found 20 
cases of possible cases with unexplained signs of mitochondrial dysfunction. Their analysis suggested 
that first exposure to lamivudine or lamivudine/zidovudine in the third trimester may be associated with 
the occurrence of possible mitochondrial dysfunction. However, to our knowledge, no cases of 
mitochondrial toxicity in children exposed to tenofovir in utero have been reported to date. 
8.2. 
Adequacy of protection against risks 
8.2.1. Recruitment and informed consent (see Consent Form in Appendix 1) 
Nineteen clinical sites will participate in this study. All co-investigators have passed a training 
curriculum course on Human Subjects Protection. As for our previous studies, a specific training for the 
co-investigators, nurses and counselors will be conducted prior to the implementation of the study. 
Training will address the specific aspects of the study, the Good Clinical Practice (GCP) requirements, 
and procedures for protection of human subjects in clinical research, emphasizing issues related to 
vulnerable populations (pregnant women, fetus, newborns and children. 
All pregnant women are screened for HBV infection in Thailand. In this study, if HBsAg positive, they 
will receive counseling and comprehensive information about HBV infection, the risk of transmission to 
their infants and the details of the proposed study and, following consent, further testing (HBeAg) to 
assess their individual risk of transmission. They will be enrolled in the study if they meet the selection 
criteria. 
The consent form has been discussed, and reviewed with the PHPT CTU Community Advisory Board. 
At each site, a member of the study team will thoroughly discuss with each woman the information 
included in the consent. The consent form describes the purpose of the study, the procedures to be 
followed and the potential risks and benefits of participation. The consent document specifies the 
woman's freedom to withdraw her participation or the participation of her baby,;~~~ny time without 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
compromising access to future medical care. Written informed consent from the father will also be 
obtained if possible, for the participation of the infant. 
The consent form includes the names and contact details of the site co-investigator, whom the study 
participant may contact with any questions. A copy of the consent document will be given to the patient. 
In addition, study participants may contact personnel from the PHPT Clinical Trial Unit, 24 hours a day 
by phone. The original consent forms will be kept in a locked cabinet at the site. If new information 
relevant to the patient's consent or her willingness to continue participation in the trial becomes 
available, the participants and potential participants will be informed. Any changes to the consent 
document will be submitted to the relevant Ethics Committees. 
8.3. 
Protection against risk 
8.3.1. Institutional Review Board 
Prior to the initiation of the study, the protocol and patient consent documents will be reviewed and 
approved by a national ethics committee at the Thai Ministry of Public Health, the Ethics Committee at 
the Faculty of Associated Medical Sciences, Chiang Mai University, and at each local hospital site. 
Subsequent modifications will be submitted for approval before implementation. 
8.3.2. Expedited Adverse Experience Reporting 
All clinical adverse events and abnormal laboratory values will be recorded and graded. For severe 
toxicity and serious adverse events, as defined by ICH GCP [83], possibly related to study drugs, an 
Expedited Adverse Experience Report (EAE) will be sent to the Thai Ministry of Public Health, Ethics 
Committees, and program scientists, within three business days of awareness. If a subject dies, events 
prior to and at the time of death will be transcribed from hospital records, and possible cause(s) of 
death will be investigated. Management of toxicities and dose modifications for patients will be 
managed with experts' advice. 
8.3.3. Confidentiality 
Every effort will be made to maintain the confidentiality of the study participants. All site staff receive 
initial and ongoing training on Human Subjects Protection and confidentiality. To minimize this risk, 
study participants will not be identified by name on any study documents but will be identified by the 
provided patient identification number. All evaluation forms, laboratory specimens, reports and other 
records will be identified only by the patient identification number to maintain subject confidentiality. All 
records will be kept in a locked file cabinet in the clinical research unit. All computer entry and 
networking programs will be processed with patient identification number only. Clinical information will 
not be released without the written permission of the patient except when necessary for monitoring by 
the PHPT Clinical Trial Unit (CTU) or the sponsors. 
8.3.4. Biohazard Containment 
As the transmission of HBV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate precautions will be used by all personnel 
in the drawing of blood and shipping and handling of all specimens for this study, as currently 
recommended by the US Centers for Disease Control. All infectious specimens will be transported 
using requirements for shipping infectious substances. 
Compensation, medical care and other services to be provided to the subjects who 
any complication 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
When appropriate. mothers are reimbursed for transportation costs. 
Policy Regarding Research Related Injuries: 
Immediate necessary care is available free of charge to mothers and her infant in the case of medical 
problems related to participation in this study. However. the study is not responsible for treatments 
unrelated to the study and no financial compensation will be provided (see consent form Appendix 1). 
Other related ethical aspects 
The subject information sheet is written in Thai language. and physician or hospital's names. contact 
address and telephone number have been included. 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
9. 
1. 
2. 
3. 
4. 
5. 
6. 
7. 
8. 
9. 
10. 
11. 
12. 
13. 
14. 
15. 
16. 
17. 
18. 
19. 
20. 
21. 
22. 
23. 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Appendices 
Appendix 1: Informed Consent Form to Participate in iTAP Study (Thai Language) 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Appendix 1 (continued): Informed Consent Form to Participate in iTAP Study (English 
Language) 
Title of Study: A phase III, placebo controlled, double blind, randomized clinical trial to assess 
the efficacy and safety of tenofovir disoproxil fumarate given from 28 weeks' gestation until 2 
months postpartum to Hepatitis B (HB) virus chronically infected, HBsAg and HBeAg positive 
pregnant women to prevent perinatal transmission of HBV to their infants who receive HBV 
passive-active immunization(iTAP). 
Short title: Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand 
Purpose 
You, as well as your baby, are being invited to participate in a research study of tenofovir, which may 
help to prevent transmission of the hepatitis B virus (called HBV), from HBV-infected pregnant women 
to their babies. The purpose of this study is to determine if taking tenofovir, during the last trimester of 
pregnancy until two months after delivery can reduce the risk of HBV transmission to your baby, 
This form, along with discussions with your physician, will provide you detailed information about the 
study so that you can decide if you want to participate. 
Your participation in this research study would be entirely voluntary. You are free to decline to 
participate today or to withdraw from the study at any future date without jeopardizing your access to 
standard medical care or your possible participation in future research studies. 
This research study is collaboration between researchers and doctors and is supported by the Ministry 
of Public Health in Thailand, the National Institutes of Health (NIH) and the Centers for Disease Control 
and Prevention (CDC) in the USA. 
Nature of the Study 
People chronically infected with hepatitis B virus have small parts of the virus called hepatitis B surface 
antigens (HBsAg) in their blood that can be detected by a simple blood test, widely available in 
Thailand. An estimated 2 to 3 million adults in Thailand are chronically infected with the Hepatitis B 
virus (HBV). The inflammation caused by HBV can damage the liver cells and cause liver cirrhosis and 
cancer after a long time, usually in adulthood. 
You are pregnant and infected with HBV, and you are not infected with HIV (HIV and HBV are two 
different viruses). Currently, all infants born to mothers infected with HBV must receive HBV vaccine at 
birth, 1, 2, 4 and 6 months of age to protect against this infection. In addition, the Pediatric Society of 
Thailand recommends that they also receive specific immunoglobulin (antibodies against HBV) within 
the first hours after birth. 
However, pregnant women with high levels of HBV in the blood have a risk of about 10% to 12% of 
transmitting the virus to their baby, despite the use of the HBV vaccine and antibodies against HBV for 
prevention. Most adults with high levels of HBV in the blood also have another antigen that can be 
detected, called HB e antigen (HBeAg). In young people with HBsAg and HBeAg, the immune system 
has not reacted to HBV infection. If it does react, the level of a liver enzyme (called AL T, or most often 
SGPT in Thailand) in the blood is higher than normal. The amount of SGPT in the blood can be 
measured using a simple blood test, also widely available in Thailand. If the level of SGPT is normal, it 
means that the immune system is not reacting against HBV. In this study, only pregnant women with 
HBeAg detected in the blood and normal levels of SGPT (less than 30 U/L) will be asked to join the 
study. 
Tenofovir is an anti-HBV drug approved by the Thai Food and Drug Administration for the treatment of 
HBV. It is unknown if taking tenofovir during the last trimester of pregnancy until two months after 
delivery will help reduce the risk of HBV transmission to the baby. More than 1370 pregnant women 
have received tenofovir and there is no evidence that tenofovir causes harm 
fetus. Tenofovir 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
interferes with bone metabolism. However, among infants of women receiving combination ARV 
regimens during pregnancy, in utero exposure to tenofovir does not appear to have an effect on infant 
birth weight or infant growth. 
In this study, 328 HBV-infected pregnant women, at least 18 years old, will be enrolled over 2 years in 
19 public hospitals throughout Thailand: provincial/regional hospitals in Phayao hospital, Chiang Rai 
Prachanukroh Hospital, Prapokklao Hospital, Chonburi Hospital, Bhumibol Adulyadej Royal Air Force 
hospital in Bangkok, Health Promotion Center Region 10, Chiang Mai, Lamphun Hospital, Chiang 
Kham Hospital, Mae Chan Hospital, Banglamung hospital, Nakornping Hospital, Nopparat Rajathanee 
Hospital, Khon Kaen Hospital, Samutsakhon Hospital, Nakhonpathom Hospital, Samutprakarn Hospital, 
Lampang Hospital, Maharaja Nakornratchasrima Hospital and Ranong Hospital. 
Each mother will be assigned by chance to one of the following two equal groups: 
• 
Group 1 (tenofovir): Women will receive one tablet of tenofovir 300 mg to take once a day from 
28 weeks' gestation until two months after delivery. 
• 
Group 2 (placebo): Women will receive one tablet of inactive sUbstance to take once a day 
from 28 weeks' gestation until two months after delivery. 
All babies will receive HBV immunoglobulin and vaccine, which is recommended by the Royal College 
of Thai Pediatricians for babies whose mothers have HBV infection. Neither you nor your doctor will be 
able to choose or to know which group you will be in. 
Study Procedures for You. 
We will first propose to draw blood (5 cc or less than half a tablespoon) for a test to know if you have 
hepatitis B e antigen (HBeAg) in your blood and to measure the level of SGPT. These tests have to be 
done during pregnancy, early enough to know the results at the latest at 28 weeks of gestation. 
We will ask for your authorization to record laboratory test results performed as part of your routine 
clinical care before your consent to participate in this study. 
Only women with HBeAg, likely to have a high quantity of virus in their body and a high risk of 
transmission of HBV, will be asked to continue to participate in the study. However, if the level of SGPT 
is too high (more than 30 U/L), you will not be asked to participate further and we will recommend you 
to visit a specialist of HBV to advise you on further tests or treatment as necessary. 
If you have hepatitis B e antigen (HBeAg) and a level of SGPT equal or below 30 U/L, it will be 
proposed that you continue in the study. At 26 weeks of pregnancy, your medical history will be 
reviewed and you will undergo a physical examination and blood will be drawn for some more blood 
tests (about 16 cc or approximately a tablespoon) to see if you qualify for the study. 
If you qualify to continue in the study, you will be assigned by chance to one of the two groups at 28 
weeks of gestation and you will receive one bottle of study drug. You will have to take one tablet once a 
day, at the same time every day until two months after delivery. You will not know if you are taking 
tenofovir or placebo tablets. After enrollment, you will receive routine medical check-ups provided at the 
antenatal clinic as for any pregnant woman, and we will evaluate your health for any apparent side 
effects of the therapy, with a blood draw (33 to 38 cc or approximately two and a half tablespoons) at 
each visit. Study visits will occur at 28, 32, 36 weeks' gestation during pregnancy. A special blood 
draws (30 cc or approximately two tablespoons) for peripheral blood mononuclear cells (PBMC) may be 
collected at different visits. The PBMC will be stored for future studies to analyze the of immune 
response against HBV before the occurrence of flares. 
When you go into labor, you will go immediately to the maternity unit. When you arrive at the maternity 
unit, a blood draw will be performed for blood tests (about 10 cc or approximately a tablespoon). The 
blood tests are for: complete blood count (CBC), SGPT, creatinine level (to measure renal function), 
serum phosphorus (to measure bone metabolism), HBV DNA viral load, and tenof£,{l~evel to follow the 
effects of the treatment. 
" 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
After delivery, you will be asked to come for study visits at 1, 2, 3, 4, 6, and 12 months to follow the 
effects of the treatment. You will have a physical exam and a blood draw (about 38 to 43 cc or 
approximately three tablespoons) to follow the evolution of SGPT, serum phosphorus and creatinine, 
HBV DNA viral load, HBeAg and complete blood count. 
During or after the period of treatment, you should call right away your doctor or the nurse in charge 
of the study (see contact numbers at the end of this form) if you suffer from another condition, in 
particular if you get the following signs or symptoms of liver problems: 
• 
Your skin or the white part of your eyes turns yellow Uaundice). 
• 
Your urine turns dark. 
• 
Your stools turn light in color. 
• 
You don't feel like eating food for several days or longer. 
• 
You feel sick to your stomach (nausea). 
• 
You have lower stomach area (abdominal) pain. 
If your level of SGPT increases to 60 lUlL or more, you will be contacted and asked to return to the 
clinic, as soon as possible within 3 days, for another blood draw to confirm the SGPT elevation. If you 
notice any of the signs or symptoms listed above, you should return immediately to the clinic. If the 
increase is confirmed on the second blood draw, you will be asked to come again two weeks later for a 
new blood draw. If, at any time, your level of SGPT is over 150 lUlL, your physiCian will consider re-
introduction of the study treatment. You will then be followed in the study until one year after delivery. If 
you are started on treatment, after the end of your participation in the study, your treatment will be 
replaced with the commercial form of tenofovir or you will be told if you were receiving the inactive form 
of the study drug" and followed by your internist according to the current guidelines. It is not known for 
how long you will have to continue this treatment. 
Study Procedures for Your Baby. 
Your baby will receive HB immunoglobulin within 12 hours of birth, and HBV vaccine within 12 hours of 
birth and at 1, 2, 4 and 6 months of age. You will be asked to bring your baby 1, 2, 4, 6, 9 and 12 
months after birth for clinical safety evaluation and determination of HBV status. 
A blood sample from your baby (2 to 4 cc or no more than a teaspoon) will be taken at each visit to 
check for any side effects of the prophylaxis and to look for evidence of HBV infection. 
Breast-feeding: You can breast-feed your baby because the risk to transmit HBV to your baby is not 
increased by breast-feeding. 
Safeguards for Your Health. You and your baby will undergo careful check-ups throughout the study. It 
is very important that you keep all study appointments and take treatments as instructed. At each visit, 
you will be asked if you or your baby have suffered from any other condition, are taking any other 
medicines or have experienced any adverse events. If you need to, you may contact us or come to the 
clinic at any time, even if no visit is planned. 
Costs to You for Participation. There is no cost to you or your baby for the medication, extra clinic visits 
or laboratory tests associated with this study. All study participants will receive 300 baht (in all sites 
except Bangkok site where the amount will be 400 Baht) at each visit to compensate for transportation 
costs (if justified, the research team at site will compensate for higher transportation costs). The study 
will pay for the cost of the immunoglobulin (HBlg) for all participants' babies. 
Significant New Findings. Any significant new findings that develop during the study that could affect 
you, your baby, or your willingness to continue participation will be made available to you as soon as 
possible. 
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Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Withdrawal from the Study. Your physician could recommend that you withdraw from the study if any 
condition or severe adverse event developed that would make continued participation harmful to you or 
your baby. In such a case, you would be treated with the standard of care available. However, you 
should not interrupt your treatment without medical advice to avoid a sudden increase of the HBV virus 
in your liver without medical supervision. 
Alternatives to Participation. You are completely free to choose not to participate in or to withdraw 
yourself or/and your baby from this study at any time. Your alternative to participation in this study is the 
usual care available to a pregnant woman with HBV infection at your health care facility. 
Confidentiality. You and your baby's participation in this study will be kept confidential and will not be 
communicated to anyone without your written permission. 
Confidentiality of Records. Efforts will be made to keep you and your child's personal information 
confidential. Your medical records will be kept confidential. They will be disclosed to you, to those heath 
care providers directly involved in your care and, for study monitoring or auditing purposes, to the 
members of the research team, the Thai Food and Drug Administration (FDA), the Ethics committee of 
Institute for the Development of Human Research Protections, local Ethics Committee in your hospital, 
study staff, study monitors, drug companies supporting this study (drug company names) and study 
sponsors. All study forms will be coded by number and your name will not be recorded on these forms. 
Only these code numbers will be kept in the study database that will be used for analysis. Any 
publication of this study will not use your child's name or identify you child personally. However, we 
cannot guarantee absolute confidentiality and your personal information may be disclosed if required by 
law. 
Repository of Blood Specimens. Blood samples taken as part of the study, identified by code, will be 
kept for confirmation of results if needed until ten years after the end of the study. Blood samples will be 
stored at the IRD-PHPT Laboratory under Faculty of Associated Medical Sciences, Chiang Mai 
University, where only approved researchers and staff will have access to them. People who work at 
the facility will also have access to you and your baby's samples to keep track of them, but these 
people won't be able to directly identify your baby. Blood samples will not be sold or directly used to 
produce commercial products. You can withdraw you and your baby's blood samples from the sample 
repository at any time, and they will be immediately destroyed by autoclave following the standard 
procedure at the Faculty of Associated Medical Sciences, Chiang Mai University. 
Remaining bloods samples may also be stored for confirmation of any test done, or other evaluations 
that may help understand the mechanism of HBV perinatal transmission and liver damage. Also, tests 
might look at how a person's genetic makeup (your DNA and RNA) either protects them or puts them at 
greater risk of HBV transmission, viral flare or drug side effects (host genetics and pharmacogenomics). 
You may approve or refuse the use of DNA and total RNA tests by ticking the right box in the informed 
consent form that selects your choice of sample storage. If other studies were deemed necessary, we 
would request additional consent and this would be submitted to the Ethics Committee as a specific 
study. 
Policy Regarding Research Related Injuries. Immediate necessary care is available free of charge to 
you if you or your baby have a medical problem related to participation in this study. However, the study 
is not responsible for treatments unrelated to the study and no financial compensation will be provided. 
Risks to You / Your Child. 
If you are assigned to take inactive substance (but you will not know during the study if you take 
tenofovir or placebo), there will be no difference from the standard of care. 
Some people who have taken medicines like tenofovir have developed serious liver problems 
called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver ~tosis). 
Page 55 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
If you are assigned to take tenofovir, side effects can include: kidney damage or failure, bone thinning, 
gas, dizziness, feeling tired, low phosphate in the blood and allergic reaction, which may include fever, 
rash, upset stomach, vomiting, loose or watery stools, abdominal pain, achiness, shortness of breath or 
general feeling of illness. 
One of the main' possible risks of taking tenofovir is a reactivation of the hepatitis (inflammation or 
)rritation of the liver). You should be aware that your liver function tests may increase, and symptoms 
associated with hepatitis may worsen at some point during the study treatment or in the weeks or 
months after you stop tenofovir. This is the reason why we will ask you to come regularly at all study 
visits and inform your physician if you cannot come so another appointment can be scheduled. 
One of the potential risks associated with tenofovir during pregnancy is bone thinning in the newborn 
and slightly slower growth of infants. 
The risks and discomforts of blood drawing include pain, swelling, bruising, inflammation of a vein and 
fainting. If necessary, you and your infant will receive appropriate care from your physician. 
Benefits to YoulYour Child. During the study, you and your baby will be provided with close medical 
follow-up for safety. 
If you are assigned to take tenofovir you may have a decreased risk of HBV transmission to your baby. 
If you are assigned to receive placebo there is no direct benefit to your child but you and your child will 
benefit from the close follow-up and monitoring with the study. 
Further Questions. At any time, if you have further questions about this study or your rights and benefits 
as a participant, you may contact: 
• 
The Ethic committee of research in Human 
Institute for the Development of Human research Protections 
Building 8, Floor 7, room 702 Medical Sciences Department 
Ministry of Public Health 11000 Tel. 02-5913541, 02 -5913517 Fax. 02-5914125 
Or the your hospital's Ethics Committee 
______________ Telephone # ________ _ 
(Representative of your hospital's Ethics Committee) 
For questions about the research project, your rights, and research-related injuries, you may contact a 
doctor independent from the research team: 
Name: Dr. Sorakij Bhakeecheep 
Address: National Health Security Office (NHSO) 
The Government Complex Commemorating His Majesty the King's 80th Birthday Anniversary 
5th December, B.E. 2550 (2007) Building B 
120 M. 3 Chaengwattana Road, Lak Si District, Bangkok 10210 
Tel: +662141 4000Fax: +6621439730-1 
Page 56 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
The investigator responsible for safeguarding your welfare and the welfare of your baby, 
Dr. _________________ (Principal investigator name at each site) 
Address: _____________________________ _ 
Telephone # Office: _______ Home: _______ .Mobile: _____ _ 
Fax:# ______________________________ __ 
or ____________________ (name and title of Hospital Director) 
Consent to participate in this study 
By signing this form, you are stating that the purpose of this study, the procedures to be followed, and 
the risks, and benefits of participation have been fully explained to you. You know that you are still 
completely free to withdraw your participation or your baby's participation at any time without affecting 
your rights or those of your baby to receive the best medical care otherwise available. Refusing to 
participate or withdrawing will not involve any penalty or loss of benefits to which you may otherwise be 
entitled. 
I agree for my participation and my child's participation in this study. 
I agree that my laboratory test results performed for clinical care before my consent to participate in this 
study can be recorded in the study documents. 
Yes D 
No D. 
Woman's Name (typed or printed) 
Signature 
Date 
Woman's legal representative 
Signature 
Date 
IGuardian (if appropriate) 
"I agree for my child's participation in this study." 
Name of the Father of the child 
Signature 
Date 
(If available and with the woman's consent, typed or printed) 
Witness Name (typed or printed) 
Signature 
Date 
Witness Name (typed or printed) 
Signature 
Date 
Page 57 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
I have explained the purpose of this study to the patient. To the best of my knowledge, she understands 
the purpose, procedures, risks and benefits to her and her baby. 
Investigator/Counselor Name 
(Typed or printed) 
Signature 
Date 
Consent for blood storage: I will tick in the check box 
of my decision 
I give my permission for the storage and use of my stored specimens for future test(s) as discussed 
in this consent form. 
I give my permission for the storage and use of my stored specimens for future test(s) as discussed 
in this consent form, except for DNA (pharmacogenomics) testing. 
I do not permit to store my blood for future test(s). 
Participant's Name (typed or printed) 
Signature 
Date 
Witness Name (typed or printed) 
Signature 
Date 
I have explained the purpose of this cohort to the patient. To the best of my knowledge, the patient of 
the patient understands the purpose, procedures, risks and benefits to the patient. 
Physician/Counselor Name 
(Typed or printed) 
Signature 
Page 58 of 77 
Date 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Appendix 2: Exempted Congenital Anomaly/Birth Defect (Listed by Body Site) 
Abdomen/Groin/Pelvis 
Diastasis recti 
Hernia, inguinal or umbilical without mention of 
obstruction or gangrene 
Hip click, with no follow-up or therapy 
Umbilical artery, single 
Umbilical cord atrophy 
Urachus, patent 
ChestlThorax 
Breast hypertrophy 
Inverted nipples 
Nipples, anomalies of 
Rib, cervical 
Face/Mouth 
Brushfield Spots 
Duct, lacrimal, stenosis, stricture, or obstruction 
of 
Epicanthal folds 
Epstein's Pearls 
Esotropia 
Exotropia 
Gum cysts - includes epulis, ranula, mucocele 
Macrocheilia (large lips) 
Microcheilia (small lips) 
Nose, congenital deviation of septum of 
Nose, flat bridge of 
Nystagmus 
Palate, high-arched 
Palsy, facial 
Protruding tongue 
Sclera, blue 
Teeth, natal 
Tongue tie 
Page 2 of 4 
Foot/Toe 
Foot, rocker-bottom 
Tibia, torsion of 
Toes, long 
Toes, overlapping 
Toes, webbing 
Hand/Finger 
Clinodactyly of fifth finger 
Fingers, long 
Metatarsus varus or adductus 
Polydactyly, postaxial 
Simian crease 
Head/Neck 
Dolichocephaly 
Ear, malformations of external ear 
Ear, preauricular sinus, cyst, or pit of 
Fontanelle, large or small 
Occiput, flat or prominent 
Scaphocephaly, no mention of craniosynostosis 
Neck, webbing or redundant skin folds of 
Neck, short 
Skin 
Albinism 
Birthmark, NOS 
Dimple, sacral, pilonidal 
Lanugo, persistent or excessive 
Mongolian spots 
Neonatal acne 
Neoplasm, benign 
Nevus, flammaeus 
Skin tags on hands or feet 
Urogenital Rectal 
Anal fissure 
Anus, skin tags of 
Clitoromegaly, enlarged clitoris, hypertrophy 
Hydrocele 
Hymen, imperforate 
Phimosis 
Redundant foreskin 
Scrotum, hypoplastic due to cryptorchidism 
Page 3 of 4 
Testes, torsion of, or torsion of spermatic cord 
Testes, retractile 
Testicle, undescended (unilateral, bilateral or 
NOS) 
Vagina, embryonal cyst of 
Vagina, tag of 
Page 59 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Exempted Congenital Anomaly/Birth Defect 
(Listed Alphabetically) 
Albinism 
Anal fissure 
Anus, skin tags of 
Birthmark, NOS 
Breast hypertrophy 
Brushfield Spots 
Clinodactyly of fifth finger 
Clitoromegaly, enlarged clitoris, hypertrophy 
Diastasis recti 
Dimple, sacral, pilonidal 
Dolichocephaly 
Duct, lacrimal, stenosis, stricture, or obstruction 
of 
Ear, malformations of external ear 
Ear, preauricular sinus, cyst, or pit of 
Epicanthal folds 
Epstein's Pearls 
Esotropia 
Exotropia 
Fingers, long 
Fontanelle, large or small 
Foot, rocker-bottom 
Gum cysts - includes epulis, ranula, mucocele 
Hernia, inguinal or umbilical without mention of 
obstruction or gangrene 
Hip click, with no follow-up or therapy 
Hydrocele 
Hymen, imperforate 
Inverted nipples 
Lanugo, persistent or excessive 
Macrocheilia (large lips) 
Metatarsus varus or adductus 
Microcheilia (small lips) 
Mongolian spots 
Neck, short 
Neck, webbing or redundant skin folds of 
Neonatal acne 
Neoplasm, benign 
Nevus, flammaeus 
Nipples, anomalies of 
Nose, congenital deviation of septum of 
Nose, flat bridge of 
Nystagmus 
Occiput, flat or prominent 
Palate, high-arched 
Page 4 of 4 
Palsy, facial 
Phimosis 
Polydactyly, postaxial 
Protruding tongue 
Redundant foreskin 
Rib, cervical 
Scaphocephaly, no mention of craniosynostosis 
Sclera, blue 
Scrotum, hypoplastic due to cryptorchidism 
Simian crease 
Skin tags on hands or feet 
Teeth, natal 
Testes, retractile 
Testes, torsion of, or torsion of spermatic cord 
Testicle, undescended (unilateral, bilateral or 
NOS) 
Tibia, torsion of 
Toes, long 
Toes, overlapping 
Toes, webbing 
Tongue tie 
Umbilical artery, single 
Umbilical cord atrophy 
Urachus, patent 
Vagina, embryonal cyst of 
Vagina, tag of 
Page 60 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Appendix 3: Screening program for symptoms possibly associated with mitochondrial 
dysfunction in the EPF cohort (68) 
List of symptoms leading to the initial selection of the file (at least 1 major sign or 2 different minor signs 
at two different follow-up consultations)* 
NEUROLOGICAL SIGNS 
Major signs 
Non-febrile seizures, including neonatal seizures 
Febrile seizures, either repeated (~2 episodes) or in children aged < 6 months 
Peripheral neuropathy 
Acquired microcephaly 
Cranial nerves paresis 
Impaired cognitive development (for children older than 1 year) 
Cerebellar dysfunction and ataxia 
Motor disabilities, paraparesis, spasticity 
Abnormalities on MRI or CT scan 
Minor signs 
Febrile seizures 
Isolated changes in muscular tone, hyper-and hypotonia 
Behavorial disturbances and hyperactivity disorder 
Hypotonia, hypertonia 
Moderate cognitive delay 
OTHER ORGANS 
Major signs 
Pancreatitis (including biological signs) 
Cardiomyopathy 
Myopathy 
Decrease in visual acuity, retinopathy 
Abnormal ocular motor function 
Nystagmus 
Deafness 
Unexplained death 
Minor signs 
Increase in transaminase levels* 
Persistent anemia, neutropenia or thrombopenia 
Tubular defect 
• The abnormalities selected for this screening correspond to factors systematically tested as part of the French perinatal 
survey (EPF). The determinations of lactates, creatine phosphor kinase and lipase plasma level introduced during 1999 were 
not taken into account in this screening. 
Page 61 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Appendix 4: Cockcroft-Gault formula for women 
(140-age [in years]) x weight [in kg] xO.85 
(72 x creatinine [in mg/dL]) 
Calculation on line at: http://nephron.com/cgi-bin/CGSl.cgi 
Page 62 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Appendix 5: How to Measure Head Circumference, Length and Weight 
Growth is assessed at each visit by measuring the weight, height, and head circumference. 
(from PACTG 219) 
a) How to Measure Head Circumference 
The measuring tape is placed across the forehead with the lower border of the tape just above the 
eyebrows, around the head, above the ears and over the occipital prominence at the back of the head. 
Pull tape firmly to compress the hair and underlying soft tissues. Positioning of the tape over the 
forehead and occiput should be done to yield the maximum head circumference. Record head 
circumference in centimeters to the nearest 0.1 cm. 
b) How to Measure Length 
For children up to 24 months, measure supine on a standard measuring board. Keep child's legs 
straight and toes up, bringing movable footboard to rest firmly against child's heels. Measure height in 
centimeters to the nearest 0.1 cm. 
c) How to Measure Weight 
All weights should be obtained without shoes, diapers and clothing; whenever possible, the same 
scales should be used for these measurements. The scale should be set to zero each time. Measure 
weight to the nearest gram. 
Page 63 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Appendix 6: Additional Informed Consent Form to Participate in Tenofovir Plasma Level 
Measurements (Thai Language) 
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Page 64 of 77 


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Page 65 of 77 


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Page 66 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
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Page 67 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Appendix 6 (continued): Additional Informed Consent Form to Participate in Tenofovir Plasma 
Level Measurements (English Language) 
Purpose 
You and your infant are participating in the study "Maternal antiviral prophylaxis to prevent perinatal 
transmission of HBV in Thailand". One of the potential risks associated with tenofovir during pregnancy 
is bone thinning in the newborn and slightly slower growth of infants. This has been studied in infants 
born to mothers with other viral infections but not in infants born to mothers with hepatitis B chronic 
infection. 
The levels of tenofovir in the blood can vary from one person to another. It is possible that high 
tenofovir blood levels during the treatment are associated with lower bone mineral density. 
To help answer these two questions, we propose that you participate in an evaluation of tenofovir 
plasma levels during pregnancy. 
This form, along with discussions with your physician or nurse, will provide you detailed information 
about these additional assessments so that you can decide if you want to participate in this part of the 
research study. Your participation in this additional research assessment is entirely voluntary. You are 
free to decline participation today, or to change your decision at any future date without jeopardizing 
your participation in the study, your standard medical care or your possible participation in future 
research studies. 
Nature of the Study 
We will look for a relationship between the levels of tenofovir in the blood during pregnancy and bone 
mineral density in mothers and infants. The average concentration of tenofovir in the blood will be 
estimated based on the concentrations observed at different time points after taking the study 
treatment. 
Study Procedures for You 
You will be asked to take your study treatment every morning before the study visits at Week 32 and 36 
of your pregnancy. At these two visits, you will be asked to come to the hospital in the morning before 
you normally take your treatment. A blood sample (2 cc or half a teaspoon) will be taken before you 
take your study treatment. After the blood draw you will take your study treatment as normal. This will 
be approximately at the same time you take the treatment every morning. You will then have the 
regular blood draw between half an hour and three hours after you have taken the study treatment, and 
then another 2 cc blood draw taken at least 1 hour later. 
Duration of the subject's participation 
These two additional blood draws will be performed at the 32 weeks and 36 weeks' pregnancy visits. 
Costs to You for Participation 
There is no additional cost for your participation. There will be a compensation for your time that you 
need to stay in the hospital for the blood draws, in addition to the reimbursement of transportation costs 
planned for your participation in these study visits. 
Significant New Findings 
Any significant new findings that are developed during the study which could affect your willingness to 
continue participation will be made available to you as soon as possible. 
Withdrawal from the Study 
You are free to decide not to participate in this evaluation at any time without jeopardizing your 
standard medical care or your possible participation in future research studies. 
Page 68 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Confidentiality 
Your participation in this study will be kept confidential and will not be communicated to anyone without 
your written permission. 
Confidentiality of Records 
Efforts will be made to keep your personal information confidential. Your medical records will be kept 
confidential. They will be disclosed to you, to those heath care providers directly involved in your care 
and, for study monitoring or auditing purposes, to the members of the research team, the Thai Food 
and Drug Administration (FDA), the Ethics committee of Institute for the Development of Human 
Research Protections, local Ethics Committee in your hospital, study staff, study monitors, drug 
companies supporting this study (drug company names) and study sponsors. All study forms will be 
coded by number and your name will not be recorded on these forms. Only these code numbers will be 
kept in the study database that will be used for analysis. Any publication of this study will not use your 
name or identify your personally. However, we cannot guarantee absolute confidentiality and your 
personal information may be disclosed if required by law. 
Policy Regarding Research Related Injuries 
Immediate necessary care is available free of charge to you if you have a medical problem related to 
participation in this study. However, the study is not responsible for treatments unrelated to the study 
and no financial compensation will be provided. 
Risks to You 
The risks associated with the two additional blood draws are those associated with any blood draw. 
The risks and discomforts of blood drawing include pain, swelling, bruising, inflammation of a vein and 
fainting. If necessary, you will receive appropriate care from your physician. 
Benefits to You 
The objective of the study is to better assess and understand a possible relationship between tenofovir 
and bone mineral density but you will not directly benefit from the results of the study because the 
results will be known only at the end of the study. 
Further Questions At any time, if you have further questions about this study or your rights and benefits 
as a participant, you may contact: 
• 
The Ethic committee of research in Human 
Institute for the Development of Human research Protections 
Building 8, Floor 7, room 702 Medical Sciences Department 
Ministry of Public Health 11000 Tel. 02-5913541,02 -5913517 Fax. 02-5914125 
Or the your hospital's Ethics Committee 
______________ Telephone # ________ _ 
(Representative of your hospital's Ethics Committee) 
For questions about the research project, your rights, and research-related injuries, you may contact a 
doctor independent from the research team: 
Name: Dr. Sorakij Bhakeecheep 
Address: National Health Security Office (NHSO) 
The Government Complex Commemorating His Majesty the King's 80th Birthday Anniversary 
5th December, B.E. 2550 (2007) Building B 
120 M. 3 Chaengwattana Road, Lak Si District, Bangkok 10210 
Tel: +662141 4000 Fax: +6621439730-1 
Page 69 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
The investigator responsible for safeguarding your welfare and the welfare of your baby, 
Dr. 
[Principal investigator name at each site] 
Address: ________________________________________________________ __ 
Telephone # Office: 
Home: 
Mobile: ______ _ 
Fax:# __________________________________________________________ __ 
or _____________________________________ (name and title of Hospital Director) 
Consent to participate in this study 
By signing this form, you are stating that the purpose of this study, the procedures to be followed, and 
the risks, and benefits of participation have been fully explained to you. You know that you are still 
completely free to withdraw your participation at any time without affecting your rights to receive the 
best medical care otherwise available. Refusing to participate or withdrawing will not involve any 
penalty or loss of benefits to which you may otherwise be entitled. 
I agree for my participation in this study. 
Woman's Name (typed or printed) 
Signature 
Date 
Woman's legal representative 
Signature 
Date 
/Guardian (if appropriate) 
Witness Name (typed or printed) 
Signature 
Date 
Witness Name (typed or printed) 
Signature 
Date 
I have explained the purpose of this study to the participant. To the best of my knowledge, she 
understands the purpose, procedures, risks and benefits to her. 
Investigator/Counselor Name 
(Typed or printed) 
Signature 
Page 70 of 77 
Date 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand. version 3.0 dated 20 April 2015 
Appendix 7: Additional Informed Consent Form to Participate in DXA Scan Assessments (Thai 
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Page 73 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
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Page 74 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Appendix 7 (continued): Additional Informed Consent Form to Participate in DXA Scan 
Assessments (English Language) 
Purpose 
You and your infant are participating in the study "Maternal antiviral prophylaxis to prevent perinatal 
transmission of HBV in Thailand". One of the potential risks associated with tenofovir during pregnancy 
is bone thinning in the newborn and slightly slower growth of infants. This has been studied in infants 
born to mothers with other viral infections but not in infants born to mothers with hepatitis B chronic 
infection. 
The levels of tenofovir in the blood can vary from one person to another. It is also unclear whether a 
lower bone mineral density could be related to high tenofovir levels in the blood during treatment. 
To help clarify these two questions, we propose that you and your infant participate in an evaluation of 
bone mineral density one year after delivery, when your infant will be one year of age. 
This form, along with discussions with your physician or nurse, will provide you detailed information 
about this additional assessment so that you can decide if you want to participate in this research. 
Your participation in this additional research assessment is entirely voluntary. You are free to decline 
participation today or to change your decision at any future date without jeopardizing your participation 
in the study, your standard medical care or your possible participation in future research studies. 
Nature of the DXA scan study 
We will measure calcium and other minerals in your and your infant's bone. This measure is called 
bone mineral density. It is done using a machine called a "Dual-energy X-ray absorptiometry" or "DXA" 
scan. The measures will be performed in the mothers one year after delivery and infants at one year of 
age. We will compare these measures between the two study groups (Le. those subjects receiving 
tenofovir and those subjects receiving tenofovir-placebo). We will also look for a relationship between 
the level of tenofovir during pregnancy and the bone mineral density in mothers and infants. 
Study Procedures for You 
Sometime before one year after delivery, the study team will contact you to organize with you an 
appointment to go with you and your infant to a facility where DXA scan can be performed). Depending 
on where you stay, you will have to spend some time to go there. A research assistant or a study nurse 
that you already know will accompany you to this facility. In case you learn that you cannot be available 
for the appointment, you can contact the study team to find another date. 
DXA uses X-rays to measure calcium and other bone minerals in a given area of bone (hip, spine, 
wrist, heel, or finger). For this assessment, there are no additional blood draws, no treatment and no 
injection. The technique is non-invasive, painless, and takes a few minutes. Radiation exposure is low 
« 5 mrem), Le. less than that of a plain radiograph of the chest. You will need to remain still during the 
test so there may be some minor discomfort from lying in the same position for 5 to 10 minutes, 
Duration of the subject's participation 
For the DXA scan measurements, there will be only one visit for you and your infant at the same time. 
Costs to You for Participation 
There are no additional costs for your participation, There will be a compensation for your time and 
reimbursement of your transportation costs. 
Significant New Findings 
Any significant new findings that are developed during the study which could affect y~~illingness to 
continue participation will be made available to you as soon as possible. 
..~ 
Page 75 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
Withdrawal from the Study 
You are free to decide not to participate in this evaluation at any time without jeopardizing your 
standard medical care or your possible participation in future research stUdies. 
Confidentiality 
You and your baby's participation in this study will be kept confidential and will not be communicated to 
anyone without your written permission. 
Confidentiality of Records 
Efforts will be made to keep you and your child's personal information confidential. Your medical 
records will be kept confidential. They will be disclosed to you, to those heath care providers directly 
involved in your care and, for study monitoring or auditing purposes, to the members of the research 
team, the Thai Food and Drug Administration (FDA), the Ethics committee of Institute for the 
Development of Human Research Protections, local Ethics Committee in your hospital, study staff, 
study monitors, drug companies supporting this study (drug company names) and study sponsors. All 
study forms will be coded by number and your name will not be recorded on these forms. Only these 
code numbers will be kept in the study database that will be used for analysis. Any publication of this 
study will not use your child's name or identify your child personally. However, we cannot guarantee 
absolute confidentiality and your personal information may be disclosed if required by law. 
Policy Regarding Research Related Injuries 
You will be receiving care according to national and international guidelines. 
Risks to You 
The risks associated to a DXA scan measurement are similar to those of a chest X-Ray. The radiations 
received from a DXA scan are lower than for a chest X-Ray. 
Benefits to You 
You will not benefit directly from the results of the study because you will have already taken the study 
treatment when bone mineral density will be measured in you and your child. 
Further Questions: At any time, if you have further questions about this study or your rights and benefits 
as a participant, you may contact: 
• 
The Ethic committee of research in Human 
Institute for the Development of Human research Protections 
Building 8, Floor 7, room 702 Medical Sciences Department 
Ministry of Public Health 11000 Tel. 02-5913541, 02 -5913517 Fax. 02-5914125 
Or the your hospital's Ethics Committee 
______________ Telephone # ________ _ 
(Representative of your hospital's Ethics Committee) 
For questions about the research project, your rights, and research-related injuries, you may contact a 
doctor independent from the research team: 
Name: Dr. Sorakij Bhakeecheep 
Address: National Health Security Office (NHSO) 
The Government Complex Commemorating His Majesty the King's 80th Birthday Anniversary 
5th December, B.E. 2550 (2007) Building B 
120 M. 3 Chaengwattana Road, Lak Si District, Bangkok 10210 
Tel: +662141 4000 Fax: +6621439730-1 
Page 76 of 77 


Maternal antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand, version 3.0 dated 20 April 2015 
The investigator responsible for safeguarding your welfare and the welfare of your baby, 
Dr. 
[Principal investigator name at each site] 
Address: ________________________________________________________ __ 
Telephone # Office: 
Home: 
Mobile: _____ __ 
Fax:# __________________________________________________________ ~ 
or _____________________________________ (name and title of Hospital Director) 
Consent to participate in this study 
By signing this form, you are stating that the purpose of this study, the procedures to be followed, and 
the risks, and benefits of participation have been fully explained to you. You know that you are still 
completely free to withdraw your participation or your baby's participation at any time without affecting 
your rights or those of your baby to receive the best medical care otherwise available. Refusing to 
participate or withdrawing will not involve any penalty or loss of benefits to which you may otherwise be 
entitled. 
I agree for my participation and my child's participation in this study. 
Woman's Name (typed or printed) 
Signature 
Date 
Woman's legal representative 
Signature 
Date 
/Guardian (if appropriate) 
"I agree for my child's participation in this study." 
Name of the Father of the child 
Signature 
Date 
(If available and with the woman's 
consent, typed or printed) 
Witness Name (typed or printed) 
Signature 
Date 
Witness Name (typed or printed) 
Signature 
Date 
I have explained the purpose of this study to the patient. To the best of my knowledge, she understands 
the purpose, procedures, risks and benefits to her and her baby. 
Investigator/Counselor Name 
(Typed or printed) 
Signature 
Page 77 of 77 
Date 

SAP_001.pdf: 
Official title: Statistical analysis plan 
NCT number: NCT01745822 
Document date: May 19, 2016 
 


Filename: W:\iTAP\documents\analysis_plan\iTAP_analysis_plan_V3.0 
Path: W maps to /home/phpt 
Printed on: May 19, 2016 
 
 
 
iTAP 
A phase III, placebo controlled, double blind, randomized clinical trial to assess the efficacy and safety 
of tenofovir disoproxil fumarate given from 28 weeks' gestation until 2 months postpartum to Hepatitis 
B (HB) virus chronically infected, HBsAg and HBeAg positive pregnant women to prevent perinatal 
transmission of HBV to their infants who receive passive-active HBV immunization 
Analysis Plan Version 3.0  
Linda Harrison 
May 19th, 2016 
 
CONTENTS 
1. 
Introduction .............................................................................................................................. 2 
1.1 
Purpose ................................................................................................................................... 2 
1.2 
Analysis Reports ..................................................................................................................... 2 
1.3 
Design ..................................................................................................................................... 2 
1.3.1 
Overview of the Randomized Trial Design .............................................................................. 2 
1.3.2 
Sample Size ............................................................................................................................ 2 
1.3.3 
Population ............................................................................................................................... 2 
1.3.4 
Randomization and Stratification ............................................................................................ 2 
1.4 
Study Objectives and Endpoints ............................................................................................. 3 
1.4.1 
Primary Objective .................................................................................................................... 3 
1.4.2 
Secondary Objectives ............................................................................................................. 3 
1.4.3 
Primary Endpoint ..................................................................................................................... 3 
1.4.4 
Secondary Endpoints .............................................................................................................. 3 
1.5 
Maternal Follow-up .................................................................................................................. 3 
1.6 
Infant Follow-up ....................................................................................................................... 4 
2. 
Analysis Principles .................................................................................................................. 5 
3. 
Pregnant Women/Mothers ....................................................................................................... 7 
3.1 
Accrual and Eligibility Violations .............................................................................................. 7 
3.2 
Baseline Characteristics .......................................................................................................... 7 
3.3 
Study Status ............................................................................................................................ 8 
3.4 
Compliance to Follow-up ......................................................................................................... 8 
3.5 
Delivery Characteristics .......................................................................................................... 8 
3.6 
Study Treatment Summaries .................................................................................................. 8 
3.7 
Safety Analysis ........................................................................................................................ 8 
3.7.1 
ALT and Severe Hepatic Disease Exacerbations or Flare ..................................................... 8 
3.7.2 
Adverse Events ....................................................................................................................... 9 
3.7.3 
Hematology and Biochemistry at Scheduled Visits ................................................................. 9 
4. 
Children ..................................................................................................................................... 9 
4.1 
Delivery Characteristics .......................................................................................................... 9 
4.2 
Study Status ............................................................................................................................ 9 
4.3 
Compliance to Follow-up ....................................................................................................... 10 
4.4 
HBV Vaccine and HB Immunoglobulin (HBIg) ...................................................................... 10 
4.5 
Safety Analysis ...................................................................................................................... 10 
4.5.1 
Growth ................................................................................................................................... 10 
4.5.2 
Assessment of Mitochondrial Dysfunction at 6 and 12 months ............................................ 10 
4.5.3 
Adverse Events ..................................................................................................................... 10 
4.5.4 
Hematology and Biochemistry at Scheduled Visits ............................................................... 10 
4.6 
HBV infection ......................................................................................................................... 10 
4.6.1 
HBV Infection Status ............................................................................................................. 10 


    iTAP Analysis Plan Version 3.0 
May 19th, 2016 
 
 
 
Page 2 of 11 
1. Introduction 
1.1 Purpose 
This document describes the planned statistical analysis for the primary final 6-month report and supplemental 12-month 
report of the iTAP trial.  Previous analysis plan documents have described the statistical analysis for the closed reports of 
the interim safety and efficacy reviews of the iTAP trial by the Data and Safety Monitoring Board (DSMB).  
1.2 Analysis Reports 
The primary analysis reports will be distributed to study team members, including the program scientists.  Data summaries 
will be presented by randomized arms (i.e. tenofovir and placebo). 
1.3 Design 
iTAP is a multicenter, controlled, double blind, randomized clinical trial to assess the efficacy to prevent HBV perinatal 
transmission, safety and tolerance of tenofovir disoproxil fumarate (TDF) versus placebo, given from 28 weeks’ gestation 
until 2 months post-partum to hepatitis B sAg and eAg positive mothers. 
1.3.1 Overview of the Randomized Trial Design 
 
 
 
 
 
 
 
 
 
 
 
1.3.2 Sample Size 
A total of 328 pregnant women will be enrolled. 
1.3.3 Population 
Consenting pregnant women ≥18 years of 28 weeks (+/- 10 days) gestational age with negative HIV serology, and 
positive HBsAg and HBeAg tests within 6 months of enrollment.  Additionally women must have ALT ≤30 U/L within 3 
months of enrollment and confirmed ≤60 U/L at the pre-entry visit. 
Exclusion criteria include women with a history of TDF or any other anti-HBV treatment during the current pregnancy, 
Cockcroft-Gault creatinine clearance <50 ml/min, confirmed dipstick proteinuria >1+ (>30 mg/dL) or normoglycemia 
glucosuria, positive serology for hepatitis C within 12 months prior to enrollment, pre-existing fetal anomalies incompatible 
with life, any concomitant condition or treatment that would contraindicate participation or concurrent participation in any 
other clinical trial without written agreement from the two study teams. 
All infants born to mothers participating in the study will be included.  Stillbirths will be excluded. 
1.3.4 Randomization and Stratification 
Pregnant women will be randomized 1:1 to receive TDF or placebo stratified by site using permuted blocks.   


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1.4 Study Objectives and Endpoints 
1.4.1 Primary Objective 
To assess the efficacy of TDF, versus placebo, in HBV infected HBsAg and HBeAg positive pregnant women, from 28 
weeks’ gestation until 2 months postpartum (5- month course) to prevent perinatal transmission of HBV to their infants 
who receive HBV passive-active immunization. 
Hypothesis: an anti-HBV agent, TDF administered from the beginning of the last trimester of pregnancy to two months 
postpartum to HBV infected, HBeAg-positive, pregnant women with ALT ≤30 U/L will reduce the risk of in utero, 
intrapartum and early postpartum transmission of their infants from 12% to 3% or less. 
1.4.2 Secondary Objectives 
 
To assess the safety of TDF administered for 5 months perinatally in HBsAg and HBeAg positive women with ALT 
≤30 U/L, and their in utero exposed infants. 
 
To compare the risk of acute exacerbation or flare (ALT >300 U/L) up to 12 months postpartum, following planned 
discontinuation of study treatment, in HBeAg positive women randomized to TDF or placebo. 
1.4.3 Primary Endpoint 
Infant’s HBV infection status, defined as HBsAg positive confirmed by HBV DNA, at 6 months of age.   
1.4.4 Secondary Endpoints 
 
Occurrence of maternal and infant adverse events (AE), including International Conference on Harmonisation 
(ICH) Serious Adverse Events (SAEs) and Division of AIDS (DAIDS) grade 3/4 signs and symptoms, regardless 
of their relatedness to the study treatment. 
 
Occurrence of acute exacerbation or flare of hepatitis B, following planned discontinuation of study treatment up 
to 12 months postpartum.  The acute exacerbation of flare of hepatitis B is defined as ALT >300 U/L regardless of 
baseline values. 
 
Infant’s HBV infection status, defined as HBsAg positive confirmed by HBV DNA, at or after 6 months through 12 
months of age. 
 
Infant growth related outcomes, including Z-scores of weight, height and head circumference (HC) at 6 and 12 
months of age. 
1.5 Maternal Follow-up 
Eligibility and pre-enrolment tests should be performed within 3 months prior to enrollment.  After enrollment, maternal 
visits will be performed at 28, 32, 36 weeks’ gestation, delivery, and at 1, 2, 3, 4, 6 and 12 months postpartum.  All effort is 
made to strictly follow the visit schedule but occasional departures of no more than one week will be considered 
acceptable.  
 
 


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Maternal assessments 
Antepartum 
Delivery 
Postpartum (months) 
 
Scr
een
ing 
Pre-
entry 
Enroll
ment 
28 wks 
32 
wks
36 
wks
 
Before 
discharge 
1 
21 
3 
4 
6
122
 
 
 
Study Treatment 
 
 
 
 
Counseling and Questionnaire 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X
X 
Physical/Obstetric exam 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X
X 
Study treatment dispensation, 
return of used study treatment 
bottles/adherence assessment 
 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
Record results of HBsAg, HIV 
serology and Ultra sound 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SGPT/ALT  
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X
X 
HBeAg test 
(if negative during postpartum 
period, anti-HBeAb will be tested) 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Complete Blood Count3 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Serum SGOT/AST, bilirubin 
(direct& conjugated), alkaline 
phosphatases, and albumin 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Hepatitis C serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum creatinine4 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X5 
 
 
Serum phosphorus 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
 
Dipstick glycosuria and proteinuria 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Urine sample collection8 
 
 
X 
X 
 
 
 
 
X 
 
 
 
X 
HBV DNA load (retrospective) 
 
 
X 
 
 
X6
 
X6 
 
 
 
 
 
Tenofovir plasma level 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Plasma/serum storage 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
RNA storage 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
PBMC isolation7 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
Total blood volume (mL) 
5 
16 
3 
8 
8 
10 
4 
8 
13 
8 
8 
8
10
Total blood volume for PBMC (mL)7 
 
 
30 
30 
30 
 
 
30 30 
30
30
 
 
Cord blood volume (mL) 
 
 
 
 
 
15
 
 
 
 
 
 
 
1 Or early study treatment discontinuation 
2 Or early study discontinuation (if subject consents)
 
3 Including platelet count
 
4 Calculate creatinine clearance using the Cockcroft-Gault formula.  Online calculation at http://nephron.com/cgi-bin/CGSI.cgi). 
5 In case of Grade 1 or higher creatinine at 2 months postpartum 
6 Funding will be sought to retrospectively measure HBV DNA load. 
7 For women enrolled in sites with PBMC isolation capacity (flares sub-studies). 
8 If possible, 10 ml will be collected.  After centrifugation, 10 aliquots will be stored frozen 
If ALT is >60 U/L it will be repeated within 3 days.  If ALT is confirmed between 60 and 150 U/L, a new ALT test will be 
scheduled 2 weeks later.  If ALT >150 U/L is confirmed immediately or if ALT is confirmed between 60 and 150 U/L 2 
weeks later, the site will contact PHPT and re-introduction of double blind study treatment will be considered.  
1.6 Infant Follow-up 
Infant visits will be performed at birth, 1, 2, 4, 6, 9 and 12 months.  
 


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Infant assessments 
Birth
1 
month
2 
months
4 
months 
6 
months 
9 
months
12 
months1 
Physical examination including length, weight and 
head circumference2 
X 
X 
X 
X 
X 
X 
X 
Mitochondrial dysfunction check list3 
 
 
 
 
X 
 
X 
Counseling and Questionnaire 
X 
X 
X 
X 
X 
X 
X 
Record date and time of HB Immune globulin (HBIg) 
injection4 
X 
 
 
 
 
 
 
Record date and time of HB immunization 
X 
X 
X 
X 
X 
 
 
Complete Blood Count  
X 
 
 
 
 
 
X 
Serum creatinine 
X 
 
 
 
 
 
 
Serum phosphorus/calcium 
X 
 
 
 
 
 
 
HBsAg1,5 
X 
X5 
X5 
X5 
X5 
X 
X 
HBV DNA1 
X 
 
 
 
X6 
X 
X6 
SGPT/ALT 
X 
 
 
 
 
 
X6 
Anti-HBsAb 
 
 
X 
X 
X 
X 
X7 
HBeAg and anti-HBeAb if positive HBsAg 
 
 
 
 
 
 
X  
Plasma storage 
X5
X5 
X5 
X5 
X5 
X5 
X 
Total blood volume (mL) 
3 
3 
2 
2 
3 
3 
4 
Additional investigations if HBsAg+ (except at birth): retrospective HBV DNA loads, HBeAg 
1Or early discontinuation, with mother’s/guardian’s/parents’ consent. 
2Including Ballard Score at birth. 
3Assessment for possible mitochondrial dysfunction: see list of major and minor neurological and other organ signs in Appendix 3. 
4InjectHBIg at a site different from HBV vaccine. 
5Draw blood before injection of HBIg and vaccine. 
6 If HBsAg positive at this time point 
7 If anti-HBs < 10 IU/L (and HBsAg/HBV DNA negative), the pediatrician in charge will be encourage to consider revaccination. 
A check list of signs and conditions suggesting possible mitochondrial dysfunction that may trigger other investigations will 
be completed at the 6 and 12 month visit. 
2. Analysis Principles 
Throughout this document, unless otherwise noted, analyses will be performed and results presented by randomized arm.  
Women (and their infants) randomized and later found ineligible as indicated on the ‘Protocol Deviation for mother’ case 
report form (CRF) will be included or excluded from all analyses at the discretion of the study chair without reference to 
the data prior to freezing the database for the 6-month report.  All included participants will be analyzed as randomized 
(i.e. intention-to-treat analyses).  Analysis will not be stratified by site. 
The following abbreviations and visit week windows will be used:  
Maternal visits:  
SC: screening  
≤3 months prior to date of enrollment and prior to pre-entry 
PE: pre-entry  
≤3 months prior to date of enrollment, after screening and prior to the M1 visit 
M1: 28 weeks gestation 
≤3 months prior to date of enrollment to 1 day after (28 weeks gestation +/- 10 days) 
M2: 32 weeks gestation  
estimated 32 weeks gestation +/-14 days 
M3: 36 weeks gestation  
estimated 36 weeks gestation +/-14 days 
LD: Labor and delivery  
date of delivery, -5/+14 days 
MPP1: 1 month post-partum  
date of delivery + 1 month, +/-15 days 
MPP2: 2 months post-partum 
date of delivery + 2 months, +/-15 days 
MPP3: 3 months post-partum 
date of delivery + 3 months, +/-15 days 
MPP4: 4 months post-partum 
date of delivery + 4 months, -15/+30 days 
MPP6: 6 months post-partum 
date of delivery + 6 months, -30/+45 days 
MPP12: 12 months post-partum 
date of delivery + 12 months, +/-45 days 


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Infant visits:  
C0: date of birth  
date of birth, -0/+5 days 
C1: 1 month of age  
date of birth + 1 month, +/-15 days 
C2: 2 months of age  
date of birth + 2 months, -15/+30 days 
C4: 4 months of age  
date of birth + 4 months, +/-30 days 
C6: 6 months of age  
date of birth + 6 months, -30/+45 days 
C9: 9 months of age  
date of birth + 9 months, +/-45 days 
C12: 12 months of age  
date of birth + 12 months, +/-45 days 
In the event of multiple evaluations in one visit window, prior to enrollment the evaluation closest to enrollment will be 
used, and after enrollment the evaluation closest in absolute value to the target visit time will be used.  If two evaluations 
are equidistant from the target visit time, the earlier evaluation will be used. 
The date of enrollment will be taken from the enrollment date on the ‘Declaration of New Enrollment’ CRF.  This CRF is 
completed at the M1 visit when the next available Study Identifier (BMxxxx) at site is assigned.  The assigning of this 
identifier indicates randomization.   
The date of delivery and date of birth will be taken from the delivered date on the ‘Declaration of Delivery/Birth’ CRF. 
Premature study discontinuation will be categorized as death, loss to follow-up or withdrawn consent from the ‘End of 
Study for Woman’ and the ‘End of Study for Child’ CRFs.   
For study visit compliance, the target number of women/infants at each scheduled visit will be calculated as the number of 
women/infants on-study that have passed the expected visit date given above by 7 days before 4 months post-partum/of 
age and by 14 days thereafter.  For women, the LD visit will be expected if 40 weeks gestation has passed by 7 days 
before the woman discontinues the study.  Woman delivering prior to 37 weeks will not be expected to have a 36 weeks 
gestational age (M3) visit. 
Premature study treatment discontinuation will be defined as discontinuing study treatment >7 days before 60 days post-
partum or discontinuing the study >7 days prior to 60 days post-partum if treatment discontinuation date is unknown.  The 
analysis of severe hepatic disease exacerbation or flare defined as SGPT/ALT >300 U/L from study treatment 
discontinuation will only include women with an SGPT/ALT measurement after study treatment discontinuation.  
With the exception of ALT/SGPT, where graded categories for event severity are specified they will be calculated as 
normal, grade 1, grade 2, grade 3 and grade 4 according to the DAIDS table for grading the severity of adult and pediatric 
adverse events, version 1.0, December 2004, clarification August 2009.  ALT/SGPT will be categorized as >60 to ≤150, 
>150 to ≤300, and >300 U/L, and >150 to ≤300 U/L will be considered grade 3 and >300 U/L grade 4.  Adverse event 
(AE) analyses will include ICH SAEs and Grade 3/4 adverse events. 
The secondary endpoints of occurrence of AEs and severe hepatic disease exacerbation or flare will employ the analysis 
method specified in the protocol based on the exact binomial distribution and Fisher’s exact test as well as sensitivity 
analysis of time to first occurrence using Kaplan-Meier methods and the log-rank test.  For the AE endpoint, time will start 
at enrollment for women and birth for infants and for women/infants event time will be at their first AE occurrence or 
censored at their last study visit if no AE occurs.  For the severe hepatic disease exacerbation or flare endpoint, time will 
start at study treatment discontinuation date and event time will be at first flare occurrence or censored at the last 
SGPT/ALT measurement if no flare occurs. 
Version 1 of the C0 visit CRF only required a Ballard score for infants born <37 weeks gestational age based on the best 
estimate by site clinician or weighing <2500 grams.  Therefore, the analysis of premature birth (<37 weeks gestational 
age) by Ballard score will assume infants ≥37 weeks gestational age based on the best estimate by site clinician and 
weighing ≥2500 grams completing CRF version 1 are not <37 weeks gestational age by Ballard score.   
Z-scores-for-age will be calculated according to WHO standards. 
At the 6-month analysis, HBsAg will be tested on infants at 6 months of age, and if positive confirmed by a HBV DNA test.  
Infants who discontinue the study before 6 months of age will be tested for HBsAg at their last available sample, and if 


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positive confirmed by a HBV DNA test.  At the 12-month analysis, HBsAg will be tested on infants at 9 and 12 months of 
age in addition, and if positive at 12 months confirmed by a HBV DNA test at 12 months.  All infants will be routinely 
tested for HBV DNA at 9 months of age. 
Due to the trial’s group sequential design, the primary endpoint will be considered significant if the one-sided p-value is 
<0.049.  The primary analysis will be conducted as a complete case analysis excluding infants without a 6 month endpoint 
and including infants whose 6 month endpoint is available in their original randomized group, regardless of the duration of 
study treatment the mother actually received if at least one dose was taken.  The visit window for the infants’ 6 month 
HBsAg and HBV DNA measurements will be extended to ≥30 days prior to 6 months to 90 days after (i.e. at <9 months).  
HBV positive at 6 months of age will be defined as a positive HBsAg test confirmed by detectable HBV DNA.  Infants with 
a negative HBsAg test or positive HBsAg test but undetectable HBV DNA will be considered as HBV negative. HBV DNA 
detectable will be defined as a quantifiable HBV DNA level above the limit of detection of the assay or a detected but un-
quantifiable HBV DNA level below than the limit of detection.  The limit of detection will be calculated as the standard 
detection limit of the assay (e.g. 15 IU/mL) multiplied by the dilution factor.  The HBV DNA test may be missing due to, for 
example, insufficient sample volume, test failure or an error (concomitant HBV antibodies).  If the HBV DNA test is 
missing for any reason other than an error, an infant will be considered HBV positive if the HBsAg test is positive.  The 
primary complete case analysis will be independently programmed by another statistician to verify the result using the 
HBsAg results dataset (wshep), HBV DNA dataset (hepvl), and the dataset containing enrollment and delivery/birth date 
(itap_enrolled).   
As stated in the protocol, transmission to one or more offspring of a multiple pregnancy will be considered as only one 
transmission, i.e. infants born from multiple pregnancies will be included in the denominator as representing one (one 
mother-infant(s) pair) and if one or more are HBV infected it will count as an event.  This approach will also be taken for 
other dichotomous infant endpoints, counting the first event in any infant from a multiple pregnancy.  However, 
descriptions of the infant population, study conduct and continuous infant endpoints (e.g. Z-scores-for-age at 6 and 12 
months) will analyze infants from multiple pregnancies separately. 
The following sensitivity/secondary supportive analyses on the primary endpoint will be performed: 
1. Considering infants from multiple pregnancies separately. 
2. Imputing infants' last available HBV infection status as their 6 months status for infants lost to follow-up prior to 6 
months.   
3. Considering women lost to follow-up prior to delivery and live born infants with missing results at 6 months as 
failures (i.e. HBV positive). 
4. In the complete case population, considering any infant that is HBsAg positive confirmed by detectable HBV DNA 
at 6, 9 or 12 months as having a HBV infection (12-month analysis only). 
5. If there is a baseline imbalance of ≥1 log10 IU in HBV DNA load between randomized arms, exact logistic 
regression to compare HBV infection status at 6 months of age in the complete-case population between 
randomized arms with and without adjustment for HBV DNA load will be performed. 
Limited validation by code review occurs for the iTAP clinical trial (see CBAR SOP exemption #28705 for details). 
3. Pregnant Women/Mothers 
3.1 Accrual and Eligibility Violations 
Table: Number of pregnant women enrolled, by month and by site. 
List or Text: Description of pregnant women randomized out of sequence order. 
List: Description of women (and their infants) randomized and later found ineligible as indicated on the ‘Protocol Deviation 
for mother’ CRF, and inclusion/exclusion from the analysis following blind review by the study chair. 
3.2 Baseline Characteristics  
Table: median, 25th and 75th percentiles, min, max, categories if given: age at enrollment (years) (categories: <25, ≥25-
<35, ≥35), sonogram information available (categories: results available, not available, not performed), best estimate of 
gestational age at enrollment by site clinician based on last menstrual period (LMP) and sonogram (weeks), height (cm), 


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weight (kg) pre-pregnancy and at enrollment, BMI pre-pregnancy (<18.5, 18.5-24.9, 25-29.9, ≥30), HBV DNA load (log10 
IU) (below limit of detection, limit of detection to ≤5, >5 - ≤7, >7).  
3.3 Study Status 
Table: Number (%): Women discontinuing the study before delivery, between delivery and 2 months postpartum visit, 
between 2 and 6 months postpartum visit, women discontinuing the study and on-study between 6 and 12 months post-
partum visits, and woman who have reached 12 month postpartum visit (completed study).  Sub-categories death, loss to 
follow-up and withdrawn consent will be given for women prematurely discontinuing the study, and those still on-study 
between 6 and 12 months will be given for the 6-month analysis. 
List: Reasons for death, loss to follow-up or withdrawn consent 
Table: median, 10th, 25th, 75th, 90th percentiles, min, max: weeks from M1 visit to last study visit (for women on-study or 
completed study). 
3.4 Compliance to Follow-up 
Table: target number of on-study women at each scheduled follow-up visits, actual number (%) of women with scheduled 
follow-up visit strictly within the visit window defined in section 2, actual gestational age at scheduled follow-up visits 
3.5 Delivery Characteristics 
Table: Number (%): births (single, multiple), delivery outcome (live-birth, stillbirth intrapartum, stillbirth antepartum), mode 
of delivery (vaginal, C-section), premature according to WHO definition (<37 weeks after LMP), C-section before labor 
(yes, no) 
Table: median, 25th and 75th percentiles, min, max, categories: best estimate of gestational age at delivery by the site 
clinician based on last menstrual period (LMP) and sonogram (≥32-<35, ≥35-<37, ≥37), time from onset of labor to 
delivery (hours) (<3, 3-<6, 6-<9, 9-<12, ≥12), time from rupture of membranes to delivery (hours) (<3, 3-<6, 6-<9, 9-<12, 
≥12) 
3.6 Study Treatment Summaries 
Table: Number (%): Days from enrollment to study treatment dispensation (0, 1, 2, 3, >3 with reasons), percentage 
compliance to study treatment from pill count at scheduled visits (<80% poor, 80-95% good, >95% excellent).  
Table: median, 25th and 75th percentiles, min, max, categories: dispensed study treatment (weeks) (<4, 4-<8, 8-<12, 12-
<16, 16-<20, ≥20), dispensed study treatment during pregnancy (weeks) (<4, 4-<8, 8-<12, ≥12), duration of study 
treatment at completion (weeks) (<4, 4-<8, 8-<12, 12-<16, 16-<20, ≥20), duration of study treatment post-partum (weeks) 
(<4, 4-<8, 8-<12, ≥12).   
Table: Number (%): Women completed study treatment and prematurely discontinued study treatment.  Sub-categories 
for women with ALT measurements after study treatment discontinuation will be given. 
List or Text: Description of randomized study treatment un-blinding and dispensation errors. 
3.7 Safety Analysis 
3.7.1 ALT and Severe Hepatic Disease Exacerbations or Flare 
Table: Number (%) with SGPT/ALT ever >60 U/L at a scheduled visit, first schedule visit >60 U/L, number of occurrences 
>60 U/L, all scheduled visits with SGPT/ALT >60 U/L, SGPT/ALT >60-≤150, >150-≤300, >300 U/L at initial rise, number 
(%) with confirmation test within 3 days categories (≤60, ≥60-≤150, >150-≤300, >300 U/L), number (%) with re-test 2 
weeks later and categories (≤60, ≥60-≤150, >150-≤300, >300 U/L) by confirmed ≥60-≤150 or >150 U/L, number of women 
that might have considered re-start of study treatment based on protocol criteria 
Figure: SGPT/ALT over time for women with severe hepatic disease exacerbation or flare defined as SGPT/ALT >300 U/L 
at any time during the study. 


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Table: Number (%), 95% exact binomial confidence interval in each arm: severe hepatic disease exacerbation or flare 
defined as ALT >300 U/L from study treatment discontinuation up to 6 months postpartum at the 6-month analysis and 12 
months postpartum at the 12-month analysis.  Comparison between treatment arms by Fisher’s exact test (p-value).   
Figure: Kaplan-Meier curve of time to first ALT >300 U/L from study treatment discontinuation including follow-up to 6 
months for the 6-month analysis and 12 months for the 12-month analysis.  Comparison between treatment arms by the 
Log-rank test (p-value). 
3.7.2 Adverse Events 
Table: Number (%) of women with any AE prior/at to 6 months for the 6-month analysis and up to 12 months for the 12-
month analysis, 95% exact binomial confidence interval in each arm, and comparison between arms by the Fisher’s exact 
test (p-value).  MedDRA primary system organ class with sub-categorization by preferred term will be used to describe 
AEs. 
Figure: Kaplan-Meier curve of time to first AE from enrollment to 6 months for the 6-month analysis and 12 months for the 
12-month analysis.  Comparison between treatment arms by the Log-rank test (p-value). 
List: AEs with text description, grade, outcome, study week, MedDRA primary system organ class, MedDRA preferred 
term, if SAE: report type, other clinically significant event.  This list will be reviewed for any data discrepancies by the 
study chair blinded to randomized arm prior to freezing the database for the 6-month report. 
3.7.3 Hematology and Biochemistry at Scheduled Visits 
Figures: jitter plots with median, 25th and 75th percentiles and grade 3 and 4 (if specified) indicated: hemoglobin (g/dL) 
(graded), hematocrit (%), white blood cells (cells/mm3) (graded), absolute neutrophils (cells/mm3) (graded), platelets (per 
mm3) (graded), serum creatinine (mg/dL) (graded), Cockcroft-Gault creatinine clearance (ml/min), phosphorus (mg/dL) 
(graded), SGPT/ALT (U/L) (graded), total bilirubin (mg/dL) (graded), SGOT (U/L) (graded), alkaline phospatase (IU/L) 
(graded), albumin (g/dL) (graded) 
Figures: Categories with number (%) indicated: glycosuria (≤1+, 2-3+, 4+), proteinuria (graded) 
4. Children 
4.1 Delivery Characteristics 
Table: Number (%): sex (male/female), APGAR score at 1, 5 and 10 minutes (0-3, 4-6, 7-10), any congenital malformation 
(no, yes) 
Table: median, 25th and 75th percentiles, min, max, categories if given: gestational age at birth according to Ballard exam 
(weeks) (<32, 32-<37, ≥37). 
Table: Number (%) of mother-infant(s) pairs and 95% exact binomial confidence interval in each arm: premature deliveries 
(birth before 37 weeks of gestational age assessed by Ballard Score) and comparison between arms by Fisher’s exact 
test (p-value). 
4.2 Study Status 
Table: Number (%): total births (multiple birth details), infants prematurely discontinuing the study before 6 months of age, 
infants between 6 and 12 months of age, reached 12 months of age (completed study).  Sub-categories death, loss to 
follow-up and withdrawn consent will be given for infants prematurely discontinuing the study, and those still on-study 
between 6 and 12 months of age will be given at the 6-month analysis. 
List: Reasons for death, loss to follow-up or withdrawn consent 
Table: median, 10th, 25th, 75th, 90th percentiles, min, max: weeks from C0 visit (immediately after birth) to last study visit 
(infants on-study or completed study) 


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4.3 Compliance to Follow-up 
Table: target number of on-study infants at each scheduled follow-up visit, actual number (%) of infants with scheduled 
follow-up visit strictly within the visit window defined in section 2, actual age at scheduled follow-up visits 
4.4 HBV Vaccine and HB Immunoglobulin (HBIg) 
Table: median, 25th and 75th percentiles, min, max, categories: duration from birth to HBV vaccine dosing (hours) (<1, 1-
2, 2-3, 3-4, >4), duration from birth to HBIg dosing (hours) (<1, 1-2, 2-3, 3-4, >4) 
Table: Compliance to HBIg and HBV vaccine, target number of infants at each visit, actual number (%) of infants at 
scheduled visits, number (%) with (<3, 3, 4, 5, >5) HBV vaccines. 
4.5 Safety Analysis 
4.5.1 Growth 
Figures: jitter plots with median, 25th and 75th percentiles indicated: height (cm), weight (grams) and HC (cm) at 
scheduled visits up to 6 months for the 6-month analysis and up to 12 months for the 12-month analysis. 
Figures: jitter plots with mean and 95% confidence interval using the t-distribution indicated: WHO Z-scores-for-age of 
weight, height and HC at scheduled visits, comparison between arms by the two sample t-test (p-value) at 6 months for 
the 6-months analysis and at 6 and 12 months for the 12-month analysis. 
4.5.2 Assessment of Mitochondrial Dysfunction at 6 and 12 months 
Table: neurological signs, other organ signs: number (%) major, minor according to the ‘Mitochondrial dysfunction check 
list’ CRF at 6 months for the 6-months analysis and at 6 and 12 months for the 12-month analysis. 
4.5.3 Adverse Events 
Table: Number (%) of mother-infant(s) pairs with any AE prior/at to 6 months for the 6-month analysis and up to 12 
months for the 12-month analysis, 95% exact binomial confidence interval in each arm, and comparison between arms by 
the Fisher’s exact test (p-value).  MedDRA primary system organ class with sub-categorization by preferred term will be 
used to describe AEs. 
Figure: Kaplan-Meier curve of time to first AE from birth including follow-up to 6 months for the 6-month analysis and to 12 
months for the 12-month analysis.  Comparison between treatment arms by the Log-rank test (p-value). 
List: AEs with text description, grade, outcome, study week, MedDRA primary system organ class, MedDRA preferred 
term, if SAE: report type, other clinically significant event.  This list will be reviewed for any data discrepancies by the 
study chair blinded to randomized arm prior to freezing the database for the 6-month report. 
4.5.4 Hematology and Biochemistry at Scheduled Visits 
Figures: jitter plots with median, 25th and 75th percentiles and grade 3 and 4 (if specified) indicated: hemoglobin (g/dL) 
(graded), hematocrit (%), white blood cells (cells/mm3) (graded), absolute neutrophils (cells/mm3) (graded), absolute 
lymphocytes (cells/mm3), platelets (per mm3) (graded), serum creatinine (mg/dL) (graded), phosphorus (mg/dL) (graded), 
SGPT/ALT (U/L) (graded), calcium (mg/dL) (graded) 
4.6 HBV infection 
4.6.1 HBV Infection Status 
Table: Number with HBsAg test at 6 months of age, number (%) and description of multiple pregnancies counted as one 
mother-infant(s) pair, number (%) HBsAg (positive negative), number with HBV DNA test at 6 months of age, number (%) 
HBV DNA (detectable, undetectable), number (%) limit of HBV DNA detection (e.g. 15, 15x2, 15x3 IU/mL), number with 
HBV infection status at 6 months of age, number (%) HBV (positive, negative), 95% confidence interval in each arm 
based on exact binomial distribution, and comparison between arms with a one-sided Fisher’s exact test (p-value). 


    iTAP Analysis Plan Version 3.0 
May 19th, 2016 
 
 
 
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Table: Number of infants with HBV infection status at 6 months of age counting infants from multiple pregnancies 
separately, number (%)  HBV (positive, negative), 95% confidence interval in each arm based on the exact binomial 
distribution, and comparison between arms with a one-sided Fisher’s exact test (p-value). 
Table: Number of infants with HBV infection status at 6 months of age or prior to 6 months if prematurely discontinued the 
study, number (%)  HBV (positive, negative) imputing the last available HBV infection status as their 6 months status for 
those who prematurely discontinued the study prior to 6 months, 95% confidence interval in each arm based on the exact 
binomial distribution, and comparison between arms with a one-sided Fisher’s exact test (p-value). 
Table: Number of infants expected to have HBV infection status at 6 months of age based on the women’s enrollment 
date (excluding stillbirths), number (%) HBV (positive, negative) imputing missing results as failures (i.e. HBV positive), 
95% confidence interval in each arm based on the exact binomial distribution, and comparison between arms with a one-
sided Fisher’s exact test (p-value). 
Table: Number of infants HBsAg positive confirmed by detectable HBV DNA result at 6, 9 or 12 months of age, 95% 
confidence interval in each arm based on the exact binomial distribution, and comparison between arms with a one-sided 
Fisher’s exact test (p-value) (12-month analysis only) 
Table: Number of infants with detectable HBV DNA result at 9 months of age, 95% confidence interval in each arm based 
on the exact binomial distribution, and comparison between arms with a one-sided Fisher’s exact test (p-value) (12-month 
analysis only)  
Table: Number of infants with sero-protection (anti-HBs antibodies >10 IU/L) at 6 months of age, 95% confidence interval 
in each arm based on the exact binomial distribution, and comparison between arms with a one-sided Fisher’s exact test 
(p-value). Number of infants with sero-protection (anti-HBs antibodies >10 IU/L) at 2, 4, 9 and 12 months will also be 
summarized (2 and 4 months at the 6-month analysis, and 9 and 12 months as the 12-month analysis only).   
Table: If a baseline imbalance of ≥1 log10 IU in HBV DNA load between randomized arms exists, the odds ratio, 95% 
confidence interval and p-value for difference between arms for HBV infection status at 6 months of age from the exact 
logistic regression models unadjusted and adjusted for HBV DNA load will be given.   
Table: Median, 25th and 75th percentiles, min, max, mean, standard deviation, categories: HBV DNA load at delivery 
(log10 IU) (below limit of detection, limit of detection to ≤5, >5 - ≤7, >7).  Comparison between arms by the two-sample t-
test (p-value) if ≤10% of the values in both arms are below the limit of detection, and by the Wilcoxon rank-sum test (p-
value) if >10% of the values in either arm are below the limit of detection.