Nejmoa1506110 Appendix

Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for
HIV-1 prevention in women. N Engl J Med 2016;375:2121-32. DOI: 10.1056/NEJMoa1506110
Table of Contents, Supplementary Material
MTN-020/ASPIRE
Supplementary Material Page
MTN-020/ASPIRE Study Team 3-7
Table S1. Enrollment, by study site 8
Table S2. Study inclusion and exclusion criteria 9
Table S3. Site Institutional Review Boards/Ethics Committees 10
Table S4. Study visits and procedures 11
Table S5. Statistical design and analysis approach 12-13
Table S6. Primary safety events, detailed listing 14-58
Table S7. Incident sexually transmitted infections during follow-up, by study arm 59
Table S8. Proportion of HIV-1 seroconverters with antiretroviral resistance, by

60-63
randomization arm
Supplement Figure Legends 64-65
Figure S1. HIV-1 testing algorithm 66
Figure S2. Dapivirine detection in plasma 67-68
Figure S3. Dapivirine detection in returned, used rings and association with detection in
69-70
plasma
Figure S4. HIV-1 incidence by study arm, overall and among pre-specified subgroups 71
Figure S5. Adverse events occurring in >0.5% of the study population (in addition to
72-75
Table 2)
Supplementary Material References 76-77
2
MTN-020/ASPIRE Study Team:
Malawi: Blantyre site (Malawi College of Medicine-John Hopkins University Research

Project): Effie Stephanie Bello, Martha Chihana, Jacqueline Chiphwanya Huwa, Patience
Chisale, Flora Chithila, Sufia S. Dadabhai, Leslie Degnan, Barbara Debevec,Tiferanji Fatch,
Esther Goliati, Daniel Kondwani Gondwe, Dumisile Huwa Kandonje, Evans Kachale, Victoria
Kaliwo, Madalitso Kamaliza, Melvin Kamanga, Mary Kamanga Chadza, Dean Kamangadazi
Soko, Thokozani Kaphiri, Newton Kumwenda, Wezi Longwe Mwenda, Blessings Madiwati,
Bonus Makanani, Jennie Makunganya, Agness Malemia, Martha Malidadi, Abel Maruwo,
Yamikani Rose Mbilizi, Jayne Mpofu, Phyllis Mulenga, Joyce Mulima, Jossen Munthali Lines
Mwafulirwa, Thoko Mwakhwawa, Linda Njete, Kondwani Nkanaunena, Mary Nyirenda, Mariana
Phingo, Grace Phiri, Linly Seyama, Harry Simkoza, Isaac Singini, Andrea Singini, Edith Sitima,
Alex Siyasiya, Taha Taha, Frank Taulo, Edna Taulo, Titus Tung'ande, Fatima Zulu
Malawi: Lilongwe site (University of North Carolina Project): Chimwemwe Baluwa, Gabriel
Banda, Blessings Banda, Towera Banda, Linda Chikopa, Mary Chindebvu, Joseph Chintedza,
Lameck Chinula, Fred Chitema, Gladys Chitsulo, Grace Chiudzu, Nelecy Chome, Ntchindi
Gondwe, Irving Hoffman, Emma Kachipapa, Ivy Kaliati, Angella Kalulu, Getrude Kamwana,
Jane Kilembe, Madawa Kumwenda, Wiza Kumwenda, Phaleda Kumwenda, Thandie Lungu,
Chalimba Lusewa, Yvonne Makala, Clement Mapanje, Francis Martinson, Wongani Mhango,
Nkhafwire Mkandawire, Tawonga Mkochi, Emmie Msiska, Lusungu Msumba, Mathews
Mukatipa, Joyce Mwese, Margret Ndovie, Thokozani Nkhalamba, Naomi Nyirenda, Dorothy
Sichali, Hannah Stambuli, Gerald Tegha, Tapiwa Tembo, Tchangani Tembo
South Africa: Cape Town site (University of Cape Town): Millicent Atujuna, Shaun
Barnabas, Linda-Gail Bekker, Dyan Belonje, Nomsa Cengimbo, Harrite Achu Chabanga,
Thobeka Coba, Danielle Crida, Jacqueline Dallimore, Nwabisa Danster, Siphuxolo Dikili, Riana
Dippenaar, Penina Dlulane, Pamella Dukwe, Lindelwa Dyabeni, Llewellyn Fleurs, Nosiphelo
Pretty Funda, Jennipher Gelant, Litha Gogo, Sibusiso Gumede, Nondumiso Hlwele, Thandiwe
Hobongwana, Lindsay Jeffery, Maria Jose, Babalwa Khaya, Thembisile Khumalo, Nicola Killa,
Melanie Maclachlan, Nocwaka Magobiane, Ferial Mahed, Pamela Makhamba, Gakiema Malan,
Avril Masters, Nombongo Mayekiso, Thobelani Mcayiya, Bukiwe Mngqebisa, Noxolo Mona,
Zanoxolo Mthethi, Norah Nandudu, Bungane Ngayi, Nontshukumo Ngqabe, Sivuyile Max
Nkomiyapi, Mluleleki Nompondwana, Vuyokazi Ntlantsana, Mzamo Ntshoko, Nazmie Pearce,
Naomi Peterson, Minah Radebe, Takalani Radzilani, Heaben Rainers, Sabelo Rasmeni,
Doerieyah Reynolds, Noluvo Rode, Surita Roux, Nokwayintombi Scotch, Kate Snyder, Natalie
Temmers, Ciska Thompson, Thandokazi Tofile, Nomvuselelo Tshongoyi, Dorothie Van Der
Vendt, Christelle Van Niekerk, Monica Vogt, Melissa Wallace, Philippa Woolley, Ntando Yola,
Katherine Young
South Africa: Durban eThekwini site (Centre for AIDS Programme of Research in South
Africa): Diana Chetty, Lorna Dias, Msizi Dladla, Tanuja Gengiah, Magashree Govender,
Ishana Harkoo, Shannie Kamal, Mona Kasaval, Isabel Khan, Siphosihle Khanyile, Christina
Khwela, Lungile Kubheka, Londiwe Luthuli, Nomusa Mabasa, Bernadette Madlala, Bhavna
Maharaj, Nonkululeko Mayisela, Asanda Mdunge, Wendy Mkhize, Avril Mngadi, Atika Moosa,
Kalendri Naidoo, Anushka Naidoo, Gonasagrie Nair, Lungani Ndwandwe, Varnika Ramdhani,
Joanne Richards, Claudia Shozi, Chandraphrabha Singh, Nompumelelo Zungu
South Africa: Durban – Botha’s Hill, Chatsworth, Isipingo, Tongaat, Umkomaas, Verulam
sites (South African Medical Research Council): Nathlee Abbai, Faeeza Arbee, Amit
Ashokumar, Asthi Aungadh, Lindiwe Baba, Sasha Baboolal, Kajal Balkaran, Sivuyisiwe Bebeza,
3
Hassen Bhayat, Bongiwe Bhengu, Rosemary Bhengu, Bongisile Biyela, Resha Boodhram,
Phindile Bulose, Phelelani Buthelezi, Samkelisiwe Buthelezi, Sifiso Buthelezi, Thobekile
Buthelezi, Lindiwe Buthelezi, Philisiwe Buthelezi, Lizo Buyeye, Samiksha Byroo, , Samkelisiwe
Cebisa, Naureen Cele, Veronica Chamane, Candice Chetty, Keisha Chitray, Phumelele
Chonco, Anil Choonilall, Kerusha Chunderduri, Siyabonga Cibane, Shellendra Devnarain,
Nischal Dhanpal, Nqubelo Dladla, Duduzile Dlamini, Ethel Dlamini, Nonhlanhla Dubazane, Faith
Dube, Cebo Duma, Ziningi Dwayisa, Nkosinathi Faya, Tasneem Gaffoor, Zakir Gaffoor, Rupa
Ganesh, Shayhana Ganesh, Sharika Gappoo, Thobile Gasa, Natasha Gounden, Dhevium
Govender, Devina Govender, Melissa Govender, Netricia Govender, Shanthie Govender,
Vaneshree Govender, Vijayanand Guddera, Phindile Guga, Edith Gumede, Sibusisiwe
Gumede, Charlene Harichund, Avika Haridutt, Jeetendra Harilal, Ishina Hemchund, Patricia
Hlangu, Thulebona Hlela, Mzophilayo Hlophe, Nivriti Hurbans, Rabia Imamdin, Lakshmi
Jagesur, Nitesha Jeenarain, Kaminee Jainarain, Marwah Jenneker, Ayanda Jokozela, Vermala
Juggernath, Nirodh Juggessar, Rookaya Kadwa, Duduzile Prudence Khaba, Vincent
Khalishwayo, Lungile Khanyile, Nombuso Khanyile, Raphael Khanyile, Mbali Khomo, Norah
Khoza, Nonhlanhla Khubone, Ntuthuko Khumalo, Thembinkosi Kleiman Khumalo, Nokukhanya
Khuzwayo, Girisha Kistansami, Nothemba Kumalo, Larin Labuschange, Paradise Lembethe,
Mbali Mabaso, Sabelo Mabaso, Phumzile Mabusela, Fathima Sayed, Pearl Maduna, Phumzile
Magwaza, Rashika Maharaj, Tabita Mahlangeni, Nonhlakanipho Makeka, Nompumelelo
Makhanya, , Nkosinathi Makhoba, Lungile Maphumulo, Nonhlanhla Maphumulo, Virginia Mavis
Busisiwe Maphumulo, Emmerentia Marx, Nkosinamandla Masinga, Sandile Sydney Mavundla,
Thandazile Mbatha, Timothy Mbeje, Mandla Mbeko, Silindile Mbhele, Sandile Mbonambi, Faith
Mbuyisa, Michael Mchunu, Nokufika Mchunu, Professor Mdepha, Mduduzi Is Mdletshe, Sihle
Meyiwa, Nonthando Mhlaba, Refilwe Mhlongo, Zaselangeni Mhlongo, , Ntombizethu Mkhabela,
Lauretta Mkhithi, Lorraine Mkhize, Zinhle Mkhize, Silindile Mkhize, Zaba Mkhize, Thokozani
Mkhize, Zwelethu Mkhunyo, Nompumelelo Mkhwanazi, Nompumelelo Mnikathi, Nonzwakazi
Mnqonywa, Mbuti Mofokeng., Jayajothi Moodley, Jeeva Moodley, Javanika Moodley, Ramona
Moodley, Sharon Moodley, Suri Moonsamy, Neetha Morar, Nonhlanhla Mphili, Innocentia
Mpofana, Lindiwe Cecilia Mshibe, Lindumusa Douglas Msomi, Samukelo Msomi, Thabile
Msomi, Simakade Msweli, Emmanuel Mthalane, Bongumusa Mthembu, Funeka Mthembu,
Thabisile Mthembu, Ntokozo Z Mthethwa, Sicelo Mthimkhulu, Mary-Ignatia Mthlane,
Samkelisiwe Mvelase, Goodness Zoh Mvuyane, Lungile Mzimela, Ntokozo Mzimela, Angeline
Mzolo, Kumari Naicker, Selvamoney Naicker, Vimla Naicker, Anika Naidoo, Sarita Naidoo,
Avashri Naidoo, Ishana Naidoo, Jason Naidoo, Jayganthie Naidoo, Keshani Naidoo, Logashvari
Naidoo, , Shereen Naidoo, Sumeshen Naidoo, Nalini Naidu, Alisha Naras, Tashni Nayager,
Nombuyiselo Ncayiya, Nonpumeleo Ndaba, Sanele Ndaba, Tholakele Ndala, Pamela Ndamase,
Sphindile Ndlovu, Zakhona Ndlovu, James Ndlovu, Senamile Ndlovu, Duduzile Edith
Ndwandwe, Khethiwe Joyce Ngobese, Hlengiwe Ngubane, Mduduzi Ngubane, Sibusiso Nhleko,
Nishi Nursayhe, Nomfanelo Nxumalo, Khombisile Nyawo, Kerusha Padayachee, Levanya
Paramanund, Arendevi Pather, Melanie Perumal, Bathandekile Phahlamohlaka, Jessica Phillip,
Jasmin Pillay, Omisha Pillay, Pragasi Pillay, Thotheravani Pillay, Yugashnee Pillay, Anamika
Premrajh, Ravendran Punianathan, Luleka Qhogwana, Presha Rajpal, Shiritha Ramdass,
Varnika Ramdhani, Gita Ramjee, Nirmala Ramluckan, Sureka Ramnarain, Anand Rampersadh,
Renita Ramsumair, Aruna Ratanjee, Meryl Reddy, Melenie Reddy, Neil Reddy, Tharuna Reddy,
Vanitha Sakloo, Nosisa Saul, Smangaliso Shangase, Zinhle Shazi, Zilungile Shembe, Zandile
Shobede, Samuel Sibisi, Thamsanqwa Sibisi, Zweni Sibiya, Nishanta Singh, Hailey Sithole,
Lindiwe Sithole, Samantha Siva, Mandisa Skhosana, , Devarani Soobryan, Elizabeth Spooner,
Sizakele Sukazi, Renate Teise, , Tholly Tenza, Themba Tshabalala, Bomkazi Tutshana, Ashvir
Udith, Leanne Vallabhjee, Arona Vijay, Hlengiwe Vilakazi, Brenton Viriah, Bhekisisa Wanda,
Kubashni Woeber, Thabile Zondi, Thembekile Zulu, Nokuthula Zungu, Phumzile Zungu, Irvin
Zwane
4
South Africa: Johannesburg site (Wits Reproductive Health and HIV Institute): Reneilwe
Boikanya, Primrose Bojosi, Rutendo Bothma, Busisiwe Cebekhulu, Sarah Cohen, Sinead
Delany-Moretlwe, Linh Diep, Clare Dott, Nosipho Gloria Duba, Ntombifuthi Maureen Dube,
Portia Ignatia Duma, Livhuwani Millicent Lucia Farisani, Lizzy Gama, Nkgolo Maria Gegana,
Nerusha Govender, Sovia Gubayo, Nomsa Gumede, Mikey Parsotham Guness, Marilyn Anne
Hoggan, Emily Kekana, Moeketsi David Kgaritsi, Farzana Khan, Themba Langa, Mavis
Mantshitseng Madi, Nomfundo Maduno, Pholo Wilson Maenetje, Busisiwe Magazi,
Moshukutjoane Lebogang Maila, Kgabo Phineas Makgoka, Bathabile Sithandokuhle Makupula,
Nolwazi Nosipho Manzingana, Faith Maputla, Mosidi Calphurnia Maraba, Romeo Martin,
Elizabeth Serati Marule, Nombulelo Maseko, Portia Maseko, Nonkululeko Mashabane, Thabang
Ephraim Mashiane, Florence Tintswalo Mathebula, Matheus Mathipa, Xolelwa Judy Matikinca,
Nkosinathi Vincent Mazibuko, Elizabeth Gugu Mlangeni, Mandla Denis Mlotshwa, Bosisiwe
Mnguni, Mampu Modau, Constance Lebohang Modise, Kebuang Mercia Mokgatle, Emelina
Tebogo Mokoena, Ann Ophilia Mothle, Magdeline Judith Mthethwa, Emmanuel Sinothi
Mthalane, Angeline Doreen Nonhlanhla Mzolo, Elizabeth Nage, Anika Devi Naidoo, Merrilee-
Anne Naidoo, Sandy Naidoo, Ishana Naidoo, Nkosinathi Lindela Emmanuel Ncgobo, Duduzile
Ethel Ncube, Thembisile Wilmah Ndhlozi, Nontokozo Thandeka Ngcobo, Jonas Ngoetjana,
Ringson Ngozo, Lerato Prudence Ngwenya, Dikeledi Nhlapo, Lindelwa Nkangane, Angel Tinny
Nyathi, Ogheneruemu Vincent Okwuolise, Thesla Palanee-Phillips, Patricia Pamacheche,
Sechaba Tumelo Pitso, Mankwana Pheida Ramafalo, Patience Ramalo, Pranitha Ramchuran,
Varnika Ramdhani, Krishnaveni Reddy, Vera Helen Rees, Altaf Sharif, Sylvia Sibongile Sibeko,
Siphokazi Sibisi, Wanile Phumzile Sibisi, Vuyane Sizane, Joel Steingo, Reginah Stuurman,
Lungiswa Phidelia Thobejane, Lavhelesani Cicilia Tjale, Mpho Tshabalala, Bart Verheyden,
Amukelani Califonia Vuma
Uganda: Kampala site (Makerere University-Johns Hopkins University Research

Collaboration): Dorothy Aanyu, Carolyne Agwau Akello, Prossy Asiimwe, Florence Asiimwe
Biira, David Balamusani, James Amos Bazira, Gad Bihabwa, Eleanor Birungi, Steven Bolton,
Luke Erasmus Bukenya, Regina Bukenya Nabatanzi, Barbara Bulya Sseguya, Billy Jimmy
Busuulwa, Ali Elbireer, Juliane Etima Ongom, Mary Glenn Fowler, Brenda Gati Mirembe,
Joseph Ggita, Abraham Juuko, Daniel Kabenge Kizza, Samuel Kabwigu, Bosco Kafufu, Abbey
Kafumbe Mukasa, Joshua Kagoda, Brenda Catherine Kakayi, Hadijah Kalule Nabunya, Betty
Kamira, Rebecca Kampi, Africano Kamugisha, Justine Kamya, Fred Kapaata Bawulira, Patrick
Karugaba, Francis Katongole, Doreen Kemigisha, Beatrice Kiiza, Bonnie King, Kenneth Kintu,
Henry Luwugge Sserwadda, Joel Lwanga, Philippa M .Musoke, Henry Makooka, Flavia Matovu
Kiweewa, Emmanuel Mayanja, Mary Specioza Mbabali, Dorothy Mirembe, Mahnaz-Oliner
Motevalli, Michael Charles Mubiru, Paula Mubiru Namayanja, Magaret Mugenyi, Mary Mukasa
Kagwa Najjemba, Mary(Maria) Musisi, Joseph Mutebo, Rosemary Muwawu, Deborah
Mwebaza, Joselyne Nabisere, Josephine Nabukeera, Christine Valerie Nagawa Kiwanuka,
Susan Najjuka, Clemensia Nakabiito, Susan Nakacwa, Joyce Nakakande, Maria Gorreti
Nakalema, Magaret Nakato Saava, Jesca Nakibuka, Teopista Nakyanzi, Justine Nakyeyune,
Stella Nalusiba Kalungi, Constance Namirembe, Judith Nampewo, Suzan Nampiira Nkalubo,
Sylivia Nankinga, Winnie Nansamba, Stella Nanyonga, Sophie Clare Nanziri, Caroline Nassozi
Kawuma, Patrick Ndawula, Monica Nolan, Jane Nsubuga Musisi, Zubayiri Nyanzi, Deo Ogema
Wabwire, David Ojok, Francis Onen, Moses Onyuthfua, Sawsan Osman, Carolyne Peris
Onyango, Godfrey Rwanzogyera, Rebecca Sakwa, Joseph Semakula, Florence Sempa
Kikonyogo, Mark Ssenyonga, Aisha Zalwango
Zimbabwe: Chitungwiza-Seke South, Chitungwiza-Zengeza, Harare-Spilhaus sites

(University of Zimbabwe-University of California San Francisco Collaborative Research
5
Program): Thembelihle N S Bafana Munatsi, Marvis Banda, Adlight Chandipwisa, Gift T
Chareka, Charles Z Chasakara, Tinashe Chidemo, Debra Chigwanha, Emilder Chihota,
Sungano Chikono, Anesu Chikonyora, Agnes Chikuni, Zvavahera M Chirenje, Tobias
Chitambo, Cathrine Chitsinde, Miria Chitukuta, Trust Chivasa, Patricia M Dhlakama, Lucy Godo,
Pardon Gomani, Rodney Goreraza, Norah S Gwete, Kudzai Hlahla, Portia Hunidzarira, Tendai
D Hwehwe, Fiona Kachingamire, Cecilia Katanda, Hilary Katema, Terrance Kufakunesu,
Margaret Kundeya, Irene Kutinyu, Tarirai Madovi, Tsitsi M Magure, Thecla C Makaya, Rujeko
Makoni, Sibongile Makwenda, Loreen Z Mangove, Trace Manyeruke, Annie Mapfunde, Chiedza
E C Maponga, Moira Masango, Tapiwa B Masara, Martha Masawi, Shingirayi I Masuko,
Angeline Matanhire, Sophia Matenda, Jacob M Matsa, Allen T Matubu, Celia M J Matyanga,
Nyaradzo M Mgodi, Felina Mhangami, Erasmus S Mhizha, Margaret Mlingo, Chido T Mlingo,
Taina M Motsi, Tariro AM Mpofu, Caroline Mugocha, Faith Mugodhi, Nkhoma Mugowe, Felix G
S Muhlanga, Shorai Mukaka, Shedina Mukova, Otillia Munaiwa, Marshall W Munjoma, Marigold
Mupunga, Tarisai Murefu, Grant Murewanhema, Petina Musara, Prisca Mutero, Fiona Mutisi,
Tariro Muvunzi, Tinaye R L Muzamhindo, Sailas Mwakurudza, Elaine Mwandiwata, Sithabile
Ncube, Egifa Ncube, Pepukai Ndadziyira, Grecenia Ndhlovu, Edward Ngwindi, Omega
Nyabadza, Sandra Nyakudya, Ennviolata C Nyawera, Fadzai Rimau, Nyaradzo Rupondo,
Chenai Rushwaya, Lydia N Samaneka, Berlindah N Shawatu, Rachel Shonhiwa, Thelma T
Tauya, Monica Thompson, Christine Vuta, Margret Zinyongo
Microbicides Trials Network Leadership and Operations Center (University of Pittsburgh

& Magee-Womens Research Institute): Orly Aridor, Linda Bezak, Katherine Bunge, Kim
Comer, Ellen Conser, Melissa DeGore, Luis Duran, Maria Foster, Beth Galaska, Sharon Hillier,
Cindy Jacobson, Judy Jones, Michelle Leszczewski, Kathy McCarthy, Ian McGowan, Lisa
Rossi, Christine Rullo, Devika Singh, Daria Smolinski
Microbicides Trials Network Leadership and Operations Center – University of

Washington: Jared Baeten, Benjamin Browning-Roberts, Toni Maddox, Deidra Montoya, Kelly
Moutsos, Patrick Ndase, Caitlin Scoville
Microbicides Trials Network Leadership and Operations Center – FHI 360: Kat Calabrese,
Cheryl Cokley, Ashley Mayo, Rachel Scheckter, Katie Schwartz, Kristine Torjesen, Rhonda
White
Microbicides Trials Network Leadership and Operations Center – Population Council:

Irene Friedland, Barbara Mensch, Stan Mierzwa, Samir Souidi, Chung Wu
Microbicides Trials Network Leadership and Operations Center – RTI International: Helen
Cheng, Miriam Hartmann, Ariana Katz, Nicole Laborde, Jonah Leslie, Alexandra Lutnick,
Elizabeth T. Montgomery, Elizabeth Pleasants, Mary Kate Shapley-Quinn, Ariane van der
Straten
Microbicides Trials Network Laboratory Center – Pharmacology Core (Johns Hopkins

University): James Johnson, Craig Hendrix, Madhuri Manohar, Mark Marzinke, Lauren
Seserko, Jameson Travers
Microbicides Trials Network Laboratory Center – Protocol Support Core (Magee-Womens

Research Institute): Michele Austin, Hilary Avolia, May Beamer, Lisa Cosentino, Allison
DeMarco, Charlene Dezzutti, Wayne Hall, Sara Hendrickson, Lynda Jones, Edward Livant,
Melinda Petrina, Lorna Rabe, Kevin Stoner
6
Microbicides Trials Network Laboratory Center – Virology Core (University of Pittsburgh):
Kristen Hamanishi, Krista Eskay, Kelley Gordon, Elias Halvas, Russell Hardesty, John Mellors,
Amy Opest, Urvi Parikh, Kerri Penrose
Microbicides Trials Network Statistical and Data Management Center (Statistical Center
for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center):
Janne Abullarade, Maija Anderson, Jennifer Balkus, Deborah Bassuk, Jen Berthiaume, Joleen
Borgerding, Elizabeth Brown, Claire Chapdu, Craig Chin, Missy Cianciola, Cheryl DeBoer,
Elaine Dinnie, Martha Doyle, Drew Edwards, Jackie Fitzpatrick, Sharavi Gandham, Haixiao
Huang, Marla Husnik, Stacie Kentop, Jenna Krause, Karen Liu, Iraj Mohebalian, Cindy Molitor,
Jason Pan, Karen Patterson, Barbra Richardson, Jenn Schille, Katie Snapinn, Daniel Szydlo,
Jenny Tseng, Christine Unten, Katie Weaver, Della Wilson
US National Institutes of Health: Bola Adedeji, Roberta Black, Ronald Barnett, Jane Bupp,
Nahida Chakhtoura, Grace Chow, Naana Cleland, Nancy Cogliano, Joanne Csedrik, Carl
Dieffenbach, Emily Erbelding, Scharla Estep, Lester Freeman, Donna Germuga, Cynthia
Grossman, Judene Hinds, Ana Martinez, Joanne O’Brien, Manizhe Payton, Amy Perez, Jeanna
Piper, Dara Potter, Anne Rancourt, Dianne Rausch, Denise Russo, Delta Saint-Vil, Usha
Sharma, Rona Siskind, Laura Sivitz Leirman, Lydia E. Soto-Torres, Kathy Stover, Steven
Towers, Fulvia Veronese, Sheryl Zwerski
International Partnership for Microbicides: Hannelie Carstens, Allison Carter, Tiffany Derrick,
Bríd Devlin, Anita Garg, Mariette Malherbe, Winel Mans, Annalene Nel, Jeremy Nuttall, Zeda
Rosenberg, Marisa Russell, Euan Seaton, Leonard Solai, Patrick Spence, John Steytler,
Neliette van Niekerk, Kathie Windle
MTN-020/ASPIRE Community Working Group: Ntokozo Bhengu, Robert Bucklew, Charles

Chasakara, Manju Chatani, Cheryl Cokley, Caiphas Dlamini, Thokozani Dlamini, Daniel
Gondwe, Phindile Guga, Zerif Kampangire, Milly Katana, Phaleda Kumwenda, Londiwe Luthuli,
Vukani Luthuli, Oupa Mafumane, Zethu Mchunu, Wendy Mkhize, Neetha Morar, Emmanuel
Mthalane, Thandi Mthiyane, Joanita Muganga, Jason Naidoo, Teopista Nakyanzi, Zodwa
Ndlovu, Susan Ngani, Siyabonga Ngqame, Mduduzi Ngubane, Sibusiso Nhleko, Jean Claude
Nkebi, Mluleki Nompondwana, Heather Samuels, Bukelwa Sontshatsha, Rhonda White,
Tiffanee Wright, Ntando Yola, Amanda Zindela, Fatima Zulu
MTN-020/ASPIRE Study Monitoring Committee: Roberta Black, Ward Cates, Connie Celum,
Charlene Dezzutti, Deborah Donnell, James Hughes, Sheena McCormack, Lei Wang
7
Table S1. Enrollment, by study site
Country: Site Total Number Total Number

Screened Enrolled
Malawi: Blantyre site 199 130
Malawi: Lilongwe site 200 142
South Africa: Cape Town site 217 166
South Africa: Durban – eThekwini site 736 244
South Africa: Durban – Botha's Hill site 436 180
South Africa: Durban – Chatsworth site 411 150
South Africa: Durban – Isipingo site 314 117
South Africa: Durban – Tongaat site 351 103
South Africa: Durban – Umkomaas site 259 103
South Africa: Durban – Verulam site 346 150
South Africa: Johannesburg site 401 213
Uganda: Kampala site 408 253
Zimbabwe: Chitungwiza – Seke South site 434 224
Zimbabwe: Chitungwiza – Zengeza site 401 224
Zimbabwe: Harare – Spilhaus site 403 230
8
Table S2. Study inclusion and exclusion criteria
Women must have met all of the following criteria to be eligible for inclusion in the study.
1) Age 18 through 45 years (inclusive) at screening,

2) Able and willing to provide written informed consent to be screened for and to take part in the study
3) Able and willing to provide adequate locator information
Inclusion 4) HIV uninfected based on testing performed at screening and enrollment
Criteria 5) Per participant report, sexually active, defined as having vaginal intercourse at least once in the 3 months prior to screening
6) Using an effective method of contraception at enrollment, and intending to use an effective method for the duration of study
participation; effective methods include hormonal methods (except contraceptive rings); intrauterine device (IUD); and
sterilization (of participant)
7) At screening and enrollment, agrees not to participate in other research studies involving drugs, medical devices, vaginal
products, or vaccines for the duration of study participation. Note: Tampons could be used for the duration of the trial.
Women who met any of the following criteria were excluded from the study.
1) Per participant report at screening:

a. Intends to become pregnant during study participation
b. Plans to relocate away from the study site during study participation
c. Plans to travel away from the study site for more than 8 consecutive weeks during study participation
2) Pregnant
3) Currently breastfeeding
4) Diagnosed with urinary tract infection (UTI), unless treated and symptoms are resolved prior to enrollment
Exclusion 5) Diagnosed with pelvic inflammatory disease, an STI or reproductive tract infection requiring treatment per current WHO
Criteria guidelines, unless treated and symptoms are resolved prior to enrollment
6) Has a clinically apparent Grade 2 or higher pelvic exam finding. Cervical bleeding associated with speculum insertion and/or
specimen collection judged to be within the range of normal is not exclusionary.
7) Participant report and/or clinical evidence of any of the following:
a. Known adverse reaction to any of the study products (ever)
b. Known adverse reaction to latex (ever)
c. Chronic vaginal candidiasis
d. Non-therapeutic injection drug use in the 12 months prior to Screening
e. Post-exposure prophylaxis (PEP) for HIV-1 exposure within 6 months prior to enrollment
f. Last pregnancy outcome 90 days or less prior to enrollment
g. Gynecologic or genital procedure (e.g., tubal ligation, dilation and curettage, piercing) 90 days or less prior to enrollment
h. Participation in any other research study involving drugs, medical devices, vaginal products, or vaccines, within 60 days of
enrollment
i. Participation in any HIV prevention study using systemic or topical antiretroviral medications, within 12 months of enrollment
j. As determined by the site investigator, any significant uncontrolled active or chronic cardiovascular, renal, liver, hematologic,
neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or infectious disease, including active
tuberculosis
8) Has any of the following laboratory abnormalities at Screening Visit:
a. Aspartate aminotransferase (AST) or alanine transaminase (ALT) Grade 1 or higher
b. Creatinine Grade 2 or higher
c. Hemoglobin Grade 2 or higher
d. Platelet count Grade 1 or higher
e. Pap result Grade 2 or higher
9) Has any other condition that, in the opinion of the site investigator, would preclude informed consent, make study participation
unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives
9
Table S3. Site Institutional Review Boards/Ethics Committees
Country: Site Institutional Review Board / Ethics Committee
Malawi: Blantyre site National Health Sciences Research Committee of Malawi

Johns Hopkins University Bloomberg School of Public Health Institutional
Review Board
Malawi: Lilongwe site National Health Sciences Research Committee of Malawi
University of North Carolina at Chapel Hill Institutional Review Board
South Africa: Cape Town site University of Cape Town: Human Research Ethics Committee
South Africa: Durban – eThekwini site Biomedical Research Ethics Committee, University of KwaZulu-Natal
South Africa: Durban – Botha's Hill site South African Medical Research Council Ethics Committee
South Africa: Durban – Chatsworth site South African Medical Research Council Ethics Committee
South Africa: Durban – Isipingo site South African Medical Research Council Ethics Committee
South Africa: Durban – Tongaat site South African Medical Research Council Ethics Committee
South Africa: Durban – Umkomaas site South African Medical Research Council Ethics Committee
South Africa: Durban – Verulam site South African Medical Research Council Ethics Committee
South Africa: Johannesburg site Wits Human Research Ethics Committee, University of Witwatersrand
Uganda: Kampala site Joint Clinical Research Centre Institutional Review Board
Johns Hopkins University School of Medicine Institutional Review Board
Zimbabwe: Chitungwiza – Seke South site Medical Research Council of Zimbabwe
Committee on Human Research, University of California - San Francisco
Zimbabwe: Chitungwiza – Zengeza site Medical Research Council of Zimbabwe
Zimbabwe: Harare – Spilhaus site Medical Research Council of Zimbabwe
10
Table S4. Study visits and procedures
Monthly Quarterly Semi-Annual Study Exit/
SCR ENR Visits Visits Visits PUEV** Term. Visit
ADMINISTRATIVE AND REGULATORY
Obtain informed consent X X
Assign a unique Participant Identification (PTID) number X
Assess and/or confirm eligibility X X
Collect/review/update locator information X X X X X X X
Randomization X
Provide reimbursement X X X X X X X
Schedule next visit * X X X X X *
BEHAVIORAL
Contraceptive counseling X X X X X
Protocol adherence, including VR adherence counseling X X X X
HIV/STI risk reduction counseling X X X X X X X
HIV pre- and post-test counseling X X X X X X X
Conduct a behavioral assessment includes sexual activity,
condom use, and intravaginal practices X X X X X
Conduct an adherence assessment X X X X
Conduct an acceptability assessment X X X
Conduct social harms assessment X X X
CLINICAL
Obtain/update medical and menstrual history X X X X X X X
Obtain/update concomitant medications X X X X X X X
Conduct a physical examination X X * X X X
Perform a pelvic exam X *₸ *₸ *₸ X X * ₸
Prescribe contraceptives * * * * * * *
Disclose available test results X X X X X X
Record/update AEs X X X X X
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for
other findings * * * * * * *
LABORATORY
hCG X X X X X X X
URINE
Urine culture * * * * * * *
NAAT for GC/CT X * * * X * *
HIV-1 Serology X X X X X X X
CBC with platelets X X X X
BLOOD
Chemistries X X X X
Syphilis serology X * * * X
Plasma ◊ X X X X
Study VR adherence assessment(s) * * * *
Rapid test for Trichomonas X *₸ * ₸ *₸ X *₸ *₸
Herpes lesion testing *₸ *₸ *₸ *₸ *₸ *₸ *₸
Vaginal fluid pH X₸ *₸ *₸ *₸ X X *₸
PELVIC
KOH wet mount for candidiasis *₸ *₸ *₸ *₸ *₸ *₸ *₸

Saline wet mount for BV *₸ *₸ *₸ *₸ *₸ *₸ *₸
Gram stain X X X
Vaginal fluid X X X X X X
Pap Smear interpretation * X
Endocervical swab X X X
STUDY PRODUCT/ SUPPLIES
Provision of study specified condoms X X X X X X X
Provision of study VR instructions X * * *
Provision of one study VR for insertion X X X X
Participant or clinician/designee to remove used study VR X X X X
Digital exam(s) by clinician to check VR placement X ₪* * *
Demonstrated attempt to remove and reinsert the ring X
Collection of used study VR X X X X
Dispense a bottle of water, at select sites * * * *
X mandatory, * If indicated, ₸ per local standard of care, ◊= for archive, ₪= required at Month 1, **= When the PUEV coincides with the timing of a Semi-
Annual Visit (Months 6, 12, 18, etc.), all procedures except for the provision of study product and related procedures will be conducted
11
Table S5. Statistical design and analysis approach
The trial was designed with 90% power to detect a 60% reduction in risk of HIV-1 infection, with a
one-sided alpha of 0.025. Like other trials of novel HIV-1 prevention interventions, the trial was powered
so that lower bound of the 95% confidence interval, if the reduction in HIV-1 achieved 60%, would
exclude a 25% reduction in risk.
This use of a non-zero null hypothesis for power calculations was done for several reasons.
First, some in the field have argued results would garner greater confidence by public health
policymakers for later implementation if interventions were demonstrated to have effects that were
definitively separate from zero. Second, if behavioral disinhibition or other factors that might undermine
HIV-1 protection effectiveness in real-world settings were to occur, then products with higher HIV-1
protection estimates in clinical trials may have some cushion for implementation. Third, when this trial
was designed it was to be the only phase III trial of this product, and thus, for regulatory reasons a more
strongly powered study was desired – specifically, if a single pivotal trial is planned, then its power must
be greater than that of a single well-powered trial (for US FDA requirements, at least one and one-half
times the power of a single trial); one way to achieve that additional power is to have a non-zero null and
to conduct interim monitoring of effectiveness against that non-zero null (thus ensuring that the trial would
not stop too early for too small of an effect that would not as a single trial meet regulatory guidelines).
However, several features of the study and developments in the field contributed to the analysis
plan for the present study. First, from its inception, the statistical plan for this trial anticipated a primary
analysis against a standard null of zero, with secondary analyses done against the non-zero null.
Consistent with this approach, interim monitoring for futility in the trial was against a null of zero, not
against a null of 25%. Second, after this trial was designed, The Ring Study, a second evaluation of the
dapivirine vaginal ring, was expanded from an extended phase II study to be a phase III study. The
design of the present study was not changed, but the regulatory plan to consider only one pivotal trial for
HIV-1 protection effects was modified to include both studies. Finally, other trials in this field that have
been designed with non-zero null effects have presented their primary findings against the standard zero
null – defined in the table below. The iPrEx example is particularly important. That trial was designed
against a non-zero null of 30%, but it failed to rule out that effect in its primary analysis (its lower bound of
12
the 95% confidence interval was 15%). However, in combination with other data from the field, it served
as a pivotal study for the regulatory approval and normative guidance regarding combination
emtricitabine/tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis against HIV-1
acquisition.
Table S5. Prior placebo-controlled phase IIB/III studies of HIV-1 antiretroviral

prophylaxis: null hypothesis for design and for primary analysis
Final HIV-1 protection
Null hypothesis
Null hypothesis effectiveness
Study for primary
for design estimate
analysis
(95% CI)
1 86%
IPERGAY 0% 0%
(40, 98)
75%
Partners PrEP Study2* 30% 0%
(55, 87)
62%
TDF23 10% 0%
(22, 83)
49%
BTS4 10% 0%
(10,72)
44%
iPrEx5 30% 0%
(15,63)
6%
FEM-PrEP6 25% 0%
(-52, 41)
-4%
VOICE7* 25% 0%
(-49, 27)
39%
CAPRISA 0048 0% 0%
(6,60)
0%
FACTS 0019 0% 0%
(-40,30)
* For the Partners PrEP Study and VOICE, where more than one active arm was tested, only the oral
emtricitabine/tenofovir disoproxil fumarate pill effectiveness estimate is provided, as an example.
13
Table S6. Primary safety events, detailed listing
The primary safety endpoint for the study was defined as a composite of any serious adverse event, any
death, any Grade 3 and 4 adverse events, and any Grade 2 adverse event assessed by the study
clinicians as related to the study product. Table S6 presents all primary safety events by type of adverse
event, treatment group, grade, and relatedness assessment: serious adverse events (Table S6a), deaths
(Table S6b), Grade 4 events (Table S6c), Grade 3 events (Table S6d), and Grade 2 events assessed as
related (Table S6e). Serious adverse events would encompass the deaths as well as any of the other
primary safety events deemed to be serious, and thus there is duplication between Table S6a and some
parts of the other tables.
14
Table S6a. Serious adverse events (page 1 of 14)
Placebo Dapivirine Total

(N=1316) (N=1313) (N=2629)
MedDRA System Organ Class
and Preferred Term/
Maximum Relationship to Study Product n (%) n (%) n (%)
Participants with Serious AEs
Not Related 48 (3.6%) 52 (4.0%) 100 (3.8%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 48 (3.6%) 52 (4.0%) 100 (3.8%)
Blood and lymphatic system disorders
Hypochromic anaemia
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Congenital, familial and genetic disorders
Arnold-Chiari malformation
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Congenital anomaly in offspring
Not Related 2 (0.2%) 5 (0.4%) 7 (0.3%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 5 (0.4%) 7 (0.3%)
Gastrointestinal disorders
Abdominal pain
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
15

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Gastrointestinal disorders (continued)
Abdominal pain upper
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Diarrhoea
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Gastritis
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Umbilical hernia
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
General disorders and administration site conditions
Oedema peripheral
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Pyrexia
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
16

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Hepatobiliary disorders
Cholecystitis
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Cholecystitis acute
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Cholelithiasis
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Immune system disorders
Anaphylactic shock
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Infections and infestations
Abscess limb
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
17

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Infections and infestations (continued)
Appendicitis
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Bartholin's abscess
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Cellulitis
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Cervicitis
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Dysentery
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Gastroenteritis
Not Related 2 (0.2%) 0 (0.0%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 0 (0.0%) 2 (0.1%)
18

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Infected bites
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Lower respiratory tract infection
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Malaria
Not Related 2 (0.2%) 3 (0.2%) 5 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 3 (0.2%) 5 (0.2%)
Meningitis tuberculous
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Pelvic inflammatory disease
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Peritonsillar abscess
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
19

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Pneumonia
Not Related 2 (0.2%) 0 (0.0%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 0 (0.0%) 2 (0.1%)
Postpartum sepsis
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Pulmonary tuberculosis
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Subcutaneous abscess
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Tuberculosis
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Tuberculosis gastrointestinal
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
20

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Upper respiratory tract infection
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Urinary tract infection
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Viral infection
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Wound infection
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Injury, poisoning and procedural complications
Abdominal injury
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Ankle fracture
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
21

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Injury, poisoning and procedural complications (continued)
Back injury
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Burns first degree
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Face injury
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Fibula fracture
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Head injury
Not Related 2 (0.2%) 1 (0.1%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 1 (0.1%) 3 (0.1%)
Joint dislocation
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
22

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Laceration
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Limb injury
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Lower limb fracture
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Procedural pain
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Snake bite
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Stab wound
Not Related 2 (0.2%) 2 (0.2%) 4 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 2 (0.2%) 4 (0.2%)
23

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Thermal burn
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Investigations
Aspartate aminotransferase increased
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Platelet count decreased
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Metabolism and nutrition disorders
Diabetes mellitus
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Nervous system disorders
Cerebrovascular accident
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
24

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Nervous system disorders (continued)
Epilepsy
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Headache
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Hepatic encephalopathy
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Seizure
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Pregnancy, puerperium and perinatal conditions
Post abortion haemorrhage
Not Related 4 (0.3%) 6 (0.5%) 10 (0.4%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 4 (0.3%) 6 (0.5%) 10 (0.4%)
Premature labour
Not Related 1 (0.1%) 2 (0.2%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 2 (0.2%) 3 (0.1%)
25

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Pregnancy, puerperium and perinatal conditions (continued)
Ruptured ectopic pregnancy
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Psychiatric disorders
Bipolar disorder
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Confusional state
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Depression
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Intentional self-injury
Not Related 2 (0.2%) 2 (0.2%) 4 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 2 (0.2%) 4 (0.2%)
Mania
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
26

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Psychiatric disorders (continued)
Suicidal ideation
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Suicide attempt
Not Related 1 (0.1%) 2 (0.2%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 2 (0.2%) 3 (0.1%)
Reproductive system and breast disorders
Adnexa uteri cyst
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Adnexa uteri mass
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Metrorrhagia
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Ovarian cyst
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
27

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Respiratory, thoracic and mediastinal disorders
Dyspnoea
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Pulmonary embolism
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Skin and subcutaneous tissue disorders
Lipohypertrophy
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Vascular disorders
Hypertension
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
28
Table S6b. Deaths (page 1 of 1)

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Participants with Grade 5 AEs
Not Related 3 (0.2%) 4 (0.3%) 7 (0.3%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 3 (0.2%) 4 (0.3%) 7 (0.3%)
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Tuberculosis gastrointestinal
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Abdominal injury
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Stab wound
Not Related 1 (0.1%) 2 (0.2%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 2 (0.2%) 3 (0.1%)
Pulmonary embolism
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
29
Table S6c. Grade 4 events (page 1 of 7)

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Not Related 23 (1.7%) 22 (1.7%) 45 (1.7%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 23 (1.7%) 22 (1.7%) 45 (1.7%)
Hypochromic anaemia
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Neutropenia
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Thrombocytopenia
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Arnold-Chiari malformation
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
30

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Abdominal pain upper
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Liver disorder
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Anaphylactic shock
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Acute hepatitis B
Not Related 0 (0.0%) 3 (0.2%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 3 (0.2%) 3 (0.1%)
Dysentery
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
31

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Malaria
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Meningitis tuberculous
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Postpartum sepsis
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Alcohol poisoning
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Stab wound
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
32

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Investigations
Alanine aminotransferase increased
Not Related 3 (0.2%) 1 (0.1%) 4 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 3 (0.2%) 1 (0.1%) 4 (0.2%)
Not Related 1 (0.1%) 2 (0.2%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 2 (0.2%) 3 (0.1%)
Lymphocyte count decreased
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Abnormal loss of weight
Not Related 2 (0.2%) 2 (0.2%) 4 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 2 (0.2%) 4 (0.2%)
33

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Cerebrovascular accident
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Epilepsy
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Premature labour
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Ruptured ectopic pregnancy
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
34

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Bipolar disorder
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Depression
Not Related 2 (0.2%) 0 (0.0%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 0 (0.0%) 2 (0.1%)
Intentional self-injury
Not Related 2 (0.2%) 2 (0.2%) 4 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 2 (0.2%) 4 (0.2%)
Suicidal ideation
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Suicide attempt
Not Related 1 (0.1%) 2 (0.2%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 2 (0.2%) 3 (0.1%)
Metrorrhagia
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
35

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Vascular disorders
Hypertension
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
36
Table S6d. Grade 3 events (page 1 of 19)

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Not Related 162 (12.3%) 151 (11.5%) 313 (11.9%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 162 (12.3%) 151 (11.5%) 313 (11.9%)
Anaemia
Not Related 1 (0.1%) 6 (0.5%) 7 (0.3%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 6 (0.5%) 7 (0.3%)
Anaemia of pregnancy
Not Related 2 (0.2%) 0 (0.0%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 0 (0.0%) 2 (0.1%)
Hypochromic anaemia
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Lymphopenia
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Microcytic anaemia
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
37

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Blood and lymphatic system disorders (continued)
Neutropenia
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Thrombocytopenia
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Cardiac disorders
Cardiac disorder
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Congenital anomaly in offspring
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Abdominal pain
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
38

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Gastrointestinal disorders (continued)
Diarrhoea
Not Related 2 (0.2%) 1 (0.1%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 1 (0.1%) 3 (0.1%)
Diarrhoea haemorrhagic
Not Related 2 (0.2%) 0 (0.0%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 0 (0.0%) 2 (0.1%)
Gastritis
Not Related 3 (0.2%) 0 (0.0%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 3 (0.2%) 0 (0.0%) 3 (0.1%)
Nausea
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Peptic ulcer
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Toothache
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
39

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Asthenia
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Oedema peripheral
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Pyrexia
Not Related 2 (0.2%) 1 (0.1%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 1 (0.1%) 3 (0.1%)
Cholecystitis
Not Related 2 (0.2%) 0 (0.0%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 0 (0.0%) 2 (0.1%)
Cholecystitis acute
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Cholelithiasis
Not Related 1 (0.1%) 2 (0.2%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 2 (0.2%) 3 (0.1%)
40

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Hypersensitivity
Not Related 2 (0.2%) 1 (0.1%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 1 (0.1%) 3 (0.1%)
Abscess limb
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Acute HIV infection
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Appendicitis
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Bartholin's abscess
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Cellulitis
Not Related 1 (0.1%) 2 (0.2%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 2 (0.2%) 3 (0.1%)
41

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Dermatitis infected
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Diarrhoea infectious
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Gastroenteritis
Not Related 5 (0.4%) 7 (0.5%) 12 (0.5%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 5 (0.4%) 7 (0.5%) 12 (0.5%)
Genitourinary chlamydia infection
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Genitourinary tract gonococcal infection
Not Related 6 (0.5%) 4 (0.3%) 10 (0.4%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 6 (0.5%) 4 (0.3%) 10 (0.4%)
Helminthic infection
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
42

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Herpes zoster
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Infected bites
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Influenza
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Lower respiratory tract infection
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Malaria
Not Related 5 (0.4%) 4 (0.3%) 9 (0.3%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 5 (0.4%) 4 (0.3%) 9 (0.3%)
Not Related 2 (0.2%) 2 (0.2%) 4 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 2 (0.2%) 4 (0.2%)
43

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Peritonsillar abscess
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Pneumonia
Not Related 2 (0.2%) 1 (0.1%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 1 (0.1%) 3 (0.1%)
Not Related 2 (0.2%) 2 (0.2%) 4 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 2 (0.2%) 4 (0.2%)
Pyelonephritis
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Sinusitis
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Subcutaneous abscess
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
44

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Tonsillitis
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Tuberculosis
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Upper respiratory tract infection
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Not Related 1 (0.1%) 3 (0.2%) 4 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 3 (0.2%) 4 (0.2%)
Viral infection
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Wound infection
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
45

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Ankle fracture
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Back injury
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Face injury
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Fibula fracture
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Head injury
Not Related 3 (0.2%) 2 (0.2%) 5 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 3 (0.2%) 2 (0.2%) 5 (0.2%)
Joint dislocation
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
46

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Laceration
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Limb injury
Not Related 2 (0.2%) 0 (0.0%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 0 (0.0%) 2 (0.1%)
Lower limb fracture
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Procedural pain
Not Related 3 (0.2%) 0 (0.0%) 3 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 3 (0.2%) 0 (0.0%) 3 (0.1%)
Skin abrasion
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Snake bite
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
47

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Soft tissue injury
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Stab wound
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Thermal burn
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Wrist fracture
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Investigations
Alanine aminotransferase increased
Not Related 6 (0.5%) 6 (0.5%) 12 (0.5%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 6 (0.5%) 6 (0.5%) 12 (0.5%)
Not Related 4 (0.3%) 7 (0.5%) 11 (0.4%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 4 (0.3%) 7 (0.5%) 11 (0.4%)
48

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Investigations (continued)
Blood bilirubin increased
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Blood pressure increased
Not Related 3 (0.2%) 4 (0.3%) 7 (0.3%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 3 (0.2%) 4 (0.3%) 7 (0.3%)
Haemoglobin decreased
Not Related 6 (0.5%) 5 (0.4%) 11 (0.4%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 6 (0.5%) 5 (0.4%) 11 (0.4%)
Lymphocyte count decreased
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Neutrophil count decreased
Not Related 5 (0.4%) 7 (0.5%) 12 (0.5%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 5 (0.4%) 7 (0.5%) 12 (0.5%)
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
49

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Not Related 51 (3.9%) 41 (3.1%) 92 (3.5%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 51 (3.9%) 41 (3.1%) 92 (3.5%)
Decreased appetite
Not Related 10 (0.8%) 8 (0.6%) 18 (0.7%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 10 (0.8%) 8 (0.6%) 18 (0.7%)
Diabetes mellitus
Not Related 5 (0.4%) 1 (0.1%) 6 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 5 (0.4%) 1 (0.1%) 6 (0.2%)
Type 2 diabetes mellitus
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Musculoskeletal and connective tissue disorders
Back pain
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Musculoskeletal pain
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
50

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Dizziness
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Generalised tonic-clonic seizure
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Headache
Not Related 3 (0.2%) 2 (0.2%) 5 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 3 (0.2%) 2 (0.2%) 5 (0.2%)
Hepatic encephalopathy
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Seizure
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Cephalo-pelvic disproportion
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
51

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Pregnancy, puerperium and perinatal conditions (continued)
Not Related 4 (0.3%) 5 (0.4%) 9 (0.3%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 4 (0.3%) 5 (0.4%) 9 (0.3%)
Premature labour
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Vomiting in pregnancy
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Depressed mood
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Major depression
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Mood altered
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
52

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Adnexa uteri cyst
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Adnexa uteri mass
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Cervical dysplasia
Not Related 1 (0.1%) 3 (0.2%) 4 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 3 (0.2%) 4 (0.2%)
Coital bleeding
Not Related 0 (0.0%) 2 (0.2%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 2 (0.2%) 2 (0.1%)
Dysmenorrhoea
Not Related 2 (0.2%) 2 (0.2%) 4 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 2 (0.2%) 4 (0.2%)
Menorrhagia
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
53

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Reproductive system and breast disorders (continued)
Metrorrhagia
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Ovarian cyst
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Pelvic pain
Not Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Perineal ulceration
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Dyspnoea
Not Related 2 (0.2%) 0 (0.0%) 2 (0.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 2 (0.2%) 0 (0.0%) 2 (0.1%)
Epistaxis
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
54

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Skin and subcutaneous tissue disorders
Lipohypertrophy
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Rash maculo-papular
Not Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Skin ulcer
Not Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Vascular disorders
Hypertension
Not Related 5 (0.4%) 0 (0.0%) 5 (0.2%)
Related 0 (0.0%) 0 (0.0%) 0 (0.0%)
Total 5 (0.4%) 0 (0.0%) 5 (0.2%)
55
Table S6e. Grade 2 events assessed by the managing clinicians as related to the study product (page 1 of 3)

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Participants with Grade 2 or Higher Adverse Experiences Related to Study Product
Related 9 (0.7%) 7 (0.5%) 16 (0.6%)
Total 9 (0.7%) 7 (0.5%) 16 (0.6%)
Application site pain
Related 2 (0.2%) 0 (0.0%) 2 (0.1%)
Total 2 (0.2%) 0 (0.0%) 2 (0.1%)
Cervicitis
Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 1 (0.1%) 1 (0.1%) 2 (0.1%)
Total 1 (0.1%) 1 (0.1%) 2 (0.1%)
Investigations
Neutrophil count decreased
Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
56

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Headache
Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Renal and urinary disorders
Urinary incontinence
Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Cervix erythema
Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Cervix oedema
Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Dysmenorrhoea
Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
Dyspareunia
Related 0 (0.0%) 1 (0.1%) 1 (<.1%)
Total 0 (0.0%) 1 (0.1%) 1 (<.1%)
Pelvic pain
Related 1 (0.1%) 2 (0.2%) 3 (0.1%)
Total 1 (0.1%) 2 (0.2%) 3 (0.1%)
57

(N=1316) (N=1313) (N=2629)
and Preferred Term/
Reproductive system and breast disorders (continued)
Vulvovaginal pruritus
Related 1 (0.1%) 0 (0.0%) 1 (<.1%)
Total 1 (0.1%) 0 (0.0%) 1 (<.1%)
58
Table S7. Incident sexually transmitted infections during follow-up, by study arm
Placebo Dapivirine
Vaginal Ring Vaginal Ring
(n=1316) (n=1313)
Chlamydia trachomatis
Number of cases during follow-up 368 359
Incidence per 100 person-years (95% CI) 17.7 (15.9-19.6) 17.4 (15.7-19.3)
Neisseria gonorrhoeae
Trichomonas vaginalis
Testing and treatment for sexually transmitted infections were performed semi-annually and more
frequently when clinically indicated.
59
Table S8. Proportion of HIV-1 seroconverters with antiretroviral resistance, by randomization arm
Plasma samples for HIV-1 antiretroviral resistance testing were obtained at the visit at which HIV-
1 seroconversion was detected (at which time study medication was withdrawn). Resistance testing was
successfully completed on plasma from 170/174 (98%) participants, which included 3/3 participants
acutely infected at enrollment, 164/168 HIV-1 seroconverters while on study product, and 3/3 participants
who seroconverted after their product use end visit. Overall, 4 participants did not have a resistance
result, 3 because of insufficient copies of HIV-1 RNA for extraction (<200 copies/mL) and 1 because of
PCR amplification failure.
RNA extracted from plasma was reverse transcribed and HIV-1 pol was PCR amplified and
sequenced using an in-house Sanger sequencing-based population genotyping assay optimized for non-
B HIV-1 subtypes. Population sequences spanned from protease codon 1 through reverse transcriptase
codon 335. The testing laboratory (Microbicide Trials Network Virology Core, University of Pittsburgh
School of Medicine, Division of Infectious Diseases) was certified to perform the in-house genotyping
assay by CLIA and the NIH-sponsored Viral Quality Assurance (VQA) Program at Rush Presbyterian,
Chicago, IL. Mutations in HIV-1 Group M subtype were identified using the Stanford HIV-1 Drug
Resistance Database version 7.0.
The frequency of all non-nucleoside reverse transcriptase (NNRTI) mutations were evaluated as
mutations of potential clinical significance for resistance to dapivirine. Of the 164 participants with
successful viral resistance results within the intention-to-treat cohort (i.e., excluding acutely infected
participants and participants that seroconverted after cessation of product use), 10 out of 96 (10.4%) in
the placebo arm had any NNRTI resistant strain, and 8 out of 68 (11.8%) in the dapivirine arm had any
NNRTI resistant strain. The overall occurrence of NNRTI mutations was not different by arm (Fisher’s
Exact Test: 0.19, p=0.80).
Additional analyses examined the frequencies of a subset of four NNRTI resistance mutations
including L100I, K103N, E138K and Y181C because of their potential relationship to dapivirine resistance
based on in vitro selection studies.10 No subjects had HIV-1 with the E138K, L100I or Y181C detected.
Four subjects had HIV-1 with the K103N mutation however the frequency of K103N detection did not
differ by arm (Table S6A). Other NNRTI mutations detected included V90I, K101E, K103S, V106M,
60
V108I, E138A/G, V179D/I/T and H221Y but the frequency of detection of these mutations also did not
differ by arm (Table S6B). Several NNRTI mutations were observed to occur in combination, including
E138A or G with V179D/I/T (n=2), V108I (n=1) or K101E (n=2); K103S with V106M (n=1) and V90I with
K103N (n=2), but the frequency of more than one NNRTI mutation was not different between study arms.
61
Table S8A. Non-nucleoside reverse transcriptase mutation conferring potential resistance to
dapivirine
Placebo Dapivirine
Vaginal Vaginal
Ring Ring
L100I
Overall 0/101 0/69
(0%) (0%)
Among subjects retrospectively found to be HIV-1 infected at enrollment 0/3 0/0
(0%) (0%)
Among subjects who acquired HIV-1 infection after enrollment while on 0/96 0/68
study product (0%) (0%)
Among subjects who acquired HIV-1 infection after the product use end 0/2 0/1
visit (0%) (0%)
K103N
Overall 2/101 2/69
(2.0%) (2.9%)
(0%) (0%)
Among subjects who acquired HIV-1 infection after enrollment 1/96 2/68
(1.0%) (2.9%)
visit (50.0%) (0%)
E138K
Overall 0/101 0/69
(0%) (0%)
(0%) (0%)
(0%) (0%)
visit (0%) (0%)
Y181C
Overall 0/101 0/69
(0%) (0%)
(0%) (0%)
(0%) (0%)
visit (0%) (0%)
62
Table S8B. Non-nucleoside reverse transcriptase mutations of potential clinical significance
among subjects who acquired HIV-1 after enrollment*
Placebo Dapivirine
Vaginal Vaginal
Ring Ring
1/96 2/68
V90I
(1.0%) (2.9%)
1/96 1/68
K101E
(1.0%) (1.5%)
0/96 1/68
K103S
(0%) (1.5%)
0/96 1/68
V106M
(0%) (1.5%)
0/96 1/68
V108I
(0%) (1.5%)
5/96 3/68
E138A
(5.2%) (4.4%)
0/96 1/68
E138G
(0%) (1.5%)
2/96 1/68
V179D
(2.1%) (1.5%)
0/96 1/68
V179I/T
(0%) (1.5%)
1/96 1/68
H221Y
(1.0%) (1.5%)
* No instances of these mutations occurred in subjects retrospectively found to be HIV-1 infected at

enrollment or among subjects who acquired HIV-1 infection after the product use end visit.
63
Supplementary Figure Legends.
Figure S1. HIV-1 testing algorithm. All study sites performed HIV-1 testing using a standard
algorithm. All sites were validated in the algorithm prior to initiating the study and all
participated in ongoing proficiency testing throughout the course of the study. The HIV-1
test kits used at each site were pre-approved prior to use; at each testing time point when
rapid tests were used at least one FDA-approved rapid test kit was used. If rapid HIV-1
testing found a positive result for either or both rapid assays, confirmatory HIV-1 Western
blot and RNA PCR were done, as well as testing for antiretroviral resistance. All Western
blot testing was performed using FDA-approved test kits. Individuals acquiring HIV-1
were offered to continue with follow-up and were referred to local services for HIV-1 care
and support. Seroconversion events were adjudicated by an HIV-1 endpoints committee
that was blinded to randomization assignment.
Figure S2. Dapivirine detection in plasma during follow-up, a) overall and b) by study site.
Plasma was collected at quarterly follow-up visits and was tested for all available
samples (n=9,459) for participants assigned to the trial’s active dapivirine ring arm. In
phase I/II studies, plasma concentrations >95 pg/mL were achieved in most subjects
within 8 hours of ring use and thus concentrations >95 pg/mL were interpreted as
indicating adherence to the dapivirine ring (dark purple). Concentrations between the
lower limit of quantification (LLQ, 20 pg/mL) and 95 pg/mL potentially reflected adherence
or, alternatively, use of the ring for only a few hours prior to the scheduled clinic visit (i.e.,
“white coat dosing”) (medium purple). Levels below the LLQ (BLQ) reflected non-use of
the ring (light purple). Visits at which the participant was on a protocol-defined product
hold (e.g., due to pregnancy) or at which a sample was not available are also indicated
(dark green and light green, respectively). The frequency of detection of dapivirine at
concentrations >95 pg/mL increased over follow-up (generalized linear mixed model with
random intercepts and adjusted for country, p<0.001). The >95 pg/mL cut-off was chosen
to distinguish cases in which the ring was removed during the month and then reinserted
immediately prior to a clinic visit (i.e., <8 hours). In a prior study of this ring, when the ring
was placed under observation, it required at least 8 hours for plasma dapivirine
concentrations to exceed 95 pg/mL in nearly all (88%) research participants.11,12 In that
same study, plasma dapivirine concentrations exceeded this concentration in nearly all
(88%) participants for at least 24 hours after removal of the ring per protocol after 28
days. Thus, the use of the >95 pg/mL cut-off to define adherence may overestimate
adherence for women who removed the vaginal ring for most of the month but reinserted
>8 hours prior to a clinic visit.
Figure S3. Dapivirine detection in returned, used rings: a) boxplot of dapivirine in returned
rings by concentration of dapivirine in concurrently collected plasma and b)
distribution of dapivirine quantity in returned rings and in unused control rings.
Dapivirine was quantified in returned, used rings for subjects assigned to the active
dapivirine vaginal ring arm. In total, 20,770 rings were tested, and for 7,106 visits,
concurrently collected plasma was available (plasma was collected quarterly while rings
were collected monthly). Dapivirine rings were loaded with 25 mg of dapivirine and, in
phase I/II studies, released ~4 mg of dapivirine over a month of continuous use. In
returned, used rings residual levels less than 23.5 mg were defined as adherent, to take
into account dapivirine release across different individuals and allowed assay
performance.
For Figure S3a, results are presented by plasma concentrations: below the lower limit of
quantification (LLQ = 20 pg/mL) (BLQ), LLQ to 95 pg/mL, and >95 pg/mL. Adjusting for
64
site and visit, compared to rings from women with no detectable plasma dapivirine (BLQ),
the average amount of dapivirine remaining in a ring was 0.29 mg (95% CI 0.07-0.51,
p=0.01) less in women with plasma levels between LLQ and 95pg/mL and 2.6 mg (95%
CI 2.37-2.77, p<0.001) less in plasma levels above 95 pg/mL.
Figure S3b shows the probability distribution functions for the amount of dapivirine
measured in rings returned at visits where a participant’s plasma dapivirine level was
greater than 95 pg/mL (green) or less than 95 pg/mL (red). In addition, the probability
distribution for unused active dapivirine arm rings, which were tested with each batch as
an internal control, is presented (black). The grey line segment indicates a residual
dapivirine amount of 23.5 mg, the definition proposed prior to the conclusion of the study
that would define adherence. For control rings (which had not been used), 2.5% had
dapivirine levels measured at less than 23.5 mg. The graph illustrates that, in general,
visits at which plasma dapivirine concentrations were less than 95 pg/mL had residual
dapivirine amounts in the rings relatively similar to, although lower than, control rings,
while visits at which plasma dapivirine concentrations were greater than 95 pg/mL had
lower residual dapivirine amounts. However, there was overlap in the distributions.
Thus, both the plasma dapivirine concentration of >95 pg/mL and the residual ring
amount of <23.5 mg are susceptible to defining a visit as adherent when adherence was
not necessarily sustained for the prior month.
Figure S4. HIV-1 incidence by study arm, overall and among pre-specified subgroups. Overall
analyses include data from all 15 sites and from 13 of the 15 sites (i.e., excluding data
from two sites, observed early in the study to have lower retention and adherence
compared to other sites). The two excluded sites were among nine sites located in South
Africa, seven of which were located in the KwaZulu-Natal province. Excluding those two
sites, the relative risk reduction for HIV-1 for South Africa sites was 38% (95% CI 7-58%,
p=0.02, n=100 events) and for KwaZulu-Natal 36% (95% CI 0-600%, p=0.05, n=78
events). The p-values for overall intention-to-treat analyses apply to the hypothesis of
any evidence of HIV-1 protection (i.e., testing against a null hypothesis of 0%), which was
defined in the trial’s Statistical Analysis Plan as the primary trial comparison.
Pre-specified subgroup analyses – defined by age, country, educational status, marital

status, the presence of a sexually transmitted infection at baseline, number of sexual
partners, and whether women reported informing their primary partner about their use of
the vaginal ring – were planned. For the subgroup analyses, p-values correspond to a
test for significant interaction in the site-stratified Cox proportional hazards model. In the
forest plots, dashed line indicates HR of 1.0 (0% HIV-1 protection). Subgroup analyses
exclude information from two study sites defined early in the study period as having lower
than anticipated retention and adherence.
Figure S5. Adverse events occurring in >0.5% of the study population. Adverse events are
ordered by the magnitude of difference between the study arms (dapivirine minus
placebo). Blue triangles and red circles indicate the absolute proportion of subjects
experiencing each adverse event in the dapivirine and placebo arms, respectively.
Forest plots define the difference in frequency and 95% confidence interval. The study
database recorded all Grade 2 or higher adverse events as well as all Grade 1 laboratory
and genitourinary system events, regardless of assessed relationship to the study
product.
65
Figure S1. HIV-1 testing algorithm
66
Figure S2a. Dapivirine detection in plasma during follow-up
67
Figure S2b. Dapivirine detection in plasma during follow-up, by study site
68
Figure S3a. Dapivirine detection in returned, used rings, by concentration of dapivirine in concurrently collected plasma
25
Ring (mg)
20
15
BLQ >LLQ, <95 pg/mL >95 pg/mL
Plasma (pg/mL)
69
Figure S3b. Distribution of dapivirine quantity in returned rings and in unused control rings
70
Figure S4. HIV-1 incidence by study arm, overall and among pre-defined subgroups.
71
Figure S5. Adverse events occurring in >0.5% of the study population (in addition to Table 2) [4 pages]
72
73
74
75
Supplementary Materials References
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Supplementary Appendix

Supplementary Material Page

MTN-020/ASPIRE Study Team 3-7

Table S1. Enrollment, by study site 8

Table S2. Study inclusion and exclusion criteria 9

Table S3. Site Institutional Review Boards/Ethics Committees 10

Table S4. Study visits and procedures 11

Table S5. Statistical design and analysis approach 12-13

Table S6. Primary safety events, detailed listing 14-58

Table S8. Proportion of HIV-1 seroconverters with antiretroviral resistance, by

Supplement Figure Legends 64-65

Figure S1. HIV-1 testing algorithm 66

Figure S2. Dapivirine detection in plasma 67-68

Supplementary Material References 76-77

Malawi: Blantyre site (Malawi College of Medicine-John Hopkins University Research

Uganda: Kampala site (Makerere University-Johns Hopkins University Research

Zimbabwe: Chitungwiza-Seke South, Chitungwiza-Zengeza, Harare-Spilhaus sites

Microbicides Trials Network Leadership and Operations Center (University of Pittsburgh

Microbicides Trials Network Leadership and Operations Center – University of

Microbicides Trials Network Leadership and Operations Center – Population Council:

Microbicides Trials Network Laboratory Center – Pharmacology Core (Johns Hopkins

Microbicides Trials Network Laboratory Center – Protocol Support Core (Magee-Womens

MTN-020/ASPIRE Community Working Group: Ntokozo Bhengu, Robert Bucklew, Charles

Country: Site Total Number Total Number

1) Age 18 through 45 years (inclusive) at screening,

1) Per participant report at screening:

Country: Site Institutional Review Board / Ethics Committee

Malawi: Blantyre site National Health Sciences Research Committee of Malawi

KOH wet mount for candidiasis *₸ *₸ *₸ *₸ *₸ *₸ *₸

exclude a 25% reduction in risk.

emtricitabine/tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis against HIV-1

Table S5. Prior placebo-controlled phase IIB/III studies of HIV-1 antiretroviral

emtricitabine/tenofovir disoproxil fumarate pill effectiveness estimate is provided, as an example.

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

Placebo Dapivirine Total

KOH wet mount for candidiasis ₸ ₸ ₸ ₸ ₸ ₸ *₸