JJV McMurray1, WT Abraham2, K Dickstein3, LV K

1
Direct renin inhibition with aliskiren alone, and
in combination with enalapril, compared with
enalapril, in heart failure Aliskiren Trial to
Minimize OutcomeS in Patients with HEart failuRE
(ATMOSPHERE)

• JJV McMurray1, WT Abraham2, K Dickstein3, LV
  Køber4, MA Ali5, Y Chiang5, AS Desai6, C
  Gimpelewicz5, Q Sho5, SD Solomon6, G Tarnesby5,
  BM Massie7, H Krum8 on behalf of the ATMOSPHERE
  committees and investigators.
• 1University of Glasgow, UK 2Ohio State
  University, USA 3Stavanger University Hospital,
  Stavanger, Norway 4Copenhagen University
  Hospital, Denmark 6Brigham and Women's Hospital,
  Boston, USA 5Novartis Pharma AG, Basel,
  Switzerland 7University of California, San
  Francisco, USA 8Monash University, Australia.

2
Background Renin inhibition in heart failure
with reduced ejection fraction (HF-REF)

• ACE inhibitors reduce mortality and reduce heart
  failure hospitalization rates in patients with
  HF-REF, across the spectrum of symptom severity
  (CONSENSUS, SOLVD).
• ARBs are an alternative in patients unable to
  tolerate an ACE inibitor because of cough
  (CHARM-Alternative).
• ARBs futher reduce cardiovascular mortality
  (CHARM-Added) and heart failure hospitalization
  (CHARM-Added, Val-HeFT) when added to an ACE
  inhibitor.
• Might a direct renin inhibitor (aliskiren) add to
  the benefit of an ACE inhibitor or be a better
  alternative to an ACE inhibitor?

3
Aliskiren Trial to Minimize OutcomeS in
Patients with HEart failuRE (ATMOSPHERE)
In reducing the risk of the primary composite
outcome of cardiovascular death or heart failure
hospitalization

• Aliskiren added to enalapril is superior to
  enalapril
• Aliskiren monotherapy is superior to enalapril

Superiority hypotheses

• Aliskiren monotherapy is non-inferior to enalapril

Non-inferiority hypothesis
https//clinicaltrials.gov NCT00853658
4
ATMOSPHERE Entry criteria

• Age 18 years. NYHA class II-IV. LVEF 0.35
• BNP 150 pg/ml (NTpro-BNP 600 pg/ml) or if HF
  hosp. within12 mo. BNP 100 pg/ml (NTpro-BNP 400
  pg/ml)
• Background ACEi therapy equivalent to enalapril
  10 mg/d
• Beta-blocker unless contraindicated/not tolerated
• SBP 95 mmHg run-in/ 90 mmHg at randomization
• eGFR 35 ml/min/1.73m2 at randomization /no
  decrease gt25 during run in
• Potassium lt5.0 mmol/l run-in/ lt5.2 mmol/l at
  randomization

5
ATMOSPHERE Trial design
Primary outcome CV death or heart failure
hospitalization (event driven target 2318
patients 2369 accrued)
89 10mg bid Target dose (titrated from 150mg
qd)
Randomization
Enalapril 5-10mg bid (n2336)
Enalapril 5-10mg bid
Enalapril Aliskiren150mg qd
Aliskiren 300mg qd (n2340)
Enalapril 5-10mg bid Aliskiren300mg qd (n2340)
Open-label run-in
Double-blind
Median follow-up 36.6 months
4-12 weeks
Prior ACEi use discontinued
6
ATMOSPHERE Baseline characteristics
AliskirenEnalapril (n2340) Aliskiren (n2340) Enalapril (n2336)
Age (years) 63.2 11.7 63.3 12.1 63.3 11.7
Women () 21.1 22.7 21.4
Ischemic etiology () 57.1 55.3 55.7
LVEF () 28.5 5.7 28.4 5.7 28.3 5.7
NYHA class II / III () 64.0 / 33.7 64.0 / 34.3 61.7 / 36.3
Systolic BP (mm Hg) 124 19 124 18 123 18
Heart rate (beats/min) 72 13 72 12 72 13
NT pro-BNP (pg/ml) 1193 (640-2351) 1167 (627-2173) 1223 (634-2194)
History of diabetes 28.4 26.8 27.9
Digitalis 32.7 32.0 31.2
Beta-blocker 92.0 91.2 91.9
MRA 36.6 36.9 37.8
CRT-P/CRT-D 6.1 5.1 5.6
ICD/CRT-D 15.0 15.5 14.4
7
ATMOSPHERE Censoring of patients with diabetes

• Following the results of ALTITUDE (aliskiren
  added to an ACE-I/ARB in patients with diabetes
  and CKD/CVD) and ASTRONAUT (aliskiren added to an
  ACE-I/ARB in patients hospitalized with HF), the
  Clinical Trials Facilitation Group of the Heads
  of Medicines Agencies in Europe requested that
  patients with diabetes have study drug
  discontinued.
• Follow-up for the efficacy analyses in patients
  with diabetes (and some others) who had treatment
  discontinued because of a regulatory request was
  censored at the date of implementation of these
  requests. Patients off study drug were still
  followed to end of the trial.
• Median follow-up for analysis of efficacy in
  patients with diabetes was 24.1 months and in
  patients without diabetes was 46.0 months.

and some others
8
ATMOSPHERE Trial conduct

• Completeness of follow-up for vital status (at
  end of trial or regulatory censoring date).
• Combination therapy 31/2340 (1.3) had unknown
  vital status.
• Aliskiren 19/2340 (0.8) had unknown vital
  status.
• Enalapril 19/2336 (0.8) had unknown vital
  status.
• Study drug dose (mean SD)
• Combination group19.0 (3.0) mg of enalapril and
  272 (58) mg of aliskiren Aliskiren group 276
  (55) mg Enalapril group 18.6 (3.5) mg.
• Study drug discontinuation
• Non-diabetics Combination 44, aliskiren 40
  enalapril 42. Proportion of possible treatment
  time patients took study drug was 77, 81 and
  80, respectively.
• Diabetics 31, 28 and 32 80, 84 and 82,
  respectively.

9
Aliskiren Trial to Minimize OutcomeS in
Patients with HEart failuRE (ATMOSPHERE)
In reducing the risk of the primary composite
outcome of cardiovascular death or heart failure
hospitalization

• Aliskiren added to enalapril is superior to
  enalapril
• Aliskiren monotherapy is superior to enalapril

Superiority hypotheses

• Aliskiren monotherapy is non-inferior to enalapril

Non-inferiority hypothesis
https//clinicaltrials.gov NCT00853658
10
ATMOSPHERE Primary outcome
11
ATMOSPHERE Components of the primary composite
outcome
HF hospitalization
CV death
12
ATMOSPHERE Effect of combination therapy in
patients with and without diabetes
Effect of combination therapy on the primary
outcome in patients without diabetes (additional
superiority hypothesis in revised statistical
analysis plan)
Aliskiren Enalapril Enalapril HR (95 CI) P value
Patients without diabetes n () 574/1675 (34.3) 592/1684 (35.2) 0.96 (0.85-1.07) 0.46
Patients with diabetes n () 196/665 (29.5) 216/652 (33.1) 0.86 (0.71-1.04) 0.13
Interaction P-value 0.35
13
Aliskiren Trial to Minimize OutcomeS in
Patients with HEart failuRE (ATMOSPHERE)
In reducing the risk of the primary composite
outcome of cardiovascular death or heart failure
hospitalization

• Aliskiren added to enalapril is superior to
  enalapril
• Aliskiren monotherapy is superior to enalapril

Superiority hypotheses

• Aliskiren monotherapy is non-inferior to enalapril

Non-inferiority hypothesis
https//clinicaltrials.gov NCT00853658
14
ATMOSPHERE Comparison of enalapril and
aliskiren monotherapy (non-inferiority)
Pre-specified criterion for declaring
non-inferiority was a P-value 0.0123 (one-sided)
Aliskiren (n2340) Enalapril (n2336) HR (95 CI) P value
All patients n () 791 (33.8) 808 (34.6) 0.99 (0.90-1.10) 0.0184
Did not meet the pre-specified P-value for
significance
15
ATMOSPHERE Secondary and exploratory outcomes

• Secondary outcome
• Kansas City Cardiomyopathy Questionnaire (KCCQ) -
  Change in the clinical summary score (CSS) from
  baseline to 12 months
• Exploratory outcomes (selected)
• Composite CV outcome CV death, HF
  hospitalization, MI, stroke or resuscitated
  cardiac arrest
• Composite renal outcome renal death, ESRD
  (initiation of dialysis, renal transplantation,
  or a serum Cr above 6.0 mg/dl 530 µmol/l), or
  doubling of serum Cr from baseline (to gtupper
  limit of normal) sustained for at least 1 month

16
ATMOSPHERE Pre-specified secondary outcome
Aliskiren Enalapril Aliskiren Enalapril Difference (95 CI) (1) Difference (95 CI) (2) P value (1) P value (2)
KCCQ change in CSS from baseline to 12 months, points (95 CI) -5.04 (0.56) -6.03 (0.57) -5.01 (0.55) -0.03 (-1.56-1.50) -1.02 (-2.56-0.52) 0.97 0.20

1. Comparison of enalapril plus aliskiren versus
   enalapril (2) Comparison of aliskiren versus
   enalapril

17
ATMOSPHERE Pre-specified exploratory outcomes
Aliskiren Enalapril (n2340) Aliskiren (n2340) Enalapril (n2336) HR (95 CI) (1) HR (95 CI) (2) P value (1) P value (2)
CV death, HF hospitalization, MI, stroke or resuscitated cardiac arrest n () 841 (35.9) 874 (37.4) 877 (37.5) 0.94 (0.86-1.04) 1.01 (0.92-1.11) 0.23 0.81
Composite renal outcome n () 39 (1.7) 26 (1.1) 18 (0.8) 2.17 (1.24-3.79) 1.50 (0.82-2.74) 0.007 0.18

• Selected pre-specified outcomes
• Comparison of enalapril plus aliskiren versus
  enalapril (2) Comparison of aliskiren versus
  enalapril
• renal death, ESRD (initiation of dialysis,
  renal transplantation, or a serum Cr above 6.0
  mg/dl 530 µmol/l), or doubling of serum Cr from
  baseline (to gtupper limit of normal) sustained
  for at least 1 month

18
ATMOSPHERE All-cause mortality
19
ATMOSPHERE Pre-specified subgroups
Aliskiren n/N ()
Enalapril n/N ()
Combination n/N ()
Interaction P-value
Interaction P-value
Enalapril n/N ()
Favors enalapril
Favors aliskiren
Favors combination
Favors enalapril
20
ATMOSPHERE Safety outcomes
Aliskiren Enalapril (n2340) Aliskiren (n2340) Enalapril (n2336) P value (1) P value (2)
Hypotension n () Symptoms Symptoms and SBP lt90mmHg 322 (13.8) 87 (3.7) 249 (10.6) 31 (1.3) 258 (11.0) 55 (2.4) 0.005 0.008 0.67 0.009
Renal impairment n () Cr 2.5mg/dl Cr 3.0mg/dl 95 (4.1) 46 (2.0) 63 (2.7) 35 (1.5) 62 (2.7) 29 (1.2) 0.009 0.06 1.00 0.53
Hyperkalemia n () K gt5.5mmol/l K gt6.0mmol/l 401 (17.1) 116 (5.0) 255 (10.9) 70 (3.0) 291 (12.5) 83 (3.6) lt0.0001 0.02 0.10 0.29
Cough n () 290 (12.4) 241 (10.3) 284 (12.2) 0.83 lt0.05

1. Comparison of enalapril plus aliskiren versus
   enalapril (2) Comparison of aliskiren versus
   enalapril

21
Summary and conclusions

• Combination therapy
• The addition of aliskiren to an evidence-based
  dose of enalapril led to more adverse events
  without an increase in benefit.
• This finding differs from the prior ARB add-on
  trials and may reflect a difference in study
  design (the previous trials did not require an
  evidence-based dose of background ACE inhibitor).
• There is probably a ceiling to RAS blockade in
  heart failure, above which there is no further
  benefit
• Aliskiren monotherapy
• Non-inferiority was not demonstrated for
  aliskiren compared with enalapril.

22
Henry Krum, 1958-2015
In memory of our colleague and friend
Henry Krum, 1958-2015
23
ATMOSPHERE43 countries, 844 Sites, 7064 Patients

The following persons participated in the
ATMOSPHERE trial Executive Committee Original
co-chairs Barry Massie and Henry Krum co-chairs
2015- Henry Krum (Deceased 2015) and John
McMurray William Abraham, Kenneth Dickstein,
Lars Køber. National Leaders Argentina
Felipe Martinez Australia Peter McDonald
Austria Martin Huelsmann, Richard Pacher
(Deceased 2015) Belgium Johan Vanhaecke
Brazil Luiz Carlos Bodanese Canada Jonathan
Howlett China Yuhua Liao Colombia Luis
Eduardo Echeverria Costa Rica Mario Speranza
Czech Republic Jiri Widimsky Denmark Lars
Køber Dominican Republic Rafael Pichardo
Estonia Riina Vettus Finland Ilkka Kantola
France Yves Juilliere Germany Matthias
Pauschinger, Stefan Anker Greece Ioannis Nanas
Ireland Brendan McAdam Italy Aldo Maggioni
Japan Hiroyuki Tsutsui Latvia Janina Romanova
Lithuania Ausra Kavoliuniene Mexico Jose Luis
Arenas Leon The Netherlands Adriaan Voors
Norway Marcel Moufack Peru Juan Lema Poland
Piotr Ponikowski Portugal Cândida Fonseca
Russia Yury Shvarts, Vyacheslav Mareev
Slovakia Gabriel Kamensky South Africa Johan
Roos Korea Byung-Hee Oh Spain López Sendón
Sweden Jan Östergren Switzerland Frank
Enseleit Taiwan Wenter Lai Thailand Piyamitr
Sritara Turkey Dilek Ural UK Iain Squire,
Martin Cowie USA Eric Velazquez Venezuela
María Inés Marulanda. Data Monitoring
CommitteeKarl Swedberg (Chair), Jeffrey S.
Borer, Bertram Pitt, Stuart Pocock, Jean L.
Rouleau. Clinical Endpoint Committee
Co-chairs Scott D. Solomon and Akshay S. Desai
Director of Operations Chau Duong Business
Administrator Renee Mercier Project
Coordinator Amanda Sullivan Physician
Reviewers Natalie Bello, Ebrahim Barkoudah,
Abdel Brahimi, Patricia Campbell, Davide
Castagno, David Charytan, Miguel Morita Fernandes
de Silva, Peter Finn, Aidan Flynn, Mauro Gori, L.
Howard Hartley, Pardeep Jhund, Jacob Joseph,
Rumen Kasabov, Wilson Nadruz Jr., Kayode Odutayo,
Anne-Catherine Pouleur, Vinutha Rajesh, Odilson
Silvestre, Olga Vasylyeva, Ali Vazir, Larry
Weinrauch. Independent statistician Nicola
Greenlaw, Robertson Centre for Biostatistics,
University of Glasgow. Countries
(patients)Argentina (501), Australia (41),
Austria (59), Belgium (73), Brazil (201), Canada
(77), China (465), Colombia (146), Costa Rica
(18), Czech Republic (307), Denmark (253),
Dominican Republic (23), Estonia (47), Finland
(24), France (34), Germany (470), Greece (59),
India (782), Ireland (16), Italy (286), Japan
(210), Republic of Korea (143), Latvia (65),
Lithuania (61), Mexico (50), Netherlands (162),
Norway (22), Peru (116), Poland (302), Portugal
(54), Romania (290), Russia (553), Slovakia
(327), South Africa (52), Spain (142), Sweden
(141), Switzerland (15), Taiwan (113), Thailand
(56), Turkey (70), United Kingdom (48), United
States (116), Venezuela (76). Investigators Arge
ntina Alvarenga Pablo, Moises Azize Guillermo,
Baroni Marcos, Bendersky Mario, Luna Alejandra,
Allende Guillermo, Colombo Hugo, Cuneo Carlos,
Montenegro Eleonora, Diez Fabian, Garcia Pinn
Jorge, Prado Aldo, Ibañez Luz, Aiub Jorge, Jure
Horacio, Resk Jorge, Luquez Hugo, Majul Claudio,
Marin Marcos, Martinez Jimena, Montana Oscar,
Muntaner Juan, Perna Eduardo, Piskorz Daniel, Poy
Carlos, Ronderos Ricardo, Scaro Graciela, Sosa
Liprandi Maria, Acosta Adriana, Vigo Santiago,
Zangroniz Pedro, García Brasca Daniela, Fernandez
Alberto, Dominguez Andrea, Caccavo Alberto,
Garcia Duran Ruben, Budassi Nadia, Sosa Carlos.
Australia J Karrasch, T Marwick, B Singh, E
Vogl, I Jeffrey, C DePasquale, P MacDonald, M
Fitzpatrick, D Cross, K Kostner. Austria
Hülsmann Martin, Jakl Gabriele, Hoppe Uta,
Fruhwald Friedrich, Frick Matthias, Siostrzonek
Peter, Breier Roland, Kunschitz Evelyn, Ebner
Christian. Belgium Vanhaecke Johan, Hollanders
Geert, Nellessen Eric, Mullens Wilfried, Thoeng
John, Missault Luc, Troisfontaines Pierre,
Marenne Frédéric, Lozano Angel, Delforge Marc,
Roelandt Raf, Gurne Olivier, Vlassak Irmien.
Brazil Bodanese Luiz, Rocha Augusto, Leaes
Paulo, Precoma Dalton, Finimundi Helius, Pelloso
Eraldo, David Joao, Saraiva Jose, Bittencourt
Marcelo, Moura Lidia Ana, Canesin Manoel,
Clausell Nadine, Marino Roberto Luis, Rassi
Salvador, Alves Silvia, Barbosa Eduardo, Abib
Eduardo, Saad Jamil, Vieira Nubia, Sampaio Roney,
Saporito Wladmir. Canada Gupta Milan, Howlett
Jonathan, Mouzayek Kouz Simon, Pandey Shekhar,
Searles Greg, Bergeron Sebastien, White Michel,
Constance Christian, Haddad Haissam, Talbot Paul.
China J Ge, M Wei, G Lu, S Wu, N Sun, Y Ke, W
ZHU, S Lv, H Li, L Zhang, Y Chen, W Ding, W Gao,
T Hu, Z Li, J Hu, X Li, H Li, Y Hao, X Li, L
Tang, G Fu, N Wang, J Wang, T Jiang, H Chen, Y
Dong, D Xu, Y Liao, W Jin, Z Yao, J Chen, X
Ji, Y Zheng, R Zhao. Colombia María Elías,
Echeverria Luis, Cotes Carlos, Botero Rodrigo,
Manzur Fernando, Urina Miguel, Torres Adriana,
Jaramillo Mónica, Roa Nubia, Moncada Miguel,
Jaramillo Carlos, Ternera Ernesto, Reynales
Humbert. Costa Rica Arce Mario, Speranza Mario,
Valerio Fernando, Camacho Sergio. Czech Republic
Skalicka Hana, Jerabek Ondrej, Kuchar Roman,
Maratka Tomas, Berka Lubomir, Kuchar Jiri, Kobza
Richard, Smid Jan, Krais Ladislav, Machova Vilma,
Homza Miroslav, Dedkova Svatava, Nechvatal Libor,
Matyasek Ivo, Belohlavek Jan, Naplava Robert, Tyl
Petr, Busak Ladislav, Kochrt Milan. Denmark J
Larsen, N Ralfkjaer, S Rasmussen, P Joergensen, N
Bruun, I Raymond, K Klarlund, J Schou, N
Nielsen, G Gislason, L Koeber, J Nielsen, J
Handberg, O Nielsen, J Petersen, S Hvitfeldt, E
Nielsen, A Vittrup, E Korup, K Egstrup, H
Andersen, J Markenvard, H Rickers, L Videbaek.
Dominican Republic Almonte Claudio, Diaz Pedro,
Pichardo Rafael, Velazco Casimiro, Martinez
Petronila. Estonia R Vettus, V Vahula, M
Reimand, J Eha. Finland I Kantola, J Rinne, T
Keski-Opas, K Nyman, H Kervinen. FranceJuilliere
Yves, Habib Gilbert, Garbarz Eric, Isnard
Richard, Cohen Ariel, Douard Herve, Eicher
Jean-Christophe, Frances Yves-Michel, Salvat
Muriel, Remaud Philippe, Regimbart Christine,
Rumeau Philippe. Germany Duengen Hans-Dirk,
Pauschinger Matthias, Abdel Qader Muwafeg, Abel
Christoph, Ammer Konrad, Aring Ralf, Auch-Schwelk
Wolfgang, Preissner Andreas, Barth Andreas,
Beermann Jens, Schmitt Susanne, Brachmann
Johannes, Brandstetter Ralf, Brode Marcus, Nuding
Sebastian, Claus Gunther, Deissner Michael,
Dengler Thomas, Faghih Markus, Voigt Jan-Gerrit,
Geschke Evelyn, Hofmann Monika, Graemer Gernot,
Grooterhorst Peter, Gutting Matthias, Wachter
Rolf, Hoenen Stefan, Horacek Thomas, Jaensch
Sybille, Jordan Ralf, Frankenstein Lutz,
Klingenheben Thomas, Konermann Martin, Kruck
Irmtraut, Landers Bernhard, Marks Hans-Joachim,
Meffert Christian, Meisel Eckhard, Mitrovic
Veselin, Mueller Otmar, Nagel Frank, Omran
Heyder, Reinig Karsten, Richard Frank,
Sarnighausen Hans-Eckart, Scheibner Thomas,
Schellong Sebastian, Schneider Diethold, Schulze
Matthias, Schweizer Johannes, Stellmach Heiko,
Stelzner Frank, Sulliga Martin, Unkelbach
Manfred, Voehringer Hans-Friedrich, Vormann
Reinhold, Weier Bernd, Werner Gerald, Winkelmann
Bernhard, Wolde Claus-Henning, Schulze Uwe,
Marschner Juergen, Schwerin Gerhard, Holmer
Stephan, Kraemer Alfred, Bott Jochen, Darius
Harald, Osterhues Hans-H, Rieker Werner, de Haan
Fokko, Baar Markus, Hanefeld Christoph, Sanuri
Mazin, Weimer Joachim, Barakat Alain, Henke
Roswitha, Moericke Ruediger, Bodammer Michael,
Schoen Norbert, Baeumer Anselm, Erlinger Rudolf,
Merke Juergen, Taggeselle Jens, Hensen Johannes,
Wichterich Klaus, Hansen Claudius, Gaub Regina,
Killat Holger, Troeger Steffen, Foerster Andreas,
Lankisch Mark, Hohensee Hartmut, Krummenerl
Annette, Becker Bernd, Stratmann Matthias,
Landgraf Irmgard, Stoerk Stefan, Melchior Klaus,
Natour Mohammed, Regner Stefan, Menzel Frank,
Schiffer Clemens, Knapp Markus. Greece J Nanas,
F Gerasimos, T Konstantinos, V Pyrgakis, C
Karvounis, P Makridis, I Zarifis, N Smyrnioudis.
India A Ravikanth, D Talwar, S Selvamani, A
Mohanty, P Kumar, M Thomas, P Reddy, S Mandyam, J
Gupta, B Pinto, N Khanna, S Kareem, T Nair, A
Khan, M Lohkare, J Arneja, V Bisne, S
Suryawanshi, P Grant, V Pai, N Patki, K Jothiraj,
T Alexanader, O Naidu, K Sharma, A Joshi, A
Kapoor, V Narain, V Sharma, V Srinath, V Kale,
K Mohan, A Awasthi, D Chauhan, R Saligrama, S
Sahu, R Polavarapu, A Mahajan, S Washimkar.
Italy Glorioso Nicola, Bernardinangeli Marino,
Aucello Giuseppe, Volpe Massimo, Di Somma
Salvatore, Mos Lucio, Fascetti Ferdinando,
Sinagra Gianfranco, Di Biase Matteo, Bertoli
Daniele, Frisinghelli Anna, Scalvini Simonetta,
Febo Oreste, Brunazzi Maria Cristiana, De
Pellegrin Annamaria, Murrone Adriano, Bosi
Stefano, Marra Sebastiano, Calò Leonardo, Saba
Pier Sergio, Minneci Calogero, Oltrona Visconti
Luigi, Pagnoni Nicoletta, Lembo Giuseppe, Baroni
Monica, Bolognese Leonardo, Caserta Carlo,
Venturini Elio, De Santis Fernando, Margonato
Alberto, De Caterina Raffaele, Piovaccari
Giancarlo, Pedretti Roberto, Agostoni Pier
Giuseppe, Anselmi Maurizio, Opasich Cristina,
Bernardi Daniele, Bianconcini Michele, Ferrini
Donatella, Metra Marco, Baldassi Mara, Cosmi
Franco, Partesana Nora, Fucili Alessandro, Borghi
Claudio, Romei Manuela, Di Lenarda Andrea,
Montagna Laura, Perna Gian Piero, Senni Michele.
Japan T Takenaka, S Taguchi, S Sakagami, A
Hanatani, K Fujii, R Tamura, M Sata, H Urata, T
Muroya, T Yamamoto, T Murohara, T Yamanouchi, M
Yasutake, T Fujii, T Wakeyama, Y Hiasa, T
Inomata, I Tei, T Sakai, T Ogawa, S Joho, Y
Kihara, M Hatano, Y Nagai, S Nanba, Y Sato, S
Kinugawa, M Isobe, H Takano, H Tsuboi, K
Aonuma, Y Seino, M Yamamuro, K Node, K Saku, H
Daida, H Kawata, M Ajioka, H Iida, K Kimura, K
Sugimura, N Hagiwara, A Yamada, S Suzuki, T
Kawasaki, T Iwasawa. Korea B Oh, S Chae, Y Kim,
D Choi, E Jeon, J Ha, H Seo, Y Ahn, J Kim, J Bae,
M Shin, K Ryu. Latvia J Romanova, N Rozkova, I
Veze, A Gersamija. Lithuania A Kavoliuniene, L
Jankauskiene, A Rudys, D Jarasuniene. Mexico
Leon Salvador, Bayram Edmundo, Cardona Ernesto,
Velasco Raul, Gonzalez Guerra Jose, Arenas Jose,
Garcia Elias, De los Rios Manuel. Netherland A
Voors, A.Breeman, R Troquay, J Herrman, J Tanka,
L Cozijnsen, P Keulen, T Lenderink, R Breedveld,
P Nierop, M Freericks, J. Cornel, M Keijzers, P
Hoogslag, J Lok, Y Pinto, M Pieterse, H
Mevissen, D Heijden, J Heymeriks, N Windy.
Norway D Atar, M Moufack, J Otterstad. Peru
Alegre Raul, Coloma Ricardo, Parra Jose, Medina
Felix, Reyes Miguel, Villanueva Francisco, Segura
Luis, Yanac Pedro, Rios Carlomagno, Lema Juan,
Sanabria Enrique, Camacho Luis, Gomez Sanchez
Jorge. Poland Ponikowski Piotr, Tarchalski
Janusz, Sciborski Ryszard, Krzciuk Malgorzata,
Kalarus Zbigniew, Loboz-Grudzien Krystyna,
Nowalany-Kozielska Ewa, Kusnierz Barbara, Derlaga
Boguslaw, Szpajer Michal, Krynicki Romulad,
Kudzelka Jolanta, Dluzniewski Miroslaw,
Swierczynska-Pusz Urszula, Kolodziejczyk Jacek,
Baska Jan, Staneta Pawel, Negrusz-Kawecka Marta,
Napora Piotr, Nadbrzezny Piotr, Wilczewski
Przemyslaw, Golba Krzysztof, Ciemniewski
Zbigniew, Berkowski Piotr, Miekus Pawel, Ogorek
Michal, Bednarski Janusz, Jaworska Krystyna,
Szyszka Andrzej, Zielinski Tomasz, Jankowski
Piotr. Portugal C Fonseca, C Aguiar, M Fiuza, N
Lousada, P Monteiro, P Bettencourt, A Andrade,
P Gago, J Alves, J Bastos. Romania Stanciulescu
Gabriela, Blajan Daniel, Spiridon Marilena,
Virgil Sandru, Pal Istvan Kikeli, Zdrenghea
Dumitru, Vida-Simiti Luminita, Pop Calin Florin,
Calomfirescu Nicoleta, Podoleanu Cristian,
Alexandru Tom Mihai, Popescu Mircea, Radoi
Mariana, Ionac Adina, Tudoran Mariana, Ott
Dragos, Stoenescu Radu, Crisu Daniela, Russia V
Zadionchenko, L Pavlova, T Morozova, S
Martsevich, V Lusov, E Akatova, B Sidorenko, A
Kuchmin, N Gratsiansky, S Yakushin, A Rebrov, Y
Shvarts, P Dovgalevskiy, O Khrustalev, A
Khokhlov, Y Lopatin, S Nedogoda, V Skibitskiy,
R Valeeva, N Maximov, K Zrazhevsky, S Shustov, M
Sitnikova, V Simanenkov, O Berkovich, N
Perepech, S Shulenin, E Maryasova, . Y Nikitin,
O Khromtsova, N Izmozherova, A Kuzin, E
Volkova, I Shaposhnik, N Koziolova, L Gapon, V
Kuznetsov, Y Karpov, V Moiseev, I Nikolskaya, N
Shilkina, Y Shapovalova, A Duda, O Solovev, A
Kuzmenko, V Dvornikov, D Dronov, L Strongin, V
Rezvan. Slovakia Dukat Andrej, Benacka Jozef,
Litvinova Jana, Bugan Viliam, Vinanska Daniela,
Dzupina Andrej, Kohlerova Edita, Kamensky
Gabriel, Uhliar Rudolf, Hranai Marian, Nociar
Jan, Radomska Maria, Farsky Stefan, Toth Peter,
Bodnar Juraj, Horvat Peter, Snincak Marian,
Lasanova Zuzana, Jakubova Ingrid, Kolikova
Veronika, Spisak Vladimir, Gonsorcik Jozef, Juhas
Stanislav, Sojka Gabriel, Spurny Peter. South
Africa E Klug, J Roos, I Ebrahim, M Essop, M
Alison, I Mitha, C Dyk. Spain Garcia Puig Juan,
Delgado Jimenez Juan, Bover Freire Jose Ramon,
Gomez Bueno Manuel, Galve Basilio Enrique, Castel
Lavilla Mª Angeles, Noguero Blum Mariana, Lupon
Roses Josep, Bardaji Alfredo, Ridocci Soriano
Francisco, De Teresa Parreno Luis, Diaz Molina
Beatriz, Castro Almudena, Formiga Perez Francesc,
Calvo Gomez Carlos, Beltran Robles Manuel,
Sanchez Aquino Rosa, Sanz Avertillo Nieves,
Fernandez Romero Antonio Jose, Castro Antonio,
Garcia del Rio Enrique, Martinez-Selles
DOliveira Soa Manuel, Sweden J Ostergren, C
Lindholm, R Zlatewa, K Lindmark, K Boman, S
Berglund, F Al-Khalili, K Jansson, Z Trivic, M
Lycksell, E Andersson, M Fu, L Klintberg, S
Cizinsky, G Vikstroem, M Schaufelberger, U
Lofstrom, S Bandh, P Cherfan, K Tolagen, G
Tasevska. Switzerland F Enseleit, P
Rickenbacher, T Moccetti, S Zbinden, T Burkard, C
Roethlisberger, A Gallino, M Romanens. Taiwan C
Lee, C Hou, M Wen, K Chang, L Tsai, S Chen, W
Lai, Z Chen. Thailand P Sritara, B
Sunsaneewitayakul, A Sukonthasarn, R
Krittayaphong, N Sansanayudh. Turkey D Ural, O
Badak, Y Guray, Z Yigit, S Aydogdu, D
Dursunoglu, T Tekten, C Barcin, M Akin, M
Yilmaz, L Koldas. USA Weiss Robert, Lowes
Brian, Krueger Steven, Wright Richard, Scott
Cranford, Vijay Nampalli, Kuiper Johannes,
VanHammersveld Daniel, Frais Michael, Dauber Ira,
Litt Marc, Wainwright William, Loh Irving, Mody
Freny, Hoagland Peter, Kapoor Divya, Kozinn Marc,
Saba Souheil, Collins Gary, Richards Mary, Saadat
Mohsen, Gress Jeffery, Vossler Mark, Karunaratne
Harischandra, Wu Lambert, Ewald Gregory, Gelernt
Mark, Skopicki Hal, Shah Ronak, Bozkurt
Biykem,Deichmann Richard, Anderson H. Vernon,
Wise Jonathan, Banchs Pieretti Hector, Van Bakel
Adrian, Shealy Neal, Smith Mark, Burnham Kenneth,
Chomsky Donald, Di Salvo Thomas, Haught Herbert,
Massey Clara, McGrew Frank, Schocken Douglas,
Lepor Norman, Johnson David, Pla Alejandro, Davis
Paul, Weber Bruce, Kraus David, Vazquez-Tanus
Jose, Rios De Alonso Maria, Chow Christopher,
Kreher Susan, Chaleff Frederick, Foucauld Jean,
Henderson David, Hargrove Joe, Brown Christopher,
Iteld Bruce, McKenzie Wilfred, Akinboboye
Olakunle, Weinstein Debra, Rama Bhola. Venezuela
Isea Jesus, Antepara Norka, Guevara Lempira,
Gonzalez Alicex, Beer Nusen, Diaz Luis, Maitas
Leonardo, Geraldino Oscar, Marulanda Maria,
Mendoza Ivan.    Sponsor, Novartis Established
Medicines Development Franchise (Current) Paul
Aftring, David Aitken, M. Atif Ali, Lutz
Hegemann, Georgia Tarnesby. Previous
(Development Franchise) Juergen Armbrecht,
Claudio Gimpelewicz, Deborah Keefe, Anastasia
Lesogor, Maria Nicolaides, Bernard
Reimund. Global Clinical Operations Current
Stephanie Barou, Ashwini Belsare, Ilse Devrieze,
Vishal Mishra, Julien Roustan, Asit Shete,
Abhishek Sople, Cathy Surdouski. Previous
Nicolas Carlo, Sreekanth Kunchetty, Arshad
Nehaljamali, Amit Padadharia, Ursula Potts.
Local Clinical Operations Gabriela Arantes
(Argentina) Kathryn Stephens (Australia) Yvonne
Tomberger, Sarah Keusch (Austria) Bart Ryckaert,
Caroline Guinee (Belgium) Oliveira Carolina
(Brazil) Pascale Raymond, Caroline Garneau
(Canada) Wu Ying (China) Andrea Romero
(Colombia) Carolina Schoua (Costa Rica,
Dominican Republic) Stepanka Vejsadova, Martina
Hajkova, Martin Vrlik (Czech Republic) Sissel
Nustad (Denmark, Finland, Norway, Sweden)
Natalija Robacevskiene (Estonia, Latvia,
Lithuania) Sabine Sauger, Thierry Gormon
(France) Frauke Krepulat, Jane Stilmann,
Jennifer Etschel (Germany) Vaia Koutra (Greece)
Akshatha Shetty (India) Rajinder Nerwan
(Ireland, United Kingdom) Ilic Orsini (Italy)
Hideki Maruyama (Japan) Hyezue Lee (Korea)
Jorge Rojas (Mexico) Nine van Zadelhoff
 (Netherland) Alexandra Lopez (Peru) Magdalena
Michalewicz (Poland) Sara Esteves
(Portugal)Silviu Morariu, Selena Boghiu
(Romania) Alexander Lents (Russia) Alexandra
Lelkesova, Robert Vavra (Slovakia) Lindie Traut
(South Africa) Enrique Fernandez Taboada
(Spain) Oliver Meub (Switzerland) Jenny Huang
(Taiwan) Supunnee Kittisiriprasert (Thailand)
Nurhat Bayraktar (Turkey) Linda Ivankoe (USA)
Odalys Sosa (Venezuela). Integrated Information
Systems Current Yanntong Chiang, Nathalie
Ezzet, Hui Fang, Santhosh Lyathakula, Sarmistha
Roy, Qing Shao. Previous Albert Kandra. Drug
Supply Management Tamara Spuergin.
Thank You