Clinical trial NCT03904693: Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
Official title: Prospective, Multi-center, Double-blind, Randomized, Active-controlled, Triple-dummy, Parallel-group, Group-sequential, Adaptive Phase 3 Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed Dose Combination in Subjects With Pulmonary Arterial Hypertension (PAH), Followed by an Open-label Treatment Period With Macitentan and Tadalafil Fixed Dose Combination Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
Keywords: Pulmonary Arterial Hypertension
PAH
macitentan
tadalafil
fixed dose combination therapy
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2019-04-05
Enrollment: 187
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In total, approximately 170 subjects are planned to be randomized into study to receive either FDC macitentan/tadalafil or macitentan 10 mg or tadalafil 40 mg given once daily and will also receive matching placebos for two other study treatments. Treatment allocation will be stratified based on prior PAH therapy (i.e., treatment-naïve or treated by an Endothelin receptor antagonist or a Phosphodiesterase type-5 inhibitor as a monotherapy) at baseline. Sample size will be re-estimated at interim analysis if study is not terminated early for efficacy/futility up to sample size of 150-250. After completion of double-blind treatment period, subjects will continue study in an open-label treatment (OLT) period for 24 months, which may be prolonged beyond 24 months until macitentan and tadalafil are accessible at required doses, through other options according to local regulations. All assessments at end of double-blind treatment must be completed before subject enters OLT period.
Primary purpose: TREATMENT

Brief summary: Combination therapy in pulmonary arterial hypertension (PAH) has been the subject of active investigation for more than a decade, with the benefit of targeting different pathways known to be involved in the pathogenesis of the disease. Adherence to prescribed therapy has an impact on clinical outcomes. Reducing the pill/tablet count and frequency has a major impact on patients' adherence to therapies and therefore the observed clinical outcomes. One way to simplify treatment is to use fixed-dose combination (FDC) products that combine multiple treatments targeting different pathways into a single tablet.

This study aims to demonstrate that the FDC of macitentan and tadalafil is more effective than therapy with 10 mg of macitentan alone or 40 mg of tadalafil alone. This phase 3 study will evaluate the efficacy and safety at 16 weeks of an FDC (macitentan 10 mg and tadalafil 40 mg) against these two PAH-approved therapies given as monotherapy to further confirm the added value of the FDC.

Detailed description: PAH is characterized by a progressive increase in pulmonary arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading to right heart failure and death. Current PAH-specific therapeutic options include treatments that target the three pathways (endothelin, nitric oxide, and prostacyclin pathways). While combination treatment is common, FDC pills or tablets that combine two or more PAH-specific therapies are not available, thereby requiring participants to take multiple pills/tablets daily. An FDC is an attractive option for PAH participants because it simplifies the treatment regimen by combining two therapies (which would otherwise involve a total of three tablets: one macitentan 10 mg tablet and two tadalafil 20 mg tablets) into a single tablet. Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B antagonist. Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). This study comprises the following consecutive periods: Screening period (lasts up to 30 days), Double-blind treatment period (consists of the titration phase \[the first 2 weeks\] and the maintenance phase \[Week 3 through Week 16\]), Open-label treatment period, End-of-Treatment (EOT), Safety follow-up (S-FU) period, and End of Study (EOS). The total study duration for a participant will be up to 30 months. Study assessments like physical examinations, vital signs, right heart catheterization, 6-minute walk test will be performed. Safety will be assessed throughout the study.

Eligibility criteria: Inclusion Criteria:

* Signed and dated informed consent form (ICF)
* Confirmed diagnosis of symptomatic PAH in WHO FC II or III
* Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary hypertension:

  * Idiopathic
  * Heritable
  * Drug- or toxin-induced
  * Associated with connective tissue disease, HIV infection, portal hypertension or congenital heart disease with simple systemic-to-pulmonary shunt with persistent pulmonary hypertension documented by a right heart catheterization (RHC) ≥ 1 year after surgical repair
* PAH diagnosis confirmed by hemodynamic evaluation at rest (through central reading), evaluated within 5 weeks prior to randomization:

  * Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, AND
  * Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg, AND
  * Pulmonary vascular resistance (PVR) ≥ 3 WU (i.e., ≥ 240 dyn∙sec∙cm-5)
* Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH. (Participants for whom no vasoreactivity test was performed at diagnosis can be eligible if currently treated with PAH therapy for more than 3 months and PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after introduction of their PAH therapy).
* Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the prespecified doses in the study protocol or no history of PAH-specific treatment
* Participant able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at Screening
* A woman of childbearing potential must:

  * have negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization
  * agree to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation
  * agree to follow the contraception scheme from Screening up to at least 30 days after study treatment discontinuation

Exclusion Criteria:

* Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period prior to start of treatment
* Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior to start of treatment or history of intolerance to ERA and PDE-5i combination therapy
* Hypersensitivity to any of the study treatments or any excipient of their formulations
* Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer in the 1-month period prior to start of treatment
* Treatment with a strong CYP3A4 inhibitor or a moderate dual CYP3A4/CYP2C9 inhibitor or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period prior to start of treatment
* Treatment with doxazosin
* Treatment with any form of organic nitrate, either regularly or intermittently
* Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of treatment
* Treatment with another investigational drug in the 3-month period prior to start of treatment
* Body mass index (BMI) \> 40 kg/m2 at Screening
* Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening:

  * BMI \> 30 kg/m2
  * Diabetes mellitus of any type
  * Essential hypertension (even if well controlled)
  * Coronary artery disease, i.e. history of stable angina or known more than 50% stenosis in a coronary artery or history of myocardial infarction or history of or planned coronary artery bypass grafting and/or coronary artery stenting
* Known presence of moderate or severe obstructive lung disease any time prior to Screening as specified in study protocol
* Known presence of moderate or severe restrictive lung disease any time prior to Screening as specified in study protocol
* Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction, in the opinion of the investigator
* Known permanent atrial fibrillation, in the opinion of the investigator
* Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism)
* Documented pulmonary veno-occlusive disease
* Hemoglobin \< 100 g/L (\<10 g/dL) at Screening
* Known severe hepatic impairment as specified in study protocol
* Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 1.5 × upper limit of normal (ULN) at Screening
* Severe renal impairment at Screening as specified in study protocol
* Systemic hypotension at Screening or Randomization and systemic hypertension at Screening as specified in study protocol
* Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening
* Known bleeding disorder, in the opinion of the investigator
* Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic neuropathy
* Hereditary degenerative retinal disorders, including retinitis pigmentosa
* History of priapism, conditions that predispose to priapism (example, sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (example, angulation, cavernosal fibrosis, or Peyronie's disease)
* Difficulty swallowing large pills/tablets that would interfere with the ability to comply with study treatment regimen
* Any planned surgical intervention (including organ transplant) during the double-blind treatment period, except minor interventions
* Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to start of treatment, or planned to be started during the double-blind period of the study
* Pregnant, planning to become pregnant or lactating
* Any known factor or disease that might interfere with treatment adherence, full participation in the study or interpretation of the results as judged by the investigator (e.g., drug or alcohol dependence etc.)
* Known concomitant life-threatening disease with a life expectancy less than (\<) 12 months
* Calcium channel blocker treatment initiated, or dose changed within 3 months prior to right heart catheterization (RHC) at screening

Primary outcomes:
measure: Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline
timeFrame: Baseline, EDBT (up to 16 weeks)
Secondary outcomes:
measure: Change From Baseline in 6-minutes Walking Distance (6MWD) to EDBT
timeFrame: Baseline, EDBT (up to 16 weeks)
measure: Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT
timeFrame: Baseline, EDBT (up to 16 weeks)
measure: Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT
timeFrame: Baseline, EDBT (up to 16 weeks)
measure: Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline to EDBT
timeFrame: Baseline, EDBT (up to 16 weeks)
Other outcomes:
Locations:
city: Fullerton
country: United States
facility: Providence Medical Foundation
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Atlanta
country: United States
facility: Piedmont Healthcare
state: Georgia
city: Marietta
country: United States
facility: WellStar Health System
state: Georgia
city: Peoria
country: United States
facility: OSF HealthCare Cardiovascular Institute
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Louisville
country: United States
facility: Norton Healthcare
state: Kentucky
city: Lansing
country: United States
facility: Sparrow Clinical Research Institute
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute Foundation
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School Of Medicine
state: Missouri
city: Reno
country: United States
facility: VA Sierra Nevada Health Care System
state: Nevada
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill
state: North Carolina
city: Greenville
country: United States
facility: Pitt County Memorial Hospital d/b/a Vidant Medical Center
state: North Carolina
city: Fargo
country: United States
facility: Sanford Health
state: North Dakota
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Youngstown
country: United States
facility: St. Elizabeth Hospital Mercy Bon Secors
state: Ohio
city: Portland
country: United States
facility: Legacy Hospital
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sanford Health
state: South Dakota
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Plano
country: United States
facility: Baylor Scott White - Plano
state: Texas
city: Morgantown
country: United States
facility: WVU Health Sciences Center
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin At Madison
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin Froedtert Hospital
state: Wisconsin
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Hobart
country: Australia
facility: Pulmonary Arterial Hypertension Clinic
city: Milton
country: Australia
facility: Core Research Group
city: Belo Horizonte
country: Brazil
facility: Universidade Federal De Minas Gerais - Hospital das Clínicas
city: Belo Horizonte
country: Brazil
facility: Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa
city: Botucatu
country: Brazil
facility: Fundacao para o Desenvolvimento Medico Hospitalar (UNESP Botucatu)
city: Fortaleza
country: Brazil
facility: Secretaria da Saude do Estado do Ceara - Hospital Doutor Carlos Alberto Studart Gomes
city: Goiania
country: Brazil
facility: Universidade Federal de Goias - Hospital das Clinicas da UFG
city: Porto Alegre
country: Brazil
facility: Hospital das Clinicas de Porto Alegre
city: Porto Alegre
country: Brazil
facility: Irmandade Santa Casa de Misericordia de Porto Alegre
city: Porto Alegre
country: Brazil
facility: Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da PUCRS
city: Sao Paulo
country: Brazil
facility: Hospital Das Clinicas Da Faculdade De Medicina Da USP
city: São Paulo
country: Brazil
facility: SPDM - Associacao Paulista para o Desenvolvimento da Medicina - Hospital Sao Paulo
city: Sofia
country: Bulgaria
facility: National Heart Hospital
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD
city: Calgary
country: Canada
facility: Alberta Health Services
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Beijing
country: China
facility: Beijing Anzhen Hospital
city: Changsha
country: China
facility: The Second Xiangya Hospital of Central South Hospital
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University
city: Nanjing
country: China
facility: Jiangsu Province Hospital
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital
city: Shenyang
country: China
facility: The General Hospital of Northern Theater Command
city: Tian Jin
country: China
facility: Tianjin Medical University General Hospital
city: Xi'An
country: China
facility: The First Affiliated Hospital of Xian Jiaotong University
city: Praha 2
country: Czechia
facility: General University Hospital II.department of Internal Medicine-cardiology and angiology
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus Dresden
city: Giessen
country: Germany
facility: Universitaetsklinikum Giessen
city: Greifswald
country: Germany
facility: Universitat Greifswald
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg Eppendorf
city: Heidelberg
country: Germany
facility: Thoraxklinik am Universitatsklinikum Heidelberg
city: Papenburg
country: Germany
facility: Kardiologische Praxis Papenburg
city: Regensburg
country: Germany
facility: Universitaetsklinikum Regensburg
city: Würzburg
country: Germany
facility: Klinikum Würzburg Mitte gGmbH Standort Missioklinik
city: Budapest
country: Hungary
facility: Semmelweis Egyetem,Pulmonológiai Klinika
city: Budapest
country: Hungary
facility: Gottsegen György Országos Kardiológiai Intézet, Felnőtt kardiológiai osztály
city: Pecs
country: Hungary
facility: Pecsi Tudomanyegyetem Klinikai Kozpont
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem
city: Bari
country: Italy
facility: Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
city: Brescia
country: Italy
facility: Cardiologia c/o Spedali Civili
city: Milano
country: Italy
facility: Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
city: Monza
country: Italy
facility: Azienda Ospedaliera San Gerardo
city: Nuoro
country: Italy
facility: Ospedale San Francesco
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo, Università degli studi di Pavi
city: Roma
country: Italy
facility: Policlinico Umberto I
city: Bunkyo
country: Japan
facility: The University of Tokyo Hospital
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Fukushima
country: Japan
facility: Fukushima Medical University Hospital
city: Gunma
country: Japan
facility: Gunma University Hospital
city: Hiroshima
country: Japan
facility: Kure Kyosai Hospital
city: Isehara
country: Japan
facility: Tokai University Hospital
city: Kagoshima City
country: Japan
facility: Kagoshima University Hospital
city: Kanazawa
country: Japan
facility: Kanazawa University Hospital
city: Kobe
country: Japan
facility: Kobe University Hospital
city: Kumamoto-City
country: Japan
facility: Kumamoto University Hospital
city: Kurume
country: Japan
facility: Kurume University Hospital
city: Kyoto
country: Japan
facility: University Hospital Kyoto Prefectural University of Medicine
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Matsumoto
country: Japan
facility: Shinshu University Hospital
city: Mitaka
country: Japan
facility: Kyorin University Hospital
city: Nagasaki-shi
country: Japan
facility: Nagasaki University Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Okayama
country: Japan
facility: National Hospital Organization Okayama Medical Center
city: Sapporo-shi
country: Japan
facility: Hokkaido University Hospital
city: Sapporo
country: Japan
facility: Sapporo Medical University Hospital
city: Sendai
country: Japan
facility: Tohoku University Hospital
city: Suita-Shi
country: Japan
facility: National Cerebral and Cardiovascular Center
city: Tokyo
country: Japan
facility: Juntendo University Hospital
city: Tsukuba City
country: Japan
facility: University of Tsukuba Hospital
city: Tsu
country: Japan
facility: Mie University Hospital
city: Kuala Lumpur
country: Malaysia
facility: Institut Jantung Negara (National Heart Institute)
city: Kuching
country: Malaysia
facility: Sarawak Heart Center
city: Mexico
country: Mexico
facility: Instituto Nacional de Cardiologia Dr. Ignacio Chavez
city: Monterrey
country: Mexico
facility: Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)
city: Bialystok
country: Poland
facility: Klinika Kardiologii Z Oddzialem Intensywnego Nadzoru Kardiologicznego UM W Bialymstoku
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 2 im dr Jana Biziela w Bydgoszczy, Klinika Kardiologii
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Katowice
country: Poland
facility: GCM SUM I Oddzial Kardiologii
city: Lodz
country: Poland
facility: Oddzial Kardiologii Wojewodzki Szpital Specjalistyczny im W Bieganskiego
city: Lublin
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego SPZOZ, Oddzial Kardiologii
city: Otwock
country: Poland
facility: ECZ Otwock Klinika Kardiologii Klinika Krazenia Plucnego Chorob Zakrzepowo Zatorowych i Kardiologii
city: Szczecin
country: Poland
facility: Uniwersytecki Szpital Kliniczny nr 2 PUM Klinika Kardiologii
city: Wroclaw
country: Poland
facility: Wojewodzki Szpital Specjalistyczny Oddzial Kardiologiczny
city: Barnaul
country: Russian Federation
facility: Altay Regional Cardiological Dispensary
city: Kemerovo
country: Russian Federation
facility: Scientific and Research Institution of Cardiovascular Diseases Complex Problems
city: Moscow
country: Russian Federation
facility: National Medical Research Center of Cardiology of MoH of Russian Federation
city: Moscva
country: Russian Federation
facility: GU Moscow Regional Research Clinical Institute n.a. M.F.Vla
city: Saint-Petersburg
country: Russian Federation
facility: National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation
city: Samara
country: Russian Federation
facility: Samara Regional Clinical Cardiological Dispensary
city: Durban
country: South Africa
facility: Abdullah, IA
city: Lenasia
country: South Africa
facility: Dr Kalla
city: Barcelona
country: Spain
facility: Hosp Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hosp Univ Vall D Hebron
city: Madrid
country: Spain
facility: Hosp. Univ. Ramon Y Cajal
city: Madrid
country: Spain
facility: Hosp Univ Fund Jimenez Diaz
city: Madrid
country: Spain
facility: Hosp. Univ. La Paz
city: Salamanca
country: Spain
facility: Hosp Clinico Univ de Salamanca
city: Santander
country: Spain
facility: Hosp. Univ. Marques de Valdecilla
city: Toledo
country: Spain
facility: Hosp. Virgen de La Salud
city: Valencia
country: Spain
facility: Hosp. Gral. Univ. Valencia
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: Chang-Gung Memorial Hospital, LinKou Branch
city: Adana
country: Turkey
facility: Cukurova University Medical Faculty
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Ankara
country: Turkey
facility: Ankara University Medical Faculty
city: Bursa
country: Turkey
facility: Bursa Yuksek Ihtisas Training and Research Hospital
city: Istanbul
country: Turkey
facility: Istanbul University - Cerrahpasa Cardiology Institution
city: Istanbul
country: Turkey
facility: Istanbul University Cerrahpasa Medical Faculty
city: Istanbul
country: Turkey
facility: Marmara University Medical Faculty
city: Izmir
country: Turkey
facility: Ege University School of Medicine
city: Izmir
country: Turkey
facility: Dokuz Eylul University Hospital
city: Kartal Istanbul
country: Turkey
facility: Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi
city: Konya
country: Turkey
facility: Konya Selcuk University Medical Faculty
city: Mersin
country: Turkey
facility: Mersin University Medical Faculty
Study officials:
affiliation: Janssen, LP
name: Hany Rofael, MD
role: STUDY_DIRECTOR
References: