Cystic FibrosisPhase 3NCT02134353
A Safety and Efficacy Trial of Inhaled Mannitol in Adult Cystic Fibrosis Subjects
A Phase 3 study testing Inhaled mannitol in people with Cystic Fibrosis, run by Syntara at 100 sites in 18 countries.
Trial summary
This trial aims to provide prospective evidence of the safety and efficacy of mannitol 400 mg b.i.d. in subjects aged 18 years and above. We hypothesize that inhaled mannitol 400 mg b.i.d. Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Cystic Fibrosis
- What is being tested?
- Inhaled mannitol
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 423 participants
- Where
- 100 sitesin 18 countries
- Study dates
- Sep 2014to Feb 2017
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Have given written informed consent to participate in this trial in accordance with local regulations;
- Have a confirmed diagnosis of cystic fibrosis (positive sweat chloride value ≥ 60 mEq/L) and/or genotype with two identifiable mutations consistent with CF, accompanied by one or more clinical features consistent with the CF phenotype);
- Be aged at least 18 years old;
- Have FEV1 > 40 % and < 90% predicted (using NHanes III [1]);
- Be able to perform all the techniques necessary to measure lung function;
- Be adherent with maintenance therapies (antibiotics and or rhDNase), if used, for at least 80% of the time in the two weeks prior to visit 1 and
- If rhDNase and/or maintenance antibiotic are being used treatment must have been established at least 1 month prior to screening (Visit 0). The subject should remain on the rhDNase and / or maintenance antibiotics for the duration of the trial. The subject should not commence treatment with rhDNase or maintenance antibiotics during the trial
Who cannot join
- Be investigators, site personnel directly affiliated with this trial, or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biologically or legally adopted;
- Be considered "terminally ill" or eligible for lung transplantation;
- Have had a lung transplant;
- Be using maintenance nebulized hypertonic saline in the 2 weeks prior to visit 1;
- Have had a significant episode of hemoptysis (> 60 mL) in the three months prior to Visit 0;
- Have had a myocardial infarction in the three months prior to Visit 0;
Show all 19Show fewer
- Have had a cerebral vascular accident in the three months prior to Visit 0;
- Have had major ocular surgery in the three months prior to Visit 0;
- Have had major abdominal, chest or brain surgery in the three months prior to Visit 0;
- Have a known cerebral, aortic or abdominal aneurysm;
- Be breast feeding or pregnant, or plan to become pregnant while in the trial;
- Be using an unreliable form of contraception (female subjects at risk of pregnancy only);
- Be participating in another investigative drug trial, parallel to, or within 4 weeks of screening (Visit 0);
- Have a known allergy to mannitol;
- Be using non-selective oral beta blockers;
- Have uncontrolled hypertension -i.e. systolic BP > 190 and / or diastolic BP > 100;
- Have a condition or be in a situation which in the Investigator's opinion may put the subject at significant risk, may confound results or may interfere significantly with the subject's participation in the trial;or
- Have a failed or incomplete MTT at trial entry (as evaluated in Section 8.1.1.1).
- The subject must not commence treatment with rhDNase or maintenance antibiotics during the trial.
Trial locations and contacts
100 sites in 18 countries.
100 sites in 18 countries
United States36 sites
Akron Children's Hospital
Akron, Ohio, 44308
John Hopkins
Baltimore, Maryland, 21287
Dartmouth-Hitchcock Specialty Care
Bedford, New Hampshire, 03110
Massachusetts General Hospital
Boston, Massachusetts, 62114
Medical University of SC
Charleston, South Carolina, 29425
University of Cincinnati
Cincinnati, Ohio, 45267-0564
One Richland Medical Park
Columbia, South Carolina, 29203
Nationwide Children's Hospital
Columbus, Ohio, 43205
The Children's Medical Center of Dayton
Dayton, Ohio, 45404
Cystic Fibrosis Center of Chicago
Glenview, Illinois, 60025
Spectrum Health Offices of Research Administration
Grand Rapids, Michigan, 49503
Hartford Hospital
Hartford, Connecticut, 06102
University of Mississippi Medical Center
Jackson, Mississippi, 39216
Dr Mitchell Rothstein
Jacksonville, Florida, 32204
University of Kansas Hospital
Kansas City, Kansas, 64081
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205
Pediatric Pulmonology
Long Beach, California, 90806
Kosair Charities Pediatric Clinical Research Unit
Louisville, Kentucky, 40202
Loyola University Medical Center
Maywood, Illinois, 60153
University of Miami
Miami, Florida, 33136
University of Minnesota
Minneapolis, Minnesota, 55455
Dr Lawrence Sinde
Mobile, Alabama, 36608
Long Island Jewish Medical Center
New Hyde Park, New York, 11040
The Cystic Fibrosis Center Beth Israel Medical Center
New York, New York, 10003
Pediatric Pulmonary & CF Center
Oklahoma City, Oklahoma, 73104
Dr Santiago Reyes
Oklahoma City, Oklahoma, 73112
Central Florida Pulmonary Group, P.A.
Orlando, Florida, 32803
Illinois Lung Institute
Peoria, Illinois, 61537
Pediatric Clinic
Portland, Oregon, 97227
University of CA, Davis
Sacramento, California, 95817
University of Washington
Seattle, Washington, 98195
Dr Joseph Ojile
St Louis, Missouri, 63143
Tampa General Hospital
Tampa, Florida, 33606
The Toledo Hospital and Toledo Childrens Hospital
Toledo, Ohio, 43606
University of Arizona
Tucson, Arizona, 85724
Dr Allen Dozor
Valhalla, New York, 10595
Italy7 sites
Spedali Civili Brescia
Brescia
IRCCS Ca' Granda Ospedale Maggiore Policlinico Mil
Milan
AOU San Luigi Gonzaga
Orbassano
Aziendao Spedaliera Universitaria
Parma
Cystic Fibrosis Center Hospital San Carlo
Potenza
Centro Fibrosi Cistica Policlinico Umberto I
Roma
Azienda Ospedaliera Universitaria Integratadi Verona
Verona
Poland7 sites
Szpital Dziecięcy Polanki im. M. Płażyńskiego w Gdańsku sp.
Gdansk, 80-308
Centrum Medyczne Karpacz SA
Karpacz, 58-540
Wojewodzki Specjalistyczny Szpital Dzieciecy im. W. Buszkowskiego
Kielce, 25-381
Wojewodzki Szpital Specjalistyczny im.
Lodz, 93-513
Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu
Poznan, 60-569
Sanatorium Cassia-Villa Medica S.C.
Rabka-Zdrój, 34-700
Podkarpacki Osrodek Pulmonologii i Alergologii
Rzeszów, 35-612
Argentina5 sites
Hospital Interzonal General de Agudos Dr. Jose Penna
Bahía Blanca, 2401 (8001)
Hospital del Tórax Cetrángolo
Buenos Aires, 1750
Hospital Regional Español de Bahía Blanca
Buenos Aires, 8000
Hospital San Roque
Córdoba, 1900 (5000)
Insares
Mendoza, Mendoza Province, M5500CCG
Russia5 sites
Tatiana I. Martynenko
Barnaul, 656045
Pulmonology Research Institute
Moscow, 105077
Research and Clinical Center of interstitial and orphan lung diseases
Saint Petersburg
Mikhail Smirnov
Vladimir, 600023
Clinical Hospital# 2
Yaroslavl, 150010
Spain5 sites
Hospital Universitario Virgen de la Arrixaca
El Palmar
Hospital Universitaro La Paz
Madrid, 28046
Hospital Universitario Central de Asturias
Oviedo, 33006
Hospital Virgen del Rocio Hospital Unidad de Fibrosis Quistica
Seville, 41013
Hospital Universitario La Fe Neumología
Valencia, 46026
Ukraine5 sites
Dnipropetrovsk State Medical Academy, Faculty Theraphy and Endocrinology Chair
Dnipropetrovsk, 49044
Municipal Institution "Kherson City Clinical Hospital n.a. Afanasiy and Olha Tropin
Kherson, 73000
Kremenchuk First City Hospital n.a. O.T.Bogaevskyy
Kremenchuk, 396170
Department of Pulmonology and Thoracic Surgery of Public Institution " Kryvyy Rig City Clinical Hospital # 8
Kryvyy Rig, 50047
Hospital Department of Municipal Institution "Zaporizhzhya Regional Clinical Hospital"
Zaporizhzhya, 69600
Hungary4 sites
Országos Korányi Tbc
Budapest, H-1125
Klinikai Farmakológiai Központ
Debrecen, H-1031
Mosdós Tüdőgyógyintézet
Mosdós, H-7257
Törökbálint Tüdőgyógyintézet
Törökbálint, H-2045
Mexico4 sites
Instituto Jaliscience de Investigacion Clinica
Guadalajara, 44100
Unidad Médica de Occidente
Guadalajara, 44220
Arke Estudios Clinicos S.A
Mexico City, CP 6700
CEPREP- Hospital Universitario
Monterrey, 64460
Romania4 sites
Institutul pentru Ocrotirea Mamei si Copilului "Alfred Rusescu"
Bucharest, 020395
Institutul de Pneumoftiziologie "Marius Nasta" Bucuresti, Sectia Clinica Pneumologie V
Bucharest, 050159
Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca
Cluj-Napoca, 400371
Spitalul Clinic de Pneumoftiziologie Lasi
Lasi, 700115
Belgium3 sites
UZ VUB
Brussels, B-1090
UZ Leuven
Leuven, B-3000
CHR Citadelle
Liège, 4000
Canada3 sites
QEII Health Sciences Center
Halifax, B3H 3A7
Institut de recherches cliniques de Montréal
Montreal, H2X 2L0
The Ottawa Hospital, General Campus
Ottawa, K1H 8L6
New Zealand3 sites
Greenlane Hospital
Auckland
Canterbury Respiratory Research Group
Christchurch, 8011
Otago Respiratory Research Unit, Dunedin Hospital
Dunedin
Slovakia3 sites
Oddelenie pneumológie a ftizeológie
Banská Bystrica, 975 17
Imuno-alergologická ambulancia
Bratislava, 825 56
Detská fakultná nemocnica Košice
Košice, 040 11
Israel2 sites
Pediatrics Pulmonary Department Rambam Healthcare Campus
Haifa, 31096
Schneider Children's Medical Center of Israel
Petah Tikva, 49202
South Africa2 sites
University of Cape Town Lung Institute
Cape Town, 7700
St. Augustine's Medical Centre 2
Durban, 4001
About this study
Official title: Long Term Administration of Inhaled Mannitol in Cystic Fibrosis - A Safety and Efficacy Trial in Adult Cystic Fibrosis Subjects
This trial aims to provide prospective evidence of the safety and efficacy of mannitol 400 mg b.i.d. in subjects aged 18 years and above.
We hypothesize that inhaled mannitol 400 mg b.i.d. will increase the mean change from baseline FEV1 (mL) compared to control over the 26-week treatment period in adult subjects with cystic fibrosis. Any improvement in FEV1 is considered clinically meaningful, however, this trial has set a threshold of 80 mL for the purposes of determining an appropriate sample size for statistical power while retaining trial feasibility in an orphan disease population
Read the detailed description
This is a double-blind, randomized, parallel arm, controlled, multicenter, and interventional clinical trial. Potential subjects will sign the informed consent form (ICF) and be assessed for eligibility. After satisfying all inclusion \& exclusion criteria, subjects will be given a mannitol tolerance test (MTT). Those subjects that pass the MTT will be randomized to receive inhaled mannitol (400 mg b.i.d.) or control b.i.d. for a period of 26-weeks.
- Conditions
- Cystic Fibrosis
- Being tested
- Inhaled mannitol, Placebo Comparator: Arm B - Control
- Medical subject headings
- Cystic Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Inhaled mannitolDrug
Inhaled mannitol 400 mg BD for 26 weeks
Placebo Comparator: Arm B - ControlDrug
Placebo Comparator: Arm B - Control BD for 26 weeks
| Study group | Role | What they receive |
|---|---|---|
| Experimental arm A | Experimental | Active treatment. Inhaled Mannitol Receives: Drug: Inhaled mannitol |
| Arm B - Control | Placebo comparator | Arm B Receives: Drug: Placebo Comparator: Arm B - Control |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4).
The mean absolute change from baseline FEV1 (mL) over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach.
Least square means presented are for the average change over the 6, 14, and 26 week visits.
Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).
Measured: 26 weeks
Secondary outcomes (1)
Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period
To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control for improving lung function as measured by mean change from baseline forced vital capacity (FVC) (mL) over the 26-week treatment period in adult subjects with cystic fibrosis (CF).
The mean absolute change from baseline FVC (mL) over 26 weeks will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach.
Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks).
Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).
Measured: 26 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2014 (estimated)
- Study startSep 2014
- Primary completionFeb 2017
- Study completionFeb 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cystic FibrosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 423 participants (actual)
Sponsor and investigators
- Lead sponsor
- Syntara
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Moira Aitken, MD, Principal investigatorBrett Charlton, MD, Study director, Medical Director
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02134353
- Sponsor's protocol ID
- DPM-CF-303
- Status last verified
- Oct 2020
- First submitted
- 16 Apr 2014
- Last updated
- 28 Oct 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Flume PA, Amelina E, Daines CL, Charlton B, Leadbetter J, Guasconi A, Aitken ML. Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study. J Cyst Fibros. 2021 Nov;20(6):1003-1009. doi: 10.1016/j.jcf.2021.02.011. Epub 2021 Mar 11.
PubMed 33715994
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Long Term Administration of Inhaled Mannitol in Cystic Fibrosis - A Safety and Efficacy Trial in Adult Cystic Fibrosis Subjects
- ClinicalTrials.gov ID
- NCT02134353
- Acronym / sponsor ID
- DPM-CF-303
- Conditions
- Cystic Fibrosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 423 participants (actual)
- Lead sponsor
- SyntaraIndustry (pharma, biotech, devices)
- Study start
- Sep 2014 (actual)
- Primary completion
- Feb 2017 (actual)
- Study completion
- Feb 2017 (actual)
- First posted
- 9 May 2014 (estimated)
- Results
- Posted 3 Sep 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This trial aims to provide prospective evidence of the safety and efficacy of mannitol 400 mg b.i.d. in subjects aged 18 years and above.
We hypothesize that inhaled mannitol 400 mg b.i.d. will increase the mean change from baseline FEV1 (mL) compared to control over the 26-week treatment period in adult subjects with cystic fibrosis. Any improvement in FEV1 is considered clinically meaningful, however, this trial has set a threshold of 80 mL for the purposes of determining an appropriate sample size for statistical power while retaining trial feasibility in an orphan disease population
Detailed description
This is a double-blind, randomized, parallel arm, controlled, multicenter, and interventional clinical trial. Potential subjects will sign the informed consent form (ICF) and be assessed for eligibility. After satisfying all inclusion \& exclusion criteria, subjects will be given a mannitol tolerance test (MTT). Those subjects that pass the MTT will be randomized to receive inhaled mannitol (400 mg b.i.d.) or control b.i.d. for a period of 26-weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Experimental arm A | Experimental | Drug: Inhaled mannitolActive treatment. Inhaled Mannitol |
| Arm B - Control | Placebo comparator | Drug: Placebo Comparator: Arm B - ControlArm B |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Have given written informed consent to participate in this trial in accordance with local regulations;
- Have a confirmed diagnosis of cystic fibrosis (positive sweat chloride value ≥ 60 mEq/L) and/or genotype with two identifiable mutations consistent with CF, accompanied by one or more clinical features consistent with the CF phenotype);
- Be aged at least 18 years old;
- Have FEV1 > 40 % and < 90% predicted (using NHanes III [1]);
- Be able to perform all the techniques necessary to measure lung function;
Key exclusion criteria (19 listed)
- Be investigators, site personnel directly affiliated with this trial, or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biologically or legally adopted;
- Be considered "terminally ill" or eligible for lung transplantation;
- Have had a lung transplant;
- Be using maintenance nebulized hypertonic saline in the 2 weeks prior to visit 1;
- Have had a significant episode of hemoptysis (> 60 mL) in the three months prior to Visit 0;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Inhaled mannitolInhaled mannitol 400 mg BD for 26 weeks | Drug | Experimental arm A |
| Placebo Comparator: Arm B - ControlPlacebo Comparator: Arm B - Control BD for 26 weeks | Drug | Arm B - Control |
Primary outcome
Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4).
Time frame: 26 weeks
The mean absolute change from baseline FEV1 (mL) over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the average change over the 6, 14, and 26 week visits. Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).
1 secondary outcome
Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period
Time frame: 26 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33715994Flume PA, Amelina E, Daines CL, Charlton B, Leadbetter J, Guasconi A, Aitken ML. Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study. J Cyst Fibros. 2021 Nov;20(6):1003-1009. doi: 10.1016/j.jcf.2021.02.011. Epub 2021 Mar 11.
Related trials for Cystic Fibrosis
RecruitingPhase 2
A Study of 24 to 52 Weeks Treatment to Evaluate The Efficacy And Safety of Galvokimig in Adult Study Participants With Non-Cystic Fibrosis Bronchiectasis
Non-cystic Fibrosis Bronchiectasis
Active, not recruitingObservational study
CFTR Modulator Effects on Bone and Muscle in Adults With Cystic Fibrosis
Cystic Fibrosis, Bone Loss
RecruitingObservational study
Natural History of Bronchiectasis
Bronchiectasis, Cystic Fibrosis
RecruitingObservational study
Role of Genetic Factors in the Development of Lung Disease
Cystic Fibrosis, Pulmonary Fibrosis
RecruitingPhase 2
Early Study on Tamoxifen Safety/Tolerability in Cystic Fibrosis Patients Unable to Use CFTR Modulators.
Cystic Fibrosis - Complete
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Moira Aitken, MD principal investigator
Brett Charlton, MD study director
Medical Director
100 sites in 18 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Inhaled mannitol in people with Cystic Fibrosis, run by Syntara at 100 sites in 18 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 100 sites in United States, Italy, Poland, Argentina, Russia and 13 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4). (time frame: 26 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02134353, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2020.