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A Rollover Safety Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

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ClinicalTrials.gov Identifier: NCT03125395
Recruitment Status : Completed
First Posted : April 24, 2017
Results First Posted : August 7, 2020
Last Update Posted : August 7, 2020
Sponsor:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Cystic Fibrosis
Intervention Drug: LUM/IVA
Enrollment 57
Recruitment Details This study was planned to have 2 cohorts: Treatment Cohort and Observational Cohort. Only the Treatment Cohort is presented in results as there were no participants enrolled in the Observational Cohort.
Pre-assignment Details This study was conducted in participants with cystic fibrosis (CF) aged 2 years and older who participated in parent study VX15-809-115 Part B (NCT02797132).
Arm/Group Title LUM/IVA
Hide Arm/Group Description LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Period Title: Overall Study
Started 57
Study 115B FAS [1] 60
Study 116 FAS [2] 57
Study 116 LCI Substudy Set 31
Completed 47
Not Completed 10
Reason Not Completed
Adverse Event             2
Withdrawal of consent (not due to AE)             1
Physician Decision             2
Commercial drug is available             5
[1]
Participants enrolled and exposed to any amount of study drug in parent study VX15-809-115.
[2]
Participants enrolled and exposed to any amount of study drug in current study VX16-809-116.
Arm/Group Title LUM/IVA
Hide Arm/Group Description LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Baseline Participants 57
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 57 participants
43.2  (12.17)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 57 participants
Female
28
  49.1%
Male
29
  50.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 57 participants
Hispanic or Latino
3
   5.3%
Not Hispanic or Latino
54
  94.7%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 57 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
0
   0.0%
White
56
  98.2%
More than one race
0
   0.0%
Unknown or Not Reported
1
   1.8%
1.Primary Outcome
Title Safety as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide Description [Not Specified]
Time Frame Day 1 up to Week 98
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 safety set included all participants dosed in study 115B who were exposed to any amount of study drug in current study 116 treatment cohort.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 57
Measure Type: Number
Unit of Measure: participants
Participants with AEs 56
Participants with SAEs 15
2.Secondary Outcome
Title Absolute Change in Sweat Chloride
Hide Description Sweat samples were collected using an approved collection device.
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 Full Analysis Set (FAS) included all participants who were enrolled and exposed to any amount of study drug in current study 116.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 57
Mean (Standard Deviation)
Unit of Measure: millimole per liter (mmol/L)
-29.6  (12.7)
3.Secondary Outcome
Title Absolute Change in Body Mass Index (BMI)
Hide Description BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2).
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 FAS.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 57
Mean (Standard Deviation)
Unit of Measure: kg/m^2
0.30  (1.21)
4.Secondary Outcome
Title Absolute Change in BMI-for-age Z-score
Hide Description BMI was defined as weight in kilograms divided by height in m^2. z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean.
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 FAS.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 57
Mean (Standard Deviation)
Unit of Measure: z-score
0.27  (0.73)
5.Secondary Outcome
Title Absolute Change in Weight
Hide Description [Not Specified]
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 FAS.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 57
Mean (Standard Deviation)
Unit of Measure: kg
6.0  (2.0)
6.Secondary Outcome
Title Absolute Change in Weight-for-age Z-score
Hide Description Z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean.
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 FAS.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 57
Mean (Standard Error)
Unit of Measure: z-score
0.23  (0.56)
7.Secondary Outcome
Title Absolute Change From Baseline in Stature (Height)
Hide Description [Not Specified]
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 FAS.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 57
Mean (Standard Deviation)
Unit of Measure: centimeter
16.1  (2.3)
8.Secondary Outcome
Title Absolute Change in Stature-for-age Z-score
Hide Description Z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean.
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 FAS.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 57
Mean (Standard Deviation)
Unit of Measure: z-score
0.07  (0.39)
9.Secondary Outcome
Title Time-to-first Pulmonary Exacerbation
Hide Description Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol-defined criteria.
Time Frame From Parent Study 115B Baseline through Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 115B FAS included all participants who were enrolled and exposed to any amount of study drug in parent study 115B
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 60
Median (Inter-Quartile Range)
Unit of Measure: days
600.0 [1] 
(98.0 to NA)
[1]
Upper limit of inter-quartile range could not be estimated because less than 75% of participants had events.
10.Secondary Outcome
Title Number of Pulmonary Exacerbations (PEx)
Hide Description Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol-defined criteria.
Time Frame From Parent Study 115B Baseline through Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 115B FAS.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 60
Measure Type: Number
Unit of Measure: pulmonary exacerbation events
82
11.Secondary Outcome
Title Number of Cystic Fibrosis (CF) Related Hospitalizations
Hide Description [Not Specified]
Time Frame From Parent Study 115B Baseline through Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 115B FAS.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 60
Measure Type: Number
Unit of Measure: hospitalizations
28
12.Secondary Outcome
Title Absolute Change in Fecal Elastase-1 (FE-1) Levels
Hide Description [Not Specified]
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 FAS.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 57
Mean (Standard Deviation)
Unit of Measure: microgram per gram (mcg/g)
132.6  (174.2)
13.Secondary Outcome
Title Absolute Change in Immunoreactive Trypsinogen (IRT) Serum Levels
Hide Description [Not Specified]
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 FAS.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 57
Mean (Standard Deviation)
Unit of Measure: nanogram per milliliter (ng/mL)
-108.5  (306.6)
14.Secondary Outcome
Title Number of Participants With Microbiology Culture Status (Positive or Negative)
Hide Description Following microbial tests were performed: Burkholderia, Methicillin Resistant Staphylococcus Aureus (MRSA), Methicillin Susceptible Staphylococcus Aureus (MSSA), Pseudomonas Aeruginosa Mucoid (P. Aeruginosa Mucoid), P. Aeruginosa Non-Mucoid, P. Aeruginosa Small Colony Variant and Stenotrophomonas Maltophilia.
Time Frame Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 FAS. Here "Overall Number of Participants Analyzed" signifies those participants who were evaluated for this outcome at Week 96.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 46
Measure Type: Number
Unit of Measure: participants
Burkholderia (Positive) 0
Burkholderia (Negative) 46
MRSA (Positive) 4
MRSA (Negative) 42
MSSA (Positive) 15
MSSA (Negative) 31
P. Aeruginosa Mucoid (Positive) 0
P. Aeruginosa Mucoid (Negative) 46
P. Aeruginosa Non-Mucoid (Positive) 1
P. Aeruginosa Non-Mucoid (Negative) 45
P. Aeruginosa Small Colony Variant (Positive) 0
P. Aeruginosa Small Colony Variant (Negative) 46
Stenotrophomonas Maltophilia (Positive) 2
Stenotrophomonas Maltophilia (Negative) 44
15.Secondary Outcome
Title Absolute Change in Lung Clearance Index (LCI) 2.5
Hide Description LCI 2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 LCI substudy set included all participants who signed the informed consent/assent to the optional LCI substudy and were enrolled and exposed to any amount of study drug in current study 116.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 31
Mean (Standard Deviation)
Unit of Measure: lung clearance index
-0.20  (1.55)
16.Secondary Outcome
Title Absolute Change in Lung Clearance Index (LCI) 5.0
Hide Description LCI 5.0 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/20th of its starting value.
Time Frame From Parent Study 115B Baseline at Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Study 116 LCI substudy set.
Arm/Group Title LUM/IVA
Hide Arm/Group Description:
LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
Overall Number of Participants Analyzed 31
Mean (Standard Deviation)
Unit of Measure: lung clearance index
0.11  (0.65)
Time Frame Day 1 up to Week 98
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title LUM/IVA
Hide Arm/Group Description LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age.
All-Cause Mortality
LUM/IVA
Affected / at Risk (%)
Total   0/57 (0.00%) 
Hide Serious Adverse Events
LUM/IVA
Affected / at Risk (%)
Total   15/57 (26.32%) 
Gastrointestinal disorders   
Constipation  1  1/57 (1.75%) 
Haematemesis  1  1/57 (1.75%) 
Pancreatitis  1  1/57 (1.75%) 
Infections and infestations   
Appendicitis  1  1/57 (1.75%) 
Chronic sinusitis  1  1/57 (1.75%) 
Gastritis viral  1  1/57 (1.75%) 
Gastroenteritis adenovirus  1  1/57 (1.75%) 
Gastroenteritis viral  1  1/57 (1.75%) 
Infective pulmonary exacerbation of cystic fibrosis  1  6/57 (10.53%) 
Pneumonia  1  2/57 (3.51%) 
Respiratory tract infection viral  1  1/57 (1.75%) 
Investigations   
Alanine aminotransferase increased  1  1/57 (1.75%) 
Aspartate aminotransferase increased  1  1/57 (1.75%) 
Metabolism and nutrition disorders   
Weight gain poor  1  1/57 (1.75%) 
Respiratory, thoracic and mediastinal disorders   
Sleep apnoea syndrome  1  1/57 (1.75%) 
1
Term from vocabulary, Meddra 22.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
LUM/IVA
Affected / at Risk (%)
Total   55/57 (96.49%) 
Ear and labyrinth disorders   
Ear pain  1  3/57 (5.26%) 
Gastrointestinal disorders   
Abdominal pain  1  7/57 (12.28%) 
Abdominal pain upper  1  4/57 (7.02%) 
Constipation  1  7/57 (12.28%) 
Diarrhoea  1  6/57 (10.53%) 
Vomiting  1  17/57 (29.82%) 
General disorders   
Fatigue  1  5/57 (8.77%) 
Pyrexia  1  23/57 (40.35%) 
Vessel puncture site pain  1  4/57 (7.02%) 
Infections and infestations   
Conjunctivitis  1  4/57 (7.02%) 
Ear infection  1  12/57 (21.05%) 
Hand-foot-and-mouth disease  1  3/57 (5.26%) 
Infective pulmonary exacerbation of cystic fibrosis  1  10/57 (17.54%) 
Influenza  1  4/57 (7.02%) 
Nasopharyngitis  1  8/57 (14.04%) 
Otitis media  1  7/57 (12.28%) 
Pharyngitis streptococcal  1  6/57 (10.53%) 
Pneumonia  1  3/57 (5.26%) 
Sinusitis  1  12/57 (21.05%) 
Upper respiratory tract infection  1  13/57 (22.81%) 
Viral upper respiratory tract infection  1  4/57 (7.02%) 
Investigations   
Alanine aminotransferase increased  1  10/57 (17.54%) 
Aspartate aminotransferase increased  1  5/57 (8.77%) 
Forced expiratory volume decreased  1  3/57 (5.26%) 
Gamma-glutamyltransferase increased  1  4/57 (7.02%) 
Pseudomonas test positive  1  9/57 (15.79%) 
Staphylococcus test positive  1  12/57 (21.05%) 
Metabolism and nutrition disorders   
Decreased appetite  1  6/57 (10.53%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  47/57 (82.46%) 
Dyspnoea  1  3/57 (5.26%) 
Lower respiratory tract congestion  1  4/57 (7.02%) 
Nasal congestion  1  25/57 (43.86%) 
Nasal discharge discolouration  1  3/57 (5.26%) 
Oropharyngeal pain  1  10/57 (17.54%) 
Productive cough  1  5/57 (8.77%) 
Rhinorrhoea  1  18/57 (31.58%) 
Sinus congestion  1  3/57 (5.26%) 
Sputum increased  1  5/57 (8.77%) 
Upper respiratory tract congestion  1  3/57 (5.26%) 
Wheezing  1  3/57 (5.26%) 
Skin and subcutaneous tissue disorders   
Rash  1  3/57 (5.26%) 
1
Term from vocabulary, MedDRA 22.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Monitor
Organization: Vertex Pharmaceuticals Incorporated
Phone: 617-341-6777
EMail: medicalinfo@vrtx.com
Layout table for additonal information
Responsible Party: Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier: NCT03125395    
Other Study ID Numbers: VX16-809-116
2019-003112-31 ( EudraCT Number )
First Submitted: April 19, 2017
First Posted: April 24, 2017
Results First Submitted: July 15, 2020
Results First Posted: August 7, 2020
Last Update Posted: August 7, 2020