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Principles and Practice of
ppcpr Climcal Research
Proqrxn in Research

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Roberta Lins Gonçalves MAN Statistically   Significant  Minds - 6 Manaus Team

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I have no conflict of interest of this presentation

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Roger Davis,  ScD   presentation  PPCR  E. John  Orav   presentations  PPCR  Jessica  Pualus ,  ScD   presentation  PPCR  Prof.  Felpi   Fregni   presentation   and  review PPCR F.  Fregni  and B.  Illigens  (Eds), Critical Thinking in Clinical Research: applied theory and practice using case studies (p.243-256).  New York, NY: Oxford  University  Press.

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Key words:  COVID-19 pneumonia, SARS-CoV-2, canakinumab

JAMA. 2021;326(3):230-239. doi:10.1001/jama.2021.9508

Research
I Original Investigation
Effect of Canakinumab vs Placebo on Survival Without Invasive
Mechanical Ventilation in Patients Hospitalized With Severe COVID-19
A Randomized Clinical Trial
Caricchio. MD; Abbate. MD. PhD; Gordeev. PhD; Jarnie Mew. MD. PhD; Priscilla Y HQJe. MD;
Tuhina Neogi. MO. PhD; Roberto Arduino. MD. Daria Fornina. MO; Roman MO;
Tatiana MD; Pilar Ruiz-Seco. MO; An&és GÖnzaIez-Gæcia. MD. PhD; Yu Cipn, MSc; Yuhan Li. MSc;
Sæah Whelan. BSc. MSc; Stes*W1ie Nov•iello. MD. M PH; for the CAN-COVID Investigators

Trial   Registration   ClinicalTrials.gov  Identifier :  NCT04362813

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From:  Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: A Randomized Clinical Trial

A  subgroup of infected patients  with SARS-CoV-2  develop  viral pneumonia  and  experience respiratory failure , which in some cases  progresses to acute respiratory distress syndrome .  Most  critically ill patients require invasive mechanical ventilation (IMV), and mortality in this group is high. Patients with  severe COVID-19  often present with  systemic hyperinflammation .

Zhou F, Yu T, Du R, et al.  Clinical   course   and   risk   factors  for  mortality   of   adult   inpatients   with  COVID-19 in Wuhan, China: a  retrospective   cohort   study . Lancet. 2020;395(10229):1054-1062.  Berlin DA,  Gulick  RM, Martinez FJ.  Severe  COVID-19. N  Engl  J Med. 2020;383(25):2451-2460.  Karagiannidis  C,  Mostert  C,  Hentschker  C, et al. Case  characteristics ,  resource  use,  and   outcomes   of  10 021  patients   with  COVID-19  admitted   to  920 German  hospitals :  an   observational   study . Lancet  Respir  Med. 2020;8(9):853-862. doi:10.1016/ S2213-2600(20)30316-7  Lucas C, Wong P, Klein J, et al; Yale IMPACT Team. Longitudinal  analyses   reveal   immunological   misfiring  in  severe  COVID-19.  Nature . 2020;584 (7821):463-469.  Henderson LA,  Canna  SW,  Schulert  GS, et al.  On   the   alert  for  cytokine   storm :  immunopathology  in COVID-19.  Arthritis   Rheumatol . 2020;72(7):1059- 1063.  Shimabukuro-Vornhagen  A, Gödel P,  Subklewe  M, et al.  Cytokine  release  syndrome.J   Immunother   Cancer . 2018;6(1):56.  Fajgenbaum  DC,  June  CH.  Cytokine   storm . N  Engl  J Med. 2020;383(23):2255-2273.  Del Valle DM, Kim- Schulze  S, Huang H-H, et al.  An   inflammatory   cytokine   signature   predicts  COVID-19  severity   and   survival . Nat Med. 2020;26 (10):1636-1643 Sterne  JAC,  Murthy  S, Diaz JV, et al; WHO  Rapid   Evidence   Appraisal  for COVID-19  Therapies  (REACT)  Working   Group .  Association   between   administration   of   systemic   corticosteroids   and   mortality   among   critically   ill   patients   with  COVID-19: a meta- analysis.JAMA . 2020;324(13): 1330-1341

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Preliminary results of the  RECOVERY trial , a platform study with large patient populations, have shown that in patients hospitalized with COVID-19, hypoxia, and systemic inflammation, the  IL-6 inhibitor tocilizumab improved survival and other clinical outcomes.

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IL-1β is an upstream proinflammatory cytokine  that is  involved in the pathogenesis of a variety of autoinflammatory  conditions and induces the production of secondary inflammatory mediators .

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Is the  anti–interleukin-1β  antibody canakinumab effective to treat patients hospitalized with COVID-19 and hyperinflammation?

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OBJECTIVE : To evaluate the efficacy of Canakinumab in patients hospitalized with severe COVID-19

JAMA I Originallnvestiptbn
Effect of Canakinumab vs Placebo on Survival Without Invasive
Mechanical Ventilation in Patients Hospitalized With Severe COVID•19
A Randomized Clinical Trial

JAMA
The Journal of the
American Medical
Association

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Phase 2
Safety study
Identify side effects
Measure effectiveness
100--200 people
Phase 1
Safety study
20-60 people
Phase 3
Measure effectiveness
Monitor side effects
500-1 ,OOO people
4
Phase 4
Monitor long term
effectiveness
and side effects
10.000+ people

A multicenter, double-blind, randomized, placebo-controlled  phase  3  trial

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The ethics committee of each site provided approval.  Participating patients provided written informed consent.  An independent safety monitoring committee provided oversight.

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Adults   with   COVID-19  induced -pneumonia  and   cytokine  release  syndrome   (CRS)

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Adults   with   COVID-19  induced -pneumonia  and   cytokine  release  syndrome   (CRS) Arm 1 :  Canakinumab   450 mg for body weight 40-80 kg in 250 mL of 5% dextrose infused IV over 2 hours.

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Adults   with   COVID-19  induced -pneumonia  and   cytokine  release  syndrome   (CRS) Arm 1 :  Canakinumab   450 mg for body weight 40-80 kg in 250 mL of 5% dextrose infused IV over 2 hours. Arm 2 :  Placebo 250 mL of 5% dextrose infused IV over 2 hours.

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Adults   with   COVID-19  induced -pneumonia  and   cytokine  release  syndrome   (CRS) Arm 1 :  Canakinumab   450 mg for body weight 40-80 kg in 250 mL of 5% dextrose infused IV over 2 hours. Arm 2 :  Placebo 250 mL of 5% dextrose infused IV over 2 hours. Primary   outcome Survival   without  IMV Secondary outcomes  COVID-19–related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluation.

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Adults   with   COVID-19  induced -pneumonia  and   cytokine  release  syndrome   (CRS) Arm 1 :  Canakinumab   450 mg for body weight 40-80 kg in 250 mL of 5% dextrose infused IV over 2 hours. Arm 2 :  Placebo 250 mL of 5% dextrose infused IV over 2 hours. Primary   outcome Survival   without  IMV Secondary outcomes  COVID-19–related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluation. During hospitalization from day 3 to  day 29.

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Canakinumab  or  placebo  infusions  will be prepared and blinded  by an unblinded pharmacist or designated staff member.

Double-Blind
Clinical Trials
Patient
Doctor

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It was implemented using an  interactive response technology system  in which a new patient meeting the inclusion and exclusion criteria was randomly assigned to a treatment group based on a  random allocation sequence .

Double-blind phase 3 CAN-COVID trial,   randomization stratified by country, with a block size of 4 within each stratum

LOCATIONS
39 Hospitals
in Europe
and the US

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Treatment, CI
Treatment, CI
Treatment, CI
control, CI
control, CI
Treatment, CI
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Treatment, CI
Control, CI
Treatment, CI
Treatment, CI
Treatment, CI
Control, CI
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Sequence was created by a separate  randomization office  of the sponsor and  kept blinded to the study team  until the scheduled unblinding for data analysis.

CLINICAL TRIALS RANDOMIZATION
Patient
I n formation
patient information is
entered into a computer
Random Selection
The computer
randomly assigns
patients to two
or more groups.
helping to
prevent bias
prevents Bias
Control group receives
standard therapy
Investigational group
receives new treatment

Randomization stratified by country, with a block size of 4 within each stratum

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Based on the literature available at the time of study design, the IMV-free survival rate in the target hospitalized population was assumed to be in the range from 20% to 50%.  With a 1:1 randomization ratio and 2-sided  type I error control at .05 :  a  sample size of 450 patients  was calculated to provide  at least 89% power  for the primary analysis  to detect a difference of at least 15% in the rate of survival without requiring IMV.  This difference was defined as the minimum clinically meaningful benefit of interest.

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Components   of  Sample  Size   calculation

Component Synonyms Definition Conventional   values α Type  I  error P- value Significance   level The  probability   of   false-positive  result. 0.05  or  0.01 β Type  II  error The  probability   of   false-negative  result. 0.20  or  0.1 Power (1- β ) - The  probability   of   finding  a  statistically   significance   difference   when one truly exists  (true positive). 80% Effect   size Example :  Minimaly   clinicaly   relevant   different (MCRD) The  minimal   difference   between   the   groups   that  a  researcher   considers   clinically   relevant   and   biologically   plausible . Its  depends Measures   of   variability   The  variability   of   outcome   measure . Based on the literature Pilot study

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A patient who  discontinued early from the study or was lost to follow-up before day 29  was considered as a  responder if they did not require IMV any time after day 2  and either  was discharged from hospital with clinical status lower than 2 or the patient’s last clinical status was obtained after day 14  and was better than at baseline. Otherwise, the patient was considered as a non responder.

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Enrollment will  stop  as soon as the  target number  of randomized patients is reached.

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Endpoint  Clinical response , defined as  survival without ever requiring IMV  from  Day 3(inclusive) up to day 29(inclusive).  A patient will be defined as a  nonresponder  if the worst clinical status at any time from Day3 (inclusive) up to Day 29 (inclusive) is requiring IMV or death (category 6, 7 or  8 on the WHO 9-point ordinary scale of clinical status).

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Patient
Named Entity
Recognition
Condition
Patient
Treatment
Dosage
Adverse
Event
Relations
Extraction
Condition
Adverse
Event
Dosage
Treatment

Efficacy and monitoring of adverse events (AEs)

Daily , and laboratory assessments every other day  until day 29 and on days 57 and 127 ,  in hospitalized patients .

For patients who had been  discharged from the hospital ,  follow-up visits conducted  by  telephone  were scheduled at  days 15, 29, 57, and 127.

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Primary   Outcome Difference  ( proportion   of   patients   who   survived   without   requiring  IMV  from   day  3  to   day  29 Categorical   Variavel Odds-ratio   comparing  response rates in  the   Canakinumab   and  placebo  groups compared based on their odds ratio (OR) —which was estimated using a  logistic regression model on the logit of probability for survival without the need for IMV with study treatment as main effect—and  adjusted by region  (United States, Europe) and baseline clinical status (≤4, ≥5) on the  WHO 9-point ordinal scale.

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Survival curves  were elaborated based on  KaplanMeier  estimates of survival functions, and  the hazard ratios were obtained using a Cox proportional hazard model .

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The  hypothesis tests for primary  and  key secondary analyses were conducted in hierarchical order with the 2-sided family-wise type I error rate controlled at 0.05 , which was also the threshold for statistical significance.

Adults   with  COVID-19  induced -pneumonia  and   cytokine  release  syndrome  (CRS)

Canakinumab   450 mg for body weight 40-80 kg in 250 mL of 5% dextrose infused IV over 2 hours.

Placebo 250 mL of 5% dextrose infused IV over 2 hours.

H0 =  There   is  no  difference  ( proportion   of   patients   who   survived   without   requiring  IMV  from   day  3  to   day  29  between   intervention   and  placebo  groups .

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Ta rget
population
Sample
Study
population

POPULATION
267 Men
187 Women
Hospitalized patients
with COVID• 19 pneumonia.
hypoxia (not requiring IMV), and
systemic hyperinflammation
Median age: 59 years
LOCATIONS
39 Hospitals
in Europe
and the US

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477
227 Randonnized to receive
canakinurnab
Patients assessed for eligibility
23 Excluded
19 Did not rneet inclusion
criteria
4 Declined to participate
454 Randornized
227 Randomized to receive placebo
223 Received placebo as
225 Received
as randonaized
2 Did not receive canal<inurnab
1
16
randomized
4 Did not receive placebo
as randonnized
3 Randon•ized in error-a
I Withdrev•v consent
Lost to follovv—up
Discontinued the study (died)
I
13
211
as randomized (vvithdrevv
consent)
Lost to follovv—up
Discontinued the study
12 Died
I Participant decision
(hospitalized)
In study on day 29
199 Had been discharged
12 Still hospitalized
206
In study on day 29
187 Had been discharged
19 Still hospitalized
223
227
225
Included in the prin•ary
analysis setb
Included in the full analysis setC
Included in the safety analysis seta
223
227
223
Included in the primary
analysis setb
Included in the futt analysis setC
Included in the safety analysis seta

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Ta ble Dernographic.
Clinical. and Laboratory Baseline Characteristicsa
Cha ra c
Age. •median (IQR)
Age > 65 Y
sex
Mate
Race/ethnicity. No-/totat
Wh ite
Black or African
ri n
Asia n
Canal<inurnab (n —
— 227)
59 (49-69)
78 (34)
135 (59)
92 (41)
159/208 (76)
35/208 (17)
10/208 (5)
3/208 (1)
1/208 (0.5)
70/224 (31)
126 (56)
25 (11)
86 (75-99)
227
29-9 (26-5-34-8)
112/227
(49)
120 (53)
79 (35)
48 (21)
23 (10)
20 (8-8)
18 (7_9)
10 (4.4)
9 (7-12)
2 (1-5)
19 (8.4)
152 (67)
49 (22)
7 (3.1)
180.1 (112.3-261.9)
124/182 (68.1)
58/182 (31.9)
89 (47-153)
681 (304-1271)
980 (540-1894)
165 (73)
92 (41)
85 (37)
49 (22)
31 (14)
Placebo (n
57 (50-68)
72 (32)
132 (58)
95 (42)
— 227)
American Indian or
Native Hawaiian or
Hispanic or Latino
Country or region
U n ited States
Russia
Western Europe
Weight. rnedian (IQR)
Median (IQR)
BMI >30.0. No./totat
CO orb i d i ti es
Hypertensi on
Diabetes
Alaska Native
other pacific Islander
Chronic cardiac disease
Chronic kidney disease
Chronic obstructive putrnonary disease
Cerebrovascular disease
Tinne frorn syn•ptorn onset to randornization. •median
Time from diagnosis to randomization. rnedian (IQR).
ASTCT CRS graded
(IQR).
Grade I least Sick
G rade 3
G rade 4
: Sickest
Pa02/Fi02
. median (IQR)
SARS-COV
—2 viral Load by nasopharyngeal
500 copies / mL
< 500 copies/ mL
Serun• bion•arkers Of inflarnrnation
C—reactive protein. median (IQR)
Ferritin. •median (IQR). wg/L
D—dimer. median (IQR). Lag/ L FEU
Medication in itiated prior to day I
Heparin (any dose)
Dexamethasone 26 mg Ide
NO. / total (36)
Azit in
Rernd r
Hyd roxyc h roqu in e
Convalescent p [asrna
156/215 (73)
37/215 (17)
9/215 (4)
8/215 (4)
5/215 (2)
66/220 (29)
127 (56)
77 (34)
23 (10)
87 (76-99)
222
30-8 (27.0-34-7)
125/222 (55)
133 (59)
85 (37)
44 (19)
17 (7.5)
13 (5.7)
17 (7-5)
17 (7.5)
9 (6-12)
2 (1-4)
18 (7.9)
154 (68)
45 (20)
6 (2.6)
179.6 (127.5-268.8)
126/175 (72.0)
49/175 (28_0)
77 (42-136)
631 (305-1160)
958 (612-1406)
165 (73)
73 (32)
85 (37)
45 (20)
29 (13)
or
ser u rn
Abbreviations: AS-I-CT. Arnerican
Society for Tra and
Cellular Therapy: BMI. body rnass
index; CRS. cytokine release
syndrorne; F EU. fibrinogen
equivalent units; 'QR. interquartile
range.- Pa02/F102. ratio Of arterial
oxygen pa rtial pressure/fraction of
inspired oxygen: W•'HO. VVorId Health
C) rga n iza t iO n.
a Baseline rneasurernents
perforrned prerandornization per
protocol. Proportions Of patients
vvith each clinical status according
to the VVHO 9- point ordinal scale at
baseline are provided in Figure 3.
Unless Othevvv•ise specified.
BMI is calculated as •væeight in
kilograrns divided by height in
rneters squared _
ASTCT CRS grade vvas ca Iculated as
described based on hypotension
and hypoxia vvith increased
intervention associated vvith
increased grading score. w Grade 1
indicates no hypotension/hypoxia;
grade 2. no vasopressors/ lovv-flovv
nasal cannula: grade 3.
vasopressor/high-flcyvv nasal
cannula. face nonrebreather
rnask. or Venturi and grade 4.
rnultiple vasopressors/positive
pressure oxygenation _
Dexarnethasone rng/d or
equivalent glucocorticoid.

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Ta ble Dermographic.
Clinical. and Laboratory Baseline Characteristicsa
Cha ra c
Age. •median (IQR)
Age > 65 Y
sex
Mate
Race/ethnicity. No-/totat
Wh ite
Black or African
ri n
Asia n
Canakinurnab (n —
— 227)
59 (49-69)
78 (34)
135 (59)
92 (41)
159/208 (76)
35/208 (17)
10/208 (5)
3/208 (1)
1/208 (0.5)
70/224 (31)
126 (56)
25 (11)
86 (75-99)
227
29-9 (26-5-34-8)
112/227
(49)
120 (53)
79 (35)
48 (21)
23 (10)
20 (8-8)
18 (7_9)
10 (4.4)
9 (7-12)
2 (1-5)
19 (8.4)
152 (67)
49 (22)
7 (3.1)
180.1 (112.3-261.9)
124/182 (68.1)
58/182 (31.9)
89 (47-153)
681 (304-1271)
980 (540-1894)
165 (73)
92 (41)
85 (37)
49 (22)
31 (14)
Placebo (n
57 (50-68)
72 (32)
132 (58)
95 (42)
— 227)
American Indian or
Native Hawaiian or
Hispanic or Latino
Country or region
U n ited States
Russia
Western Europe
Weight. rnedian (IQR)
Median (IQR)
BMI >30.0. No. [totat
CO orb i d i ti es
Hypertensi on
Diabetes
Alaska Native
other pacific Islander
Chronic cardiac disease
Chronic kidney disease
Chronic obstructive putrnonary disease
Cerebrovascular disease
Tinne frorn syn•ptorn onset to randornization. •median
Time from diagnosis to randomization. rnedian (IQR).
ASTCT CRS graded
(IQR).
Grade I least Sick
G rade 3
G rade 4
: Sickest
Pa02/Fi02
. median (IQR)
SARS-COV
—2 viral Load by nasopharyngeal
500 copies / mL
< 500 copies/ mL
Serun• bion•arkers Of inflarnrnation
C—reactive protein. median (IQR)
Ferritin. •median (IQR). wg/L
D—dimer. median (IQR). Lag/ L FEU
Medication in itiated prior to day I
Heparin (any dose)
Dexamethasone 26 mg Ide
NO. / total (9-6)
Azit in
Rernd r
Hyd roxyc h roqu in e
Convalescent p [asrna
156/215 (73)
37/215 (17)
9/215 (4)
8/215 (4)
5/215 (2)
66/220 (29)
127 (56)
77 (34)
23 (10)
87 (76-99)
222
30-8 (27.0-34-7)
125/222 (55)
133 (59)
85 (37)
44 (19)
17 (7.5)
13 (5.7)
17 (7-5)
17 (7.5)
9 (6-12)
2 (1-4)
18 (7.9)
154 (68)
45 (20)
6 (2.6)
179.6 (127.5-268.8)
126/175 (72.0)
49/175 (28_0)
77 (42-136)
631 (305-1160)
958 (612-1406)
165 (73)
73 (32)
85 (37)
45 (20)
29 (13)
or
ser u rn
Abbreviations: AS-I-CT. Arnerican
Society for Tra and
Cellular Therapy: BMI. rnass
index; CRS. cytokine release
syndrorne; F EU. fibrinogen
equivalent units; 'QR. interquartile
range.- Pa02/F102. ratio Of arterial
oxygen pa rtial pressure/fraction of
inspired oxygen: W•'HO. VVorId Health
C) rga n iza t iO n.
a Baseline rneasurernents
perforrned prerandornization per
protc»col. Proportions Of patients
vvith each clinical status according
to the VVHO 9- point ordinal scale at
baseline are provide-cd in Figure 3.
Unless Othevvv•ise specified.
BMI is calculated as •væeight in
kilograrns divided by height in
rneters squared _
ASTCT CRS grade vvas ca Iculated as
described based on hypotension
and hypoxia vvith increased
intervention associated vvith
increased grading score. w Grade 1
indicates no hypotension/hypoxia;
grade 2. no vasopressors/ Iovv-flovv
nasal cannula: grade 3.
vasopressor/high-flcyvv nasal
cannula. face nonrebreather
rnask. or Venturi and grade 4.
rnultiple vasopressors/positive
pressure oxygenation _
Dexarnethasone rng/d or
equivalent glucocorticoid.

There were no notable differences in demographics or baseline disease characteristics between the canakinumab and placebo groups.

Scene 39

The proportion of patients who survived without requiring IMV from day 3 to day 29

canakinumab group  placebo group 198  of  223 ( 88.8% )  191  of  223 ( 85.7% )

Rate difference of 3.1% (95% CI, −3.1% to 9.3%) and an OR of 1.39 (95% CI, 0.76 to 2.54; P = .29).

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canakinumab group  placebo group 198  of  223 (88.8%)  191  of  223 (85.7%)

The minimum clinically meaningful benefit of interest:  difference of at least 15% in the rate of survival without requiring IMV.

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Figure 2. Use of IMV and Discharge From Hospital
use IMV or death
Cana kinumab
No. at risk
Canakiumab
227
227
205
201
15
Time, d
202
195
197
192
29
197
191

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No. at risk
Canab•wmab
hospital
227
227
Cana&lumab
15
Tine. d
129
22
39
29
24
35

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The hazard ratios using a Cox proportional hazard model .

Secondary Outcome The proportion of patients with COVID-19–related death by day 29

11 of 223 ( 4.9% ) in the canakinumab group  16 of 222 ( 7.2% ) in the placebo group

A rate difference of −2.3% (95% CI, −6.7% to 2.2%) and an OR of 0.67 (95% CI, 0.30 to 1.50).

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Table 2. Sumnary of Adverse Evelts•
Any AE
Most common AEs (23%)
Acute respiratory failure
Leukocytosis
Hypokalemia
Hypaxia
ConstipatiM
C-reactive protein
Acute distress syndrome
Hypoproteinemia
pneumonia
Hyperglycemia
Acute kidney injury
Infection sb
rreatrnent•related AEs
Serious inf«tions•
Treatment-related SAES
AEs with of death (all cause)'
AEs requiring discontiruation of stiÆy dirt"
AEs requiring therapy
Patients. No. (X)
(n • 225)
122 (54.2)
13 (5.8)
11 (4.9)
10 (4.4)
9 (4.0)
9 (4.0)
9 (4.0)
9 (4.0)
8 (3.6)
7 (3.1)
6 (2.7)
6 (2.7)
3 (1.3)
3 (1.3)
23 (102)
11 (4.9)
36 (16.0)
11 (4.9)
17 (7.6)
1 (0.4)d
83 (36.9)
(n • 223)
120 (S 3B)
14 (0)
8 (3.6)
4 (1.8)
11 (4.9)
10 (4.5)
(3.1)
2 (0.9)
8 (3.6)
4 (1.8)
(3.1)
7 (3.1)
9 (4.0)
8 (3.6)
43 (19_3)
9 (4.0)
46 (20_6)
21 (9.4)
1 (0.4)
21 (9.4)
92 (41_3)
MedDRA U&al Dictl.:rwy for
Activities;
e-ænt.
• The tabk reflects AEs obseved
until day 29 in tte safety
A with mLAiple
AEs orxe for exh
cat.ry.
b Systen Class of
inf«tions and infestations
c Æs until day 29. bLR
&aths to ttpm caki
Xcur after day 29.
d Due to erythna.

Serious adverse events  were observed in 36 of 225 patients ( 16%) treated with canakinumab  vs 46 of 223 ( 20.6%) who received placebo.

The AE rates were numerically similar for the canakinumab and placebo groups.

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QUESTION Is the anti-interleukin-lß antibody canakinumab effective to treat patients hospitalized with COVID-19
and hyperinflammation?
CONCLUSION This randomized clinical trial found that among patients hospitalized with severe COVID-19, treatment with canakinumab,
compared with placebo, did not significantly increase the likelihood of survival without invasive mechanical ventilation (IMV).
POPULATION
267 Men
187 Women
Hospitalized patients
with COVID-19 pneumonia,
hypoxia (not requiring IMV), and
systemic hyperinflammation
Median age: 59 years
LOCATIONS
39 Hospitals l'
in Europe
and the US
INTERVENTION
454 Patients randomized
FINDINGS
Survived without requiring IMV
227
Canakinumab
Single intravenous infusion
(450 mg for body weight of
40-<60 kg, 600 mg for 60-80 kg,
and 750 mg for kg)
PRIMARY OUTCOME
227
Placebo
Placebo in 250 mL
of 5% dextrose infused
intravenously over
2 hours
Canakinumab
198 of 223 patients
88.8%
Placebo
191 of 223 patients
85.7%
Survival without IMV from day 3 to day 29
Rate difference, 3.1% (95% -3.1% to 9.3%)
Odds ratio, 1.39 (95% 0.76 to 2.54)
AMA
Caricchio R, Abbate A, Gordeev l. et al; CAN-COVID Investigators. Effect of canakinumab vs placebo on survival without invasive mechanical ventilation
in patients hospitalized with severe COVID- 19: a randomized clinical trial. JAMA. Published July 20, 2021. doi: 10, 1001/Jama-2021.9508

Among  patients hospitalized with severe COVID-19 ,  treatment with canakinumab,  compared with  placebo ,  did not significantly increase the likelihood of survival without IMV at day 29.

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Internal Validity:  -  Appropriate experimental design - Without sources of confusion

MODULE 2 BONUS ASSIGNMENT

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