Interferon Beta vs Standard care/Placebo (RCT)

Hospitalized patients

FOREST PLOTS -2021-06-18

Studies description

Trial NCT04343768
Publication COVIFERON - Darazam IA, Scientific Reports (2021) (published paper)
Dates: 2020-04-09 to 2020-04-30
Funding: No specific funding
Conflict of interest: No

Methods
RCT
Blinding: Unblinded
Location : Single center / Iran
Follow-up duration (days): 21
Inclusion criteria
  • Male, non-lactating, and non-pregnant female patients
  • at least 18 years of age
  • confirmed COVID-19, defined as a positive test of Reverse Transcriptase Polymerase-Chain Reaction (RT-PCR)
  • confirmed COVID-19 compatible lung involvement were admitted - all patients included in the study, also had a positive Computed Tomography Scan (CT Scan)
  • [having a 1peripheral capillary oxygen saturation level (SpO2) ≤ 93% on pulse oximetry OR a respiratory frequency ≥ 24/minute while breathing ambient air] AND [at least one in every of the following: contactless infrared forehead thermometer temperature of ≥ 37·8, muscle ache, rhinitis, headache, cough or fatigue on admission] AND [acute onset time for the symptoms (Days ≤ 14)].
Exclusion criteria
  • Patients with cardiac arrhythmias (prolonged PR or QT intervals, third- or second-degree heart block)
  • consumption of potentially interacting medications with Lopinavir/Ritonavir + HCQ, IFNβ1a, IFNβ1b
  • history of alcohol use disorder, or any illicit drug dependence within the past five years
  • blood AST/ALT levels ≥ 5-fold the maximum limit of normal range on laboratory findings
  • participation refusal.
Interventions
Treatment
INF-beta-1a+INF-beta-1b
IFN beta 1b (Ziferon)(Subcutaneous injections of 0·25mg (8,000,000 IU) on days 1, 3, 6)

Interferon beta-1a
IFN beta 1a (Recigen) (Subcutaneous injections of 44mcg (12,000 IU) on days 1, 3, 6)

Interferon beta-1b
IFN beta 1b (Ziferon)(Subcutaneous injections of 0·25mg (8,000,000 IU) on days 1, 3, 6)
Control
Standard care

Participants
Randomized
participants :
INF-beta-1a+INF-beta-1b=40
Standard care=20
Interferon beta-1a=20
Interferon beta-1b=20
Characteristics of participants
N= 100
Mean age : NR
40 males
Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
In the register
Time to clinical improvement [ Time Frame: From date of randomization until 14 days later. ] Improvement of two points on a seven-category ordinal scale (recommended by the World Health Organization: Coronavirus disease (COVID-2019) R&D. Geneva: World Health Organization) or discharge from the hospital, whichever came first.
In the report
Our primary outcome measure was TTCI [time to clinical improvement], defined as the time from enrollment to discharge from the hospital or a decline of two steps on the seven-step ordinal scale. (I) Not hospitalized, and has no activity limitations; (II) Not hospitalized, but has activity limitations; (III) Hospitalized, but does not need any supplemental oxygen; (IV) Hospitalized, and needs supplemental oxygen; (V) Hospitalized, and needs either High-Flow Nasal Cannula (HFNC) or non-invasive ventilation; (VI) Hospitalized, and needs invasive ventilation; and (VII) Dead
Documents
avalaible

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing willing stated in the publication:

Yes
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment In addition to the pre-print article, published protocol summary and prospective trial registry were used in data extraction and assessment of risk of bias. There were some differences in outcomes and endpoints between the pre-print article, the published protocol summary and trial registry, although overall the study was reported as planned. The study achieved its pre-stated sample size. Altough the study is reported as 'open-label' it is stated that outcomce assessors were blinded to treatment arms.
On 20th of April, 2021, this study was updated based on the published report.

Trial IRCT20100228003449N28
Publication Davoudi-Monfared E, Antimicrob Agents Ch (2020) (published paper)
Dates: 2020-02-29 to 2020-04-03
Funding: drug donation only (No funding; CinnaGen Co. (drug donation))
Conflict of interest: No

Methods
RCT
Blinding: Unblinded
Location : Single center / Iran
Follow-up duration (days): 28
Inclusion criteria
  • Patients with the severe disease according the previous definition with following criteria were included:
    (1) hypoxemia (need for non invasive or invasive respiratory support to provide capillary oxygen saturation above 90%)
    (2) Hypotension (systolic blood pressure less than 90 mmHg or vasopressor requirement)
    (3) renal failure secondary to COVID-19 (according to KDIGO definition)
    (4) neurologic disorder secondary to COVID-19 (decrease of 2 or more scores in Glasgow Coma Scale)
    (5) thrombocytopenia secondary to COVID-19 (platelet count less than 150000 /mm3)
    (6) severe gastrointestinal symptoms secondary to COVID-19 (vomiting/diarrhea that caused at least mild dehydration).
Exclusion criteria
  • Patients with each of the following characteristics were excluded: allergy to IFNs, receiving IFNs for any other reasons, previous suicide attempts, alanine amino transferase (ALT)> 5× the upper limit of the normal range and pregnant women.
Interventions
Treatment
Interferon beta-1a
44 mcg/mL subcutaneous injection, 3 times a week for 2 consecutive weeks
Control
Standard care

Participants
Randomized
participants :
Standard care=46
Interferon beta-1a=46
Characteristics of participants
N= 92
Mean age : NR
43 males
Severity : Mild: n=0 / Moderate: n=57 / Severe: n=4 Critical: n=20
Primary outcome
In the register
Response to the treatment and Complications of the treatment
In the report
Time to reach clinical response
Documents
avalaible

Protocol

NR

Statistical plan

NR

Data-sharing willing stated in the publication:

Not reported
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
High
General comment In addition to all available versions of the published report, the study registry and the pre-print article were used in data extraction and risk of bias assessment. The study achieved the target sample size specified in the registry. The primary outcome indicated in registry does not reflect the primary outcome reported in the paper. There is a discrepancy between the number of events in 28-day mortality reported in Table 5 and the number of deaths on day 28 reported in Table 4.
The extraction and risk of bias assessment for this study was updated with the published report on 17/07/2020.

Trial ISRCTN83971151; NCT04315948
Publication SOLIDARITY (IFN) - Pan H, N Engl J Med (2020) (published paper)
Dates: 2020-03-22 to 2020-10-04
Funding: Mixed (World Health Organization; Merck KGaA and Faron (drug donation))
Conflict of interest: No

Methods
RCT
Blinding: Unblinded
Location : Multicenter / Multinational (30)
Follow-up duration (days): 28
Inclusion criteria
  • Age ≥18 years, hospitalized with a diagnosis of COVID-19, not known to have received any study drug, without anticipated transfer elsewhere within 72 hours, and, in the physician’s view, with no contra-indication to any study drug.
Exclusion criteria
  • The only exclusions were patients without clear consent to follow-up
Interventions
Treatment
Interferon beta-1a
44 mcg subcutaneous injection on day of randomization, day 3 and day 6
Control
Standard care

Participants
Randomized
participants :
Interferon beta-1a=2063
Standard care=2064
Characteristics of participants
N= 4127
Mean age : NR
2581 males
Severity : Mild: n=972 / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
In the register
All-cause mortality, subdivided by the severity of disease at the time of randomization, measured using patient records throughout the study
In the report
In-hospital mortality
Documents
avalaible

Protocol

Yes. In English

Statistical plan

NR

Data-sharing willing stated in the publication:

Yes
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Low
General comment In addition to all available versions of the published manuscript, the pre-print article, the study registry and protocol were used in data extraction and risk of bias assessment. This was a report of interim results of an adaptive trial evaluating 4 drugs: Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon-β1a. No target sample size was pre-specified.
Quote: "The protocol stated “The larger the number entered the more accurate the results will be, but numbers entered will depend on how the epidemic develops… it may be possible to enter several thousand hospitalised patients with relatively mild disease and a few thousand with severe disease, but realistic, appropriate sample sizes could not be estimated at the start of the trial.” The Executive Group, blind to any findings, decided the timing of release of interim results."
Quote: "The hydroxychloroquine, lopinavir, and interferon regimens were discontinued for futility on, respectively, June 19, July 4, and October 16, 2020."
Of the 2063 patients allocated to the active interferon arm, 1412 were allocated interferon and local standard of care, while 651 patients were allocated interferon and lopinavir. Furthermore, of the 2064 patients allocated to the control arm for interferon, 1385 were allocated local standard of care, while 679 were allocated lopinavir.
There was no change from the trial registration in the intervention and control treatments, nor in the primary and secondary outcomes. QUote: "The regimen for interferon (mainly subcutaneous) was three doses over a period of 6 days (the day of randomization and days 3 and 6) of 44 μg of subcutaneous interferon beta-1a; where intravenous interferon was available, patients receiving high-flow oxygen, ventilation, or extracorporeal membrane oxygenation (ECMO) were instead to be given 10 μg intravenously daily for 6 days."

This study was updated on December 9th using data from the published manuscript.

Trial IRCT20100228003449N27
Publication Rahmani H, Int Immunopharmacol (2020) (published paper)
Dates: 2020-04-20 to 2020-05-20
Funding: Public/non profit (The authors did not receive any fund for this work)
Conflict of interest: No

Methods
RCT
Blinding: Unblinded
Location : Single center / Iran
Follow-up duration (days): 28
Inclusion criteria
  • Adult patients (≥18 years old) with positive PCR and clinical symptoms/signs of pneumonia (including dyspnea, cough and fever), peripheral oxygen saturation (SPO2) ≤ 93% in ambient air or arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) < 300 or SPO2/FiO2 < 315 and lung involvement in chest imaging were included
Exclusion criteria
  • Patients with serious allergic reactions to IFN, history of suicide thoughts and attempts, alanine amino transferase (ALT) > 5× the upper limit of the normal range, uncontrolled underlying diseases such as neuropsychiatric disorders, thyroid disorders, cardiovascular diseases and also pregnant and lactating women were not included. During the study period, patients who received less than 4 doses of IFN β-1b were excluded.
Interventions
Treatment
Interferon beta-1b
250 mcg subcutaneously every other day for 14 days
Control
Standard care

Participants
Randomized
participants :
Interferon beta-1b=40
Standard care=40
Characteristics of participants
N= 80
Mean age : NR
39 males
Severity : Mild: n=0 / Moderate: n=65 / Severe: n=1 Critical: n=0
Primary outcome
In the register
Response to the treatment (according the clinical, paraclinical and laboratory findings); Complications of the treatment (Interview and patient's record)
In the report
Time to clinical improvement
Documents
avalaible

Protocol

NR

Statistical plan

NR

Data-sharing willing stated in the publication:
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment In addition to the published report, the study registry was used in data extraction. The study almost achieved the target sample size reported in the registry (30 patients in each arm). There is no change from the trial registration in the intervention and control treatments. No protocol or pre-specified statistical analysis plan were available.