Ruxolitinib in the Treatment of Covid-19

COVID-19 Clinical Trial

Official title:

Safety and Efficacy Study of Ruxolitinib in the Treatment of Severe Acute Respiratory Syndrome Due to SARS-COV-2

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04414098
• Other study ID #: CZabala
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: June 1, 2020
• Est. completion date: September 15, 2020

Study information

• Verified date: June 2020
• Source: Clinica Zabala
• Contact: Marcelo Iastrebner, MD
• Phone: +5491169816300
• Email: miastrebner[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The treatment of COVID-19 severe acute respiratory syndrome with ruxolitinib 5 mg orally every 12 hours during 14 days would stop the disproportionate inflammatory response, causing a reduction in the proportion of patients who show a progression and worsening of the severe acute respiratory syndrome.

Description:

Primary Objective

Evaluate the efficacy of ruxolitinib in the treatment of COVID-19 severe acute respiratory syndrome by means of measuring the proportion of patients with clinical worsening (defined by a requirement of FIO2 50% and/or mechanical respiratory assistance) during 14 days after the commencement of treatment.

Secondary Objectives

1. Evaluate the median duration of hospitalization. Median duration after 45 days of commencement of treatment.

2. Evaluate the evolution of systemic inflammation parameters. Evaluation at the beginning (baseline), middle and end of the treatment with ruxolitinib of PCR, LDH, ESD, Ferritin and IL-6.

3. Evaluate COVID-19 mortality rate after 45 days of treatment.

4. Evaluate the proportion of the requirement of mechanical ventilation.

5. Evaluate ruxolitinib adverse reactions with a total follow-up of 45 days.

6. Evaluate the proportion of secondary infections during the treatment with ruxolitinib.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: September 15, 2020
• Est. primary completion date: August 15, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patients = 18 years.

2. SARS-Cov2 infection confirmed by a validated method.

3. Presence of COVID-19 severe acute respiratory syndrome with:

Respiratory rate = 20/min O2 saturation =93% with FiO2 of 0.21 Lung images by means of computerized tomography or thorax radiography compatible with respiratory involvement due to COVID-19.

4. Signed informed consent.

Exclusion Criteria:

1. Pregnancy or breast-feeding.

2. Platelets < 50,000/mm3.

3. Neutrophils < 1,000/mm3.

4. Hemoglobin < 6 g/dl

5. Creatinine =2 mg/dl or creatinine clearance =30 ml/min.

6. Total serum bilirubin > 2.0 x upper limit of normal and/or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal.

7. Known active infection due to HIV, HVC, HVB, Herpes Zoster or Micob Tuberculosis

8. Treatment with Tocilizumab, Baricitinib or Interferon.

9. History of hypersensitivity to ruxolitinib or to any medicine with similar chemical compounds

10. Patients with mechanical respiratory assistance

11. Patients under treatment with Ruxolitinib due to hematological disease

12. Any condition that, according to the Investigator, may interfere with the complete participation of the patient in the study, including the administration of the medicinal product, the limitation of visits, the implication of a risk for the patient or that prevents the correct interpretation of the results.

Treatment Suspension Criteria

1. Voluntary decision of the patient

2. Treating physician's decision to discontinue the treatment

3. Drug toxicity grade 3 or higher (CTCAE 5.0).

Study Design

Experimental, open-label, prospective, single center, add-on (added to the standard treatment) study, compared with the historical control arm.

Control arm: It will include patients with COVID-19 Respiratory Syndrome who meet the aforementioned selection criteria and have received the standard of care (SOC). Efforts will be made so that both arms share similar demographic characteristics as regards gender and age group. Ten centers will participate, which will share the same protocol and their results may be jointly analyzed. The expected n per center is 10-15 patients.

For the safety assessment as part of the objective, the following parameters will be taken into account:

1. Biochemical changes: (day 1, 8 and 14) Leukocytes, Formula, Hemoglobin, platelets, creatinine, glycemia, PT, Bilirubin, GOT/GPT.

2. Grade 3/4 Toxicity, SAE (Serious Adverse Event)

3. Incidence of discontinuation, suspension or dose-reduction of the study drug.

4. Incidence of secondary infections.

Efficacy Assessment:

1. Efficacy will be graded according to the ordinal scale of 8 points.

2. Time to Improvement

3. Time of response consolidation

4. Changes in NEWS table

Related Conditions & MeSH terms

• COVID-19

Intervention

Drug:
• INC424 / Ruxolitinib
Ruxolitinib 5 mg orally every 12 hours during 14 days. Total Follow-up time will be of 45 days. The reduction of ruxolitinib dose will be considered in cases of drug-related cytopenias. During hospitalization, clinical and laboratory evolution parameters will be recorded daily in the medical history of the patient and in the data collection table of the study. Upon patient's discharge, a follow-up will be conducted until day +45 During hospitalization, adverse events will be monitored daily by means of clinical assessment and laboratory data. After discharge, monitoring of adverse events will continue during the outpatient follow-up. Pro-inflammatory parameters will be assessed at baseline, after one week (day +7) and at the end of treatment (day +14) Ruxolitinib will be associated to the standard of care for COVID-19 of each center. In case of an adverse effect or a need to discontinue the treatment, ruxolitinib should be suspended.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Marcelo Iastrebner	Novartis

References & Publications (7)

Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs. 2017 Apr;77(5):521-546. doi: 10.1007/s40265-017-0701-9. Review. Erratum in: Drugs. 2017 May;77(8):939. Drugs. 2017 Jun 12;:. — View Citation

Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation and Treatment Coronavirus (COVID-19). 2020 May 18. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK554776/ — View Citation

Gadina M, Le MT, Schwartz DM, Silvennoinen O, Nakayamada S, Yamaoka K, O'Shea JJ. Janus kinases to jakinibs: from basic insights to clinical practice. Rheumatology (Oxford). 2019 Feb 1;58(Suppl 1):i4-i16. doi: 10.1093/rheumatology/key432. Review. — View Citation

Harrison CN, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Gisslinger H, Knoops L, Cervantes F, Jones MM, Sun K, McQuitty M, Stalbovskaya V, Gopalakrishna P, Barbui T. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016 Aug;30(8):1701-7. doi: 10.1038/leu.2016.148. Epub 2016 May 23. Erratum in: Leukemia. 2017 Mar;31(3):775. — View Citation

McGonagle D, Sharif K, O'Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020 Jun;19(6):102537. doi: 10.1016/j.autrev.2020.102537. Epub 2020 Apr 3. Review. — View Citation

Slostad J, Hoversten P, Haddox CL, Cisak K, Paludo J, Tefferi A. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A single patient experience. Am J Hematol. 2018 Feb;93(2):E47-E49. doi: 10.1002/ajh.24971. Epub 2017 Dec 4. — View Citation

Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14. doi: 10.1038/s41421-020-0153-3. eCollection 2020. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluate the efficacy of ruxolitinib in the treatment of COVID-19 severe acute respiratory syndrome	Measuring the proportion of patients with clinical worsening (defined by a requirement of FIO2 >50% and/or mechanical respiratory assistance)	during 14 days after the commencement of treatment
Secondary	Evaluate the median duration of hospitalization.		after 45 days of commencement of treatment.
Secondary	Evaluate the evolution of systemic inflammation parameters.	Evaluation at the beginning (baseline), middle and end of the treatment with ruxolitinib of PCR, LDH, ESD, Ferritin and IL-6 (if available).	after 45 days of commencement of treatment.
Secondary	Evaluate COVID-19 mortality rate		after 45 days of treatment.
Secondary	Evaluate the proportion of the requirement of mechanical ventilation.		with a total follow-up of 45 days
Secondary	Evaluate ruxolitinib adverse reactions		with a total follow-up of 45 days.
Secondary	Evaluate the proportion of secondary infections during the treatment with ruxolitinib		after 45 days of commencement of treatment.