TABLE 4.

Modulating immune system

Drug name and structure	Original mechanism	FDA‐approved indication(s)	Possible mechanism for anti‐COVID‐19	Clinical trials ID (stage)	The highest anti‐COVID‐19 phase/ID/status/start–(estimated)end dates	References
Methotrexate	Enzyme dihydrofolate reductase inhibitor, an immunosuppressant and antineoplastic agent	Rheumatoid arthritis, ophthalmopathy, thyroid‐associated, psoriatic arthritis	Immunomodulatory agent, preventing excessive immunereaction	NCT04352465 (Phase 2) NCT04610567 (Phase 2)	Phase 2/NCT04610567/recruiting/October 27, 2020–March 15, 2021	(Abuo‐Rahma et al., 2020)
Leflunomide	Dihydroorotate dehydrogenase inhibitor	Rheumatoid arthritis, psoriatic arthritis, immunoglobulin G4 related sclerosing disease, juvenile idiopathic arthritis	Immunomodulatory agent, preventing excessive immunereaction	NCT04532372 (Phase 2) NCT04361214 (Phase 1)	Phase 2/NCT04532372/recruiting/January 7, 2021–September 18, 2022	(Abuo‐Rahma et al., 2020)
Fingolimod	Sphingosine 1‐phosphate (S1P) antagonist, pak1 activator, a immunosuppressant	Multiple sclerosis, relapsing–remitting	Immune modulator, S1P1 receptors antagonist	NCT04280588 (Phase 2)	Phase 2/NCT04280588/withdrawn (no participants enrolled)/February 22, 2020–July 1, 2020	(Barzegar et al., 2020; Pelletier & Hafler, 2012)
Tamoxifen	Selective estrogen receptor modulator (SERM), Hsp90 activator	Breast cancer, infertility, menorrhagia, endometrium	Modulation of NK cells activity and reduce viral replication, through reducing PGE2 production	NCT04389580 (Phase 2)NCT04568096 (Phase 2)	Phase 2/NCT04568096/not yet recruiting/November 2020–December 2020	(Almosawey et al., 2020; Hamouda Elgarhy, 2020)
Isoprinosine	Immunostimulant	Immunostimulant	Immunostimulant	NCT04360122 (Phase 3) NCT04383717 (Phase 3)	Phase 3/NCT04360122/not yet recruiting/May 20, 2020–November 1, 2020	(Clinical trial ID: NCT04360122, n.d.; Kumar et al., 2020)
IMU‐838 (vidofludimus calcium)	Immunomodulatory agent, DHODH inhibitor, inhibiting IL‐17 secreting	Not yet approved	Selective immunomodulatory effect against highly activated immune cells	NCT04516915 (Phase 2) NCT04379271 (Phase 3)	Phase 3/NCT04379271/recruiting/June 11, 2020–September 2020	(Clinical trial ID: NCT04379271, n.d.; Immunic Therapeutics website)
All‐trans retinoic acid	Neutrophil elastase inhibitor, RAR nuclear receptor agonist	Acute promyelocytic leukemia	Enhance neutralizing antibodies	NCT04396067 (Phase 2) NCT04568096 (Phase 2) NCT04730895 (Phase 2) NCT04578236 (Phase 2) NCT04353180 (Phase 3)	Phase 3/NCT04353180/not yet recruiting/April 2021–June 2021	(Clinical trial ID: NCT04396067, n.d.)
Melatonin	Selective ATF‐6 inhibitor	Parkinson's disease, infertility, immediate dental implant, immediate dental implant, postoperative pain, anxiety, acute ischemic stroke	Modulate the immune response and neuroinflammation	Approximately 8 clinical trials, some of the examples are: NCT04474483 (Phase 2) NCT04470297 (Phase 2) NCT04568863 (Phase 2) NCT04353128 (Phase 3) NCT04409522 (not applicable) NCT04531748 (Phase 2) NCT04530539 (not applicable)	Phase 3/NCT04353128/recruiting/April 20, 2020–October 2020	(Bahrampour Juybari et al., 2020)
Cyclosporinea(Synonyms: cyclosporine; Ciclosporin)	Immunosuppressant, inhibiting CD11a/CD18 adhesion	End‐stage renal disease, renal function and chronic allograft vasculopathy, kidney transplantation, etc	Immunomodulatory agent acting on T cells	NCT04540926 (Phase 2) NCT04412785 (Phase 1) NCT04492891 (Phase 2) NCT04392531 (Phase 4) NCT04451239 (not applicable)	Phase 4/NCT04392531/recruiting/April 16, 2020–March 2021	(Rudnicka et al., 2020; Tian et al., 2020)
AZD1656	Glucokinase activator	Type II diabetes	Activate the migration of T regulatory cells to sites of inflammation	NCT04516759 (Phase 2)	Phase 2/NCT04516759/completed/August 18, 2020–April 25, 2021	(Clinical trial ID: NCT04516759, n.d.)