Title: Pulmonary radiological change of COVID-19 patients with 99mTc-MDP

treatment

Authors: Xiaolin Yuan1#, Ph.D., Wanrong Yi2#, M.D., Baoyi Liu3#, M.D., Simiao Tian3, Ph.D., Fang Cao3, Ph.D. student, Ruoyu Wang3, M.D., Baiwen Qi2, M.D., Faqiang Lu3, M.D., Meiyun Fang4, M.D., Fuyang Pei5, M.D., Ming Chen2, M.D., Lichuan Zhang5, M.D., Yong Zhang2, M.D., Xiuzhi Zhang3, Ph.D., Zhenyu Pan2, M.D., Dewei Zhao3, M.D., Aixi Yu2, M.D. Affiliations: 1 Central laboratory, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, Liaoning, 116001, China 2 Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China 3 Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, Liaoning, 116001, China 4 Department of Rheumotology, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, Liaoning, 116001, China 5 Department of Respiratory Medicine, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, Liaoning, 116001, China # contributed equally.

*Corresponding author: Dr. Dewei Zhao and Dr. Aixi Yu

Address correspondence to Dr. Dewei Zhao at Department of Orthopaedics, Affiliated

Zhongshan Hospital of Dalian University, NO. 6 Jiefang Street Zhongshan District,

Dalian, Liaoning Province, China, 116001. E-mail: Zhaodewei2016@163.com

Address correspondence to Dr. Aixi Yu at Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China. E-mail: yuaixi@whu.edu.cn

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 14, 2020. ; https://doi.org/10.1101/2020.04.07.20054767doi: medRxiv preprint

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Abstract:

Background: As increasing cases of COVID-19 around world, urgent need for

effective COVID-19-specific therapeutic drugs is necessary; therefore, we conducted

a pilot randomized-controlled study to evaluate the efficacy of 99mTc-MDP for

COVID-19 therapeutic treatment.

Methods: A total of 21 mild patients with COVID-19 were enrolled in this pilot RCT

from February 2020 through March 2020, and then were assigned, in a 1:1 ratio, into

control (11 patients) and 99mTc-MDP group (10 patients). Patients in the control group

received routine treatment and patients assigned to the 99mTc-MDP group received a

combination of routine treatment and an administration of 99mTc-MDP injection of

5ml/day. Both of the patients in the control and 99mTc-MDP groups were treated for 7

days with the primary end point of CT-based radiological pulmonary changes during

7-day follow-up.

Findings: From baseline to the day 7, 8 (80%) of 10 mild patients in the 99mTc-MDP

group had a significant radiological improvement in lung and a decline in

inflammatory infiltration, whereas only 1 (9.1%) of 11 patients in the control group

had a radiological improvement in lung. None of the patients in the 99mTc-MDP group

had disease progression from mild to severe, as well as an inflammatory cytokine

storm, and 2 mild patients (18.2%) in the control group developed severe. During

days 7 through 14, the number of patients with radiological improvement in the

99mTc-MDP group remained consistent, and only 1 additional case (22%) in the

control group were reported.

Conclusion: In this randomized pilot study, 99mTc-MDP had an effective inhibitory

effect on the inflammatory disease progression for the therapy of COVID-19, and it

can accelerate the absorption of pulmonary inflammation in a short period of time

during the process of treatment.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 14, 2020. ; https://doi.org/10.1101/2020.04.07.20054767doi: medRxiv preprint

The recent outbreak of the novel coronavirus (2019-nCoV) is currently beginning

spread to many countries around the world, and is becoming a pandemic according to

World Health Organization (WHO).1 The increasing cases and fatality highlight the

urgent need for effective COVID-19-specific therapeutic drugs, which would

prevent the progression of the disease, especially for decreasing the

deterioration rate of respiratory and pulmonary infection. In the process of

COVID-19, the cytokine storm is trigged by excessive inflammatory response and

macrophage activation, which lead to multiple organ damages and even fatality;

therefore, suppressing inflammatory response and targeting macrophage are both

crucial for COVID-19 treatment. 99mTc-methylene diphosphonate (99mTc-MDP) is a

first-in-class, highly active inhibitor of inflammation response and macrophage

infiltration, and it is common drug therapy for use in autoimmune diseases such as

rheumatoid arthritis with no significant adverse effects in clinical use.2. In this pilot

randomized controlled trial (RCT) study, 99mTc-MDP were administered in

combination, with or without standard treatment for 7 days in patients with

COVID-19. We report preliminary results from this exploratory cohort, with main

focus of computed tomography (CT)-based radiological pulmonary changes at 7 days.

A total of 21 mild patients with COVID-19 were enrolled in this pilot RCT from

February 2020 through March 2020 (Trial Registration: ChiCTR2000029431).

Patients were considered eligible in this study on the basis of the WHO interim

guidance3 and they were laboratory-confirmed positive on by the means of real-time

reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay of nasal and

pharyngeal swab specimens. Randomization was performed and ensured with the use

of Web-based randomization system. Patients were assigned, in a 1:1 ratio, into

control (11 patients) and 99mTc-MDP group (10 patients). Patients in the control group

received routine treatment according to Diagnostic of COVID-19 criteria issued by

National Health Commission of China. Patients assigned to the 99mTc-MDP group

received a combination of routine treatment and an administration of 99mTc-MDP

injection of 5ml/day. Both of the patients in the control and 99mTc-MDP groups were

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 14, 2020. ; https://doi.org/10.1101/2020.04.07.20054767doi: medRxiv preprint

treated for 7 days. The primary end point was the CT-based radiological pulmonary

changes from baseline to 7 days. The secondary end points were disease progression

from mild to severe on the day 7, as well as radiological pulmonary changes during 7

days to 14 days after treatment.

Demographic characteristics were similar in the two groups except that patients in

the control group were older than those in the 99mTc-MDP group (median age, 62

years vs. 57 years), there were fewer women in the control group than in the

99mTc-MDP group (55 % vs. 60%) (Table 1). On the day 7, 8 (80%) of 10 mild

patients in the 99mTc-MDP group had a significant radiological improvement in lung

and a decline in inflammatory infiltration, whereas only 1 (9.1%) of 11 patients in the

control group had a radiological improvement in lung (Figure 1 and Figure S1 in the

Supplementary Appendix). None of the patients in the 99mTc-MDP group had disease

progression from mild to severe, as well as an inflammatory cytokine storm, and 2

mild patients (18.2%) in the control group developed severe. During days 7 through

14, the number of patients with radiological improvement in the 99mTc-MDP group

remained consistent, and only 1 additional case (22%) in the control group were

reported (Table 1).

In conclusion, in this randomized pilot study, the clinical drug, 99mTc-MDP had an

effective inhibitory effect on the inflammatory disease progression from mild to

severe for the therapy of COVID-19, and it can accelerate the absorption of

pulmonary inflammation in a short period of time during the process of treatment.

Besides, there were no serious adverse events including body immunity during the

clinical use of 99mTc-MDP. Additional potential advantage for application of

99mTc-MDP is to avoid excessive use of glucocorticoids in the treatment of severe

COVID-19 patients, in order to prevent further incidence of some glucocorticoids

caused complications such as osteonecrosis of femoral head.4 Limited by the small

sample size, larger and longer trials are warranted to determine the efficacy of

99mTc-MDP in the treatment of COVID-19.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 14, 2020. ; https://doi.org/10.1101/2020.04.07.20054767doi: medRxiv preprint

References: 1. World Health Organization 2020.

(https://www.who.int/emergencies/diseases/novel-coronavirus-2019).

2. Lai K, Xu L, Jin C, et al. Technetium-99 conjugated with methylene

diphosphonate (99 Tc-MDP) inhibits experimental choroidal neovascularization

in vivo and VEGF-induced cell migration and tube formation in vitro. Invest

Ophthalmol Vis Sci 2011;52:5702-12.

3. World Health Organization. Clinical management of severe acute respiratory

infection when novel coronavirus (2019-nCoV) infection is suspected: interim

guidance. January 28, 2020

(https://www.who.int/docs/default-source/coronaviruse/clinical-management-of-n

ovel-cov.pdf).

4. Zhao FC, Guo KJ, Li ZR. Osteonecrosis of the femoral head in SARS patients:

seven years later. Eur J Orthop Surg Traumatol 2013;23:671-7.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 14, 2020. ; https://doi.org/10.1101/2020.04.07.20054767doi: medRxiv preprint

Table1. Characteristics of the patients and End Points

Total (N=21)

99mTc-MDP Group (N=10)

Control Group (N=11)

P value

Characteristics of the patients

Age, median (IQR), y 61 (47-67) 57 (47-66) 62 (54-68) 0.417

Male sex - n (%) 9 (42.9%) 4 (40%) 5 (45%) >0.99

End Points Patients with significant radiological pulmonary changes at day 7- n (%) of patients

9 (42.9%) 8 (80%)* 1 (9.1%) 0.002

Disease progression from mild to severe on the day 7 - n (%) of patients

2 (9.5%) 0 (0%) 2 (18.2%) 0.48

Patients with significant radiological pulmonary changes at day 14- n (%) of patients

10 (47.6%) 8 (80%)* 2 (22%) 0.009

IQR, interquartile range. *P<0.05 between the 99mTc-MDP and control groups.

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 14, 2020. ; https://doi.org/10.1101/2020.04.07.20054767doi: medRxiv preprint

Figure 1: Computed Tomography (CT)-based radiographs of the patients' lung. On the top, shown are pulmonary radiographs for one patient in the 99mTc-MDP group at admission (A), at day 7 (B) and at day 14 (C); on the bottom, shown are pulmonary radiographs for one patient in control group at admission (D), at day 7 (E) and at day 14 (F).

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 14, 2020. ; https://doi.org/10.1101/2020.04.07.20054767doi: medRxiv preprint

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 14, 2020. ; https://doi.org/10.1101/2020.04.07.20054767doi: medRxiv preprint