key: cord-0714856-93amoypt authors: Ashraf, S.; Ashraf, M.; Imran, M. A.; Kalsoom, L.; Siddiqui, U. N.; Ghufran, M.; Majeed, N.; Farooq, I.; Habib, Z.; Hilal, A.; Abdin, Z. u.; Khaqan, A.; Akram, M. K.; Akmal, R.; Rafique, S.; Nawaz, K.; Arshad, S.; Ahmad, S.; Hayat, K.; Arshad, A.; Nadeem, M. F.; Hassan, M.; Awais, A. b.; Azam, M.; Suhail, M.; Zulfiqar, S.; Anwar, I.; Sarfraz, S.; Humayun, A.; Malik, A.; Zheng, H.; Mahmud, T.; Ayyaz, M.; Ahmad, A.; Saboor, Q. A.; Izhar, M. title: Therapeutic efficacy of Honey and Nigella sativa against COVID-19: A multi-center randomized controlled clinical trial (HNS-COVID-PK) date: 2020-11-03 journal: nan DOI: 10.1101/2020.10.30.20217364 sha: 88e01a7c6307bd4d5fad15defc91c0d339235b2b doc_id: 714856 cord_uid: 93amoypt BACKGROUND: COVID-19 has caused havoc across the globe since, no specific treatment exists for this disease, thus, far. Hence, there is an urgent need to find an effective treatment to mitigate this scourge. Honey and Nigella sativa are two natural substances with anti-inflammatory, anti-viral, anti-microbial and immune modulating properties. They could be potentially beneficial in these patients. METHODS: We conducted an add-on, randomized, open label, placebo-controlled clinical trial using parallel group design. This was a multi-centered study with superiority framework conducted in RT-PCR confirmed COVID-19 patients showing moderate or severe disease. All patients receiving standard care were randomized into treatment and control groups. In the treatment arm, patients received HNS (honey plus Nigella sativa) in predefined doses for up to 13 days. The primary outcome measures (time taken for alleviation of symptoms, viral clearance and clinical status improvement on day 6) outcomes were assessed. RESULTS: Of 1046 patients testing positive for the SARS-CoV-2, 210 showing moderate and 103 showing severe disease were randomized into treatment and control groups as per inclusion criteria. In the moderate cases, 107 were assigned to the HNS group and 103 to the control group. Among 103 severe cases, 50 were assigned to the HNS group and 53 to the control group. In the moderate and severe cases, the HNS treatment was associated with a normalized median symptoms alleviation time reduction of 3 and 7 days (HR: 6.11; 95% CI: 4.23-8.84 and HR: 4.04; 95% CI, 2.46-6.64) respectively. The HNS treatment in both groups were further associated with 4 days earlier reduction in median viral clearance time (Moderate HR: 5.53; 95% CI: 3.76-8.14) and Severe HR: 4.32; 95% CI: 2.62-7.13). Moreover, in the intention-to-treat analysis, the HNS groups led to a lower (better) clinical score on day 6 with resumption of normal activity among 63.6% of the moderate (OR: 0.07; 95% CI: 0.03-0.13) and 28% of severe cases (OR: 0.03; 95% CI: 0.01-0.09). Furthermore, a significant (14.87%) reduction (OR: 0.18; 95% CI: 0.02-0.92) in mortality was observed in the HNS arm. No difference in adverse effects were seen between the HNS and control arms. CONCLUSIONS: A significant reduction in in the severity of disease, the time taken for viral clearance and mortality was observed with HNS treatment in COVID-19 patients. HNS represents a safe, effective, over the counter and affordable therapy for this pandemic essentially lowering health care burden. It can be used alone or in combination with other expensive treatments and give an additive effect. Hence, the potential of HNS against COVID-19 should be explored in future larger studies. (Funded by Smile Welfare Organization, Shaikh Zayed Medical Complex and Services Institute of Medical Sciences; NIH Clinical Trial Register number: NCT04347382.) BACKGROUND: 123 The COVID-19 pandemic, caused by the novel coronavirus named SARS-CoV-2, has infected 124 more than forty million people and has resulted in more than a million deaths in the world (1) . In Both components of HNS have anti-viral, anti-microbial, anti-inflammatory and immune 136 stimulating effects with proven safety profiles (9) (10) (11) (12) (13) . Beneficial effects of honey against different 137 viruses including rubella virus, Herpes Simplex virus, Hepatitis virus, and Varicella Zoster virus 138 have been reported earlier (14, 15) . Moreover, in silico molecular docking studies have shown that 139 six flavonoid compounds from honey might inhibit SARS-CoV-2 replication by binding to the 140 viral 3-chymotrypsin-like-cysteine protease (16) . Honey has also shown efficacy against several 141 multidrug resistant bacteria, especially in synergism with antibiotics (17, 18) . Honey also exhibits 142 immunity-boosting effects mainly via its polyphenolic components, which stimulate both innate 143 and adaptive immune responses (19) . Its use has been shown to be beneficial in upper respiratory 144 tract infections (20) . (21) (22) (23) . It has also been shown to decrease 149 replication of SARS-CoV in vitro in cell cultures (24) . Moreover, molecular docking studies have 150 shown that some of its components such as nigelledine, α-hederin and thymoquinone, etc., have 151 high affinity with several SARS-CoV-2 enzymes and proteins. In fact, they exhibit an energy 152 complex score better than that of chloroquine, hydroxychloroquine and favipiravir, the drugs that 153 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020. 10.30.20217364 doi: medRxiv preprint have shown some anti-SARS-CoV-2 effects (25) . The components' antimicrobial properties against 154 various microbes as well as their anti-inflammatory and immunomodulatory effects have also been 155 established (13, 26, 27) . As honey and Nigella sativa show similar pharmacological profiles, we reasoned that the 158 combination could be more effective in attenuating severity of the disease, controlling viral 159 replication and curing COVID-19 patients. In fact the combination has been used successfully in 160 a variety of disease conditions (28) (29) (30) (31) (32) . We report here that the HNS treatment results in earlier 161 recovery and viral clearance in COVID-19 patients. (3, 4) . Body temperature was measured, and fever was 209 graded as no fever (0; 98-99 °F), mild (1; >99-<100 °F), moderate (2; 100-101.9 °F) and severe CC-BY 4.0 International license It 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 November 3, 2020. ; https://doi.org/10.1101/2020.10.30.20217364 doi: medRxiv preprint physician. Trial safety was monitored by the trial steering committee. For the patients who were 216 discharged before day 13 or were home-quarantined, the follow-up was done by telemedicine. The primary outcomes were viral clearance (negative RT-PCR for the SARS-CoV-2 RNA), 219 alleviation of clinical symptoms and the lowering of CGS on day 6. Secondary outcomes included 220 reduction in fever degree (day 4), CRP levels (day 6), severity of symptoms (day 8), CGS score 221 (day 10) and mortality on day 30. In univariate analyses, we used a log-rank test to compare time taken for viral clearance, alleviation CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.30.20217364 doi: medRxiv preprint shown in Table 1 . Paracetamol and azithromycin were the top two prescribed drugs as part of the 245 SCT. Two patients opted for home quarantine despite needing oxygen therapy. Primary outcomes are shown in Table 2 . Alleviation of COVID-19 symptoms for patients in the 248 HNS groups occurred earlier than control groups: 4 versus 7 days for the moderate patients (HR: There were significant differences in all secondary outcomes between the treatment and control 260 groups (see Table 2 for secondary outcomes). In moderate COVID-19 patients, degree of fever . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. P=0.09) (3) . In our study, in ~50% of cases, SARS-CoV-2 RT-PCR became negative 4 days sooner 300 in HNS than in control groups. Mortality among severe cases in comparison to control group was 301 27.0% (versus 25.0%) for hydroxychloroquine (2) , 19.2% (versus 25.0%) for lopinavir-ritonavir (3) , 302 15.7% (versus 24.0%) for convalescent plasma (34) , 11.4% (versus 15.2%) for remdesivir (5) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.30.20217364 doi: medRxiv preprint lopinavir-ritonavir failed to provide statistical improvement in mortality (35) . In contrast to these 307 drugs, HNS represents a safer and more affordable option that can be used as an in-house remedy. and immune stimulating effects of honey and Nigella sativa (9) (10) (11) (12) (13) . Anti-diabetic, anti-hypertensive, 314 cardio-protective and broncho-dilatory properties of HNS make it even more beneficial in diabetic, 315 hypertensive, cardiac and asthmatic patients which have a higher COVID-19 associated mortality 316 (36, 37) . Furthermore, anti-platelet and anti-coagulant effects of HNS also shield COVID-19 patients 317 from thromboembolic complications, which are main cause of morbidity and death in this 318 disease (38) . Hepato-and reno-protective nature of HNS gives added advantage over other drugs in 319 limiting COVID-19 related hepatic and renal injuries (36, 37) . Anti-pyretic, analgesic and antitussive 320 properties of HNS also provide symptomatic relief (39, 40) . Furthermore, HNS's antimicrobial 321 properties and synergism with other antibiotics against superadded infections prevent sepsis 322 related deaths (17, 18) . These findings strengthen the use of HNS as a potential candidate for 323 combating SARS-CoV-2 worldwide. HNS is a safe and effective therapy for COVID-19 patients and promotes viral clearance, quicker 335 recovery and survival. Its affordability (< $5 for the whole treatment course), over the counter 336 availability and ease of administration (as an easily practicable home-based remedy) will make 337 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; this treatment very attractive. Furthermore, as an inexpensive nutraceutical, HNS could be used 338 alone or in combination with other drugs for additive effects. The treatment is very likely to reduce 339 burden on health care systems in a significant manner. The corresponding authors attest the authenticity of that all listed authors meet authorship criteria. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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