key: cord-0698103-m55cydjl authors: Nayak, Debadatta; Gupta, Juhi; Chaudhary, Anupriya; Singh, Krishna Gopal; Deshmukh, Abhijeet; Das, Deblina; Saha, Abhishek; Kumar, Deepak; Kumar, Ashwini; Goenka, Ajay; Mishra, S.K.; Gupta, Sanjay; Khurana, Anil title: Efficacy of individualized homeopathy regimen as an adjunct to standard of care of COVID-19: A randomized, single-blind, placebo-controlled study date: 2022-05-08 journal: Complement Ther Clin Pract DOI: 10.1016/j.ctcp.2022.101602 sha: 68048e010587b6ea63d9621be96655eb96273261 doc_id: 698103 cord_uid: m55cydjl nan Efficacy of individualized homeopathy regimen as an adjunct to standard of care of COVID-19: A randomized, single-blind, placebo-controlled study The Coronavirus disease 2019 (COVID-19) pandemic due to SARS-CoV-2 spread rapidly, encountering a population that had no immunity and unprepared healthcare systems. The virus claimed many lives. So far, the pandemic has led to 93,805,612 cases and 2,026,093 deaths as of 19 th Jan. 2021. 1 COVID-19 has indeed perplexed the medical system with its pervasive symptomatology, multiorgan involvement, and a wide spectrum of disease severity ranging from asymptomatic to symptomatic, mild, moderate, to severe requiring intensive care management, and to the disease being fatal. 2 As per World Health Organization (WHO), about 80% of infections are mild-to-moderate or asymptomatic; 15% develop severe disease and 5% have a critical disease with complications. 3 Presently, there is no anti-viral specific to COVID-19. Multiple different therapeutic options like antimalarial, HIV medications, antivirals, antihelminthics, and steroids have been repurposed for the management of COVID-19 in various phases of the pandemic and studies have been undertaken to estimate their efficacy [4] . Similarly, various homeopathic medicines were also suggested for prophylaxis and treatment of COVID-19, and research studies are in progress. 5 Recently, remdesivir has been widely recommended for COVID-19, including the United States Food and Drug Administration (US FDA), but further clinical trials have not been able to support significant clinical benefit. Currently, no other therapeutic agents have been proven to be effective in the treatment of patients with COVID- 19. 6 Homeopathy is one of the popular systems of complementary medicine and has been used in epidemic outbreaks in the past. Homeopathy has been used for treatment and prevention in the epidemics of Cholera, Spanish flu, Dengue, Chikungunya, acute encephalitis syndrome, etc with variable success. 7, 8 There is anecdotal evidence that homeopathy was successful during the Spanish flu epidemic of 1918, in which at least 20-50 million people died worldwide. 9 According to Dewey, 10 the death rates for patients treated with homeopathy were 1% to 2% compared with a 30% to 60% mortality for those treated with conventional medicines. Clinical studies have been conducted on Dengue and acute encephalitis syndrome with homeopathy as an adjunct to usual care in tertiary care setups. In dengue hemorrhagic fever, adjunct homeopathy could bring early J o u r n a l P r e -p r o o f 2 improvement in platelet count and a decrease in hospital stay by 2 days. 11 Similarly, in acute encephalitis syndrome, homeopathy as an adjunct to the institutional management protocol, could decrease the death rate by 15% in comparison to those who received the institutional management protocol only. 12 In both studies, severe adverse effects related to homeopathic medicines were not observed. At the outbreak of the SARS-CoV-2 pandemic, the Ministry of Ayush, Government of India, had notified the advisory to use homeopathic medicines in the prophylaxis and management of COVID-19. The advisory recommends giving homeopathic medicines as an adjunct to the standard of care for treatment of the cases 13 in the spirit of the National Health Policy of India-2017 for integrative therapy. 14 This study was undertaken to explore the efficacy of the adjunct homeopathic treatment to the standard of care in the management of COVID-19. This was a randomized, placebo-controlled, single-blind study to assess the efficacy of the adjunctive individualized homeopathic medicine in adults ( and October 2020. Written informed consent was obtained from each patient before enrolling in the study. This trial was registered in Clinical Trial Registry-India (CTRI/2020/06/026195). The study's protocol has not been published. Patients who were reverse transcription polymerase chain reaction (RT-PCR) positive for SARS-CoV-2 and admitted to the COVID-19 ward of Chirayu Hospital were screened for study eligibility. Symptomatic patients aged 18-80 years, both sexes, willing to give written informed consent were included in the study. However, patients with severe heart, lung, kidney, brain, blood diseases or J o u r n a l P r e -p r o o f 3 other important systemic diseases, patients on ventilatory support, immunocompromised patients evident from medical history, pregnant women and lactating mothers, and also patients considered to be unable to complete the study, or not suitable by investigators were excluded from the study. Posthoc classification of patients was done according to their presentation into mild, moderate, and severe as per prevailing guidelines. 15, 16 -Mild disease: symptomatic patients meeting the case definition for COVID-19 without evidence of viral pneumonia or hypoxia. -Moderate disease: adolescent or adult with clinical signs of pneumonia (fever, cough, dyspnoea, fast breathing) but no signs of severe pneumonia, including SpO2 ≥ 90% on room air. -Severe disease: adolescent or adult with clinical signs of pneumonia (fever, cough, dyspnoea, fast breathing) plus one of the following: respiratory rate > 30 breaths/min; severe respiratory distress; or SpO2 < 90% on room air. In the standard of care + homeopathy (SC+H) group, patients were prescribed homeopathic medicine, selected based on the totality of symptoms, and given as an adjunct to the standard of care for COVID-19. However, in some cases, as per requirement, more than one homeopathic medicine was required and used one after another based on relationships between the remedies (complementary medicine, follows well medicines/intercurrent) . 17 Sucrose globules were used as vehicle to administer medicine or placebo to the patients. All the homeopathic medicines were prescribed in the centesimal scale of potencies. The repetition of the medicines was as per the decision of the treating homeopathic physician following the guidelines of homeopathy for centesimal potencies given in the 5th edition of Organon of medicine. 18 Placebo was also repeated following a similar pattern followed for medicine. As an adjunct to the standard of care, patients in the standard of care + placebo (SC + P) group received sucrose globules impregnated with unsuccussed dispensing ethyl alcohol (90%, v/v) (placebo). The homoeopathic medicines were procured from Willmar Schwabe, India, a good manufacturing practice-certified pharmaceutical company. The medicine/placebo pills were prepared by the study team (DD, AS, DK, and AK). All patients received supportive care according to the standard of care of the hospital as per the prevailing recommendation of the state government for COVID-19. It consisted of azithromycin 500 J o u r n a l P r e -p r o o f 4 mg (once daily), pantaprazole 40 mg (once daily), calcium 500 mg (twice daily), Montelukast 10 mg/Levicetirizin 5 mg (once daily, during hours of sleep), Zinc 50 mg (once daily), vitamin D3 60000 IU (weekly). This regimen of standard care was given for 5 days. However, this protocol was modified as per the requirement and patient prognosis. Medicines were also given for symptomatic management of cough and pain, etc. as per the symptoms of the patient. Anti-hypertensive, antidiabetic and others were given to patients as per the needs of the individual case. The primary outcome of the study was clinical recover. Clinical recovery was estimated through change in the total symptom score. Each symptom's severity was measured on a 10-point numerical rating patient-reported scale. The patients were asked by the homeopathic treating physicians to rate their symptoms experienced over the past 24 h, 0 being no symptom to 10 being the worst suffering from the symptom imaginable. The score of each symptom was added to get the total symptom score for each patient. The outcome was assessed every day between 8 a.m. and 12 noon. The secondary outcomes were time to fever clearance and time to clinical recovery. Time to fever clearance was defined as the time from the first dose of the study drug until the temperature dropped to ≤ 37.5 °C and remained below this temperature for at least 48 h. The body temperature of patients was recorded every 6 h. Time to clinical recovery was the time from enrolment till the total symptom score became '0'. As per the hospital's standard procedure, on admission, all patients underwent basic laboratory investigations such as complete blood count, liver function test, kidney function test, lactate dehydrogenase, C-reactive protein, serum ferritin, and high-resolution Computed tomography scan of the chest. The follow-up investigations were done for the patients, who did not improve clinically, as per the need of the case. The clinical data of each patient was recorded systematically on a pre-designed case-recording format for age, sex, duration of fever, symptom severity and resolution, laboratory parameters, date J o u r n a l P r e -p r o o f 5 of being COVID-19 positive, exposure and travel history, and others as per the homeopathic case recording format for homeopathic prescriptions. All the data were collected prospectively. Considering that this was the first research of its kind in homeopathy and COVID-19, and based on the study team's earlier experience, it was expected that 30% of patients in the SC + H group and 14% of patients in the SC + P group would have total symptom score '0' within 10 days of followup. With a power of 90%, and an alpha error of 5%, the required sample per group was 139. Assuming a 10% withdrawal rate, a total of 305 patients were needed for enrolment. G-power software available from Heinrich-Heine-Universität, Düsseldorf, Germany was utilized to compute sample size. 19 Eligible patients were randomly allocated following simple randomization procedures (1:1 allocation ratio) to either the SC + H group or the SC + P group through a computer-generated randomization chart. One of the investigators, JG was responsible for the randomization of the patients. She was not involved in the screening of patients for enrolment. Once a patient was found to be eligible and consented, the screening physician called telephonically to JG for group assignment. JG kept a record of the name of the patient against the serial no of randomization chart. Treating homeopathic physicians were aware of group allocations, whereas the enrolled participants, conventional physicians, nursing staffs, radiologists, and laboratory personnel were unaware of the study group assignment. The statistician was aware of the group assignment. The overall patient assessment for improvement and discharge was decided by conventional physicians. The homeopathic medicines were dispensed through medicated sucrose pills; similarly, the placebo group received sucrose pills impregnated with ethyl alcohol. Both medicated and placebo pills are identical in colour, odour, and appearance. The medicine or placebo sucrose pills were given in small vials and consecutively numbered for each participant according to the randomization schedule. In the case of a change of medicine, the vial was replaced with another vial of subsequently prescribed medicine, but the vial had the same number as mentioned in the previous vials. The medicine and placebo were dispensed by the treating homeopathic physicians to the patients. The quantitative variables were reported as mean ± standard deviations (SD), if they had normal distributions or as median with interquartile range (IQR), if they were skewed. Standard deviation (SD) was used for descriptive statistics and standard error (SE) for inferential statistics. The qualitative ones were reported as numbers (percent). For comparing the quantitative variables, t-test or Mann-Whitney test was used. The qualitative variables were compared by a chi-square test. The analysis was performed on an intention to treat basis. For patients who stayed in the hospital for less than 10 days, the last observed status of symptoms was carried forward for analysis. A longitudinal analysis with the main outcome (total symptom score) was carried out using multivariate general linear modeling repeated-measure analysis of variance (GLM-ANOVA) with total symptom score as the dependent variable, treatment assignment, and times of outcome assessment (days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) as between-and within-subject factors, respectively, and baseline total symptom score as a covariate 20 . Kaplan-Meier curve was used to estimate time to fever clearance and time to clinical recovery and the statistical significance of the difference between the groups was assessed by the log-rank test. The rate of recovery was calculated as the cumulative percentage of patients becoming symptom free, i.e., the total symptom score becoming zero. Logistic regression was carried out, after adjusting for total symptom score at baseline, for clinical recovery on day 10 of follow-up. The symptoms (dyspnoea, sputum production, fatigue, cough, headache) which were frequently associated with adverse outcomes in COVID-19 patients were analyzed for the percentage of patients getting relieved from them. The day-wise cumulative percentage was calculated for the no. of patients who had resolution of each pathognomonic symptom. A P value less than 0.05 was considered statistically significant. All statistical analyses were carried out using Statistical Package for Social Sciences, version 20.0 (IBM corp., IBM SPSS ® Statistics for Windows, Armonk, New York, United States). A total of 320 patients with RT-PCR positive for SARS-CoV-2 admitted to the hospital were screened for eligibility. Of these, 15 patients refused to participate, 5 patients did not meet inclusion criteria and the remaining 300 patients consented to participate in the study. They were assigned to J o u r n a l P r e -p r o o f 7 either SC + H group (n = 151) or SC + P (n = 149). The CONSORT flow diagram of patients in the study is given in Fig. 1 . The mean age was (42.54 ± 13.57) years and (41.51 ± 14.27) years in the SC + H and SC + P groups, respectively. About 63% of patients were of male sex, and the sex-wise distribution of participants was comparable. The most common comorbidity was hypertension followed by diabetes mellitus and chronic lung diseases. At the time of enrolment 62.91% (n = 95) had pneumonia in the SC + H group, while 51% (n = 76) had pneumonia in the SC + P group. Among all the patients, 1.39% (n = 2) had oxygen saturation below 90%, 27.27% (n = 39) had between 90%-95% in the SC + H group and 3.54% (n = 5) had oxygen saturation below 90%, 28.36% (n = 40) had between 90% -95% in the SC + P group. The patients were classified into mild, moderate, and severe as per the presentation at baseline. The severe (n = 21) patients were comparably distributed between the groups i.e. 7.28% (n =11) and 6.71% (n = 10) in SC+H and SC+P respectively. 55.62% (n = 84) and 44.29% (n = 66) of moderate patients and 37.08% (n = 56) and 48.99% (n = 73) of mild patients belonged to the SC + H and SC + P groups, respectively. The median time from RT-PCR positive to enrolment to study was 1 day (IQR = 1) in both the groups. The median time from onset of symptoms to initiating treatment was 5 days (IQR = 3) in the groups. The baseline demographic, epidemiological, and clinical characteristics of the patients in the two groups are given in Table 1 . A Kaplan-Meier curve was drawn to compare the time taken for recovery (Fig.3) . We observed that in the SC + H group, time to clinical recovery was about 2 days earlier than that in the SC + P group (SC + H: 5.95 ± SE 0.16 days, 95% CI: 5.63 to 6.27; SC + P: 7.69 ± SE 0.12 days; 95% CI: 6.58 to 7.03; P = 0.0001). Fifty-six participants had fever at baseline and another 11 developed fever post-enrolment in the study. A Kaplan-Meier curve was drawn to compare the time taken for the resolution of fever (Fig. 4 ). We observed that in the SC + H group the resolution of fever was 20 hours earlier than in the SC+P group (SC + H: 35.04 ± SE 6.48 hours, 95% CI: 22.32 to 47.75; SC + P: 55.79 ± SE 9.05 hours; 95% CI: 38.04 to 73.54; P = 0.04). On day 10 of treatment, 75.50% of patients recovered in homeopathy in comparison to 36.91% in the control group. A graph depicting the trend of recovery between the groups is given in Fig. 5A An adverse effect was observed in 1.6% (n = 5) of patients who were shifted to ICU support; of which 1.98% (n = 3) from the SC + H group, and 1.34% (n = 2) from the SC + P group. Among the 2 patients from SC + P group, one had uncontrolled blood sugar and the other patient had a nonresponsive fever. Out of 3 patients of SC + H, one had severe dehydration with bedsores, one had a non-responsive fever, one had fluctuating oxygen saturation. No deaths were reported from both groups. Our study found that adjunct individualized homeopathic medicine with the standard of care significantly improves clinical recovery with early resolution of symptoms compared to those who received placebo along with the standard of care. This study is the first of its kind with adjunct individualized homeopathic treatment of COVID-19. As the pandemic progressed and more people recovered from COVID-19, it was realized that post-COVID symptoms were a healthcare burden. About 82% of post-COVID-19 patients reported suffering from at least one symptom related to COVID-19. 21 In our study in the standard care group, 63% had at least one symptom at the time of discharge from the hospital. However, in the adjunct treatment group, only 24% of patients had any residual symptom related to COVID-19 at discharge from the hospital. Adjunct homeopathy could significantly shorten the time for fever clearance, thereby reducing the need for antipyretics. It has been reported that symptoms such as dyspnea, sputum production, J o u r n a l P r e -p r o o f fatigue, and headache are frequently observed in patients with fatal outcomes 22 ; however, in our study, these symptoms resolved earlier in patients who received adjunct homeopathy than in those who received standard of care only. It is observed that patients in the SC + H group required fewer antipyretics and other medications for symptom relief. In our study, we found that Arsenicum album, Phosphorus, and Bryonia were the most prescribed medicines. It corroborated with the finding of physicians of Italy, 23 which was not a systematic study. Resolution of pneumonia could not be assessed due to non-availability of follow-up chest CT/HRCT. However, symptoms related to pneumonia were resolved earlier in the SC + H group than in the SC + P group. Nonetheless, objective evidence of the resolution of pneumonia will be more appropriate. In our study, we did not estimate the viral load and the time to its clearance. It will be of interest to see the virus clearance in relation to clinical improvement following homeopathic medication. Due to the large number of COVID-19 patients during the study at the hospital, the follow-up laboratory tests of all the patients could not be done due to a resource crunch. Future studies may estimate the changes in laboratory parameters. However, this does not limit the applicability of the study results as clinical improvement is evident from an early resolution of symptoms of the patients. Restricted access to patients due to high transmission of COVID-19 infection is also a limitation for homeopathic prescriptions; because, to select homeopathic medicine, various attributes of patients are essential along with the disease features. Various inflammatory markers have been identified as prognostic indicators for COVID-19. Future studies may target to study the effect of homeopathic medicine on these markers and ultimately on cytokine storm. 25 Our study being a single-blinded trial, it has its limitation due to experimenter bias, J o u r n a l P r e -p r o o f 11 as the physicians responsible for the group allocation and homeopathic treatment were aware of the group assignment. Further, the primary outcome of our study was a patient-rated subjective score, hence, there is the possibility of bias favouring the treatment group 26 , however, the patients were not aware of the group assignment. In spite of the randomized allotment of patients to the groups, our study had differences between groups for total symptom score at baseline, no. of patients having pneumonia, and few other parameters. However, the no. of moderate/severe (based on the presence of pneumonic changes in the lung) cases and patients having higher total symptom scores at baseline were more in the SC + H group. Further, it is suggested that future studies need to consider stratified randomization based on the severity of the illness to achieve balanced groups. Keeping in view the evolving understanding of disease and treatment, the team was allowed to conduct the single-blinded study by the COVID-19 task force of the Ministry of Ayush. Further, due to limited access to patient and stressed health care during the pandemic, limited logistics and treating physicians getting infected with COVID-19, implementing a double-blind study might have been difficult. Future studies may be planned as double-blind to avoid experimenter biases. The standard of care protocol also evolved with the progress of the pandemic. So, the treatment outcome of later guidelines may be different than the standard of care provided in this study. Serious adverse events were not observed in this study. The beneficial effect of this integrative approach refutes the possibility of drug-to-drug interaction. This also fulfills the vision envisaged in the National Health Policy of India for integrative management of diseases. 14 Adjunctive individualized homeopathic management with an integrated standard of care has resulted in better clinical outcomes in patients with COVID-19 in terms of early recovery. Further, doubleblind, controlled studies are needed to confirm these results. 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Accessed 21 Adjunctive homeopathic treatment of hospitalized COVID-19 patients (COVIHOM): a retrospective case series The cytokine storm in COVID-19: an overview of the involvement of the chemokine/chemokine-receptor system Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study BMI: body mass index; COPD: chronic obstructive pulmonary disease; HRCT: high-resolution computed tomography; IQR: interquartile range; RT-PCR: reverse transcription-polymerase chain reaction; SD: standard deviation J o u r n a l P r e -p r o o f The authors declare no conflict of interest.