Dhaka Medical College and Hospital, a public medical college and hospital based in Dhaka, the capital of Bangladesh, houses one of the most prestigious medical schools and the country’s largest tertiary care hospital. Known as the most advanced of health institutions in this country with a population of 161.5 million—Bangladesh, the 8th most populous nation in world with an entrepreneurial spirit and nascent economy—the nation emerges as a research center targeting pragmatic and economical approaches to treating COVID-19. The combination of Ivermectin and doxycycline has become front and center in that strategy, with the goal of ensuring a pragmatic, safe and effective treatment for COVID-19. Recently, Dhaka Medical College produced the results of a randomized controlled study demonstrating the efficacy of ivermectin as a treatment for COVID-19. Although not as yet peer reviewed or even documented for preprint server, TrialSite shares with the TrialSite Network worldwide a description of the study results as well as the study protocol. The findings appear to indicate the potential benefit of ivermectin and doxycycline for patients with mild to moderate SARS-CoV-2 infection. However, the medical community worldwide will make that final call.
Basis for the Study
Led by Principal Investigator Dr. Reaz Mahmud, a professor with Dhaka Medical College, the study (NCT04523831) team based the rational for this study on a number of factors, such as a published study in the American Journal of Tropical Medicine, the research in vitro originating at Monash University as well as undoubtedly works out of Bangladesh ongoing such as the peer reviewed, published results of an observational study by Dr. Tarek Alam and the positive results from the study sponsored by the Upazila Health & Family Planning Officer’s (UHFPO) Office, Chakoria, Cox’s Bazar.
The authors of this yet to be peer reviewed study, led by Dr. Mahmud, articulated that in one study Doxycycline evidenced promising results in the treatment of COVID-19 infection. They note in their Clincialtrials.gov disclosure that, “It is highly lipophilic antibiotics that are known to chelate zinc component of matrix metalloproteinases (MMP). Coronaviruses are known to rely heavily on MMPs for survival, cell infiltration and replication. It also has an anti-inflammatory effect which might be effective in combating cytokine storm of COVID-19 infection.”
Based on this background, Dhaka Medical College embarked on an experimental study using a combination of ivermectin and doxycycline coupled with the standard of care in randomized controlled trial.
The Study Design
Titled “A Phase III Trial to Promote Recovery from COVID 19 with Combined Doxycycline and Ivermectin Along Standard of Care,” this interventional, double blind and randomized trial involved 400 participants. Initiated in June 2020, the study concluded at the end of August. A total of 235 males and 165 females were recruited and randomized into the study. Ultimately, a total of 363 patients completed the randomized, controlled trial.
Study participants had to be aged 18 and up, and confirmed positive with only mild to moderate COVID-19 via polymerase chain reaction (PCR) test within 3 days from enrollment. Of course, the study team declared the enforcement of informed consent requirements.
Patients that couldn’t take oral medication, were pregnant or breast feeding; or for that matter evidenced severe COVID-19 infection couldn’t’ participate in this study. Neither could those patients with known allergies to the study drugs, those requiring ventilation and patient with certain enzymes, such as Alanine Aminotransferase (ALT) or Aspartate transaminase (AST) over 5 the limit of normal (ULN).
The study drug included 6mg of Ivermectin, (2 tablets) and Doxycycline 100mg twice daily for five (5) days. This was combined with the Standard of Care including Paracetamol, Vitamin D, Oxygen if indicated, Low molecular weight heparin and dexamethasone if indicated. The placebo comparator included just the same standard of care above. For all the details of this study, TrialSite includes the study protocol here.
Primary outcome measures for this randomized controlled trial included 1) number of patients with early clinical improvement within 7 days; and 2) Number of participants with lengthy recovery—that is more than 12 days for clinical improvements.
Secondary outcome measures included 1) Number of patients exhibiting clinical deterioration within a one month period, and 2) Number of patients that remained persistently positive with SARS-CoV-2 within a 14 day period.
TrialSite reminds readers that these results are not, as of yet, peer reviewed and published and consequently, what follows is simply a description of what the study team at Bangladesh Medical College shared with the public Clinicaltrials.gov study registry.
The study team evaluated the effects of the study drug from June 1 to August 30, 2020 in the largest hospital dedicated to COVID-19 patients, Dhaka Medical College Hospital in Bangladesh. Of the 556 patients screened for eligibility, 400 underwent randomization with 200 of them receiving the active drug and 200 the placebo.
Of the total number of patients starting the study, 183 out of 200 completed the endeavor in the active drug group while 180 finished in the placebo group. 15 patients were lost to follow up in the active study group and 17 were lost to follow up in the placebo group. No patients were lost to death in the active study group while 3 were lost to death in the placebo group.
Using the statistical package SPSS (Statistical Package for Social Sciences) version 20, the team analyzed the sociodemographic data and utilized data analysis including the use of chi square test for mean of delta between the two study groups.
The study team found for the primary outcome measure of Number of Patients with Early Clinical Improvement that 111 out of 180 (60.7%) in the active study drug group achieved that milestone while 80 out 180 (44.4%) in the placebo group wound up in this category.
Using a regression analysis, the study team reported for the active drug study group P-value of <0.03, using Cox Proportional Hazard method the estimated value was reported at 0.53 with confidence interval (2-sided) of 95% (0.30 to 0.96).
What about Number of Participants with Late Clinical Recovery? The results reveal that those patients in the placebo group fared worse than those patients in the Ivermectin/doxycycline group. For example, 42 out of 183 (23%) of the patients in the active study drug group experienced a late recovery—e.g. required over 12 days to experience better conditions (e.g. body temperature, respiratory symptom improvement, etc.). However, in the placebo group 67 out of 180 (37.2%) took over 12 days to improve.
Again, regression analysis for the active study group reveals a P value of <0.004, Cox proportional hazard estimated value of .51 with confidence interval (2 sided) of 95% (0.32 to 0.80). With hindsight, these numbers indicate anyone, if given the chance, would opt for the active study drug group.
Secondary Outcome Measures included Number of Patients Having Clinical Deterioration. That is, for example, those patients at presentation that had exhibited mild SARS-CoV-2 infection but with subsequent follow up, monitoring reveals that the patient exhibits worsening conditions. This is, of course, when the risk associated with COVID-19 become greater, especially for those that are elderly, those with comorbidities, etc. This outcome measure looked over a month long period.
Employing binary logic regression the study team found that in the active study drug group, 16 patients out 183 (8.7%) experienced a worsening of conditions (e.g. dyspnea, respiratory distress, tachypnea [>30 breaths/min], and hypoxia ) while the patients in the placebo arm 32 out of 180 (17.8%) experienced a material clinical deterioration associated with their SARS-CoV-2 infection.
This comparison group’s statistics included a Superiority test equaling P value of <0.013, .45 and confidence interval (2-sided) of 95% (0.23 to 0.85).
Finally, the last Secondary Outcome Measure included Number of Patients Remain Persistently Positive for RT-PCR of COVID-19, revealing whether the investigational combination makes a difference, statistically. Over a period of 14 days, the study team calculated that in the active study drug group 14 of 183 (7.7%) still remained positive at day 14 while in the placebo group 36 out of 180 (20%) fell in this category, substantially more.
For this last result, the Dhaka-based study team used a Superiority test generating a P value of <0.0001, 0.58 with confidence interval (2-sided) of 95% (0.44 to 0.81).
TrialSite News reports that based on disclosed results, it would appear that the group of patients that were given the ivermectin/doxycycline combination fared substantially better than those patients in the standard of care arm. Of course, this data must be peer reviewed, published and discussed and debated by the medical community for any authoritative declarations. TrialSite is an online media platform and nascent social network dedicated to not only clinical trials accessibility and transparency worldwide, but also the advancement of research with the ultimate goal of improving human health.
About Dhaka Medical College & Hospital
An elite public medical school in Bangladesh’s capital, Dhaka Medical College and Hospital is considered the most prestigious in the nation and house the largest tertiary care hospital in this nation, again the 8th most populated worldwide. Dhaka Medical College has pioneered many novel medical achievements in Bangladesh, such as bone marrow transplants.
With 2,600 beds, the teaching hospital at Dhaka Medical College Hospital (DMCH) is located on the same campus as the medical school. The hospital is now actively expanding to 5,000 beds. A tertiary referral hospital, it has specialty units such as the Sheikh Hasina National Institute of Burn and Plastic Surgery. The hospital treats approximately 800,000 patients annually according to some reports. The country’s first bone marrow transplant center was established here in 2013 in collaboration with Massachusetts General Hospital. And this unit achieved the first successful autologous bone marrow transplant within Bangladesh by 2014. The first allogeneic bone marrow transplant capability was introduced here in 2019.
Dr. Reaz Mahmud, FCPS (Medicine), MD (Neurology), Assistant Professor Department of Neurology, Dhaka Medical College.
- Mujibur Rahman Professor and Head, Department of Medicine, Dhaka Medical College
- Dr. Iftikher Alam Assistant Professor, Department of Neurology, Dhaka Medical College
- Dr. Kazi Gias Uddin Ahmed Associate Professor and Head, Department of Neurology, Dhaka Medical College
- Dr. AKM. Humayon Kabir Associate Professor, Department of Medicine, Dhaka Medical College
The list of co-investigators can be viewed in the study protocol.
Call to Action: Check the protocol for study details.