Approval to carry out the research was obtained from the University of Abuja Health Research Ethics Committee. The study adhered to the tenets of the Declaration of Helsinki9.
While the cases for the triple therapy were enrolled between the 20th of April until the 18th of June 2021, the NIVM cases were enrolled between the 20th of September and the 24th of November. From Figure 1, this would coincide with the second and third waves of the COVID-19 epidemic in Nigeria, specifically towards the tail end of the beta wave (B 1.351 variant) for the IVM series and the tail end of the delta (B.1.617.2 variant) wave for the non-IVM series.10 However, we did not determine variants in our study population.
Inclusion criteria: Consecutive COVID-19-positive patients of all ages and sexes notified to the Federal Capital Territory COVID-19 Control Center based in Gwagwalada were eligible for inclusion in the trial, provided informed consent was not withheld.
Exclusion criteria were lack of a positive COVID-19 test, refusal to give informed consent, pregnancy, history of heart disease and known or reported allergy to any of the trial medications.
This was a parallel group comparison of ivermectin-based and non-ivermectin-based regimens in COVID-19-positive Nigerian patients. Sixty-one subjects were recruited into the IVM-based comparison study 8, while 26 subjects were subsequently recruited into the NIVM group. The NIVM group received varying combinations of clexane (enoxaparin, a low molecular weight heparin), alluvia (lopinavir/ritonavir), zithromax (azithromycin) and remdesivir (for those who could afford it), but NOT received IVM. Furthermore, all patients in both the IVM and NIVM groups received zinc succinate and vitamin C.
The IVM group was subdivided as follows:
- Thirty patients received 200 mcg/kg ivermectin daily for five days. In addition, one patient received Alluvia,
- Thirty-one patients received HIA triple therapy
- Hydroxychloroquine 200 mg per day for three days
- Ivermectin 200 mcg/kg daily for five days,
- Azithromycin 500 mg per day for three days
In addition, 2 patients received Alluvia, and 3 received remdesivir.
The NIVM group consisting of 26 patients was treated as follows:
a) All 26 patients received clexane (enoxaparin) intramuscularly at a dose of 40 i.u. daily throughout admission.
b) Five patients received Alluvia. 200 mg. bd. for 5-7 days depending on the response.
c) Four patients received remdesivir. 200 mg stat, then 100 mg daily, for at least six days, maximum 11 days.
Thus, spanning both groups, eight patients received alluvia, while seven patients received remdesivir.
Patients across the board also received the Standard of Care for COVID-19 patients in Nigeria, including zinc sulfate at 50-100 mg daily and vitamin C at 1000 mg daily for 7 days.
Ventilators and Oxygen. A total of ten patients required supplemental high-flow nasal oxygen therapy (HFNOT), 3 in IVM and 7 in NIVM. Three patients required a ventilator, two in the IVM group and one in the NIVM group.
Virology: A GeneXpert machine was used to perform quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Two different RNA particles were measured: N-gene (Nucleocapsid) and E-gene (Envelope). A semiquantitative measure of cycle threshold (Ct) values was derived. Ct is inversely related to viral load. All two marker genes must be negative before a patient was deemed ‘negative’ for SARS-CoV-2. A Ct of 38 or more is regarded as negative for the E-gene, while a Ct of 40 or more is regarded as negative for the N-gene.
- Viral Ct was quantified at enrolment (baseline or day 0), day 5, day 14 and day 21 after dosing. The proportion with negative PCR outcomes at days 5, 14 and 21 was assessed for the two groups.
- SpO2% was assessed using a pulse oximeter on a daily basis at approximately the same time of the day. Details of the impact of IVM versus NIVM on SPO2% time course, pharmacodynamics, determinants and correlates are reported in a separate paper.
- The symptom checklist was assessed at baseline. These included the following:
Respiratory symptoms: Cough.
GIT symptoms: nausea, vomiting, diarrhea, and abdominal pain.
CVS: Tiredness, lassitude, dyspnea
CNS: Headache, Anosmia, Ageusia.
MSS: Myalgia. This was scored using a Likert scale as a sentinel proxy measure for the patient’s clinical progress.
The following serious adverse events were monitored: dizziness, diarrhea, vomiting, nausea, appetite loss, stomach pain, tiredness, and others (to be specified).
4. Inflammatory markers were measured at baseline and day 7. These were erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and D-dimer.
5. Haematological variables were measured at baseline and day 7, including haemoglobin, white blood cells, neutrophils, lymphocytes and platelet count. The neutrophil/lymphocyte ratio (NLR) was assessed as a measure of systemic inflammation.
Data were collected into Android tablets on the JotForm platform and uploaded in real time to the internet cloud, making it accessible by all researchers on the team. The data were ultimately translated into Excel and cleaned. Data were subsequently uploaded into STATA analysis package Stata/IC 16.1 for Mac (Intel 64-bit) and prepared for analysis.
Descriptive and inferential statistics (both parametric and nonparametric where indicated) were performed. Repeated measures analysis of variance (RMANOVA)/Student’s t-test and the chi-squared test were performed to assess the effects of treatment on
- Change in viral load over time
- Change in oxygen saturation over time
- Proportion negative at fixed end points.
- Changes in the levels of inflammatory markers and hematological variables.
- Disposition of patients was assessed on a daily basis with regard to whether 1. treatment was maintained, 2. the patient was well enough to be discharged from active care, 3. the patient was referred for further treatment in intensive care, or 4. the patient was deceased.
Statistical rejection of the null hypothesis was p < 0.05, and the 95% confidence intervals are quoted.
Propensity matching was carried out where there was a noticeable statistically significant difference at baseline between the IVM and NIVM arms. The initial propensity adjustment was carried out with regard to the baseline SpO2 value, where the assessment was limited to only cases with SpO2 <94% at baseline in room air, equivalent to the classification of “Severe COVID-19 diseases” by the National Institute of Health NIH11.
This propensity matching after adjusting for baseline SpO2 meant that 21 in the IVM group and all 26 in the NIVM group were included in the matched analysis.
Furthermore, for the RMANOVA of the change in the rt-PCR cycle threshold over time, the analysis was restricted to cases with Ct values between 20-25 for the N gene and between 14 and 18 at baseline for the E gene.
Univariate analysis was carried out where indicated. where there is a zero in one of the cells, and 1 is added to all cells to derive approximate odds ratios.
A serious adverse event form was designed and completed for every case enrolled in the trial. A detailed clinical description of such adverse events was captured and evaluated. Immediate steps were taken to ameliorate such incidents.
Main outcome measures: Change in cycle threshold (viral load) over time, change in positivity status by day 5, improvement in clinical status using myalgia scores, days-to-discharge from care, change in SpO2 over time and death.