The baseline values for both arms of the study were compared to assess the adequacy of randomization. (Table 1). The findings suggest that there were no significant differences in the two groups (ivermectin-only IVM and the HIA triple therapy (IVM+) group) with regard to all the variables. Age and sex were similar, as were dose of ivermectin based on weight, need for supplemental oxygen, and need for ventilator. None of the patients had been vaccinated. Hematological indices such as hemoglobin, white blood count, lymphocyte and neutrophil count, neutrophil/lymphocyte ratio, and platelet count were comparable for both groups. There was also no difference with regard to viral load at baseline for either the N-gene or E-gene. Inflammatory markers such as ESR, C-reactive protein, and D-dimer values were also similar in both groups. SPO2 was slightly higher for the ivermectin only (IVM) group (93.8% versus 92.0%), but the difference was not statistically significant (P=0.09). Clinical symptoms at baseline, such as diarrhea (23.7%), anosmia (20%), ageusia (18%), dyspnea (25%), headache (50%) and cough (72.1%), were similar in both groups. Therefore, cough was the most common symptom with which patients presented but was slightly less common in the IVM group.
Description of the study population (Table 1)
Considering the two groups together, the average age of participants was 40.4 years, with more males (63%) than females. Figure 1 depicts the age distribution of the study participants. This indicates that the modal age group is between 25-30 years.
Based on the weight, the patients required an average of 5 tablets of 3 mg each (15 mg) daily. The hematological indices were within normal limits at baseline. These included hemoglobin Hb, white blood cell WBC count, lymphocyte count, neutrophil count, neutrophil to lymphocyte ratio NLR, and platelet count. Viral loads at baseline were moderately high, with mean CT counts of 26.5 and 21 for the N and E genes, respectively. All these indices were similar in both groups.
With regard to the inflammatory markers, erythrocyte sedimentation rate ESR was within the normal range, but the C-reactive protein CRP was higher than normal at 14.6 mg/l compared with a normal range of less than 10 mg/l.
D-dimer is the degradation product of factor XIII crosslinked fibrin. It reflects ongoing activation of the hemostatic system. The reference concentration of D-dimer was < 250 ng/mL.
A mean study D-dimer level of 222.2 ng/ml was thus within normal limits.
Mean entry SPO2% was low at 92.9%. Three of the patients had entry values of less than 80.
In the federal capital territory where this study took place, there were six area councils (local governments). The most urbanized local governments are the Abuja Municipal Area Council (AMAC) and Gwagwalada Area Council, where the teaching hospital and the main COVID isolation center are located. The majority of the patients come from these two urbanized area councils (local governments). (Figure 2).
Differential change in parameters with time over the two arms.
Table 3 quantifies changes over time, particularly between baseline and day 7. (Except for viral gene CT, which compares baseline and day 2).
A repeated measures analysis of variance (RAMOVA) was carried out on the cycle threshold times for the N- and E-genes, taking into account baseline (day 0), day 2, day 5 and day 14. There was a steady increase in CT values in both arms of the study. This increase was already significant by day 2. (P<0.0001). Figures 3 and 4 indicate changes in the N-gene and E-gene cycle thresholds, respectively, over time using adjusted predictions of treatment-by-day interactions with 95% confidence interval error bars. In both situations, there was no treatment difference between the IVM and IVM+ groups. However, there is a significant time effect P<0.0001.
Table 2 indicates the progression of the PCR test change from ‘positive’ to ‘negative’ as the days went by. This assumes a cutoff of N-Ct > 38 and E-Ct > 40. negative, one in each arm. (Other authors use a cutoff point of >35 Ct as negative) RAMOVA of the N-Ct and E-Ct genes time-treatment interactions suggested that there was no treatment difference between the two arms, but there was a time effect in both arms, P<0.0001. There was also minimal time x treatment interaction. See figures 3 and 4
Changes in SPO2%: RAMOVA analysis suggested that there was a significant time effect in both arms with a steady increase in SPO2%, P<0.0001. There was a weak treatment x time interaction (P=0.10) from the likelihood ratio test. However, there was no significant treatment difference between the two arms (P=0.797). See figure 5.
Changes in laboratory parameters (Table 3).
Inflammatory markers: For the two arms of the study, there was a statistically significant drop in the levels of all inflammatory markers by day 7 relative to baseline. (ESR P<0.0025, D-dimer P<0.0001and CRP, P<0.0001). (Figures 6,7,8). The drop was steeper in the IVM arm (except for CRP, where the drop was parallel), but the difference between the two groups was not statistically significant at baseline or by day 7.
Hematological variables were assessed. There was an insignificant drop in hemoglobin levels by day 7 in both arms (P= 0.138). However, there was a significant drop in the WBC count overall (P<0.0002), with a similar degree of drop in both arms.
Overall, there was no statistically significant decrease in the lymphocyte count. However, there was a slight increase in the IVM arm of 0.27 X 109 cells/l as opposed to a decrease in the IVM+ arm (2.2 X 109). This difference in direction did not achieve statistical significance (P=0.233). Difference -3.16, 95% CI -8.42-2.49
There was, however, a significant decrease in the neutrophil count across both arms compared to baseline (P=0.0006), with a consequent decrease in the neutrophil to lymphocyte ratios, more so in the IVM arm. 0.23 versus 0.08.
There was also a significant drop in the platelet counts across arms (P<0.0001) more so in the IVM arm (47% drop) than in the IVM+ arm (18.7% drop). However, the difference in percentage drop did not achieve statistical significance. (p=0.155). See Figure 9. (Actual difference was 25.8 95% CI -10.0-61.8)
Change in Clinical status with time. Figure 10. The clinical status was reported by the patients on a Likert scale in response to the question ‘How do you feel today?’ ranging from 1 (much worse) to 5 (much improved). Figure 10 indicates that in both arms, there was steady progress in mean wellness scores. Assuming no time treatment/interaction, there was no difference between the two groups (P=0.760). However, there was a significant improvement with time in both arms. P= 0.102 by day 2 and P=0.000 by day 5. By day 11, the average Likert score was over 4.5 in both arms and marginally higher in the IVM+ arm (P=0.0731).
The likelihood of being discharged by day 7 in either arm of the study: Patients were discharged after a negative PCR test, their perception of wellness, and the absence of concerning signs and symptoms such as fever, cough, myalgia and malaise. Sixty-three percent of patients in the IVM arm were discharged, compared to 44% in the IVM+ arm by day 7. OR 2.13 (95% CI 0.63-7.27) p=0.172. Thus, there is a weak suggestion that patients are more likely to be discharged by day 7 in the IVM arm, but this did not achieve significance. (Table 4)
Complaints/adverse events were recorded on a daily basis and are depicted in Figure 11. It is difficult to know which complaints are due to the disease and which are due to the drug, but all are assessed together. A total of 11 patients had complaints of one form or the other on the first day of treatment, 8 in the IVM group and 3 in the IVM+ group. Complaints in the IVM group included tiredness (4) and stomach pain, nausea, vomiting and dizziness. Only 3 people had complaints of stomach pain in the IVM+ group. By day 2, 4 people still complained of tiredness, and two of stomach pain in the IVM arm, while 3 people complained of tiredness in the IVM+ arm. There was an overall decrease in the number of complaints by day 5, by which time only 3 people complained.
Overall, there were 23 complaint events in the IVM group compared to 14 in the IVM+ group. However, four subjects in the IVM+ group had been dropped from the study because of reaction to HCQ and did not form part of this analysis. Their reaction, mainly consisting of itchiness, had not responded to loratadine. Two other subjects developed severe itching around the armpits attributable to HCQ but were successfully treated with Loratadine and so continued in the study and formed part of this analysis.