Of the 130 SARS-CoV-2 males included in the Duta AndroCoV trial, 87 underwent a sequence of biochemical analyses and were included in the present study. Of these, 44 men were included in the investigational arm and 43 men in the placebo group (Figure 1). Average interval between first symptoms and beginning of treatment was 4.3 days for both groups (p = n/s). Baseline characteristics, prevalence of comorbidities and use of medications in the two study groups are displayed in Table 1 and were similar for all parameters.
Table 1. Characteristics of the study populations.
|
|
|
|
Placebo
(n = 43)
|
Dutasteride
(n = 44)
|
p-value
|
|
AVG (STD)
|
AVG (STD)
|
|
AGE (y/o)
|
43.8 (14.1)
|
40 (10.8)
|
n/s
|
BMI (Kg/m2)
|
26.1 (2.2)
|
26.0 (3.2)
|
n/s
|
Time-to-treat
|
4.4 (1.4)
|
4.3 (1.4)
|
n/s
|
|
N (%)
|
N (%)
|
|
Obesity
|
4 (9.3%)
|
5 (11.4%)
|
n/s
|
Hypertension
|
12 (27.9%)
|
7 (15.9%)
|
n/s
|
Mi
|
0
|
0
|
n/a
|
Stroke
|
0
|
0
|
n/a
|
Hf
|
0
|
1 (2.3%)
|
n/a
|
Lipid disorders
|
9 (20.9%)
|
9 (20.4%)
|
n/s
|
Other cardiac dysfunctions
|
0
|
1 (2.3%)
|
n/a
|
Diabetes
|
4 (9.3%)
|
4 (9.1%)
|
n/s
|
Pré-dm2
|
8 (18.6%)
|
5 (11.4%)
|
n/s
|
Dysglycemia
|
12 (28.0%)
|
9 (20.6%)
|
n/s
|
Asthma
|
1 (2.3%)
|
0
|
n/a
|
COPD
|
0
|
0
|
n/a
|
Chronic renal dis.
|
0
|
0
|
n/a
|
Liver fibrosis/chirrosis
|
1 (2.3%)
|
0
|
n/a
|
Clinical depression
|
2 (4.6%)
|
3 (6.8%)
|
n/s
|
Anxiety
|
6 (13.9%)
|
8 (18.2%)
|
n/s
|
ADHD
|
5 (11.6%)
|
3 (6.8%)
|
n/s
|
Insomnia
|
4 (9.3%)
|
1 (2.3%)
|
n/s
|
Hypothyroidism
|
1 (2.3%)
|
4 (9.1%)
|
n/a
|
Autoimmune disorders
|
1 (2.3%)
|
1 (2.3%)
|
n/a
|
Cancer
|
0
|
0
|
n/a
|
Hypogonadism
|
8 (18.6%)
|
8 (18.2%)
|
n/a
|
BPH
|
2 (4.6%)
|
2 (4.5%)
|
n/s
|
DRUGS
|
N (%)
|
N (%)
|
|
Beta-blocker
|
2 (4.6%)
|
1 (2.3%)
|
n/a
|
ECAi
|
1 (2.3%)
|
0
|
n/a
|
ARB
|
11 (25.6%)
|
7 (15.9%)
|
n/s
|
Loop diur.
|
1 (2.3%)
|
0
|
n/a
|
Thiazide diuretics
|
4 (9.3%)
|
1 (2.3%)
|
n/a
|
CCB
|
2 (4.6%)
|
2 (4.5%)
|
n/s
|
Statins
|
8 (18.6%)
|
8 (18.2%)
|
n/s
|
Others
|
0
|
0
|
n/a
|
Aspirin
|
0
|
1 (2.3%)
|
n/a
|
Clopidogrel
|
0
|
0
|
n/a
|
Warfarin
|
0
|
0
|
n/a
|
Xa factor inhibitors
|
0
|
0
|
n/a
|
Direct thrombin inhibitors
|
0
|
0
|
n/a
|
Heparins
|
0
|
0
|
n/a
|
Metformin
|
10 (23.3%)
|
6 (13.6%)
|
n/s
|
GLP1R analogue
|
2 (4.6%)
|
3 (6.8%)
|
n/a
|
SGLT2 inhibitors
|
7 (16.3%)
|
3 (6.8%)
|
n/s
|
DPP4 inhibitors
|
2 (4.6%)
|
1 (2.3%)
|
n/a
|
Sylfonylureas
|
0
|
0
|
n/a
|
Glitazone
|
0
|
0
|
n/a
|
Acarbose
|
0
|
0
|
n/a
|
Insulin
|
0
|
0
|
n/a
|
Orlistat
|
2 (4.6%)
|
2 (4.5%)
|
n/a
|
Levothyroxine
|
1 (2.3%)
|
4 (9.1%)
|
n/a
|
Liothyronine
|
1 (2.3%)
|
0
|
n/a
|
Testosterone
|
7 (16.3%)
|
6 (13.6%)
|
n/s
|
Aromatase inhibitors or SERMs
|
2 (4.6%)
|
2 (4.5%)
|
n/s
|
Hipnotics
|
3 (7.0%)
|
1 (2.3%)
|
n/a
|
Selective serotonin reuptaker inhibitors (SSRI)
|
3 (7.0%)
|
6 (13.6%)
|
n/s
|
Other antidepressants and humor stabilizers
|
4 (9.3%)
|
4 (9.1%)
|
n/s
|
Benzodiazepines
|
1 (2.3%)
|
0
|
n/a
|
Atypical antipsychotics
|
3 (7.0%)
|
2 (4.5%)
|
n/a
|
CNS stimulants
|
5 (11.6%)
|
5 (11.4%)
|
n/s
|
Alpha-1 adren. Blockers
|
2 (4.6%)
|
2 (4.5%)
|
n/s
|
Gnrh analogues and inh., NSAA, others
|
0
|
0
|
n/a
|
Erectile dysfunction
|
2 (4.6%)
|
1 (2.3%)
|
n/a
|
Omega-3
|
3 (7.0%)
|
1 (2.3%)
|
n/a
|
Vitamin D
|
13 (30.2%)
|
15 (34.1%)
|
n/s
|
Zinc
|
6 (13.9%)
|
7 (15.9%)
|
n/s
|
Biotin
|
1 (2.3%)
|
0
|
n/a
|
Vitamin C
|
8 (18.6%)
|
7 (15.9%)
|
n/s
|
Multivitamin
|
1 (2.3%)
|
2 (4.5%)
|
n/a
|
BCG
|
43 (100%)
|
44 (100%)
|
n/s
|
Influeza (in 2020)
|
14 (32.6%)
|
14 (31.8%)
|
n/s
|
Pneumococcal (since 2017)
|
3 (7.0%)
|
5 (11.4%)
|
n/s
|
Current smoking
|
2 (4.6%)
|
2 (4.5%)
|
n/a
|
Regular physical activity
|
28 (65.1%)
|
32 (72.7%)
|
n/s
|
ADDITIONAL COVID TREATMENTS
|
|
|
|
Ivermectin
|
6 (13.9%)
|
6 (13.6%)
|
n/s
|
Hydroxychlorouquine
|
4 (9.3%)
|
3 (6.8%)
|
n/s
|
Xa factor inhibitors
|
8 (18.6%)
|
3 (6.8%)
|
n/s
|
Enoxaparin
|
3 (7.0%)
|
3 (6.8%)
|
n/s
|
Glucocorticoids
|
6 (13.9%)
|
7 (15.9%)
|
n/s
|
Vitamin c
|
4 (9.3%)
|
4 (9.1%)
|
n/s
|
Zinc
|
3 (7.0%)
|
3 (6.8%)
|
n/s
|
Vitamin d
|
1 (2.3%)
|
2 (4.5%)
|
n/a
|
Colchicine
|
0
|
0
|
n/a
|
Bromexhine
|
0
|
0
|
n/a
|
N-acetylcysteine
|
0
|
0
|
n/a
|
|
|
|
|
|
None of the parameters was statistically significant between groups.
Congestive heart failure = CHF; type 2 diabetes mellitus = T2DM, chronic obstructive pulmonary disorder = COPD, chronic kidney disease = CKD, attention deficit hyperactivity disorder = ADHD, benign prostate hyperplasia = BPH, angiotensin converting enzyme inhibitors = ACEi; angiotensin-2 receptor blockers = ARB; calcium channel blocker = CCB; glucagon-like peptide-1 receptor analogues = GLP1Ra; sodium-glucose cotransporter-2 inhibitors = SGLT2i; dipeptidyl-peptidase 4 inhibitors = DPP4i; progesterone = P; estradiol = E; gonadotropin release hormone = GnRH; selective estrogen receptor modulators = SERM; non-steroidal antiandrogen = NSAA; selective serotonin reuptake inhibitors = SSRI; central nervous system = CNS; Bacillus Calmette-Guérin = BCG.
Table 2 reports the average times to remission for major clinical symptoms and overall time to remission, patient reported outcome rating disease severity in Days 1, 2, 3 and 7, and oxygen saturation in Days 0, 7 and 14, in men taking 5ARis versus men not taking a 5ARi.
The average (± standard deviation) remission time for fatigue was 5.5 (±3.2) days in the dutasteride group versus 10.3 (±8.4) days in the placebo group (p < 0.001), or 46.6% reduction. The average remission time for loss of taste or smell was 5.6 (±4.0) days in the dutasteride group versus 11.1 (±6.6) days in the placebo group (p < 0.001), or 49.6% reduction. Time to full remission was 9.2 (±4.3) days in the dutasteride group versus 16.3 (±8.3) days in the placebo group (43.2% reduction; p < 0.001). When anosmia and ageusia are excluded from the analysis, the average time to full remission was 7.0 (±2.9) days in the dutasteride group versus 11.7 (±7.7 (43.6% reduction; p < 0.001).
Level of recovery was significantly improved in the dutasteride group compared to the placebo group for Days 1, 2, 3 and 7 (p < 0.0001 for all days). The percentage of patients still affected at Day 7 was 15.9% in the dutasteride group and 42.5% in the placebo group.
Mean oxygen saturation was statistically higher in the dutasteride group for Days 7 (p = 0.02) and 14 (p = 0.0012), as well as level of oxygen saturation increase between Days 0 and 7 (p = 0.047).
Table 2. Clinical outcomes.
|
|
|
Mean ± SD
|
Placebo (n=66)
|
Dutasteride (n=64)
|
p-value
|
Time-to-remission
(Mean ± SD)
|
|
|
|
Fatigue
|
10.3 (±8.4)
|
5.5 (±3.2)
|
< 0.001
|
Loss of Taste or Smell (Ageusia or Anosmia)
|
11.1 (±6.6)
|
5.6 (±4.0)
|
< 0.001
|
Remission Minus Taste or Smell Loss
|
11.7 (±7.7)
|
7.0 (±2.9)
|
< 0.001
|
Overall symptoms
|
16.3 (±8.3)
|
9.2 (±4.3)
|
< 0.001
|
Clinical recovery
(Mean ± SD)
|
|
|
|
% fully clinically recovered at Day 7
|
57.5%
|
84.1%
|
0.03
|
% of clinical recovery at Day 1
|
34.2 (±21.4)
|
60.4 (±24.2)
|
< 0.0001
|
% of clinical recovery at Day 2
|
52.9 (±21.3)
|
78.5 (±17.8)
|
< 0.0001
|
% of clinical recovery at Day 3
|
66.8 (±20.7)
|
89.2 (±12.3)
|
< 0.0001
|
% of clinical recovery at Day 7
|
82.9 (±15.0)
|
97.4 (±5.7)
|
< 0.0001
|
Oxygen saturation (%)
(Mean ± SD)
|
|
|
|
Day 0
|
95.4 ± 1.4
|
96.0 ± 1.5
|
n/s (0.21)
|
Day 7
|
95.7 ± 2.0
|
97.0 ± 1.4
|
0.02
|
Day 14
|
96.2 ± 1.4
|
97.5 ± 1.2
|
0.0012
|
D Day 7-0
|
+0.3
|
+1.3
|
0.047
|
D Day 14-0
|
+0.9
|
+1.3
|
n/s (0.25)
|
|
|
|
|
|
Both groups used nitazoxanide plus azithromycin.
n/s = non significant; n/a = non applicable; STD = standard deviation
Table 3 displays biochemical parameters in the dutasteride and placebo groups, including the percentage of subjects with negative rtPCR SARS-CoV-2 in Days 0, 7 and 14, and levels of usCRP, lactate, ESR, LDH, ultrasensitive troponin, D-dimer and ferritin levels in Days 0, 7, 14, changes between Days 0 and 7 and between Days 0 and 14, and percentage of men with specific goals for each parameter between Days 0 and 7 and between Days 0 and 14.
In Day 7, 64.7% and 11.8% of men from the dutasteride and placebo group were free from SARS-CoV-2 virus or fragments, respectively (increase of 444.9% in the percentage of subjects cured in Day 7; p = 0.0094). In Day 14, 88.3% of the dutasteride group and 54.2% of the placebo group yielded non-detectable SARS-CoV-2.
In Day 7, median usCRP was 0.34 in the dutasteride group and 1.47 in the placebo group (p < 0.0001). In Day 14, median usCRP was 0.36 in the dutasteride group and 0.39 in the placebo group (p = 0.0026). Compared baseline levels, usCRP was reduced in Day 7 in 83.4% of men from the dutasteride and 64.7% of men from the placebo group, and in 93.7% and 73.3% of men from dutasteride and placebo group, respectively, in Day 14.
In Days 7 and 14 men from the dutasteride group had lower lactate levels than placebo group (p = 0.0049 and p = 0.014 for Days 7 and 14, respectively, and lack of lactate increase above 0.5 mmol/L between Days 0 and 7 was observed in 60% of subjects of the dutasteride group and 19.2% of subjects of the placebo group (p = 0.007).
Median ESR was 5.0 mm/1h in the dutateride group and 14.0 mm/1h in the placebo group in Day 7 (p = 0.0007), and 4.0 mm/1h in the dutasteride group and 11.5 mm/1h in the placebo group (p < 0.0001) in Day 14. Between Days 0 and 7, ESR reduced more than 10 mm/1h in 41.4% of men from the dutasteride group and 16.1% of those from the placebo group. Between Days 0 and 7, ESR reduced more than 10 mm/1h in 59.4% of men from the dutasteride group and 30.0% of those from the placebo group
LDH levels were statistically lower in the dutasteride group than placebo group in Day 7 (p = 0.0013) and Day 14 (p = 0.0004).
In Day 7, ultrasensitive troponin levels were significantly lower in the dutasteride group (median = 0.005 ng/mL) than placebo group (median = 0.007 ng/mL) (p = 0.048). In Day 7, ultrasensitive troponin levels reduced more than 0.003 ng/mL in 80% of participants in the dutasteride group and 52.8% in the placebo group. In Day 7, ultrasensitive troponin levels reduced more than 0.003 ng/mL in 66.7% of participants in the dutasteride group and 33.3% in the placebo group.
The only parameter that disclosed significant differences in D-dimer levels was in Day 14, with median D-dimer of 220 ng/mL in the dutasteride group and 305 ng/mL in the placebo group (p = 0.019). Ferritin levels and changes were similar between dutasteride and placebo group for all times and intervals.
No severe adverse effects, hospitalizations, mechanical ventilation or deaths were reported. Figure 2 summarizes the main clinical and biochemical findings of the present study.
Table 3. Biochemical results.
|
|
|
|
Placebo (n=66)
|
Dutasteride (n=64)
|
p-value
|
rtPCR SARS-CoV-2 remission
(CT > 40 cycles) (%)
|
|
|
|
Day 0
|
0%
|
0%
|
n/s (1.00)
|
Day 7
|
11.8%
|
64.3%
|
0.0094
|
Day 14
|
54.2%
|
88.3%
|
0.036
|
usCRP (mg/L)
Median (95% CI)
|
|
|
|
Pre-COVID
|
0.18
(0.08-0.41)
|
0.38
(0.10-0.56)
|
n/s (.45)
|
Day 0
|
1.44
(0.72-2.54)
|
1.22
(0.83-2.26)
|
n/s (.42)
|
Day 7
|
1.47
(0.70-3.37)
|
0.34
(0.23-0.66)
|
< .0001
|
Day 14
|
0.39
(0.21-2.32)
|
0.36
(0.08-0.34)
|
.0026
|
usCRP decrease
D Day 7-0
|
64.7%
|
83.9%
|
n/a
|
usCRP decrease
D Day 14-0
|
73.3%
|
93.7%
|
n/a
|
Lactate (mmol/L)
Median (95% CI)
|
|
|
|
Pre-COVID
|
0.93
(0.82-1.18)
|
0.88
(0.72-1.23)
|
n/s (.58)
|
Day 0
|
1.72
(1.35-2.11)
|
1.51
(1.16-2.01)
|
n/s (.27)
|
Day 7
|
2.66
(2.05-3.55)
|
2.01
(1.12-2.43)
|
.0049
|
Day 14
|
1.92
(1.38-2.89)
|
1.48
(1.22-1.89)
|
.014
|
D Day 7-0
|
+0.97
(+0.57 - +1.69)
|
+0.28
(+0.02 - +0.85)
|
.025
|
Lactate increase < 0.5mmol/L DDay(7-0)
|
19.2%
|
60%
|
n/a
|
D Day 14-0
|
+0.22
(-0.64 - +0.79)
|
-0.19
(-1.15 - +0.27)
|
n/s (.24)
|
Lactate increase < 0.5mmol/L DDay(14-0)
|
67.8%
|
83.3%
|
n/a
|
ESR (mm/1h)
Median (IQT)
|
Placebo
(n = 43)
|
Dutasteride
(n = 44)
|
p-value
|
Pre-COVID
|
4.5
(2.25-8.0)
|
4.0
(2.0-7.0)
|
n/s (.76)
|
Day 0
|
13.5
(7.0-22.5)
|
13.0
(6.5-22.0)
|
n/s (.69)
|
Day 7
|
14.0
(7.25-18.5)
|
5.0
(3.0-11.0)
|
.0007
|
Day 14
|
11.5
(6.5-18.0)
|
4.0
(3.0-5.0)
|
< .0001
|
D Day 7-0
|
-4.0
(-6.75 - +4.5)
|
-8.0
(-13.0 – -1.0)
|
.017
|
ESR decrease > 10mm/1h DDay(7-0)
|
16.1%
|
41.4%
|
n/a
|
D Day 14-0
|
-4.5
(-11.0 - +4.25)
|
-11.5
(-19.25 - -2.75)
|
.003
|
ESR decrease > 10mm/1h DDay(14-0)
|
30%
|
59.4%
|
n/a
|
LDH (U/L)
Median (95% CI)
|
|
|
|
Pre-COVID
|
175
(158-211)
|
183
(156-199)
|
n/s (.76)
|
Day 0
|
207
(175-234)
|
200
(172-222)
|
n/s (.69)
|
Day 7
|
210
(179-249)
|
165
(144-198)
|
.0013
|
Day 14
|
177
(154-202)
|
147
(135-160)
|
.0004
|
D Day 7-0
|
+4
(-32.5 - +40.25)
|
-21
(-53 - +18)
|
.087
|
LDH reduction > 30 U/L between Days 0 and 7
|
26.5%
|
50.0%
|
n/a
|
D Day 14-0
|
-26
(-68 - -10)
|
-35
(-76 - -15)
|
n/s
(.31)
|
LDH reduction > 30 U/L between Days 0 and 7
|
46.4%
|
64.3%
|
n/a
|
Ultrassensitive
troponin (ng/mL)
Median (95% CI)
|
|
|
|
Pre-COVID
|
n/a
|
n/a
|
n/a
|
Day 0
|
0.008
(0.005-0.012)
|
0.010
(0.008-0.015)
|
n/s (.23)
|
Day 7
|
0.007
(0.006-0.010)
|
0.005
(0.003-0.009)
|
.048
|
Day 14
|
0.005
(0.004-0.008)
|
0.004
(0.003-0.005)
|
n/s (.14)
|
D Day 7-0
|
-0.003
(-0.005 –
0)
|
-0.004
(-0.007 –
-0.003)
|
.094
|
Troponin decrease > 0.003ng/mL
DDay(7-0)
|
52.8%
|
80%
|
n/a
|
D Day 14-0
|
-0.003
(-0.007 –
-0.001)
|
-0.007
(-0.011 –
-0.004)
|
.16
|
Troponin decrease > 0.005ng/mL DDay(14-0)
|
33.3%
|
66.7%
|
n/a
|
D-dimer (ng/mL)
Median (95% CI)
|
|
|
|
Pre-COVID
|
343
(215-427)
|
366
(255-438)
|
n/s (1.00)
|
Day 0
|
404
(289-575)
|
406
(266-584)
|
n/s (.77)
|
Day 7
|
310
(220-495)
|
189
(242-373)
|
n/s (.29)
|
Day 14
|
305
(216-420)
|
220
(200-306)
|
.019
|
D Day 7-0
|
-80
(-182 - +52)
|
-104
(-190 - -35)
|
n/s (.30)
|
D-dimer decrease D Day 7-0
|
63.6%
|
84.2%
|
n/a
|
D Day 14-0
|
-70
(-241 - +31)
|
-137
(-325 - -16)
|
n/s (.20)
|
D-dimer decrease > 100ng/mL D Day 14-0
|
42.8%
|
61.6%
|
n/a
|
Ferritin (ng/mL)
Median (95% CI)
|
|
|
|
Pre-COVID
|
173
(133-241)
|
190
(113-310)
|
n/s (.61)
|
Day 0
|
389
(295-588)
|
471
(279-584)
|
n/s (.85)
|
Day 7
|
321
(248-476)
|
310
(198-476)
|
n/s (.41)
|
Day 14
|
240
(186-377)
|
241
(180-352)
|
n/s (.66)
|
D Day 7-0
|
-83
(-139 - -52)
|
-68
(-214 - -9)
|
n/s (.99)
|
D Day 14-0
|
-128
(-262 - -72)
|
-135
(-289 - -55)
|
n/s (.82)
|
|
|
|
|
|
|
|
|
|
Both groups used nitazoxanide plus azithromycin.
IQT = interquartile n/s = non significant; n/a = non applicable; rtPCR = real time polymerase chain reaction; usCRP: ultrasensitive C-reactive protein; ESR = erythrocyte sedmentation rate; LDH = lactate dehydrogenase