A total of 101 participants were randomized into three study groups, with 34 participants in the Native CT-II® group, 33 in the G+C group, and 34 participants in the placebo group. One hundred and sixty-nine participants were screened for the study, with 39 participants being screening failures, 28 participants withdrawing or dropping out of the study before randomization and one participant being a randomization failure. Figure 1 below depicts the participant disposition for the study.
Participant demographics and baseline characteristics
The mean age for the randomized study population was stated to be 50.37 (40.00, 64.00) years, with no statistically significant difference between the groups; p=0.2272. Furthermore, most of the participants fell in the BMI overweight class between 25.00 to 29.9 kg/m2, the BMI between each treatment group being statistically insignificant.; p=0.6857. As per the eligibility criteria, all the participants had a knee joint pain VAS score ≥ 60 and the scores for each group were comparable during the baseline visit. The other demographic and baseline characteristics for the randomized study population are given in Table 3
Table 3
Participant demographic and baseline characteristics
Parameter
|
Categories
|
Native CT-II®
(N=34)
|
G+C
(N=33)
|
Placebo
(N=34)
|
Total
(N=101)
|
p-value*
|
Age (Years)
|
Mean
|
50.94
|
51.48
|
48.71
|
50.37
|
0.2272
|
SD
|
7.13
|
6.44
|
7.31
|
7.01
|
|
Range (Min., Max.)
|
(41.00, 64.00)
|
(41.00, 64.00)
|
(40.00, 64.00)
|
(40.00, 64.00)
|
|
Gender
|
Female
|
24 (70.59%)
|
19 (57.58%)
|
18 (52.94%)
|
61 (60.40%)
|
0.3048
|
Male
|
10 (29.41%)
|
14 (42.42%)
|
16 (47.06%)
|
40 (39.60%)
|
|
BMI (kg/m2)
|
Mean
|
24.79
|
25.30
|
25.24
|
25.11
|
0.6857
|
SD
|
2.62
|
3.03
|
2.34
|
2.66
|
|
Range (Min., Max.)
|
(19.19, 29.59)
|
(18.63, 29.52)
|
(21.19, 29.23)
|
(18.63, 29.59)
|
|
X-ray Grade
|
Grade-II
|
20 (58.82%)
|
20 (60.61%)
|
20 (58.82%)
|
60 (59.41%)
|
0.9855
|
Grade-III
|
14 (41.18%)
|
13 (39.39%)
|
14 (41.18%)
|
41 (40.59%)
|
|
Index Knee VAS Score
|
Mean
|
72.65
|
70.30
|
71.18
|
71.39
|
0.5338
|
SD
|
9.63
|
7.28
|
8.80
|
8.61
|
|
Range (Min., Max.)
|
(60.00, 90.00)
|
(60.00, 90.00)
|
(60.00, 90.00)
|
(60.00, 90.00)
|
|
mWOMAC total score
|
Mean
|
86.06
|
86.67
|
86.45
|
86.39
|
0.9386
|
SD
|
7.57
|
7.21
|
6.46
|
7.03
|
|
Range (Min., Max.)
|
(75.00, 100.00)
|
(75.00, 99.00)
|
(75.00, 98.00)
|
(75.00, 100.00)
|
|
*p values were calculated using ANOVA for continuous variables and Chi-Square/ Fisher Exact test for categorical variables.
|
Effect of Native-CT II® on joint health
The overall joint health as assessed by WOMAC total scores was comparable between all the study groups (p=0.9386), at baseline. A significant reduction of the total scores from baseline was seen in all the treatment groups (p<0.05) on Days 28, 56, and 84. The change in the score for groups, when compared with the placebo, revealed that the Native CT-II® group had significantly after 28 days, and a similar change was observed in the G+C group when compared to the placebo. Subsequently, at 84 days, both the Native CT-II® and G+C groups showed a gradually greater reduction in the total score. Furthermore, despite the substantially lower dose, the reduction in the score for the Native CT-II® group remained statistically and clinically comparable to G+C as shown in Table 4 and 5.
Table 4
Summary for WOMAC index total scores - mITT Population
Visit (Day)
|
Categories
|
Native CT-II®
(N=32)
|
G+C
(N=31)
|
Placebo
(N=31)
|
Baseline (Day 0)
|
N
|
32
|
31
|
31
|
Mean
|
85.91
|
87.03
|
86.45
|
SD
|
7.21
|
7.17
|
6.67
|
Range (Min, Max)
|
(75.00, 99.00)
|
(75.00, 99.00)
|
(75.00, 98.00)
|
Week 12 (Day 84)
|
N
|
32
|
31
|
31
|
Mean
|
53.44
|
53.29
|
72.61
|
SD
|
18.40
|
22.27
|
19.11
|
Range (Min, Max)
|
(27.00, 97.00)
|
(0.00, 95.00)
|
(22.00, 103.00)
|
Abbreviation: SD = Standard deviation, n = Number of participants
|
Table 5: Absolute change in mWOMAC total scores (mITT population)
Change on Day 84
|
Native CT-II® (n = 32)
|
G+C (n = 31)
|
Placebo (n = 31)
|
Mean (SD)
|
95% CI
|
p-value*
|
Mean (SD)
|
95% CI
|
p-value*
|
Mean (SD)
|
95% CI
|
p-value*
|
Min
|
Max
|
Min
|
Max
|
Min
|
Max
|
Total mWOMAC Score
|
-32.47
|
-39.50
|
-25.44
|
<.0001
|
-33.74
|
-42.78
|
-24.70
|
<.0001
|
-13.84
|
-20.30
|
-7.38
|
<.0001
|
p-value**
|
0.0003
|
0.0003
|
|
* p value calculated using paired t-test as compared to baseline.
**p value calculated using ANCOVA as compared to placebo
Abbreviation: SD - Standard deviation, n - Number of participants, CI – Confidence Interval
|
Effect of Native-CT II ®on pain
The baseline mWOMAC-P subscale scores for all the treatment groups were comparable (p>0.05) as presented in Table 6. Within-group analysis for all the treatment groups demonstrated a statistically significant difference being observed in each group for all the study visits when compared to the baseline, with the extent of reduction increasing with the longer treatment duration. However, through intergroup analysis, it was observed that while the absolute change in the mWOMAC-P scores for the G+C group were statistically significant when compared to the placebo (p<0.05) for all the study visits, the statistical difference when comparing the Native CT-II® and placebo group absolute changes in mWOMAC-P scores was only significant for the Day 56 and 84 visits. There was no statistically significant difference observed between the changes in the scores of the Native CT-II® and G+C groups (Day 84: p=0.9777) (Table 7).
Effect of Native-CT II® on stiffness
The baseline mWOMAC-S subscale scores for all the treatment groups were comparable (p>0.05). For this subscale, the within-group analysis for all the treatment groups demonstrated a statistically significant difference being observed in the Native CT-II® and the G+C group for all the study visits when compared to the baseline, with the extent of reduction increasing with the longer treatment duration. Within the placebo group, the significant difference was only observed during the Day 56 and 84 visits. When both the Native CT-II® and G+C group change in scores was compared with that of the placebo, each of the groups showed a statistically significant difference during all the treatment visits. Furthermore, no statistically significant difference was observed between the changes in the scores of the Native CT-II® and the G+C groups (Day 84: p=0.7035) (Table 6 and 7).
Effect of Native-CT II® on physical function
The baseline mWOMAC-PF subscale scores for all the treatment groups were comparable (p>0.05). Within-group analysis for all the treatment groups demonstrated a statistically significant difference being observed in each group for all the study visits when compared to the baseline, with the extent of reduction increasing with longer treatment duration. Again, when both the Native CT-II® and G+C group change in scores was compared with that of the placebo, each of the groups showed a statistically significant difference during all the treatment visits. Furthermore, no statistically significant difference was observed between the changes in the scores of the Native CT-II® and the G+C groups (Day 84: p=0.9445) (Table 6 and 7).
Table 6
Summary- mWOMAC subscale scores (mITT population)
Visit (Day)
|
Categories
|
Native CT-II®
(N=32)
|
G+C
(N=31)
|
Placebo
(N=31)
|
WOMAC Pain Scores
|
Baseline (Day 0)
|
N
|
32
|
31
|
31
|
Mean (SD)
|
14.41 (±2.08)
|
14.90 (±1.92)
|
14.61 (±1,93)
|
Range (Min., Max.)
|
(11.00, 19.00)
|
(11.00, 19.00)
|
(11.00, 19.00)
|
Week 12 (Day 84)
|
N
|
32
|
31
|
31
|
Mean (SD)
|
8.72
|
8.87
|
11.90
|
Range (Min., Max.)
|
(4.00, 17.00)
|
(0.00, 20.00)
|
(3.00, 19.00)
|
WOMAC Stiffness Scores
|
Baseline (Day 0)
|
N
|
32
|
31
|
31
|
Mean (SD)
|
5.94 (±1.01)
|
6.42(±0.92)
|
6.23(±0.92)
|
Range (Min., Max.)
|
(3.00, 8.00)
|
(5.00, 8.00)
|
(5.00, 8.00)
|
Week 12 (Day 84)
|
n
|
32
|
31
|
31
|
Mean (SD)
|
3.75(±1.32)
|
3.71(±1.79)
|
5.39(±1.58)
|
Range (Min., Max.)
|
(2.00, 7.00)
|
(0.00, 8.00)
|
(2.00, 7.00)
|
WOMAC Physical Function Scores
|
Baseline (Day 0)
|
n
|
32
|
31
|
31
|
Mean
|
65.56(±5.45)
|
65.71(±5.88)
|
65.61(±4.89)
|
Range (Min., Max.)
|
(55.00, 75.00)
|
(55.00, 75.00)
|
(55.00, 73.00)
|
Week 12 (Day 84)
|
n
|
32
|
31
|
31
|
Mean
|
40.97(±14.01)
|
40.71(±16.69)
|
55.32(±14.02)
|
Range (Min., Max.)
|
(20.00, 74.00)
|
(0.00, 72.00)
|
(16.00, 77.00)
|
Abbreviation: SD = Standard deviation, n = Number of participants
|
Table 7
Change-mWOMAC subscale scores (mITT population)
mWOMAC-Pain
|
Change on Day 84
|
Native CT-II® (n = 32)
|
G+C (n = 31)
|
Placebo (n = 31)
|
Mean (SD)
|
95% CI
|
p-value*
|
Mean (SD)
|
95% CI
|
p-value*
|
Mean (SD)
|
95% CI
|
p-value*
|
Min
|
Max
|
Min
|
Max
|
Min
|
Max
|
-5.69 (3.66)
|
-7.01
|
-4.37
|
<.0001
|
-6.03 (4.72)
|
-7.76
|
-4.30
|
<.0001
|
-2.71 (3.95)
|
-4.16
|
-1.26
|
0.0006
|
p-value**
|
0.0024
|
0.0024
|
|
mWOMAC-Stiffness
|
Change on Day 84
|
Native CT-II® (n = 32)
|
G+C (n = 31)
|
Placebo (n = 31)
|
Mean (SD)
|
95% CI
|
p-value*
|
Mean (SD)
|
95% CI
|
p-value*
|
Mean (SD)
|
95% CI
|
p-value*
|
Min
|
Max
|
Min
|
Max
|
Min
|
Max
|
-2.19 (1.75)
|
-2.82
|
-1.56
|
<.0001
|
-2.71 (2.05)
|
-3.46
|
-1.96
|
<.0001
|
-0.84 (1.27)
|
-1.30
|
-0.37
|
0.0009
|
p-value**
|
0.0002
|
<.0001
|
|
mWOMAC- Physical Function
|
Change on Day 84
|
Native CT-II® (n = 32)
|
G+C (n = 31)
|
Placebo (n = 31)
|
Mean (SD)
|
95% CI
|
p-value*
|
Mean (SD)
|
95% CI
|
p-value*
|
Mean (SD)
|
95% CI
|
p-value*
|
Min
|
Max
|
Min
|
Max
|
Min
|
Max
|
-24.59 (15.00)
|
-30.00
|
-19.19
|
<.0001
|
-25.00 (18.90)
|
-31.93
|
-18.07
|
<.0001
|
-10.29 (13.07)
|
-15.08
|
-5.50
|
0.0001
|
p-value**
|
0.0003
|
0.0002
|
|
*p value calculated using paired t-test as compared to baseline.
**p value calculated using ANCOVA as compared to placebo
Abbreviation: SD - Standard deviation, n - Number of participants, CI – Confidence Interval
|
Effect of Native-CT II®on quality of life (EQ-5D-5L)
During the baseline visit, the scores for each of the 5 domains and the VAS assessment were comparable between all the study groups (p>0.05). After the treatment period of 84 days, a significant difference was seen within all the study domains and the VAS scale when compared to the baseline. Furthermore, the absolute change within the Native CT-II® was statistically significant when compared to the placebo for four of the 5 domains, except for the “anxiety or depression” domain, as well as the VAS score. The same trend was seen within the G+C group scores, however, Native CT-II® saw a more significant change in the “Usual activities” than in the G+C group when compared to placebo (p=0.0156 & p=0.1997 respectively) (Table 8).
Table 8
Change in EQ-5D-5L scores (mITT population)
EQ-5D Mobility
|
Change on Day 84
|
Native CT-II® (n = 30)
|
G+C (n = 29)
|
Placebo (n = 30)
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Min
|
Max
|
Min
|
Max
|
Min
|
Max
|
-1.00 (0.74)
|
-1.28
|
-0.72
|
<.0001
|
-1.21 (0.73)
|
-1.48
|
-0.93
|
<.0001
|
-0.73 (0.98)
|
-1.10
|
-0.37
|
0.0003
|
p-value**
|
0.0255
|
0.0179
|
|
EQ-5D Self Care
|
Change on Day 84
|
Native CT-II® (n = 30)
|
G+C (n = 29)
|
Placebo (n = 30)
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Min
|
Max
|
Min
|
Max
|
Min
|
Max
|
-0.90 (0.84)
|
-1.22
|
-0.58
|
<.0001
|
-1.00 (0.89)
|
-1.34
|
-0.66
|
<.0001
|
-0.47 (0.97)
|
-0.83
|
-0.10
|
0.0136
|
p-value**
|
0.0112
|
0.0340
|
|
EQ-5D Usual Activities
|
Change on Day 84
|
Native CT-II® (n = 30)
|
G+C (n = 29)
|
Placebo (n = 30)
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Min
|
Max
|
Min
|
Max
|
Min
|
Max
|
-1.17 (0.87)
|
-1.49
|
0.84
|
<.0001
|
-0.93 (0.92)
|
-1.28
|
-0.58
|
<.0001
|
-0.83 (1.02)
|
-1.21
|
-0.45
|
0.0001
|
p-value**
|
0.0156
|
0.1997
|
|
EQ-5D Pain or Discomfort
|
Change on Day 84
|
Native CT-II® (n = 30)
|
G+C (n = 29)
|
Placebo (n = 30)
|
Mean (SD)
|
95% C.I.
|
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Min
|
Max
|
p-value*
|
Min
|
Max
|
Min
|
Max
|
-1.13 (0.68)
|
-1.39
|
-0.88
|
<.0001
|
-0.97 (1.02)
|
-1.35
|
-0.58
|
<.0001
|
-0.60 (0.72)
|
-0.87
|
-0.33
|
<.0001
|
p-value**
|
0.0020
|
0.0117
|
|
EQ-5D Anxiety or Depression
|
Change on Day 84
|
Native CT-II® (n = 30)
|
G+C (n = 29)
|
Placebo (n = 30)
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Min
|
Max
|
Min
|
Max
|
Min
|
Max
|
-0.90 (0.76)
|
-1.18
|
-0.62
|
<.0001
|
-1.00 (1.07)
|
-1.41
|
-0.59
|
<.0001
|
-0.93 (1.17)
|
-1.37
|
-0.50
|
0.0001
|
p-value**
|
0.3435
|
0.2770
|
|
EQ-5D VAS Score
|
Change on Day 84
|
Native CT-II® (n = 30)
|
G+C (n = 29)
|
Placebo (n = 30)
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Mean (SD)
|
95% C.I.
|
p-value*
|
Min
|
Max
|
Min
|
Max
|
Min
|
Max
|
17.73 (13.78)
|
12.59
|
22.88
|
<.0001
|
18.97 (15.55)
|
13.05
|
24.88
|
<.0001
|
4.50 (13.73)
|
-0.63
|
9.63
|
0.0831
|
p-value** vs. placebo
|
0.0003
|
0.0009
|
|
*p value calculated using paired t-test as compared to baseline.
**p value calculated using ANCOVA as compared to placebo
|
Safety evaluations
No statistically significant difference was found in the Pulse rate and blood pressure values during baseline (p>0.05). Random changes were found in mean blood pressure and pulse rate at the end of the treatment period; however, they did not have any pattern and were deemed to be random type 1 errors. Furthermore, none of the changes in any of the values were beyond the normal range.
An insignificant decrease in the AST levels was observed in the G+C and the placebo groups when compared to their baseline values. Similar decreases were observed in all the study groups for the other biomarkers, however, none of the changes were statistically significant when compared to baseline, or the other study groups. Furthermore, the levels for each of the biomarkers did not change beyond the normal range.
All but one, the adverse events (AEs) reported in the study were mild and resolved completely. None of the AEs observed in any of the groups were related to the study products. The serious adverse event observed in the study was reported for the participant diagnosed with COVID-19 and was definitely not related to the study product.