Table 1.
CTS results for each treatment arm based on a parallel-study design (ten trial replicates)
| (A) Treatment duration | Median number of patients transitioning to combination therapy (90% CI) |
|---|---|
| Start of treatment | 0 |
| 01 month | 489 (487, 493) |
| 03 months | 428 (413, 444) |
| 06 months | 284 (266, 306) |
| 12 months | 174 (163, 188) |
| 24 months | 157 (153, 173) |
| 36 months | 0 |
| 48 months | 0 |
| (B) Treatment arm | Baseline IPSSa | Response rate (%)b | IPSS at 48 months | RespondersCT− Respondersx (%) |
|---|---|---|---|---|
| Combination therapy (CT) | 17.1 [8–35] | 79.7 (78.6, 81.2) | 6.3 (6, 6.7) | |
| Tamsulosin | 17.3 [8–35] | 65.5 (63.1, 68.1) | 9.4 (8.8, 9.9) | |
| Tamsulosin non-responders to CT at 1 month | 17.1 [8–35] | 79.5 (76.6, 81.4) | 6.4 (6.2, 6.6) | 0.2 |
| Tamsulosin non-responders to CT at 3 months | 17.2 [8–33] | 78.1 (76.8, 81.0) | 6.8 (6.4, 7.1) | 1.6 |
| Tamsulosin non-responders to CT at 6 months | 16.9 [8–34] | 74.1 (72.3, 75.5) | 7.6 (7.2, 8.1) | 5.6* |
| Tamsulosin non-responders to CT at 12 months | 16.9 [8–35] | 70.3 (67.3, 72.1) | 8.1 (7.5, 8.6) | 9.4* |
| Tamsulosin non-responders to CT at 24 months | 17.0 [8–35] | 71.0 (68.6, 72.1) | 8.0 (7.8, 8.3) | 8.7* |
| (C) Treatment arm | Transition from moderate to mild at different study visits, cumulative % (range) | |||||
|---|---|---|---|---|---|---|
| 1 month | 3 months | 6 months | 12 months | 24 months | 48 months | |
| Combination therapy (CT) |
4.6 (3.8, 5.2) |
12.3 (11.2, 13.8) |
22.3 (20.5, 23.3) |
35.3 (34.4, 37.0) |
44.7 (43.4, 46.4) |
45.5 (44.2, 46.6) |
| Tamsulosin |
3.0 (2.8, 3.42) |
8.0 (6.5, 8.4) |
13.6 (13.4, 14.6) |
25.2 (23.4, 26.1) |
32.9 (32.0, 34.8) |
32 (31.0, 34.2) |
| Tamsulosin non-responders switching to CT at 1 month |
4.1 (3.6, 5) |
11.0 (10.6, 12.2) |
21.6 (20.6, 23.0) |
35.1 (34.4, 37.3) |
43.3 (41.7, 45.8) |
43 (41.4, 46.1) |
| Tamsulosin non-responders switching to CT at 3 months |
3.9 (3.29, 4.4) |
7.7 (6.3, 9.2) |
17.3 (15.9, 21.0) |
33.0 (31.1, 36.1) |
41.6 (39.2, 44.6) |
40.7 (38.3, 44.0) |
| Tamsulosin non-responders switching to CT at 6 months |
3.2 (2.6, 3.5) |
7.6 (7.0, 8.9) |
14.4 (12.8, 15.8) |
30.5 (29.1, 33.6) |
40.7 (38.6, 42.6) |
40.4 (37.9, 42.5) |
| Tamsulosin non-responders switching to CT at 12 months |
3.6 (3.4, 4.2) |
8.4 (7.4, 9.4) |
14.8 (13.2, 15.9) |
25.2 (23.0, 27.5) |
37.9 (35.9, 40.9) |
37.2 (35.7, 40.7) |
| Tamsulosin non-responders switching to CT at 24 months |
3.3 (3.0, 4.2) |
8.1 (7.0, 9.6) |
14.7 (12.7, 16.4) |
25.4 (23.1, 27.0) |
34.3 (32.7, 35.0) |
38.9 (37.0, 40.6) |
| (C) Treatment arm | Transition from severe to mild at different study visits, cumulative % (range) | |||||
|---|---|---|---|---|---|---|
| 1 month | 3 months | 6 months | 12 months | 24 months | 48 months | |
| Combination therapy (CT) |
0 (0, 0.1) |
0.4 (0.2, 0.8) |
2.2 (1.6, 2.8) |
6.6 (4.8, 7.1) |
12.8 (11.5, 13.4) |
15.7 (13.8, 16.4) |
| Tamsulosin |
0 (0, 0) |
0.2 (0, 0.7) |
1.1 (0.8, 1.5) |
2.8 (2.6, 4.3) |
6.8 (6.1, 9.0) |
10.2 (9.0, 12.2) |
| Tamsulosin non-responders switching to CT at 1 month |
0 (0, 0) |
0.4 (0, 1.0) |
1.8 (1.6, 2.9) |
6.8 (5.3, 8.0) |
13.3 (12.2, 14.8) |
16.7 (15.2, 17.2) |
| Tamsulosin non-responders switching to CT at 3 months |
0 (0, 0.4) |
0.2 (0, 0.5) |
1.3 (1.0, 2.3) |
6.3 (5.0, 8.0) |
13.6 (11.5, 15.4) |
16.2 (14.6, 18.4) |
| Tamsulosin non-responders switching to CT at 6 months |
0 (0, 0) |
0.3 (0, 0.7) |
0.9 (0.8, 1.9) |
4.3 (3.0, 4.9) |
9.3 (8.6, 10.7) |
11.6 (10.8, 12.9) |
| Tamsulosin non-responders switching to CT at 12 months |
0 (0, 0.2) |
0.4 (0.2, 0.6) |
1.0 (0.8, 1.2) |
3.4 (2.2, 4.4) |
9.4 (7.1, 10.1) |
12.6 (9.7, 13.1) |
| Tamsulosin non-responders switching to CT at 24 months |
0 (0, 0.1) |
0.3 (0.2, 0.6) |
1.2 (0.8, 1.7) |
3.0 (2.6, 4.0) |
7.1 (6.4, 8.2) |
10.6 (9.8, 12.0) |
| (D) IPSS improvement | Percentage of patients (CI) showing improvement at month 48 | |||
|---|---|---|---|---|
| ≥ 25% | ≥ 35% | ≥ 50% | ≥ 75% | |
| Combination therapy (CT) | 79.7 (78.6, 81.2) | 73.1 (71.6, 74.8) | 60.8 (59.0, 62.4) | 31.2 (27.4, 32.6) |
| Tamsulosin | 65.5 (63.0, 68.0) | 57.4 (55.6, 60.0) | 44.0 (42.5, 46.5) | 17.0 (15.2, 18.6) |
| Tamsulosin non-responders switching to CT at 1 month | 79.5 (76.5, 81.4) | 71.1 (69.3, 74.7) | 59.3 (56.6, 60.9) | 29.1 (27.2, 29.9) |
| Tamsulosin non-responders switching to CT at 3 months | 78.1 (76.8, 81.0) | 71.0 (69.9, 73.9) | 59.9 (56.3, 61.2) | 28.4 (25.8, 31.3) |
| Tamsulosin non-responders switching to CT at 6 months | 74.1 (72.3, 75.5) | 65.8 (64.1, 68.6) | 52.7 (50.6, 55.6) | 22.4 (20.3, 24.2) |
| Tamsulosin non-responders switching to CT at 12 months | 70.3 (67.2, 72.1) | 62.4 (58.7, 64.6) | 48.4 (45.1, 51.9) | 20.2 (18.1, 24.4) |
| Tamsulosin non-responders switching to CT at 24 months | 71.0 (68.5, 72.1) | 63.2 (61.3, 65.0) | 49.6 (46.9, 52.2) | 19.4 (18.0, 21.0) |
Panel (A): overview of the patient population transitioning from tamsulosin to tamsulosin–dutasteride combination therapy due to non-response to tamsulosin. Panel (B): primary endpoint, i.e. proportion of responders (response rate) and IPSS values at 48 months in patients responding to treatment. The difference in the proportion of responders in each virtual treatment arm relative to the combination therapy arm [RespondersCT − Respondersx (%)] summarises the impact of immediate combination therapy. Panel (C): cumulative percentage of subjects switching from moderate or severe to mild symptom scores at each visit. Panel (D): Impact of immediate versus delayed start of tamsulosin–dutasteride combination therapy on the magnitude of response, as assessed by the proportion of patients showing changes in IPSS ≥ 35%, ≥ 50% and ≥ 75% relative to baseline at month 48. The statistical significance of the differences between treatment arms for each response threshold is shown for a single replicate trial in Table S5 (see Supplemental Materials)
The results presented above refer to a CTS scenario including placebo effect only after the initial treatment phase. Placebo effect is an important component of the initial response and can last more than 6 months, as assessed by its half-life. No studies included a placebo treatment arm for > 2 years, so it was not possible to establish whether inter-individual differences might allow for a longer placebo effect. Unless indicated otherwise, values represent median (90% CIs) from ten trial replicates. Symptom severity: mild = IPSS 1–7, moderate = IPSS 8–19, and severe = IPSS ≥ 20
CI confidence interval, CTS clinical trial simulation, IPSS International Prostate Symptom Score
*Log rank test: p < 0.01
aBaseline IPSS [range] in each treatment arm
bpercentage of responders (IPSS drop ≥ 25% relative to baseline) at 48 months