Table 3.
Change from baseline and percentage change from baseline at EOT
| OL 400 mg, 12-wk cohort (n = 15)∗,‡ |
MAD pooled placebo (n = 4)∗,†,‡ |
MAD1, 300 mg (n = 8)∗,†,‡,§ |
MAD2, 600 mg (n = 8)∗,†,‡ |
|||||
|---|---|---|---|---|---|---|---|---|
| Mean (± SD) | Median (min, max) |
Mean (± SD) | Median (min, max) |
Mean (± SD) | Median (min, max) |
Mean (± SD) | Median (min, max) |
|
| 2,3-DPG, μg/mL per g/mL Hb | ||||||||
| Baseline | 5956.5 (2050.8) | 6181.8 (541, 8350) |
4349.7 (2904.8) | 4689.5 (541, 7479) |
6109.7 (621.8) n = 7 |
6053.8 (5368, 7071) n = 7 |
6821.8 (1764.2) | 6103.9 (5067, 10693) |
| EOT | 4099.2 (833.8) n = 14 |
4090.2 (2732.1, 5555.6) n = 14 |
5890.9 (800.4) | 5642.6 (5253, 7025) |
4263.6 (507.3) n = 7 |
4193.5 (3595, 4915) n = 7 |
4643.8 (2374.7) | 3968.8 (2852, 10338) |
| CFB EOT | −1732.9‖ (2213.6) n = 14 |
−1988.4‖ (−4511.8, 3595.3) n = 14 |
1541.2 (2430.4) | 873.1 (−454, 4872) |
−1846.1‖ (494.2) n = 7 |
−1860.2‖ (−2665, –1156) n = 7 |
−2177.9 (2919.3) | −2115.2 (−7457, 3310) |
| ATP, μg/mL per g/mL Hb | ||||||||
| Baseline | 2037.7 (947.3) n = 13 |
2250.0 (321, 3111) n = 13 |
1284.5 (1128.5) | 1152.2 (313, 2521) |
2355.5 (418.5) n = 7 |
2149.4 (1989, 3170) n = 7 |
2117.9 (601.6) | 2217.5 (989, 3033) |
| EOT | 3802.0 (1276.1) n = 11 |
4117.0 (1484.9, 5276.8) n = 11 |
1854.7 (1096.4) | 2209.5 (333, 2667) |
3202.9 (516.2) n = 7 |
3265.0 (2577, 4150) n = 7 |
3218.1 (739.2) | 3391.6 (2024, 4255) |
| CFB EOT | 1939.4‖ (1483.7) n = 11 |
2067.5‖ (−802.4, 4112.1) n = 11 |
570.2 (1196.2) | 57.7 (−189, 2354) |
847.3‖ (656.4) n = 7 |
680.1‖ (127, 2101) n = 7 |
1100.2‖ (528.0) | 1282.3‖ (251, 1596) |
| Hb, g/dL | ||||||||
| Baseline | 8.7 (1.0) | 8.7 (7.2, 10.1) |
7.6 (0.4) | 7.6 (7.1, 8.0) |
9.0 (1.1) | 9.1 (6.9, 10.1) |
8.7 (0.9) | 8.9 (7.3, 10.2) |
| EOT | 9.8 (1.1) | 9.5 (8.4, 12.0) | 7.7 (0.2) | 7.7 (7.5, 7.9) | 10.1 (1.6) | 10.8 (6.8, 11.7) | 9.8 (1.5) | 9.8 (7.4, 12.3) |
| CFB EOT | 1.1‖ (0.8) n = 14 |
1.2‖ (−0.2, 2.7) n = 14 |
0.1 (0.5) | 0.0 (−0.4, 0.8) | 1.2‖ (0.9) | 1.2‖ (−0.1, 2.3) | 1.1‖ (1.1) | 1.0‖ (−0.1, 3.5) |
| Absolute reticulocytes, ×109/L | ||||||||
| Baseline | 229.4 (116.9) | 219.3 (80.5, 511.0) |
275.3 (74.1) n = 3 |
238.4 (227.0, 360.6) n = 3 |
252.3 (70.4) | 274.1 (125.6, 329.6) |
227.3 (105.8) | 226.8 (29.4, 366.0) |
| EOT | 163.3 (85.8) n = 14 |
133.1 (48.7, 351.6) n = 14 |
241.9 (115.7) | 261.8 (85.2, 358.9) |
144.0 (121.1) | 99.2 (60.0, 433.9) |
130.1 (64.0) | 135.2 (24.8, 219.1) |
| CFB EOT | −66.8‖ (107.0) n = 14 |
−44.6‖ (−305.0, 118.1) n = 14 |
18.8 (98.0) n = 3 |
11.0 (−75.0, 120.5) n = 3 |
−108.3‖ (114.7) | −142.0‖ (−233.8, 133.4) |
−97.2‖ (66.3) | −87.4‖ (−217.2, −4.6) |
| iBIL, mg/dL | ||||||||
| Baseline | 1.9 (1.4) | 1.3 (0.8, 5.2) | 3.3 (1.6) n = 3 |
2.8 (2.0, 5.0) n = 3 |
3.1 (3.4) | 1.7 (0.5, 10.5) | 1.9 (1.4) | 1.3 (0.7, 4.5) |
| EOT | 1.2 (0.7) n = 13 |
0.9 (0.5, 2.9) n = 13) |
2.6 (1.5) | 2.6 (0.8, 4.4) | 1.8 (1.5) | 0.9 (0.3, 3.8) | 1.1 (0.8) | 0.7 (0.5, 2.6) |
| CFB EOT | −0.5‖ (0.8) n = 13 |
−0.5‖ (−2.3, 0.5) n = 13 |
−0.03 (0.5) n = 3 |
0.21 (−0.6, 0.3) n = 3 |
−1.3 (2.5) | −0.5 (−7.0, 0.9) |
−0.8‖ (0.7) | −0.6‖ (−1.9, −0.1) |
| LDH, U/L | ||||||||
| Baseline | 375.2 (142.9) | 367.0 (186, 683) |
391.8 (210.5) | 352.0 (180, 683) |
430.4 (159.0) | 381.5 (207, 699) |
391.4 (129.7) | 368.5 (251, 683) |
| EOT | 319.1 (87.7) n = 14 |
323.0 (193, 470) n = 14 |
449.8 (209.5) | 486.5 (192, 634) | 311.4 (155.3) | 280.0 (159, 641) | 315.5 (94.0) | 308.5 (199, 492) |
| CFB EOT | −38.4‖ (77.7) n = 14 |
−23.0‖ (−213, 57) n = 14 |
58.0 (151.4) | 17.0 (−77, 275) |
−119.0‖ (113.3) | −97.5‖ (−283, 61) |
−75.9 (173.2) | −54.5 (−461, 90) |
| P50, mmHg | ||||||||
| Baseline | 29.9 (2.4) n =14 |
30.3 (25.8, 34.4) n = 14 |
29.2 (5.9) n = 3 |
30.5 (22.8, 34.4) n = 3 |
30.4 (1.3) n = 6 |
30.8 (28.3, 31.6) n = 6 |
30.1 (2.2) | 30.4 (26.2, 33.2) |
| EOT | 26.6 (2.5) n = 14 |
25.8 (23.8, 32.1) n = 14 |
31.4 (2.6) | 31.3 (28.5, 34.6) |
26.4 (1.6) n = 7 |
26.6 (23.8, 28.4) n = 7 |
26.3 (1.9) | 26.5 (23.2, 28.9) |
| CFB EOT | −3.3‖ (2.0) n = 13 |
−3.8‖ (−5.9, 1.9) n = 13 |
2.0 (3.2) n = 3 |
0.2 (0.2, 5.7) n = 3 |
−4.3‖ (1.9) n = 6 |
−4.3‖ (−7.2, −1.6) n = 6 |
−3.9‖ (1.6) | −3.5‖ (−6.7, −2.3) |
| PoS, mmHg | ||||||||
| Baseline | 43.2 (7.1) n = 14 |
43.1 (22.0, 50.0) n = 14 |
45.8 (4.9) n = 3 |
48.1 (40.1, 49.2) n = 3 |
36.3 (9.2) n = 6 |
39.1 (19.0, 45.0) n = 6 |
38.5 (8.6) | 39.7 (26.2, 49.2) |
| EOT | 35.1 (12.3) n = 14 |
36.5 (9.5, 51.0) n = 14 |
63.2 (34.2) | 52.8 (34.6, 112.7) |
31.0 (9.7) | 28.5 (18.1, 47.3) |
31.3 (3.8) | 31.1 (25.6, 36.2) |
| CFB EOT | −8.6‖ (8.2) n = 13 |
−8.6‖ (−22.8, 3.0) n = 13 |
19.8 (38.1) n = 3 |
1.3 (−5.6, 63.5) n = 3 |
−8.0‖ (5.7) n = 6 |
−9.0‖ (−15.1, −0.9) n = 6 |
−7.3‖ (7.0) | −7.2‖ (−15.4, 4.6) |
| Elmin | ||||||||
| Baseline | 0.12 (0.07) n = 14 |
0.11 (0.0, 0.3) n = 14 |
0.13 (0.15) n = 3 |
0.18 (0.0, 0.3) n = 3 |
0.11 (0.10) n = 6 |
0.07 (0.0, 0.3) n = 6 |
0.19 (0.11) | 0.15 (0.1, 0.4) |
| EOT | 0.16 (0.14) n = 14 |
0.12 (0.0, 0.5) n = 14 |
0.06 (0.11) | 0.03 (0.0, 0.2) | 0.18 (0.15) | 0.12 (0.1, 0.5) | 0.23 (0.10) | 0.21 (0.1, 0.5) |
| CFB EOT | 0.05 (0.10) n = 13 |
0.04 (−0.1, 0.2) n = 13 |
−0.06 (0.19) n = 3 |
0.04 (−0.3, 0.1) n = 3 |
0.10 (0.11) n = 6 |
0.05 (0.0, 0.2) n = 6 |
0.04 (0.05) | 0.06 (0.0, 0.1) |
| Elmax | ||||||||
| Baseline | 0.45 (0.10) n = 14 |
0.46 (0.2, 0.5) n = 14 |
0.38 (0.19) n = 3 |
0.49 (0.2, 0.5) n = 3 |
0.43 (0.14) n = 6 |
0.43 (0.3, 0.6) n = 6 |
0.48 (0.06) | 0.49 (0.4, 0.6) |
| EOT | 0.47 (0.08) n =14 |
0.49 (0.2, 0.5) n = 14 |
0.40 (0.14) | 0.44 (0.2, 0.5) | 0.49 (0.08) | 0.51 (0.3, 0.6) | 0.51 (0.04) | 0.51 (0.4, 0.6) |
| CFB EOT | 0.02 (0.05) n = 13 |
0.01 (−0.1, 0.1) n = 13 |
0.00 (0.05) n = 3 |
0.02 (−0.1, 0.0) n = 3 |
0.05 (0.08) n = 6 |
0.02 (0.0, 0.2) n = 6 |
0.03 (0.05) | 0.02 (0.0, 0.1) |
| DRBCs (hyper), % | ||||||||
| Baseline | 3.2 (2.5) n = 14 |
2.8 (1.0, 11.1) n = 14 |
5.0 (5.4) n = 3 |
2.7 (1.1, 11.1) n = 3 |
4.0 (3.1) n = 7 |
3.3 (0.9, 8.9) n = 7 |
2.5 (1.1) | 2.6 (1.0, 4.1) |
| EOT | 2.8 (2.1) n = 14 |
2.0 (1.2, 8.9) n = 14 |
4.8 (3.3) | 3.9 (1.9, 9.6) | 2.6 (1.8) | 2.1 (1.1, 6.9) | 1.9 (0.9) | 1.9 (0.7, 3.3) |
| CFB EOT | −0.3 (1.6) n = 13 |
−0.4 (−2.5, 2.7) n = 13 |
0.2 (1.5) n = 3 |
0.8 (−1.5, 1.3) n = 3 |
−1.3 (1.7) n = 7 |
−1.8 (−4.2, 0.7) n = 7 |
−0.6 (1.1) | −0.8 (−2.1, 1.4) |
| CHCM, g/dL | ||||||||
| Baseline | 33.0 (1.3) n = 14 |
32.8 (30.6, 35.3) n = 14 |
32.6 (2.3) n = 3 |
32.3 (30.5, 35.1) n = 3 |
33.0 (0.9) n = 7 |
33.0 (31.7, 34.3) n = 7 |
32.3 (1.3) | 32.6 (30.3, 34.3) |
| EOT | 32.5 (1.5) n = 14 |
32.2 (30.8, 36.1) n = 14 |
33.5 (1.0) | 33.4 (32.5, 34.8) |
32.4 (0.9) | 32.2 (31.3, 33.8) |
31.7 (1.3) | 31.6 (29.2, 33.6) |
| CFB EOT | −0.6 (1.1) n = 13 |
−0.9 (−1.8, 2.3) n = 13 |
1.0 (1.2) n = 3 |
1.3 (−0.3, 2.0) n = 3 |
−0.7‖ (0.6) n = 7 |
−0.7‖ (−1.4, 0.3) n = 7 |
−0.6 (0.8) | −0.9 (−1.3, 0.6) |
| TNF-α, pg/mL | ||||||||
| Baseline | 1.2 (0.5) n = 14 |
1.1 (0.6, 2.2) n = 14 |
1.7 (0.7) n = 2 |
1.7 (1.3, 2.2) n = 2 |
1.2 (0.5) | 1.1 (0.6, 2.0) | 1.4 (0.5) n = 7 |
1.2 (0.8, 2.0) n = 7 |
| EOT | 0.8 (0.4) n = 13 |
0.9 (0.2, 1.6) n = 13 |
1.3 (0.1) | 1.2 (1.1, 1.5) | 1.4 (0.6) n = 7 |
1.4 (0.7, 2.3) n = 7 |
0.7 (0.4) | 0.8 (0.2, 1.3) |
| CFB EOT | −0.3 (0.7) n = 12 |
−0.1 (−1.7, 0.4) n = 12 |
−0.5 (0.6) n = 2 |
−0.5 (−0.9, −0.1) n = 2 |
0.1 (0.6) n = 7 |
0.0 (−0.6, 1.0) n = 7 |
−0.5‖ (0.6) n = 7 |
−0.3‖ (−1.7, 0.0) n = 7 |
| MMP-9, ng/mL | ||||||||
| Baseline | 440.1 (282.4) n = 13 |
434.7 (90.3, 929.4) n = 13 |
573.1 n = 1 |
573.1 (573.1, 573.1) n = 1 |
ND | ND | 451.2 (313.5) n = 7 |
434.7 (97.2, 929.4) n = 7 |
| EOT | 296.0 (354.0) n = 13 |
175.6 (0.0, 1280.9) n = 13 |
280.9 (96.6) n = 2 |
280.9 (212.6, 349.1) n = 2 |
ND | ND | 282.2 (176.2) | 242.4 (69.3, 602.3) |
| CFB EOT | −149.8‖ (259.3) n = 11 |
−175.6‖ (−627.8, 351.5) n = 11 |
−224.0 n = 1 |
−224.0 (−224.0, −224.0) n = 1 |
ND | ND | −193.3‖ (215.4) n = 7 |
−96.3‖ (−615.5, −18.5) n = 7 |
| Leukocytes, ×109/L | ||||||||
| Baseline | 9.6 (4.9) | 7.9 (5.0, 24.5) |
11.2 (4.6) | 10.4 (6.9, 17.3) |
8.8 (4.4) | 7.5 (4.4, 15.8) |
8.6 (2.9) | 7.9 (6.0, 14.7) |
| EOT | 8.2 (3.3) n = 14 |
8.9 (2.7, 13.1) n = 14 |
11.1 (6.1) | 9.0 (6.3, 20.1) | 7.1 (3.4) | 5.9 (3.9, 14.4) | 6.2 (2.1) | 5.5 (4.1, 9.9) |
| CFB EOT | −1.4 (3.7) n = 14 |
−1.1 (−12.1, 3.0) n = 14 |
−0.1 (2.3) | −0.3 (−2.8, 2.8) |
−1.7‖ (2.1) | −1.5‖ (−6.4, 0.2) |
−2.4 (2.7) | −1.7 (−6.9, 1.2) |
| Prothrombin fragment 1.2, pmol/L | ||||||||
| Baseline | 672.4 (1235.1) n = 14 |
350.5 (150, 4900) n = 14 |
377.0 (234.7) n = 3 |
366.0 (148, 617) n = 3 |
2305.7 (4750.1) n = 6 |
380.5 (252, 12000) n = 6 |
1341.2 (1768.7) n = 6 |
665.0 (371, 4900) n = 6 |
| EOT | 297.0 (151.0) n = 13 |
260.0 (106, 659) n = 13 |
352.3 (23.7) | 352.5 (323, 381) | 408.5 (189.3) n = 6 |
394.0 (177, 663) n = 6 |
1923.6 (4078.4) | 543.0 (154, 12000) |
| CFB EOT | −91.1 (249.2) n = 12 |
1.0 (−720, 154) n = 12 |
−25.0 (205.7) n = 3 |
−14.0 (−236, 175) n = 3 |
25.0 (171.8) n = 5 |
35.0 (−199, 278) n = 5 |
−912.3 (1843.3) n = 6 |
−323 (−4611, 353) n = 6 |
| D-dimer, μg/mL FEU | ||||||||
| Baseline | 2.4 (1.4) n = 13 |
2.1 (0.6, 5.9) n = 13 |
2.5 (1.2) n = 3 |
2.1 (1.6, 3.8) n = 3 |
2.5 (2.3) n = 5 |
1.9 (0.2, 6.3) n = 5 |
3.4 (1.5) n = 6 |
3.3 (1.6, 5.9) n = 6 |
| EOT | 1.9 (1.0) n = 13 |
1.8 (0.2, 3.7) n=13 |
2.2 (0.6) | 2.2 (1.6, 2.9) | 3.0 (1.7) n = 6 |
3.4 (1.1, 5.1) n = 6 |
2.7 (1.5) | 2.6 (0.9, 5.0) |
| CFB EOT | −0.6 (1.5) n = 12 |
−0.4 (−3.2, 1.6) n = 12 |
−0.3 (1.7) n = 3 |
−0.2 (−2.1, 1.4) n = 3 |
0.3 (1.2) n = 5 |
0.7 (−1.2, 1.8) n = 5 |
−0.6 (1.5) n = 6 |
−0.6 (−3.0, 1.7) n = 6 |
| Erythropoietin, mIU/mL | ||||||||
| Baseline | 104.7 (63.6) n = 13 |
94.4 (17.0, 244.9) n = 13 |
157.1 n = 1 |
157.1 (157.1, 157.1) n = 1 |
92.1 (50.1) n = 2 |
92.1 (56.6, 127.5) n = 2 |
152.0 (130.4) n = 7 |
106.7 (65.9, 441.6) n = 7 |
| EOT | 88.0 (65.9) n = 13 |
56.7 (17.5, 234.1) n = 13 |
159.0 (94.6) n = 2 |
159.0 (92.1, 225.9) n = 2 |
82.8 (35.6) n = 2 |
82.8 (57.6, 108.0) n = 2 |
149.3 (142.5) | 128.2 (17.8, 473.8) |
| CFB EOT | −18.6‖ (44.8) n = 11 |
−29.4‖ (−76.0, 73.9) n = 11 |
−65.0 n = 1 |
−65.0 (−65.0, −65.0) n = 1 |
−69.9 n = 1 |
−69.9 (−69.9, −69.0) n = 1 |
6.3 (70.5) n = 7 |
32.2 (−109.6, 81.5) n = 7 |
The “n” values represent the number of patients with nonmissing values.
ATP, adenosine triphosphate; CFB, change from baseline; CHCM, cellular Hb concentration mean; 2,3-DPG, 2,3 diphosphoglycerate; DRBCs, dense red blood cells; EI, elongation index; Elmax, maximum EI; Elmin, minimum EI; EOT, end of treatment; FEU, fibrinogen equivalent unit; Hb is 50% saturated; Hb, hemoglobin, iBIL, indirect bilirubin; LDH, lactate dehydrogenase; LS, least square; max, maximum; min, minimum; MMP-9, matrix metalloproteinase 9; ND, not done; OL, open-label; P50, oxygen tension at which MAD, multiple ascending dose; PoS, point of sickling; SD, standard deviation; TNF-α, tumor necrosis factor alpha.
Sample sizes that deviate from those in the column header are indicated in the appropriate cells.
For the MAD cohorts, baseline was defined as the last measurement obtained before the first dose of study drug. For the 12-week cohort, baseline was defined as average of pretreatment measurements (screening and predose on day 1) for patients who were newly enrolled in the 12-week cohort; for patients who were enrolled in the MAD2 (600 mg) cohort and later rolled over into the 12-week cohort, baseline was defined as the average of prior treatment measurements (screening and predose on day 1) in the MAD2 (600 mg) period.
EOT was day 14/15 (24 hours after last dosing) in the MAD cohorts and day 84/85 (24 hours after last dosing) in the OL cohort.
One MAD1 (300 mg) patient was excluded from 2,3-DPG, ATP, and P50 analyses because the patient only took 1 dose of study drug on day 1.
P <.05 for baseline vs EOT comparison. For the MAD cohorts, P values were obtained from a Wilcoxon signed rank test. For the OL cohort, P values for Hb, LDH, reticulocytes, iBIL, were derived from LS means using a mixed model for repeated measurement, with hematology/hemolysis assessment as dependent variable and scheduled visit during treatment period as a fixed effect. An unstructured covariance was used for Hb, LDH, and reticulocytes. A compound symmetry covariance was used for iBIL, normalized ATP, and normalized 2,3-DPG. In the OL cohort, P values for normalized 2,3-DPG, normalized ATP, P50, PoS, Elmin, Elmax, hyper RBCs, CHCM, TNF-α, MMP-9, leukocytes, prothrombin fragment 1.2, D-dimer, and erythropoietin were derived from a Wilcoxon signed rank test.