Table 3.
Clinical research on combining and co-delivering strategies against PAH, MCD, RA, IBD, metabolic disorders and ND diseases
| Disease | Combining or co-delivering drugs | Duration | Patient numbers | Efficacy | Study Phase | References | Additional information |
|---|---|---|---|---|---|---|---|
| PAH |
Epoprostenol + Sildenafil vs. Epoprostenol + Placebo |
2.6 years |
Sildenafil (n = 134) Placebo (n = 131) |
A placebo-adjusted increase of 28.8 meters (95% CI, 13.9 to 43.8 meters) in the 6-minute walk distance occurred in patients in the sildenafil group. | – | 511 | – |
|
Macitentan + Tadalafil + Selexipag vs. Macitentan + Tadalafil + Placebo |
4 years |
Selexipag (n = 123) Placebo (n = 122) |
The risk for disease progression (to the end of the main observation period) is reduced with initial triple versus initial double therapy. | Phase 4 | 512 |
TRITON |
|
|
Sildenafil + Bosentan vs. Sildenafil + Placebo |
7.2 years |
Bosentan (n = 159) Placebo (n = 175) |
17% risk reduction for time to first morbidity/mortality event. (P = 0.25) | Phase 4 | 513 |
COMPASS-2 |
|
|
3 or 10 mg Macitentan vs. placebo (63.7% receiving study drug combined with other therapy—PDE5, inhaled or oral Prostanoid) |
3.8 years |
Macitentan (n = 492) Placebo (n = 250) |
10-mg macitentan dose reduced 45% the risk of M/M events. (P < 0.001) | Phase 3 | 514 |
SERAPHIN |
|
| Selexipag (80% combining with ERA, PDE5, or both) | 4.3 years | n = 1156 | 40% risk reduction of M/M event. (P < 0.0001) | Phase 3 | 515 |
GRIPHON |
|
|
Tadalafil + Ambrisentan vs. monotherapy with either agent |
3.7 years |
Tadalafil + Ambrisentan (n = 302) Ambrisentan (n = 152) Tadalafil (n = 151) |
50% risk reduction of clinical failure. (P = 0.0002) | Phase 3 | 516 |
AMBITION |
|
|
Treprostinil + Beraprost vs. Treprostinil + Placebo |
6.8 years |
Beraprost (n = 137) Placebo (n = 136) |
A reduced number of participants experienced clinical worsening. | Phase 3 | – | NCT01908699 | |
|
Sildenafil + Sitaxsentan vs. Sildenafil + Placebo |
2.3 years |
Sitaxsentan (n = 91) Placebo (n = 92) |
6MWD increased significantly at week 12. (P = 0.0104) | Phase 3 | – | NCT00795639 | |
|
Sitaxsentan + Sildenafil vs. Sitaxsentan + Placebo |
1.8 years |
Sildenafil (n = 64) Placebo (n = 67) |
PEP not met. 6MWD increased significantly at week 12. (P = 0.0049) | Phase 3 | – | NCT00796666 | |
| Treprostinil (50% combining with ERA, PDE5, or both) | 4.2 years |
Treprostinil (n = 174) Placebo (n = 176) |
PEP not met. 6MWD increased at week 12. | Phase 3 | 517 |
FREEDOM-C |
|
| 1.5 mg or 2.5 mg Riociguat vs. Placebo (50% of participants pre-treated with an ERA or a Prostacyclin analog) | 3.5 years |
Riociguat (n = 317) Placebo (n = 126) |
The change in 6MWD increased 36% with Riociguat, compared with the placebo, and both PVR and NT-proBNP levels decreased significantly. (P < 0.0001) | Phase 3 | 518 | NCT00810693 | |
|
Epoprostenol + Sildenafil vs. Epoprostenol + Placebo |
3 years |
Sildenafil (n = 134) Placebo (n = 133) |
6MWD improved or maintained in 59%, 44%, and 33% of patients at 1, 2, and 3 years, respectively. | Phase 3 | 519 |
OLE |
|
| MCD |
Prednisone + Azathioprine vs. Prednisone + Placebo |
0.5 year |
Azathioprine (n = 43) Placebo (n = 42) |
Compared with baseline, a combination of prednisone and azathioprine significantly improved left ventricular ejection fraction and decreased left-ventricular dimensions and volumes. | – | 274 | TIMIC |
|
Immunoglobulin + Ciclosporin vs Immunoglobulin |
3 years |
Immunoglobulin + Ciclosporin (n = 86) Immunoglobulin (n = 87) |
The combination of immunoglobulin and ciclosporin reduced the incidence of coronary artery abnormalities. (P = 0.01) | Phase 3 | 279 |
KAICA CCT-B-2503 |
|
|
Gamma globulin + Creatine phosphate+ Routine treatment vs. Routine treatment |
0.5 years |
Gamma globulin + Creatine phosphate + Routine treatment (n = 62) Routine treatment (n = 59) |
The combination significantly increased the response rate (P < 0.05) and improved cardiac function. (P < 0.05), | – | 280 | – | |
| RA |
Methotrexate + MP-435 vs. Methotrexate + Placebo |
1.8 years |
MP-435 (n = 50) Placebo (n = 49) |
The combination significantly increased the response rate of ACR 20, and decreased the incidence of serious adverse events. | Phase 2 | – | NCT01143337 |
|
Methotrexate + 300 mg, 150 mg, 75 mg, 25 mg Secukinumab vs. Methotrexate + Placebo |
1.2 years |
Secukinumab (n = 186) Placebo (n = 50) |
PEP was not met. Symptom alleviation after long-term treatment with 150 mg of secukinumab. | Phase 2 | 520,521 | NCT00928512 | |
|
Methotrexate + 20 mg, 40 mg Adalimumab vs. Methotrexate + Placebo |
1 year |
Adalimumab (n = 419) Placebo (n = 200) |
(a) Meeting ACR20 Response Criteria: 63% and 61% Adalimumab, 30% Placebo. (P ≤ 0.001) (b) Achieving more comprehensive disease control |
Phase 3 | 522 |
DE019 |
|
|
Methotrexate + Adalimumab vs. Methotrexate + Placebo |
1.6 years |
Adalimumab (n = 515) Placebo (n = 517) |
Achieving the sLDA. | Phase 4 | 523 |
OPTIMA |
|
|
Adalimumab + Methotrexate vs. Adalimumab or Methotrexate |
2 years |
Adalimumab + Methotrexate (n = 268) Adalimumab (n = 274) Methotrexate (n = 257) |
The combination significantly improved physical functioning and HRQOL in patients. (P < 0.0001) | Phase 3 | 524 |
PREMIER |
|
|
Methotrexate + Golimumab vs. Methotrexate + Placebo |
48 weeks |
Golimumab (n = 132) Placebo (n = 132) |
The combination significantly improved the response of ACR 20 and DAS 28. (P < 0.001) | Phase 3 | – | NCT01248780 | |
|
Methotrexate + 100, 150 mg Peficitinib vs. Methotrexate + Placebo |
52 weeks |
100 mg Peficitinib (n = 175) 150 mg Peficitinib (n = 174) Placebo (n = 170) |
The combination significantly improved ACR 20 response. (P < 0.001) | Phase 3 | 525 | NCT02305849 | |
| Methotrexate + Baricitinib vs. Methotrexate + Placebo | 52 weeks |
Baricitinib (n = 488) Placebo (n = 489) |
The combination significantly improved ACR 20 response and mTSS. (P < 0.001) | Phase 3 | 526 | NCT01710358 | |
|
Methotrexate + Certolizumab Pegol vs. Methotrexate + Placebo |
52 weeks |
Certolizumab Pegol (n = 660) Placebo (n = 219) |
The combination significantly achieved more patients with sREM and sLDA. (P < 0.001) | Phase 3 | 527 | NCT01519791 | |
| IBD |
Azathioprine + Infliximab vs. Azathioprine + Placebo |
0.7 year |
Infliximab (n = 169) Placebo (n = 170) |
The combination s attained significantly higher rates of corticosteroid-free clinical remission and mucosal healing. (P < 0.001) | Phase 3 | 528 |
SONIC |
|
5-Aminosalicylic Acid + Budesonide vs. 5-Aminosalicylic Acid + Placebo |
8 weeks |
Budesonide (n = 255) Placebo (n = 255) |
The combination s allowed higher clinical and endoscopic remission. (P = 0.049) | Phase 3 | 529 | NCT01532648 | |
| Hyper-thyroidism | Atorvastatin + Methylprednisolone vs. Methylprednisolone | 0.75 years | n = 500 | The combination improved the outcome of Graves’ orbital disease in patients with moderate to severe active eye disease with hypercholesterolemia. | Phase 2 | 530 | NCT03110848 |
| Methimazole + selenium + calcifediol vs. Methimazole | 0.8 years | n = 30 | The combination improved the early efficacy of hyperthyroidism. | - | 374 | EUDRACT2017-005050-11 | |
| Rituximab + thioamide antithyroid drug (ATD) | 2 years | n = 27 | Rituximab can assist ATD treatment to relieve Graves’ hyperthyroidism in young people. | Phase 2 | 531 | ISRCTN20381716 | |
| Rituximab + antithyroid drug | 2 years | n = 27 | The combination improved remission of Graves’ hyperthyroidism in young patients. | Phase 2 | 532 | ISRCTN20381716 | |
| Mycophenolate + methylprednisolone vs. methylprednisolone | 0.7 years | Mycophenolate n = 83 Methylprednisolone n = 81 | The combination improved the remission rate of patients with active moderate-to-severe Graves’ orbitopathy. | – | 533 |
MINGO EUDRACT2008-002123-93 |
|
| Diabetes |
Aspirin + Rivaroxaban vs. Aspirin + Placebo |
3 years |
No diabetes mellitus (n = 11356) Diabetes mellitus (n = 6922) |
The combination showed especially advantageous in individuals with diabetes mellitus. (2.7% vs. 1.0%; P = 0.001) | Phase 3 | 534 | NCT01776424 |
|
Metformin + Vildagliptin vs. Metfromin + Placebo |
5 years |
Combination treatment group (n = 998) Metformin monotherapy group (n = 1003) |
The combination decreased in the relative risk for time to initial treatment failure was seen in the early (hazard ratio 0:51; 95 percent confidence interval. (0:45–0:58; p = 0.0001) | Phase 4 | 535 | NCT01528254 | |
|
Empagliflozin + Loop diuretics vs. Empagliflozin + Placebo |
6 weeks | n = 23 | The combination increased the 24 h urine volume without increasing urinary sodium. | Phase 4 | 536 | NCT03226457 | |
|
Dorzagliatin + Metformin vs. Placebo + Metformin |
4 years | n = 767 | The combination produced efficient glycemic control with a good tolerance and safety profile in T2D patients. (P < 0.0001) | Phase 3 | 409 | NCT03141073 | |
| AD | ChEIs + Memantine | 4 years | n = 382 | The combination decreased cognitive and functional degeneration. | – | 537 | – |
| Rivastigmine + Memantine | 0.5 year | n = 150 | The combination maintained global and cognitive function and behavioral outcomes. | Phase 4 | 538 | NCT00305903 | |
|
Masupirdine + Donepezil + Memantine vs. Placebo |
0.5 year |
Masupirdine (n = 375) Placebo (n = 189) |
Concurrent administration of masupirdine adversely affected with memantine so necessary for further research on masupirdine. | Phase 2 | 539 | NCT02580305 | |
| PD | Levodopa-carbidopa intestinal gel (LCIG) | 1.2 year | n = 39 | The combination reduced the number of non-motor symptoms and motor fluctuations in advanced PD patients. | Phase 3 | 540 | NCT01736176 |
| Carbidopa (25 mg) + Levodopa (100 mg) + Entacapone (200 mg) | 0.7 year | n = 493 | The combination improved symptoms, without raising the risk of motor problems. | Phase 3 | 541 | NCT00134966 | |
| Carbidopa + Levodopa | 3.5 months | n = 38 | The combination offered preliminary evidence of efficacy, safe and feasible for PD. | Phase 2 | 542 | NCT02577523 | |
| ALS | Celecoxib + Creatine + Minocycline | 6 weeks | n = 86 | The combination significantly improved protection against anterior horn motor neuron depletion. | Phase 2 | 543 | NCT00919555 |
| Triumeq (dolutegravir 50 mg, abacavir 600 mg, lamivudine 300 mg) | 5.5 months | n = 43 | Transposable element activity can be a therapeutic target for human tauopathies. | Phase 2 | 544 | NCT02868580 |
PEP primary endpoint, ERA endothelin receptor antagonist, PDE5 phosphodiesterase-5 inhibitor, 6MWD change from baseline in total distance walked during 6-minute walk distance, PVR pulmonary vascular resistance, ACR20 American College of Rheumatology 20% response criteria, ACR50 American College of Rheumatology 50% response criteria, HRQOL health-related quality of life, mTSS change from baseline in van der Heijde-modified total sharp score, ACR 20 response ≥20% improvement in RA symptoms and disease activity, DAS 28 response disease activity index score response, sREM sustained remission, sLDA sustained low disease activity