Table 1.
Trial design for the DUAL phase III clinical trial program in type 2 diabetes
| Previous treatment regimen | DUAL trial | Study design | Previous regimena | HbA1c range for inclusion | Comparators | Starting dose | Maximum dose | Titration schedule |
|---|---|---|---|---|---|---|---|---|
| OAD(s) | DUAL I | 26-Week, randomized, open-label (N = 1663) | Metformin ± pioglitazone | 7.0–10.0% (53–86 mmol/mol) | Degludec and liraglutide | 10 units/dose steps IDegLira; 10 units degludec; 0.6 liraglutide | IDegLira titrated to a maximum 50 units/dose steps; degludec no maximum dose; liraglutide 1.8 mg | IDegLira and degludec were titrated twice per week based on a pre-breakfast target SMBG of 4–5 mmol/L |
| DUAL IV | 26-Week, randomized, double-blind (N = 435) | SU ± metformin | 7.0–9.0% (53–75 mmol/mol) | Placebo | 10 units/dose steps IDegLira; matching placebo | IDegLira and placebo titrated to a maximum 50 units/dose steps | IDegLira and degludec were titrated twice per week based on a pre-breakfast target SMBG of 4–6 mmol/L | |
| DUAL VI | 32-Week, randomized, open-label (N = 420) | Metformin ± pioglitazone | 7.0–10.0% (53–86 mmol/mol) | Once-weekly IDegLira titration | 10 units/dose steps IDegLira | IDegLira titrated to a maximum 50 units/dose steps | IDegLira was titrated either once weekly or twice weekly based on a pre-breakfast target SMBG of 4–5 mmol/L | |
| DUAL VIII | 104-Week randomized, open-label (N = 1012) | Metformin ± SU ± glinides ± pioglitazone ± DPP-4i | 7.0–11.0% (53–97 mmol/mol) | IGlar U100 | 10 units/dose steps IDegLira; 10 units of IGlar U100 | IDegLira titrated to a maximum 50 units/dose steps; IGlar U100 no maximum dose | IDegLira was titrated twice weekly based on a pre-breakfast target SMBG of 4–5 mmol/L | |
| DUAL IX | 26-Week, randomized, open-label (N = 420) | SGLT2i ± metformin ± DPP4i ± pioglitazone | 7.0–11.0% (53–97 mmol/mol) | IGlar U100 | 10 units/dose steps IDegLira; 10 units of IGlar U100 | IDegLira titrated to a maximum 50 units/dose steps; no maximum dose for IGlar, SGLT2i and OAD | IDegLira and IGlar U100 were titrated twice per week based on a pre-breakfast target SMBG of 4–5 mmol/L | |
| GLP-1RA | DUAL III | 26-Week, randomized, open-label (N = 438) | GLP-1RA + metformin ± SU ± glinides ± pioglitazone | 7.0–9.0% (53–75 mmol/mol) | Pre-trial liraglutide or exenatide | 16 units/dose steps IDegLira; pre-trial dose (maximum dose) of GLP-1RA | IDegLira titrated to a maximum 50 units/dose steps | IDegLira was titrated twice per week based on a pre-breakfast target SMBG of 4–5 mmol/L |
| Basal insulin | DUAL II | 26-Week, randomized, double-blind (N = 413) | Basal insulin (20–40 U) + metformin ± SU or glinides | 7.5–10.0% (59–86 mmol/mol) | Degludec | 16 units/dose steps IDegLira; 16 units degludec | IDegLira titrated to a maximum 50 units/dose steps; degludec had a maximum dose of 50 units | IDegLira and degludec were titrated twice weekly based on a pre-breakfast target SMBG of 4–5 mmol/L |
| DUAL V | 26-Week, randomized, open-label (N = 557) | Metformin + IGlar U100 (20–50 U) | 7.0–10.0% (53–86 mmol/mol) | IGlar U100 | 16 units/dose steps IDegLira; pre-trial dose of IGlar | IDegLira titrated to a maximum 50 units/dose steps; IGlar U100 no maximum dose | IDegLira and IGlar U100 were titrated twice weekly based on a pre-breakfast target SMBG of 4–5 mmol/L | |
| DUAL VII | 26-week, randomized, open-label (N = 506) | Metformin + IGlar U100 (20–50 U) | 7.0–10.0% (53–86 mmol/mol) | IGlar U100 + IAsp (≤ 4 times) | 16 units/dose steps IDegLira; IGlar U100 at a dose equivalent to the pre-trial dose; IAsp at 4 units at each main meal | IDegLira titrated to a maximum 50 units/dose steps; no maximum dose for IGlar U100 or IAsp | IDegLira and IGlar U100 were titrated twice weekly, aiming for a mean fasting SMBG target range of 4.0–5.0 mmol/L; IAsp was titrated twice weekly, aiming for a mean pre-prandial and bedtime SMBG target range of 4.0–6.0 mmol/L |
DPP4i dipeptidyl peptidase-4 inhibitor, GLP-1RA glucagon-like peptide-1 receptor agonist, HbA1c glycated hemoglobin, IAsp insulin aspart, IDegLira insulin degludec/liraglutide, IGlar insulin glargine, OAD oral antidiabetic therapy, SMBG self-measured blood glucose, SGLT2i sodium-glucose co-transporter 2 inhibitor, SU sulfonylureas, U units of insulin
aDPP-4 inhibitors in DUAL IX were discontinued at randomization, but all other OADs were continued at pre-trial doses, unless there was a safety concern