Study design and treatment features of tocilizumab phase III randomized controlled trials and open-label extensions.
| Study | Patient Population | Treatment Duration | Treatment | Combination Therapy | Rescue Therapya | Efficacy Population*, n = 3986 | All-exposed Safety Population*, n = 4009 | All-control Safety Population**, n = 4199b |
|---|---|---|---|---|---|---|---|---|
| Randomized Controlled Studies | ||||||||
| LITHE N = 1196c | Moderate to severe active RA MTX-IR | 2 yrs | TCZ 4 mg/kg Q4W TCZ 8 mg/kg Q4We Placebo Q4W | MTX 10–25 mg QW | Wk 16: blinded TCZ 4 mg/kg (from placebo) or 8 mg/kg (from 4 mg/kg) After 12 wks of escape 1 treatment: TCZ 8 mg/kg | DMARD-IR group: n = 1149 | n = 1149 initially randomly assigned to: Control: n = 351 TCZ 4 mg/kg: n = 399 TCZ 8 mg/kg: n = 399 | Control: n = 392 TCZ 4 mg/kg: n = 399 TCZ 8 mg/kg: n = 399 |
| OPTION N = 623c | Moderate to severe active RA MTX-IR | 24 wks | TCZ 4 mg/kg Q4W TCZ 8 mg/kg Q4W Placebo Q4W | MTX 10–25 mg QW | Wk 16: TCZ 8 mg/kg | DMARD-IR group: n = 597 | n = 597 initially randomly assigned to: Control: n = 179 TCZ 4 mg/kg: n = 212 TCZ 8 mg/kg: n = 206 | Control: n = 204 TCZ 4 mg/kg: n = 212 TCZ 8 mg/kg: n = 206 |
| TOWARD N = 1220c | Moderate to severe active RA DMARD-IR | 24 wks | TCZ 8 mg/kg Q4W Placebo Q4W (randomized 2:1) | DMARD | Wk 16: adjustment of background DMARD | DMARD-IR group: n = 1158 | n = 1158 initially randomly assigned to: Control: n = 356 TCZ 8 mg/kg: n = 802 | Control: n = 414 TCZ 8 mg/kg: n = 802 |
| RADIATE N = 499c | Moderate to severe active RA TNF-IR | 24 wks | TCZ 4 mg/kg Q4W TCZ 8 mg/kg Q4W Placebo Q4W | MTX 10–25 mg QW | Wk 16: TCZ 8 mg/kg | TNF-IR group: n = 464 | n = 464 initially randomly assigned to: Control: n = 126 TCZ 4 mg/kg: n = 163 TCZ 8 mg/kg: n = 175 | Control: n = 160 TCZ 4 mg/kg: n = 163 TCZ 8 mg/kg: n = 175 |
| AMBITION N = 673c | Active RA No MTX during last 6 mo and no MTX failure | 24 wks | TCZ 8 mg/kg Q4Wf MTX 7.5–20 mg weekly Substudy: placebo 8 wks then TCZ 8 mg/kg Q4W for 16 wks | None | Substudy only up to wk 8: TCZ 8 mg/kg | NE/NF MTX group: n = 618 | n = 618 initially randomly assigned to: Control: n = 330 TCZ 8 mg/kg: n = 288 | Control: n = 385g TCZ 8 mg/kg: n = 288 |
| Phase 1 Drug Interaction N = 23 | RA patients | Single dose | TCZ 10 mg/kg TCZ 10 mg/kg + simvastatin on days 1, 15, and 43 | MTX 10–25 mg QW | NA | NA | n = 23 initially randomly assigned to: TCZ 10 mg/kg: n = 23 | NA |
| Longterm Extension, Open-label Studies | ||||||||
| LITHE extension phase N = 909d | Ongoing study; moderate to severe active RA MTX-IR | 3 yrs (planned) | TCZ 8 mg/kg Q4W | MTX 10–25 mg/wk | NA | NA | 909 | NA |
| GROWTH95 N = 537 | Patients completing treatment in OPTION | −5 yrs (planned) | TCZ 8 mg/kg Q4W | MTX 10–25 mg/wk | NA | NA | 537 | NA |
| GROWTH96 N = 2066 | Patients completing treatment in AMBITION, RADIATE, TOWARD, and drug interaction study | −5 yrs (planned) | TCZ 8 mg/kg Q4W | Study dependent None (AMBITIONf) MTX, 10–25 mg/wk (RADIATE) Other DMARD (TOWARD) | NA | NA | 2066 | NA |
Abbreviations
↵* TCZ-treated patients (from controlled and extension studies).
↵** TCZ- or control-treated (from controlled studies).
↵a Patients who did not attain 20% improvement in swollen joint count (SJC) or tender joint count (TJC) could receive rescue therapy during the randomized phase.
↵b Does not include 23 patients from the phase I clinical pharmacology study and 12 patients initially randomly assigned in the randomized controlled studies who did not receive study treatment: LITHE (n = 6), OPTION (n = 1), TOWARD (n = 4), and RADIATE (n = 1).
↵c No. patients randomly assigned during phase III study.
↵d Estimated no. patients who entered extension phase (study is ongoing; final data not available).
↵e At Week 52, all patients were required to start open-label TCZ 8 mg/kg for Year 2 unless they had attained ≥ 70% improvement in SJC and TJC, allowing them to continue the blinded therapy they were receiving at the end of Year 1 to Week 104.
↵f Patients who attained ≥ 50% reduction in TJC and SJC (assessed from baseline) while receiving initially randomized study treatment at weeks 20 and 24 could opt to continue their current blinded treatment in a transition phase that lasted until the last patient enrolled in AMBITION completed the 24-week randomized phase of the study; 234 AMBITION patients continued to receive TCZ 8 mg/kg monotherapy for all evaluations.
↵g 284 patients from blinded study; 101 patients from placebo substudy. DMARD: disease-modifying antirheumatic drug; IR: inadequate response; MTX: methotrexate; NA: not applicable; NE/NF: never exposed/never failed; QW: once every week; Q4W: once every 4 weeks; RA: rheumatoid arthritis; SJC: swollen joint count; TCZ: tocilizumab; TJC: tender joint count; TNF: tumor necrosis factor.