At a glance: The ORAL trials of tofacitinib for the treatment of RA

Author: Claire Barnard

Updated April 2019

The efficacy and safety of the Janus kinase (JAK) inhibitor tofacitinib – approved for the treatment of moderate-to-severe rheumatoid arthritis (RA) in the USA, Europe, and several other locations – was investigated in the ORAL (Oral Rheumatoid Arthritis triaL) phase 3 trials.

Here, we provide a quick guide to the eight completed ORAL trials to date, all of which are sponsored by tofacitinib’s manufacturer, Pfizer, and published in peer-reviewed journals.

ORAL Solo

Patient population: Active RA; inadequate response to at least one treatment	Comparator treatment: Placebo
https://clinicaltrials.gov/show/NCT00814307

The results of the ORAL Solo trial were published in The New England Journal of Medicine in 2012. They showed that a significantly higher proportion of patients receiving tofacitinib at a dose of 5 mg or 10 mg twice daily achieved at least a 20% improvement in ACR criteria (ACR20) after 3 months of treatment compared with those receiving placebo, at 59.8% and 65.7% versus 26.7%.

ORAL Standard

Patient population: Active RA and receiving stable doses of methotrexate	Comparator treatment: Placebo
https://clinicaltrials.gov/show/NCT00853385

Also published in The New England Journal of Medicine in 2012, the ORAL Standard trial compared the efficacy of tocilizumab or the anti-tumor necrosis factor (TNF) biologic adalimumab versus placebo, finding that a significantly higher proportion of patients receiving 5 mg or 10 mg tofacitinib twice a day, or adalimumab had an ACR20 response at 6 months compared with those in the placebo group (51.5, 52.6, and 47.2 vs 28.3%).

Patients receiving tofacitinib or adalimumab also had greater reduction in disability at 3 months than those in the placebo group, and a larger proportion of patients receiving active treatment had a Disease Activity Score at 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) below 2.6 points at 6 months

ORAL Scan

Patient population: Moderate-to-severe RA; inadequate response to methotrexate	Comparator treatment: Placebo
https://clinicaltrials.gov/show/NCT00847613

The 12-month interim analysis of the ORAL Scan study, published in Arthritis & Rheumatology in 2013, showed that participants receiving tofacitinib at a dose of 5 mg or 10 mg twice daily had significantly higher ACR20 response rates at 6 months than those receiving placebo, at 51.5% and 61.8% versus 25.3%.

Patients in the 10 mg tofacitinib group also experienced significantly less worsening in radiographic joint damage – as measured by changes in total modified Sharp/van der Heijde score – from baseline to month 6 compared with those in the placebo group.

ORAL Step

Patient population: Moderate-to-severe RA; inadequate response to TNF inhibitors	Comparator treatment: Placebo
https://clinicaltrials.gov/show/NCT00960440

In ORAL Step, 3-month ACR20 response rates were significantly higher among patients receiving 5 mg or 10 mg twice daily tofacitinib compared with placebo, at 41.7% and 48.1% versus 24.4%, and patients receiving tofacitinib had significantly greater improvements in disability. All participants received background methotrexate treatment.

The ORAL Step results were published in The Lancet in 2013.

ORAL Sync

Patient population: Active RA despite treatment with nonbiologic DMARDs	Comparator treatment: Placebo
https://clinicaltrials.gov/ct2/show/NCT00856544

The results of the ORAL Sync trial were published in the Annals of Internal Medicine in 2013, and showed that ACR20 response rates at month 6 were significantly higher in the 5 mg or 10 mg twice daily tofacitinib groups compared with the placebo group. Furthermore, a greater proportion of patients receiving tofacitinib versus placebo were in remission according to DAS28-ESR scores at month 6.

ORAL Start

Patient population: Moderate-to-severe RA; no prior treatment with methotrexate	Comparator treatment: Methotrexate
https://clinicaltrials.gov/ct2/show/NCT01039688

The ORAL Start trial results showed that patients receiving either 5 mg or 10 mg of tofacitinib twice a day experienced significantly less progression in structural joint damage at 6 months than participants in the methotrexate group. Furthermore, a significantly greater proportion of participants in both tofacitinib groups achieved at least a 70% improvement in ACR criteria (ACR70) compared with those receiving methotrexate, at 25.5% and 37.7% versus 12.0%. The results were published in The New England Journal of Medicine in 2014.

ORAL Strategy

Patient population: Active RA despite methotrexate therapy	Comparator treatment: Adalimumab plus methotrexate
https://clinicaltrials.gov/ct2/show/NCT02187055

The results of the phase3b/4 ORAL Strategy trial – published in June 2017 in The Lancet – showed that tofacitinib given in combination with methotrexate, but not alone, was noninferior to adalimumab plus methotrexate. A total of 46% of participants receiving tofacitinib plus methotrexate achieved at least a 50% improvement in ACR criteria (ACR50) at 6 months, compared with 44% of patients in the adalimumab plus methotrexate group and 38% of those receiving tofacitinib monotherapy.

ORAL Sequel

Patient population: RA patients who participated in eligible phase 1, 2, or 3 studies	Comparator treatment: Tofacitinib 5 mg or 10 mg twice daily
https://clinicaltrials.gov/ct2/show/NCT00413699

Findings from the open-label ORAL Sequel long-term extension study demonstrated that tofacitinib has consistent safety and efficacy profiles over a maximum follow-up of 9.5 years. The investigators say that the safety profile was “generally similar” among patients given tofacitinib in combination with conventional DMARDs versus monotherapy.