SUMMARY

• Two phase 3 studies investigated the effect of OPSUMIT in patients with digital ulcers (DUs) associated with systemic sclerosis (SSc): DUAL-1 and DUAL-2.¹
• On December 2, 2013, an independent data monitoring committee (DMC) recommended that DUAL-2 should be terminated. The DMC determined that there were no unexpected safety findings, but that additional data was unlikely to result in a positive primary outcome measure. The results from DUAL-1 and DUAL-2 are described below.¹
• Additional citations are included in the REFERENCES section for your review.^2-5

CLINICAL DATA

DUAL-1 and DUAL-2 Studies

DUAL-1 and DUAL-2 were phase 3, prospective, randomized, placebo-controlled, doubleblind, multicenter, parallel group studies to assess the efficacy, safety, and tolerability of macitentan in patients with ischemic DUs associated with SSc.^1,6,7 Patients were randomized 1:1:1 to OPSUMIT, macitentan 3 mg, or placebo once daily. Treatment allocation was stratified by number of DUs at randomization (≤3 and >3) with a block size of 6.¹

Select inclusion criteria included patients who were at least 18 years of age; physician diagnosis of SSc according to the 1980 American College of Rheumatology classification criteria⁸ with limited or diffuse cutaneous SSc⁹; at least 1 visible, active ischemic DU located at or distal to the proximal interphalangeal joint that developed or worsened within 8 weeks prior to screening; and a history of additional active DUs prior to screening (≥1 within 6 months or ≥2 within 12 months).¹ Patients were excluded if they had DUs not due to SSc, or if they had comorbidities that could affect assessment of hand function. For a full list of inclusion and exclusion criteria for DUAL-1 and DUAL-2, please refer to https://www.clinicaltrials.gov (identifiers NCT01474109 [DUAL-1] and NCT01474122 [DUAL-2]).

Both studies were designed as 2-period studies with an initial fixed 16-week period 1, followed by a period 2 of variable duration from week 16 to end of study (EOS) visit.^6,7 All patients completing period 1 continued on their original randomized treatment into period 2, until the last randomized patient completed period 1 (Figure: DUAL-1 and DUAL-2 Study Design). Patients were assessed at randomization and every 4 weeks up to week 16.¹ Between week 16 and EOS, patients were assessed every 3 months.

The primary efficacy endpoint was the cumulative number of new DUs from baseline to week 16.¹ DUs that occurred and healed between visits were not recorded as new. Complete healing was defined as complete epithelialization of the ischemic DU, regardless of residual pain. Other prespecified endpoints included the evaluation of hand function (assessed by the change between baseline and week 16 in Health Assessment Questionnaire-Disability Index [HAQ-DI]¹⁰ and Hand Disability in Systemic Sclerosis-Digital Ulcers [HDISS-DU] scores); the evaluation of DU burden (assessed by the proportion of patients with or without multiple new DUs at week 16 and by the change from baseline to week 16 in the total number of DUs); the change from baseline to week 16 in the patient and physician-reported global assessment of DU activity (severity of illness and global improvement; score range, 1-7); the proportion of patients with complete healing of all DUs at week 16; the change from baseline to week 16 in overall hand pain related to DUs (score range, 1-10); the change from baseline to week 16 in the Scleroderma Health Assessment Questionnaire visual analog scales (SHAQ-VAS; score range, 1-3) for overall global assessment of disease and for activity limitation due to DUs and to Raynaud phenomenon¹¹; and the evaluation of DU complications (assessed by the proportion of patients with DU complications at end of treatment [EOT] and the time from randomization to first DU complication up to EOT). The primary endpoint analysis was performed in the intention-to-treat population, whereas all other efficacy endpoint analyses were performed in the modified intention-to-treat population (defined as all randomized patients who received ≥1 dose of study treatment and had ≥1 post-baseline primary efficacy assessment). The safety analysis included all randomized patients who received at least 1 dose of study treatment.¹

Study Results

In the DUAL-1 study, 289 patients were randomized to receive macitentan 3 mg (n=95), OPSUMIT (n=97), or placebo (n=97). In the DUAL-2 study, 265 patients were randomized to macitentan 3 mg (n=88), OPSUMIT (n=88), or placebo (n=89). In each study, groups were balanced with respect to patient demographics, disease characteristics, and concomitant medications. In DUAL-1, the mean (range) number of DUs at baseline was 3.4 (1-13), and 201 patients (69.6%) presented with 3 or fewer DUs. In DUAL-2, the mean (range) number of DUs at baseline was 3.5 (1-18), and 180 patients (67.9%) presented with 3 or fewer DUs. DUAL-2 was terminated prematurely based on recommendations by the independent DMC due to the possibility of any benefit being small and additional data were not expected to result in a positive primary outcome.¹

DUAL-1 and DUAL-2 did not achieve the primary endpoint of a reduction of cumulative number of new DUs over 16 weeks. In DUAL-1, the adjusted mean numbers of new DUs per patient over 16 weeks were 0.94 in the macitentan 3 mg group, 1.08 in the OPSUMIT group, and 0.85 in the placebo group, and observations were similar in DUAL-2 (adjusted mean number of new DUs per patient over 16 weeks: 1.44 in the macitentan 3 mg group, 1.46 in the OPSUMIT group, and 1.21 in the placebo group).¹

In DUAL-1, the absolute difference for the cumulative number of new DUs from baseline to week 16 was 0.09 (95% CI, −0.37 to 0.54) and the rate ratio was 1.10 (95% CI, 0.661.83; P=0.71) for macitentan 3 mg vs placebo; for OPSUMIT vs placebo, the absolute difference was 0.23 (95% CI, −0.27 to 0.72) and the rate ratio was 1.27 (95% CI, 0.762.11; P=0.36). In DUAL-2, the absolute difference for the cumulative number of new DUs from baseline to week 16 was 0.23 (95% CI, -0.35 to 0.82) and the rate ratio was 1.19 (95% CI, 0.77-1.86; P=0.43) for macitentan 3 mg vs placebo; for OPSUMIT vs placebo, the absolute difference was 0.25 (95% CI, -0.34 to 0.84) and the rate ratio was 1.21 (95% CI, 0.77-1.89; P=0.41). The absence of a treatment effect was also observed in the subgroups of patients with 3 or fewer DUs at baseline vs greater than 3. In DUAL-1, 64.1% (n=59) of patients in the macitentan 3 mg group, 63.0% (n=58) of patients in the OPSUMIT group, and 67.0% (n=63) of patients in the placebo group had no new DUs by week 16. In DUAL2, 56.0% (n=47) of those in the macitentan 3 mg group, 54.8% (n=46) of patients in the OPSUMIT group, and 59.8% (n=52) of patients in the placebo group had no new DUs by week 16.¹

There were no treatment effects with either dose of macitentan vs placebo in either trial with respect to other efficacy endpoints, including hand function, DU burden, patient- and physician-reported outcomes, complete healing of DUs, and overall hand pain related to DUs and SHAQ. In all groups, patients showed reduction from baseline to week 16 in total number of DUs, severity of disease (patient- and physician-rated), pain, and interference with daily activity. There was little change in hand function. In both trials, no differences between groups were observed in time to first DU complications. DU complications were observed in 17.6% of patients in DUAL-1 and in 21.2% of patients in DUAL-2.¹

Safety and Tolerability

In both trials, patients were exposed to treatment on average for 40 weeks. In this period, the frequency of patients in DUAL-1 with at least 1 adverse event (AE) was 71.3% among those in the macitentan 3 mg group, 76.3% for OPSUMIT, and 73.2% for the placebo group, and in DUAL-2, the frequency of patients with at least 1 AE was 83.0% among those in the macitentan 3 mg group, 85.1% for OPSUMIT, and 78.7% for the placebo group. The most frequently reported AEs (incidence rate, 10% and >3% difference between placebo and either macitentan group) in each trial were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis. AEs leading to premature discontinuation occurred in 13.8% of patients in the macitentan 3 mg group, 14.4% for OPSUMIT, and 10.3% of patients in the placebo group in DUAL-1, and in DUAL-2, AEs leading to premature discontinuation occurred in 9.2% of patients in the macitentan 3 mg group, 17.2% for OPSUMIT, and 14.6% of patients in the placebo group. Skin ulcer, infected skin ulcer, and increased alanine transaminase (ALT)/aspartate aminotransferase (AST) were the most frequently reported AEs leading to treatment discontinuation. Incidences of serious AEs in DUAL-1 were 18.1% in the macitentan 3 mg group, 14.4% for OPSUMIT, and 13.4% in the placebo group, and in DUAL-2, 11.4% in the macitentan 3 mg group, 24.1% for OPSUMIT, and 14.6% in the placebo group, with infections being the most common. There was 1 death due to cardiac arrest in DUAL-1 in a patient receiving OPSUMIT. There were 2 deaths (1 due to unspecified natural causes and 1 due to cardiac failure) in DUAL-2. Both patients were in the OPSUMIT group. All deaths were considered unrelated to study treatment. There were no differences in ALT, AST, bilirubin, or hemoglobin between study groups.¹

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 20 January 2025.