Four clinical trial studies were reviewed including one study from a pasireotide trial [
18] and three from the SEISMIC trial [
19‐
21]. Clinical outcome assessments (COA) used across these four studies included the 36-item short form survey of quality of life (QOL; SF-36) [
21], CushingQoL [
18,
19], Beck Depression Inventory (BDI) [
18,
20], and Trail Making A and B tests (TMT A and B), a brief performance outcome (PerfO) of neurocognitive processing speed and executive functioning [
20].
Pasireotide trial
In a randomized, double-blind, phase III study involving 162 persistent/recurrent or de novo CS patients, who were treated with Pasireotide 600 μg and 900 μg subcutaneous twice daily, results from the CushingQoL and BDI were reported. Timing of the BDI assessments was not reported. HRQL was assessed at baseline and months 3, 6 and 12 using the 12-item CushingQoL questionnaire. Clinically meaningful change in CushingQoL score was estimated to be > 10.1. Overall HRQL improved for 76 patients who had a second evaluation a year later, from a mean score of 41.1 at baseline (
N = 159) to 52.5 at month 12 (
N = 76; mean increase: 11.1; 95% CI: 6.8, 15.5). In both dose groups, HRQL improved with rapid and sustained decreases in urine free cortisol (UFC) levels. Twenty-nine patients whose UFC levels were controlled had a clinically meaningful improvement in HRQL at 12 months (mean improvement: 12.8; 95% CI: 7.1, 18.5). Results are similar for 17 partially UFC controlled patients (mean improvement: 10.7; 95% CI: 0.8, 20.5). However, the improvement in HRQL did not reach the specified 10.1 change threshold in the 30 patients uncontrolled group (mean improvement: 9.9; 95% CI: 2.3, 17.6). The highest HRQL improvements (≥20 points) were seen in the five patients with the largest UFC decreases (from >10xupper limits of normal to ≤5xupper limits of normal). Significant moderate negative correlations were detected between changes in the CushingQoL scores and changes in mean UFC (
r = − 0.40;
n = 68); as well as, the BDI score (
r = − 0.59,
n = 72), (
p < 0.01). In addition, statistically significant mild positive correlations were observed between CushingQoL HRQL improvements and body mass index (BMI) and weight (
r = 0.32,
n = 74). A notable limitation of these findings is the significant amount of missing data from baseline to month 12 as results for 83 out of 159 patients were not reported [
18].
SEISMIC trial and extension
In a SEISMIC trial study, a 24-week, open-label safety and efficacy trial of mifepristone, 50 patients who were included in the trial had endogenous CS [
20]. Administered COAs included the BDI version 2 (BDI-II), TMT, and SF-36. At 24-weeks, for patients with at least mild depression at baseline (BDI-II scores of 14 or greater) median BDI-II depression scores improved from 23 (range 14–49) to 12 (range 0–34) in the modified intent-to-treat group,
p < 0.001. These scores indicate an overall improvement falling within the minimal to no depression range (a BDI-II score of zero to 12 indicates minimal depression). However, unlike mild depression patients the range of scores for patients within the severe depression range at 24-weeks indicates a persisting depression burden. Cognition scores derived from the TMT improved on the Trail A, a measure of cognitive efficiency (median decrease of 4.0 s,
p < 0.01), and Trail B, a measure of executive functioning (median decrease of 12 s, p < 0.01). The SF-36 scores significantly improved on the mental composite score (Mean = 40.0, SD = 14.5 vs. Mean = 45.4, SD = 12.5,
p = 0.01) and the physical composite score (Mean = 34.9, SD = 11.0 vs. Mean = 39.1, SD = 10.8,
p = 0.02) [
19,
20].
In another SEISMIC report of data from 46 out of the 50 CS patients, HRQL as measured by the SF-36 was reported after taking mifeprestone [
21]. At 24 weeks, statistically significant (
p ≤ 0.05) improvements in HRQL from baseline were reported for the following subscales: general health, (Mean = 4.4, SD = 8.3,
p = 0.004); physical function (Mean = 7.1, SD = 9.4,
p < 0.0001); role physical (Mean = 3.3, SD = 10.4,
p = 0.05); social functioning (Mean = 7.7, SD = 11.6,
p = 0.0003); vitality (Mean = 6.3, SD = 11.1,
p = 0.002); mental health (Mean = 4.1, SD = 10.5,
p = 0.03); role emotional (Mean = 4.9, SD = 12.4,
p = 0.03) which denotes progressive clinical improvement in patients’ physical appearance and QoL enhancement [
21].
In a report of the open label follow-up extension study from the SEISMIC trial, HRQL was measured with the CushingQoL among 23 patients with persistent or recurring CS [
19]. CushingQoL assessments were administered prior to beginning the SEISMIC study and during the extension study 6 weeks later. Change in score was calculated as % change over baseline. These twenty-three patients improved their item scores by 52% from the baseline, (
p < 0.001), and statistically significant improvements between baseline and the extension study were shown in the following areas: bruising (86%,
p = 0.037), socialization (74%,
p < 0.001), physical appearance (73%,
p < 0.001), sleep (59%,
p = 0.001), mood swings (54%,
p = 0.005), wound healing (52%,
p = 0.002), desire for leisure activities (50%, p < 0.001), illness impact on activities of daily living (45%,
p = 0.027), worries about future health (45%, p = 0.027), pain (44%, p = 0.037) and confidence (44%,
p = 0.003). Notable limitations of these findings include sampling representativeness (i.e., only 23 out of the original 50 patients in the SEISMIC trial consented to the CushingQoL administration at the 3 months study visit following extension study entry), small sample size, and the unclear report of assessment timing.