Abstract
Objective:
We evaluated the safety and efficacy of metyrapone treatment for Cushing’s syndrome (CS).
Design:
International, prospective, single-arm, open-label study.
Methods:
Fifty adults with endogenous CS (either unsuitable for or uncontrolled after surgery) and 3 urinary free cortisol (UFC) concentrations each ≥1.5-fold the upper limit of normal (ULN) were enrolled. After 12 weeks of metyrapone titration, participants with mean 24 h UFC (mUFC) ≤ 2-fold ULN could enter a 24-week extension phase. Safety was assessed, and doses adjusted at weeks 1–5, 8, 12, and 24. Pre-defined endpoints included normalization of mUFC at weeks 12 (primary), 24, and 36, and proportion of “responders” (normalization or ≥50% decrease of baseline mUFC), time to eucortisolemia, salivary cortisol day-curve, and quality of life (QoL).
Results:
Of the 49 evaluable participants, 47 completed the 12-week visit; 40 were evaluated at week 24 and 35 at week 36. The primary endpoint was met in 46.9% of participants (95% CI 32.5%−61.7%), with efficacy maintained at week 24 (52.5%; 95% CI 37.5%−67.1%) and week 36 (48.6%; 95% CI 33.0%−64.4%). The responder rates were 80.9%, 77.5%, and 71.4% at weeks 12, 24, and 36, respectively. Forty-seven participants (94%) developed mild-to-moderate adverse events (AEs), mostly during the first 12 weeks and most commonly nausea (38%), fatigue (26%), and headache (22%); 8 experienced severe AEs. Six participants developed reversible adrenal insufficiency during titration. Clinical features and QoL improved.
Conclusion:
Metyrapone is a safe and effective treatment for endogenous CS.
Keywords: Cushing’s syndrome, late-night salivary cortisol, metyrapone, urinary free cortisol
Introduction
Endogenous Cushing’s syndrome (CS) is a rare disorder characterized by chronic exposure to excess cortisol. It may be caused by excessive adrenocorticotropic hormone (ACTH) production from a pituitary tumor (Cushing’s disease, CD) or a non-pituitary tumor (ectopic ACTH secretion [EAS]), or by autonomous cortisol secretion from 1 or both adrenal glands.1,2
CS increases morbidity and mortality.3 First-line surgical resection4 of the causal lesion(s) is not always feasible due to patient condition, unresectable disease, or occult tumors. Second-line medical therapy may control hypercortisolism and avoid permanent adrenal insufficiency resulting from bilateral adrenalectomy. Current medical treatment options include drugs targeting the pituitary, adrenal gland, or glucocorticoid receptors with variable adverse effects and efficacy.5 There is still an unmet need for other options.
Metyrapone inhibits 11β-hydroxylase, reducing cortisol production and increasing 11-deoxycortisol, its immediate precursor. This ability to reduce cortisol production has been exploited for CS treatment, for which it can be effective and well tolerated.6,7 Metyrapone’s most common adverse events (AEs) are mild and transient, including gastrointestinal AEs and signs of hypoadrenalism (eg, dizziness and hypotension). The main treatment-related risk is adrenal insufficiency, as for all steroidogenesis inhibitors.6
Apart from 2 cohort studies,8,9 previous reports regarding metyrapone treatment of CS were retrospective.6 Additionally, the response to metyrapone was assessed either by immunoassays that cross-reacted with 11-deoxycortisol (potentially under-estimating the rate of cortisol normalization7) or by liberal response criteria that over-estimated normalization of cortisol production.10 Here, we report findings from our prospective study that evaluated whether metyrapone can safely normalize mean 24 h urinary free cortisol (mUFC) levels in patients with CS, as assessed by liquid chromatography/tandem mass spectrometry (LC-MS/MS).
Methods
Study design
PROMPT (ClinicalTrials.gov identifier: NCT02297945) was a PROspective, single-arm, open-label, multicenter international study to assess the ability of MetyraPone Treatment to normalize mUFC in patients with endogenous CS. Participants underwent a 12-week titration period. Those with a mUFC < 2-fold the upper limit of normal (ULN) and clinical improvement at week 12 could enter a 24-week extension phase (Figure S1).
The study was conducted at 21 centers in 8 countries according to the Declaration of Helsinki and Good Clinical Practice guidelines. An institutional review board/independent ethics committee approved the protocol at each site. All participants gave written informed consent.
We recruited adults with de novo CS deemed unsuitable for surgery or with persistent or recurrent disease after surgery; those taking medical treatment underwent a washout period (Supplementary Methods; Figure S1). Active CS was confirmed by 3 UFC measurements ≥ 1.5-fold ULN during the screening period. Exclusion criteria included cyclic CS, certain malignancies, pregnancy, and various medical conditions or confounding treatments (Supplementary Methods).
Procedures
After the screening and baseline visits, participants returned to the study site at weeks 1, 2, 4, 8, 12, 24, and 36 (plus optional visits at weeks 3 and 5) for blood collection and to provide 24 h urine collection. For the baseline and week 1, 12, and 36 visits, salivary samples were collected using Salivette® Cortisol containers before breakfast (~0600 h) and at 1100 h, 1300 h, 1500 h, 1800 h, and 2300 h. Cushing’s Quality of Life (CSQoL)11 and Tuebingen CD Quality of Life12 questionnaires were completed at baseline and weeks 4, 12, 24, and 36.
The initial daily dose of metyrapone (250 mg Metopirone® capsules, HRA Pharma Rare Diseases, Châtillon, France) was 750 mg for UFC ≤ 5-fold ULN and 1500 mg for UFC > 5-fold ULN, divided into 3 or 4 doses spaced over the day; if the daily dose could not be divided equally, the highest dose was taken at bedtime.
Dose adjustment at weeks 1–5, 8, 12, and 24 was based on efficacy and tolerability. The treatment goals were a normal mUFC (≤165 nmol/24 h by 3 or 2 measurements at weeks 12 and 24, respectively, or 1 measurement) and/or a pre-dose serum cortisol value of 193–330 nmol/L (7–12 μg/dL) without adrenal insufficiency. The serum cortisol target range was chosen based on the assumption that a morning value would approximate the 24 h mean because of decreased diurnal variation in CS. In young men (who have the highest day-time cortisol levels), the mean daily cortisol level is approximately 218 nmol/L (7.9 g/dL).13 Based on this, and recognizing that LC-MS/MS reads lower than immunoassays, the serum cortisol target was chosen to avoid adrenal insufficiency and remain within the normal range. Participants with lower values or features of adrenal insufficiency were considered over-treated; in those with initial UFC < 5-fold ULN, the daily dose was decreased by 250–500 mg, and in those with higher initial values, it was decreased by 500–1000 mg or temporarily withheld. Conversely, participants with cortisol levels above the target thresholds were considered under-treated; their daily metyrapone dose was increased to a maximum of 6000 mg, by the same dosage changes used in over-treated participants. Off-schedule adjustments were allowed.
Endpoints
The primary endpoint was normalization of mUFC at week 12. The key secondary endpoints were mUFC normalization at weeks 24 and 36, and the proportion of “responders” (defined as participants with complete response [normal mUFC] or partial response [mUFC > ULN but ≥50% decrease from baseline]) at weeks 12, 24, and 36. Other secondary endpoints included change from baseline in mUFC, time to eucortisolemia, salivary cortisol day-curve, and patient-reported outcomes (symptoms, change in total score on the CSQoL11 and Tuebingen CD Quality of Life12 questionnaires). Seated blood pressure (mean of 3 consecutive measures performed at each visit) was also measured. Additional secondary endpoints included cardiovascular and metabolic CS-related parameters (fasting plasma glucose and insulin; glycated hemoglobin; total, high- and low-density lipoprotein cholesterol; and triglycerides; weight; body mass index; and waist circumference).
Safety endpoints included 12-lead electrocardiogram read centrally, laboratory endpoints (alanine transaminase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], bilirubin, electrolytes, serum creatinine), and AEs.
All hormones were measured using LC-MS/MS by a central laboratory (Department Clinical Biochemistry, University Hospital of South Manchester), except for local immunoassays for insulin. UFC, serum, and/or salivary cortisol could be measured on-site to facilitate rapid dose adjustment; for these analytes, only central laboratory results are presented. The parameters of each analyte are provided in the Supplementary Methods.
Investigators graded AEs as mild, moderate, or severe, and coded them according to the Medical Dictionary for Regulatory Activities, version 18.1. Attention was paid to hypertension, edema, and hypokalemia, which may occur in response to increased 11-deoxycortisol or deoxycorticosterone concentrations (due to 11-beta-hydroxylase blockade), as well as hirsutism, potentially caused by accumulation of adrenal androgens. Per protocol, adrenal insufficiency was diagnosed if low cortisol levels were accompanied by biochemical and clinical features (anorexia, nausea, vomiting, diarrhea, fatigue, hypotension, hyponatremia, and/or hyperkalemia) and reported as a serious AE (SAE). There was no Data and Safety Monitoring Board.
Participants provided their medication bottles at each visit, at which compliance with metyrapone treatment was assessed by capsules count.
Statistical analysis
The planned sample size of 55 participants was derived from a desired precision of ±12.5% from the previously published rate of effective metyrapone-induced serum cortisol reduction (70%).10 The safety population comprised all participants who took metyrapone and had at least 1 safety assessment. The modified intent-to-treat (mITT) population (participants who received at least 1 dose of metyrapone and had at least 1 subsequent UFC measurement) was assessed for all pre-specified analyses. The last observation (at days 56 and 60) was carried forward for the 2 participants who dropped out.
Pre-specified analyses included the exact 95% CI of the proportion of participants with normal mUFC at week 12 (primary endpoint) and the proportion of responders (normal mUFC or ≥50% decrease in mUFC from baseline) at weeks 12, 24, and 36. Changes in mUFC from baseline were analyzed using a mixed model for repeated measures (MMRM), with time (3 levels: week 1, 12, 24, and 36) as a fixed effect. A Huynh-Feldt covariance matrix was employed to account for within-participant correlations across repeated measures. Salivary cortisol day-curves were assessed using a linear MMRM, with the log-transformed salivary cortisol level as the dependent variable and time of day as the fixed effect, and by comparing participants’ AM:PM ratio with the minimum normal AM:PM reference ratio of 1.92 (reference range AM = 5–46 nmol/L, PM < 2.6 nmol/L; ratio 5/2.6 = 1.92).14 Time to eucortisolemia was assessed by Kaplan-Meier analysis. Concordance between endpoints was evaluated by Kappa coefficient analysis.
Data are shown as means with SD or SE, medians with interquartile ranges (IQR) and/or ranges, and proportions as percentiles with 95% CIs. Statistical analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC, USA) and Prism, version 9.4.1 for macOS (GraphPad Software, San Diego, CA, USA).
Results
Participants
Between April 15, 2015 and May 31, 2019, 50 of the 89 patients screened (56.2%) met the eligibility criteria and received at least 1 dose of metyrapone (safety population). The mITT population included 49 participants, excluding 1 patient who discontinued participation without post-baseline UFC data. Forty-seven participants completed the week 12 visit, and 41 entered the extension study, of whom 40 were evaluated at week 24 and 35 at week 36 (Figure 1).
Figure 1.
Flow chart of study participants. aSAE was septic shock and pneumonia. bSurgery was transsphenoidal surgery or bilateral adrenalectomy for CS. cSAE was growth of remnant pituitary. dAE was hirsutism and edema. eSAEs were bilateral acute angle closure glaucoma (n = 1) and hypotension associated with respiratory arrest, cellulitis, renal failure, and possible pulmonary embolism (n = 1). AE, adverse event; CS, Cushing’s syndrome; mITT, modified intent to treat; SAE, serious adverse event; UFC, urinary free cortisol.
Participants’ median age was 47 years (Table 1). There were more women (n = 34) than men (n = 15), and CD (n = 44/49) was the most common cause of CS. At baseline, mUFC was nearly 14-fold ULN. Most participants (63.3%) had moderate hypercortisolism; 4.1% and 32.7% had mild and severe hypercortisolism, respectively. Previous treatments included medical therapy (n = 29), and/or pituitary surgery (n = 30) and irradiation (n = 5) among participants with CD.
Table 1.
Demographic and baseline characteristics of the modified intent-to-treat population (mITT, N = 49).
| Characteristics | N = 49 |
|---|---|
| Median [range] age, years | 47 [22–73] |
| Age ≥ 65 years, n (%) | 6 (12.2) |
| Women, n (%) | 34 (69.9) |
| Median [range] BMI, kg/m2 | 27.7 [22.5–55.4] |
| Race White, n (%) | 49 (100.0) |
| Cause of Cushing’s syndrome, n (%) | |
| Cushing’s disease | 44 (89.8) |
| Ectopic ACTH secretiona | 4 (8.2) |
| Bilateral adrenal hyperplasia | 1 (2.0) |
| Cushing’s syndrome morbidities, n (%) | |
| Hypertension | 34 (69.4) |
| Dyslipidemia | 20 (40.8) |
| Osteoporosis | 20 (40.8) |
| Diabetes mellitus | 21 (42.9) |
| Disease duration and previous treatment | |
| Median [range] time since symptom start, years | 3.9 [0.3–21.8] |
| Previous pituitary irradiation (CD only, n = 44), n (%) | 5 (11.4) |
| Previous pituitary surgery (CD only, n = 44), n (%) | 30 (68.2) |
| Median [range] time since surgery, years | 1.41 [0.1–20.9] |
| Previous medical treatment, n (%) | 25 (51.0) |
| Mean (SD) 24 h UFC, nmol/24 h | 1041.7 (1336.9) |
| Median [range] mUFCb, nmol/24 h | 570 [291–8476] |
| Disease severity, n (%) | |
| Mild hypercortisolismc | 2 (4.1) |
| Moderate hypercortisolismd | 31 (63.3) |
| Severe hypercortisolisme | 16 (32.7) |
| Median [range] salivary cortisol day-curve, nmol/Lf | 14.7 [3.2–96.6] |
| Median [range] late-night salivary cortisol (2300 h), nmol/L | 12.4 [1.2–64.7] |
Abbreviations: ACTH, adrenocorticotropic hormone; BMI, body mass index; CD, Cushing’s disease; mUFC, mean 24 h urinary free cortisol; SD, standard deviation; ULN, upper limit of normal.
Cause unknown in all 4 patients; no underlying malignancy detected.
mUFC = mean of 3 collections, ULN for UFC = 165 nmol/24 h.
mUFC > 1.5 to ≤2.0-fold ULN, 291–330 nmol/24 h.
mUFC > 2.0 to ≤5-fold ULN, 330–825 nmol/24 h.
mUFC > 5-fold ULN, 825–8476 nmol/24 h.
Median salivary day-curve uses all results from pre-breakfast (~0600 h) to 2300 h; normal ranges: 0800–0900 h, 5.0–46.0 nmol/L; 2300–0000 h, ≤ 2.6nmol/L.
Compliance was assessed in 48 participants, with a compliance rate of >90% (46/48).
Efficacy
Titration phase (to week 12)
At week 12, 23/49 participants (46.9%, 95% CI 32.5–61.7) had normal mUFC (met the primary endpoint) at a median metyrapone dose of 1500 mg/day (Table 2; Figure 2A). This included 20/44 (46%) with CD, 2/4 (50%) with EAS, and the 1 participant with bilateral adrenal hyperplasia. Mean (SE) change in mUFC from baseline to week 12 was −679.1 (68.7) nmol/24 h (Figure 2B), corresponding to a 65.2% decrease in mUFC. When the 5 participants who received previous radiotherapy were excluded, 21/44 participants (47.7%; 95% CI 32.7–63.1) had normal mUFC.
Table 2.
The proportion of participants with normal mean 24-h urinary free cortisol (mUFC) values (and median time to eucortisolemia), the proportion who were responders (and the median time to response), the proportion with normal late-night salivary cortisol (LNSC) values, and the median mUFC and adrenocorticotropic hormone (ACTH) values throughout the study.
| Baseline | Week 12 | Week 24 | Week 36 | P-valuea | |
|---|---|---|---|---|---|
| Normal mUFC,b n/N | 0/49 | 23/49 | 21/40 | 17/35 | NS |
| Percent [95% CI] | 0 | 46.9 [32.5–61.7] | 52.5 [37.1–67.1] | 48.6 [33.0–64.4] | |
| Median time to eucortisolemia,c days [95% CI] | 34.0 [16.0–57.0] | — | |||
| Responders,d n/N | 0/49 | 38/47 | 31/40 | 25/35 | ND |
| Percent [95% CI] | 0 | 80.9 [67.5–89.6] | 77.5 [62.5–87.7] | 71.4 [54.9–83.7] | |
| Median time to response,c days [95% CI] | 14.0 [8.0–15.0] | — | |||
| Normal LNSC,e n/N | 1/47 | 10/46 | ND | 9/33 | ND |
| Percent [95% CI] | 2.1 [0.4–11.1] | 21.7 [12.3–35.6] | — | 27.3 [15.1–44.2] | |
| Median (range) mUFC, nmol/24 h | 570.3 (291.0–8476.2) | 171.3 (5.0–816) | 160.2 (5.0–710.0) | 173.0 (5.0–810.0) | <0.0001 |
| Median (range) ACTH, ng/L | 40.0 (10.0–211.0) | 40.5 (6.0–286.0) | ND | 40.0 (5.0–461.0) | NS |
Abbreviations: CI, confidence interval; ND, not determined; NS, not significant.
Significance between timepoints was calculated by repeated measures method.
Defined as mUFC ≤ 165 nmol/24 h by 3 or 2 measurements at weeks 12 and 24, respectively, or 1 measurement.
Kaplan Meier Analysis. N = 49; with 14 (time to eucortisolemia) and 3 (time to be a responder) censored events, respectively.
Responders were participants who either achieved a mUFC < ULN or had ≥50% decrease in UFC from baseline.
8/44 participants (18.2%) had normal LNSC at week 1 (95% CI 8.7–33.2).
Figure 2.
Mean 24 h urinary free cortisol (mUFC) response to metyrapone (A) during the titration phase (baseline to week 12; mean [SE] 1041.7 [200] to 249.0 [68.7] nmol/24 h, respectively; median [range] 570 [291–8476] to 171.3 [5.0–816.0] nmol/24 h, respectively); and (B) mean change from baseline during the titration phase (to week 12) and extension phase (to week 36). In (A), each vertical set of data points is for an individual study participant, with the blue cross representing baseline and the red circle week 12. In (B), the bars indicate standard error. Estimate corresponds to change from baseline at each timepoint. SE, standard error; ULN, upper limit of normal.
The median time to eucortisolemia was 34.0 days (95% CI 16.0–57.0 days; Table 2).
From baseline to week 12 the proportion of participants with mUFC > 2- and >5-fold ULN decreased (from 63.3% to 10.6% and from 32.7% to 0%, respectively) and the proportion of participants with mUFC < 2-fold ULN increased (from 4.1% to 40.4%; P < .001 [chi-squared test]; Figure S2).
Extension phase (to week 36)
The normalization in mUFC at week 12 was maintained throughout the 24-week extension period (Table 2).
In contrast to the initial titration phase, the only dose adjustment during the extension phase was scheduled at week 24. Nine of 17 participants with elevated mUFC at week 24 had a dose increase at that visit or later, but mUFC remained elevated at week 36 in 7 participants (mUFC remained high in 1 participant despite multiple dose adjustments; Figure 3A).
Figure 3.
Swimmer plots of individual participant’s values at baseline and weeks 12, 24, and 36 for (A) for mean 24 h urinary free cortisol (mUFC) and (B) for plasma adrenocorticotropic hormone (ACTH) levels (except week 24) during metyrapone treatment. The values on the central x-axis represent the final total daily dose of metyrapone (mg) for each participant. In (A), the horizontal dotted line at 165 nmol/24 h denotes the UFC upper limit of normal (ULN) for UFC and the second horizontal line at 330 nmol/24 h represents 2-fold ULN. The vertical dotted lines link values at baseline, week 12, and week 36. The light arrows indicate metyrapone dose adjustment between weeks 24 and 36 (extension phase), and the dark arrows indicate no dose adjustment. At week 36, abnormal values are shown as a dark diamond and normal values as a light diamond. The asterisk denotes 1 participant in whom the metyrapone dose was adjusted up and down many times during the extension phase. In (B), the horizontal dotted line at 46 pg/mL denotes the ULN for ACTH. The vertical dotted line arrow denotes the single participant with ectopic ACTH syndrome who finished the study. The solid line arrows indicate participants with Cushing’s syndrome whose elevated baseline ACTH levels increased to >3-fold ULN, while the dashed line arrows indicate participants with CD whose elevated ACTH values improved during the study. Values are missing for 1 participant.
The proportion of responders (key secondary endpoint) was 81% (38/47 participants) at week 12, 78% (31/40) at week 24, and 71% (25/35) at week 36 (Table 2; Figure 4). The median time to response was 14.0 days (95% CI 8.0–15.0 days).
Figure 4.
Participants with response at weeks 12, 24, and 36. Complete response was defined as normalized mean 24 h urinary free cortisol (mUFC; < the upper limit of normal [ULN]); partial response as a ≥50% decrease in mUFC from baseline but still >ULN; non-response as a <50% decrease in mUFC from baseline.
The salivary cortisol day-curve decreased significantly at all timepoints starting at week 1 (P = .02), with a nadir at week 12 (P < .0001) that was maintained at week 36 (P = .0033; Figure 5). The proportion of participants with a normal late-night (2300 h) salivary cortisol (LNSC) progressively increased from baseline to week 36 (Table 2), while the rate of abnormal diurnal cortisol excursions (AM:PM salivary cortisol < 1.9214) decreased from week 1 (74%; 32/43) to week 36 (45%; 15/33; P = .019). The concordance between LNSC and mUFC was weak (k = −0.19 at week 12 and −0.20 at week 36).
Figure 5.
Mean salivary cortisol day-curve by visit during the study, using a linear mixed model for repeated measures with log-transformed salivary cortisol as the dependent variable and time of day as fixed effect. The bars indicate standard error.
Mean ACTH levels were unchanged during the study (Table 2), although individual participant data showed increases that were not associated with UFC normalization (ie, “escape”; Figure 3B). When participants who had undergone previous radiotherapy were excluded, there was a significant correlation between the ACTH level and metyrapone dose at 36 weeks (P = .048). CS signs and symptoms and metabolic function parameters improved or normalized (Table 3). Consistent with these findings, scores for the Tuebingen CD and CSQoL questionnaires improved during the study (Figure S3a and b). The clinically relevant CSQoL score change of >10.1 was nearly achieved at week 12 and was met at weeks 24 and 36. Changes in weight and waist circumference are reported in the Supplementary Results.
Table 3.
Metabolic parameters and clinical signs of Cushing’s syndrome during the study.
| Metabolic parametersa | Baseline | Week 12 | Week 36 |
|---|---|---|---|
| FPG, median [range], mmol/L | 5.1 [3.9–11.3] | 5.2 [3.2–8.0] | 50 [3.4–8.0] |
| >ULN values, n/N (%) | 12/45 (26.7) | 9/44 (20.5) | 9/35 (25.7) |
| HbA1c, mean (SD), % | 5.7 (1.2) | 5.4 (1.0) | 5.4 (0.9) |
| >ULN values, n/N (%) | 21/47 (44.7) | 11/40 (27.5) | 11/36 (30.6) |
| Fasting insulin, median [range], pmol/L | 93.4 [13.9–287.8] | 83.0 [20.1–376.4] | 78.3 [17.2–239.6] |
| >ULN values, n/N (%) | 9/46 (19.6) | 8/38 (21.1) | 6/30 (20.0) |
| Total cholesterol, mean (SD), mmol/L | 5.7 (1.4) | 5.0 (1.2) | 4.9 (1.1) |
| >ULN values, n/N (%) | 28/48 (58.3) | 17/41 (41.5) | 14/36 (38.9) |
| HDL-C, mean (SD), mmol/L | 1.5 (0.4) | 1.2 (0.3) | 1.2 (0.3) |
| >ULN values, n/N (%) | 4/48 (8.3) | 2/41 (4.9) | 1/36 (2.8) |
| LDL-C, mean (SD), mmol/L | 3.5 (1.2) | 3.1 (1.0) | 3.1 (1.0 |
| >ULN values, n/N (%) | 28/46 (60.9) | 17/38 (44.7) | 14/31 (45.2) |
| Triglycerides, median [range], mmol/L | 1.5 [0.5–6.6] | 1.7 [0.4–8.4] | 1.4 [0.61–5.9] |
| >ULN levels, n/N (%) | 16/48 (33.3) | 15/41 (36.6) | 10/36 (27.8) |
| SBP,b mean (SD), mmHg | 133.6 (19.7) | 130.3 (16.8) | 132.8 (16.1) |
| DBP,b mean (SD), mmHg | 86.2 (12.5) | 83.2 (11.4) | 84.6 (10.3) |
| Clinical signs and symptomsc | Baseline | Week 2 | Week 12 | Week 24 | Week 36 |
|---|---|---|---|---|---|
| Improvement/normal CS clinical signs, n/N (%) | — | 23/47 (48.9) | 31/47 (36.0) | 25/40 (62.5) | 28/36 (77.8) |
| Hirsutism in women,d n/N (%) | 20/33 (60.6) | ND | 20/33 (60.6) | 18/27 (66.7) | 16/24 (66.7) |
| >ULN testosterone levels in women, n/N (%) | 2/32 (6.3) | ND | 26/32 (81.3) | ND | 21/24 (87.5) |
Abbreviations: DBP, diastolic blood pressure; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ND, not determined; SBP, systolic blood pressure; SD, standard deviation; ULN, upper limit of normal.
Normal range values: FPG = 3.33–5.55 mmol/L; HbA1c = 2.0%−4.2%; fasting insulin 0.0–104.0, pmol/L; total cholesterol = 0.0–4.92 mmol/L; HDL-C > 1.0 mmol/L (men) > 1.2 mmol/L (women); LDL-C = 0.0–3.0 mmol/L; triglycerides = 0.0–1.70 mmol/L.
Week 36 values included 3 participants whose last measurement was on week 24.
Signs and symptoms of CS at baseline were: supraclavicular fullness (n = 40 [81.6%]), facial plethora (n = 36 [73.5%]), dorsocervical fat pad (n = 33 [67.3%]), presence of bruising (n = 19 [38.8%]), and presence of violaceous striae (n = 16 [32.7%]).
Assessed by Ferriman-Gallwey score.15
Safety
Forty-seven participants (94.0%) experienced 322 AEs with any relationship to metyrapone, 237 (74%) of which occurred by week 12 (Table 4), with only 85 AEs (26%) during the 24-week extension period. The most common AEs were nausea (38%), fatigue (26%), and headache (22%). AEs were mostly mild-to-moderate in severity; 5 participants discontinued the study because of AEs.
Table 4.
Summary of adverse events during the titration phase (to 12 weeks) and cumulative events from baseline to 36 weeks.
| By week 12 | By week 36 | |||
|---|---|---|---|---|
| AEs, n | Participants, n (%) | AEs, n | Participants, n (%) | |
| Any AE | 237 | 42 (84.0) | 322 | 47 (94.0) |
| Drug-related AE | 89 | 26 (52.0) | 122 | 31 (62.0) |
| SAEa | 12 | 10 (20.0) | 21 | 12 (24.0) |
| Severity of AEs | ||||
| Mild | 181 | 35 (70.0) | 239 | 40 (80.0) |
| Moderate | 51 | 25 (50.0) | 68 | 28 (56.0) |
| Severe | 5 | 4 (8.0) | 15 | 8 (16.0) |
| Death | — | 0 | — | 0 |
| Most common (≥10% of participants) AEs (regardless of relationship with metyrapone)b | ||||
| Nausea | 24 | 16 (32.0) | 30 | 19 (38.0) |
| Dyspepsia | 4 | 3 (6.0) | 6 | 5 (10.0) |
| Diarrhea | 4 | 3 (6.0) | 8 | 5 (10.0) |
| Decreased appetite | 12 | 9 (18.0) | 14 | 9 (18.0) |
| Fatigue | 19 | 9 (18.0) | 32 | 13 (26.0) |
| Arthralgia | 9 | 5 (10.0) | 12 | 6 (12.0) |
| Headache | 19 | 10 (20.0) | 24 | 11 (22.0) |
| Dizziness | 6 | 6 (12.0) | 7 | 7 (14.0) |
| Hypertension | 7 | 6 (12.0) | 9 | 7 (14.0)c |
| Adrenal insufficiencyd | 6 | 6 (12.0) | 6 | 6 (12.0) |
| Peripheral edema | 8 | 6 (12.0) | 9 | 6 (12.0) |
| AEs leading to treatment discontinuation | ||||
| Related to study drug | 0 | 0 | 7 | 3 (6.0) |
| Not related to study drug | 4 | 3 (6.0) | 0 | 1 (2.0) |
Events are shown as the number of events (n) and as the number of study participants experiencing at least 1 event among the safety population of 50 study participants in each time period.
Abbreviations: AE, adverse event; SAE, serious adverse event.
SAEs considered related to metyrapone included adrenal insufficiency (n = 5 events), hypokalemia (n = 1 event), respiratory arrest (n = 1 event), closed angle glaucoma (n = 1 event), and pulmonary embolism, respiratory arrest, hypotension, renal failure, and cellulitis (all same participant, n = 1 event).
Other AEs included hirsutism (9% of women), asthenia (8%), hypokalemia (6%), and acne (4%).
Severity of hypertension was mild in 5 participants and moderate in 2 participants.
Adrenal insufficiency diagnosis required both clinical features and biochemical validation and was required to be reported as an SAE; of these AEs, 5 were moderate and 1 was severe.
During the titration period, 26 participants (52%) had AEs likely related to metyrapone exposure. Most were consistent with hypocortisolism. Reversible adrenal insufficiency occurred in 6 participants (12.0%) during titration and was managed by dose adjustments (n = 2) or treatment interruption (n = 4), with/without short-term hydrocortisone treatment. Hypocortisolism symptoms without biochemically confirmed adrenal insufficiency led to temporary drug discontinuation (n = 5) or dose decrease (n = 4).
By week 36, 21 SAEs were reported in 12/50 participants. Six of 12 SAEs during titration were considered related to metyrapone (adrenal insufficiency [n = 5] and hypokalemia [n = 1]). Six others (adrenal insufficiency, pneumonia, septic shock, urinary tract infection, worsening of rheumatoid arthritis, and recurrent pituitary tumor) were considered unrelated to metyrapone exposure. Nine SAEs were reported during the extension period; all resolved without sequelae. There were no deaths.
Testosterone levels were > ULN in 6.3%, 81.3%, and 87.5% of women at baseline, week 12, and week 36, respectively, corresponding to an increase from baseline of 1.9- and 2.8-fold ULN, respectively. However, hirsutism rates (by Ferriman-Gallway scores15) were similar at baseline and week 36 (60.6% [20/33] and 66.7% [16/24], respectively; Table 3).
QT interval corrected for heart rate by Fridericia’s cube root formula (QTcF) remained <480 ms in all participants, including 3 with an asymptomatic increase of >60 ms from baseline.
As per investigator judgment, worsening of pre-existing hypertension occurred in 7 participants, mostly during titration (n = 6); this resolved spontaneously in 4 and after medication change in 3 participants. Peripheral edema resolved spontaneously (n = 1) or with diuretic therapy (n = 4). Another participant, whose edema was related to joint pain, received non-steroidal anti-inflammatory therapy. Four participants developed mild or moderate hypokalemia (2.80–3.11 mEq/L) during titration that resolved with supplementation or diuretic discontinuation. The proportion of participants with hypokalemia and the rates of potassium supplementation were unchanged during the study. Nearly all baseline elevations in ALT (11/11), AST (2/2), and GGT (5/12) normalized during treatment or remained <3-fold ULN.
Discussion
In this single-arm, multicenter, prospective, 9-month study, the primary endpoint of normal mUFC at week 12 was met by almost 50% of the study participants (46.9%). The mUFC normalization rate remained similar after exclusion of participants who underwent prior radiotherapy, indicating that radiation did not affect these results. Normalization of mUFC was maintained in 48.6% of participants during the 24-week extension phase. In addition, 80.9%, 77.5%, and 71.4% of participants were responders at weeks 12, 24, and 36, respectively.
Evidence for the efficacy of metyrapone in the treatment of CS has been demonstrated in other prospective8,9,16 and retrospective studies,7,17–20 as well as case series and individual case reports. Given that these studies have been conducted using different response criteria and assays and in patients with differing characteristics, comparisons between studies should be considered carefully. Nevertheless, the efficacy findings reported here are in line with already published studies, showing reductions in UFC and/or serum cortisol levels and improvement in clinical features and cortisol-related comorbidities in most patients.7–10,20
As UFC does not provide information on circadian fluctuations in cortisol, salivary cortisol day-curves were obtained. At baseline, participants showed a flat cortisol day-curve with a loss of the LNSC nadir. During metyrapone treatment, LNSC improved significantly as early as week 1, and decreased further through week 36. Ceccato and colleagues observed normal LNSC in 37% of patients,8 while the LNSC normalization was numerically lower in our study (27.3%). In theory, the near-even spacing of metyrapone administration should result in similar suppression of cortisol throughout the day, which would result in very low morning cortisol levels if the diurnal rhythm were absent at baseline. Thus, LNSC as a treatment target may increase the risk of adrenal insufficiency unless a lower morning dose of a short-acting agent is used.
In our study, frequent metyrapone dose adjustments up to week 12 allowed for rapid improvement in UFC, beginning 1 week after treatment initiation. However, subsequent dose adjustments were not scheduled until week 24, at which point not all protocol-advised adjustments were made. Indeed, the variability in UFC between weeks 24 and 36 in some participants who did not undergo dose titration suggests that outcomes may have been further improved if dose up-titration had been conducted for participants with abnormal UFC levels. Additionally, the known variability of UFC in patients with CD21 potentially explains the lack of normalization observed in some participants, even in those who received an increased dose. Thus, efficacy might have been improved if dose escalations had been performed as per protocol and if dose adequacy was checked after up-titration. Optimization of metyrapone treatment may require additional strategies to improve efficacy, including use of block-and-replace, chronotherapy (time-adjusted dosing), and combination therapy approaches.
The favorable safety profile of metyrapone was confirmed in this study. Most AEs occurred during the first 12 weeks of treatment and decreased in frequency over time. AEs were generally mild-to-moderate in intensity, and SAEs resolved without sequelae.
The rate of adrenal insufficiency (12%) was similar to previously reported rates of 7%22 and 11%.10 Another study reported no adrenal insufficiency, possibly because of lower metyrapone doses.8
QTc prolongation was not reported in our study. Although slight (but significant) decreases in blood pressure occurred, further analyses of cardiovascular parameters are warranted, specifically in patients with hypertension at baseline and in those with improvement in blood pressure during the study.
This study had some limitations, including its relatively small sample size and limited number of participants with adrenal or EAS etiologies (10.2% compared with approximately 19% in other studies), reducing our ability to extrapolate these results to other causes of CS.7,8,10 However, as metyrapone acts by inhibiting cortisol synthesis, it is likely that the drug would work equally well in other patients with similarly elevated cortisol levels. Although endpoint data were based on central laboratory measurements to limit variability, there may have been some differences between centers in local cortisol assays that resulted in variations in metyrapone dose adjustment. As discussed earlier, dose titration during the extension phase was applied less often than in the first 12 weeks.
It should be noted that our study did not include a placebo-comparison group, due to ethical concerns regarding the use of placebo over 36 weeks. By design, this study did not exclude individuals with severe hypercortisolism. There are medical and ethical concerns that including such individuals in placebo-controlled studies exposes them to the well-known risks of pulmonary embolism and infection, which are increased by severe hypercortisolism. This study included individuals with severe hypercortisolism so that the true efficacy of titration over the full range of cortisol levels could be evaluated.23
Various factors mitigate against bias in this uncontrolled study. The inclusion criteria required that all screening UFC values were >1.5-fold ULN, in contrast to other studies that allowed normal or near normal UFC values.22,24,25 This requirement helped to exclude patients with cyclic CS, which might have influenced the results if cyclicity, not metyrapone, caused eucortisolism. Additionally, in contrast to other studies,26,27 participants with severe hypercortisolism were included in this study, requiring greater treatment efficacy to meet the primary endpoint. Furthermore, frequent UFC measurements (every 1–3 weeks rather than monthly) during the first 8 weeks increased our confidence that metyrapone caused the observed hormonal improvements.
Conclusions
These results from the prospective PROMPT study validate the utility of metyrapone treatment for endogenous CS. In addition to rapid normalization of mUFC and improvements in the cortisol circadian rhythm, metyrapone demonstrated good safety and tolerability and improvements in QoL and clinical outcomes.
Supplementary Material
Supplementary material is available at European Journal of Endocrinology online.
Significance.
PROMPT was a prospective study of metyrapone in Cushing’s syndrome. Metyrapone rapidly reduced mean 24 h urinary free cortisol (mUFC) within 2 weeks. From week 12 onwards, almost half of the participants had normal mUFC, and between 70% and 80% had mUFC that was normal or decreased by 50% or more from baseline. The cortisol circadian rhythm, as assessed by a salivary cortisol day-curve, improved by week 1 and thereafter. Metyrapone was well tolerated, with no unexpected adverse events (AEs). Most AEs occurred during the first 12 weeks with few later events. Seven participants discontinued treatment because of AEs that were related (n = 3) or unrelated (n = 4) to metyrapone administration. The PROMPT study validates existing evidence of metyrapone as an effective and safe therapy for Cushing’s syndrome.
Acknowledgments
This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH). The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. The authors would like to thank Professor Dilek Berker, formally of the Private Clinic of Endocrinology and Metabolism in Ankara, Turkey, and Professor Narin Nasıroglu Imga of the Private Clinic of Endocrinology and Metabolism in Ankara, Turkey, for their contributions to this study. We also thank Kate Palmer and Sarah Greig, PhD, CMPP, of Springer Health+ for editorial support. This support was funded by Esteve (previously HRA Pharma Rare Diseases).
Funding
This study was funded by HRA Pharma. The editorial support was funded by ESTEVE (formerly HRA Pharma Rare Diseases).
Conflict of interest:
L.K.N. has been an author and editor of UpToDate. T.D. has received travel costs from Recordati Rare Diseases; lecture fees from Recordati Rare Diseases; honoraria for scientific board activities from HRA Pharma; and has served as a principal investigator and national study coordinator for clinical studies for Corcept Therapeutics. A.H.-D. has received speaker honoraria from IBSEN, Merck, Berlin, Chemie/Menarini, and Recordati. B.J. has received honoraria from Amgen, AstraZeneca, Bayer Health Care, Eisai, Ewopharma, Exelixis, Ipsen, Oxygene, Lilly, Pfizer, Sanofi-Genzyme, and Sobi. M.R. has been a consultant for Recordati Rare Diseases, Lundbeck, HRA Pharma/Esteve, and Crinetics; and has received speaking fees from HRA Pharma/Esteve and Recordati. F.A.H. has been a speaker and consultant for Esteve. Ma.T. has been a consultant for Corcept Therapeutics, Recordati Rare Diseases, and Esteve; and has received speaking fees from Esteve. M.B.N. has acted as a consultant for HRA Pharma Rare Diseases. Mi.T. has been a speaker and occasional consultant for Medis and Recordati. Marc.B., C.S., E.M., N.D., C.E.G., M.M., D.M., P.L., B.Z., A.A., C.B., A.B., Mare.B., F.C., N.U., R.G., N.S., and J.T. have no conflicts of interest to declare. HRA Pharma, the sponsor and funder, contributed to the study design, the analysis and interpretation of the data, and the writing of this report. Data were available to all authors. The corresponding author wrote the initial protocol, analyzed the data, and wrote the report; the National Institute of Health and HRA Pharma statisticians performed the statistical analysis. All other authors were responsible for patient accrual and protocol procedures. All authors revised the manuscript and agreed to submit the report for publication.
Data availability
The datasets used and/or analyzed during the current study are available from Esteve on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study are available from Esteve on reasonable request.