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Dienogest 2 mg Daily in the Treatment of Adolescents with Clinically Suspected Endometriosis: The VISanne Study to Assess Safety in ADOlescents

Open AccessPublished:February 08, 2017DOI:https://doi.org/10.1016/j.jpag.2017.01.014

      Abstract

      Study Objective

      To study the safety and efficacy of dienogest 2 mg in adolescents with suspected endometriosis.

      Design

      A 52-week, open-label, single-arm study.

      Setting

      In 21 study centers, in 6 European countries.

      Participants

      Adolescents aged 12 to younger than 18 years with clinically suspected or laparoscopically confirmed endometriosis.

      Interventions

      Dienogest 2 mg once daily.

      Main Outcome Measures

      The primary end point was relative change in lumbar spine (L2-L4) bone mineral density (BMD) measured using dual-energy x-ray absorptiometry. A key secondary end point was change in endometriosis-associated pain assessed using a visual analogue scale.

      Results

      Of 120 patients screened, 111 comprised the full-analysis set (ie, patients who took ≥1 dose of study drug and had ≥1 post-treatment observation) and 97 (87.4%) completed the study. Mean lumbar BMD at baseline was 1.1046 (SD, 0.1550) g/cm2. At the end of dienogest treatment (EOT; defined as at 52 weeks or premature study discontinuation), mean relative change in BMD from baseline was −1.2% (SD, 2.3%; n = 103). Follow-up measurement 6 months after EOT in the subgroup with decreased BMD at EOT (n = 60) showed partial recovery in lumbar BMD (mean change from baseline: −2.3% at EOT, −0.6% 6 months after EOT). Mean endometriosis-associated pain score was 64.3 (SD, 19.1) mm at baseline and decreased to 9.0 (SD, 13.9) mm by week 48.

      Conclusion

      In adolescents with suspected endometriosis, dienogest 2 mg for 52 weeks was associated with a decrease in lumbar BMD, followed by partial recovery after treatment discontinuation. Endometriosis-associated pain was substantially reduced during treatment. Because bone accretion is critical during adolescence, results of the VISanne study to assess safety in ADOlescents (VISADO) study highlights the need for tailored treatment in this population, taking into account the expected efficacy on endometriosis-associated pain and an individual's risk factors for osteoporosis.

      Key Words

      Introduction

      Relative to adults, there are limited data on the frequency and symptoms of endometriosis in adolescents,
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      The rationale for hormonal therapies is to reduce circulating concentrations of estrogen, which decreases endometriotic lesion size and symptoms. Hormonal therapies available include COCs (unapproved by regulatory authorities for use in endometriosis), progestins, gonadotropin-releasing hormone (GnRH) agonists, androgens, and antiprogestagens.
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      There is debate regarding whether early diagnosis and treatment of teenage endometriosis provides better long-term outcomes or simply increases the number of interventions without preventing disease progression.
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      Effective treatment of endometriosis in adolescents, however, has the potential to reduce symptoms as well as improve quality of life.
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      Most adult treatments have not been tested in this age group. Whereas oral contraceptives are reported to be effective in trials of adolescents,
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      COCs,
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      and many progestins,
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      have safety profiles that are unsatisfactory for adolescents.
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      Specifically, the potential for bone mineral density (BMD) loss associated with hormonal treatments, through reduction in circulating estrogen levels, is of particular concern.
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      Endometriosis in adolescence.
      Further research is needed on the risk-benefit profile of treatments in adolescents.
      Dienogest is a progestin indicated as monotherapy at an oral dose of 2 mg once daily for patients with endometriosis.

      Visanne 2 mg tablets. Summary of product characteristics. Available at: http://mri.medagencies.org/download/NL_H_1569_001_FinalSPC.pdf. Accessed August 10, 2016.

      Dienogest is highly selective for the progesterone receptor, exhibiting strong progestational effects and moderate antigonadotrophic effects, with limited androgenic, glucocorticoid, or mineralocorticoid activity.
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      Dienogest suppresses estradiol levels only moderately
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      and, in a 6-month study in adults, did not alter mean lumbar spine BMD.
      • Strowitzki T.
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      Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial.
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      Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis.
      The safety and efficacy of dienogest for providing pain relief in the adult population have been confirmed in several clinical trials, differing in design and ethnicity of populations.
      • Harada T.
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      • et al.
      Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial.
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      Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial.
      • Harada T.
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      During development of dienogest, the Paediatric Committee (PDCO) of the European Medicines Agency requested a Paediatric Investigational Plan for the indication of endometriosis in symptomatic patients after menarche (age 12 to younger than 18 years). Bayer initiated the phase II safety study in 2011 (VISanne study to assess safety in ADOlescents [VISADO]; ClinicalTrials.gov Identifier: NCT01283724). The primary objective of the VISADO study, agreed with the PDCO, was to evaluate the long-term (52-week) effects of dienogest 2 mg once daily on BMD of the lumbar spine, measured using dual-energy x-ray absorptiometry (DEXA), in adolescents with confirmed or clinically suspected endometriosis.
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      Materials and Methods

      VISADO was a multicenter, single-arm, open-label study conducted at 21 study centers in 6 European countries (Austria, Czech Republic, Finland, France, Germany, and Spain) between March 2011 and June 2014. In discussion with the PDCO, it was agreed to conduct the study in an uncontrolled design because no other treatments have been approved for treatment of endometriosis in adolescents. Furthermore, placebo treatment was excluded because of an ethical perspective in this age group.
      Adolescent girls postmenarche, aged 12 to younger than 18 years, with clinically suspected or laparoscopically diagnosed endometriosis were eligible for study inclusion. Appropriate definitions of the study population (age, diagnostic criteria) were discussed with the PDCO during development of the Paediatric Investigational Plan. Laparoscopic confirmation of endometriosis was not made mandatory because surgical procedures are commonly avoided in this age group. Furthermore, empirical treatment is common in adolescents with pelvic pain and dysmenorrhea when other causes of pelvic pain symptoms are excluded.
      • Dunselman G.A.
      • Vermeulen N.
      • Becker C.
      • et al.
      ESHRE guideline: management of women with endometriosis.
      Inclusion criteria included dysmenorrhea of moderate to severe intensity, with or without chronic pelvic pain, for 2 or more cycles in the previous 4 months, and either: (1) clinically suspected endometriosis (pelvic pain incompletely relieved by NSAIDs and/or oral contraceptives); (2) abdominal pain associated with ultrasound findings suggestive of endometriosis; or (3) failure of surgical treatment for endometriosis (with cyclic or chronic pelvic pain of ≥4 months’ duration after confirmation of endometriosis). Patients were required to have an endometriosis-associated pelvic pain score of 30 or higher on a 100-mm unit visual analogue scale (VAS), evaluated at screening retrospectively for the previous 4 weeks.
      Patients were excluded from the study if laparoscopy had been performed in the past and endometriosis was absent; chronic pelvic pain might have been related to genitourinary or gastrointestinal disease; there was undiagnosed abnormal genital bleeding; or amenorrhea had been present in the previous 3 months. Patients were also excluded if they received hormonal therapies, including oral contraceptives within the previous 2 months, progestins, or danazol within 3 months, or GnRH agonists within 6 months before the start of study. Patients with a clinically established need for surgical treatment of endometriosis were excluded. Diseases or conditions precluded study enrollment if they might worsen during study treatment, influence BMD, or result in altered absorption, accumulation, metabolism, or excretion of study drug. Investigators excluded any patient with clinically relevant findings at general physical or gynecological examination or with laboratory values outside the inclusion range.
      Patients received oral dienogest 2 mg as a single daily dose. Tablets were taken with or without food, preferably at the same time each day, continuously through the 52-week study period. Information on medication intake and data for the evaluations described in the results section were collected by patients using e-diaries. Patients were allowed NSAIDs for pain but no other medicines specific for endometriosis. Drugs or foods with potential to interact with dienogest were prohibited during the study, in particular: anticoagulants (heparin or coumarin) and drugs known to influence the study medication (ie, influence the CYP3A4 isoenzyme of the cytochrome P-450 pathway), such as barbiturates, primidone, carbamazepine, phenytoin, rifampicin, and possibly also oxcarbazepine, topiramate, griseofulvin, felbamate, nevirapine, and products containing St John's wort, azole antifungals (eg, ketoconazole, itraconazole, fluconazole), verapamil, macrolides (eg, erythromycin, clarithromycin, roxithromycin), diltiazem, protease inhibitors (eg, ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (eg, nefazodone, fluvoxamine, fluoxetine), or broad-spectrum antibiotics lasting more than 2 weeks.
      The study was approved by the PDCO, pertinent national competent authorities, and each study site's independent ethics committee or institutional review board, and was conducted according to Good Clinical Practice guidelines, the Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population, Declaration of Helsinki, and local laws and regulations. Written informed consent was provided by patients and parents/other legal representative before the start of the study. If contraception was required, a nonhormonal barrier method (eg, condom) could be used during the study.
      Patients attended the clinic for screening (weeks −4 to −1), at baseline (week 0), every 4 weeks to end of treatment (EOT; week 52 or premature discontinuation from study medication), and at follow-up 4 weeks after EOT.
      BMD of the lumbar spine (L2-L4) and whole body was measured using DEXA at baseline and EOT. Patients with decreased lumbar spine BMD at EOT relative to baseline were invited to revisit 6 months later. For BMD of the lumbar spine, the mean of 2 measurements was calculated at each visit, whereas whole-body BMD was measured once per time point. BMD measurements were validated by Imaging Core Lab Services for Clinical Trials (SYNARC Inc, Portland, OR).
      Endometriosis-associated pelvic pain on a 100-mm unit VAS was assessed by patients retrospectively for the previous 4 weeks at screening, baseline, and every 4 weeks (“Please indicate your subjective level of endometriosis pain looking back at the past 4 weeks”). The VAS is a validated measure of pain used previously in trials of dienogest in adults with endometriosis.
      • Strowitzki T.
      • Marr J.
      • Gerlinger C.
      • et al.
      Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial.
      • Petraglia F.
      • Hornung D.
      • Seitz C.
      • et al.
      Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment.
      • Strowitzki T.
      • Faustmann T.
      • Gerlinger C.
      • et al.
      Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study.
      • Gerlinger C.
      • Schumacher U.
      • Wentzeck R.
      • et al.
      How can we measure endometriosis-associated pelvic pain?.
      The Biberoglu and Behrman (B&B) severity scale was used at screening, baseline, and every 4 weeks during treatment. The B&B severity profile for symptoms and signs (0 = none; 1 = mild; 2 = moderate; 3 = severe) is widely used to assess treatment response in endometriosis, including trials of dienogest in adults.
      • Strowitzki T.
      • Marr J.
      • Gerlinger C.
      • et al.
      Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial.
      • Strowitzki T.
      • Faustmann T.
      • Gerlinger C.
      • et al.
      Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study.
      Clinical Global Impressions rating scale scores (1 = very much improved to 7 = very much worse) were assessed at weeks 12, 24, 36, and 52. Investigators rated total improvement, whereas patients rated satisfaction with treatment. The Endometriosis Health Profile (EHP-30) was self-administered by patients at baseline and at weeks 12, 24, and 52, retrospectively for the previous 4 weeks. This quality of life questionnaire comprises 30 items covering 5 domains: pain, control and powerlessness, emotional well-being, social support, and self-image, and is validated in patients with endometriosis.
      • Jones G.
      • Jenkinson C.
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      • Jenkinson C.
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      Adverse events (AEs) were reported throughout the study, including their nature, seriousness, intensity, and relationship to study drug. Vital signs and clinical laboratory variables (estradiol, bone metabolism markers, hematology, coagulation, blood chemistry, liver, diabetes mellitus, lipids, and urinalysis) were assessed at screening and preplanned intervals. Laboratory determinations were performed by a central laboratory (Laboratorium für Klinische Forschung GmbH, Germany). Uterine bleeding intensity (none, spotting, light, normal, or heavy) was recorded daily in an e-diary. Gynecological examination and transvaginal ultrasound (if patients consented) were performed to assess pelvic tenderness and induration at screening and preplanned intervals to week 52. Alternatively, abdominal ultrasound examination was offered. A complete physical examination was performed at screening and EOT.
      A sample size of 80 evaluable subjects was agreed with the PDCO. On the basis of earlier studies,
      • Strowitzki T.
      • Marr J.
      • Gerlinger C.
      • et al.
      Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial.
      an SD of approximately 3 percentage points for the change in BMD was assumed. With a total of 80 subjects, a 95% confidence interval (CI) of a width of 1.3 percentage points could be provided.
      Efficacy analyses were conducted on the full-analysis set (FAS) and per-protocol set (PPS), and safety was evaluated on the FAS. The FAS included all patients who took 1 or more doses of study drug and had 1 or more post-treatment observation. The PPS excluded patients from the FAS who had major protocol deviations affecting primary safety and efficacy end points.
      Statistical analysis was performed using SAS version 9.2 (SAS Institute Inc, Cary, NC). Descriptive statistics were used for assessment of BMD, including arithmetic mean and SD, at baseline and EOT. Bleeding episodes were described over 90-day reference periods, as recommended by the World Health Organization.
      • Gerlinger C.
      • Endrikat J.
      • Kallischnigg G.
      • et al.
      Evaluation of menstrual bleeding patterns: a new proposal for a universal guideline based on the analysis of more than 4500 bleeding diaries.
      Other data were evaluated using descriptive statistics for continuous variables and frequency tables for categorical data. There were no adjustments for covariates.

      Results

      Of 120 adolescents screened, 111 were eligible for study treatment and 97 (87.4%) completed the study (Fig. 1). Among 14 patients who discontinued study medication prematurely, the most common reason was withdrawal of informed consent (n = 6). The FAS included 111 patients and the PPS 81 patients. Baseline demographic characteristics and characteristics of patients are shown in Table 1. The mean patient age was 15.4 years (range, 12 to <18 years) and mean age at menarche was 12.1 (SD, 1.2) years. Ninety-seven patients (87.4%) were diagnosed according to clinical symptoms and/or findings, 13 patients (11.7%) had imaging findings consistent with the diagnosis of endometriosis, and only 1 patient (0.9%) was diagnosed surgically. Mean compliance with study treatment, assessed using e-diary, was 87.3% (SD, 16.6%; median, 94.3%) in the FAS and 92.7% (SD, 7.1%; median, 94.8%) in the PPS.
      Figure thumbnail gr1
      Fig. 1Flow diagram of patients through the VISanne study to assess safety in ADOlescents (VISADO).
      Table 1Demographic and Baseline Patient Characteristics (FAS); n = 111
      CharacteristicDienogest 2 mg
      Age, years
       Mean (SD)15.4 (1.3)
       Median16.0
       Range12-17
      Race, n (%)
       White105 (94.6)
       Black/African American1 (0.9)
       Not reported5 (4.5)
      Weight, kg
       Mean (SD)61.8 (11.2)
       Range41.0-97.0
      BMI
       Mean (SD)22.5 (3.7)
       Range16.0-34.8
      Country, n (%)
       Czech Republic50 (45.0)
       Finland19 (17.1)
       Germany16 (14.4)
       Austria13 (11.7)
       Spain8 (7.2)
       France5 (4.5)
      Diagnosis of endometriosis, n (%)
       Clinical suspicion97 (87.4)
       Laparoscopy1 (0.9)
       Imaging findings consistent with endometriosis13 (11.7)
      BMI, body mass index; FAS, full-analysis set
      Mean BMD of the lumbar spine (L2-L4) was 1.1046 (SD, 0.1550) g/cm2 at baseline (FAS). At EOT, mean percent change from baseline was −1.2% (SD, 2.3%; 95% CI, −1.70% to −0.78%; n = 103; Fig. 2). Lumbar spine BMD was lower at EOT than at baseline in 73 of the 103 patients (70.9%; mean change, −2.3%). Follow-up lumbar spine BMD measurements in 60 of these 73 patients 6 months after EOT showed partial recovery (mean change, −0.6% vs baseline; SD, 2.4%; 95% CI, −1.20% to 0.06%). For 22 (36.7%) of the 60 patients with decreased BMD at EOT who attended measurement 6 months later, BMD had returned to baseline or had increased. Changes in lumbar spine BMD in the PPS were similar to that in the FAS (data not shown).
      Figure thumbnail gr2
      Fig. 2Box and whisker plots of (A) lumbar spine (L2-L4) bone mineral density (BMD) and (B) relative change in L2-L4 BMD in all patients (gray boxes) and in the subgroup of patients who had a decrease in L2-L4 BMD at the end of treatment (EOT; white boxes). Boxes show median values (horizontal rules) and 25% and 75% quartiles (borders of boxes); whiskers indicate 2.5% and 97.5% quantiles; and crosses indicate individual outliers. * For 1 subject a BMD measurement from the lumbar spine at 6 months after EOT is available, although the relative change in L2-L4 BMD from baseline to EOT showed an increase. The reason this subject had a second BMD measurement at 6 months after EOT is that eligibility for this BMD examination was on the basis of adjusted but not yet corrected BMD values. The adjusted results for the relative change of L2- L4 BMD from baseline to EOT showed a decrease, whereas the adjusted and corrected results—which are relevant for reporting—showed an increase.
      Lumbar spine BMD decreased in 1 patient by 6.2% at EOT, from a baseline of 1.269 g/cm2; this was reported as a study drug-related serious AE (SAE). By 6 months after EOT, lumbar spine BMD decreased 8.7% vs baseline. Of note, this patient received medications between EOT and 6 months later that might have contributed to the further BMD decrease, including cyproterone acetate (50 mg) in combination with estradiol gel (0.1% daily, cutaneous) and chlormadinone acetate (10 mg). She had started smoking (5 cigarettes per day) 10 months before enrollment. Estradiol values in the patient were 311.7 pmol/L at baseline, 102.1 pmol/L at week 24, and 143.9 pmol/L at EOT.
      Post hoc subanalyses, including regression analyses, were performed on relative BMD changes in different age groups, body mass index (BMI) levels, and smoking status at baseline. There was a small numerical tendency for greater decreases in lumbar BMD in “older” patients and smokers, with high variation (Supplemental file 1). Subanalyses of lumbar BMD change in patients grouped according to time after menarche and pain symptoms indicated that greater BMD decrease was associated with longer time after menarche, but no correlation existed with intensity of pain (Supplemental files 2 and 3).
      Mean whole-body BMD was 1.0932 (SD, 0.0924) g/cm2 at baseline (FAS). At EOT, mean percent change from baseline was +0.8% (SD, 1.6%; 95% CI, 0.50%-1.14%). Whole-body BMD was at or above baseline in 101 patients (98.1%). In the 60 patients with decreased lumbar spine BMD at EOT, change in whole-body BMD at EOT was +0.5% (SD, 1.3%). By 6 months after EOT, change of whole-body BMD vs baseline in this subgroup was +0.8% (SD, 1.5%; 95% CI, 0.37%-1.16%). In the patient who experienced a 6.2% reduction in lumbar spine BMD (reported previously), whole-body BMD decreased more than 6% at EOT. Changes in whole-body BMD in the PPS were similar to those in the FAS (data not shown).
      Three biochemical markers of bone metabolism were assessed: collagen C-telopeptide (CTX) type I (CTX-1) in serum and CTX type II (CTX-2) in urine, markers of bone resorption and cartilage degradation, respectively, and procollagen 1 N-terminal propeptide in blood, a marker of bone formation. All CTX-1, CTX-2, and procollagen 1 N-terminal propeptide concentrations in the adolescent patients exceeded upper reference values for adult premenopausal women. The adult reference ranges were applied because, at the time of starting the study, no reference data for adolescent populations were available. All analyzed markers showed a decrease from baseline to EOT, although they did not reach the normal range for adult women. Age- and method-specific reference ranges have since become available for CTX-1, and post hoc analysis revealed that values exceeded the upper reference range in less than 10 samples; these increases were less than 10% above the normal range.
      Mean endometriosis-associated pelvic pain at baseline assessed using a VAS was 64.3 mm (SD, 19.1 mm). By week 4, the VAS score decreased to 36.8 mm (SD, 26.1 mm) and by week 48 to the lowest mean value of 9.0 mm (SD, 13.9 mm; Supplemental file 4). The proportion of responders (ie, ≥30% reduction in VAS score from baseline) was 81.0% (81 of 100 patients) at week 24. B&B scores showed increased proportions of patients without endometriosis symptoms between baseline and EOT: pelvic pain (from 9.1% to 71.2%; n = 110), dysmenorrhea (3.6% to 78.8%; n = 110), and dyspareunia (9.1% to 23.1%; n = 21). Only 21 patients provided data on dyspareunia, probably because of the low frequency of intercourse in this population. There were accompanying decreases in the proportions of patients with moderate to severe symptoms of pelvic pain (from 67.2% to 4.8%) and dysmenorrhea (from 74.6% to 5.8%). At baseline and EOT, 33 and 56 patients, accordingly, underwent a gynecological investigation. The proportion of patients without gynecological signs of endometriosis increased between baseline and EOT: pelvic tenderness (from 63.6% to 80.4%) and induration (from 60.6% to 87.5%). The proportion of patients with moderate or severe pelvic tenderness decreased at EOT vs baseline (from 6.1% to 1.8%), whereas no patients had induration of moderate or severe severity at baseline or EOT.
      Investigators rated patient status as “much improved” or “very much improved” in 85.6% (89/104) at week 12, with a further increase to 89.9% (98/109) at EOT. A total of 74.0% (77/104) patients were “much satisfied” or “very much satisfied” at week 12, with a further increase to 84.5% (87/103) at EOT. Health-related quality of life assessed according to the EHP-30 showed improvements in all items assessed (Supplemental file 5).
      AEs were reported by 92 patients (82.9%). The most frequent AEs (>5% of patients) were headache (9.0%), breast discomfort (7.2%), weight increase (6.3%), and abdominal pain (5.4%). Frequencies of individual AEs were similar to those reported previously in adults (Supplemental file 6). In 40 patients (36.0%), AEs were judged to be related to study medication. Five patients experienced 7 SAEs during the 52-week study, of which 1 was considered related to study medication: a case of a ruptured ovarian cyst on the right side; the patient recovered fully 4 days later. Other SAEs included suspected adenomyosis and ovarian adhesions, right acute pyelonephritis, sprain of the cervical spine, pyelonephritis, and depression. AEs in 5 patients (4.5%) led to study drug discontinuation: hypogastric pain and ruptured ovarian cyst (SAE; previously mentioned); major depression; cholecystitis; nausea, headache, and vomiting; and 1 patient discontinued because of amenorrhea not acceptable for her. Two patients reported a SAE after the 52-week treatment period: right ovary dermoid cyst (this patient also had the SAE of acute pyelonephritis) and bone densitometry decrease (related to study medication, described previously).
      Mean body weight increased by 1.87 (SD, 3.82) kg between screening and EOT. Weight increase was reported as an AE in 10 patients (9.0%) and weight decrease in 3 patients (2.7%). Blood pressure values were stable during the study and no changes in clinical laboratory parameters were judged to be clinically relevant by investigators.
      Estradiol concentrations ranged widely, as expected, at different phases of the menstrual cycle at screening (41.1-1388.0 pmol/L) and EOT (47.0-1848.0 pmol/L), while remaining within the normal range (46.0-1827.9 pmol/L). The mean serum estradiol concentration decreased from 374.8 (SD, 278.6; median 275.0) pmol/L at baseline to 201.5 (SD, 235.3; median, 139.5) pmol/L at EOT.
      The number of bleeding/spotting days decreased during study (Fig. 3). Similarly, the mean (SD) number of bleeding days in 90-day reference periods 1, 2, 3, and 4 decreased from 12.0 (12.0), 4.1 (7.0), 3.8 (7.5), to 2.4 (6.3), and the mean (SD) number of bleeding/spotting episodes decreased from 3.1 (2.3), 1.9 (2.1), 1.5 (2.1), to 1.6 (2.0), respectively. With continued use of dienogest an increasing number of patients experienced amenorrhea (Fig. 3).
      Figure thumbnail gr3
      Fig. 3Uterine bleeding/spotting days and amenorrhea rate in World Health Organization 90-day reference periods 1-4 (full-analysis set).
      No pregnancies were detected during study treatment. One subject became pregnant shortly after the EOT. Her pregnancy test 20 days after the last study medication dose showed a positive result. Her pregnancy test at EOT had been negative. She underwent surgical abortion.

      Discussion

      In this 52-week multicenter study of adolescent patients, dienogest 2 mg once daily was effective in relieving the symptoms (pelvic pain, dysmenorrhea, and dyspareunia) and signs (pelvic tenderness and induration) of endometriosis. Dienogest was generally well tolerated, consistent with previously reported trials of adults with endometriosis.
      Change in mean lumbar spine BMD was the primary study end point. Dienogest was associated with a mean decrease in lumbar spine BMD of 1.2% at EOT. Follow-up assessment in 60 of the 73 patients with decreased lumbar spine BMD at EOT showed a partial recovery 6 months later. In contrast to the change in lumbar spine BMD, whole-body BMD increased 0.8% from baseline to EOT in the study population. Discordance in DEXA data between whole-body and regional (for example, spinal) sites is a well recognized observation in patients with osteoporosis and other studies, and is attributed to differences in the relative proportion of cortical vs cancellous bone.
      • Abrahamsen B.
      • Stilgren L.S.
      • Hermann A.P.
      • et al.
      Discordance between changes in bone mineral density measured at different skeletal sites in perimenopausal women–implications for assessment of bone loss and response to therapy: the Danish Osteoporosis Prevention Study.
      • Moayyeri A.
      • Soltani A.
      • Tabari N.K.
      • et al.
      Discordance in diagnosis of osteoporosis using spine and hip bone densitometry.
      • Mounach A.
      • Abayi D.A.
      • Ghazi M.
      • et al.
      Discordance between hip and spine bone mineral density measurement using DXA: prevalence and risk factors.
      Post hoc subanalyses detected no clear correlations between BMD changes and patient age, time after menarche, or BMI, whereas current smokers showed a higher mean BMD decrease than nonsmokers.
      In studies of adults with endometriosis, dienogest has shown limited effects on BMD. Strowitzki et al,
      • Strowitzki T.
      • Marr J.
      • Gerlinger C.
      • et al.
      Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial.
      in a 24-week trial, observed a 0.25% increase in mean lumbar spine BMD with dienogest 2 mg, vs a decrease of 4.04% with leuprolide acetate (P = .0003, treatment comparison). In a 24-week trial by Harada et al,
      • Harada T.
      • Momoeda M.
      • Taketani Y.
      • et al.
      Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis–a randomized, double-blind, multicenter, controlled trial.
      a reduction in BMD during dienogest 1 mg twice-daily treatment was significantly lower than with buserelin acetate (−1.0 ± 2.3% vs −2.6 ± 2.3%; P = .003). In a 52-week trial, Momoeda et al
      • Momoeda M.
      • Harada T.
      • Terakawa N.
      • et al.
      Long-term use of dienogest for the treatment of endometriosis.
      reported the long-term effect of dienogest 1 mg twice-daily treatment on lumbar spine BMD, with a mean change from baseline of −1.7% (SD, 2.2%). These results are similar to those of the VISADO study.
      Other hormonal treatments for endometriosis, including GnRH agonists and other progestins, showed substantial adverse effects on BMD in adults.
      • Giudice L.C.
      Clinical practice. Endometriosis.
      • Harada T.
      • Momoeda M.
      • Taketani Y.
      • et al.
      Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial.
      • Crosignani P.
      • Olive D.
      • Bergqvist A.
      • et al.
      Advances in the management of endometriosis: an update for clinicians.
      • Rahman M.
      • Berenson A.B.
      Predictors of higher bone mineral density loss and use of depot medroxyprogesterone acetate.
      • Vercellini P.
      • Somigliana E.
      • Vigano P.
      • et al.
      Endometriosis: current therapies and new pharmacological developments.
      • Dessole M.
      • Melis G.B.
      • Angioni S.
      Endometriosis in adolescence.
      GnRH agonists, in particular, induce low levels of circulating estrogens,
      • Sagsveen M.
      • Farmer J.E.
      • Prentice A.
      • et al.
      Gonadotrophin-releasing hormone analogues for endometriosis: bone mineral density.
      which can reduce BMD by 4%-5% after 6 months.
      • Roux C.
      • Pelissier C.
      • Listrat V.
      • et al.
      Bone loss during gonadotropin releasing hormone agonist treatment and use of nasal calcitonin.
      Among the progestins, medroxyprogesterone acetate is noted to have an adverse effect on BMD.
      • Rahman M.
      • Berenson A.B.
      Predictors of higher bone mineral density loss and use of depot medroxyprogesterone acetate.
      Although COCs are commonly prescribed, their effect on bone metabolism and effect on peak bone mass in adolescents remain unclear.
      • Gai L.
      • Jia Y.
      • Zhang M.
      • et al.
      Effect of two kinds of different combined oral contraceptives use on bone mineral density in adolescent women.
      • Trémollières F.
      Impact of oral contraceptive on bone metabolism.
      • Warholm L.
      • Petersen K.R.
      • Ravn P.
      Combined oral contraceptives’ influence on weight, body composition, height, and bone mineral density in girls younger than 18 years: a systematic review.
      When interpreting the BMD data in the VISADO study, it is important to note that decreased BMD is a surrogate marker to identify osteoporosis and assess fracture risk, particularly in postmenopausal women. In addition, BMD addresses bone quantity, not bone quality.
      • Grimes D.A.
      • Schulz K.F.
      Surrogate end points in clinical research: hazardous to your health.
      Although loss of BMD is of concern during adolescence and early adulthood—a critical period of bone accretion—measurement of BMD in premenopausal women should be interpreted with caution.
      • Grimes D.A.
      • Schulz K.F.
      Surrogate end points in clinical research: hazardous to your health.
      In particular, it is unknown whether a decrease of BMD in adolescents will reduce peak bone mass and increase risk for fracture in later life.
      Baseline concentrations of biochemical markers of bone turnover assessed in the VISADO study exceeded the upper reference range for adult premenopausal women. This might be partially explained by the effects of ongoing bone formation in adolescents. Post hoc analysis of CTX-1 data using newly available reference ranges for adolescents indicated that almost all values in the VISADO study were within the expected range or exceeded it minimally. Because of the lack of established reference ranges for other markers in the healthy adolescent population, no final conclusions can be drawn on the clinical relevance of these findings.
      Dienogest 2 mg substantially decreased endometriosis-associated pelvic pain evaluated using the VAS. By week 4, pain was nearly one-half the level at baseline, and pain continued to decrease, with the lowest mean value at week 48. Consistent with VAS outcomes, B&B scores improved substantially and global assessments by physicians and patients showed marked improvements. Efficacy assessments were accompanied by improvements in quality of life reported using the EHP-30.
      The efficacy findings for dienogest 2 mg in this adolescent population are consistent with data in adults with endometriosis, in whom the reductions in pain score were similar at equivalent time points.
      • Strowitzki T.
      • Marr J.
      • Gerlinger C.
      • et al.
      Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial.
      • Strowitzki T.
      • Faustmann T.
      • Gerlinger C.
      • et al.
      Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study.
      Also consistent with adult studies,
      • Strowitzki T.
      • Marr J.
      • Gerlinger C.
      • et al.
      Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis.
      • Petraglia F.
      • Hornung D.
      • Seitz C.
      • et al.
      Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment.
      • Strowitzki T.
      • Faustmann T.
      • Gerlinger C.
      • et al.
      Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study.
      dienogest 2 mg showed favorable tolerability in the adolescent population, with a predictable AE profile. The VISADO study showed modest suppression of estradiol levels, with median values (139.5 pmol/L; FAS) that remained within the therapeutic window suggested for endometriosis treatment.
      • Barbieri R.L.
      Endometriosis and the estrogen threshold theory. Relation to surgical and medical treatment.
      A progressive reduction in bleeding/spotting days and episodes over time, and an amenorrhea rate of 35.3% during dienogest treatment in the 90-day reference period 2, are consistent with a study in adults (amenorrhea rate 38.9% in the reference period 2
      • Strowitzki T.
      • Marr J.
      • Gerlinger C.
      • et al.
      Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial.
      ). By reference period 4 in the VISADO study, the amenorrhea rate had increased to 40.9%.
      Limitations of the VISADO study include the open-label design with lack of a control group. An uncontrolled study design was agreed with the PDCO, because there is no comparator treatment appropriately tested in the adolescent population and a placebo-controlled study was considered unethical. The study allowed inclusion of patients with suspected endometriosis in the absence of definitive diagnosis using laparoscopy. In this regard, VISADO is representative of routine clinical practice, in which laparoscopy (particularly in adolescents) is frequently avoided and empirical treatment is standard. Third, the study was not primarily designed to identify predictive factors for BMD decrease during dienogest treatment, which would help the treating physician considering dienogest treatment. Subgroup analyses on the basis of age, BMI, and smoking status were performed, but did not permit clear conclusions for treatment decisions because of the limited sample sizes. Fourth, the study included patients with limited racial diversity. Finally, follow-up BMD data after EOT were available only in patients with decreased BMD at EOT, not in those with unchanged or increased BMD.
      In conclusion, the treatment of endometriosis in adolescents with 2 mg dienogest once daily for 52 weeks was associated with a decrease in lumbar spine BMD, followed by partial recovery after treatment discontinuation. Individual patients might show more substantial changes in lumbar spine or whole-body BMD than observed in the VISADO study. Because bone accretion is critical during adolescence, the physician would need to weigh the benefits of dienogest 2 mg against potential risks in individual adolescent patients, as well as take into account any significant risk factors for osteoporosis.
      The efficacy of dienogest in relieving endometriosis-associated symptoms and signs and the profile of common AEs were comparable with those in adult populations.
      The VISADO study constitutes a rare resource for evidence-based treatment of endometriosis in adolescents and highlights the need for individualized treatment in these patients.

      Acknowledgments

      Editorial support was provided by Bill Wolvey at PAREXEL, which was funded by Bayer AG. The study was funded by Bayer AG.

      Supplementary Data

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