Pooled analysis of menstrual irregularities from three major clinical studies evaluating everolimus for the treatment of tuberous sclerosis complex

Steven Sparagana, David N Franz, Darcy A Krueger, John J Bissler, Noah Berkowitz, Karin Burock, J Christopher Kingswood, Steven Sparagana, David N Franz, Darcy A Krueger, John J Bissler, Noah Berkowitz, Karin Burock, J Christopher Kingswood

Abstract

Objectives: To determine the impact of everolimus on female fertility, including menstrual irregularities, secondary amenorrhea, and luteinizing and follicle stimulating hormone levels in female patients.

Design: A pooled analysis from 3 prospective studies consisting of a core phase (≥6 months) and a long-term follow-up open-label extension.

Setting: One phase 2 single-center and two phase 3 multicenter studies.

Participants: Data were obtained from female participants, restricted to those between 10 and 55 years of age, during 1 of 3 of the described clinical trials of everolimus. Patients had received ≥ 1 dose of everolimus.

Main outcome measures: Incidence of fertility events.

Results: A total of 43/112 patients (38.4%) experienced at least 1 menstrual irregularity. The most common events were amenorrhea (24.1%) and irregular menstruation (17.0%). Seven patients (6.3%) experienced grade 3/4 amenorrhea. When only the longest duration period of amenorrhea for each patient was considered, the median duration was 291 days. Fifteen patients attained menarche during the treatment period in any of the pooled studies. The mean age of menarche for this group was 12.4 years, similar to that of patients who were postmenarche at study entry (12.2 years). A total of 19/92 patients (20.7%) who were postmenarche at baseline or during the study experienced an irregular menstruation event. An increased luteinizing hormone level was reported as an adverse event in 3/112 patients (3%), and follicle-stimulating hormone levels were within normal limits for these patients.

Conclusions: No new safety concerns emerged regarding endocrine function and menstruation in female patients with tuberous sclerosis complex-associated subependymal giant cell astrocytoma or angiomyolipoma, who were receiving everolimus.

Trial registration: ClinicalTrials.gov NCT00411619, NCT00789828, NCT00790400.

Conflict of interest statement

Competing Interests: SS, DNF, DAK, JJB, and JCK have served as investigators on these studies and received research grants (to their institutions) from Novartis. SS, DNF, DAK, JJB, and JCK have served as consultants and/or participated in advisory boards for Novartis. SS, DNF, DAK, JJB, and JCK have received travel honoraria from Novartis. NB and KB are employees of Novartis. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Novartis supports the publication of scientifically rigorous analysis that is relevant to patient care, regardless of a positive or negative outcome. Qualified external researchers can request access to anonymized patient-level data, respecting patient informed consent, through www.clinicalstudydatarequest.com, according to requirements noted on the web portal.

Figures

Fig 1. Study design of the phase…
Fig 1. Study design of the phase 2 study.
MRI, magnetic resonance imaging; SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis complex. aDefinite diagnosis per modified Gomez criteria or a positive genetic test. bUpon completion of the core phase, patients could continue to receive everolimus if evidence of therapeutic benefit.
Fig 2. Study design of EXIST-1.
Fig 2. Study design of EXIST-1.
EIAED, enzyme-inducing antiepileptic drug; SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis complex. aEnrollment occurred between August 20, 2009, and September 2, 2010. bEverolimus starting dose: 4.5 mg/m2/day, adjusted to blood trough levels of 5–15 ng/mL. Dose could be adjusted in cases of toxicity. cSEGA progression was defined as an increase in SEGA volume ≥ 25% from lowest value to a value greater than baseline or as appearance of new SEGA lesions ≥ 1 cm in longest diameter, worsening of nontarget lesions, or new or worsening hydrocephalus.
Fig 3. Study design of EXIST-2.
Fig 3. Study design of EXIST-2.
AML, angiomyolipoma; CT, computed tomography; EIAED, enzyme-inducing antiepileptic drug; MRI, magnetic resonance imaging; sLAM, sporadic lymphangioleiomyomatosis; TSC, tuberous sclerosis complex. aEnrollment occurred between April 28, 2009, and December 30, 2010. bDose adjusted based on toxicity. cRenal angiomyolipoma progression by central review or occurrence of adverse event of angiomyolipoma-related bleeding grade 2 or worse.
Fig 4. Time to onset of menstrual…
Fig 4. Time to onset of menstrual irregularities in patients who were postmenarche at baseline.

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