Fertility of Women Treated during Childhood with Triptorelin (Depot Formulation) for Central Precocious Puberty: The PREFER Study.

BACKGROUND: Gonadotropin-releasing hormone analogues (GnRHa) administered as depot formulations are the standard of care for children with central precocious puberty (CPP). Puberty resumes after treatment discontinuation, but little is known concerning fertility in women who have been treated with GnRHa for CPP during childhood. METHODS: The PREFER (PREcocious puberty, FERtility) study prospectively analysed fertility, via a series of questionnaires, in women treated during childhood with triptorelin (depot formulation) for CPP. Co-primary endpoints were the proportion of women wanting a pregnancy any time before study inclusion and during the follow-up period but not pregnant 6 and 12 months after stopping contraception and the waiting time to pregnancy (WTP). RESULTS: A total of 574 women were identified, and 194 women were included in the analysis. Although there were not enough data for primary endpoint assessment, few women (1.7%) reported issues with fertility or were unable to become pregnant despite trying to conceive. Most pregnancies (84.4%, 95% CI [67.2-94.7%]) occurred within 1 year of trying to conceive, in line with the WTP for women without previous CPP. CONCLUSION: The results, based on a limited sample of patients, suggest that CPP treated with triptorelin does not negatively impact women's fertility in adulthood. These results need to be consolidated with a subsequent study performed when these women will have reached their mid-thirties.

A 6-Month Trial of the Efficacy and Safety of Triptorelin Pamoate (11.25 mg) Every 3 Months in Children with Precocious Puberty: A Retrospective Comparison with Triptorelin Acetate.

BACKGROUND/AIMS: To evaluate the efficacy and safety of a triptorelin pamoate (11.25 mg) 3-month formulation in the management of central precocious puberty (CPP) (TP Study) and to retrospectively compare it with a triptorelin acetate (11.25 mg) 3-month formulation (TA Study). METHODS: We conducted two phase III, multicentre, single-stage, non-comparative, open-label studies. In the TP Study, patients with CPP received an intramuscular injection of triptorelin pamoate 11.25 mg at baseline and 3 months after baseline. Hormonal changes as well as safety and efficacy endpoints were measured at baseline, 3 months, and 6 months. RESULTS: The baseline characteristics of the 37 patients in the TP Study were similar to those of the TA Study population. A suppressed luteinising hormone (LH) response (LH peak ≤3 IU/l) to the gonadotrophin-releasing hormone test at 3 months (primary endpoint) occurred in 83.8 and 82.8% of the cases in the TP and the TA Study, respectively. At 6 months, a suppressed LH response occurred in 86.5 and 96.8% of the cases in the TP and the TA Study, respectively. Pubertal development was slowed in both studies. Adverse events were mild to moderate and resolved without sequelae in the TP Study. CONCLUSION: Triptorelin pamoate 11.25 mg administered at 3-month intervals is an effective and well-tolerated treatment in patients with CPP. The efficacy and safety profiles appear similar to those reported in the literature for triptorelin acetate 11.25 mg. © 2016 S. Karger AG, Basel.

Lanreotide in metastatic enteropancreatic neuroendocrine tumors.

BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

Symptomatic treatment with lanreotide microparticles in inoperable bowel obstruction resulting from peritoneal carcinomatosis: a randomized, double-blind, placebo-controlled phase III study.

PURPOSE: To investigate the somatostatin analog lanreotide as symptomatic treatment for inoperable bowel obstruction due to peritoneal carcinomatosis. PATIENTS AND METHODS: In all, 80 patients with peritoneal carcinomatosis, inoperable malignant digestive obstruction, and two or more vomiting episodes per day or nasogastric tube (NGT) who were previously treated with intravenous corticosteroids and proton pump inhibitors were randomly assigned to one 30-mg injection of lanreotide microparticles (n = 43) or placebo (n = 37) in a 10-day, double-blind, parallel-group phase. The primary end point was the proportion of patients responding on day 7 (one or fewer episodes of vomiting per day or no vomiting recurrence after NGT removal [for ≥ 3 consecutive days in both cases]). Vomiting frequency/NGT secretion volumes, nausea, abdominal pain, well-being, and safety were also assessed. Patients could then enter an open-label lanreotide-only phase. The study was conducted at 22 European hospitals. RESULTS: More patients receiving lanreotide than placebo were responders; this difference was not statistically significant for the intent-to-treat (ITT) population on the basis of diary cards (primary analysis; 41.9% [18 of 43] v 29.7% [11 of 37], respectively; odds ratio, 1.75; 95% CI, 0.68 to 4.49; P = .24) but was statistically significant for the corresponding supportive per protocol analysis (57.7% [15 of 26] v 30.4% [seven of 23]; P < .05) and ITT analysis, on the basis of investigators' assessments (50.0% [19 of 38] v 28.6% [10 of 35]; P < .05). Improvements in well-being were significantly greater with lanreotide on days 3, 6, and 7. No significant differences were observed for other secondary end points. Only two (mild/moderate) treatment-emergent adverse events were considered related to lanreotide. CONCLUSION: These results show that lanreotide has some efficacy and is safe in the symptomatic treatment of patients with inoperable bowel obstruction due to peritoneal carcinomatosis.

Randomized, placebo-controlled, double-blind study of the efficacy of lanreotide 30 mg PR in the treatment of pancreatic and enterocutaneous fistulae.

OBJECTIVE: Continuous intravenous infusion of somatostatin improves the natural course of digestive fistulae. Lanreotide 30 mg PR is a synthetic analogue of somatostatin with pharmacological activity extending to at least 10 days after intramuscular administration. Its effectiveness was assessed in patients with simple externalized digestive fistulae in a randomized, doubleblind, placebo-controlled study. METHODS: Patients demonstrating a reduction of at least 50% of fistula output within 72 hours after a first double-blind intramuscular injection of lanreotide or placebo were considered to be responders (primary end point) and continued the double-blind treatment to a maximum of 6 injections at 10-day intervals. Other endpoints included fistula closure rate and time to closure. Blind was lifted for nonresponders, and those initially on placebo were then treated with open-label lanreotide. RESULTS: Following the first double-blind injection, 35 of 54 patients (64.8%) on lanreotide were responders versus 20 of 53 (37.7%) on placebo, ie, a 3.1 times higher response likelihood on lanreotide compared with placebo (P = 0.006). Group mean reduction of fistula output at 72 hours was 45.1% and 8.9%, respectively (P = 0.005). Lanreotide compared with placebo had no effect on closure rate which averaged 77% but median time to fistula closure was shorter on lanreotide, based on Kaplan-Meier analysis, although no statistical significance was achieved. CONCLUSION: Compared with placebo, intramuscular lanreotide 30 mg PR significantly decreases digestive fistulae output at Day 3 and shortens time to fistula closure by 9 days. ClinicalTrials.gov registration number: NCT00729313.

Long-acting lanreotide in adolescent girls with constitutional tall stature.

BACKGROUND/AIMS: The aim of the study was to evaluate the efficacy and safety of lanreotide prolonged release (PR) 30 mg (long-acting lanreotide) in girls with constitutional tall stature (CTS). METHODS: This open label prospective study included 35 girls (mean age 12.6 years) with CTS and a predicted adult height of >180 cm. Intramuscular injections of lanreotide PR 30 mg were given every 14 days, for a minimum of 12 months and up to 36 months. Adult height was compared with pretreatment predicted height. RESULTS: The mean predicted adult height was reduced by 3.8 cm (95% CI 3.7-4.9 cm) in the restricted intent-to-treat population. Mean growth velocity decreased from 7.9 +/- 1.5 cm/year at preinclusion to 1.7 +/- 2.3 cm/year at the last visit on treatment (n = 35). Gastrointestinal adverse events and cholelithiasis were reported in 35/37 patients and 5/37 patients, respectively. There was 1 withdrawal due to gastrointestinal disorders. CONCLUSIONS: Biweekly intramuscular lanreotide PR 30 mg given to girls with CTS after the onset of pubertal development reduced adult height as compared with predicted height. Treatment-associated adverse events were consistent with the overall safety profile of lanreotide 30 mg PR and did not deter most patients from long-term treatment.

Control of IGF-I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly.

BACKGROUND: An essential criterion for control of acromegaly is normalization of IGF-I levels. Somatostatin analogues act to suppress IGF-I and GH levels. OBJECTIVE: To assess the efficacy and safety of 48 weeks titrated dosing of lanreotide Autogel. DESIGN: Open-label, multicentre, phase III, 48-week trial. METHODS: Patients with active acromegaly (IGF-I levels > 1.3 times upper limit of age-adjusted normal range) were recruited. Twelve injections of lanreotide Autogel were given at 28-day intervals: during the 16-week fixed-dose phase, patients received 90 mg; in the 32-week dose-titration phase, patients received 60, 90 or 120 mg according to GH and IGF-I levels. Intention-to-treat analysis was performed to determine the proportion of patients with normalized age-adjusted IGF-I levels at study end. Secondary evaluations included GH levels, clinical acromegaly signs and safety. RESULTS: Fifty-seven of 63 patients completed the study. Lanreotide Autogel resulted in normalized age-adjusted IGF-I levels in 27 patients (43%, 95% CI 31-55). Mean GH levels decreased from 6.2 to 1.5 microg/l at study end, with 53 of 62 patients (85%) having GH levels < or = 2.5 microg/l (95% CI 76.7-94.3) and 28 of 62 patients (45%) with levels < 1 microg/l (95% CI 32.8-57.6). Twenty-four (38%) had both normal IGF-I levels and GH levels < or = 2.5 microg/l. Acromegaly symptoms reduced significantly in most patients throughout the study. The most common adverse events were gastrointestinal, as expected for somatostatin analogues. CONCLUSIONS: Using IGF-I as primary end-point, 48 weeks lanreotide Autogel treatment, titrated for optimal hormonal control, controlled IGF-I and GH levels effectively, reduced acromegaly symptoms and was well tolerated.

Luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer: a review of their discovery, development, and place in therapy.

BACKGROUND: Early identification of the biological activity of luteinizing hormone-releasing hormone (LHRH) paved the way for the synthesis of analogues with enhanced potency and biological properties. Early testing in animal models and humans provided insight into the potential clinical uses of these substances, and, within 10 years, LHRH-agonist therapy had become available for use in patients with advanced prostate cancer (PC). Over time, the role of LHRH-agonist therapy has expanded to include use as part of multimodal treatment regimens throughout the course of the disease. OBJECTIVES: This article reviews the discovery and development of LHRH agonists and summarizes the clinical evidence for their efficacy in PC. METHODS: Relevant clinical studies were identified through searches of the English-language literature indexed on MEDLINE through May 2006. The main search terms were prostate cancer and LHRH agonist. RESULTS: Results of the initial therapeutic trials of sustained-release depot formulations of LHRH agonists in patients with PC were reported in the mid-1980s, indicating that these agents were effective and well tolerated in improving clinical symptoms and producing medical castration. Longer-term studies and subsequent meta-analyses of randomized controlled trials in patients with advanced PC found no significant differences in overall survival when single-therapy androgen suppression was achieved through the use of LHRH-agonist therapy or orchiectomy. Randomized trials have reported significant improvements in disease-free and overall survival in patients with locally advanced or high-grade PC treated with LHRH agonists in addition to radiotherapy. Several prospective randomized trials have reported decreases in rates of positive surgical margins with short-term (6 weeks to 4 months) neoadjuvant LHRH-agonist therapy in patients with stage T1 to T3a PC undergoing prostatectomy. Definitive comparisons of immediate and delayed treatment in patients with biochemical relapse have not been reported. However, the results of several studies suggest that immediate LHRH-agonist therapy (or orchiectomy) may improve the course of disease progression and survival. The risks of long-term treatment (eg, osteoporosis; fracture; anabolic loss of muscle mass, with a tendency toward weight gain) must be considered carefully in patients who are likely to receive chronic LHRH-agonist therapy. Intermittent schedules have been developed to reduce the adverse effects associated with LHRH-agonist therapy; some reports support sparing effects on bone and muscle mass and relative improvements in toxicities during off-therapy periods, whereas others have documented continuing decreases in bone mineral density (BMD), with the rate of bone loss highest during the early cycles of therapy. Bisphosphonate therapy has been shown to increase BMD in patients with PC and may therefore be beneficial when overt symptoms of osteopenia or osteoporosis are present. CONCLUSIONS: LHRH-agonist therapy has been the mainstay of treatment for advanced PC for >20 years. Clinical evidence supports expanding use of these agents at an earlier stage of disease and as part of multimodal regimens that include radiotherapy. There is a need for further study of the efficacy of adjuvant LHRH-agonist therapy along with prostatectomy, in patients with biochemical failure, in intermittent regimens, and in conjunction with cytotoxic therapies in late-stage disease.

Three-month sustained-release triptorelin (11.25 mg) in the treatment of central precocious puberty.

OBJECTIVE: Depot GnRH agonists are commonly used in the treatment of central precocious puberty (CPP). The triptorelin 11.25 mg 3-month depot, currently used in adult indications, had not previously been evaluated in CPP. DESIGN: This was a multicenter, open-label, 12 month trial conducted in 64 CPP children (54 girls and 10 boys), treated quarterly. METHODS: Children with a clinical onset of pubertal development before the age of 8 years (girls) or 9 years (boys), pubertal response of LH to GnRH > or = 7 IU/l, advanced bone age > 1 year, enlarged uterus (> or = 36 mm) and testosterone level > or = 0.5 ng/ml (boys), were included. Suppression of gonadotropic activation, as determined from serum LH, FSH, estradiol or testosterone, and pubertal signs were assessed at Months 3, 6 and 12. RESULTS: GnRH-stimulated peak LH < or = 3 IU/l, the main efficacy criterion, was met in 53 out of 62 (85%), 60 out of 62 (97%) and 56 out of 59 (95%) of the children at Months 3, 6 and 12 respectively. Serum FSH and sex steroids were also significantly reduced, while pubertal development regressed in most patients. Mean residual triptorelin levels were stable from Month 3 through to Month 12. The triptorelin 3-month depot was well tolerated. Severe injection pain was experienced in only one instance. Five girls experienced mild-to-moderate or severe (one girl) withdrawal bleeding. CONCLUSIONS: The triptorelin 3-month depot efficiently suppresses the pituitary-gonadal axis and pubertal development in children with CPP. This formulation allows a 3-fold reduction, over the once-a-month depot, in the number of i.m. injections required each year.

Pharmacodynamic equivalence of a decapeptyl 3-month SR formulation with the 28-day SR formulation in patients with advanced prostate cancer.

AIMS: The objective of the study was to assess the pharmacodynamic equivalence of LHRH analogue triptorelin 3-month and 28-day SR formulations. METHODS: Patients with documented locally advanced or metastatic prostate cancer were randomized to receive one injection of the 3-month formulation (n = 63) or three injections at 28-day intervals of the 28-day formulation (n = 68). Group-chemical castration rates defined as the percentage of patients reaching a testosterone plasma level

Efficacy of lanreotide 30 mg on prevention of pain relapse after oral refeeding in patients with necrotizing acute pancreatitis. A phase II prospective multicentre study.

BACKGROUND: Pain relapse after oral refeeding occurs in 21% of the patients with acute pancreatitis, and in 35% of those with CT Balthazar's score > or =D [Gut 1997;40:262]. Somatostatin analogues may decrease the pain relapse rate by inhibiting exocrine pancreatic secretion. AIMS, PATIENTS AND METHODS: To assess the frequency of pain relapse in patients with acute necrotizing pancreatitis after treatment with one intramuscular injection of lanreotide 30 mg on the day before refeeding. The refeeding procedure was standardized and progressive. RESULTS: 23 patients were included in 4 centres. Acute pancreatitis was alcoholic (n = 11), biliary (n = 7), other (n = 5). Twelve patients had > or =3 Ranson's criteria. Balthazar's score (1985) was D or E in 7 and 16 patients, respectively. Median duration of pain and of interruption of oral feeding were 11 (3-23) and 16 (5-34) days, respectively. Median hospital stay was 22 (9-41) days. Only 1 patient (4.3 %) had pain occurring 3 days after refeeding. CONCLUSION: Pain relapse occurred in 4.3% of patients pretreated with the somatostatin analogue lanreotide, and this figure is lower than the expected 35% rate which was previously reported without preventive treatment. This suggests that one intramuscular injection of lanreotide 30 mg on the day before refeeding could decrease pain relapse in patients with acute necrotizing pancreatitis, but has to be confirmed in a phase III study.

Equivalence of the 3-month and 28-day formulations of triptorelin with regard to achievement and maintenance of medical castration in women with endometriosis.

OBJECTIVE: The present study aims at demonstrating the equivalence of the 28-day and 3-month formulations of triptorelin SR (sustained release) in terms of percentage of patients achieving castration levels of estradiol (<==50 pg/mL) 84 days after treatment initiation. DESIGN: A phase II, prospective, randomized, multicenter, open study was conducted in two parallel groups of women with endometriosis. SETTING: Academic hospitals. PATIENT(S): Seventy-two women with endometriosis. were treated with a single intramuscular injection of 3-month triptorelin SR, and 74 patients were treated with one intramuscular injection of 28-day triptorelin SR every 28 days for 3 months. INTERVENTION(S): As part of two parallel treatment groups, 72 women were given a single intramuscular injection of 3-month triptorelin SR, and 74 women were given one intramuscular injection of 28-day triptorelin SR every 28 days for 3 months. MAIN OUTCOME MEASURE(S): Percentage of patients achieving castration levels of estradiol at the end of the treatment period. RESULT(S): Patients participated in the study until resumption of menses. Ninety-seven percent of patients given the 3-month formulation and 94% of those given the 28-day formulation were in a state of medical castration on day 84. The mean time to achieve castration was shorter for the 3-month formulation, and the duration of castration was significantly longer. The FSH and LH parameters were comparable, though not always identical. CONCLUSION(S): The pharmacodynamic effects of the Decapeptyl SR 3-month formulation are equivalent to those of the 28-day formulation. The 3-month formulation provides the added advantage of a longer maintenance of medical castration in women who have endometriosis.