Efficacy and Safety of an Octreotide Implant in theTreatment of Patients with Acromegaly

Carla Chieffo1, David Cook2, Qinfang Xiang1, Lawrence A. Frohman3

1 Endo Health Solutions, Inc., Clinical Research & Development, Malvern PA, USA; 2 Oregon Health &Science University, Portland Oregon, USA; 3 University of Illinois at Chicago, Department of Medicine,Chicago, IL, USA CLINICAL TRIALS REGISTRATION NUMBER: NCT00765323

Context: Acromegaly is caused by excessive GH secretion and IGF-1 overproduction. The goals oftreatment are to reduce GH and IGF-1 values to normal and relieve associated symptoms.

Objective: To demonstrate that octreotide implant (84 mg) is safe and efficacious in patients withacromegaly who were responsive to prior monthly octreotide LAR injections.

Design: Phase 3, open-label study. Before treatment, subjects received a stable monthly dose ofoctreotide LAR injections (10 to 40 mg) for �3 months. Randomization was in a 3:1 ratio to either6-month octreotide implant or monthly octreotide LAR injections.

Setting: This was a multicenter, international study conducted in private or institutional practices.

Subjects: Enrollment included 163 subjects (aged �18 years) with acromegaly.

Main Outcome Measure: To evaluate the efficacy, safety, and tolerability of the octreotide implantduring 24 weeks of treatment.

Results: After 24 weeks, the success rate of the implant for maintenance of IGF-1 and GH levels was86% (95% CI: 80.3%) compared to 84% (95% CI: 73.8%) for octreotide LAR. Serum octreotideconcentrations after implant insertion increased within 8 days and peaked between day 14 and 28.Overall safety of the octreotide implant and octreotide LAR were similar. Diarrhea and headachewere more frequent with the implant, while cholecystitis and hypertension were more frequentwith octreotide LAR.

Conclusions: In this pivotal phase 3 study, the octreotide implant maintained reduced blood levelsof GH and IGF-1 with continuous octreotide release over 6 months, which was well tolerated.

Acromegaly is a rare, slowly progressive, chronic dis-order that is the consequence of excess GH secre-

tion, most commonly caused by a pituitary adenoma. Hy-persecretion of GH leads to overproduction of IGF-1, aprincipal mediator of GH activity in a feedback loop thatin turn causes enlargement of bones and soft tissues. Othereffects of excessive GH levels are an increased incidence ofdiabetes and glucose intolerance in patients with acromeg-aly. Thus, the goal of treatment in acromegaly is to reduceGH and IGF-1 to normal levels, decrease or eliminate theassociated symptoms, and prevent comorbidities associ-ated with the disease.

Primary treatment for most patients with acromegaly issurgical excision of the pituitary tumor (1, 2). Radiother-apy can be used as an adjunct to surgery; however, due toits adverse effects, the enthusiasm for radiation has dimin-ished (3). Medical treatment is intended for subjects withacromegaly not adequately treated by surgery, in subjectswhom surgery is contraindicated, refused by the subject orposes a high-risk, or for those subjects waiting for radio-therapy to become effective. Currently available medicaltherapies consist of somatostatin analogs (i.e., octreotide,lanreotide), dopamine agonists (cabergoline and bro-mocriptine), and a GH receptor antagonist (pegvisomant).

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2013 by The Endocrine SocietyReceived May 17, 2013. Accepted August 5, 2013.

Abbreviations:

doi: 10.1210/jc.2013-2262 J Clin Endocrinol Metab jcem.endojournals.org 1

J Clin Endocrin Metab. First published ahead of print August 22, 2013 as doi:10.1210/jc.2013-2262

Copyright (C) 2013 by The Endocrine Society

Octreotide is a synthetic derivative of the endogenoushormone somatostatin (4, 5). It inhibits GH secretion andis the most extensively studied and used somatostatin an-alog (6, 7). Octreotide acetate is currently approved by theUnited States Food and Drug Administration (US FDA) asSandostatin® (octreotide acetate) Injection and as longacting Sandostatin LAR® Depot (octreotide acetate forinjectable suspension) (octreotide LAR).

Treatment with multiple daily injections of octreotideacetate and octreotide LAR (every 3 to 4 wk) results inrelatively high fluctuations of octreotide concentrationsover short dosing intervals. A longer-lasting treatmentthat provides less variable peak-to-trough variation over alonger dosing interval would likely result in more constantoctreotide levels, potentially leading to more stable GHand IGF-1 concentrations and a better tolerability profile.A long-term treatment option for suppression of GH andIGF-1 would be more convenient for the patient vis-à-visthe benefit of less frequent office visits and a significantreduction in the discomfort of monthly intramuscular(IM) injections. By extension, the associated health careburden provided by the physician would be decreased aswell.

Implant technologies provide a potential means toachieve continuous drug release while improving conve-nience by extending the treatment interval. Hydrogel im-plant technology is currently used in once-yearly gonad-otropin-releasing hormone (GnRH)–containing implantsfor the treatment of advanced prostate cancer (8) and forthe treatment of children with central precocious puberty(9). The GnRH hydrogel implant provided more consis-tent drug release and a longer dosing interval (1 y) whencompared with a depot injectable GnRH agonist admin-istered once every 6 mo for prostate cancer (10).

Using this technology, a subcutaneous octreotide hy-drogel implant (hereafter referred to as the octreotide im-plant) was developed that contains octreotide in pelletizedform within a hydrogel capsule that controls the rate ofdiffusion into the systemic circulation, offering continu-ous release over 6 mo.

The purpose of this study was to determine whether theoctreotide implant provides adequate octreotide levels tosuppress GH and IGF-1 in patients with acromegaly whowere previously successfully treated with a monthly oc-treotide LAR injection.

Materials and Methods

SubjectsEligible subjects in this multicenter, international, phase 3

study were � 18 y of age, with a confirmed diagnosis of acro-megaly, defined as a serum IGF-1 concentration � 20% above

the upper limit of age-adjusted levels and a serum GH concen-tration � 1.0 ng/mL following an oral glucose tolerance test(OGTT) or confirmation of a GH-secreting tumor on pathologicexamination of surgically removed tissue. Subjects had demon-strated responsiveness to octreotide treatment (IGF-1 � 20%above the upper limit of normal age-adjusted levels and GH �

2.5 ng/mL) during the screening period (�2 mo).All subjects provided informed consent prior to participation

in the study. The study was approved by the independent ethicscommittee or institutional review board (IRB) at each center andcomplied with the Declaration of Helsinki, the Harmonized Tri-partite Guideline for Good Clinical Practice from the Interna-tional Conference on Harmonization, and local laws.

Study Design and TreatmentsThis was a phase 3, open-label study evaluating the safety and

efficacy of an 84-mg octreotide implant in 163 subjects (safetypopulation) with acromegaly. After a screening period (�2 mo),subjects entered a 6-mo treatment phase. Prior to screening, sub-jects received a stable dose of monthly octreotide depot injections(10 to 40 mg) for a minimum of 3 consecutive months.

On day 1 of treatment, eligible subjects were randomly as-signed in a 3:1 ratio to either the 6-mo octreotide implant oroctreotide LAR injections given every 4 wk. Subjects randomizedto the implant arm, had one 84-mg octreotide implant insertedsubcutaneously in the inner aspect of their upper nondominantarm under local anesthesia using an insertion tool (trocar device).Subjects in the injection arm started 4-weekly injections of oc-treotide LAR at their previous effective and stable dose (i.e., 10to 40 mg every 4 wk). Subjects returned every 4 wk for safety,efficacy and pharmacokinetic assessments. Subjects had theirimplant removed after 6 mo under local anesthesia using a he-mostat. The implantation and removal procedures were per-formed by a health care provider.

Efficacy AssessmentsBlood samples (4 mL) for the measurement of serum IGF-1

and GH concentrations were taken at screening, baseline (justprior to treatment), and at each visit. Samples were sent to acentral laboratory (Esoterix Endocrinology, Belgium and USA)for analysis of IGF-1 and GH concentrations using validatedchemiluminescent assays. The coefficient of variation (CV) foraccuracy of the calibration standards and for the interand intra-day precision of the quality control (QC) samples were all � 7%for both methods. Subjects were asked to complete a quality oflife (QOL) questionnaire at screening, month 3, and before im-plant removal at month 6. The questionnaire was a Short Formhealth survey of 36 questions (SF-36; Quality of Life Question-naire) (11). Subjects were also asked to complete a treatmentassessment form at screening and before implant removal atmonth 6. The questionnaire asked subjects specific questionsabout their satisfaction with their current and previous treatmentfor acromegaly. At screening, baseline, month 3, and month 6(before implant removal), the physician assessed the signs andsymptoms of acromegaly (i.e., headache, arthralgias, fatigue,perspiration, paresthesias, and soft-tissue swelling). Addition-ally, tumor size was evaluated by MRI imaging at screening andprior to implant removal at month 6 by a centralized reader whowas unaware of the form of treatment the subjects received.

2 Octreotide implant for acromegaly J Clin Endocrinol Metab

Safety AssessmentsSafety was assessed by adverse events (AEs) categorized by

severity and relationship to study medication, physical exami-nation, vital signs, electrocardiograms, gallbladder ultrasound,hematology, clinical chemistry, thyroid profiles, and glycosy-lated hemoglobin. All nondiabetic subjects, regardless of treat-ment arm, had an OGTT at screening, month 3 and month 6(before implant removal) after an overnight fast of at least 12 hprior to the test. Blood samples were drawn before at 30, 60, 90,and 120 min after 75 g of glucose administration for the deter-mination of serum GH and glucose. Subjects with diabetes wereexcluded from the OGTT and had their IGF-1 and GH drawn inthe fasting state.

Pharmacokinetic AssessmentsBlood samples (4 mL) for the determination of serum oc-

treotide concentrations were collected monthly from all subjects.For subjects in the implant arm only, blood samples were col-lected on day 1 (prior to implant insertion [0 hr], at 2 and 6 h postimplant insertion) and at week 24 or early termination (at 2 and6 h post implant removal).

In addition, a subset of 15 subjects returned for additionalblood sampling at 12, 24, 48, and 72 h after implantation, andon days 8, 12, 16, 20, 24, 32, and 40, with a visit window of �1 d.

Serum octreotide concentrations were determined by Phar-maNet Canada Inc. by a validated assay using high performanceliquid chromatography with tandem mass spectrometry detec-tion. All samples from each subject were, when possible, ana-lyzed in the same assay. Study samples were analyzed singly witha calibration curve and 4 sets of QC samples analyzed in dupli-cate using the same procedure. The validated calibration rangefor the assay was from 50 to 4000 pg/mL. Values below 50 pg/mLwere reported as � 50, and were treated as zero in the PKanalysis.

Statistical MethodsThe intent-to-treat (ITT) population consisted of all random-

ized subjects who were treated with either the implant or at least1 injection of octreotide LAR. They had a baseline mean GHlevel � 2.5 ng/mL and a baseline mean IGF-1 within 20% abovethe age-adjusted normal range and had at least 1 on-treatmentGH or IGF-1 concentration during the treatment phase. Baselinewas defined as the mean GH and IGF-1 values obtained duringscreening and pretreatment (basal). Because basal IGF-1 and GHlevels were not available prior to treatment, 26 subjects wereexcluded from the ITT population.

The primary efficacy endpoint of the study was to assess thesuccess rate of treatment based on the average concentration ofGH and IGF-1 levels over the 24 wk treatment period comparedwith pretreatment concentrations in the implant arm. The nullhypothesis of this study, assessed for the implant arm only, wasthat the octreotide acetate subcutaneous implant, given onceevery 6 mo, does not provide adequate maintenance of IGF-1 andGH in subjects with acromegaly.

This hypothesis was assessed via the following decision rulesfor the pharmacodynamic outcomes. A subject was required tosatisfy both decision rules in order to be determined a “success”:

Maintenance of mean on-treatment IGF-1 within the age-adjusted normal range or � 20% above the Baseline mean valueand;

Maintenance of mean on-treatment GH � 2.5 ng/mL or �

20% above the Baseline mean value.The primary analysis was performed using the observed cases

(OC) data from the ITT population. The mean on-treatmentIGF-1 and GH values over the 24-wk treatment period werecalculated as the average of the nonmissing IGF-1 and GH valuesat weeks 4, 8, 12, 16, 20, and 24, respectively.

This study was not powered to compare the implant andoctreotide LAR arms. Subgroup analyses included: sex, agegroup (�65, �65 y), country, history of diabetes and pretreat-ment octreotide LAR dose (10–20 mg, 30–40 mg). The successrate for the subgroup of subjects who entered the study withnormal pretreatment concentrations of IGF-1 and GH was de-fined as the percent of subjects with mean on-treatment IGF-1within the age-adjusted normal range and mean on-treatmentGH � 2.5 ng/mL. The proportion of subjects deemed a successwas derived and a 95% one-sided confidence interval (CI) (CI,with a lower bound) for that proportion was constructed. If thelower bound of the observed one-sided CI was � 75%, the nullhypothesis for this study was rejected in favor of the alternativethat the implant did provide adequate maintenance of IGF-1 andGH in subjects with acromegaly.

Secondary efficacy was descriptively assessed for each treat-ment group for the ITT data set and included: success rates;physician assessment of signs and symptoms of acromegaly;QOL SF-36 questionnaire; SF-36 physical and mental compo-nent scores; pituitary tumor size (volume); Patient’s TreatmentAssessment; maintenance of mean on-treatment GH � 1 ng/mLand mean on-treatment IGF-1 within the age-adjusted normalrange or � 20% above the baseline mean value over the 24-wktreatment period. Additional supportive efficacy parameters in-cluded success rates over 24 wk of treatment.

Results

Study PopulationThe study population consisted of 163 subjects (im-

plant, n � 122; octreotide LAR, n � 41; Table 1). Sixsubjects in the implant arm and 1 subject in the octreotideLAR arm were withdrawn due to AEs prior to completingthe study. The ITT population consisted of 137 subjectswho were treated with either the implant (n � 100) or withat least one injection of octreotide LAR (n � 37), had astarting (Days –60, –30, and 0) mean GH level � 2.5ng/mL, and a starting mean IGF-1 � 20% above the age-adjusted normal range with at least one GH or IGF-1 con-centration measured during treatment. Prior to enroll-ment, more than half the subjects (53%) in the ITTpopulation had received octreotide LAR 20 mg (Table 2).

EfficacyIn the implant arm, the success rate for adequate main-

tenance of combined IGF-1 and GH levels at week 4 for theITT population was 83% (95% CI: 76.8%) which in-creased to 86% (95% CI: 80.3%) by week 24, as the pri-mary endpoint. In comparison, in the octreotide LAR arm,

doi: 10.1210/jc.2013-2262 jcem.endojournals.org 3

success rate for adequate maintenance of combined IGF-1and GH levels was 79% (95% CI: 67.2%) at week 4 and

84% (95% CI: 73.8%) by week 24. The profiles of meanGH and IGF-1 levels in the implant and octreotide LARarms were similar throughout the 24-wk duration of thestudy (Figure 1). Subgroup analyses by gender, age, base-line BMI, and country showed similar results to the overallpopulation in both the implant and octreotide LAR arms(data not shown).

There were no significant differences in the efficacyrates between subjects in either treatment arm related tothe pretreatment octreotide LAR dose (Table 3).

There were no observed trends based on reported val-ues or changes from baseline in any of the parametersevaluated that related to the physician assessment of signs

Table 1. Demographics Characteristics

ImplantOctreotide

LAR

Parameter (n � 122) (n � 41)Age (Years)

Mean (SD) 54.3 (11.4) 51.3 (11.9)Median 55 55

Gender (n, %)Male 35 (28.7%) 14 (34.2%)Female 87 (71.3%) 27 (65.9%)

Race (n, %)Caucasian 119 (97.5%) 41 (100.0%)Asian 2 (1.6%) 0Hispanic 1 (0.8%) 0

Weight (kg)Mean (SD) 85.6 (18.1) 90.2 (28.6)Median 83 82

BMI (kg/m2 )Mean (SD) 29.9 (5.0) 30.8 (6. 3)Median 29 30

Diabetes Mellitus 33 (27.05%) 7 (17.07%)Glucose Intolerance 18 (14.75%) 11 (26.83%)Years Since Diagnosis of Acromegaly

Mean (SD) 7.8 (6. 2) 6.2 (5.0)Median 5.4 5.1Min, Max 0.4, 27.2 0.3, 20.9

Baseline GH Level (n, %) a

�1 ng/mL 42 (34.4%) 15 (36.6%)�1 ng/mL and �2.5 ng/mL 62 (50.8%) 22 (53. 7%)�2.5 ng/mL and �5 ng/mL 17 (13.9%) 4 (9.8%)�5 ng/mL 1 (0.8%) 0

Baseline IGF-1 Level (n, %) a

Below Lower Limit of Age-AdjustedNormal Range

1 (0.8%) 2 (4.9%)

Within Age-Adjusted Normal Range 86 (70.5%) 34 (82.9%)Above Upper Limit of Age-AdjustedNormal Range to �20% above UpperLimit of Age-Adjusted Normal Range

29 (23.8%) 5 (12.2%)

�20% Above Upper Limit of Age-Adjusted Normal Range

6 (4.9%) 0

Baseline mean GH Level < 2.5 ng/mLand Baseline mean IGF-1 < 20%above age-adjusted normal range (n, %)No 22 (18.03%) 4 (9.76%)Yes 100 (81.97%) 37 (90.24%)

a Baseline GH and IGF-1 are means of values at Days �60, �30, and 1 (pre-treatment)). Of the 163 subjects in the safety population, 137 wereincluded in the ITT population.

Table 2. Prior Octreotide LAR Dose - ITT Population

Parameter ImplantOctreotide

LAR Total

Pre-Treatment Octreotide LAR Dose (n, %)N 100 a 37 13710 mg 5 (5.0%) 5 (13.5%) 10 (7.3%)20 mg 51 (51.0%) 21 (56.8%) 72 (52.6%)30 mg 36 (36.0%) 10 (27.0%) 46 (33.6%)40 mg 7 (7.0%) 1 (2.7%) 8 (5.8%)

a The dose was not recorded for one subject in the implant arm

4 Octreotide implant for acromegaly J Clin Endocrinol Metab

and symptoms. A mean score (SD) of 50 (10) in the Qualityof Life (SF 36) questionnaire would be expected for thegeneral population. All SF-36 scores obtained during thisstudy, regardless of visit and treatment arm, were � 50, aswould be expected in this population of subjects with ac-romegaly. No clinically significant changes in tumor vol-ume or shape were observed during the study in either theimplant or octreotide LAR arm.

When subjects (n � 97) were asked to select their pre-ferred treatment method for acromegaly, 82.5% (n � 80)selected the octreotide implant for its comfort. No changesfrom baseline were observed in the scores of other patienttreatment assessment scales, including assessment of treat-ment pain, for either the implant or octreotide LAR arm.

PharmacokineticsFollowing insertion of the octreotide subcutaneous im-

plant, serum octreotide concentrations increased within8 d and generally peaked between week 2 and 4 (Figure 2).The octreotide concentrations decreased modestly by48.6% (from 1544 to 93 pg/mL) from week 8 to week 24.The latter value was comparable to the mean serum oc-treotide concentration prior to implantation (817 pg/mL).The trough concentrations following octreotide LAR in-jections for the combined dose groups of 10 � 20 mg and30 � 40 mg remained relatively constant throughout the24-wk treatment period (Figure 2) suggesting that steady-state conditions had been established. There was a dosedependent increase in trough octreotide serum concentra-

Figure 1. Mean (�SE) serum GH and IGF-1 vs. time in the ITT population.

Table 3. Primary Efficacy Analyses as related to Pre-Treatment Octreotide LAR Dose

Implant (n � 100) Octreotide LAR (n � 37)

Pre-Treatment Octreotide LAR Dose Pre-Treatment Octreotide LARDose

Statistic /Visits

10 mg 20 mg 30 mg 40 mg 10 mg 20 mg 30 mg 40 mg

(n � 5) (n � 51) (n � 36) (n � 7) (n � 5) (n � 21) (n � 10) (n � 1)Weeks 4–24 5

(100.0%)48(94.1%)

26(72.2%)

6 (85.7%) 5(100.0%)

17(81.0%)

9(90.0%)

0

Figure 2. Mean (�SE) serum octreotide vs. time in the implant (n � 100) and octreotide LAR (n � 36) arms.

doi: 10.1210/jc.2013-2262 jcem.endojournals.org 5

tion between the 2 combined dosing groups. The studywas not designed to measure peak octreotide concentra-tions in subjects receiving monthly octreotide-LARinjections.

Higher serum octreotide concentrations were observedin female than in male subjects in the PK population. Thisappeared irrespective of how octreotide was administered(subcutaneous implant or injected intramuscularly (IM)).In the PK population approximately 70% of the implantarm and 64% of the octreotide LAR were females.

SafetyThe overall safety profile of the octreotide implant and

octreotide LAR were similar. A summary of AEs reportedby � 5 subjects is presented in Table 4. Diarrhea andheadache were more frequently reported in the implantarm, while cholecystitis and hypertension were more fre-quent in the octreotide LAR arm. Except for cholelithiasiswhich occurred at the end of the treatment period, therewas no apparent temporal relationship to the AE events,nor did the AE severity change over time.

There were no clinically significant changes in clinicalchemistry, hematology, vital signs, ECGs, physical exam-inations, thyroid hormone, glucose, or HbA1c levels.There were no clinically significant changes in number ofgallstones in the implant arm based on ultrasound anal-yses. However, in the octreotide LAR arm, the percentageof subjects with � 10 gallstones increased from 15% atbaseline to 22% at last visit and may have contributed tothe increased percentage of cholecystitis AEs in this arm.In the nondiabetic subjects, mean glucose levels during theOGTT remained normal in both treatment arms duringthe study. No significant changes occurred in HgbA1c orin fasting glucose in either nondiabetic or diabetic subjects(Supplementary Table 1).

Adverse events related to local tolerability in the im-plant arm were reported by 13% of subjects. These eventswere primarily due to implant site reaction, pain, and pru-ritus. There was 1 case each of implant site hematoma,

hemorrhage, inflammation, necrosis, edema, scar, and in-jection site pain. All 122 implants used in this study wereinserted per the study protocol. Four subjects withdrewdue to complications related to the implant. One subjectexperienced an implant breakage during implantation andone subject had a breakage during the treatment phase ofthe study. Four subjects had incomplete removal of theirimplants at the time of explantation. During the time ofexplantation 32 of 122 explants were broken. None of theimplant breakages or incomplete removals was associatedwith significant safety-related events. Sixteen (13.1%)subjects had reactions at the implantation site which werepredominantly associated with complications due to theimplantation procedure. Because of the breakages that oc-curred at implantation, the implantation procedure waschanged during the study to include the use of a hemostatfor creation of a pocket prior to implant insertion with theinsertion tool. After implementing this procedural change,no breakages occurred at implantations.

Two subjects with implants had higher than expectedoctreotide concentrations. In one subject, high octreotidelevels occurred on day 1 (Cmax�99,250 pg/mL), suggest-ing the implant had broken at the time of implantation.The octreotide concentration decreased by 50% within 4hr and was below 10,000 pg/mL by the next samplingperiod 8 d later. The octreotide concentration data becameavailable 6 wk post implantation, and at week 9 the im-plant was removed confirming the breakage. GH andIGF-1 data for this subject were not collected. A secondsubject had an elevated octreotide concentration at week12 (Cmax�19,812 pg/mL), suggesting that the implant hadbroken during the study period and not at the time ofimplantation. Octreotide concentrations collected 2-h af-ter implantation for this subject were within the expectedrange (496 pg/mL) also suggesting that the implant hadbroken during the study period. An ultrasound of the im-plant site confirmed implant breakage; however, the im-plant was not removed. This patient completed the 24-wktreatment schedule during which preimplantation GH andIGF-1 levels were maintained. Octreotide concentrationsremained elevated at the next sampling period 4 wk later(11,442 pg/mL), and then declined to concentrations ob-served in other subjects. No associated AEs or other clin-ically significant safety findings were observed in eithersubject.

Discussion

The primary goals for the treatment of acromegaly are tosuppress levels of GH and IGF-1 to the normal range andto minimize the associated symptoms and complications

Table 4. Summary of Adverse Events Reported by�5% of Overall Subjects

System Organ ClassPreferred Term

ImplantOctreotide

LAR Overall

(n � 122) (n � 41) (n � 163)n (%) n (%) n (%)

Diarrhea 12 (9.8%) 3 (7.3%) 15 (9.2%)Headache 12 (9.8%) 2 (4.9%) 14 (8.6%)Hypertension 10 (8.2%) 6 (14.6%) 16 (9.8%)Cholelithiasis 9 (7.4%) 3 (7.3%) 12 (7.4%)Nasopharyngitis 9 (7.4%) 1 (2.4%) 10 (6.1%)Arthralgia 6 (4.9%) 3 (7.3%) 9 (5.5%)Cholecystitis 1 (0.8%) 5 (12.2%) 6 (3.7%)

6 Octreotide implant for acromegaly J Clin Endocrinol Metab

of the disease. Currently, the primary medical treatment ofacromegaly is the use of the injectable synthetic soma-tostatin analogues (SSAs), octreotide or lantreotide. In thecurrent phase 3 study, we have shown that a new implantdelivery system of octreotide has an efficacy profile similarto that of octreotide LAR in subjects who were previouslytreated with the drug.

During the 6-mo duration of this study, GH and IGF-1levels were maintained in both the implant and octreotideLAR arms of the study. An advantage of the implant for-mulation is patient convenience, avoiding monthly IM in-jections and decreased discomfort. In the treatment as-sessment questionnaire, a majority of subjects selected theimplant for its comfort as their preferred treatmentmethod.

Another major potential advantage of the octreotideimplant delivery technology is the avoidance of large peakto trough fluctuations in octreotide concentrations as ob-served with other formulations (12). It can be speculatedthat reducing fluctuations in drug concentrations could beresponsible for the observation that both cholecystitis andoverall gall bladder-related AEs were lower in the implantarm than in the octreotide LAR arm. The inhibitory effectsof somatostatin (and SSAs) on gall bladder contractilityand bile flow, if dose dependent, could provide an expla-nation for this observation.

The pharmacokinetic profile of the 84-mg octreotideimplant showed a relatively stable and continuous drugdelivery over 6 mo. Subjects maintained serum octreotideconcentrations at or above those immediately prior to im-plantation (octreotide LAR trough concentration levels)over the 24-wk treatment phase.

The apparent release rate of octreotide from the im-plant over the total 24-wk time course was not constant,appearing higher during the first 2 mo compared to the last4 mo. Part of the higher octreotide serum concentrationsobserved during the first 2 mo may have been due to con-tinuing contribution of octreotide from the preimplantoctreotide LAR injection. Quantitative assessment of thispossibility to the circulating octreotide levels was not eval-uated in this study. Regardless, the overall release ratefrom the implant was sufficient to maintain the mean se-rum concentration of octreotide above preimplant con-centrations over the total time course of the treatmentphase and to achieve overall efficacy in subjects previouslymaintained on varying doses (10 to 40 mg) of monthly IMinjections of octreotide LAR.

There was a lag period from the time of implantation tothe time serum octreotide concentrations rose above pre-implant levels. Although, the precise duration of this lagperiod was not assessed in this study, the lag period in aprevious phase 2 study was found to be approximately 1

wk (13). The Tmax was determined to be approximately15 d in the present study, which was similar to that pre-viously reported.

There was an apparent gender difference in the serumoctreotide concentrations. Female subjects had higherconcentrations regardless of the route of administration.The precise mechanism for higher concentrations in fe-males is not known; however, possible causes may be alower volume of distribution, a lower clearance of oc-treotide, or a combination of both. Higher octreotide con-centrations in females after adjusting for BMI and oc-treotide LAR dose have been previously reported (12) andwe have observed similar results in preclinical studies inBeagle dogs (unpublished data).

Treatment with both the 84-mg octreotide implant andoctreotide LAR was well tolerated during this study. Themost commonly reported AEs with SSAs have been gas-trointestinal (GI) disorders, cholelithiasis, headache, andinjection site reactions (13, 14). Since SSAs inhibit thesecretion of insulin, glucagon, and thyroid stimulatinghormone, changes in glucose metabolism and thyroidfunction were monitored and no clinically relevantchanges were found.

As expected, in the current study, the most frequentlyreported AEs in the octreotide implant group were diar-rhea, headache, hypertension, cholelithiasis, nasopharyn-gitis, and arthralgias. There were no significant changes inthe number of gallstones in the implant arm.

The cardiac abnormalities observed in this study wereconsistent with those reported with injectable SSAs. Themost frequently reported cardiovascular AE in both theimplant and octreotide LAR arms was hypertension.There was no treatment-related edema or clinically signif-icant changes in the 12-lead ECG parameters in either theimplant or the octreotide LAR arm of the study. Relativeto the octreotide LAR arm, there was a trend for increasedQTcB prolongation in the subjects in the implant arm;however, no subject had prolongations � 500 msec.

Although there were several implant breakages and in-complete removals, none was associated with any signif-icant safety related events. Higher than expected serumoctreotide concentrations were observed in two subjectsduring this study. In a previous phase 2 study, an evenhigher serum octreotide concentrations was observed in 1subject (Cmax � 100,790 pg/mL) (15). No significant AEswere reported in any of these subjects despite the fact thatelevated serum octreotide levels may have persisted forseveral weeks after implant breakage. Based on the pre-scribing information, Sandostatin® Injection has beenwell tolerated even at high doses (13). Intravenous admin-istration of up to 120 mg did not result in serious adverseeffects. However, subcutaneous doses of 2.5 mg of San-

doi: 10.1210/jc.2013-2262 jcem.endojournals.org 7

dostatin® Injection have caused hypoglycemia, flushing,dizziness, and nausea. The plasma concentration of oc-treotide is not reported in the label for these dosing situ-ations, with the exception of the 1-mg intravenous (IV)dose, where the peak concentration was 2,800 pg/mL.

Pharmacokinetic modeling of Sandostatin® 30 mggiven as an IV infusion over 20 min and of Sandostatin®

120 mg infused over 8 h in healthy volunteers, based on theestimated Sandostatin® pharmacokinetic parameters pro-vided in the label, resulted in estimated Cmax concentra-tions of 1,298,000 pg/mL and 1,640,000 pg/mL, respec-tively. These concentrations are 13 to 16.5 times higherthan the maximal concentration observed in subjects withimplant breakages (�100,000 pg/mL). The greater than10-fold margin for the maximal serum concentrationsmay be underestimated, since as stated in the Sandosta-tin® label, octreotide clearance may be nonlinear, de-creasing at doses greater than 600 �g/day.

In this pivotal phase 3 study, octreotide implants had asimilar efficacy profile to injectable octreotide LAR, main-tained normal blood levels of GH and IGF-1 with contin-uous octreotide release over 6 mo, and was well tolerated.Its efficacy, tolerability, and patient acceptance suggestthat the implant is a viable alternative for long term oc-treotide therapy of acromegaly in patients that are cur-rently well-controlled on other SSAs.

Acknowledgments

Guissou Dabiri, PhD provided editorial assistance in the prep-aration of this manuscript.

Address all correspondence and requests for reprints to: Law-rence A. Frohman, MD University of Illinois at Chicago Depart-ment of Medicine Section of Endocrinology, Diabetes, & Me-tabolism, 1747 W Roosevelt Rd. Room 517, Chicago, IL 60608USA Phone: 312–996-7525 Fax: 312–355-3590 E-mail:frohman@uic.edu.

DISCLOSURE STATEMENT: CC and QX are employed byEndo Health Solutions, Inc. DC and LF were consultants forEndo Health Solutions Inc.

REPRINT REQUEST: Lawrence A. Frohman, MD Univer-sity of Illinois at Chicago Department of Medicine Section ofEndocrinology, Diabetes, & Metabolism, 1747 W Roosevelt Rd.Room 517, Chicago, IL 60608 USA Phone: 312–996-7525 Fax:312–355-3590 E-mail: frohman@uic.edu

This work was supported by .

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