Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly

Clinical Endocrinology (2000) 53, 577±586 Paper 1134

577q 2000 Blackwell Science Ltd

Comparison of octreotide acetate LAR and lanreotideSR in patients with acromegaly

P. Chanson², V. Boerlin*, C. Ajzenberg³,

Y. Bachelot¶, P. Benito§¶, J. Bringer**, P. Caron²²,

B. Charbonnel³³, C. Cortet§§, B. Delemer¶¶,

F. Escobar-JimeÂnez***, L. Foubert§, S. Gaztambide**²,

F. Jockenhoevel²¶, J. M. Kuhn*², J. Leclere*³,

Y. Lorcy³³, L. Perlemuter*¶, H. Prestele*, P. Roger²*,

V. Rohmer²³, R. Santen³§, G. Sassolas²§,

W. A. Scherbaum³§, J. Schopohl³¶, E. Torres***,

C. Varela**³, F. Villamil**§ and S. M. Webb**¶

*Novartis Pharma AG, Clinical Research and

Development, Basel, Switzerland; ²Centre Hospitalier

Universitaire de BiceÃtre, Le Kremlin-BiceÃtre; ³HoÃpital

LariboisieÁ re; §HoÃpital PitieÂ SalpeÂtrieÁre, Paris; ¶Centre

Hospitalier Universitaire de Grenoble, Grenoble;

**HoÃpital Lapeyronie, Montpellier; ²²Centre Hospitalier

Universitaire de Rangueil, Toulouse; ³³HoÃtel Dieu,

Nantes; §§Centre Hospitalier R Universitaire, Lille;

¶¶HoÃpital Maison Blanche, Reims; *²HoÃpital de Bois

Guillaume, Bois Guillaume; *³HoÃpital Brabois,

Vandoeuvre-LeÁs-Nancy; *§HoÃpital Sud, Rennes;

*¶Centre Hospitalier Henri Mondor, CreÂteil; ²*HoÃpital du

Haut-Leveque, Pessac; ²³Centre Hospitalier R

Universitaire, Angers; ²§HoÃpital Neuro-Cardiologique,

Lyon, France; ²¶Universitaetsklinik KoÈ ln, Klinik II und

Poliklinik fuÈr Innere Medizin, Cologne;

³§UniversitaÈ tsklinik DuÈsseldorf, Dusseldorf;

³¶Medizinische Klinik, Klinikum Innenstadt der LMU,

Munich, Germany; §¶Hospital Reina So®aÂ, CoÂrdoba;

***Hospital ClõÂnico `San Cecilio', Granada; **²Hospital de

Cruces, Barakaldo; **³Hospital RamoÂn y Cajal, Madrid;

**§Hospital Universitario Virgen del RocõÂo, Endocrinology

Department, Sevilla; **¶Hospital de la Santa Creu I Sant

Pau, Barcelona, Spain

(Received 24 January 2000; returned for revision 6 March 2000;

®nally revised 13 June 2000; accepted 4 August 2000)

Summary

BACKGROUND AND OBJECTIVE The most effective

option for the medical treatment of patients with

acromegaly is the use of somatostatin analogues.

Long-acting depot formulations for intramuscular

injection of two somatostatin analogues have

recently become available: octreotide acetate LAR

(SandostatinÒ LARÒ, Novartis Pharma AG) and lan-

reotide SR (SomatulineÒ, Ipsen Biotech). We wished

to compare ef®cacy of octreotide LAR and lanreotide

SR in acromegalic patients.

PATIENTS AND METHODS A group of 125 patients

with acromegaly (67 females; mean age, 47 years; 59

patients had previous pituitary irradiation) from 26

medical centres in France, Spain and Germany were

studied. Before the study, all patients had been

treated with intramuscular injections of lanreotide

SR (mean duration, 26 months) at a dose of 30 mg

which was injected every 10 days in 64 and every

14 days in 61 patients, respectively. All patients were

switched from lanreotide SR to intramuscular injec-

tions of 20 mg of octreotide LAR once monthly for

three months. In order to obtain ef®cacy and safety

data of lanreotide SR under study conditions, it was

decided to randomly assign at day 1, in a 3 : 1 ratio, the

time point of the treatment switch; 27 of the patients

were randomly assigned to continue the lanreotide SR

treatment for the ®rst 3 months of the study (group A);

they were on octreotide LAR 20 mg from month 4±6.

The other 98 patients were assigned to be switched to

treatment with octreotide LAR 20 mg at day 1 (group

B). In group B patients, octreotide LAR treatment was

continued until month 6, with an adjustment of the

dose based on GH levels obtained at month 3.

RESULTS The mean GH concentration decreased

from 9´6 6 1´3 mU/l at the last evaluation on lanreotide

SR to 6´8 6 1´0 mU/l after three injections of octreotide

LAR (P <0´001). The percentages of patients with

mean GH values # 6´5 mU/l (2´5 mg/l) and # 2´6 mU/l

(1´0 mg/l) at the last evaluation on lanreotide SR were

54% and 14%, and these values increased after

3 months treatment with octreotide LAR to 68% and

35% (P < 0´001), respectively. IGF-I levels were normal

in 48% at the last evaluation on lanreotide SR and in

65% after 3 months on octreotide LAR (P < 0´001).

Patients with pre-study pituitary irradiation had

lower mean GH and IGF-I concentrations. But the

effects of the treatment change did not differ between

the irradiated and the nonirradiated patients. In

general both drugs were well tolerated.

Correspondence: Prof. Philippe Chanson, CHU de BiceÃtre, Service

d'Endocrinologie et des Maladies de la Reproduction, 78 Rue du

GeÂneÂral Leclerc, F-94275 Le Kremlin-BiceÃtre, France. Fax:� 33

14521 2829.

CONCLUSION Octreotide LAR 20 mg administered

once monthly was more effective than lanreotide SR

30 mg administered 2 or 3 times monthly in reducing

GH and IGF-I in patients with acromegaly.

The somatostatin analogue octreotide has been used in the

treatment of acromegaly for more than 15 years and is known to

be effective both in relieving symptoms and lowering GH as

well as IGF-I concentrations (Plewe et al., 1984; Lamberts et al.,

1985; Vance & Harris, 1991). The conventional formulation

of octreotide is usually administered 2±3 times daily by

subcutaneous injection.

Recently, long-acting depot formulations for intramuscular

injection of two somatostatin analogues, octreotide (octreotide

LAR, SandostatinÒ LARÒ, Novartis Pharma AG, Basel,

Switzerland) and lanreotide (lanreotide SR, SomatulineÒ,

Ipsen Biotech, Paris, France), have become available in several

countries. Octreotide and lanreotide are both octapeptide

somatostatin analogues which bind selectively to the somato-

statin receptor subtypes 2 (sst2) and 5 (sst5). Their binding

af®nity is moderate at the sst3 receptor and low at sst1 and sst4receptors (Bruns et al., 1996; Ho¯and et al., 1994).

Both depot formulations consist of active compound encap-

sulated within microspheres of a biodegradable polylactide-

polyglycolide copolymer. After intramuscular injection, both

formulations result in a biphasic drug release. However, the

pharmacokinetic pro®les of the two formulations are quantita-

tively different (Heron et al., 1993; Lancranjan et al., 1995;

Lancranjan et al., 1996).

In two recently published clinical studies the ef®cacy of

octreotide LAR and lanreotide SR were compared (Turner et al.,

1999; Cozzi et al., 1999). The sample size in these trials was

small (n� 10 and 12, respectively) and therefore not suited to

give a ®nal answer to the comparative ef®cacy. The objective of

our pragmatic study was to compare the ef®cacy of octreotide

LAR treatment with that observed during pretreatment with

lanreotide SR in a large number of acromegalic patients.

Patients and methods

Patients

A total of 125 acromegalic patients (58 men and 67 women;

age: mean, 47 years; range, 18±76 years; body weight: mean,

82 kg; range, 42±142 kg) from 26 medical centres in France,

Spain and Germany were treated in the study between 12

November 1997 and 8 February 1999. No patient was receiving

dopamine agonist or octreotide s.c. treatment or had undergone

pituitary surgery within 4 weeks before the study or had

received pituitary radiation within 12 months prior to screening.

Fifty-nine patients had pituitary irradiation which was

performed 1±43 years (mean 7 years) before the study. Patients

were included irrespective of their response to prior somato-

statin analogue treatment. All patients had been treated with at

least three lanreotide SR injections before study day 1; the

mean length of previous lanreotide SR therapy was 26 months

(2±117 months). Before the study, lanreotide SR 30 mg had

been injected every 10 days in 64 patients (51%) and every

14 days in 61 patients (49%) (Table 1). The prestudy injection

interval was maintained, independent of GH and IGF-I

concentrations. The study protocol was approved by institu-

tional review boards and each patient gave written informed

consent to participate in the study.

Study design

The trial was a prospective, open, multicentre, within-subject

controlled study. In all patients treatment was switched from

lanreotide SR to 20 mg of octreotide LAR per month for

3 months without any wash-out period. The time point of the

treatment switch (day 1 or month 4) was randomised in a 3 : 1

578 P. Chanson et al.

q 2000 Blackwell Science Ltd, Clinical Endocrinology, 53, 577±586

Table 1 Characteristics of the study

population Characteristic n Mean Range

Age (years) 125 47 18±76

Sex

Male 58 (46%)

Female 67 (54%)

Body weight (kg) 124 82 42±142

Duration of prestudy lanreotide SR treatment (months) 125 26 2±117

Prestudy injection schedule of lanreotide SR

10 days 64 (51%)

14 days 61 (49%)

Previous pituitary irradiation (years before study) 59 (47%) 7 1±43

ratio in order to collect in a group of patients information on

effects of lanreotide SR under study conditions. Randomization

was carried out in blocks of four at day 1. Each centre had a

multiple of four numbers corresponding to the assigned time

point for the switch. The numbers were used sequentially as the

patients were enrolled in the study: group A patients (n� 27)

were randomly assigned to continue the lanreotide SR

treatment with the prestudy injection schedule for another

three months and group B patients (n� 98) were randomly

assigned to receive octreotide LAR from day 1 onwards. In

group B patients, the dose of octreotide LAR was individually

adjusted based on the GH pro®le mean serum level at the end of

month 3:< 2´6 mU/l (1´0 mg/l), 2´6±6´5 mU/l (1´0 ÿ2´5 mg/l),

and > 6´5 mU/l (2´5 mg/l) determined the octreotide LAR doses

of 10, 20 and 30 mg for months 4±6 (Fig. 1).

GH and IGF-I measurements

Serum GH concentrations were determined in ®ve samples

taken hourly during 4 h at the screening day (10±14 days before

randomization; results not shown because they were not

statistically signi®cantly different from day 1 concentrations),

the day 1, and the month 3 and 6 visits before injection of the

next dose of the test drug. IGF-I levels were measured in the

serum of the ®rst sample at each visit with hormonal

assessments. Both GH and IGF-I concentrations were deter-

mined in samples from all centres in a central laboratory

(Medinet Laboratories, Breda, the Netherlands). For GH

measurements a commercially available solid phase, two-site

¯uoroimmunometric assay based on the direct sandwich

technique in which two monoclonal antibodies are directed

against two separate antigenic determinants on the hGH

molecule was used (DELFIAÒ hGH kit, Wallac Oy, Turku,

Finland). To convert mU/l to mg/l divide by 2´6. For

determination of IGF-I concentrations a RIA kit was employed

(Nichols Institute Diagnostics, San Juan Capistrano, CA, USA).

The normal range for IGF-I was age-, but not sex-adjusted

(16±24 years: 24±102 nmol/l, 25±39 years: 15±64 nmol/l,

40±54 years: 12±47 mg/l, and 55±99 years: 9±38 nmol/l). To

convert from nmol/l to mg/l divide by 0´1307.

Symptoms of acromegaly

Signs and symptoms of acromegaly (headache, perspiration,

paresthesia, fatigue, osteoarthralgia, and carpal tunnel syndrome)

were evaluated at day 1 and at monthly intervals using a ®ve point

verbal rating scale (0, not present; 1, mild; 2, moderate; 3,

severe but not disabling; and 4, severe and incapacitating).

Tolerability, injection site reactions

Adverse events were recorded throughout the trial. Blood

pressure and pulse rate in the sitting position were measured at

the screening, day 1, month 3 and 6 visits. Ultrasound

examination of the gallbladder and biliary tract were performed

at day 1, and after 3 and 6 months of treatment. The patients

were asked at each visit whether any injection site reactions

(pain, erythema and/or swelling) had occurred; each symptom

was rated on a four point scale (0 � none, 1 � mild, 2 �

moderate, and 3 � severe).

Statistical analysis

Descriptive statistics were applied to background data and

study medication usage. For the main ef®cacy analyses, GH

pro®le means were calculated from the up to ®ve GH

measurements at the four visits with hormonal assessments.

Wilcoxon signed rank tests were used for within-patient

comparisons of GH pro®le means and IGF-I data under

lanreotide SR and octreotide LAR treatment, separately for

the two treatment groups A and B. In addition, a pooling of

group A (months 4±6) and group B (day 1 to month 3) was

performed in order to compare the last GH and IGF-I results

under lanreotide SR with those after 3 months of octreotide

LAR treatment. These analyses were applied to log-trans-

formed data because of the skewness of the distribution of these

data. Differences are therefore expressed by the ratio of the

geometric means. Bowker's test of symmetry was used to

assess the shift over time (day 1 vs. month 3 and month 6,

month 3 vs. month 6) with respect to four categories for the GH

pro®le means (# 2´6 mU/l,> 2´6±6´5 mU/l,> 6´5±13´0 mUg/l

and > 13´0 mU/l), and McNemar's test with respect to two

categories for IGF-I levels (normal or above the upper limit of

age-dependent normal range). Descriptive statistics were

applied for the analyses of further ef®cacy and safety results

Octreotide LAR versus Lanreotide SR in acromegaly 579


Fig. 1 Study ¯ow chart. Scr, screening period; LAN SR, lanreotide

SR 30 mg; OCT LAR 10, 20 or 30, octreotide LAR 10 mg, 20 mg or

30 mg.

including signs and symptoms of acromegaly, injection site

reactions, ®ndings in abdominal ultrasound and adverse

events. Wilcoxon signed rank tests were also used for the

within patient analyses of blood pressure, pulse rate and weight

results.

Individual endocrine or clinical ef®cacy data were excluded

from analysis for the following reasons: visit outside the

planned injection interval (for octreotide LAR > 35 days;

for lanreotide SR 10 or 14 days 6> 3 days), wrong drug

injected, study drug not injected, wrong octreotide LAR

dose administered, incomplete injection, injection of study

drug prior to blood sampling for endocrine assessments,

samples arrived unfrozen or haemolysed at central laboratory,

or hormonal assessments performed at local laboratory only.

The descriptive statistics for GH and IGF-I concentrations

were calculated using all data for which no protocol violation,

as described above, was recorded. For the analyses of within

patient changes of endocrine parameters between two time-

points, only patients who had assessments at both time points

were included. The patient numbers (n) in the text or in the

tables indicate the number of patients for whom data were

available for the speci®c analysis.

Results

A group of 125 acromegalic patients entered this trial and 116

completed the full course of the investigation. Of the nine

patients who discontinued prematurely, two died (see toler-

ability and safety section), three withdrew because of adverse

events (see tolerability and safety section), two withdrew

because of administrative reasons, one withdrew consent and

one patient dropped out of the study to have pituitary tumour

resection (see tolerability and safety section).

GH and IGF-I

The day 1 serum GH and IGF-I concentrations and the number

of patients with normal IGF-I levels for all patients and

corresponding data for patients receiving lanreotide SR 30 mg

every 10 days or every 14 days before the study are given in

Table 2.

Table 3 shows GH and IGF-I levels and the number of

patients with normal IGF-I concentration over time and with

respect to the study drug for group A and B. Ten of 21 evaluable

group A patients received lanreotide SR every 10 days and 11

patients every 14 days. There was no statistically signi®cant

difference between the GH and IGF-I concentrations at day 1

and at month 3 in the group A patients, while these patients

were being treated under study conditions with lanreotide SR

(Wilcoxon Signed Rank Test, P� 0´801 for GH and P� 0´187

for IGF-I). This condition had to be ful®lled for a pooling of the

last average GH pro®le mean values during lanreotide SR

therapy (day 1 for group B and month 3 for group A,

respectively) and those after three injections of octreotide LAR

from group A and B (month 3 for group B and month 6 for

group A, respectively). The last mean GH concentration on

lanreotide SR from both groups together was 9´5 6 1´3 mU/l. It

decreased to 6´8 6 1´0 mU/l 3 months after the switch to

octreotide LAR. This difference was statistically highly

signi®cant (ratio of geometric means � 0´65; P < 0´001,

Wilcoxon signed rank test). The last IGF-I concentration on

lanreotide SR was 57 6 3 nmol/l, and 47 6 3 nmol/l after three

injections of octreotide LAR (ratio of geometric means � 0´80;

P< 0´001, Wilcoxon signed rank test). Fifty-three patients

(48%) had an IGF-I level within the normal range at the last

evaluation during lanreotide SR therapy; after three octreotide

LAR injections the IGF-I level was normal in 70 patients (65%)

(P< 0´001, McNemar's change test).



n (%) with

Time on lanreotide SR n GH (mU/l) IGF-I (nmol/l) normal IGF-I

14 days 53 34 (64%)

Mean 6 SEM 6´2 6 1´0 44 6 3

Range 0´5±98´0 12±135

10 days 58 19 (33%)

Mean 6 SEM 13´0 6 2´1 69 6 4

Range 0´5±58´8 16±136

10 or 14 days 111 53 (48%)

Mean 6 SEM 9´9 6 1´3 57 6 3

Range 0´5±98´0 12±136

Note: 104 subjects had valid assessments at day 1. Seven subjects have had their screening values

substituted.

Table 2 Mean (6 SEM) GH and IGF-I serum

concentrations at day 1 while patients were still

on prestudy dosing regimens of lanreotide SR

30 mg for 10 or 14 days

In Table 4, the shift of the individual GH pro®le means from

the last value on lanreotide SR to that after 3 months on octreotide

LAR are shown for four prede®ned GH ranges and Fig. 2 shows

the distribution of the GH pro®le means at the last evaluation on

lanreotide SR and after 3 months on octreotide LAR.

In group B patients, an adjustment of the octreotide LAR

dose after three months of therapy with 20 mg of octreotide

LAR was performed. The GH pro®le mean concentrations were

< 2´6 mU/l in 31 of the 85 evaluable patients at month 3. These

patients were to receive 10 mg of octreotide LAR for months 4±

6. In 26 patients the GH means were between 2´6 mU/l and

6´5 mU/l; they were supposed to remain on 20 mg of octreotide

LAR. Twenty-eight patients had GH mean concentrations

above 6´5 mU/l, and their dose of octreotide LAR was expected

to be increased to 30 mg for months 4±6. Table 5 shows the

time course of GH and IGF-I concentrations and the number of

patients with normal IGF-I levels for the subgroups of patients

treated with 10 mg, 20 mg or 30 mg of octreotide LAR during

months 4±6.

Table 6 shows the mean GH and IGF-I concentrations and

the number of patients with normal IGF-I levels in patients with

or without prestudy pituitary irradiation. In the upper part of the

table the results of group A patients are given for day 1 and

month 3, i.e. during a period without change of the trial drug. In

the lower part, the results last evaluations on lanreotide SR and

those after 3 months on octreotide LAR for group A and B

patients are shown.

Symptoms of acromegaly

Headache (40%), increased perspiration (38%), paraesthesia

(26%), fatigue (57%), osteoarthralgia (46%) and carpal tunnel



Table 3 GH and IGF-I concentrations (mean 6 SEM), and number (percentage) of patients with IGF-I levels within the normal

range over time. The study drug relevant for the different time points is indicated

Time point GH IGF-I n (%) with

(Study drug) n (mU/l) (nmol/l) normal IGF-I

Groups A�B pooled

A/Month 3�B/Day 1 (LAN SR) 111 9´5 6 1´3 57 6 3 53 (48%)

A/Month 6�B/Month 3 (OCT LAR 20) 107 6´8 6 1´0 47 6 3 70 (65%)

Group A

Day 1 (LAN SR) 21 9´4 6 4´4 50 6 5 11 (52%)

Month 3 (LAN SR) 21 8´1 6 3´4 49 6 5 11 (52%)

Month 6 (OCT LAR 20) 21 7´7 6 3´1 43 6 4 14 (67%)

Group B

Day 1 (LAN SR) 90 9´9 6 1´3 59 6 3 42 (47%)

Month 3 (OCT LAR 20) 86 6´6 6 0´8 48 6 3 56 (65%)

(LAN SR, lanreotide SR 30 mg; OCT LAR 20, octreotide LAR 20 mg.

Table 4 Number of patients (%) with GH

pro®le mean levels according to GH ranges at

last evaluation on lanreotide SR and after

3 months on octreotide LAR 20 mg from

groups A and B pooled; n� 107 (GH levels at

both time points available).

Last evaluation on lanreotide SR

3 months on GH range (mU/l) # 2´6 > 2´6±6´5 > 6´5±13´0 > 13´0

octreotide LAR

GH range (mU/l) n (%) 15 (14) 43 (40) 28 (26) 21 (20)

# 2´6 37 (35) 14 (13) 23 (22) 0 0

> 2´6±6´5 36 (34) 1 (1) 18 (17) 14 (13) 3 (3)

> 6´5±13´0 21 (20) 0 2 (2) 12 (11) 7 (7)

> 13´0 13 (12) 0 0 2 (2) 11 (10)

P-value < 0´001; Bowker's test of symmetry; the P-value < 0´001 from this test indicates a

signi®cant improvement of octreotide LAR over lanreotide SR

Patients within the same GH range at the two time points account for the numbers on the diagonal

(14, 18, 12, 11); improvements and deteriorations over time are displayed above and below the

diagonal, respectively

syndrome (10%) were reported at day 1. The intensity of these

symptoms was predominantly mild or moderate. The percen-

tage of patients reporting these symptoms and their intensity did

not change signi®cantly over time and after the change from

lanreotide SR to octreotide LAR.

Tolerability and safety

The duration of the exposure to the two study drugs during the

study was 754 patient-months for any dose of octreotide LAR

and 116 patient-months for lanreotide SR. Therefore only

descriptive statistics were applied to compare tolerability and

safety data.

Two patients died during the study: one secondary to

pancreatic adenocarcinoma at day 141, the other due to

pulmonary embolism at day 29. The investigators did not

suspect a relationship of these deaths to octreotide LAR

administration.

Three patients discontinued the study prematurely because of

adverse events while on octreotide LAR treatment. The ®rst

patient had fever 17 days after both the ®rst and the second

injections of octreotide LAR; he withdrew from the study after

the second episode. The second patient developed urticaria of

moderate severity after the second injection of octreotide LAR

and discontinued the study after this event. In the third patient a

severe depression was diagnosed on study day 76; this adverse

event was not thought to be causally related to octreotide LAR.

There was one patient whose pituitary adenoma increased in

size during lanreotide SR treatment; this patient was referred to

the neurosurgeon for pituitary surgery and dropped out of the

study.

The numbers of patients reporting at least one adverse event

were 70 (56%) and 12 (44%) of patients treated with octreotide

LAR and lanreotide SR, respectively. In the opinion of the

investigators, 24 (19%) and two (7%) patients had at least one



100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

Perc

enta

ge

of

pat

ien

ts

Last evaluation onIanreotide SR

After 3 months onoctreotide LAR

Fig. 2 Distribution of GH pro®le mean values according to GH

ranges [B, # 2´6 mU/l (1´0 mg/l); , > 2´6±6´3 mU/l (1´0±2´5 mg/l);

, > 6´3±13´0 mU/l (2´5±5´0 mg/l); and A, > 13´0 mU/l (5´0 mg/l)] from

group A and B patients pooled (n� 107) at the last evaluation on

lanreotide SR and after 3 months on octreotide LAR treatment.

GH IGF-I n (%) with

Treatment/time point n (mU/l) n (nmol/l) normal IGF-I

Octreotide LAR 10 mg

Day 1 (or screening) 28 3´1 6 0´3 28 39 6 3 18 (64%)

Month 3 31 1´3 6 0´3 31 30 6 2 27 (87%)

Month 6 25 2´1 6 0´3 25 38 6 3 21 (84%)

P-value* (month 6/3) 0´003 < 0´001


Day 1 (or screening) 28 7´5 6 0´8 28 58 6 5 12 (43%)

Month 3 26 4´4 6 0´3 26 45 6 4 16 (62%)

Month 6 26 4´9 6 0´3 26 52 6 5 12 (46%)

P-value* (month 6/3) 0´205 0´019


Day 1 (or screening) 28 19´2 6 3´1 28 80 6 7 7 (25%)

Month 3 28 13´0 6 1´3 28 68 6 6 13 (46%)

Month 6 28 10´1 6 1´3 26 68 6 6 11 (42%)

P-value* (month 6/3) < 0´001 25 0´804

* Wilcoxon signed rank test on log transformed data

Day 1 or screening if day 1 not available (treatment, 30 mg lanreotide SR 10 or 14 days), month 3

(treatment, 20 mg of octreotide LAR) and month 6 (after adjustment of octreotide LAR dose).

Table 5 GH and IGF-I levels (mean 6 SEM)

in group B patients

adverse event which was suspected to be related to octreotide

LAR or lanreotide SR treatment, respectively. In 15 out of the

24 patients with octreotide LAR-related adverse events the

gastrointestinal tract was affected. Most of the adverse events

were mild and disappeared without speci®c treatment. How-

ever, there were two serious adverse events attributed to the

study drugs which did not lead to premature discontinuation:

one patient had biliary colic on study day 78 while on lanreotide

SR, and another experienced an episode of acute pancreatitis on

study day 106 during treatment with octreotide LAR.

Average body weight, mean systolic blood pressure and

mean pulse rate did not change signi®cantly during the study in

any of the treatment groups.

Pain, erythema or swelling at the injection site was reported

in less than 20% of patients after injection of either of the test

drugs. It was mostly mild to moderate.

The prevalence of gallstones and/or microlithiasis was both

18% at the last evaluation on lanreotide SR. The switch of the

treatment did not signi®cantly change these ®gures.

Discussion

This open, randomised multicentre study compared the ef®cacy

of the two depot formulations of somatostatin analogues which

are currently available for clinical use, octreotide LAR and

lanreotide SR, in a group of 125 acromegalic patients who had

been pretreated with lanreotide SR. The design of this

pragmatic trial took the following considerations into account:

(1) Acromegaly is a rare disease, with a yearly incidence of

three to four new cases per million (Alexander et al., 1980;

Bengtsson et al., 1988; Ritchie et al., 1990; Etxabe et al., 1993)

making a comparison of the two long-acting formulations in

untreated acromegalic patients practically impossible; (2)

Neither patients nor investigators were blinded with respect

to treatment because no placebo for octreotide LAR is available

and because the two formulations have different dosage

intervals. (3) Lanreotide SR was available in a few European

countries before the start of this study and before octreotide

LAR obtained marketing authorization. Therefore it was

decided to include only patients who had been treated with at

least three injections of lanreotide SR before randomization. As

a consequence, the sequence of the two drugs to be compared

was not randomised but was always lanreotide SR followed by

octreotide LAR. This study design may have in¯uenced

subjective assessments (e.g. symptoms of acromegaly or

adverse events) but should not have affected GH and IGF-I

levels, since the ®rst endocrine assessment was performed

3 months after the switch of the treatment.

No retrospective information on GH and IGF-I levels or on

clinical symptoms of acromegaly before any somatostatin

analogue treatment (subcutaneously administered octreotide or

lanreotide SR) was collected for this study. Furthermore, the

study was performed without wash-out from lanreotide SR

treatment before randomization. Hence, the effects of lanreo-

tide SR and octreotide LAR on the activity of untreated

acromegaly in the study participants is not documented. GH

pro®le mean concentrations at day 1 ranged from 0´5 to

98´0 mU/l. This large range makes it likely that the acromegalic

patients of this study comprised a mixed population of good,

partial and even nonresponders to somatostatin analogues

predominantly acting through the somatostatin receptor sub-

types 2 and 5.



Table 6 GH and IGF-I concentrations (mean

6 SEM), and number (percentage) of patients

with IGF-I levels within the normal range in

patients with/without prestudy pituitary

irradiation.

GH IGF-I n (%) with

Time point (study drug) n (mU/l) (nmol/l) normal IGF-I

Group A patients with previous radiotherapy 10

Day 1 (LAN SR) 3´9 6 0´5 50 6 8 6 (60%)

Month 3 (LAN SR) 3´6 6 0´5 45 6 8 7 (70%)

Group A patients without previous radiotherapy 10

Day 1 (LAN SR) 6´2 6 1´3 47 6 7 5 (50%)

Month 3 (LAN SR) 6´0 6 1´3 50 6 7 4 (40%)

Group A and B patients with previous radiotherapy 53

Last evaluation on LAN SR 7´7 6 1´1 53 6 4 27 (51%)

After 3 months on OCT LAR 20 4´9 6 0´7 42 6 3 40 (75%)

Group A and B patients without radiotherapy 54

Last evaluation on LAN SR 10´4 6 2´0 62 6 4 23 (43%)

After 3 months on OCT LAR 20 8´2 6 1´6 52 6 4 30 (56%)

Only patients with GH and IGF-I evaluations at both relevant time points are shown. The study drug

relevant for the different time points is indicated (LAN SR, lanreotide SR 30 mg; OCT LAR 20,

octreotide LAR 20 mg).

In group A, ef®cacy data for lanreotide SR were collected for

three months under study conditions. There was no statistically

signi®cant difference in the GH and IGF-I levels between the

day 1 and the month 3 evaluation, i.e. a signi®cant effect on

these parameters due to study participation was not detected.

Therefore pooling of the last evaluation during lanreotide SR

treatment and that after 3 months on octreotide LAR from

groups A and B was considered acceptable.

The GH serum concentration fell in a statistically signi®cant

fashion from the last evaluation on lanreotide SR, to that after

three injections of 20 mg of octreotide LAR (Table 3). The

percentages of patients with GH pro®le mean levels # 6´5 mU/l

(2´5 mg/l) and # 2´6 mU/l (1´0 mg/l) increased after the change

of the treatment (Fig. 2). Furthermore, there was a statistically

signi®cant rise in the percentage of patients with a normal IGF-I

concentration after the switch of the therapy. The authors of two

recently published small studies (n� 10 and n� 12) comparing

the ef®cacy of lanreotide SR and octreotide LAR in

acromegalic patients concluded that `octreotide LAR treatment

leads to signi®cantly lower mean GH' (Turner et al., 1999) and

`the once-monthly octreotide LAR administration schedule

proved more ef®cacious than lanreotide SR given every 7±

21 days' (Cozzi et al., 1999). The results of this study support

these conclusions in a much larger group of acromegalic

patients.

The inhibition of GH and IGF-I in long-term trials with

octreotide LAR (Lancranjan et al., 1996; Davies et al., 1998) is

generally better than that achieved with the conventional

formulation of octreotide administered by the subcutaneous

route (Vance & Harris, 1991; Lancranjan et al., 1996; Newman

et al., 1998; Colao et al., 1999), and is in the same range as that

observed in this trial. However, it should be noted that there is a

bias in the selection of patients for treatment with long-acting

formulations of somatostatin analogues; generally, only

acromegalic patients whose GH levels are at least somewhat

lowered following a short course of subcutaneously adminis-

tered octreotide are candidates for treatment with the depot

formulations.

The effects of a dose adjustment of octreotide LAR based on

GH concentrations were investigated in the second part of this

study in group B patients (Table 5). Those with a GH pro®le

mean level < 2´6 mU/l after 3 months of 20 mg of octreotide

LAR treatment, the dose reduction to 10 mg led to small,

however, statistically signi®cant increases of the average GH

and IGF-I levels (P� 0´003 and < 0´001, respectively). The

mean GH levels remained < 2´6 mU/l and the mean IGF-I

concentration was within the normal range at the month 6

evaluation. In patients who continued on 20 mg of octreotide

LAR during the second part of the study, there were slight

increases of the mean GH concentration (P� 0´205) and the

IGF-I levels (P� 0´019), as well as a decrease in the number of

patients with normalized IGF-I values. In patients who received

30 mg of octreotide LAR in the second part of the study, a

statistically signi®cant decrease of the average GH levels was

found (P < 0´001) between month 3 and 6. The mean IGF-I

concentrations in this subgroup remained, however, unchanged

(P� 0´804). In all three subgroups, the mean GH and IGF-I

concentrations at month 6 remained below those at the last

evaluation on lanreotide SR. The results of this study

demonstrate that patients with a high sensitivity to octreotide

LAR may achieve good biochemical control of their disease

with 10 mg of octreotide LAR once monthly. An increase of the

octreotide LAR dose from 20 mg to 30 mg may further decrease

the GH concentration in some patients. The ®nding of the slight

deterioration of the control of acromegaly in patients remaining

on 20 mg of octreotide LAR is not in agreement with earlier

observations that a prolongation of the treatment duration with

the same dose of octreotide LAR leads to better results

(Lancranjan et al., 1996; Davies et al., 1998). There is no

obvious reason to explain why the results of this trial were

different.

GH and IGF-I concentrations on lanreotide SR differed

between the two injection schedules at Day 1 (Table 2). Patients

receiving an injection of lanreotide SR every 10 days had higher

mean GH and IGF-I concentrations than those on a 14-day

injection schedule. These data demonstrate that patients

receiving lanreotide SR every 10 days were not responding to

lanreotide SR as well as those who were maintained on a 14-day

injection schedule despite attempts to optimize lanreotide SR

treatment. The most likely explanation for the differences in

sensitivity to lanreotide or octreotide is that the density of the

somatostatin receptor subtypes, mainly sst2, in the pituitary

adenomas shows large interindividual differences in acro-

megalic patients (Reubi et al., 1987).

Fifty-nine patients (47%) had pituitary irradiation 1±47 years

before inclusion into this study; the mean GH and IGF-I

concentrations were lower in this subgroup. For the group A

patients, with or without history of radiotherapy, no signi®cant

changes of the endocrine parameters occurred during the

3 months they were treated with lanreotide SR during the study.

However, the switch of the treatment from lanreotide SR to

octreotide LAR resulted in a signi®cant decrease of the mean

GH and IGF-I concentrations in a 3 month period in both

previously irradiated and nonirradiated patients (Table 6).

These ®ndings make it unlikely that prestudy irradiation has a

relevant effect on the interpretation of the ef®cacy of the two

test drugs.

The typical clinical manifestations of acromegaly including

headache, perspiration, paresthesia, fatigue, osteoarthralgia,

and carpal tunnel syndrome changed only minimally during the

study and were not in¯uenced by the improvement of the

endocrine markers for disease activity, following the switch of



the somatostatin analogue. This may be explained by the ability

of lanreotide SR (Marek et al., 1994; Giusti et al., 1996; Caron

et al., 1997) and octreotide LAR (Lancranjan et al., 1996;

Kvistborg Flùgstad et al., 1997) therapy to control adequately

clinical symptoms of acromegaly even in the presence of

moderately elevated GH and IGF-I levels.

The systemic tolerability of octreotide LAR was generally

good. Adverse events which were considered to be related to

therapy with octreotide LAR were reported in less than 25% of

the patients. Most of the drug-related adverse events were

among those known to occur after administration of somato-

statin analogues, i.e. gastrointestinal. The design of the study

does not allow a comparison of the systemic tolerability and

safety of octreotide LAR and lanreotide SR treatment because

all patients were pretreated with lanreotide SR, and because the

duration of exposure to octreotide LAR during the study was

about six times longer than that to lanreotide SR.

The number of patients with gallstones and microlithiasis

was remarkably stable during the study period and no clinically

relevant change was observed following the switch to therapy

with octreotide LAR.

Reactions at the injection site such as pain, erythema or

swelling were mostly mild and occurred in less than 20% of

patients after injection of either drug.

In conclusion, this study has shown that octreotide LAR once

monthly is signi®cantly more effective in reducing GH and

IGF-I levels in acromegalic patients than lanreotide SR

administered two or three times monthly. Both depot formula-

tions were generally well tolerated.

Acknowledgements

The authors thank Sally Watson (Novartis Pharma Ltd,

Horsham, UK) for data management; Chris Rose, B.Sc.,

M.Sc., C.Stat. (Rose and Sellek Associates Ltd, Brixham,

UK) for statistical analysis of the data; Carole Maurer for

logistical support as well as Tony Williams, M.Sc., Pascal

P®ster, MD (Novartis Pharma AG, Basel, Switzerland) and

Christine Simonetta, MD (Novartis Pharma S.A., Rueil-

Malmaison, France) for support in designing the study.

Part of this work has been presented at the 6th International

Pituitary Congress, Long Beach, California, USA, June 15±

17 1999 and at the 9th Meeting of the European Neuroendo-

crine Association, Odense, Denmark, September 3±7, 1999.

This study was sponsored by Novartis Pharma AG, Basel,

Switzerland.

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Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly

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