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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 Pitie 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
q 2000 Blackwell Science Ltd, Clinical Endocrinology, 53, 577±586
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).
580 P. Chanson et al.
q 2000 Blackwell Science Ltd, Clinical Endocrinology, 53, 577±586
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
Octreotide LAR versus Lanreotide SR in acromegaly 581
q 2000 Blackwell Science Ltd, Clinical Endocrinology, 53, 577±586
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
582 P. Chanson et al.
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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
Octreotide LAR 20 mg
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
Octreotide LAR 30 mg
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.
Octreotide LAR versus Lanreotide SR in acromegaly 583
q 2000 Blackwell Science Ltd, Clinical Endocrinology, 53, 577±586
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
584 P. Chanson et al.
q 2000 Blackwell Science Ltd, Clinical Endocrinology, 53, 577±586
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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