Efficacy and safety of once-monthly pasireotide in Cushing's disease

a 12 month clinical trial

for the, Pasireotide G2304 Study Group

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. Methods In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5–5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to <2·0 × ULN and 2·0–5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. Findings Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5–53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7–52·7]) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis (15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] and 16 [21%]). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. Interpretation Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. Funding Novartis Pharma AG.

Original languageEnglish (US)
Pages (from-to)17-26
Number of pages10
JournalThe Lancet Diabetes and Endocrinology
Volume6
Issue number1
DOIs
StatePublished - Jan 1 2018

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Pituitary ACTH Hypersecretion
Clinical Trials
Safety
Hydrocortisone
pasireotide
Pituitary Irradiation
Mitotane
Phase III Clinical Trials
Cholelithiasis
Random Allocation
Hyperglycemia
Pharmaceutical Preparations
Adrenocorticotropic Hormone
Nausea
Pulmonary Artery
Diarrhea
Diabetes Mellitus
Appointments and Schedules

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Efficacy and safety of once-monthly pasireotide in Cushing's disease : a 12 month clinical trial. / for the; Pasireotide G2304 Study Group.

In: The Lancet Diabetes and Endocrinology, Vol. 6, No. 1, 01.01.2018, p. 17-26.

Research output: Contribution to journalArticle

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title = "Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial",
abstract = "Background Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. Methods In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5–5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to <2·0 × ULN and 2·0–5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. Findings Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49{\%}] patients) or 30 mg (76 [51{\%}] patients). The primary efficacy endpoint was met by 31 (41·9{\%} [95{\%} CI 30·5–53·9]) of 74 patients in the 10 mg group and 31 (40·8{\%} [29·7–52·7]) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49{\%}] in the 10 mg group and 36 [47{\%}] in the 30 mg group), diarrhoea (26 [35{\%}] and 33 [43{\%}]), cholelithiasis (15 [20{\%}] and 34 [45{\%}]), diabetes mellitus (14 [19{\%}] and 18 [24{\%}]), and nausea (15 [20{\%}] and 16 [21{\%}]). Serious adverse events suspected to be study drug related were reported in eight (11{\%}) patients in the 10 mg group and four (5{\%}) in the 30 mg group. Two (3{\%}) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. Interpretation Long-acting pasireotide normalised mUFC concentration in about 40{\%} of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. Funding Novartis Pharma AG.",
author = "{for the} and {Pasireotide G2304 Study Group} and Andr{\'e} Lacroix and Feng Gu and Wilson Gallardo and Rosario Pivonello and Yerong Yu and Przemysław Witek and Marco Boscaro and Roberto Salvatori and Masanobu Yamada and Libuse Tauchmanova and Michael Roughton and Shoba Ravichandran and Stephan Petersenn and Biller, {Beverly M.K.} and John Newell-Price and Giorgio Arnaldi and Asha, {Hesarghatta Shyamasunder} and Tushar Bandgar and Ariel Barkan and Henrik Biering and Marie Bex and Marek Bolanowski and Bronstein, {Marcello Delano} and Thierry Brue and Dario Bruera and Francesco Cavagnini and Abdurrahman Comlekci and {De Block}, Christophe and Tuncay Delibasi and Carmen Fajardo-Monta{\~n}ana and Feelders, {Richard Abraham} and Maria Fleseriu and Gadelha, {Monica Roberto} and Geer, {Eliza Brevoort} and Anthony Heaney and Ghislaine Houde and Atsuhiro Ichihara and Imran, {Syed Ali} and Adriana Ioachimescu and Pinar Kadioglu and Yiming Li and Paola Loli and Mitsuru Nishiyama and Liudmila Rozhinskaya and Marek Ruchala and Youichi Saitoh and Christof Sch{\"o}fl and Jochen Schopohl and Akira Shimatsu and Chikara Shimizu",
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month = "1",
day = "1",
doi = "10.1016/S2213-8587(17)30326-1",
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volume = "6",
pages = "17--26",
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TY - JOUR

T1 - Efficacy and safety of once-monthly pasireotide in Cushing's disease

T2 - a 12 month clinical trial

AU - for the

AU - Pasireotide G2304 Study Group

AU - Lacroix, André

AU - Gu, Feng

AU - Gallardo, Wilson

AU - Pivonello, Rosario

AU - Yu, Yerong

AU - Witek, Przemysław

AU - Boscaro, Marco

AU - Salvatori, Roberto

AU - Yamada, Masanobu

AU - Tauchmanova, Libuse

AU - Roughton, Michael

AU - Ravichandran, Shoba

AU - Petersenn, Stephan

AU - Biller, Beverly M.K.

AU - Newell-Price, John

AU - Arnaldi, Giorgio

AU - Asha, Hesarghatta Shyamasunder

AU - Bandgar, Tushar

AU - Barkan, Ariel

AU - Biering, Henrik

AU - Bex, Marie

AU - Bolanowski, Marek

AU - Bronstein, Marcello Delano

AU - Brue, Thierry

AU - Bruera, Dario

AU - Cavagnini, Francesco

AU - Comlekci, Abdurrahman

AU - De Block, Christophe

AU - Delibasi, Tuncay

AU - Fajardo-Montañana, Carmen

AU - Feelders, Richard Abraham

AU - Fleseriu, Maria

AU - Gadelha, Monica Roberto

AU - Geer, Eliza Brevoort

AU - Heaney, Anthony

AU - Houde, Ghislaine

AU - Ichihara, Atsuhiro

AU - Imran, Syed Ali

AU - Ioachimescu, Adriana

AU - Kadioglu, Pinar

AU - Li, Yiming

AU - Loli, Paola

AU - Nishiyama, Mitsuru

AU - Rozhinskaya, Liudmila

AU - Ruchala, Marek

AU - Saitoh, Youichi

AU - Schöfl, Christof

AU - Schopohl, Jochen

AU - Shimatsu, Akira

AU - Shimizu, Chikara

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. Methods In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5–5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to <2·0 × ULN and 2·0–5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. Findings Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5–53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7–52·7]) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis (15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] and 16 [21%]). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. Interpretation Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. Funding Novartis Pharma AG.

AB - Background Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. Methods In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5–5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to <2·0 × ULN and 2·0–5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. Findings Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5–53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7–52·7]) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis (15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] and 16 [21%]). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. Interpretation Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. Funding Novartis Pharma AG.

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